A Platform Study of Novel Therapies for Children, Adolescents and Young Adults With Recurrent/Progressive Atypical Teratoid Rhabdoid Tumor (ATRT)
Overview
- Phase
- Phase 2
- Status
- Not yet recruiting
- Sponsor
- Sabine Mueller, MD, PhD
- Enrollment
- 29
- Locations
- 1
- Primary Endpoint
- Arm A (Phase I): Proportion of participants who experience dose-limiting toxicity (DLT)
Overview
Brief Summary
This is a multi-treatment arm study that will be conducted through the Pacific Pediatric Neuro-oncology Consortium (PNOC).The study will assess the safety and efficacy of novel therapies and combinatorial strategies for participants with recurrent or progressive ATRT.
Detailed Description
PRIMARY OBJECTIVES:
I. To assess efficacy of each treatment arm based on arm-specific endpoints. II. To evaluate the safety and tolerability of each treatment arm for patients with recurrent/progressive ATRT.
EXPLORATORY OBJECTIVES:
I. To collect additional treatment arm-specific safety and tolerability information as applicable.
II. To determine additional treatment arm-specific time-to-event endpoints. III. To assess the correlations between methylation-based subgroups and objective response and outcome measures.
IV. To collect biologic samples (tumor, blood, CSF) for future biomarker discovery.
V. Additional treatment arm-specific exploratory objectives may be added in each interventional arm.
OUTLINE: Participants will enroll onto a treatment arm as treatment arms open for enrollment. Participants who are taken off treatment on one trial arm for progression or toxicity may enroll on a new treatment arm, if arm-specific eligibility criteria are met. If the study is opened at the treating institution, participants will be followed under the Pediatric Neuro-oncology Consortium (PNOC) COMP protocol until death or withdrawal from study.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 1 Year to 39 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •In addition to the below, investigators are to refer to arm-specific inclusion criteria in the appendix.
- •Participants must have a pathologic diagnosis of central nervous system (CNS) ATRT, with confirmation of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 (SMARCB1) (INI1) loss by immunohistochemistry (IHC) and/or biallelic loss of function of SMARCB1 by molecular report. Loss of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 4 (SMARCA4) as confirmed by IHC or molecular report is also acceptable but requires study chair approval.
- •Participants must have confirmation of methylation report, co-enrollment on PNOC-030 or sufficient tumor tissue available for methylation-based subgrouping
- •Participants must have recurrent or progressive ATRT.
- •Participants age must be ≥1 and ≤ 39 years at the time of study enrollment. Please refer to arm specific inclusion criteria for potential variations in lower age eligibility limit.
- •Prior Therapy: Participants must have fully recovered from the acute effects of prior anti-cancer therapy, and the following wash-out periods need to be observed prior to enrollment:
- •Systemic myelosuppressive therapy: ≥ 21 days after the last dose (42 days for nitrosoureas or mitomycin C).
- •Intrathecal/intraventricular chemotherapy: \> 7 days after the last dose.
- •Small molecule/targeted/biologic agent: ≥ 7 days after the last dose.
- •Monoclonal antibodies: ≥ 21 days after the last dose. Other non-myelosuppressive anti-cancer agents: ≥ 3 drug half-lives after the last dose.
Exclusion Criteria
- •Evidence of synchronous tumors or other extra-CNS malignancy
- •Participants who are receiving any other investigational agents
- •Participants who are currently receiving other anti-cancer agents
- •Participants with uncontrolled infection or other uncontrolled systemic illness
- •Female participants of childbearing potential who are pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy and throughout study treatment.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition as the intended treatment regimen, as detailed in that arm's treatment description.
- •Inclusion Criteria:
- •Subjects must meet all inclusion criteria for the overall study.
- •Patients must be evaluable per Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria for medulloblastoma and other leptomeningeal seeding tumors to be evaluated for the primary endpoint (Warren et al. 2018); patients with evaluable but non-measurable disease, including leptomeningeal disease or positive CSF cytology only are eligible.
- •Patients with recurrent or progressive ATRT who receive surgery only for their disease progression and do not have evaluable disease may be eligible for study treatment but would not be included towards the primary efficacy endpoint (to be discussed with study chairs).
Arms & Interventions
Treatment Arm A: Phase I
Participants will receive a combination of gemcitabine and paxalisib with starting dose, 1,200mg/m2 gemcitabine and 15mg/m2 paxalisib (phase I). If this dose level is tolerated, it will be confirmed as the RP2D. However, if the dose limiting toxicity (DLT) is not tolerated, the RP2D will be set at the highest dose level tolerated by the previous group.
Intervention: Gemcitabine (Drug)
Treatment Arm A: Phase I
Participants will receive a combination of gemcitabine and paxalisib with starting dose, 1,200mg/m2 gemcitabine and 15mg/m2 paxalisib (phase I). If this dose level is tolerated, it will be confirmed as the RP2D. However, if the dose limiting toxicity (DLT) is not tolerated, the RP2D will be set at the highest dose level tolerated by the previous group.
Intervention: Paxalisib (Drug)
Treatment Arm A: Phase I
Participants will receive a combination of gemcitabine and paxalisib with starting dose, 1,200mg/m2 gemcitabine and 15mg/m2 paxalisib (phase I). If this dose level is tolerated, it will be confirmed as the RP2D. However, if the dose limiting toxicity (DLT) is not tolerated, the RP2D will be set at the highest dose level tolerated by the previous group.
Intervention: Lumber Puncture (Procedure)
Treatment Arm A: Phase I
Participants will receive a combination of gemcitabine and paxalisib with starting dose, 1,200mg/m2 gemcitabine and 15mg/m2 paxalisib (phase I). If this dose level is tolerated, it will be confirmed as the RP2D. However, if the dose limiting toxicity (DLT) is not tolerated, the RP2D will be set at the highest dose level tolerated by the previous group.
Intervention: Blood Specimen Collection (Procedure)
Treatment Arm A: Phase I
Participants will receive a combination of gemcitabine and paxalisib with starting dose, 1,200mg/m2 gemcitabine and 15mg/m2 paxalisib (phase I). If this dose level is tolerated, it will be confirmed as the RP2D. However, if the dose limiting toxicity (DLT) is not tolerated, the RP2D will be set at the highest dose level tolerated by the previous group.
Intervention: Magnetic resonance imaging (MRI) (Procedure)
Treatment Arm A: Phase I
Participants will receive a combination of gemcitabine and paxalisib with starting dose, 1,200mg/m2 gemcitabine and 15mg/m2 paxalisib (phase I). If this dose level is tolerated, it will be confirmed as the RP2D. However, if the dose limiting toxicity (DLT) is not tolerated, the RP2D will be set at the highest dose level tolerated by the previous group.
Intervention: Tumor Biopsy (Procedure)
Treatment Arm A: Efficacy (Phase II)
All participants will receive a combination of gemcitabine and paxalisib over a 28-day cycle, for up to 24 cycles or until they meet criteria to stop treatment, whichever comes first. Gemcitabine will be administered via infusion on days 1, 8, and 15 of each cycle, while paxalisib will be taken daily throughout each cycle.
Intervention: Lumber Puncture (Procedure)
Treatment Arm A: Efficacy (Phase II)
All participants will receive a combination of gemcitabine and paxalisib over a 28-day cycle, for up to 24 cycles or until they meet criteria to stop treatment, whichever comes first. Gemcitabine will be administered via infusion on days 1, 8, and 15 of each cycle, while paxalisib will be taken daily throughout each cycle.
Intervention: Blood Specimen Collection (Procedure)
Treatment Arm A: Efficacy (Phase II)
All participants will receive a combination of gemcitabine and paxalisib over a 28-day cycle, for up to 24 cycles or until they meet criteria to stop treatment, whichever comes first. Gemcitabine will be administered via infusion on days 1, 8, and 15 of each cycle, while paxalisib will be taken daily throughout each cycle.
Intervention: Magnetic resonance imaging (MRI) (Procedure)
Treatment Arm A: Efficacy (Phase II)
All participants will receive a combination of gemcitabine and paxalisib over a 28-day cycle, for up to 24 cycles or until they meet criteria to stop treatment, whichever comes first. Gemcitabine will be administered via infusion on days 1, 8, and 15 of each cycle, while paxalisib will be taken daily throughout each cycle.
Intervention: Gemcitabine (Drug)
Treatment Arm A: Efficacy (Phase II)
All participants will receive a combination of gemcitabine and paxalisib over a 28-day cycle, for up to 24 cycles or until they meet criteria to stop treatment, whichever comes first. Gemcitabine will be administered via infusion on days 1, 8, and 15 of each cycle, while paxalisib will be taken daily throughout each cycle.
Intervention: Paxalisib (Drug)
Treatment Arm A: Efficacy (Phase II)
All participants will receive a combination of gemcitabine and paxalisib over a 28-day cycle, for up to 24 cycles or until they meet criteria to stop treatment, whichever comes first. Gemcitabine will be administered via infusion on days 1, 8, and 15 of each cycle, while paxalisib will be taken daily throughout each cycle.
Intervention: Tumor Biopsy (Procedure)
Outcomes
Primary Outcomes
Arm A (Phase I): Proportion of participants who experience dose-limiting toxicity (DLT)
Time Frame: up to 28 days
Tolerability is defined as the proportion of participants receiving at least one dose of combination gemcitabine and paxalisib with a reported dose-limiting toxicity (DLT) during cycle 1 for all participants in Phase I.
Arm A (Phase I): Recommended Phase 2 Dose (RP2D) (Phase I)
Time Frame: up to 28 days
The confirmed RP2D of combination gemcitabine and paxalisib implemented for participants enrolled in Phase II will be reported.
Arm A (Phase II): Rate of Clinical Benefit
Time Frame: up to 2 years (24 cycles)
Assess the efficacy of combination gemcitabine and paxalisib for participants in Phase II. Clinical Benefit rate (CBR) is defined as complete response (CR) + partial response (PR) + stable disease (SD), where SD is sustained over 4 months.
Secondary Outcomes
No secondary outcomes reported
Investigators
Sabine Mueller, MD, PhD
Principal Investigator
University of California, San Francisco