Canadian clinical trial registry

Go to family friendly version

Centres

Study Description

This is an open-label, single arm, multi-center, pilot study of Nivolumab in pediatric patients with recurrent or refractory hypermutant malignancies aged 12 months to 18 years of age. This study is to assess clinical and radiological benefits of treatment with Nivolumab in children with hypermutated cancers, including those with bMMRD syndrome. It is our expectation that patients with bMMRD syndrome will account for the majority of patients enrolled on this study.

Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. Nivolumab will be administered every 14 days until disease progression or treatment discontinuation due to unacceptable toxicities. Treatment may extend up to 2 years in patients who show clinical and radiological benefit (dose: 3 mg/kg intravenously as a continuous infusion over 60 min).

Primary Outcome Measures  :

1. To evaluate the objective response rate to Nivolumab in bMMRD positive pediatric patients with refractory hypermutated malignancies 

   Objective response rate will assessed by physical assessments, lab values, disease assessments and adverse events that are related to treatment. Scheduled time-points and the above assessments are detailed further in section "9.1 Study Calendar" of the protocol.

2. To evaluate the objective response rate to Nivolumab in bMMRD positive pediatric patients with recurrent hypermutated malignancies.

   Objective response rate will assessed by physical assessments, lab values, disease assessments and adverse events that are related to treatment. Scheduled time-points and the above assessments are detailed further in section "9.1 Study Calendar" of the protocol.

3. Estimating the feasibility of using Nivolumab as a treatment in bMMRD positive, pediatric patients with refractory or recurrent hypermutated malignancies. Feasibility of treatment will be measured using a patient's disease response assessment. This means using standard RECIST criteria for solid tumours, iRANO/RANO criteria for CNS malignancies and the revised AML International Working Group (IWG) Criteria for haematological malignancies; modified RECIST criteria for immune response may be considered during the time of study.

Secondary Outcome Measures  :

1. The progression free survival (PFS) of pediatric patients with progressive or recurrent hypermutated malignancies including bMMRD patients treated with Nivolumab.
2. Number of Participants with Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment. These will be assessed by abnormal findings in physical assessments, lab values, disease assessments and adverse events

 Time Frame: 5 years (60 months) from date of enrollment 

Inclusion Criteria

Inclusion Criteria:

Part I

1. Consent/ Assent: Patient and/or Legally Acceptable Representative (LAR; such as a parent or guardian, as applicable) must be willing and able to provide written informed consent/assent for the trial as per local requirements.
2. Age: patients must be ≥ 12 months and <25 years of age at time of Part I enrollment. Local centres are only obligated to treat/ admit patients in accordance their age range capabilities.

3. Recurrent or relapse paediatric cancer patients suspected to be hypermutant, including those exhibiting evidence of one or more of the following:

   1. high microsatellite instability (MSI-H) in current or previous tumour;
   2. a mutation causing loss of mismatch repair gene (MLH1, MSH2, MSH6, PMS2, EPCAM or MSH3) expression;
   3. hypermutation by local sequencing in current or previous tumour;
   4. a history of CMMRD, Lynch syndrome, xeroderma pigmentosum (XP), or other established disorder affiliated with an elevated hypermutation rate;
   5. a functional mutation of polymerase genes (POLE or POLD1) in current or previous tumour;
   6. a functionally impaired RRD pathway by other means;
   7. a temozolomide (TMZ) treated current or previous CNS tumour;
   8. a predisposing hypermutant cancer signature (i.e. dysregulation of an apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deamination or UV-associated);
   9. other factors, which may predicate an elevated mutation burden at the discretion of the Study Chair or Co-Chair.
4. Diagnosis: patients must have histologic or cytologic confirmation of malignancy at the time of initial diagnosis or relapse (as specified above). Patients with multiple concurrent and/or sequential neoplasms are eligible, including CNS and haematological malignancies.
5. Specimen availability: patients must be able to provide specimen (archival or newly obtained biopsy) of a tumor lesion, appropriately obtained and preserved in a manner compatible for TMB analysis or applicable IHC staining for MMR gene protein expression, if applicable (as described in the Lab Manual). Only those with an already ascertained TMB level report from the laboratory specified in the Lab Manual or those with proof of RRD as outlined in the Lab Manual will be exempt from mandatory tissue submission.

If tissue (including archival) is not available, a new tissue specimen may be obtained if deemed clinically appropriate. Any such biopsy will not be considered a trial-related procedure.

Inclusion Criteria Part II

1. Consent/ Assent: Patient and Legally Acceptable Representative (LAR; such as a parent or guardian, as applicable) must be willing and able to provide written informed consent/assent for the trial as per local requirements.
2. Confirmation of hypermutation or Proof of RRD: patient must have completed and verified a sufficient TMB level or have proof of RRD diagnosed in the appropriate lab, as outlined in the Lab Manual.
3. Age: patients must be ≥ 12 months and < 25 years of age at the time of Part II enrollment. Local centres are only obligated to treat/ admit patients in accordance their age range capabilities.
4. Diagnosis: patients must have had histologic verification of malignancy at the time of initial diagnosis or at relapse (as specified above). Patients with multiple concurrent and/or sequential neoplasms are eligible, including CNS and haematological malignancies.
5. Disease status: patients must have either measurable or evaluable disease in accordance with criteria as outlined in Section 10. Tumour lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
6. Treatment options: patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life. Chemotherapy-naïve patients will be eligible in cases where first-line therapy does not include chemotherapy (e.g. surgery alone for management of ependymoma).
7. Performance status: Karnofsky ≥ 50% for patients > 16 years of age or Lansky ≥ 50 for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

8. Previous treatment: patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy.

   1. Myelosuppressive chemotherapy: at least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea).
   2. Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the Study Chair or Co-Chair.
   3. Biologic (anti-neoplastic agent): at least 14 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 14 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the Study Chair or Co-Chair.
   4. Monoclonal antibodies: at least three (3) half-lives of the antibody after the last dose of a monoclonal antibody.
   5. Radiation Therapy (XRT): at least 14 days after local palliative XRT (small port). At least 150 days must have elapsed if prior Total Body Irradiation, craniospinal XRT or if ≥ 50% radiation of pelvis. At least 42 days must have elapsed if other substantial BM radiation.
   6. Stem Cell Infusion without Total Body Irradiation (TBI): no evidence of active graft vs. host disease and at least 56 days must have elapsed after transplant or stem cell infusion. Patients with prior allogeneic transplants (including solid organ) are not eligible.

9. Organ Function Requirements:

   a. Adequate BM Function Defined as i. Peripheral absolute neutrophil count (ANC) ≥0.75 x 109/L or 750/mm3. ii. Platelet count ≥75 x 109/L or 75,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment.

   iii. Hemoglobin ≥ 90g/L (transfusion permitted). iv. Patients with known BM metastatic disease or haematological malignancies will be eligible for study provided they meet haematological criteria. These patients may receive transfusions (e.g. to achieve platelet threshold) provided they are not known to be refractory to platelet transfusions but will not be evaluable for hematologic toxicity.

   b. Adequate Renal Function Defined as: A serum creatinine based on age/gender as provided in Table 3 (see Section 4.2.2) c. Adequate Liver Function Defined as: i. Bilirubin (sum of conjugated + unconjugated or total bilirubin) ≤1.5x institutional upper limit of normal (ULN) for age (except for patients with Gilbert's Syndrome, when bilirubin of < 51 µmol/L or 3.0 mg/dL is permitted).

   ii. ALT/AST:

1. ≤ 2.5 x institutional ULN for patients without liver metastases. 2. ≤ 5 x institutional ULN for patients with liver metastases. d. Adequate Pulmonary Function Defined as: No history of chronic pulmonary disease (such as Cystic Fibrosis) and no evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency and a pulse oximetry > 92% on room air.

e. Adequate Pancreatic Function Defined as: Serum lipase ≤ ULN. Patients with glucose intolerance should be on a stable regiment and be monitored.

10. For patients with brain tumors, debulking surgery prior to treatment with nivolumab should be considered when appropriate to reduce the risk of pseudoprogression-associated toxicities. Such debulking surgery is not mandatory for trial enrollment. Patients should be recovered from surgery and wait at least 7 days from surgery before first dose.

Exclusion Criteria

Part II Only

1. Women who are pregnant or breastfeeding and men who are sexually active with women of childbearing potential (WOCBP)* who are not willing to use effective contraception, or to practice abstinence if this is the usual lifestyle and preferred contraception for the patient. **

   • Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as there is yet no available information regarding human fetal or teratogenic toxicities.
   • WOCBP must have a negative serum pregnancy test every 4 weeks. and During Part II screening, WOCBP must have a negative serum pregnancy test. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab administration. WOCBP who are sexually active, must be willing to adhere to effective contraception during treatment and for 5 months after the last dose of nivolumab.
   • Men who are sexually active with WOCBP must be willing to adhere to effective contraception during treatment and for 7 months after the last dose of nivolumab.
   • Women who are surgically sterile, as well as azoospermic men do not require contraception.

2. Concomitant Medications

   1. Corticosteroids: Patients requiring systemic steroid therapy or any other form of immunosuppressive therapy within seven (7) days prior to first dose of trial therapy or while on trial are not eligible. The use of physiologic doses of corticosteroids (up to 5mg/m2/day prednisone equivalent) is permitted following discussion with the Study Chair or Co-Chair.
   2. Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
   3. Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible.

3. Patients with a History of Autoimmune Disease

   • Patients with a history of autoimmune disorder that has required systemic treatment in the previous two (2) years are not eligible. Asymptomatic laboratory abnormalities (e.g. ANA, rheumatoid factor, altered thyroid function studies) will not render a patient ineligible in the absence of a diagnosis of an autoimmune disorder. Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy) is not considered a form of systemic treatment.

4. Infection: Patients who have an uncontrolled infection are not eligible.
5. HIV and/or Hepatitis B/C patients: Patients with known HIV/AIDS or acute/chronic Hepatitis B or C are excluded.
6. Transplant patients: Patients who have received prior allogeneic Bone Marrow (BM) transplants or prior solid organ transplantation are not eligible.
7. Non-Compliance: Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
8. Previous anti-PD-1 and/or anti-PD-L1 therapy: Patients who have received prior anti-PD-1 and/or anti-PD-L1 directed therapy (mAb or small molecule) are not eligible.
9. Live vaccines: Patients who have received a live vaccine within 30 days of start of study treatment are not eligible.

Go to family friendly version

Centres

Study Description

Brief Summary:

This research study is studying an investigational drug called BMS-986158 as a possible treatment for pediatric solid tumors, lymphoma, or brain tumors.

Detailed Description:

This is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved BMS-986158 as a treatment for any disease.

BMS-986158 is currently still being studied in adults. This is the first time that BMS-986158 will be evaluated in younger children, though children 12-17 years of age may also be included in parts of adult studies of BMS-986158.

Research in the laboratory has shown that BMS-986158 may have activity against cancer cells. BMS-986158 belongs to a group of drugs called Bromodomain (BRD) and Extra-Terminal Domain (BET) inhibitors. These drugs block proteins that are important in reading DNA, which is a process important for cancer cells.

Inclusion Criteria

• Age ≤ 21 years at time of enrollment. Note the requirement in section 3.1.6 that all patients must be able to swallow intact capsules.
• Karnofsky performance status ≥ 50% for patients ≥16 years of age or Lansky ≥ 50% for patients <16 years of age (see Appendix A)

• Diagnosis requirement

  • Participants must have evaluable or measurable disease (see Section 11).
  • Must have disease that is relapsed or refractory and for which standard curative measures do not exist or are no longer effective.
  • For Cohort A, participants must have histologically confirmed non-CNS primary solid tumors or lymphoma based upon biopsy or surgery at relapse/progression. Patients without biopsy or surgery at relapse/progression and with tissue only available from initial diagnosis may still be considered after discussion with the overall Primary Investigator.
  • For Cohort B, participants must have histologically confirmed solid tumors, lymphoma, or primary CNS tumor based upon biopsy or surgery at relapse/progression as well as documentation of one of the following confirmed tumor molecular features obtained in a laboratory certified to return results for clinical purposes. Patients without biopsy or surgery at relapse/progression and with tissue only available from initial diagnosis may still be considered after discussion with the overall Primary Investigator.
  • MYCN amplification or high copy number gain
  • MYC amplification or high copy number gain
  • Translocation involving MYC or MYCN
  • Translocation involving BRD4 or BRD3
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy except organ function as noted in Section 3.1.5. Patients must meet the following minimum washout periods prior to enrollment:
• Myelosuppressive chemotherapy: At least 14 days after the last dose of myelosuppressive chemotherapy (42 days for nitrosourea or mitomycin C).

• Radiotherapy:

  • At least 14 days after local XRT (small port, including cranial radiation);
  • At least 90 days must have elapsed after prior TBI, craniospinal XRT or if >50% radiation of pelvis;
  • At least 42 days must have elapsed if other substantial BM radiation;
  • At least 42 days must have passed since last MIBG or other radionuclide therapy.
• Small molecule biologic therapy: At least 7 days following the last dose of a small molecule biologic agent. For agents with known adverse events occurring beyond 7 days, this duration must be extended beyond the time in which adverse events are known to occur. If extended duration is required, this must be discussed with and approved by the overall PI.
• Monoclonal antibody: At least 28 days must have elapsed after the last dose of therapeutic monoclonal antibody.
• Myeloid growth factors: At least 14 days following the last dose of long-acting growth factor (e.g. Neulasta) or 7 days following short-acting growth factor.
• Autologous hematopoietic stem cell transplant and stem cell boost: Patients must be at least 60 days from day 0 of an autologous stem cell transplant or autologous stem cell boost.
• Cellular therapies (including CAR-T cells) and other non-cellular, non-antibody immunotherapies (e.g., vaccines): At least 42 days must have elapsed after last dose.
• Major Surgery: At least 2 weeks from prior major surgical procedure. Note: Major surgical procedure will be considered all surgical procedures aside from the following: Biopsy; central line placement/removal; bone marrow aspirate/biopsy; lumbar puncture; dental procedures; gastrostomy tube placement; and VP shunt placement/revision.
• BET inhibitors: Patients must not have received prior treatment with a BET inhibitor.
• Participants must have normal organ function as defined below.
• Bone Marrow Function

• For Patients without Documented Bone Marrow Involvement by Disease:

  • Hemoglobin > 8 g/dL (may be transfused)
  • Absolute neutrophil count ≥ 1,000 /uL
  • Platelets ≥ 100,000 /uL and transfusion independent, defined as not receiving a platelet transfusion for at least 5 days prior to CBC documenting eligibility.

• For Patients with Documented Bone Marrow Involvement by Disease:

  • Hemoglobin > 8 g/dL (may be transfused)
  • Absolute neutrophil count ≥ 750 /uL
  • Platelets ≥ 75,000 /uL and transfusion independent, defined as not receiving a platelet transfusion for at least 5 days prior to CBC documenting eligibility.

• Hepatic Function:

  • Total bilirubin ≤ 1.5 x upper limit of normal for age (patients with known Gilbert's may be considered after discussion with overall PI and if direct bilirubin is at or below the upper limit of normal for age)
  • ALT (SGPT) ≤ 3 x upper limit of normal (135 U/L) For the purpose of this study, the ULN for ALT is 45 U/L
  • Serum albumin > 2 g/dL

• Adequate Pancreatic Function:

  --Lipase < upper limit of normal

• Adequate GI Function:

  --Diarrhea < grade 1 by CTCAE version 5

• Coagulation Factors:

  • International Normalized Ratio (INR) < 1.5
  • Partial thromboplastin time (PTT) < 1.5 times upper limit of normal
• For patients having labs drawn via heparinized catheters, it is important to request heparin-absorbed values.

• Adequate Cardiac Function:

  --QTc < 480 msec

• Renal Function:

  • A serum creatinine within protocol limits based on age/sex.

OR

• Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels greater than the above age/sex maximum allowed values.
• Able to swallow intact capsules.
• Patient (or parent or legally authorized representative, if minor) is able to understand and willing to provide informed consent, using an institutionally approved informed consent procedure.
• Participants of childbearing or child-fathering potential must agree to use adequate contraception throughout their participation following the guidance in Appendix H.

Exclusion Criteria

• Prior solid organ or allogeneic stem cell transplantation.

• Patients with primary or metastatic CNS tumors, except:

  • Patients with primary CNS tumor meeting definition for Cohort B;
  • Patients with a history of CNS metastatic disease that has been resected and/or radiated without evidence of active CNS disease for 3 months preceding enrollment;
  • Patients with lymphoma and CSF involvement.

• Patients receiving any of the following prohibited foods and medications:

  • Agents listed in Appendix B within 7 days prior to enrollment
  • Grapefruit or Seville oranges and/or their juices within 7 days prior to enrollment
  • Non-steroidal anti-inflammatory drugs, oral anticoagulants, and therapeutic heparins (unfractionated or low molecular weight heparin) at the time of enrollment. Note: Use of heparin to maintain patency of a central or peripheral catheter is allowed
  • Other investigational agents being administered under an IND.
• Pregnant participants will not be entered on this study given that the effects of BMS-986158 on the developing human fetus are unknown. Female participants of childbearing potential must have a documented negative pregnancy exam within 24 hours prior to dosing.
• Breastfeeding mothers are not eligible, because there is an unknown risk for adverse events in nursing infants secondary to treatment of the mother with BMS-986158.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to BMS-986158.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with a known history of HIV, hepatitis B, and/or hepatitis C (testing not required as part of screening).
• Patients with gastrointestinal disease or disorder that could interfere with absorption of BMS-986158, such as bowel obstruction or inflammatory bowel disease.
• Patients with a body surface area < 0.3 m2

Go to family friendly version

Centres

Study Description

This study includes a dose-escalation phase in Part A to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) followed by 5 monotherapy expansion arms in Part B to further evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of 23ME-00610 in patients with solid malignancies. Only Part B is open at pediatric sites. 

Primary Outcome Measures:

1. Part A: Incidence and severity of dose-limiting toxicities (DLTs) 
2. Part B adolescents: Incidence and severity of dose-limiting toxicities (DLTs) 
3. Part A: Incidence and severity of adverse events (AEs) 
4. Part B adolescents: Incidence and severity of adverse events (AEs)
5. Part A: Incidence and severity of serious adverse events (SAEs) 
6. Part B adolescents: Incidence and severity of serious adverse events (SAEs) 
7. Part A: Incidence of withdrawals due to AEs
8. Part B adolescents: Incidence of withdrawals due to AEs 
9. Part B: Objective response rate (ORR) 

   ORR based on investigator assessment against RECIST 1.1 criteria

Secondary Outcome Measures:

1. Prevalence and incidence of antidrug antibodies (ADA) to 23ME-00610 [ Time Frame: Up to 5 days post treatment discontinuation ]
2. Part A: Objective response rate (ORR) [ Time Frame: From baseline until disease progression (up to 5 years) ]

   ORR based on investigator assessment against RECIST 1.1 criteria

3. Duration of response (DoR) [ Time Frame: Up to 5 years ]

   Duration of response based on investigator assessment against RECIST 1:1 criteria

4. Disease Control Rate (DCR) [ Time Frame: Up to 5 years ]

   Disease control rate based on investigator assessment against RECIST 1:1 criteria

5. Progression free survival (PFS) [ Time Frame: Up to 5 years ]

   Progression free survival based on investigator assessment against RECIST 1:1 criteria

6. Overall survival (OS) [ Time Frame: Up to 5 years ]
7. Maximum serum concentration (Cmax) following a single dose of 23ME-00610 
8. Time of maximum serum concentration (Tmax) following a single dose of 23ME-00610 
9. Area under the concentration-time curve from zero to the last measurable concentration (AUClast) following a single dose of 23ME-00610 
10. Last measurable serum concentration (Clast) following a single dose of 23ME-00610
11. Area under the concentration-time curve from zero extrapolated to infinity (AUCinf) following a single dose of 23ME-00610 
12. Terminal half-life (T1/2) following a single dose of 23ME-00610
13. Maximum serum concentration (Cmax) following multiple doses of 23ME-00610
14. Time of maximum serum concentration (Tmax) following multiple doses of 23ME-00610
15. Area under the concentration-time curve from time zero to the end of the dosing interval (AUCtau) following multiple doses of 23ME-00610
16. Serum concentration at the end of the dosing interval (Ctau) following multiple doses of 23ME-00610
17. Terminal half-life (T1/2) following multiple doses of 23ME-00610

Inclusion Criteria

• Part A: Adults ≥ 18 years of age; Part B: ≥ 12 to years of age, weighing at least 40 kg (total body weight)
• Histologically-diagnosed locally advanced (unresectable), or metastatic solid cancer that has progressed after all available standard therapy for the specific tumor type, or for which all available standard therapy has proven to be ineffective or if no further standard therapy exists.
• Part A: Adults 18+: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1; Part B: Adolescents ≥ 12 to < 16 years of age: Lansky Play Scale ≥ 50; Adolescents ≥ 16 years of age: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1;
• Life expectancy ≥ 12 weeks
• Part A: Patients without RECIST measurable disease (e.g., evaluable disease only) will be eligible for enrollment in Part A, regardless of tumor type; Part B: Patients enrolled in Part B must have measurable disease by per RECIST 1.1 and have ≥ 1 site of measurable disease that has not been previously irradiated.

Additional inclusion or exclusion criteria may apply and will be discussed with you by the study team 

Exclusion Criteria

1. Females who are pregnant (positive serum pregnancy test within 7 days prior to study drug administration) or breastfeeding.
2. Immune Related Medical History:
   • Active autoimmune disease that has required systemic disease-modifying or immunosuppressive treatment within the last 2 years
   • Receipt of systemic immunosuppressive therapy (e.g. steroids) within 4 weeks prior to the start of study drug administration
   • History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia, non-infectious pneumonia that required steroids, or evidence of active, non-infectious pneumonitis
   • History of Grade ≥ 3 immune-mediated toxicity
3. Prior allogeneic or autologous bone marrow transplant, or other solid organ transplant.
4. History of a positive test for:
   • Hepatitis C virus (HCV) infection, except for those who have completed curative therapy for HCV and have undetectable HCV RNA
   • Hepatitis B virus (HBV) infection, except for those who are receiving treatment with HBV-active nucleos(t)ide antiviral therapy at the time of study entry and have undetectable HBV DNA
   • Human Immunodeficiency Virus (HIV) infection, except those who meet the following criteria: CD4+ T cells ≥ 350 cells/μL, no history of Acquired Immunodeficiency Syndrome (AIDS)-defining opportunistic infections, HIV RNA < 50 copies/mL, and on a stable antiretroviral regimen for at least 3 months.
5. Prior radiation therapy with an inadequate washout between the last dose and the start of study drug, defined as follows: 1) at least 2 weeks for palliative radiation to the extremities for osseous bone metastases is required; 2) at least 4 weeks for radiation to the chest, brain, or visceral organs is required; and 3) at least 6 weeks for large-field radiation is required.
6. Prior anticancer therapy, including chemotherapy, targeted therapy, biological therapy or immune-checkpoint inhibitors within 4 weeks or 5 drug half-lives (whichever is shorter)
7. History of another malignancy in the previous 2 years, unless cured by surgery alone and continuously disease free.
8. Recent history of cardiovascular disease
9. Uncontrolled or symptomatic CNS (central nervous system) metastases and/or carcinomatous meningitis

Additional inclusion or exclusion criteria may apply and will be discussed with you by the study team 

Go to family friendly version

Centres

Study Description

Historically, medulloblastoma treatment has been determined by the amount of leftover disease present after surgery, also known as clinical risk (standard vs. high risk). Recent studies have shown that medulloblastoma is made up of distinct molecular subgroups which respond differently to treatment. This suggests that clinical risk alone is not adequate to identify actual risk of recurrence. In order to address this, we will stratify medulloblastoma treatment in this phase II clinical trial based on both clinical risk (low, standard, intermediate, or high risk) and molecular subtype (WNT, SHH, or Non-WNT Non-SHH). This stratified clinical and molecular treatment approach will be used to evaluate the following:

• To find out if participants with low-risk WNT tumors can be treated with a lower dose of radiation to the brain and spine, and a lower dose of the chemotherapy drug cyclophosphamide while still achieving the same survival rate as past St. Jude studies with fewer side effects.
• To find out if adding targeted chemotherapy after standard chemotherapy will benefit participants with SHH positive tumors.
• To find out if adding new chemotherapy agents to the standard chemotherapy will improve the outcome for intermediate and high risk Non-WNT Non-SHH tumors.
• To define the cure rate for standard risk Non-WNT Non-SHH tumors treated with reduced dose cyclophosphamide and compare this to participants from the past St. Jude study.

All participants on this study will have surgery to remove as much of the primary tumor as safely possible, radiation therapy, and chemotherapy. The amount of radiation therapy and type of chemotherapy received will be determined by the participant's treatment stratum. Treatment stratum assignment will be based on the tumor's molecular subgroup assignment and clinical risk.

The participant will be assigned to one of three medulloblastoma subgroups determined by analysis of the tumor tissue for tumor biomarkers:

• WNT (Strata W): positive for WNT biomarkers
• SHH (Strata S): positive for SHH biomarkers
• Non-WNT Non-SHH, Failed, or Indeterminate (Strata N): negative for WNT and SHH biomarkers or results are indeterminable

Participants will then be assigned to a clinical risk group (low, standard, intermediate, or high) based on assessment of:

• How much tumor is left after surgery
• If the cancer has spread to other sites outside the brain [i.e., to the spinal cord or within the fluid surrounding the spinal cord, called cerebrospinal fluid (CSF)]
• The appearance of the tumor cells under the microscope
• Whether or not there are chromosomal abnormalities in the tumor, and if present, what type (also called cytogenetics analysis)

Detailed Description:

Primary Objectives:

• To estimate the progression free survival distribution of WNT-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide.
• To estimate progression-free survival distribution of Non-WNT Non-SHH medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide.
• To estimate the progression free survival distribution of skeletally mature SHH medulloblastoma patients assigned to Stratum S1 and treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after the adjuvant chemotherapy regimen is complete and to compare the outcome to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts.
• To evaluate the effect of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on cardiopulmonary fitness.
• To assess the impact of a computer-based working memory intervention (administered prophylactically at the end of chemotherapy), relative to standard of care, on a performance-based measure of working memory.

Secondary Objectives:

• To estimate overall survival distribution of WNT-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
• To estimate the progression free (in S1 skeletally immature and S2 both sub-strata) and overall survival distributions of SHH medulloblastoma patients enrolled on Strata S1 and S2 some of whom will be treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after adjuvant chemotherapy regimen is complete and compare these outcomes to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts.
• To estimate the progression free and overall survival distributions of Non-WNT Non-SHH medulloblastoma patients treated on Strata N2 and N3 with 3 cycles of pemetrexed and gemcitabine in addition to 4 cycles of conventional adjuvant chemotherapy and compare the progression-free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study separately for each stratum.
• To estimate the overall survival distribution of Non-WNT Non-SHH medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
• To evaluate the feasibility and toxicity of adding pemetrexed and gemcitabine to adjuvant chemotherapy regimen of intermediate and high risk Non-WNT Non-SHH medulloblastoma patients (Strata N2 and N3).
• To evaluate the feasibility and toxicity of oral maintenance therapy with the targeted SHH inhibitor (vismodegib) after conventional adjuvant chemotherapy regimen is complete.
• To estimate the cumulative incidence of local disease failure at 2 and 5 years based on treatment regimen, strata, and clinical and treatment factors.
• To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on physical performance, fatigue, health related quality of life, memory, attention and executive function at the end of the intervention, at the end of adjuvant chemotherapy, and one, two and five years off adjuvant chemotherapy, among children treated for medulloblastoma.
• To evaluate the impact of an aerobic training intervention on sleep quality and quantity in children with medulloblastoma.
• To evaluate the relation between baseline cognitive performance and the variables of sleep quality and quantity, and fatigue in children with medulloblastoma.
• To estimate change in neurocognitive performance using a comprehensive assessment battery (e.g., measures of intellectual function, academic abilities, attention, memory, processing speed and executive functions) and investigate the relationship of change to relevant demographic factors (e.g., gender, age at treatment, time since treatment and socioeconomic status) and clinical factors (e.g., treatment intensity/risk group, posterior fossa syndrome).
• To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measures of attention, processing speed and executive functions.
• To compare the impact of a computer-based working memory intervention in conjunction with an aerobic training intervention, relative to either intervention in isolation, on measures of attention, processing speed and executive functions.
• To evaluate the maintenance of improvements on measures of attention, working memory, processing speed and executive functions six months following participation in the computer-based working memory intervention program.

Outline: This is a multicenter study. Patients are stratified according to molecular subgroup assignment (WNT, SHH, or Non-WNT Non- SHH) and then by clinical risk stratification (extent of resection, M stage, histologic subtype, and cytogenetic features). All patients will be treated with risk-adapted radiation therapy and adjuvant chemotherapy. Patients assigned to Stratum W1 will receive reduced dose radiation therapy. Patients assigned to Stratum W2, S1, N1, or N2 will receive standard dose radiation therapy. Patients assigned to Stratum W3, S2, or N3 will receive high dose radiation therapy. Radiation therapy will be followed by 4 cycles of adjuvant conventional chemotherapy with cyclophosphamide, cisplatin and vincristine for all patients. Patients assigned to Stratum N2 or N3 (Non-WNT Non-SHH with high risk factors) will receive 3 additional cycles of pemetrexed and gemcitabine chemotherapy intermixed into the conventional adjuvant chemotherapy cycles. Patients with SHH subtype (Stratum S1 or S2) who are skeletally mature will receive 12 months additional maintenance therapy with vismodegib.

Patients may consent to provide tumor tissue, blood, and CSF samples for biological studies. Tumor tissues are analyzed for the activation of the WNT signaling pathway, activation of the SHH signaling pathway, validation of novel patterns of gene expression via immunohistochemical (IHC) analysis; validation of genetic abnormalities via interphase fluorescence in situ hybridization (iFISH); construction of gene expression profiles via microarray analysis; construction of DNA methylation profiling via microarrays; single nucleotide polymorphism (SNP) analysis for DNA copy number aberrations; potential oncogenes and tumor suppressor genes via DNA sequence analysis; expression of a number of cell signal proteins implicated in the biology of medulloblastoma via western blot; expression of additional proteins encoded by genes associated through SNP and gene expression array analysis with clinical disease behavior. Blood samples are analyzed from patients whose tumors contain gene mutations via sequence analysis of constitutional DNA. CSF and blood samples are analyzed for identification of potential tumor markers. Parents may consent to have blood samples analyzed for inheritable gene mutations associated with medulloblastoma.

Patients may also consent to exploratory research that include additional functional MRI imaging to investigate damage to neural connections from therapy; additional psychological testing to identify neurocognitive effects of therapy; additional heart and lung testing to identify treatment effects; additional endocrine studies to identify treatment effect on growth and development.

After completion of study treatment, patients are followed every 6 months for 5 years.

Inclusion Criteria

• Medulloblastoma or medulloblastoma variants including posterior fossa PNET as documented by an institutional pathologist.
• Participant's age meets one of the following: (1) Age greater than or equal to 3 years and less than 22 years of age at the time of diagnosis (may enroll on Strata W, S or N), OR (2) age is greater than or equal to 22 years and less than 40 years AND patient has SHH medulloblastoma (must enroll on Stratum S).
• No previous radiotherapy, chemotherapy or other brain tumor directed therapy other than corticosteroid therapy and surgery.
• Patients must begin treatment as outlined in the protocol within 36 days of definitive surgery (day of surgery is day 0; definitive surgery includes second surgeries to resect residual tumor).
• Adequate performance status: children < 10-Lansky Score ≥ 30; children ≥ 10-Karnofsky ≥ 30 (except for posterior fossa syndrome).
• Females of child-bearing potential cannot be pregnant or breast-feeding. Female participants > 10 years of age or post-menarche must have a negative serum or urine pregnancy test prior to enrollment.
• Biological parent(s) of participant (child) enrolling on this protocol. These parents will be assigned to cohort P. The exclusion criteria below do not apply to this cohort.

Exclusion Criteria

• CNS embryonal tumor other than medulloblastoma or PNET in the posterior fossa, for example, patients with diagnosis of Atypical Teratoid / Rhabdoid Tumor (ATRT), supratentorial PNET, pineoblastoma, ependymoblastoma, ETANTR are excluded.
• Research participants with other clinically significant medical disorders that could compromise their ability to tolerate protocol therapy or would interfere with the study procedures or results history.

Participants in the Stratum S maintenance chemotherapy portion of the study must meet the criteria below prior to start of vismodegib therapy:

• Participants must be Stratum S (SHH)
• Participants must be skeletally mature defined as females with a bone age ≥ 15 years and males with a bone age ≥ 17 years.
• Must be able to swallow pills
• BSA must be >0.67 and <2.5 m2
• Male and female participants of reproductive potential must agree to effective contraception during and after study treatment. See Appendices I and II for further guidance for participants receiving vismodegib
• ANC ≥ 1000/mm^3 (after G-CSF discontinued)
• Platelets ≥ 50,000/mm^3 (without support)
• Hgb ≥ 8 g/dL (with or without transfusion support)
• Serum creatinine ≤ 1.5 mg/dL
• Total bilirubin ≤ 1.5X the institutional ULN
• SGPT (ALT) ≤ 2.5X the institutional ULN
• SGOT (AST) ≤ 2.5X the institutional ULN
• Alkaline Phosphatase ≤ 1.5X the institutional ULN
• Serum albumin ≥ 2.5 g/dL

Participants in the exercise intervention portion of the study must meet all criteria below:

• Must be ≥ 5 years and < 22 years at the time of enrollment
• Must have no congenital heart disease
• Must be capable of performing the exercise intervention at the time of baseline assessment as determined by the treating physician.

Participants in the cognitive remediation intervention portion of the study must meet all criteria below:

• Completed protocol-directed radiation therapy
• ≥5 years at the time of remediation intervention consent or age is greater than or equal to 22 years and less than 40 years and patient has SHH medulloblastoma
• English as primary language and training aide who speaks English available to participate in required sessions
• No significant cognitive impairment operationalized as either an IQ < 70 for children with St. Jude SJMB12 study baseline testing or based on clinician judgment baseline IQ missing
• No major sensory or motor impairment that would preclude valid cognitive testing (e.g., unresolved posterior fossa syndrome, blindness, poorly controlled seizures/photosensitive epilepsy, psychosis) or a major psychological condition that would preclude completion of the intervention (e.g., significant oppositionality, autism spectrum disorder, severe anxiety or depressive symptoms)

Go to family friendly version

Centres

Study Description

This is a Phase I/II, multicenter, open-label, multi-arm study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of idasanutlin, administered as a single agent or in combination with chemotherapy or venetoclax, in pediatric and young adult participants with acute leukemias or solid tumors.

This study is divided into three parts: Part 1 will begin with dose escalation of idasanutlin as a single agent in pediatric participants with relapsed or refractory solid tumors to identify the maximum tolerated dose (MTD)/maximum administered dose (MAD) and to characterize dose-limiting toxicities (DLTs). Following MTD/MAD identification, three separate safety run-in cohorts in neuroblastoma, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) will be conducted to identify the recommended Phase 2 dose (RP2D) of idasanutlin in each combination, with chemotherapy or venetoclax. Part 2 will evaluate the safety and early efficacy of idasanutlin in combination with chemotherapy or venetoclax in newly enrolled pediatric and young adult participants in neuroblastoma, AML,and ALL cohorts at idasanutlin RP2D. Part 3 will potentially be conducted as an additional expansion phase of the idasanutlin combination cohorts in neuroblastoma, AML, or ALL for further response and safety assessment.

Inclusion Criteria

• The participants ages are < 18 for part 1a, < 30 for Parts 1b. 2 and 3
• Study Part 1 (single-agent therapy dose escalation): histologically confirmed diagnosis of neuroblastoma or other solid tumor that has progressed or recurred despite standard therapy, and for which there is no therapy proven to prolong survival with an acceptable quality of life
• Study Part 1 (combination safety run-in), Study Part 2 (initial expansion), and Study Part 3 (additional expansion): histologically confirmed diagnosis of neuroblastoma, AML, or precursor-B ALL that has progressed or recurred despite, or is refractory to, standard therapy
• Adequate performance status: Participants <16 years of age: Lansky ≥50%; Patients ≥16 years of age: Karnofsky ≥50%
• Adequate end-organ function, as defined in the protocol
• For females of childbearing potential: agreement to remain abstinent, use contraception, agreement to refrain from donating eggs. Females must remain abstinent or use two methods of contraception with a failure rate of <1% per year during the treatment and follow-up period (variable depending on the combination agent) or in accordance with national prescribing information guidance regarding abstinence, contraception
• For males: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm, with a female partner of childbearing potential or pregnant female partner, males must remain abstinent or use a condom during the treatment period and for follow-up period (variable, depending on the combination agent) or in accordance with national prescribing information guidance regarding abstinence, contraception

Additional Inclusion Criteria for Participants with Solid Tumors (including Neuroblastoma)

• At least one evaluable or measurable radiological site of disease as defined by standard criteria for the participant's tumor type, or measurable bone marrow disease by morphology
• Adequate hematologic end-organ function, as defined in the protocol
• Tumor tissue from relapsed disease

Additional Inclusion Criteria for Patients with Leukemia

• Bone marrow with ≥5% lymphoblasts by morphologic assessment at screening
• Available bone marrow aspirate or biopsy from screening

Exclusion Criteria

• Primary Central Nervous System (CNS) tumors
• Symptomatic CNS metastases that result in a neurologically unstable clinical state or require increasing doses of corticosteroids or local CNS-directed therapy to control the CNS disease
• CNS3 leukemia
• Acute promyelocytic leukemia
• White blood cell count >50 × 10^9 cells/Liter (L)
• Down syndrome, Li-Fraumeni syndrome, history of severe aplastic anemia, or any known bone marrow failure predisposition syndrome
• Burkitt-type acute lymphoblastic leukemia
• T-cell lymphoblastic leukemia
• Prior treatment with a MDM2 antagonist
• Prior treatment with venetoclax (if potential for enrollment in a venetoclax arm)
• Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the participant
• Any uncontrolled medical condition or other identified abnormality that precludes the patient's safe participation in and completion of the study
• Systemic anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to initiation of study treatment
• Treatment with monoclonal antibodies, antibody drug conjugates, or cellular therapy for anti-neoplastic intent within 30 days prior to initiation of study treatment
• I-131 meta-iodobenzylguanidine (MIBG) therapy within 6 weeks prior to initiation of study treatment
• Myeloablative therapy with autologous or allogeneic hematopoietic stem cell rescue within 100 days of study treatment initiation
• Immunosuppressive therapy for treatment of graft-versus-host disease within 2 weeks of study treatment initiation
• Radiotherapy within 3 weeks prior to study treatment initiation
• Specific restrictions are applicable for patients treated with drugs interacting with CYP2C8, CYP3A4, OATP1B1/B3, and P-gp
• Received anti-coagulant or anti-platelet agent within 7 days or 5 half-lives prior to study treatment initiation
• Underwent major surgical procedure within 21 days of study treatment initiation, or anticipate need for major surgical procedure during the course of the study

Go to family friendly version

Centres

Study Description

This study will evaluate the safety, pharmacokinetics, and efficacy of alectinib in children and adolescents with ALK fusion-positive solid or CNS tumors for whom prior treatment has proven to be ineffective or for whom there is no satisfactory standard treatment available.

Inclusion Criteria

• Histologically confirmed diagnosis of CNS or solid tumors harboring ALK gene fusions as determined locally by an appropriately validated assay performed in a CLIA-certified or equivalently-accredited diagnostic laboratory, or centrally by a Foundation Medicine Clinical Trial Assay (CTA) or the alternative, approved central laboratory for that region
• Disease status: prior treatment proven to be ineffective (i.e. relapsed or refractory), or for whom there is no satisfactory standard treatment available. Disease should be measurable and evaluable as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, or Response Assessment in Neuro-oncology criteria (RANO) +/- bone marrow criteria for primary CNS tumors or International Neuroblastoma Response Criteria (INRC)
• Available tumor tissue for submission to the Sponsor from active disease, obtained subsequent to last anti-cancer therapy regiment administered and obtained prior to study enrollment, or willingness to undergo a core or excisional biopsy sample collection prior to enrollment
• For participants < 16 years old, Lansky Performance Status >/= 50%
• For participants >/= 16 years old, Karnofsky Performance Status >/= 50%
• Adequate bone marrow function as defined by the protocol within at least 28 days prior to initiation of study drug
• Participant and/or caregiver willingness and ability to complete clinical outcome assessments throughout the study using either electronic, paper, or interviewer methods
• For females of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined by the protocol
• For males who are not surgically sterile: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm, as defined by the protocol

Exclusion Criteria

• Medical history of: prior use of ALK inhibitors; any gastrointestinal disorder that may affect absorption of oral medications, such as mal-absorption syndrome or status post-major bowel resection; history of organ transplant; stem cell infusions as defined by the protocol
• Substance abuse within 12 months prior to screening
• Familial or personal history of congenital bone disorders, bone metabolism alterations, or osteopenia
• Treatment with investigational therapy 28 days prior to initiation of study drug
• Liver or kidney disease as defined by the protocol
• National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade >/=3 toxicities attributed to any prior therapy such as radiotherapy (excluding alopecia), which have not shown improvement and are strictly considered to interfere with alectinib
• Co-administration of anti-cancer therapies other than those administered in this study
• Active hepatitis B or C virus (HBV, HBC), or known HIV-positivity or AIDS-related illness
• Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the participant in this study
• Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; such conditions should be discussed with the participant before trial entry
• Planned procedure or surgery during the study except as permitted treatment as defined by the protocol
• Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the participant upon induction of neutropenia, including participants who are, or should be, on antimicrobial agents for the treatment as active infection
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of alectinib

Go to family friendly version

Centres

Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

This phase I trial studies the side effects and best dose of volitinib in treating patients with primary central nervous system (CNS) tumors that have come back (recurrent) or does not respond to treatment (refractory). Volitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and recommend a phase II dose of volitinib (savolitinib) administered orally daily in children with refractory, progressive or recurrent primary CNS tumors.

II. To define and describe the toxicities of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors.

III. To characterize the pharmacokinetics of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of savolitinib within the confines of a phase I study.

II. To perform a genomic analysis within the confines of a phase I study to investigate correlation between response to treatment (as measured by objective response or progression free survival [PFS]) and the presence of specific genomic alterations (e.g. MET amplification, chromosome 7q aneuploidy, MET mutation, or HGF amplification) and/or specific subgroups of disease.

OUTLINE: This is a dose-escalation study.

Patients receive volitinib orally (PO) once daily (QD). Treatment repeats every 28 days for up to 39 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then periodically for up to 2 years.

Inclusion Criteria

• Patients with a histologically confirmed diagnosis of a primary CNS tumor (medulloblastoma, high-grade glioma, or diffuse intrinsic pontine glioma [DIPG]) that is recurrent, refractory, or progressive. All tumors must have histologic verification at either the time of diagnosis or recurrence except patients with diffuse intrinsic brain stem tumors. These patients must have radiographic or clinical evidence of progression. Patients with a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology, are also eligible to the Phase I component of this study
  • Note: Refractory disease is defined as the presence of persistent abnormality on conventional magnetic resonance imaging (MRI) imaging that is further distinguished by histology (biopsy or sample of lesion) or advanced imaging, OR as determined by the treating physician and discussed with the primary investigator prior to enrollment
• Efficacy Expansion Cohort: Patients must have a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology. The submitted specimen can be from diagnosis or recurrence and there is no time limit from when the specimen was obtained to enrollment onto the efficacy expansion cohort. The assessment will be performed in a Clinical Laboratory Improvement Act (CLIA) certified laboratory. MET pathway activation status must be confirmed using Food and Drug Administration (FDA) approved testing prior to enrollment. MET pathway activation is defined as:
  • MET kinase domain mutations, allelic frequency >= 5% OR
  • MET or HGF amplification, >= 6 copies OR
  • Chromosome 7 gain OR
  • MET fusion
    • If a MET aberration is identified using local testing at a Pediatric Brain Tumor Consortium (PBTC) institution, final confirmation for eligibility to the efficacy cohort will be confirmed using Memorial Sloan Kettering Cancer Center's (MSKCC's) FDA approved IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) panel. Alternatively, if a MET aberration is identified at a PBTC site using another FDA approved panel (Foundation Medicine or Oncomine), the result will be considered sufficient for eligibility following study chair review
• Recurrent or refractory primary malignant CNS tumor patients must have adequate pre-trial frozen or formalin-fixed paraffin-embedded (FFPE) tumor material available for the required correlative studies. If target amounts of tissue or number of slides are not available, the site must obtain study chair/co-chair approval for adequacy of submitted tumor samples and prioritization of studies to be performed, prior to patient enrollment
  • Patients with DIPG who have pre-trial tumor tissue available are requested to submit tissue; however, this is not required for eligibility
• Patients must have evaluable disease to be eligible. Evaluable disease is defined as the presence of at least one lesion that can be measured accurately in at least 2 (two) dimensions
• Patients must be > 5 years and =< 21 years of age at the time of study enrollment
• Body surface area (BSA)
  • Patients enrolled on 75 mg/m^2/day (dose level 0) must have a BSA >= 1.00 m^2
  • Patients enrolled on 150 mg/m^2/day (dose level 1) must have a BSA >= 0.55 m^2
  • Patients enrolled on 240 mg/m^2/day (dose level 2) must have a BSA >= 0.67 m^2
  • Patients enrolled on 350 mg/m^2/day (dose level 3) must have a BSA >= 0.73 m^2 and =< 2.10 m^2 (the upper BSA restriction for dose level 3 applies during the dose finding phase only)
• Patients must have failed prior standard therapy for their tumor. Patients with medulloblastoma must have received radiation therapy in addition to platinum and alkylator-based chemotherapy. Patients with high-grade glioma (HGG) and DIPG must have at least received radiation therapy. Patients must have recovered from the acute treatment related toxicities (defined as =< grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to entering this study
• Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if it included nitrosourea
• Biologic or investigational agent (anti-neoplastic):
  • Patients must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment
    • For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
  • Monoclonal antibody treatment and agents with known prolonged half-lives:
    • Patients must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent >= 28 days prior to study enrollment
• Patients must have had their last fraction of:
  • Craniospinal irradiation or total body irradiation or radiation to >= 50% of pelvis > 3 months prior to enrollment
  • Focal irradiation > 4 weeks prior to enrollment
• Patients must be:
  • >= 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft versus (vs.) host disease
  • >= 3 months since autologous stem cell transplant prior to enrollment
• Both males and females of all races and ethnic groups are eligible for this study
• Neurologic Status
  • Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study
  • Patients with seizure disorders may be enrolled if seizures are well controlled
  • Patients must be able to swallow whole tablets to be eligible for study enrollment
• Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 50
  • Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Absolute neutrophil count >= 1.0 x 10^9 cells/ L
• Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (hemoglobin should be unsupported, i.e., red blood cell transfusions are not allowed within 14 days prior to enrollment)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x the upper limit of normal (ULN) with total bilirubin =< 1x ULN OR total bilirubin > ULN - =< 1.5 x ULN with ALT and AST =< 1 x ULN
• Albumin >= 2 g/dL
• Serum creatinine based on age/gender. Patients that do not meet the criteria below but have a 24 hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible
  • Age: Maximum serum creatinine (mg/dL)
  • 2 to < 6 years: 0.8 (male and female)
  • 6 to < 10 years: 1 (male and female)
  • 10 to < 13 years: 1.2 (male and female)
  • 13 to < 16 years: 1.5 (male), 1.4 (female)
  • >= 16 years: 1.7 (male), 1.4 (female)
• International normalized ratio (INR) < 1.5 x ULN and activated partial thromboplastin time (aPTT) < 1.5 x ULN unless patients are receiving therapeutic anti-coagulation which affects these parameters
• Patients with known tumor thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for >= 2 weeks
• Cardiac function:
  • Mean resting corrected QT interval (QTc) =< 450 msec on screening obtained from 3 electrocardiograms (EKGs)
• Oxygen saturation as measured by pulse oximetry is > 93% on room air
• Patients who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment
• Patients must be off all colony-stimulating factor(s) (e.g., filgrastim, sargramostim or erythropoietin) for at least 1 week prior to enrollment. Two (2) weeks must have elapsed if patients received polyethylene glycol (PEG) formulations
• Pregnancy Prevention
  • Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study
  • Women of child-bearing potential should use effective contraception from the time of enrollment until 4 weeks after discontinuing study treatment
  • Male study participants should use a condom with female partners of child-bearing potential during the study and for 4 weeks after discontinuing study treatment
  • If the female partner of a male study participant is not using effective contraception, men must use a condom during the study and for 6 months after discontinuing study treatment
  • Male study participants should avoid fathering a child and refrain from sperm donation from study start to 6 months after discontinuing study treatment
• The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines

Other inclusion criteria may apply and will be discussed with you by the study team.

Exclusion Criteria

• Pregnant women or nursing mothers are excluded from this study. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnant women are excluded from this study because there are unknown but potential risks to an unborn baby from savolitinib. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with savolitinib, breastfeeding should be discontinued if the mother is treated with savolitinib
• Patients with a known serious active infection including, but not limited to, viral hepatitis, human immunodeficiency virus, tuberculosis
• Patients with any clinically significant unrelated systemic illness or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
• Patients with uncontrolled hypertension (i.e., a blood pressure [BP] > 95th percentile for age, height, and gender, patients with values above these levels must have their blood pressure controlled with medication prior to starting study drug)
  • The normal blood pressure by height, age and gender tables can be assessed in the Generic Forms section of the PBTC member's webpage
• Patients with any of the following cardiac diseases
  • Congestive heart failure (New York Heart Association >= grade 2)
  • Clinically significant cardiac arrhythmia
  • Mean resting corrected QT interval (QTc) > 450 msec on screening obtained from 3 electrocardiograms (EKGs) or
  • Factors that may increase the risk of QTc prolongation such as chronic hypokalemia not correctable with supplements, congenital or familial long QT syndrome, or
  • Family history of unexplained sudden death under 40 years of age in first-degree relatives or
  • Any concomitant medication known to prolong the QT interval and cause Torsade de Pointes. These drugs must have been discontinued prior to the start of administration of study treatment in accordance with guidance
  • Any clinically important abnormalities in rhythm, conduction or morphology of resting EKG, e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec.
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial
• Concurrent Therapy
  • Patients who are receiving any other anticancer or investigational drug therapy
  • Patients receiving strong inducers of CYP3A4, strong inhibitors of CYP3A4 or CYP1A2 or CYP3A4 substrates with a narrow therapeutic index within 2 weeks of the first dose of savolitinib (3 weeks for St John's Wort). Strong inducers of CYP3A4 and CYP3A4 substrates which have a narrow therapeutic range or CYP3A4 sensitive substrates should not be used during the trial or used with caution. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. Patient drug information handout and wallet card should be provided to patients
  • Prior or current treatment with a MET inhibitor (e.g., foretinib, crizotinib, cabozantinib, or onartuzumab)
• Patient is currently receiving any of the following herbal preparations or medications and cannot be discontinued 1 week (7 days) prior to enrollment (3 weeks for St. John's wort). These herbal medications include, but are not limited to: cannabis products, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng
• Patient has undergone major surgical procedure =< 28 days prior to beginning study drug or a minor surgical procedure =< 7 days prior to beginning study drug. No waiting is required following port-a-cath placement
• Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition
• Prisoners will be excluded from this study

Other exclusion criteria may apply and will be discussed with you by the study team.

Go to family friendly version

Centres

Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

This is a multicenter pilot study of SurVaxM (SVN53-67/M57-KLH) for children and young adults with progressive or relapsed medulloblastoma, high grade glioma, ependymoma and newly diagnosed diffuse intrinsic pontine glioma.

Survivin (BIRC5) is an inhibitor of apoptosis (IAP) protein that is highly expressed in many cancers. Survivin's high level of expression in certain pediatric malignancies makes it an attractive molecular target for new therapies, including active specific vaccination-based immunotherapy.

The design of the SurVaxM vaccine employs several strategies to create an effective antitumor immunogen, including: 1) incorporation of multiple MHC class I epitopes, 2) peptide modification to enhance binding to certain MHC class I molecules, 3) cytokine helper support, and 4) antibody-mediated tumor cell killing. All of these effects would not be expected with the unmodified class-I restricted short survivin peptides employed in previously studied glioma vaccines.

There are no prior clinical trials of SurVaxM in pediatric patients; however, SurVaxM has been studied in several adult trials, including a phase I study conducted at Roswell Park Comprehensive Cancer Center. Following the single-institution phase I trial, a multicenter phase IIa trial (NCT024455557) was conducted in 63 patients with newly diagnosed glioblastoma. All patients in this study underwent surgical resection of their tumors. Patients then underwent chemoradiation with temozolomide according to the Stupp protocol. This was followed by a one-month hiatus from chemotherapy, during which priming doses of SurVaxM were initiated. The priming phase of vaccination was then followed by initiation of standard adjuvant chemotherapy with temozolomide and maintenance doses of SurVaxM as an add-on to standard chemotherapy. There have been no regimen-limiting toxicities (RLT) or grade ≥ 3 SAE attributable to SurVaxM, with most toxicities being related to temozolomide. The most common AE was grade 1-2 injection site reaction with 2 patients experiencing Montanide-related granulomatous panniculitis with local skin ulceration at vaccine injection sites, both of which resolved. Humoral and survivin-specific CD8+ T cell responses were observed in almost all patients. Twelve-month overall survival (OS12) was 86% from first immunization and 93.4% from diagnosis. OS12 for meMGMT was 93.1% and unMGMT was 78% from first immunization. Median time to tumor progression (mPFS) was 13.9 months from diagnosis. Although not a randomized trial, these results are superior to overall survival reported in various studies in which patients received standard of care treatment for this disease. A randomized phase IIb clinical trial of standard therapy plus SurVaxM is currently being developed with intent for drug registration, if successful.

The primary objective of this trial is to assess the toxicity profile of SurVaxM in emulsion with Montanide plus sargramostim in children with relapsed or progressive medulloblastoma and high-grade glioma, ependymoma and non-recurrent diffuse intrinsic pontine glioma post-radiation therapy. Patients will be enrolled into three separate strata based on age and diagnosis. Enrollment will be staged to allow for safety evaluations between strata.

Each patient will receive 500 micrograms SurVaxM as a 1:1 mixture with Montanide ISA 51 in a water-in-oil emulsion. The SurVaxM-Montanide emulsion injection will be followed immediately by sargramostim (or biosimilar) given via a second separate subcutaneous injection in close proximity to the vaccine injection site. Patients will receive four injections administered over a 6-week period, followed by 14 days of follow-up, called the Priming Phase (8 weeks total). Beginning 8 weeks after the fourth priming dose, a maintenance dose of SurVaxM with Montanide ISA 51 may be given every 8 weeks (± 2 weeks) for two years or until an off-treatment criterion is met.

Inclusion Criteria

• DIAGNOSIS: Patients with a histologically confirmed diagnosis of a primary CNS tumor that is progressive or recurrent defined as progression in any known residual tumor, or the appearance of one or more new lesions, or new cerebrospinal fluid (CSF) positivity for malignant cells, after having failed standard therapy. At the time of diagnosis or recurrence, all tumors must have histologic verification of one of the following:
  • Medulloblastoma
  • Glioblastoma multiforme (GBM)
  • Anaplastic astrocytoma
  • High-grade astrocytoma, NOS
  • Anaplastic oligodendroglioma
  • Anaplastic ependymoma (WHO Grade III)
  • Ependymoma (WHO Grade II)
  • Diffuse Intrinsic Pontine Gliomas (DIPG) Patients:
    • Patients with diffuse intrinsic pontine gliomas (DIPGs) will be eligible 14 to 56 days post-completion of radiation therapy if they do not have any evidence of progression. Patients with diffuse intrinsic pontine gliomas (DIPGs), defined as tumors with a pontine epicenter and diffuse involvement of 2/3 or more of the pons, are eligible without histologic confirmation. Patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors have been biopsied and are proven to be a glioblastoma multiforme (GBM), or astrocytoma (Grade II or Grade III). DIPG patients with disseminated disease are not eligible, and MRI of spine must be performed if disseminated disease is suspected by the treating physician.
• DEMONSTRATION OF SURVIVIN EXPRESSION: For patients with relapsed or progressive medulloblastoma, HGG, or ependymoma, demonstration of survivin expression as assessed after screening consent/assent of at least 1% on tumor tissue by immunohistochemistry (ICH) is required and must have been performed in the central laboratory at Roswell Park Comprehensive Cancer Center (RPCCC) to confirm eligibility. For patients with DIPG, diagnostic biopsy for histologic confirmation is not required, and tumor expression of survivin is therefore not required for eligibility for these patients.
• DISEASE STATUS: Patients must have either measurable or evaluable disease. Patients with recurrent or progressive GBM, anaplastic astrocytoma, high grade astrocytoma (NOS), anaplastic oligodendroglioma, anaplastic ependymoma (WHO Grade III) or ependymoma (WHO Grade II) with metastatic disease or leptomeningeal disease are eligible so long as there is clear MRI evidence of evaluable disease.
• AGE: 
  • Stratum 1 (progressive or recurrent) patients must be ≥10 years of age and ≤ 21 years of age at the time of study screening.
  • Stratum 2 (progressive or recurrent) patients must be ≥1 year of age and < 10 years of age at the time of study screening.
  • Stratum 3 (newly diagnosed DIPG) patients must be ≥1 year of age and ≤ 21 years of age at the time of study enrollment
• PRIOR THERAPY: 
  • Patients with recurrent or progressive disease must have received prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality.
  • Patients must have recovered from the acute treatment related toxicities (defined as ≤ Grade 1 if not defined in eligibility criteria; excludes alopecia) prior to entering this study.
  • Patients with newly diagnosed DIPG must have completed radiation therapy
• CHEMOTHERAPY - Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea. Patients must have received their last dose of non-myelosuppressive chemotherapy at least 7 days prior to enrollment.
• INVESTIGATIONAL/ BIOLOGIC AGENT:
  • Biologic or investigational agent (anti-neoplastic): Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment.
  • For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
  • Monoclonal antibody treatment and agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study enrollment.
• RADIATION:
  • Recurrent or Progressive CNS tumor patients must have had their last fraction of:
  • Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to spine ≥ 6 weeks (42 days) prior to enrollment.
  • Focal irradiation ≥ 14 days prior to enrollment.
  • DIPG Patients: Patients with DIPG are eligible after completion of initial radiotherapy (with or without concurrent treatment) and in the absence of progressive disease.
  • Patients must have completed radiation therapy at least 14 days prior to enrollment but no longer than 56 days and cannot have received any other tumor-directed treatment except the following: Patient may have received temozolomide or other non-investigational agents during irradiation at the treating physician's discretion. If the patient has received such agents concurrently with radiation, then patient must have recovered from the acute treatment related toxicities (defined as < Grade 1) prior to enrollment.
• CELLULAR THERAPY: Patient must be:
  • ≥ 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft vs. host disease.
  • ≥ 3 months since autologous stem cell transplant prior to enrollment.
  • > 42 days since completion of any other type of adoptive cellular therapy prior to enrollment.
• CRANIAL SURGERY: Patients who have had recent cranial surgery (VP shunt, ETV, tumor resection) are eligible for inclusion, but the vaccine may not be administered prior to post-operative Day 14.
• NEUROLOGIC STATUS: Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. A baseline neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study.
• PERFORMANCE STATUS: Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within 2 weeks prior to enrollment must be ≥ 60%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• ORGAN FUNCTION - Patients must have adequate organ and marrow function as defined below:
  • Absolute neutrophil count ≥ 0.75 x 109 cells/L
  • Platelets ≥ 100 x 109 cells/L (unsupported, defined as no platelet transfusion within 7 days prior to enrollment)
  • Hemoglobin ≥ 8 g/dl (may receive transfusions)
  • PT/INR, PTT ≤ 1.5 x ULN
  • Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN)
  • ALT(SGPT) ≤ 3 x institutional upper limit of normal
  • Albumin ≥ 2 g/dl
  • Blood creatinine based on age/gender as noted below. Patients that do not meet the criteria below but have a 24-hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 ml/min/1.73 m2 are eligible. Maximum Serum Creatinine for age/gender:
  • Age 1 to < 2 years: 0.6 mg/dL (male); 0.6 mg/dL (female)
  • Age 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)
  • Age 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)
  • Age 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)
  • Age 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
  • Age ≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)
• INFECTIOUS DISEASES
  • Human Immunodeficiency Virus (HIV) Infected Individuals: Patients who are known to be Human immunodeficiency virus (HIV)-infected must be on effective anti-retroviral therapy with undetectable viral load for 6 months prior to study enrollment.
  • Hepatitis B Chronically Infected Individuals: For patients with known evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Hepatitis C (HCV) Infected Individuals: Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with known HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
• CORTICOSTEROIDS: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment. A maximum dose of 0.1 mg/kg/day (and maximum total daily dose 4 mg) of dexamethasone (or equivalent) is permitted at study entry. Effort should be made to reduce to lowest tolerated steroid dose. Patients must be willing to use brief courses (at least 72 hours) of steroids as directed for potential inflammatory side effects of the therapy if recommended by their treating physician.
• GROWTH FACTORS - Patients must be off all colony-forming growth factor(s) for at least 14 days prior to enrollment (i.e. filgrastim, sargramostim or erythropoietin). Two (2) weeks must have elapsed if the patient received a long-acting formulation.
• PREGNANCY - Pregnant women or nursing mothers are excluded from this study because SurVaxM is an agent with the potential for teratogenic effects. Female patients of childbearing potential must have a negative serum or urine pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• PREGNANCY PREVENTION - Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study.
• INFORMED CONSENT - The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria

• BREAST FEEDING WOMEN - Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with SurVaxM breastfeeding should be discontinued if the mother is treated with SurVaxM. Female patients who are breastfeeding are not eligible for this study unless they agree not to breastfeed.
• CONCURRENT ILLNESS:
  • Active, uncontrolled infection requiring treatment (including HIV infection)
  • Patients with spinal cord primary tumors
  • Patients with relapsed or progressive DIPG or midline glioma
  • Patients with Grade I myxopapillary ependymoma
  • Patients with WHO Grade I or II gliomas are not eligible unless tumor is located within the pons or brainstem
  • Patients with active autoimmune disease or documented history of autoimmune disease/syndrome that requires ongoing systemic steroids or systemic immunosuppressive agents, with the exception of:
  • Patients with vitiligo or resolved asthma/atopy
  • Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome
  • History of or ongoing pneumonitis or significant interstitial lung disease
  • Patients with any clinically significant unrelated systemic illness (significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
  • Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial.
  • Any medical condition that, in the opinion of the Principal Investigator, would compromise the patient's ability to participate in the study.
• CONCOMITANT MEDICATIONS:
  • Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible.
  • Patients who are receiving any cannabidiol (CBD) or medical marijuana treatment are ineligible.
  • Patients who have received the last vaccination of a live vaccine ≤ 30 days prior to enrollment are ineligible. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and must meet timeline for live vaccine.
  • Patients who have received an inactivated virus, peptide, or mRNA vaccine within 14 days of the start of protocol therapy are ineligible.
  • Patients may not be on immunosuppressive therapy, including corticosteroids (except as defined in the corticosteroids inclusion criteria) at time of enrollment. However, patients who require intermittent use of bronchodilators, local steroid injections, or topical steroids will not be excluded from the study.
  • Patients may not be receiving concomitant chemotherapy, immunotherapy, radiotherapy, radiosurgery, interferon, allergy desensitization injections, growth factors, interleukins, or any investigational therapeutic medication at the time of enrollment.
• INABILITY TO PARTICIPATE: Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity of therapy or to adhere to drug administration plan, other study procedures, and study restrictions.
• ALLERGY: Known allergy or hypersensitivity to Keyhole Limpet Hemocyanin (KLH), granulocyte colony-macrophage stimulating factor (sargramostim) or MRI contrast agent.
• BLEEDING DISORDER: Patients with a known coagulopathy or bleeding diathesis or requires the use of systemic, anticoagulant medication are not eligible.
• BULKY DISEASE: Patients with bulky tumor on imaging are ineligible. Bulky tumor is defined as any of the following:
  • Tumor with evidence of clinically significant uncal herniation causing midbrain compression or midline shift greater than 5 mm
  • Tumor with a diameter >4cm in one dimension on T2/FLAIR
  • Tumor that in the opinion of the site investigator, shows significantly rapid progression of mass effect in either the brain or spinal cord such that the priming phase of vaccination (i.e., 6 weeks) cannot be completed before clinical deterioration is likely to occur.