A Dose Escalation Study Using Eflornithine (DFMO) and AMXT 1501 Followed by a Randomized Controlled Trial of DFMO With or Without AMXT 1501 for Neuroblastoma, CNS Tumors, and Sarcomas
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 289
- Locations
- 11
- Primary Endpoint
- Phase I- Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Overview
Brief Summary
The purpose of this study is to evaluate the investigational oral drug AMXT 1501 in combination with oral eflornithine (DFMO). 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 AMXT 1501 in combination with DFMO
- Test the safety and tolerability of AMXT 1501 in combination with DFMO
- 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
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- — to 21 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •All subjects: Must be a maximum of 21 years of age at diagnosis
- •Age at enrollment by Phase:
- •Phase I-AYA (adolescents and young adult) Cohort: ≥12 years of age at enrollment.
- •Phase I-Pediatric Cohort: \< 12 years of age at enrollment; may start only after DSMB review confirms the RP2D from the AYA cohort. No subject \< 12 years will be treated at a dose level higher than the RP2D established in the Phase I-AYA Cohort.
- •Phase II: ≤ 21 years of age at diagnosis (with possibly two different age-specific RP2Ds).
- •All subjects must have a confirmed pathologic diagnosis of tumor type (except for DIPG):
- •Relapsed/refractory Neuroblastoma (NB)
- •Relapsed/refractory Embryonal tumor with multilayer rosettes (ETMR)
- •Relapsed/refractory Atypical teratoid rhabdoid tumor (ATRT)
- •Newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG)- radiologic diagnosis acceptable
Exclusion Criteria
- •BSA 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 the 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.
Arms & Interventions
Phase I- AYA Cohort
The initial phase I will be an AYA (adolescents and young adult) cohort that will be for subjects ≥12 years of age at enrollment in a standard 3+3 design in which groups of 3 subjects per cohort will be treated and assessed. Subjects will receive up to twenty-four (24), 28-day cycles of AMXT 1501 combined with DFMO. Subjects will receive oral AMXT 1501 at a starting dose of 350 mg/m2 BID each day. The dose escalation scheme for subsequent groups and modifications for dose limiting toxicities (DLT) are detailed in the protocol.
Intervention: Eflornithine (DFMO) (Drug)
Phase I- Pediatric Cohort
The second phase I will be a pediatric cohort that will be for subjects < 12 years of age at enrollment in a standard 3+3 design in which groups of 3 subjects per cohort will be treated and assessed. Subjects will receive up to twenty-four (24), 28-day cycles of AMXT 1501 combined with DFMO. Subjects will receive oral AMXT 1501 at a starting dose of 350 mg/m2 BID each day. The dose escalation scheme for subsequent groups and modifications for dose limiting toxicities (DLT) are detailed in the protocol.
Intervention: Eflornithine (DFMO) (Drug)
Phase II- Arm A: AMXT 1501 + DFMO
In this portion of the study, cohort 1 will be randomized to either receive Arm A: oral AMXT 1501 at the recommended phase 2 dose (RP2D) found in the Phase I along with oral DFMO at the RP2D found in the Phase I on each day of study or Arm B: oral DFMO alone at the recommended phase 2 dose (RP2D) found in the Phase I. Subjects will receive up to twenty-four (24), 28-day cycles of their assigned treatment. Cohorts 2 (ETMR/ATRT), 3 (DIPG), and 4 (Sarcomas) will automatically be assigned to Arm A with AMXT 1501 in combination with DFMO.
Subjects in cohort 1 who progress on DFMO alone (and have met the primary PFS endpoint) may cross over to AMXT 1501+DFMO.
Intervention: Eflornithine (DFMO) (Drug)
Phase II- Arm B: DFMO Alone
In this portion of the study, cohort 1 will be randomized to either receive Arm A: oral AMXT 1501 at the recommended phase 2 dose (RP2D) found in the Phase I along with oral DFMO at the RP2D found in the Phase I on each day of study or Arm B: oral DFMO alone at the recommended phase 2 dose (RP2D) found in the Phase I. Subjects will receive up to twenty-four (24), 28-day cycles of their assigned treatment. Cohorts 2 (ETMR/ATRT), 3 (DIPG), and 4 (Sarcomas) will automatically be assigned to Arm A with AMXT 1501 in combination with DFMO.
Subjects in cohort 1 who progress on DFMO alone (and have met the primary PFS endpoint) may cross over to AMXT 1501+DFMO.
Intervention: Eflornithine (DFMO) (Drug)
Phase I- Pediatric Cohort
The second phase I will be a pediatric cohort that will be for subjects < 12 years of age at enrollment in a standard 3+3 design in which groups of 3 subjects per cohort will be treated and assessed. Subjects will receive up to twenty-four (24), 28-day cycles of AMXT 1501 combined with DFMO. Subjects will receive oral AMXT 1501 at a starting dose of 350 mg/m2 BID each day. The dose escalation scheme for subsequent groups and modifications for dose limiting toxicities (DLT) are detailed in the protocol.
Intervention: AMXT 1501 Dicaprate (Drug)
Phase I- AYA Cohort
The initial phase I will be an AYA (adolescents and young adult) cohort that will be for subjects ≥12 years of age at enrollment in a standard 3+3 design in which groups of 3 subjects per cohort will be treated and assessed. Subjects will receive up to twenty-four (24), 28-day cycles of AMXT 1501 combined with DFMO. Subjects will receive oral AMXT 1501 at a starting dose of 350 mg/m2 BID each day. The dose escalation scheme for subsequent groups and modifications for dose limiting toxicities (DLT) are detailed in the protocol.
Intervention: AMXT 1501 Dicaprate (Drug)
Phase II- Arm A: AMXT 1501 + DFMO
In this portion of the study, cohort 1 will be randomized to either receive Arm A: oral AMXT 1501 at the recommended phase 2 dose (RP2D) found in the Phase I along with oral DFMO at the RP2D found in the Phase I on each day of study or Arm B: oral DFMO alone at the recommended phase 2 dose (RP2D) found in the Phase I. Subjects will receive up to twenty-four (24), 28-day cycles of their assigned treatment. Cohorts 2 (ETMR/ATRT), 3 (DIPG), and 4 (Sarcomas) will automatically be assigned to Arm A with AMXT 1501 in combination with DFMO.
Subjects in cohort 1 who progress on DFMO alone (and have met the primary PFS endpoint) may cross over to AMXT 1501+DFMO.
Intervention: AMXT 1501 Dicaprate (Drug)
Outcomes
Primary Outcomes
Phase I- Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Time Frame: 28 days
To evaluate the safety, tolerability and recommended phase 2 dose (RP2D) of AMXT 1501 in combination with oral DFMO in pediatric and young adult subjects.
Phase II- Number of Cohort 1 participants with progression free survival (PFS) during study
Time Frame: 2 years plus 5 years follow up
To evaluate, in a prospective randomized clinical trial, the efficacy of eflornithine (DFMO) in combination with AMXT 1501 compared to DFMO alone in neuroblastoma (Cohort 1) based upon Progression Free Survival (PFS)
Phase II- Number of Cohort 2-4 participants with progression free survival (PFS) during study
Time Frame: 2 years plus 5 years follow up
To evaluate the efficacy of eflornithine (DFMO) in combination with AMXT 1501 in non-randomized (Cohorts 2-4) based upon Progression Free Survival (PFS): 2\. Cohort 2-Relapsed/refractory Embryonal Tumor with Multilayered Rosettes (ETMR) Atypical Teratoid Rhabdoid Tumor (ATRT) 3. Cohort 3-Diffuse Intrinsic Pontine Glioma (DIPG) at diagnosis after standard of care radiation therapy 4. Cohort 4- Relapsed/refractory Ewing Sarcoma (EWS) and Osteosarcoma (OST)
Phase I- Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Time Frame: 28 days
To evaluate the safety, tolerability and recommended phase 2 dose (RP2D) of AMXT 1501 in combination with oral DFMO in pediatric and young adult subjects.
Secondary Outcomes
- Phase I- Number of participants with progression free survival (PFS) during study(2 years plus 5 years follow up)
- Phase I- Determine the Overall Response Rate (ORR) of Participants using INSS Response(2 years)
- Phase II- Determine the Overall Response Rate (ORR) of Participants using INSS Response(2 years)
- Phase II- Length of time that participants experience Overall Survival (OS)(2 years plus 5 years follow up)
- Phase II-Number of Participants with Adverse Events as a Measure of Safety and Tolerability(2 years plus 30 days)
- Phase I- Number of participants with progression free survival (PFS) during study(2 years plus 5 years follow up)
- Phase I- Determine the Overall Response Rate (ORR) of Participants using INSS Response(2 years)
Investigators
Giselle Sholler
Beat Childhood Cancer Chair
Milton S. Hershey Medical Center