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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.

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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

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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 

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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)

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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

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Study Description

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

Brief Summary:

This phase I trial is to find out the best dose, possible benefits and/or side effects of magrolimab in combination with dinutuximab in treating patients with neuroblastoma that has come back (relapsed) or does not respond to treatment (refractory) or relapsed osteosarcoma. Magrolimab and dinutuximab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. The combination of magrolimab and dinutuximab may shrink or stabilize relapsed or refractory neuroblastoma or relapsed osteosarcoma. In addition, this trial may help researchers find out if it is safe to give magrolimab and dinutuximab after surgery to remove tumors from the lungs.

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of Hu5F9-G4 (magrolimab) in combination with dinutuximab in children and young adults with relapsed/refractory (R/R) neuroblastoma (NBL) or relapsed osteosarcoma.

II. Determine the recommended phase 2 dose (RP2D) of Hu5F9-G4 (magrolimab) given in combination with dinutuximab in children and young adults.

III. Determine the safety and feasibility of administering Hu5F9-G4 (magrolimab) in combination with dinutuximab to patients that undergo pulmonary resection of metastatic osteosarcoma within three weeks of surgery.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics (PK) of Hu5F9-G4 (magrolimab) in children and young adults.

II. Evaluate the event free survival (EFS) in two cohorts of patients who are treated at the recommended phase 2 dose (RP2D) (measurable relapsed osteosarcoma and patients with pulmonary relapse undergoing resection) and compare to historical controls.

III. Observe and record anti-tumor activity. IV. Evaluate the overall response rate (ORR) of patients in the NBL cohorts (measurable R/R NBL and evaluable R/R NBL) and osteosarcoma patients (measurable relapsed osteosarcoma) in the expansion cohorts treated at the RP2D.

EXPLORATORY OBJECTIVES:

I. To explore biomarkers of response and resistance including genomic (CD47 expression, Fc receptor [FcR] polymorphisms, SIRPa polymorphisms, and KiR phenotype) and immunologic (dinutuximab HACA, magrolimab ADA, peripheral and bone marrow immune subsets, and circulating cytokines).

II. To explore biomarkers of response in the tumor microenvironment through multiplexed ion beam imaging (MIBI) on resected tissue or archival tissues including comparison of pre- and post- treatment tumor tissues from patients undergoing staged resection of pulmonary osteosarcoma.

OUTLINE: This is a dose de-escalation study of magrolimab with fixed-dose dinutuximab followed by a dose-expansion study. Patients are assigned to 1 of 2 arms.

ARM A: Patients receive magrolimab intravenously (IV) over 2 hours on days 1, 8, and 15 of cycles 1-2 and days 1 and 15 of subsequent cycles, and dinutuximab IV over 10 hours on days 2-5. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive magrolimab IV over 2 hours on days 1, 8, and 15 of cycles 1-2 and days 1 and 15 of subsequent cycles, and dinutuximab IV over 10 hours on days 2-5. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients with pulmonary osteosarcoma may undergo surgical resection of tumor after cycle 1. After surgery, these patients continue receiving magrolimab and dinutuximab every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, at 2, 4, 6, 9, and 12 months, and then yearly for 4 years.

Inclusion Criteria

• Patients must have a history of histologically or cytologically confirmed NBL or osteosarcoma

• Patients must have:

  • Relapsed/refractory high-risk neuroblastoma (NBL) (defined as disease recurrence after completion of therapy, progressive disease on therapy, or refractory disease during induction therapy) or
  • Relapsed osteosarcoma (relapsed after frontline therapy and/or there must not be any potentially curative treatment options available at the time of enrollment)
• Cohort B1: Measurable NBL (defined as those lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm by chest x-ray, as >= 10 mm with CT scan, or >= 10 mm with calipers by clinical exam)
• Cohort B2: Evaluable NBL (iobenguane [MIBG] and/or bone marrow disease only)
• Cohort B3: Measurable osteosarcoma (defined as those lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam)
• Cohort B4: Patients with relapsed resectable pulmonary osteosarcoma who are scheduled for a surgical resection
• Note: Subjects will not have measurable disease due to recently resected pulmonary metastases. Investigational therapy must begin within three weeks of resection. Staged resections are permissible; investigational therapy will be administered in between resections. Patients should receive one cycle of investigational therapy in between resections but can receive additional cycles to accommodate the most appropriate surgical schedule as determined by the treating physicians. Every effort will be made to have at least half of this cohort (five of ten patients) be those requiring a staged resection

• There is no limit to the number of prior treatment regimens. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment. Acute toxicity of any previous therapy must have resolved to grade 1 or less or stabilized, unless specified elsewhere

  • Myelosuppressive chemotherapy: Patients must not have received myelosuppressive chemotherapy within 3 weeks of enrollment (6 weeks if prior nitrosourea)
  • Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim
  • At least 7 days must have elapsed since the completion of therapy with a biologic agent, targeted agent, tyrosine kinase inhibitor or a metronomic non-myelosuppressive regimen
  • At least 4 weeks must have elapsed since prior therapy with 131I-MIBG
  • Monoclonal antibodies: At least 3 weeks must have elapsed since prior therapy that included a monoclonal antibody
  • Patients who have received prior therapy with GD2 antibodies, regardless of response to therapy, will be eligible
  • At least 7 days must have elapsed since the last pharmacologic dose of systemic steroids
• Arm A: Age >= 1 or < 18 years of age
• Arm B: Age >= 1 or =< 35 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2; Subjects > 16 years of age: Karnofsky >= 50%; Subjects =< 16 years of age: Lansky scale >= 50%
• Absolute neutrophil count >= 1,000/mcL
• Hemoglobin >= 9.5 g/dL, transfusion support acceptable
• Platelets >= 100,000/mcL, independent of transfusions
• Total bilirubin =< 1.5 X institutional upper limit of normal (ULN) for age (sum of conjugated and unconjugated)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional ULN
• Creatinine =< institutional ULN OR glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better

• Female patients of childbearing potential must not be nursing or planning to be pregnant and must have a negative urine or serum pregnancy test within 30 days before enrollment and within 72 hours before the first administration of study treatment

  • Note: Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential

• The effects of Hu5F9-G4 (magrolimab) monoclonal antibody on the developing human fetus are unknown and dinutuximab is known to be teratogenic. For this reason, female patients of childbearing potential must be willing to use one highly effective method of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study and continue for 4 months after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

  • Male patients who are sexually active with a woman of childbearing potential (WOCBP) and who have not had vasectomies must be willing to use a barrier method of contraception (condom plus spermicidal gel) and refrain from sperm donation during the study and for 4 months after the last dose of study treatment. If the partner is pregnant, male patients must use barrier method contraception (condom) during the study and for 4 months after the last dose of study treatment to prevent fetal exposure to study treatment
• All patients and/or their parents or legally authorized representatives must have the ability to understand and the willingness to sign a written informed consent. Assent, where appropriate, will be obtained according to local institutional policy

Exclusion Criteria

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to anti-GD2 monoclonal antibody (dinutuximab) or Hu5F9-G4 (magrolimab) monoclonal antibody or other agents used in this study
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients who are receiving any other investigational agents
• Pregnant women are excluded from this study because Hu5F9-G4 (magrolimab) is a monoclonal antibody on the developing human fetus are unknown and dinutuximab may cause fetal harm. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Hu5F9-G4 (magrolimab) or dinutuximab, breastfeeding should be discontinued if the mother is treated with Hu5F9-G4 (magrolimab) or dinutuximab
• Patients who have received prior treatment with CD47 or SIRPalpha-targeting agents
• Patients with red blood cell (RBC) transfusion dependence, defined as requiring more than 2 units of RBCs transfused during the 4-week period prior to screening. RBC transfusions are permitted during the screening period and prior to enrollment
• Patients with known inherited or acquired bleeding disorders are not eligible
• Patients with prior hemolytic anemia or Evans syndrome in the last 3 months
• Patients with significant medical diseases that would worsen the risk-benefit ratio of participating in this study. This includes but is not limited to acute myocardial infarction within the last 6 months, unstable angina, significant acute or chronic infections, or severely immunocompromised state

• Patients on the following medications at the time of enrollment:

  • Immunotherapy or immunosuppressive drugs (e.g. chemotherapy or systemic corticosteroids) EXCEPT for the following:

    • The only exception is for patients known to require 2 mg/kg or less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as premedication for blood product administration in order to avoid allergic transfusion reactions. The use of conventional doses of inhaled steroids for the treatment of asthma is permitted, as is the use of physiologic doses of steroids for patients with known adrenal insufficiency
  • Growth factors (granulocyte colony stimulating factor or granulocyte macrophage colony stimulating factor) EXCEPT for erythropoietin and darbepoetin alpha
  • Herbal remedies with immunostimulating properties (e.g., mistletoe extract) or known to potentially interfere with major organ function (e.g. hypericin)
• Patients administered a live vaccine within 28 days prior to enrollment

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Study Description

Brief Summary:

This phase II trial studies the side effects and how well larotrectinib works in treating patients with previously untreated TRK fusion solid tumors and TRK fusion acute leukemia that has come back. Larotrectinib may stop the growth of cancer cells with TRK fusions by blocking the TRK enzymes needed for cell growth.

Detailed Description:

PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control.

SECONDARY OBJECTIVES:

I. To determine event-free survival (EFS), overall survival (OS), and duration of response (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control.

II. To determine the ORR, EFS, OS, and DoR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control.

III. To describe the toxicity of larotrectinib in children with solid tumors and acute leukemia.

IV. To determine the percentage of patients with TRK fusion solid tumors with detectable circulating tumor deoxyribonucleic acid (DNA) at baseline and after 1 week, 4 weeks, 24 weeks of treatment, at the time of discontinuation of larotrectinib therapy, and at progression.

EXPLORATORY OBJECTIVES:

I. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors other than IFS treated with adjuvant larotrectinib following upfront surgery with positive margins after neoadjuvant larotrectinib.

II. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors who experience a complete response to larotrectinib and subsequently discontinue larotrectinib therapy.

III. To determine the remission induction rate for patients with recurrent/refractory TRK fusion leukemia when treated with larotrectinib.

IV. To evaluate the surgical morbidity and extent of resection of initially unresectable tumors in patients with TRK fusion solid tumors who undergo surgical resection following neoadjuvant larotrectinib.

V. To evaluate mechanisms of response and resistance to larotrectinib in children with TRK fusion cancers.

VI. To evaluate the morphologic features of TRK fusion solid tumors at time of initial biopsy to further define criteria for pathologic diagnosis of these tumors.

VII. To evaluate immunohistochemistry for pan-TRK as a screening method for TRK fusion tumors and in resection specimens following neoadjuvant treatment with larotrectinib.

VIII. To evaluate the histologic response to larotrectinib in resection specimens following neoadjuvant treatment.

IX. To evaluate circulating tumor DNA for the detection of the emergence of resistance mutations and recurrence in patients with TRK fusion solid tumors treated with larotrectinib.

X. To evaluate the ratio of cerebrospinal fluid (CSF) to concurrent plasma concentrations of larotrectinib in patients with leukemia.

XI. To evaluate the change in neurocognitive/behavioral functioning over time between baseline and 2 years post-diagnosis of patients treated on this protocol using parent-reported adaptive functioning (Adaptive Behavior Assessment System [ABAS]-III General Adaptive Composite), executive function (Behavior Rating Inventory of Executive Function Scales-Preschool Version [BRIEF-P] or BRIEF Global Executive Composite Score), psychosocial functioning (Behavior Assessment System for Children [BASC]-3 Internalizing, Externalizing and Behavioral Symptoms Indices) and quality of life (Pediatric Quality of Life Inventory [PedsQL] Total score).

OUTLINE:

Patients receive larotrectinib orally (PO) or by nasogastric (NG) or gastric tube (G-tube) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients whose tumors shrink sufficiently while taking larotrectinib may undergo surgical resection of their tumor while on study.

After completion of study treatment, patients are followed up at 3, 6, 12, 18, 24, 30, 36, and 48 months and annually thereafter for up to 5 years from the date of study entry.

Inclusion Criteria

• COHORT A: Patients must have a histologic diagnosis of infantile fibrosarcoma with an NTRK1, NTRK2, or NTRK3 fusion identified in a Clinical Laboratory Improvement Act/College of American Pathologists (CLIA/CAP) certified laboratory. Fusions may be identified by fluorescence in situ hybridization (FISH) or molecular techniques (reverse transcriptase-polymerase chain reaction [RT-PCR] using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, an ETV6 rearrangement is sufficient for eligibility in Cohort A. Identification of the upstream TRK fusion partner is not required.
• COHORT B: Patients must have a histologic diagnosis of any solid tumor other than infantile fibrosarcoma, including central nervous system (CNS) tumors but excluding high grade gliomas. An NTRK1, NTRK2, or NTRK3 fusion must be identified in a CLIA/CAP certified laboratory. Fusions may be identified by FISH or molecular techniques (RT-PCR using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, there must be an identified rearrangement in NTRK1, NTRK2, or NTRK3 (e.g., an ETV6 rearrangement is not sufficient for eligibility) unless the patient has a diagnosis of congenital mesoblastic nephroma in which case an ETV6 rearrangement is sufficient for eligibility. Identification of the upstream TRK fusion partner is not required.
• COHORT C: Patients must have a histologic diagnosis of relapsed or refractory acute leukemia with an NTRK1, NTRK2, or NTRK3 fusion identified in a CLIA/CAP certified laboratory. Fusions may be identified by FISH or molecular techniques (RT-PCR using primers flanking the fusion junction or next generation sequencing). For fusions identified by FISH, there must be an identified rearrangement in NTRK1, NTRK2, or NTRK3 (e.g., an ETV6 rearrangement is not sufficient for eligibility). Identification of the upstream TRK fusion partner is not required.
• SOLID TUMORS (COHORTS A AND B): Patients must have measurable disease. Patients must have disease that cannot be completely resected without a predicted functional, neurologic, or significant cosmetic deficit in the opinion of the investigator.
• LEUKEMIA (COHORT C): Patients must have >= 5% blasts in the bone marrow. Extramedullary disease is permitted.
• Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age. NOTE: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. 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.

• COHORTS A AND B: No prior anti-cancer therapy, including radiotherapy, other than surgical resection is permitted.

  • Patients who experience recurrence after surgery alone and no other anti-cancer therapy will be eligible.
  • If not eligible due to prior anticancer therapy, patients may be eligible for the larotrectinib arm of Pediatric MATCH (APEC1621A) or treatment with commercial larotrectinib off study.

• COHORT C: Patients with relapsed leukemia (Cohort C) must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately.

  • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment.

    • A waiting period prior to enrollment is not required for patients receiving standard cytotoxic maintenance chemotherapy (i.e., corticosteroid, vincristine, thioguanine [6MP], and/or methotrexate).
    • A waiting period is not required for patients receiving a single dose of intrathecal methotrexate, hydrocortisone, and/or cytarabine within 7 days prior to enrollment

    • >= 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea, for patients not receiving standard maintenance therapy. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy.

      • Note: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to the start of protocol therapy.
  • Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil [ANC] counts): >= 7 days after the last dose of agent. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment.
  • Anti-cancer agents that are antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1. There is an exception for blinatumomab infusions, for which patients must have been off for at least 3 days and all drug related toxicity must have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria.
  • Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid. A waiting period prior to enrollment is not required for patients receiving corticosteroid for leukemia therapy/cytoreduction.
  • Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) 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 and the study-assigned research coordinator.
  • Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors )

  • Stem cell infusions (with or without total body irradiation [TBI]):

    • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD).
    • Autologous stem cell infusion including boost infusion: >= 42 days.
  • Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
  • Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial BM radiation.
  • Radiopharmaceutical therapy (e.g., radiolabeled antibody): >= 42 days after systemically administered radiopharmaceutical therapy.
  • Patients must not have received prior exposure to TRK inhibitors (including larotrectinib, LOXO-195, entrectinib, lorlatinib, crizotinib, or lestaurtinib).
• For patients with solid tumors without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement: Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement: Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions).
• Patients with solid tumors with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts above (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These patients will not be evaluable for hematologic toxicity.
• For patients with leukemia: Platelet count >= 20,000/mm^3 (within 7 days prior to enrollment) (may receive platelet transfusions; must not be known to be refractory to red cell or platelet transfusion)
• For patients with leukemia: Hemoglobin >= 8.0 g/dL at baseline (within 7 days prior to enrollment) (may receive RBC transfusions; must not be known to be refractory to red cell or platelet transfusion)

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):

  • 1 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL)
  • 6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL)
  • 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL)
  • 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL)
  • 6 to < 10 years (male 1 mg/dL, female 1 mg/dL)
  • 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL)
  • 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL)

  • >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL)

    • For patients < 1 month of age, serum creatinine levels must be < 1.5 x the treating institution's creatinine upper limit of normal (ULN) for patients < 1 month of age or the creatinine clearance or radioisotope GFR must be >= 70 mL/min/1.73 m^2.
• Patients with solid tumors: Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment). After approval of the study chair or designee, infants with a higher total bilirubin due to physiologic or breast milk jaundice are eligible if the conjugated (direct) bilirubin is =< 2 mg/dL
• Patients with solid tumors: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
• Patients with solid tumors: Serum albumin >= 2 g/dL (within 7 days prior to enrollment).
• Patients with leukemias: Conjugated (direct) bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment).
• Patients with leukemias: SGPT (ALT) =< 225 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
• Patients with leukemias: Serum albumin >= 2 g/dL (within 7 days prior to enrollment).
• Patients with seizure disorder may be enrolled if on a stable antiepileptic regimen for >= 14 days and well controlled.
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5) except tendon reflex decreased resulting from prior therapy must be =< grade 2.

Exclusion Criteria

• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Female patients of reproductive potential may not participate unless they have agreed to use a highly effective contraceptive method for the duration of study therapy and for at least one month after the final dose of larotrectinib. Males of reproductive potential with a non-pregnant female partner of child-bearing potential must use a highly effective contraception for the duration of the study and for at least one month after the final dose of larotrectinib. Because of the unknown risk of larotrectinib in nursing infants, nursing women should discontinue breastfeeding during treatment with larotrectinib and for 3 days following the final dose.
• Patients with solid tumors, including CNS tumors, requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. Patients with leukemia may receive systemic corticosteroids for cytoreduction up to 24 hours prior to the start of protocol therapy. If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid.
• Patients who are currently receiving another investigational drug are not eligible.
• Patients who are currently receiving other anti-cancer agents are not eligible [except leukemia patients receiving corticosteroids or hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy]. Patients with leukemia should receive a single dose of intrathecal cytarabine, hydrocortisone, and/or methotrexate within 7 days prior to Day 1 of Cycle 1 at the time of the baseline lumbar puncture.
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial.
• Patients currently receiving a strong CYP3A4 inducer or inhibitor are not eligible. Strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study. Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed.
• Patients with malabsorption syndrome or other conditions that significantly limit enteral absorption are not eligible.
• Patients who are unable to swallow capsules or liquid and do not have gastric access via a nasogastric or gastrostomy tube are not eligible.
• Patients who have an uncontrolled infection are not eligible.
• Patients who have received prior solid organ transplantation are not eligible.
• 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.
• Patients with high grade gliomas (HGG) are not eligible.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

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Study Description

The primary purpose of this study is to assess the safety and tolerability of RP-6306 in patients with eligible advanced solid tumors, determine the maximum tolerated dose (MTD) and assess preliminary anti-tumor activity.

Phase 1, multi-center, open-label, dose-escalation study to:

• Evaluate the safety profile and MTD of RP-6306 when administered orally to establish the recommended Phase 2 dose and schedule
• Characterize the PK and pharmacodynamics of RP-6306 monotherapy
• Assess preliminary anti-tumor activity associated with RP-6306 monotherapy

Inclusion Criteria

• Male or female and ≥12 years-of-age at the time of informed consent.
• Lansky performance status ≥50% for patients ≤16 years of age, or ECOG score of 0, 1, or 2 for patients >16 years of age.
• Locally advanced or metastatic resistant or refractory solid tumors.
• Patients <18 years of age must weigh at least 40 kg.
• Submission of available tumor tissue at screening or willingness to have a biopsy performed if safe and feasible
• Next generation sequencing (NGS) report obtained in a CLIA-certified or equivalent laboratory demonstrating eligible tumor biomarker.
  • CCNE1 amplification (non-equivocal) as determined by tumor NGS or FISH
  • FBXW7 deleterious mutations (e.g., hotspot, truncating, splice site, frameshift) identified by either a tumor or plasma NGS test
  • PPP2R1A deleterious mutations (e.g., hotspot, truncating, splice site, frameshift) identified by either a tumor or plasma NGS test
• Measurable disease as per RECIST v1.1.
• Ability to swallow and retain oral medications.
• Acceptable hematologic and organ function at screening.
• Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening.
• Resolution of all toxicities of prior therapy or surgical procedures.
• Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment.

Exclusion Criteria

• Chemotherapy or small molecule antineoplastic agent given within 21 days or <5 half-lives, whichever is shorter, prior to first dose of study drug.
• History or current condition, therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation for the full duration of the study treatment.
• Patients who are pregnant or breastfeeding.
• Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the participating patient's safety.
• Major surgery within 4 weeks prior to first dose of RP-6306.
• Uncontrolled, symptomatic brain metastases.
• Uncontrolled hypertension.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.