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Study Description

The Phase I part of the study aims to evaluate the safety, efficacy, and tolerability of subcutaneous (SC) blinatumomab for treatment of Relapsed or Refractory B cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL), to determine the maximum tolerated dose (MTD), and recommended phase 2 dose(s) (RP2D) of SC administered blinatumomab.

The Phase II part of the study will evaluate the safety, efficacy, and tolerability of SC blinatumomab for treatment of R/R B-ALL and Minimum Residual Disease Positive (MRD+) B-ALL in participants 12 years old and greater. It will also conduct a clinical pharmacokinetic (PK) evaluation of SC1 and SC2 blinatumomab formulations.

Inclusion Criteria

• Age: 
  • Ph-IIRb and Ph-IIMb: Age ≥ 12 years and < 17 years at time of informed consent.
  • Ph-IIRa and Ph-IIMa: Aged ≥ 17 years at time of informed consent.
  • Ph-IIC, Dose Escalation and Dose Expansion: Aged 18 years or older
• Diagnosis:
  • Ph-IIR, Ph-IIC, Dose escalation, Dose Expansion: Participants with R/R B-precursor ALL.
  • Relapsed or Refractory B-precursor ALL at any time after first salvage therapy.
  • Relapsed B-precursor ALL at any time after allogenic hematopoietic stem cell transplant (HSCT).
• Bone Marrow:
  • Ph-IIR, Ph-IIC, Dose escalation, Dose expansion: Greater than or equal to 5% blasts in the Bone Marrow per local assessment.
  • Ph-IIM: B-precursor ALL and bone marrow blasts (BMB) ≥ 0.01% and < 5% per local assessment.
  • Ph-IIM: Availability of an appropriate archival BM specimen from initial or relapse diagnosis and the screening BM sample.
• Participants aged ≥ 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2.
• Participants aged 16 to < 18 years old: Karnofsky Performance Score ≥ 50%.
• Participants aged < 16 years old: Lansky Performance Score ≥ 50%.
• Any Ph+ participant intolerant or refractory to prior tyrosine kinase inhibitors (TKIs) are eligible.
• Ph-IIM: BM function as follows:
  • Absolute Neutrophil Count (ANC) ≥ 500/μL
  • Platelet count ≥ 50 000/μL (transfusion permitted)
  • Hemoglobin level ≥ 9 g/dL (transfusion permitted)

The above is a summary, other inclusion criteria details may apply.

Exclusion Criteria

• Active ALL in the central nervous system (CNS). Presence of greater than 5 white blood cells per cubic millimeter in cerebrospinal fluid (CSF) with lymphoblasts present and/or clinical signs of CNS leukemia. If CSF leukemia is present subjects will have to receive intrathecal therapy and have documented negative CSF prior to enrolling.
• History or presence of clinically relevant CNS pathology (excluding headache) such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis or severe (≥ grade 3) CNS events including immune effector cell-associated neurotoxicity syndrome (ICANS) from prior chimeric antigen receptor T-cell (CAR T) or other T cell engager therapies.
• Isolated Extramedullary (EM) Disease.
• For Ph-IIM only: Current EM disease or presence of circulating leukemia blasts.
• Current autoimmune disease or history of autoimmune disease with potential CNS involvement.
• Active acute or chronic graft versus host disease requiring systemic treatment with immunosuppressive medication.
• Symptoms and/or signs that indicate an acute or uncontrolled chronic infection, any other disease or condition that could be exacerbated by the treatment or would complicate protocol compliance.
• Testicular leukemia.
• History of malignancy (with certain exceptions) other than ALL within 3 years prior to start of protocol-specified therapy.
• Allogeneic HSCT within 12 weeks before the start of protocol-specified therapy.
• Cancer chemotherapy within 2 weeks before the start of protocol-specified therapy (with certain exceptions).
• Immunotherapy within 4 weeks before start of protocol-specified therapy.
• Prior failed cluster of differentiation (CD19) directed therapy such as prior blinatumomab or CD19 CAR T cells will be allowed (with demonstrated continued CD19+ expression), if treatment ended more than 4 weeks prior to start of protocol therapy and no prior CNS complications.
• Currently receiving treatment in or less than 30 days or 5 half-lives since ending treatment on another investigational study(ies).
• Abnormal screening laboratory parameters.
• Female participant: Pregnant or breastfeeding or planning to become pregnant or donate eggs, or expected to breastfeed during treatment and for 96 hours after the last dose of investigational product (SC blinatumomab).

The above is a summary, other exclusion criteria details may apply.

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Study Description

Brief Summary:

Phase 1 will evaluate the safety and tolerability at different dose levels of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring anaplastic lymphoma kinase (ALK), receptor tyrosine kinase encoded by the gene ROS1 (ROS1), or neurotrophic receptor kinase genes encoding TRK kinase family (NTRK1-3) alterations to estimate the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the Pediatric Recommended Phase 2 Dose (RP2D).- PHASE 1 IS NOW CLOSED

Phase 2 will determine the anti-tumor activity of repotrectinib in pediatric subjects with advanced or metastatic malignancies harboring ALK, ROS1, or NTRK1-3 alterations.

Detailed Description:

Enrollment of subjects into Phase 1 will proceed concurrently by age as follows:

• Subjects <12 years old will initially be enrolled in the Phase 1 part to determine the pediatric RP2D for this age group; once the pediatric RP2D is determined, subjects age <12 years old may be enrolled into the Phase 2 part of the study.
• Subjects 12 to 25 years old will be directly enrolled into the Phase 2 part concurrent with Phase 1 enrollment.

Phase 1:

Approximately 12 pediatric subjects with locally advanced or metastatic solid tumors, including a primary central nervous system (CNS) tumor, or anaplastic large cell lymphoma (ALCL), with disease progression or who are non-responsive or intolerant to available therapies and for which no standard or available curative therapy exists.

Phase 2:

Subjects will be enrolled in one of 3 cohorts as follows:

Cohort 1: approximately 10-20 subjects with solid tumors characterized by NTRK fusion, TRK tyrosine kinase inhibitor (TKI)-naïve, and centrally confirmed measurable disease at baseline.

Cohort 2: approximately 23 subjects with solid tumors characterized by NTRK fusion, TRK TKI-pretreated, and centrally confirmed measurable disease at baseline.

Cohort 3 (NOW CLOSED): approximately 20 subjects with solid tumors or ALCL characterized by other ALK/ROS1/NTRK alterations or NTRK fusions without centrally confirmed measurable disease not otherwise eligible for Cohort 1 or 2. 

Inclusion Criteria

Key Inclusion Criteria:

1. Documented genetic ALK, ROS1, or NTRK1-3 alteration (point mutation, fusion, amplification) as identified by local testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab outside the United States (US) is required.
2. Age <12 years.
3. Prior cytotoxic chemotherapy is allowed.
4. Prior immunotherapy is allowed.
5. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Grade less than or equal to 1.
6. All subjects must have measurable disease by RECIST v1.1 or Response Assessment in Neuro-Oncology Criteria (RANO) criteria at time of enrollment.
7. Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 14 days prior to enrollment.
8. Subjects must have a Lansky (< 16 years) or Karnofsky (≥ 16 years) score of at least 50.
9. Life expectancy greater than or equal to 12 weeks.
10. Adequate hematologic, renal and hepatic function.

Phase 2 Inclusion Criteria:

1. Age 12 to <25 years

2. Cohort Specific Inclusion Criteria:

   • Cohort 1: Subjects with NTRK fusion gene positive (NTRK+) advanced solid tumors (including primary CNS tumors), that are tropomyosin receptor kinase (TRK) TKI naïve;
   • Cohort 2: subjects with NTRK+ advanced solid tumors (including primary CNS tumors), that are TRK TKI pre-treated;
   • Cohort 3: subjects with tumors or ALCL characterized by other ALK/ROS1/NTRK alterations or NTRK fusions without centrally confirmed measurable disease or not otherwise eligible for Cohort 1 or 2.
3. Subjects in Cohorts 1 and 2 must have prospectively confirmed measurable disease by BICR prior to enrollment.

Exclusion Criteria

1. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow aspiration only.
2. Major surgery within 14 days (2 weeks) of start of repotrectinib treatment. Central venous access (Broviac, Mediport, etc.) placement does not meet criteria for major surgery.
3. Known active infections (bacterial, fungal, viral including HIV positivity).
4. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.

5. Any of the following cardiac criteria:

   • Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) > 470 msec obtained from three ECGs, using the screening clinic ECG machine-derived QTc value
   • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec)
   • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval
6. Peripheral neuropathy of CTCAE ≥grade 2.
7. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.

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Study Description

This is a phase 1/2, open label, interventional clinical trial that will study the response rate of newly diagnosed pediatric low-grade glioma (PLGG) to oral administration of mirdametinib in combination with weekly vinblastine. Patients meeting all inclusion criteria for a given study group will receive mirdametinib twice daily (continuous) at a fixed dose (2 mg/m2 po BID up to 4 mg BID) for a total of 13 cycles (28 days cycle). Weekly intravenous vinblastine at MTD will be given for a total of 17 cycles.

The lead-in feasibility phase will be conducted to establish the maximum tolerated/recommended phase 2 dose (MTD/RP2D) of vinblastine in combination with mirdametinib combination using a modified Rolling-6 design. The established RP2D for mirdametinib (2 mg/m2 po BID up to 4 mg BID) will be used on this study. Mirdametinib will be administered on a continuous dosing schedule and de-escalated as necessary to an intermittent (3 weeks on, 1 week off) dosing schedule. Vinblastine will be escalated (or de-escalated) as necessary. Since these classes of agents do not have overlapping toxicities, the starting dose (i.e., Dose Level 0) for vinblastine is 4 mg/m2/week, which is 20% lower than the recommended single agent dose of vinblastine of 5 mg/m2/week. Dose Level 1 for vinblastine is 5 mg/m2/week and Dose Level -1 for vinblastine is 3 mg/m2/week.

Following the end of treatment, patients will be scheduled for a follow-up visit every 6 months for 36 months to evaluate PFS, TTP and OS. A total of 50 patients will be recruited as part of this clinical study.

Patients aged between 2 and 25 years old will be eligible, in order to include a maximum of patients affected by glioma. This study includes PLGG patients with neurofibromatosis type 1 (NF1) with a KIAA1549-BRAF fusion and patients with activation of the MAPK pathway with the exception of patients with a BRAFV600E mutation.

Response to treatment will be evaluated using the modified Response Assessment in Pediatric Neuro-Oncology (RAPNO), Response Assessment in Pediatric Neuro-Oncology (RANO) 1. Evaluation of quality of life will be measured using the Pediatric Quality of Life inventory (PedsQL) (Generic/Brain tumor modules).

This study will explore the genetic and epigenetic landscape of PLGG. Our biological study may include SNP array, nanoString studies, methylation array and RNAseq.

Inclusion Criteria

• Signed written informed consent prior to study participation.
• Study activities compliance: 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.
• Aged ≥ 2 years to ≤ 25 years when starting mirdametinib.
• BSA ≥ 0.40m2
• Diagnosis:
  • Participants must have PLGG with NF1 gene mutation (based on clinical NIH criteria, germline NF1 mutation or molecular analysis of the tumor) or PLGG with KIAA1549-BRAF fusion (based on molecular analysis of the tumor) or PLGG with evidence of MAPK pathway alteration with the exception of patients with BRAF V600E mutation (based on molecular analysis of the tumor).
• Tumor tissue is required (at minimum, paraffin-embedded tissue block and additionally fresh frozen tissue [if available]). Patients with NF1 and Low Grade Glioma (LGG) can still be enrolled without tissue if no surgery or biopsy was conducted.
• Baseline MRI.
• Life expectancy greater than 6 months.
• Lansky/Karnofsky score ≥ 50.
• Normal organ and marrow function (see study protocol for specifics).
• Female and male patients of fertile age must agree to use highly effective contraceptive measures.
• Must be able to ingest by mouth and retain entirely the administered medication. Mirdametinib can not be administered via nasogastric tube or gastrostomy tube.

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

Exclusion Criteria

• Patients who are receiving other investigational agents.
• Cardiac: QTcB ≥ 480 msec or an absolute resting left ventricular ejection fraction (LVEF) of ≤ 49%.
• Patients who have any other malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
• Tumor with BRAF V600E mutation.
• Patients who received previous systemic or radiotherapy treatment.
• Other severe and uncontrollable medical disease
• Blood pressure higher than 95th percentile for patient's age, height and gender.
• Increased risk of serious retinopathy and retinal vein occlusion.
• Known diagnosis of human immunodeficiency virus infection, hepatitis B or C.
• Previous major surgery within 2 weeks.
• History of allergic reactions to compounds of similar chemical or biological composition to mirdametinib.
• Pregnant or breastfeeding.

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Study Description

Difluoromethylornithine (DFMO) will be used in an open label, single agent, multicenter, study for patients with neuroblastoma in remission. In this study subjects will receive 730 Days of oral difluoromethylornithine (DFMO) at a dose of 500 to 1000 mg/m2 BID on each day of study. This study will focus on the use of DFMO in high risk neuroblastoma patients that are in remission as a strategy to prevent recurrence.

Inclusion Criteria

• All patients must have a pathologically confirmed diagnosis of neuroblastoma, < 30.99 years of age and classified as high risk at the time of diagnosis. Exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible.

• All patients must be in complete remission (CR):

  1. No evidence of residual disease on scan
  2. No evidence of disease metastatic to bone marrow.
• Specific Criteria by Stratum:

Stratum 1: All patients must have completed standard upfront therapy that replicates treatment which patients who were enrolled on ANBL0032 received, including:

intensive induction chemotherapy and (if feasible) resection of primary tumor, followed by: consolidation with high-dose chemotherapy with stem cell transplant and radiotherapy, followed by: immunotherapy with Ch14.18/IL-2/GM-CSF (dinutuximab) and retinoic acid;.

All subjects on Stratum 1 must have also met the following criteria:

• A pre-transplant disease status evaluation that met International Neuroblastoma Response Criteria (INRC) for CR (complete response), VGPR (very good partial response), or PR (partial response) for primary site, soft tissue metastases and bone metastases. Patients who meet those criteria must also meet the protocol-specified criteria for bone marrow response prior to transplant as outlined below: No more than 10% tumor involvement (based on total nucleated cellular content) seen on any specimen from a bilateral bone marrow aspirate/biopsy.

Stratum 2: Neuroblastoma that is in first complete remission following standard upfront therapy different from that described for Stratum 1.

Stratum 3: Neuroblastoma that failed to have a response of at least PR following induction chemotherapy and surgical resection of the primary tumor, but that has achieved CR following additional therapy.

Stratum 4: Patients who have achieved a second or subsequent CR following relapse(s).

• Pre-enrollment tumor survey: Prior to enrollment on this study, a determination of mandatory disease staging must be performed:

  • Tumor imaging studies including
  • Bilateral bone marrow aspirates and biopsy
  • This disease assessment is required for eligibility and preferably should be done within 2 weeks prior to enrollment, but must be done within a maximum of 4 weeks before enrollment.
• Timing from prior therapy:

Stratum 1: Enrollment no later than 60 days after completion of upfront therapy, (last dose of cis-retinoic acid) with a maximum of 6 cycles of cis-retinoic acid maintenance therapy.

Stratum 2, 3 and 4: Enrollment no later than 60 days from last dose of the most recent therapy.

• Patients must have a Lansky or Karnofsky Performance Scale score of > 50% and patients must have a life expectancy of ≥ 2 months.
• All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated below.

• Patients must have adequate organ functions at the time of registration:

  • Hematological: Total absolute phagocyte count ≥1000/μL
  • Liver: Subjects must have adequate liver function
  • Renal: Adequate renal function
• Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
• Written informed consent in accordance with institutional and FDA (food and drug administration) guidelines must be obtained from all subjects (or patients' legal representative).

Exclusion Criteria

• BSA (Body Surface Area) of <0.25 m2.
• Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from hematological and bone marrow suppression effects of prior chemotherapy.
• Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.

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Study Description

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

This is a phase I dose-finding trial of an autologous CD22 targeting chimeric antigen receptor (CAR)-T cell product, called CLIC-2201, for participants with relapsed/refractory B cell malignancies. In the proposed trial, eligible enrolled participants will undergo leukapheresis for autologous T cell collection to enable CLIC-2201 manufacturing, followed by lymphodepletion with cyclophosphamide and fludarabine, then intravenous infusion of the autologous CLIC-2201 product. The trial will use the 3+3 design to escalate or de-escalate the dose level of CLIC-2201 administered. Participants will be monitored for safety and tolerability up to day 365 following CLIC-2201 infusion.

The primary objective is to evaluate the safety and tolerability of CLIC-2201 and estimate the maximum tolerated dose (MTD) of CLIC-2201 in B-cell malignancies.

The secondary objectives are to evaluate the (i) feasibility; (ii) anti-tumour activity of CLIC-2201; (iii) and characterize the pharmacokinetic (PK) profile of CLIC-2201.

Exploratory objectives will include: i) characterizing the cellular and humoral immune responses against CLIC-2201 up to 1 year following infusion of CLIC-2201; (ii) characterizing the phenotype and gene expression profile of CLIC-2201 cells; (iii) evaluating immune and tumour cells at baseline and relapse for biomarkers of response or toxicity; (iv) evaluating serum cytokines, circulating tumour DNA (ctDNA) and B cell aplasia as biomarkers of clinical outcomes; and (v) assessing the quality of life.

Inclusion Criteria

Cohort A (B cell lymphoma):

• Participants in the cohort A must be 18 years of age or older of age at time of informed consent.
• Participants must provide written informed consent. The investigator is responsible for obtaining written informed assent/consent for the subject after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• Participants must have a relapsed or refractory B cell lymphoma, including one of the following:
  • diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS)
  • high grade B cell lymphoma NOS
  • grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
  • primary mediastinal large B-cell lymphoma (PMBCL)
  • aggressive B cell lymphoma transformed from an indolent lymphoma
  • mantle cell lymphoma (MCL)
• Participants must have refractory or relapsed disease, defined as one of the following:
  • Relapse or refractory disease after at least 2 lines of therapy, OR
  • Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
  • Any relapse after CAR-T cell therapy
• Participants must have adequate organ function at enrolment, defined as:
  • Left ventricular ejection fraction (LVEF) ≥40%,
  • Creatinine clearance using Cockcroft-Gault of > 30 mL/min, AND
  • ALP/ALT < 5X upper limit of normal (ULN), conjugated bilirubin < 2X ULN, and no evidence or history of liver cirrhosis.
• Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 or Karnofsky Score ≥50%.
• Females of child-bearing potential and sexually active males must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• Participants with accessible disease, willingness to undergo a tumour biopsy at enrolment. For participants with a recent (within 3 months) tumor biopsy, access to the archival biopsy is acceptable.

Cohort B (B-ALL):

• Participants in the cohort B must be between 1-21 years of age at the time of consent.
• Parent or legal guardian of the participant signed the informed consent and the participant's assent/consent is obtained (if applicable). The investigator is responsible for obtaining written informed assent/consent for the subject or legally acceptable representative (e.g. parent, legal guardian) after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• Participants must have a relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL)
• Participants must have refractory or relapsed disease, defined as one of the following:
  • Relapse or refractory disease after at least 2 lines of therapy, OR
  • Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
  • Any relapse after CAR-T cell therapy.
• Participants in cohort B and/or those who have received CD22 targeted therapy must have documentation of CD22 tumour expression within the 6 months prior to study screening, and after any prior CD22 directed therapy (if applicable).
• Participants must have adequate organ function at enrolment, defined as:
  • Left ventricular ejection fraction (LVEF) ≥45%,
  • Creatinine clearance using Cockcroft-Gault or Schwartz equation of > 30 mL/min, AND
  • ALP/ALT < 5X upper limit of normal (ULN), conjugated bilirubin < 2X ULN, and no evidence or history of liver cirrhosis.
• Participants must have a Karnofsky or Lansky Score ≥50%.
• Participants in reproductive age must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• Participants willingness to undergo a bone marrow biopsy at enrolment.

Publications

Both Cohorts A and B

• Any uncontrolled or serious active infection at the time of enrolment.
• Active autoimmune disease requiring immunosuppressive therapy within 4 weeks of enrolment.
• Live vaccine ≤6 weeks prior to enrolment
• Active Graft Versus Host Disease (GVHD) requiring systemic immunosuppressive therapy within 4 weeks of enrolment.
• Treatment with any of the following in the specified time period before leukapheresis:
  • Allogeneic HCT within 3 months,
  • Autologous HCT within 3 months,
  • CD19 CAR-T cell infusion within 3 months,
  • Donor lymphocyte infusion (DLI) within 3 months,
  • Bendamustine within the last 6 months,
  • Any investigational agent within 30 days or 5 half-lives (whichever is shorter),
  • Systemic administration of therapeutic dose corticosteroids (>20 mg/day prednisone or equivalent for adults and ≥ 12 mg/m2/day for paediatric participants) within 7 days prior to leukapheresis.
  • Immunosuppressive therapies (i.e., calcineurin inhibitors, methotrexate, mycophenolate, rapamycin) within 4 weeks.
  • Oral chemotherapy agents (i.e., venetoclax) within 5 half-lives. An exception to this is that bruton tyrosine kinase (BTK) inhibitors like ibrutinib can be continued in participants with mantle cell lymphoma throughout the trial period.
• Other concurrent malignancy or a prior malignancy treated within the past 2 years, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
• Concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure or immunodeficiency syndrome.
• Active (confirmed by PCR) hepatitis B or hepatitis C at time of screening confirmed by PCR.
• Any Human Immunodeficiency Virus (HIV) infection at time of screening.
• Hypersensitivity to fludarabine or cyclophosphamide.
• Any allergy to gentamycin or its derivatives
• Pregnant or nursing participants.

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Study Description

The purpose of this study is to evaluate the investigational drug, silmitasertib (a pill taken by mouth), in combination with FDA approved drugs for solid tumors. An investigational drug is one that has not been approved by the U.S. Food & Drug Administration (FDA), or any other regulatory authorities around the world for use alone or in combination with any drug, for the condition or illness it is being used to treat.

The goals of this part of the study are:

• Establish a recommended dose of silmitasertib in combination with chemotherapy
• Test the safety and tolerability of silmitasertib in combination with chemotherapy in subjects with cancer
• To determine the activity of study treatments chosen based on:
• How each subject responds to the study treatment
• How long a subject lives without their disease returning/progressing

Inclusion Criteria

• Age: Less than 30 years old at initial diagnosis
• Pathology All subjects must have a confirmed diagnosis of tumor type. Phase I: Relapsed/refractory solid tumors: Neuroblastoma, Ewing Sarcoma, Osteosarcoma, Rhabdomyosarcoma, Liposarcoma
  • Phase II: 
    • Relapsed/refractory Neuroblastoma
    • Relapsed/refractory Ewing sarcoma
• Tumor assessment: Disease assessment is required for eligibility and must be done after last dose of previous therapy and prior to first dose of study drug.
• Disease Status: Relapsed/Refractory Neuroblastoma Relapsed disease defined as neuroblastoma that was previously in remission after standard therapy (at least 4 cycles of aggressive multi-drug induction chemotherapy, with or without radiation and surgery, followed by immunotherapy, or according to a standard high-risk treatment/neuroblastoma protocol) and has now relapsed and is in any number of relapses. Refractory disease defined as High-risk neuroblastoma (as defined by INRG) that failed to achieve CR after at least 4 cycles of aggressive multi-drug induction chemotherapy, progression during upfront therapy or with disease remaining after standard immunotherapy. 
  • International Neuroblastoma Risk Group Staging System (INRG) High Risk NB defined as one of the following:
    • Any age with International Neuroblastoma Risk Group (INRG) Stage L2, MS, or M with MYCN amplification
    • Age ≥ 547 days and INRG Stage M regardless of biologic features
    • Any age initially diagnosed with INRG Stage L1 MYCN amplified NBL who have progressed to Stage M without systemic chemotherapy
    • Age ≥ 547 days of age initially diagnosed with INRG Stage L1, L2, or MS who have progressed to Stage M without systemic chemotherapy
  • Relapsed/refractory Sarcoma Subjects that have relapsed following standard of care therapy or having progressed during standard of care therapy. Standard of care therapy for sarcoma includes multi-agent chemotherapy with local control consisting of either surgery or radiation therapy.
• Measurable or evaluable disease, including at least one of the following:
  • Measurable tumor by CT or MRI
  • MIBG or PET that is positive for disease
  • Bone Marrow biopsy/aspirate that is positive for disease
• Timing from prior therapy:
  • Subjects must have fully recovered from the acute toxic effects of all prior anti- cancer therapy and be within the following timelines:
    • Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study.
    • Small Molecule Inhibitors (anti-neoplastic agent): At least 2 weeks from the completion of therapy with a small molecule inhibitor.
    • Immunotherapy: At least 4 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines, CAR-T cells, anti-GD2 Monoclonal antibodies (ex. naxitamab, dinutuximab, etc.).
    • Radiotherapy: At least 30 days since the last treatment except for radiation delivered with palliative intent to a non-target site.
    • Stem Cell Transplant:
      • Allogeneic: No evidence of active graft vs. host disease
      • Allogeneic/Autologous: ≥ 2 months must have elapsed since transplant.
    • MIBG Therapy: At least 6 weeks since treatment with MIBG therapy.
• Subjects must have a Lansky or Karnofsky Performance Scale score of >/= 50.
• Subjects must have adequate organ function at the time of enrollment:
  • Cardiac: Subjects must have a QTcF ≤ 480 msc.
  • Hematological: Hematological recovery as defined by ANC ≥750/μL
  • Liver: Adequate liver function as defined by AST and ALT <5x upper limit of normal
  • Renal: Subjects must have adequate renal function defined as an estimated Glomerular Filtration rate (eGFR) as calculated from the Bedside Schwartz equation (in units of mL/min/1.73 m2) or via radioisotope GFR ≥ 70. The Bedside Schwartz equation is: [(0.413) X (Height in cm)] / SCr
• Subjects of childbearing potential must have a negative serum pregnancy test. Subjects of childbearing potential must agree to use effective measures to avoid pregnancy.
• Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or subjects' legal representative).

Exclusion Criteria

• Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the hematological and bone marrow suppression effects of prior therapy.
• Subjects who are currently receiving Vitamin K antagonists (warfarin).
• Subjects who are currently receiving the class of lipid-lowering medications HMG-CoA reductase inhibitors (statins).
• Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.
• Subjects with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the subject's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
• Subjects with any of the following gastrointestinal disorders:
  • Active malabsorption (e.g. short gut) syndrome.
  • Uncontrolled diarrhea (excess of 4 stools/day)
  • Gastritis, ulcerative colitis, Chron's disease or hemorrhagic coloproctitis
  • History of gastric or small bowel surgery involving any extent of gastric or small bowel resection
• Lactating subjects are not eligible unless they have agreed to not breastfeed their infants. There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the nursing subject with silmitasertib. (NOTE: breast milk cannot be stored for future use while the nursing subject is being treated on study.)
• Subjects with a history of any other malignancy.

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Study Description

This is a pilot study to determine feasibility of adding intrathecal (IT) chemotherapy and maintenance therapy after high dose chemotherapy for treatment of newly diagnosed HR-EBTs in patients less than 6 years of age. Patients meeting all inclusion criteria will receive 3 cycles of multiagent chemotherapy induction (vinCRIStine, cyclophosphamide, CISplatin, etoposide) with IT cytarabine and hydrocortisone, and 3 cycles of consolidation with CARBOplatin, thiotepa, and autologous stem cell rescue (as per CCG 99703). Maintenance chemotherapy will then be given immediately after the completion of consolidation therapy and consist of risk-stratified oral chemotherapy using either "Maintenance A" (48 weeks) using tamoxifen and retinoic acid or "Maintenance B" (54 weeks) using metronomic isotretinoin, celecoxib, etoposide, temozolomide, and cyclophosphamide. Both arms of maintenance will receive monthly IT topotecan.

Following the end of treatment, patients will be scheduled for a follow-up visit every 3 months for 24 months to evaluate PFS and OS. Approximately 15 patients will be recruited as part of this clinical study.

Patients aged between 0 and 6 years old at the time of enrollment will be eligible. This study will only enrol patients with high risk Central Nervous System Embryonal Brain Tumors (CNS-EBTs) with histologic and/or molecular confirmation of diagnosis for ATRT intrinsic to the brain and spinal cord, group 3 and group 4 MB, pineoblastoma, CNS neuroblastoma, ETMR, including embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma and ETMR not otherwise specified), medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI-1 intact) and CNS embryonal tumor, not otherwise specified.

Response to treatment will be evaluated using the modified RAPNO (Response Assessment in Pediatric Neuro-Oncology) 1.

This study will also explore the genetic landscape of CNS HR-EBTs. Our biological study will include genomic analyses of tumor and CSF with use of epigenomic analyses (methylation profiling) arrays, Nanostring sub-typing studies, Next generation sequencing analyses for DNA and/or RNA.

Inclusion Criteria

• Tumor Tissue Sample
• Age: Patient must be aged ≥ 0 years to ≤ 6 years at the time of definitive confirmation of histologic diagnosis of eligible CNS tumor.
• Diagnoses. Participants must have Central nervous system (CNS) HR-EBT including atypical teratoid rhabdoid tumour (ATRT), group 3 and group 4 medulloblastoma (MB), pineoblastoma, CNS neuroblastoma, embryonal tumor with multi-layered rosettes (ETMR including embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma and ETMR not otherwise specified), medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI-1 intact) and CNS embryonal tumor, not otherwise specified. Metastatic disease included. Any extent of resection included.
• Cranial and Spine MRI. A baseline MRI brain and spine with and without contrast is required for all patients. cranial MRI (with and without gadolinium) must be done pre-operatively. Post-operatively, cranial MRI (with and without gadolinium) must be done.
• Lumbar Puncture (LP) CSF for cytopathology (strongly recommended but not mandatory; if medically feasible). A baseline LP CSF cytology either pre-operatively or post-operatively at least 10 days after definitive surgery for all patients if medically feasible (This is not mandatory and will not make the patient ineligible).
• Life expectancy: Patients must have a life expectancy of greater than 8 weeks from diagnosis.
• Performance level: Patients must have a performance status corresponding of a Lansky score ≥ 50.
• Organ Function Requirements: Participants must have normal organ and marrow function as defined below:
  • Adequate renal function defined as:
    • Creatinine clearance (12-24-hour urine collection) or radioisotope glomerular filtration rate (GFR) ≥ 60 ml/min/1.73m2
  • Adequate cardiac function defined as:
    • Shortening fraction of ≥ 27% by echocardiogram, or
    • Ejection fraction of ≥ 47% by radionuclide angiogram.
  • Adequate pulmonary function defined as:
    • No evidence of dyspnea at rest and a pulse oximetry > 94% on room air.
  • Adequate Bone Marrow Function defined as:
    • Peripheral absolute neutrophil count (ANC) > 1000/μL
    • Platelet Count > 100,000/μL (without transfusion for 3 days)
    • Hemoglobin greater than 8 gm/dL (may have received red blood cell (RBC) transfusions)
  • Adequate liver function defined as:
    • Total bilirubin ≤ 1.5X upper limit of normal (ULN) within normal institutional limits for age (patients with documented Gilbert's Disease may be enrolled with Study Chair approval and total bilirubin ≤ 2.0 × ULN)
    • Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 100 U/L

Other inclusion and exclusion criteria may apply. 

Exclusion Criteria

• Patients who are receiving any other conventional anti-cancer agents or investigational agents.
• Patients who received previous therapy including radiotherapy or chemotherapy other than corticosteroids.
• Presence of another malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
• Concomitant medications restrictions: Concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and carbamazepine), selected strong inhibitors of cytochrome P450 3A4 include azole antifungals, such as fluconazole, voriconazole, itraconazole, ketoconazole, and strong inducers include drugs such as rifampin, phenytoin, phenobarbitol, carbamazepine, and St. John's wort or CYP450 3A4 stimulators or inhibitors.
• Other uncontrollable medical disease: Patient has a severe and uncontrollable medical disease (i.e., uncontrolled diabetes, hyperglycemia, chronic renal disease or active uncontrolled infection), has chronic liver disease (i.e., chronic active hepatitis and cirrhosis), hypercholesterolemia (serum cholesterol >300 mg/dL), intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active hyperparathyroidism, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients who have a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C.
• Ineligible diagnoses for study entry by neuropathology: This includes sonic hedgehog (SHH) and wingless (WNT) MBs, all ependymomas, all choroid plexus carcinomas, all high grade glial and glio-neuronal tumors, all diffuse midline gliomas, all primary CNS germ cell tumors, all primary CNS sarcomas, all primary or metastatic CNS lymphomas and solid leukemic lesions (chloromas, granulocytic sarcomas).
• The participant or parent(s)/guardian(s) cannot comply with the study visit schedule and other protocol requirements, in the investigator's opinion.

Other inclusion and exclusion criteria may apply. 

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Centres

Study Description

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

The phase I portion of this study is designed for children or adolescents and young adults (AYA) with a diagnosis of a solid tumor that has recurred (come back after treatment) or is refractory (never completely went away). The trial will test 2 combinations of therapy and participants will be randomly assigned to either Arm A or Arm B. The purpose of the phase I study is to determine the highest tolerable doses of the combinations of treatment given in each Arm.

In Arm A, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and talazoparib. Onivyde works by damaging the DNA of the cancer cell and talazoparib works by blocking the repair of the DNA once the cancer cell is damaged. By damaging the tumor DNA and blocking the repair, the cancer cells may die. In Arm B, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and temozolomide. Both of these medications work by damaging the DNA of the cancer call which may cause the tumor(s) to die.

Once the highest doses are reached in Arm A and Arm B, then "expansion Arms" will open. An expansion arm treats more children and AYAs with recurrent or refractory solid tumors at the highest doses achieved in the phase I study. The goal of the expansion arms is to see if the tumors go away in children and AYAs with recurrent or refractory solid tumors. There will be 3 "expansion Arms". In Arm A1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and talazoparib. In Arm A2, children and AYAs with recurrent or refractory solid tumors, whose tumors have a problem with repairing DNA (identified by their doctor), will receive Onivyde and talazoparib. In Arm B1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and temozolomide.

Once the highest doses of medications used in Arm A and Arm B are determined, then a phase II study will open for children or young adults with Ewing sarcoma that has recurred or is refractory following treatment received after the initial diagnosis. The trial will test the same 2 combinations of therapy in Arm A and Arm B. In the phase II, a participant with Ewing sarcoma will be randomly assigned to receive the treatment given on either Arm A or Arm B.

Inclusion Criteria

• Age: Patients must be > 12 months and < 30 years at the time of enrollment on study.
• Diagnosis:
  • Phase I (Only expansion cohort open)
    • Patients with refractory or recurrent non-central nervous system (CNS) solid tumors not amenable to curative treatment are eligible. Patients must have had histologic verification of malignancy at original diagnosis or at the time of relapse. Patients eligible for the expansion cohort, A2, will include non-ES patients with refractory or recurrent non-CNS solid tumors with a deleterious alteration in germline or somatic genes involved in HR repair and DSBs signaling, germline or somatic assessed by prior comprehensive sequencing performed in a CLIA-approved (or equivalent) facility.
  • Phase II (Open)
    • Patients with refractory or recurrent Ewing sarcoma (during or after completion of first-line therapy). Refractory disease is defined as progression during first line treatment or within 12 weeks of completion of first line treatment. Recurrent disease includes patients who received first line treatment and experienced disease progression at any time point >12 weeks from the completion of first line therapy.
    • Patients must have a histologic diagnosis of Ewing sarcoma with EWSR1- FLI1 translocation or other EWS rearrangement at the time of initial diagnosis. Repeat biopsy at the time of disease recurrence is strongly encouraged but it is not required/mandated for enrollment.
• Disease status
  • Patients must have either measurable or evaluable disease (see Section 7.0 for definitions). Measurable disease includes soft tissue disease evaluable by cross-sectional imaging (RECIST). Patients with bone disease without a measurable soft tissue component or bone marrow disease only are eligible for the phase 1 and phase 2 study but will not be included in the OR endpoint.
• Performance level: Karnofsky > 50% for patients > 16 years of age and 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.
• Prior therapy
  • Phase I: Patients who have received prior therapy with an irinotecan-based or temozolomide-based regimen are eligible. Patients who have received prior therapy with a PARP inhibitor other than talazoparib are eligible.
  • Phase II: Patients should have received first line therapy and developed either refractory or recurrent disease (first relapse).
• Organ function: Must have adequate organ and bone marrow function as defined by the following parameters:
  • Patients with solid tumors not metastatic to bone marrow:
    • Peripheral absolute neutrophil count (ANC) >1,000/mm3 (1x109/L)
    • Platelet count > 75,000/mm3 (75x109/L) (no transfusion within 7 days of enrollment)
    • Hemoglobin > 9 g/dL (with or without support)
  • In the phase I study, patients with solid tumors metastatic to bone marrow or with bone marrow hypocellularity defined as <30% cellularity in at least one bone marrow site will be eligible for study, but they will not be evaluable for hematologic toxicity. These patients must not be refractory to red cell or platelet transfusions. At least 2 of every cohort of 3 patients (in the phase I study) must be evaluable for hematologic toxicity. If dose limiting hematologic toxicity is observed at any dose level, all subsequent patients enrolled at that dose level must be evaluable for hematologic toxicity.
  • Adequate renal function defined as: Creatinine clearance or radioisotope GFR > 60ml/min/1.73m2 or a serum creatinine maximum based on age/sex: age 6months to <1 year, creatinine 0.4; 1 to < 2 years, creatinine 0.6; 2 < 6 years, creatinine 0.8; 6 < 10 years, creatinine 1; 10 to <13 years, creatinine 1.2; 13 to < 16 years creatinine 1.5 (males) or 1.4 (females); > 16 years, creatinine 1.7 (males) 1.4 (females)
  • Adequate liver function defined as: normal liver function as defined by SGPT (ALT) concentration <5x the institutional ULN, a total bilirubin concentration <2x the institutional ULN for age, and serum albumin > 2g/dL.
  • Adequate pulmonary function defined as no evidence of dyspnea at rest and a pulse oximetry > 94% if there is a clinical indication for determination. Pulmonary function tests are not required.
• Patients must have fully recovered from the acute toxic effects of chemotherapy, immunotherapy, surgery, or radiotherapy prior to entering this study:
  • Myelosuppressive chemotherapy: Patient has not received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (8 weeks if received prior myeloablative therapy).
  • 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.
  • Biologic (anti-neoplastic agent): At least 7 days must have elapsed since completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur.
  • Monoclonal antibodies: At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody or 28 days have elapsed since last dose of the monoclonal antibody with complete resolution of symptoms related to treatment.
  • Radiotherapy: At least 2 weeks must have elapsed since any irradiation; at least 6 weeks must have elapsed since craniospinal RT, 131I-mIBG therapy or substantial bone marrow irradiation (e.g., >50% pelvis irradiation).
• Female participant who is post-menarchal must have a negative urine or serum pregnancy test and must be willing to have additional serum and urine pregnancy tests during the study.
• Female or male participant of reproductive potential must agree to use effective contraceptive methods at screening and throughout duration of study treatment.
• Written informed consent/assent from the patient and/or parent/legal guardian

Exclusion Criteria

Pregnant or breastfeeding

• Pregnant or breast-feeding women will not be entered on this study. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two methods of birth control: a medically accepted barrier of contraceptive method (e.g., male or female condom) and a second method of birth control during protocol therapy. Two highly effective methods of contraception are required for female patients during treatment and for at least 7 months after completing therapy. Male patients with female partners of reproductive potential and/or pregnant partners are advised to use two highly effective methods of contraception during treatment and for at least 4 months after the final dose.
• Male and female participants must agree not to donate sperm or eggs, respectively, after the first dose of study drug through 105 days and 45 days after the last dose of study drug. Females considered not of childbearing potential include those who are surgically sterile (bilateral salpingectomy, bilateral oophorectomy, or hysterectomy).