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75 results found

Title
Status

 

SJMB12 - A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma

Closed to enrollment

SJMB12 - A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma

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DiagnosisMedulloblastomaStudy StatusClosed to enrollment
PhaseII
AgeChild, Adult - (3 years to 39 years)RandomisationNO
Line of treatmentFirst line treatment
Routes of Treatment AdministrationVismodegib - Oral. Other drugs are given as usually administered for medulloblastoma therapy
Last Posted Update2022-10-04
ClinicalTrials.gov #NCT01878617
International Sponsor
St. Jude Children's Research Hospital
Principal Investigators for Canadian Sites
Alberta Children's Hospital - Dr. Douglas Strother
The Hospital for Sick Children - Dr. Ute Bartels
CHU Ste-Justine- Dr. Sébastien Perreault
Centres
Medical contact
Dr. Victor Lewis

 

Social worker/patient navigator contact
Wendy Pelletier
Clinical research contact
Debra Rich
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

New Agent and Innovative Therapies (NAIT) 

nait.info@sickkids.ca

 

Medical contact
Dr. Henrique Bittencourt
Dr. Monia Marzouki
Dr. Sebastien Perreault (neuro-onc)
 
Social worker/patient navigator contact
Marie-Claude Charrette
 
Clinical research contact
Marie Saint-Jacques
 

 

 

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)

20110261 - A Phase 1, Multi-center, Open-label, Dose De-escalation Study to Evaluate the Safety and Efficacy of Talimogene Laherparepvec in Pediatric Subjects With Advanced Non Central Nervous System Tumors That Are Amenable to Direct Injection

Closed to enrollment

20110261 - A Phase 1, Multi-center, Open-label, Dose De-escalation Study to Evaluate the Safety and Efficacy of Talimogene Laherparepvec in Pediatric Subjects With Advanced Non Central Nervous System Tumors That Are Amenable to Direct Injection

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DiagnosisAdvanced Non-CNS Tumors, Other solid tumours Study StatusClosed to enrollment
PhaseI
AgeChild, Adult - (2 Years to 21 Years)RandomisationNO
Line of treatmentFirst line treatment, Disease relapse or progression
Routes of Treatment AdministrationIntralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance
Last Posted Update2022-10-04
ClinicalTrials.gov #NCT02756845
International Sponsor
Amgen
Principal Investigators for Canadian Sites
CHU Ste Justine - Dr. Pierre Teira
Centres
Medical contact
Dr. Henrique Bittencourt
Dr. Monia Marzouki
Dr. Sebastien Perreault (neuro-onc)
 
Social worker/patient navigator contact
Marie-Claude Charrette
 
Clinical research contact
Marie Saint-Jacques
 

 

 

Study Description

Brief Summary:

This is a phase 1 study to evaluate the safety of intralesional talimogene laherparepvec administration in pediatric subjects with advanced non-CNS tumors that are amenable to direct injection.

Detailed Description:

This is a phase 1, multicenter, open-label study of talimogene laherparepvec in pediatric subjects with advanced non-CNS tumors that are amenable to direct injection in the clinical setting. Approximately 18 -27 treated pediatric subjects are expected to be enrolled into 2 cohorts stratified by age (permissible based on the incidence of DLTs, a minimum of 6 subjects/cohort and a minimum of 18 subjects total). DLT will be evaluated based on 6 to 12 DLT-evaluable subjects in each cohort. The DLT evaluation period is 35 days from the initial administration of talimogene laherparepvec.

Inclusion Criteria
  • Subject's legally acceptable representative has provided informed consent/assent when the subject is legally too young to provide informed consent/assent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.
  • Should be willing to submit local HSV-1 serostatus within 28 days prior to enrollment.
  • Subject must be a candidate for intralesional injection, defined as one or more of the following:
    • at least 1 injectable lesion ≥ 10 mm in longest diameter
    • multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm
  • Life expectancy > 4 months from the date of enrollment.
  • Male or female subjects 2 to ≤ 21 years of age at the time of informed consent/assent.
  • Histologically or cytologically confirmed non-CNS solid tumor that recurred after standard/frontline therapy, or for which there is no standard/frontline therapy available.
  • Presence of measurable or non-measurable lesions as defined by irRC-RECIST
  • Performance status as per protocol
  • Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to dosing.
  • Adequate organ function as defined in protocol
Exclusion Criteria
  • Diagnosis of leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, or other hematologic malignancy.
  • Radiotherapy to the bone marrow within 6 weeks prior to enrollment OR within 3 months prior to enrollment if prior radiotherapy to the craniospinal axis or to at least 60% of the pelvis was received; within 2 weeks prior to enrollment if local palliative radiotherapy was received.
  • Primary ocular or mucosal melanoma.
  • History of other malignancy within the past 5 years with the following exception:

    • malignancy treated with curative intent and with no known active disease present and has not received chemotherapy for > 5 years before enrolment and felt to be at low risk for recurrence by the treating physician.

  • History or evidence of active autoimmune disease that requires systemic treatment (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis).
  • Prior treatment with talimogene laherparepvec or any other oncolytic virus.
  • Prior treatment with a tumor vaccine.
  • Requires intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.
  • Expected to require other cancer therapy while on study with the exception of local palliative radiation treatment.
  • Has acute or chronic active hepatitis B virus or hepatitis C virus infection or received treatment with nucleotide analogs such as those used in the treatment of hepatitis B virus (eg, lamivudine, adefovir, tenofovir, telbivudine, and entecavir), ribavirin, or interferon alpha within 12 weeks of initiation of study treatment.
  • Known or suspected human immunodeficiency virus (HIV) infection.
  • Received live vaccine within 28 days prior to enrollment.
  • No antiplatelet or anticoagulation medications allowed within 7 days prior totalimogene laherparepvec injection except low-dose heparin needed to maintain venous catheter patency.
  • Female subject is pregnant or breast-feeding, or planning to become pregnant during study treatment and through 3 months after the last dose of talimogene laherparepvec.
  • Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception during study treatment and through 3 months after the last dose of talimogene laherparepvec. Note: Acceptable methods of effective contraception are defined in the informed consent/assent form. Where required by local laws and regulations, additional country-specific contraception requirements may be outlined in a country-specific protocol supplement at the end of the Appendix Section of protocol.
  • Subject has known sensitivity to any of the products or components to be administered during dosing.
  • Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge.
  • History or evidence of any psychiatric disorder, substance abuse or any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
  • Subject who is unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for HSV-1 induced complications (immunosuppressed individuals, HIV-positive individuals, pregnant women, or children under the age of 1 year) during talimogene laherparepvec treatment and through 28 days after the last dose of talimogene laherparepvec.
  • Evidence of clinically significant immunosuppression such as the following:

    • primary immunodeficiency state such as severe combined immunodeficiency disease
    • concurrent opportunistic infection
    • receiving systemic immunosuppressive therapy (> 2 weeks prior to enrollment), including oral steroid doses (with the exception of maintenance physiologic replacement). Subjects who require intermittent use of steroids for inhalation or local steroid injection will not be excluded from the study
    • less than 6 months from autologous bone marrow transplant or stem cell infusion
    • history of allogeneic bone marrow transplant
  • History or evidence of xeroderma pigmentosum.
  • Sexually active subjects and their partners unwilling to use a male or female latex condom to avoid potential viral transmission during sexual contact while on treatment and within 30 days after treatment with talimogene laherparepvec. For those with latex allergies, polyurethane condoms may be used.
  • Prior chemotherapy, treatment dose radiotherapy, or biological cancer therapy within 14 days prior to enrollment or has not recovered to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) grade 1 or better from adverse event due to cancer therapy administered more than 14 days prior to enrollment.
  • CNS tumor or clinically active brain metastases (patient with a history of treated brain metastases are eligible if there is radiographic evidence of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study).
  • Currently receiving treatment in another investigational device or drug study, or less than 14 days since ending treatment on another investigational device or drug study(ies) or has not recovered to CTCAE version 4.0 grade 1 or better from adverse event due to other investigational device or drug study administered more than 14 days prior to enrollment. Other investigational procedures while participating in this study are excluded.
  • Major surgery ≤ 14 days prior to enrollment or has not recovered to CTCAE version 4.0 grade 1 or better from adverse event due to surgery performed more than 14 days prior to enrollment.

TRAM-01 - A Phase 2 Study of Trametinib for Patients With Pediatric Glioma or Plexiform Neurofibroma With Refractory Tumor and Activation of the MAPK/ERK Pathway.

Closed to enrollment

TRAM-01 - A Phase 2 Study of Trametinib for Patients With Pediatric Glioma or Plexiform Neurofibroma With Refractory Tumor and Activation of the MAPK/ERK Pathway.

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DiagnosisLow grade glioma, high grade glioma, plexiform neurofibromaStudy StatusClosed to enrollment
PhaseI/II
AgeChild, Adult - (1 Month to 25 Years)RandomisationNO
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationTrametinib (oral)
Last Posted Update2022-09-30
ClinicalTrials.gov #NCT03363217
International Sponsor
St. Justine's Hospital
Principal Investigators for Canadian Sites
Montreal Children’s Hospital – Dr. Genevieve Legault
CHU Ste-Justine – Dr. Sébastien Perreault
CHU de Quebec – Dr. Valerie Larouche
Alberta Children’s Hospital – Dr. Lucie Lafay-Cousin
BC Children’s Hospital – Dr. Juliette Hukin
The Hospital for Sick Children - Dr. Uri Tabori
Centres
Medical contact
Dr. Victor Lewis

 

Social worker/patient navigator contact
Wendy Pelletier
Clinical research contact
Debra Rich
Medical contact
Rebecca Deyell

 

Social worker/patient navigator contact
Ilana Katz 

 

Clinical research contact
Hem/Onc/BMT Clinical Trials Unit

 

Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

New Agent and Innovative Therapies (NAIT) 

nait.info@sickkids.ca

 

Medical contact
Dr. Henrique Bittencourt
Dr. Monia Marzouki
Dr. Sebastien Perreault (neuro-onc)
 
Social worker/patient navigator contact
Marie-Claude Charrette
 
Clinical research contact
Marie Saint-Jacques
 
Medical contact
Clinical Research Unit
 
Social worker/patient navigator contact
Clinical Research Unit
 
Clinical research contact
Stephanie Badour
 
Medical contact
Raoul Santiago
 
Social worker/patient navigator contact
Isabelle Audet
 
Clinical research contact
Barbara Desbiens
 

 

 

 

Study Description

This is a phase 1/2, open-label, interventional clinical trial that will study the response rate of pediatric glioma and plexiform neurofibroma (PN) to oral administration of trametinib. Patients meeting all inclusion criteria for a given study group will receive the study medication at a daily dose of 0.025 mg/kg up to a total of 18 cycles, in 28-day cycles. A total of 150 patients will be recruited as part of this clinical study.

Patients aged between 1 month (corrected age) and 25 years old will be eligible, in order to include a maximum of patients affected by low-grade glioma (LGG) and PN.

This study includes four groups:

All patients except patients with PN must have failed at least one line of treatment.

The study will also explore the molecular mechanisms behind tumor development, progression and resistance to treatment. Patients with neurofibromatosis type 1 (NF1) and LGG, NF1 patients with PN, patients with LGG with a B-Raf Serine/Threonine-protein Kinase/Proto-oncogene Encoding B-Raf (BRAF) fusion and patients with glioma of any grade with activation of the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinases (MAPK/ERK) pathway.rmore, this study will also explore important aspects for patients with brain tumors by including assessment of quality of life and neuropsychological evaluation.

Inclusion Criteria
  1. Signed written informed consent Prior to study participation, written informed consent from participants, or in the case of minors, written permission (informed consent) from parents, guardians, or legally acceptable representatives must be obtained according to local laws and regulations.
  2. Assent Assent from minor participants should be obtained per local laws and regulations and should be documented in accordance with local requirements.
  3. Study activities compliance. Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study, including disease assessment by contrast-enhanced MRI.
  4. Age Patient must be aged ≥ 1 month (corrected age) to ≤ 25 years at the time of study enrollment
  5. Study group Participants must belong to one of the following groups to be eligible. Group 1: NF1 with progressing/refractory LGG Group 2: NF1 with PN Group 3: Progressing/refractory LGG with KIAA 1549-BRAF fursion Group 4: Progressing/refractory glioma with activation of the MAPK/ERK pathway who do not meet criteria for other study groups
  6. Tumor Tissue Sample Tumor tissue will be required for all patients (fresh tissue recommended when available). Patients with NF1 and LGG or PN can still be enrolled without tissue if no surgery or biopsy was conducted.

7 Previous MRI At least two previous MRIS fro Group 1, 3, 4 and one previous MRI for Group 2 must be available for central review.

8. Prior therapy Participants must have failed at least one line of treatment including chemotherapy and/or radiation therapy except for plexiform neurofibroma (since there is no recognized standard treatment for his tumor).

9. Prior therapy toxicity Patients must have recovered to grade ≤ 1 from acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy prior to enrollment. Toxicities will be graded as per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

10. Prior therapy timeline Participants having previously received a chemotherapy agent(s) and/or radiation must conform to the timeline described below. There is no limitation on the number of previous treatments or cycles received.

  • An interval of at least 28 days after the last dose of a myelosuppressive chemotherapy, and at least 42 days after the last dose of Nitrosoureas is required prior to starting trametinib.
  • An interval of at least 28 days after the last dose of any biologic agents including monoclonal antibody treatment, immunotherapy, viral therapy and other investigational agent is required prior to starting trametinib.
  • An interval of at least 84 days after the end of the radiation therapy is required prior to starting trametinib.
  • An interval of at least 48 hours for short-acting colony stimulating factor agents and 10 days interval for long-acting colony stimulating factor agents are required prior to starting trametinib.

    11. Life expectancy Patients must have a life expectancy of greater than 6 months.

    12. Performance level Patients must have a performance status corresponding to a Lansky/Karnofsky score ≥50.

    13. Organ Function Requirements

Participants must have normal organ and marrow function as defined below:

  • Total leukocytes ≥ 3,000/µL
  • Absolute neutrophil count (ANC) ≥ 1, 000/µL
  • Hemoglobin > 80 g/l (transfusion independent within last 2 weeks)
  • Platelet count ≥ 100,000/µL (transfusion independent within last 2 weeks)
  • Total bilirubin ≤ 1.5 times the ULN within normal institutional limits for age
  • Alanine Aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN)*
  • Creatinine serum within normal institutional limits for age OR creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.
  • Creatine phosphokinase ≤ 2x ULN
  • A cardiac function defined as Corrected QT (QTcB) interval < 480 msec and LVEF ≥ lower limit of normal (LLN) by echocardiogram (ECHO).
  • Blood pressure must be smaller or equal to the 95th percentile for patient's age, height and gender.

    • For uniformity reasons, the ULN for ALT will be 45 U/L in this study

      14. Reproductive status Children of childbearing and child-fathering potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a female become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males and females treated or enrolled in this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of trametinib administration. Furthermore, females of childbearing potential (older than 10 years old for this study) must have a negative serum pregnancy test within 7 days prior to the start of study drug. A urine pregnancy test will be done according to evaluation calendar at at 30 days and at 6 months following the last does of study medications.

      15. Administration of oral medication Patients must be able to ingest and retain enterally (per os, nasogastric tube or gastrostomy) administered medication and be free of any clinically significant gastrointestinal abnormalities limiting the absorption of the medication. Tablets cannot be crushed. If the patient cannot swallow tablets, the liquid form should then be used.

SPECIFIC INCLUSION CRITERIA

Participants must belong to one of the following groups to be eligible.

  • Group 1: NF1 with Progressing/Refractory LGG (42 patients).
  • Group 2: NF1 with Progressing/Refractory PN (46 patients).
  • Group 3: Progressing/Refractory LGG with KIAA1549-BRAF fusion (42 patients).
  • Group 4: Progressing/Refractory CNS Glioma with activation of the MAPK/ERK pathway who do not meet criteria of other study groups (20 patients).
Exclusion Criteria
  1. Other investigational agents Patients who are receiving any other investigational agents.
  2. Cardiac exclusion criteria Patients who have an ejection fraction inferior to the institution LLN, a QTcB ≥ 480 msec or an absolute resting left ventricular ejection fraction (LVEF) of ≤ 39% are not eligible for enrolment.
  3. Presence of another malignancy Patient has any other malignancy except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
  4. Previous MEK inhibitor treatment Participants previously treated with a MEK inhibitor who showed less than stable disease during treatment.
  5. Tumor with BRAF V600E mutation Patients with a tumor presenting a positive BRAF V600E mutation.
  6. Other uncontrollable medical disease Patient has a severe and uncontrollable medical disease (i.e., uncontrolled diabetes, chronic renal disease or active uncontrolled infection), has a chronic liver disease (i.e., chronic active hepatitis and cirrhosis), 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.
  7. Known HIV infection Patient has a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C.
  8. Previous surgery Patients who had major surgery within 2 weeks prior to study entry.
  9. Allergy History of allergic reactions attributed to compounds of similar chemical or biologic composition to trametinib.
  10. Previous history of non-compliance Patients with a previous significant history of non-compliance to their treatment or medical regimen.
  11. Pregnant or breastfeeding patients Pregnant or breastfeeding female patients are not eligible for this study.
Publications

Perreault S, Larouche V, Tabori U, Hawkin C, Lippé S, Ellezam B, Décarie JC, Théoret Y, Métras MÉ, Sultan S, Cantin É, Routhier MÈ, Caru M, Legault G, Bouffet É, Lafay-Cousin L, Hukin J, Erker C, Jabado N. A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01. BMC Cancer. 2019 Dec 27;19(1):1250. doi: 10.1186/s12885-019-6442-2.

CO40778 (STARTRK-NG) - A Phase 1/2, Open-Label, Dose-Escalation And Expansion Study Of Entrectinib (Rxdx-101) In Pediatrics With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

Closed to enrollment

CO40778 (STARTRK-NG) - A Phase 1/2, Open-Label, Dose-Escalation And Expansion Study Of Entrectinib (Rxdx-101) In Pediatrics With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

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DiagnosisAll solid and brain tumors with NTRK1/2/3 or ROS1 gene fusionsStudy StatusClosed to enrollment
PhaseI/II
AgeChild, Adult - (up to 18 Years)RandomisationNO
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationEntrectinib taken by mouth
Last Posted Update2022-08-05
ClinicalTrials.gov #NCT02650401
International Sponsor
Hoffmann-La Roche
Principal Investigators for Canadian Sites
The Hospital for Sick Children - Dr. Daniel Morgenstern
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

New Agent and Innovative Therapies (NAIT) 

nait.info@sickkids.ca

 

 

 

Study Description

This is an open-label, Phase 1/2 multicenter dose escalation study in pediatric patients with relapsed or refractory extracranial solid tumors (Phase 1), with additional expansion cohorts (Phase 2) in patients with primary brain tumors harboring NTRK1/2/3 or ROS1 gene fusions, and extracranial solid tumors harboring NTRK1/2/3 or ROS1 gene fusions.

Inclusion Criteria
  1. Disease status:

    • Phase 1 portion (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1
    • Phase 2 portion:

      • Part B: Participants must have measurable or evaluable disease, as defined by RANO
      • Part C (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1 ± Curie Scale
      • Part D: Participants must have measurable or evaluable disease, as defined by RECIST v1.1
      • Part E (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1 ± Curie Scale or RANO
  2. Tumor type:

    • Phase 1 portion:

      * Part A: Relapsed or refractory extracranial solid tumors

    • Phase 2 portion

      • Part B: Primary brain tumors with NTRK1/2/3 or ROS1 gene fusions; gene fusions are defined as those predicted to translate into a fusion protein with a functional TRKA/B/C or ROS1 kinase domain, without a concomitant second oncodriver as determined by a nucleic acid-based diagnostic testing method
      • Part D: Extracranial solid tumors (including NB) with NTRK1/2/3 or ROS1 gene fusions; gene fusions are defined as those predicted to translate into a fusion protein with a functional TRKA/B/C or ROS1 kinase domain, without a concomitant second oncodriver as determined by a nucleic acid-based diagnostic testing method
  3. Histologic/molecular diagnosis of malignancy at diagnosis or the time of relapse
  4. Archival tumor tissue from diagnosis or, preferably, at relapse
  5. Performance status: Lansky or Karnofsky score ≥ 60% and minimum life expectancy of at least 4 weeks
  6. Prior therapy: Participants must have a disease that is locally advanced, metastatic, or where surgical resection is likely to result in severe morbidity, and who have no satisfactory treatment options for solid tumors and primary CNS tumors that are neurotrophic tyrosine receptor kinase (NTRK) or ROS1 fusion-positive
  7. Participants must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment
  8. Adequate organ and neurologic function
  9. Females of childbearing potential must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation. Agreement to remain abstinent or use use combined contraceptive methods prior to study entry, for the duration of study participation and in the following 90 days after discontinuation of study treatment.
  10. For male participants with a female partner of childbearing potential or a pregnant female partner: Agreement to remain abstinent or use a condom during the treatment period and for at least 3 months after the last dose of study drug
Exclusion Criteria
  1. Receiving other experimental therapy
  2. Known congenital long QT syndrome
  3. History of recent (3 months) symptomatic congestive heart failure or ejection fraction ≤50% at screening
  4. Known active infections
  5. Familial or personal history of congenital bone disorders, bone metabolism alterations or osteopenia
  6. Receiving Enzyme Inducing Antiepileptic Drugs (EIAEDs) within 14 days of first dose.
  7. Prior treatment with approved or investigational TRK or ROS1 inhibitors
  8. Known hypersensitivity to entrectinib or any of the other excipients of the investigational medicinal product
  9. Patients with NB with bone marrow space-only disease
  10. Incomplete recovery from acute effects of any surgery prior to treatment.
  11. Active gastrointestinal disease or other malabsorption syndromes that would impact drug absorption.
  12. Other severe acute or chronic medical or psychiatric condition or lab abnormality that may increase the risk associated with study participation, drug administration or may interfere with the interpretation of study results.
Publications

Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, Blakely CM, Seto T, Cho BC, Tosi D, Besse B, Chawla SP, Bazhenova L, Krauss JC, Chae YK, Barve M, Garrido-Laguna I, Liu SV, Conkling P, John T, Fakih M, Sigal D, Loong HH, Buchschacher GL Jr, Garrido P, Nieva J, Steuer C, Overbeck TR, Bowles DW, Fox E, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Demetri GD; trial investigators. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb;21(2):271-282. doi: 10.1016/S1470-2045(19)30691-6. Epub 2019 Dec 11. Erratum in: Lancet Oncol. 2020 Feb;21(2):e70. Lancet Oncol. 2020 Jul;21(7):e341. Lancet Oncol. 2020 Aug;21(8):e372.

BLU-285-3101 - A Phase 1/2, Single-arm Study to Evaluate the Safety, Pharmacokinetics, and Antitumor Activity of Avapritinib in Pediatric Patients With Solid Tumors Dependent on KIT or PDGFRA Signaling

Open

BLU-285-3101 - A Phase 1/2, Single-arm Study to Evaluate the Safety, Pharmacokinetics, and Antitumor Activity of Avapritinib in Pediatric Patients With Solid Tumors Dependent on KIT or PDGFRA Signaling

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DiagnosisSolid Tumor, Relapsed Solid Neoplasm, CNS TumorStudy StatusOpen
PhaseI/II
Age2 Years to 17 YearsRandomisationNO
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationDrug: avapritinib (Route: Oral) Other Name: BLU-285
Last Posted Update2022-07-19
ClinicalTrials.gov #NCT04773782
International Sponsor
Blueprint Medicines Corporation
Principal Investigators for Canadian Sites
The Hospital for Sick Children - Dr. Daniel Morgenstern
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

New Agent and Innovative Therapies (NAIT) 

nait.info@sickkids.ca

 

 

 

Study Description

This is a Phase 1/2, multicenter, open-label trial of avapritinib in patients aged 2 to less than 18 years of age with with relapsed/refractory (R/R) solid tumors with mutations (including non-synonymous point mutations, insertions, and deletions) in KIT or PDGFRA, or gliomas with the H3K27M mutation, and no available alternative treatment options. This is a single-arm trial in which all patients will receive avapritinib. The study consists of 2 parts: dose confirmation, safety, and PK (Part 1) and initial efficacy, safety, and PK at the Part 2 recommended dose (Part 2).

Inclusion Criteria
  • Patient has confirmed diagnosis of a R/R solid or CNS tumor with a mutation in KIT or PDGFRA (confirmed by local mutational testing of tumor sample) that has progressed despite standard therapy and no alternative treatment option is available OR Confirmed diagnosis of H3K27M mutant glioma that has failed standard therapy or for which no standard therapy that may convey clinical benefit exists, as judged by the Investigator.
  • Patients with CNS disease should be on a stable dose (≤10% change) of corticosteroids for at least 7 days prior to first dose of avapritinib, with no plans for dose escalation.
  • Disease extent
    1. Part 1: All patients must have at least 1 measurable lesion as defined by RECIST v1.1 or RANO (for CNS tumors). If radiation therapy has been administered, at least 1 measurable lesion must not have been irradiated, or must have clearly progressed since being irradiated.

    2. Part 2: At least one measurable lesion as defined by RECIST v1.1 (RANO for CNS tumors). If radiation therapy has been administered, at least 1 measurable lesion must not have been irradiated within the previous 12 weeks, or must have clearly progressed since being radiated (per RANO). For up to 5 patients with H3K27M mutant gliomas where there is no standard therapy that may convey clinical benefit as judged by the investigator, progression of disease of a measurable lesion after irradiation is not required.
  • A Lansky (≤16 years of age) or Karnofsky (>16 years of age) score of at least 50. If the patient is unable to walk due to paralysis, but is mobile in a wheelchair, the patient is considered ambulatory for the purpose of assessing their performance status.
  • Patient agrees to utilize contraception consistent with local regulations
Exclusion Criteria
  • Patient has any of the following within 14 days before the first dose of study treatment:

    1. Platelet count <75 × 109/L (<100 × 109/L if a CNS tumor).
    2. Absolute neutrophil count (ANC) <1.0 × 109/L.
    3. Hemoglobin <8.0 g/dL (RBC transfusion ≥14 days before test is permitted to meet criterion).
    4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × the upper limit of normal (ULN) for age; except in patients with tumor involvement of the liver who must not have AST and ALT >5 × ULN for age.
    5. Total bilirubin >1.5 mg/dL for age; and in presence of Gilbert's syndrome, total bilirubin > 3 × ULN or direct bilirubin > 1.5 × ULN.
    6. Serum creatinine >1.5 × ULN for age.
    7. International normalized ratio (INR) or prothrombin time (PT) >ULN (>1.5 × ULN if on prophylactic reversible anticoagulants).
  • Patient has a QT interval corrected using Fridericia's formula (QTcF) >470 msec. Patient has a familial or personal history of prolonged QT syndrome or Torsades de pointes.
  • Patient has clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association (NYHA) classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension (>99th percentile for age), or clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (eg, Type II second degree heart block or third-degree heart block).
  • Patient received the following systemic antineoplastic therapies:
    1. Systemic antineoplastic therapy (including experimental therapy within 5 half-lives or 28 days [6 weeks if prior nitrosurea], whichever is shorter).
    2. Focal external beam radiotherapy, including stereotactic radiosurgery, within 6 weeks prior to the first dose of avapritinib to either target or non-target lesions. Systemic radiopharmaceuticals, including nonstereotactic radiosurgery, within 2 weeks of the first dose of avapritinib (within 6 weeks for patients with CNS tumors). Craniospinal irradiation within 12 weeks prior to the first dose of avapritinib.
    3. All AEs related to other antineoplastic therapies (eg, systemic antineoplastics, radiotherapy) must have resolved to Grade ≤1 (Grade ≤2 for peripheral neuopathy and/or ototoxicity) prior to the first dose of avapritinib.
  • Patient has previously received treatment with avapritinib.
  • Patient received autologous stem cell transplant (SCT) following myeloablative therapy or chimeric antigen receptor T cell (CAR-T) therapy within 3 months prior to the first dose of avapritinib or prior allogeneic SCT within 1 year and no evidence of Grade 1 or greater graft-versus-host disease and no immunosuppressants for graft-versus-host disease (steroids for primary malignancy being permitted). Patients who received stem cell reinfusion following nonmyeloablative therapy are eligible once they meet the peripheral blood count criteria in Exclusion Criterion #1.
  • Patient requires on going treatment or has received treatment within 28 days before the start of avapritinib administration with drugs or foods that are strong CYP3A inhibitors or inducers or EIAEDs (eg, carbamazepine, phenytoin, phenobarbital, and primidone). Please refer to Appendix 1 for a list of these drugs and/or foods.
  • Patient has had a major surgical procedure within 14 days of the first dose of study treatment (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures).
  • Patient has a history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of avapritinib. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.
  • Female subjects of childbearing potential who are unwilling, if not post-menopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 6 weeks after the last dose of study treatment. Male subjects who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 6 weeks after the last dose of study treatment. Refer to Section 5.4.2 for acceptable methods of contraception.
  • Patient is pregnant
  • Patient is breastfeeding.
  • Patient has prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results.
  • History of thrombosis requiring treatment within the past 6 months.
  • Patients who require anticoagulants, with the exception of stable doses of prophylactic reversible anticoagulants.
  • Patients who are unable to swallow tablets (in Part 1) or mini-tablets (in Part 2) within the sprinkle capsules.
  • Patients with a known risk of intracranial bleeding, such as a brain aneurysm that has not been removed or repaired, or a history of intracranial bleeding within the past year, or radiographic evidence of hemorrhage on Screening MRI. Exceptions are patients with primary CNS tumors who are eligible unless CNS bleeding has occurred within 2 weeks of the first dose of avapritinib and patients with punctate hemorrhages <3 mm.
  • History of a seizure disorder that is not well controlled on current antiepileptic medications. EIAEDs carbamazepine, phenytoin, phenobarbital, and primidone are prohibited.
  • Patient is unwilling or unable to comply with scheduled visits, treatment administration plan, laboratory tests, or other study procedures and study restrictions

ACNS1721 - A Phase 2 Study of Veliparib (ABT-888) and Local Irradiation, Followed by Maintenance Veliparib and Temozolomide, in Patients With Newly Diagnosed High-Grade Glioma (HGG) Without H3 K27M or BRAFV600 Mutations

Closed to enrollment

ACNS1721 - A Phase 2 Study of Veliparib (ABT-888) and Local Irradiation, Followed by Maintenance Veliparib and Temozolomide, in Patients With Newly Diagnosed High-Grade Glioma (HGG) Without H3 K27M or BRAFV600 Mutations

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DiagnosisAnaplastic Astrocytoma, Glioblastoma, Malignant GliomaStudy StatusClosed to enrollment
PhaseII
Age3 Years to 25 YearsRandomisationNO
Line of treatmentFirst line treatment
Routes of Treatment AdministrationRadiation Therapy (Undergo radiation therapy) Drug: Temozolomide (Given by mouth) Drug: Veliparib (Given by mouth)
Last Posted Update2022-06-01
ClinicalTrials.gov #NCT03581292
International Sponsor
National Cancer Institute (NCI)
Principal Investigators for Canadian Sites
BC Children's Hospital -
Hamilton Health Sciences Centre, McMaster University - Dr. Uma H. Athale
Centres
Medical contact
Rebecca Deyell

 

Social worker/patient navigator contact
Ilana Katz 

 

Clinical research contact
Hem/Onc/BMT Clinical Trials Unit

 

Medical contact
Dr. Carol Portwine
 
Social worker/patient navigator contact
Jane Cassano 
 
Clinical research contact
Sabrina Millson
 
 

 

 

Study Description

This phase II trial studies how well veliparib, radiation therapy, and temozolomide work in treating patients with newly diagnosed malignant glioma without H3K27M or BRAFV600 mutations. Poly adenosine diphosphate (ADP) ribose polymerases (PARPs) are proteins that help repair DNA mutations. PARP inhibitors, such as veliparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving veliparib, radiation therapy, and temozolomide may work better in treating patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations compared to radiation therapy and temozolomide alone.

Inclusion Criteria
  • Stratum 1 (IDH wild-type): Patients must be >= 3 years of age and =< 21 years of age at the time of enrollment
    • Please note Stratum 1 was closed to accrual on January 24, 2020
  • Stratum 2 (IDH mutant): Patients must be >= 3 years of age and =< 25 years of age at the time of enrollment
  • Patients must have eligibility confirmed by rapid central pathology and central molecular screening reviews performed on APEC14B1:
    • Newly-diagnosed high-grade glioma such as anaplastic astrocytoma or glioblastoma
    • Negative results for H3 K27M by immunohistochemistry (IHC)
    • Negative results for BRAFV600 mutation by next-generation sequencing (NGS)
  • Patients must have histological verification of diagnosis. Patients with M+ disease (defined as evidence of neuraxis dissemination) are not eligible. Cerebrospinal fluid (CSF) cytology is not required but may be obtained if clinically indicated prior to study enrollment. If cytology is positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible
  • Pre-operative and post-operative brain magnetic resonance imaging (MRI) with and without contrast must be obtained. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. A spine MRI is not required, but may be obtained if clinically indicated. If the spine MRI is positive, the patient would be considered to have M+ disease (defined as neuraxis dissemination) and would be ineligible
  • Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
  • Peripheral absolute neutrophil count (ANC) >= 1,000/uL (within 7 days prior to enrollment)
  • Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment)
  • Hemoglobin >= 8.0 gm/dL (can be transfused) (within 7 days prior to enrollment)
  • 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):
    • 3 to < 6 years: 0.8 (male and female) maximum serum creatinine (mg/dL)
    • 6 to < 10 years: 1 (male and female) maximum serum creatinine (mg/dL)
    • 10 to < 13 years: 1.2 (male and female) maximum serum creatinine (mg/dL)
    • 13 to < 16 years: 1.5 (male), 1.4 (female) maximum serum creatinine (mg/dL)
    • >= 16 years: 1.7 (male), 1.4 (female) maximum serum creatinine (mg/dL)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
  • Patients with seizure disorder may be enrolled if seizures are well-controlled (i.e., patients must not have required rescue medications for uncontrolled seizures within 14 days prior to enrollment)
  • Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive surgery (Day 0). If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery
  • 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

Other inclusion and exclusion criteria may apply and will be discussed with you by the study doctor

Exclusion Criteria
  • Patients with the following histologies:
    • Diffuse astrocytoma (grade 2)
    • Oligodendrogliomas (any grade)
    • Pleomorphic xanthoastrocytoma (PXA, any grade)
  • Patients with primary tumor location of brainstem or spinal cord
  • Patients with M+ disease (defined as neuraxis dissemination either by imaging or by cytology)
  • Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS) or with features suggestive of AML/MDS
  • Prior allogenic bone marrow transplant or double umbilical cord blood transplantation
  • Patients must not have received any prior tumor-directed therapy including radiation therapy, chemotherapy (tumor-directed therapy), molecularly targeted agents, or immunotherapy for the treatment of HGG other than surgical intervention and/or corticosteroids
  • Lumbar CSF cytology is not required, but may be performed if clinically indicated prior to study enrollment. If lumbar CSF cytology is positive, the patient is considered to have M+ disease and is ineligible
    • Note: False positive cytology can occur within 10 days of surgery
  • Patients with gliomatosis cerebri type 1 or 2
  • Patients who are not able to receive protocol specified radiation therapy
  • Patients must not be currently receiving other anti-cancer agents
  • Patients with known constitutional mismatch repair deficiency syndrome (CMMR-D)/biallelic mismatch repair deficiency (bMMRD)
  • Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies
  • Lactating females are not eligible unless they have agreed not to breastfeed their infants
  • Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
  • Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 6 months after the last dose of protocol-specified chemotherapy

 

MS100070_0087 - Single-arm, Multicenter Phase I/Ib Study of Avelumab + Lenvatinib in Children With Primary CNS Tumors

Open

MS100070_0087 - Single-arm, Multicenter Phase I/Ib Study of Avelumab + Lenvatinib in Children With Primary CNS Tumors

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DiagnosisCentral Nervous System (CNS) Tumours Study StatusOpen
PhaseI
Age2 Years to 18 YearsRandomisationNO
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationDrug: Avelumab (Given through IV Infusion, every 2 weeks) Drug: Lenvatinib (Given orally, daily)
Last Posted Update2022-04-25
ClinicalTrials.gov #NCT05081180
International Sponsor
EMD Serono Research & Development Institute, Inc.
Merck KGaA
Principal Investigators for Canadian Sites
The Hospital for Sick Children - Dr. Ute Bartels
CHU Ste. Justine - Dr. Sebastien Perreault
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

New Agent and Innovative Therapies (NAIT) 

nait.info@sickkids.ca

 

Medical contact
Dr. Henrique Bittencourt
Dr. Monia Marzouki
Dr. Sebastien Perreault (neuro-onc)
 
Social worker/patient navigator contact
Marie-Claude Charrette
 
Clinical research contact
Marie Saint-Jacques
 

 

 

Study Description

This study consists of 2 parts: Dose Escalation Part 1 and Dose Expansion Part 2.

The Dose Escalation Part 1 will evaluate the safety and tolerability of Avelumab in combination with Lenvatinib and determine the recommended Avelumab and Lenvatinib dose for expansion.

Dose Expansion Part 2 will assess the efficacy of Avelumab in combination with Lenvatinib by Progression-free Survival in participants with pre-defined primary central nervous system (CNS) tumors.

Inclusion Criteria
  • Participants with histologically confirmed diagnosis of primary CNS malignancy as follows: a) Primary CNS tumors: the tumor should be considered high-grade histologically; prior radiotherapy is allowed; participants must have progressed after at least 1 prior systemic therapy, except for those with diffuse midline glioma with or without the H3 K27M mutation. b) Specific for participants with diffuse midline glioma with or without the H3 K27M mutation: prior radiotherapy is allowed; no more than 1 prior systemic therapy is allowed; participants with diffuse midline glioma with or without the H3 K27M mutation who have not received prior systemic therapy but have prior radiotherapy only are allowed to enroll
  • On screening scans, measurable disease by RANO criteria
  • Participants must have a Lansky performance status >= 50 for age <= 16 years or Karnofsky performance status >= 50 for age > 16 years at Screening

Other protocol defined inclusion criteria could apply

Exclusion Criteria
  • Participants with low-grade gliomas, for example but not limited to, subependymal giant cell astrocytoma, pilocytic astrocytoma and World Health organization (WHO) Grade 1 tumors
  • Participants demonstrating evidence of worsening of neurologic deficit within 1 week prior to initiation of study interventions
  • Participants with bulky tumor, defined as: a) Tumor with any evidence of uncal herniation or midline shift; b) Tumor with a diameter of > 4 centimeters (cm) in 1 dimension on T2/ fluid-attenuated inversion recovery (FLAIR) images; c) Tumor that in the opinion of the Investigator shows significant mass effect
  • Participants are not eligible if they experience uncontrolled seizures, defined as: a) Seizures requiring regular use of rescue medications. b) Seizures requiring increasing doses of antiepileptic medications. c) Seizures that in the opinion of the Investigator compromise the ability of the participant to tolerate study intervention or interfere with study procedures
  • Participants who have received major surgery (including but not limited to neurosurgical resection, brain biopsy, or radiation to the primary brain tumor) within 28 days prior to the first dose of study interventions
  • Participants with history of intracranial hemorrhage/spinal cord hemorrhage within 28 days prior to the first dose of study interventions

Other protocol defined exclusion criteria could apply

1200.120 - Phase I/II Open Label, Dose Escalation Trial to Determine the MTD, Safety, PK and Efficacy of Afatinib Monotherapy in Children Aged ≥1 Year to <18 Years With Recurrent/Refractory Neuroectodermal Tumours, Rhabdomyosarcoma and/or Other Solid Tumours With Known ErbB Pathway Deregulation Regardless of Tumour Histology

Closed to enrollment

1200.120 - Phase I/II Open Label, Dose Escalation Trial to Determine the MTD, Safety, PK and Efficacy of Afatinib Monotherapy in Children Aged ≥1 Year to <18 Years With Recurrent/Refractory Neuroectodermal Tumours, Rhabdomyosarcoma and/or Other Solid Tumours With Known ErbB Pathway Deregulation Regardless of Tumour Histology

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DiagnosisNeuroectodermal Tumors, Rhabdomyosarcoma, CNS tumors, Other brain tumours, Other solid tumors, PNET, Tumour with Erb pathway deregulationStudy StatusClosed to enrollment
PhaseI/II
AgeChild, Adult - (1 Year to 18 Years)RandomisationNO
Line of treatmentFirst line treatment, Disease relapse or progression
Routes of Treatment AdministrationOral
Last Posted Update2022-04-25
ClinicalTrials.gov #NCT02372006
International Sponsor
Boehringer Ingelheim
Principal Investigators for Canadian Sites
The Hospital for Sick Children – Dr. Vijay Ramaswamy
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

New Agent and Innovative Therapies (NAIT) 

nait.info@sickkids.ca

 

 

 

Study Description

Open-label, dose escalation, monotherapy, basket trial with biomarker specific MTD expansion cohort/Phase II part.

The trial will consist of 2 parts:

  1. Dose finding part to determine the MTD
  2. Biomarker specific MTD expansion cohort/Phase II part to assess clinical anti-tumour activity in included tumour types
Inclusion Criteria
  • Paediatric patients aged 1 year to <18 years at the time of informed consent
  • Diagnosis of HGG, DIPG, low grade astrocytoma, medulloblastoma/PNET, ependymoma, neuroblastoma, RMS and tumours with ErbB deregulation
  • Recurrent/refractory disease after they received at least one prior standard treatment regimen
  • No effective conventional therapy exists
  • Performance status >= 50% (Lansky for =<12ys; Karnofsky for >12ys)
  • Further inclusion criteria apply
Exclusion Criteria
  • Relevant toxicity from previous treatment
  • Known pre-existing relevant cardiac , hepatic, renal, bone marrow dysfunction, ILD, keratitis
  • Further exclusion criteria apply