A Phase I/II Study Using Eflornithine (DFMO) and AMXT 1501 for Relapsed and Refractory Neuroblastoma, CNS Tumors, and Sarcomas
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 265
- 试验地点
- 15
- 主要终点
- Phase I- Number of Participants with Adverse Events as a Measure of Safety and Tolerability
研究概览
简要总结
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 26 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All participants : Must be a maximum of 26 years of age at diagnosis
- •Age at enrollment by Phase:
- •Safety Run-in (Dose level 1)-The first three (3) participants enrolled will be ≥ 12 years of age at enrollment. Once evaluated for safety by DSMB, we will move on to the next three (3) participants enrolled who will be ≥6 years of age at enrollment. Once evaluated for safety by DSMB, we will move on to the Phase I.
- •Phase I and II: ≤ 26 years of age at diagnosis.
- •All participants 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
- •Relapsed/refractory Ewing Sarcoma (EWS)
- •Relapsed/refractory Osteosarcoma (OST)
- •Tumor assessment:
- •Disease staging must be performed at baseline during the 28 day screening period prior to first dose of study drug.
- •Disease Status:
- •Relapsed or Refractory Neuroblastoma Relapsed disease defined as: High-risk neuroblastoma that was previously in remission after standard therapy (at least 4 cycles of aggressive multi-drug induction chemotherapy, with or without radiation, surgery, and immunotherapy, or according to a standard high-risk treatment/neuroblastoma protocol).
- •Refractory disease defined as: High-risk neuroblastoma that 1) failed to achieve CR after 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, or 2) progression during upfront therapy or 3) with disease remaining after standard immunotherapy.
- •Eligible NB participants may have active disease or no active disease.
- •NB participants with no active disease need to meet the following criteria:
- •Timing from prior therapy: Enrollment (first dose of study drug) no later than 60 days from most recent therapy.
- •NB participants with active disease need to meet the following criteria:
- •Received at least one recent treatment for their relapse/refractory disease and is stable (SD) or better on this treatment.
- •Participants must not have disease in any organs (including lungs, liver, or brain).
- •Relapsed or refractory ETMR/ATRT Participants that have relapsed following standard of care therapy or having progressed during standard of care therapy and non-responsive/progressive to accepted curative therapy, including up-front chemotherapy and radiation and/or high-dose chemotherapy with stem cell rescue.
- •ETMR/ATRT participants with no active disease need to meet the following criteria:
- •Timing from prior therapy: Enrollment (first dose of study drug) no later than 60 days from most recent therapy.
- •ETMR/ATRT participants with active disease need to meet the following criteria:
- •Received at least one recent treatment for their relapse/refractory disease and is stable (SD) or better on this treatment.
- •Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) Participants with DIPG to start greater than 30 days, and no longer than 60 days, after standard of care radiation therapy.
- •Participants with newly-diagnosed typical DIPG, defined as tumors with a pontine epicenter and diffuse involvement of the pons on at least 1 axial T2-weighted image, are eligible. No histologic confirmation is required. Participants with metastatic disease are not eligible. Participants with a biopsy and no evidence of H3K27m mutations are eligible as long as they meet radiographic criteria. Participants with H3K27m altered DMG outside of the brainstem are not eligible. Participants with progression or recurrence after initial standard of care radiation are ineligible.
- •Relapsed or refractory Ewing sarcoma and osteosarcoma Participants that have relapsed following standard of care therapy or having progressed during standard of care therapy. Standard of care therapy for Ewing sarcoma and osteosarcoma includes multi-agent chemotherapy with local control consisting of either surgery or radiation therapy.
- •EWS/OST Participants with no active disease need to meet the following criteria:
- •Timing from prior therapy: Enrollment (first dose of study drug) no later than 60 days from most recent therapy.
- •EWS/OST Participants with active disease need to meet the following criteria:
- •Received at least one recent treatment for their relapse/refractory disease and is stable (SD) or better on this treatment.
- •Participants must be able to swallow capsules.
- •Participants with CNS disease currently taking steroids must have been on a stable dose of steroids for at least one week and must not have progressive hydrocephalus at enrollment.
- •Participants must have fully recovered from the acute toxic effects of all prior anti- cancer chemotherapy and be within the following timelines:
- •Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
- •Small Molecule Inhibitor (anti-neoplastic agent): At least 7 days since the completion of therapy with a small molecule inhibitor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the Study Chair.
- •Immunotherapy: At least 4 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines, CAR-T cells except for anti-GD2 Monoclonal antibodies (ex. naxitamab, dinutuximab, etc.) which should be at least 2 weeks since prior treatment with a monoclonal antibody.
- •XRT: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site.
- •Note: Participants with DIPG will be required to have had up front standard of care radiation. As above, participants with DIPG must be between 30-60 days post initial up- front radiation therapy.
- •Stem Cell Transplant:
- •Allogeneic: No evidence of active graft vs. host disease
- •Allo/Auto: ≥ 45 days must have elapsed since transplant.
- •MIBG Therapy: At least 6 weeks since treatment with MIBG therapy.
- •Participants must have a Lansky or Karnofsky Performance Scale score of >/= 60
- •Participants must have adequate organ function at the time of enrollment:
- •Hematological: Hematological recovery as defined by ANC ≥750/μL (unsupported- >24 hrs off G-CSF and 7 days off neulasta)
- •Liver: Adequate liver function as defined by AST and ALT <10x upper limit of normal
- 另有 13 项未显示
排除标准
- •BSA of <0.25 m2
- •Investigational Drugs: Participants who are currently receiving another investigational drug are excluded from participation.
- •Anti-cancer Agents: Participants who are currently receiving other anticancer agents are not eligible. Participants must have fully recovered from the hematological and bone marrow suppression effects of prior chemotherapy.
- •Infection: Participants who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.
- •Participants 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.
研究组 & 干预措施
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. Participants 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.
Participants in cohort 1 who progress on DFMO alone (and have met the primary PFS endpoint) may cross over to AMXT 1501+DFMO.
干预措施: AMXT 1501 Dicaprate (Drug)
Phase I
Phase I will use a standard 3+3 design in which groups of 3 participants per dose level will be treated and assessed. Participants will receive up to twenty-four (24), 28-day cycles of AMXT 1501 combined with DFMO. Participants 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.
干预措施: 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. Participants 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.
Participants in cohort 1 who progress on DFMO alone (and have met the primary PFS endpoint) may cross over to AMXT 1501+DFMO.
干预措施: 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. Participants 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.
Participants in cohort 1 who progress on DFMO alone (and have met the primary PFS endpoint) may cross over to AMXT 1501+DFMO.
干预措施: Eflornithine (DFMO) (Drug)
Safety Run-in
This study will include a safety run-in of 6 participants. The first 3 participants will be ≥ 12 years of age. The next 3 participants will be ≥ 6 years of age. The study will then move on to the Phase I.
干预措施: AMXT 1501 Dicaprate (Drug)
Safety Run-in
This study will include a safety run-in of 6 participants. The first 3 participants will be ≥ 12 years of age. The next 3 participants will be ≥ 6 years of age. The study will then move on to the Phase I.
干预措施: Eflornithine (DFMO) (Drug)
Phase I
Phase I will use a standard 3+3 design in which groups of 3 participants per dose level will be treated and assessed. Participants will receive up to twenty-four (24), 28-day cycles of AMXT 1501 combined with DFMO. Participants 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.
干预措施: Eflornithine (DFMO) (Drug)
结局指标
主要结局
Phase I- Number of Participants with Adverse Events as a Measure of Safety and Tolerability
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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 participants.
次要结局
- 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 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-Number of Participants with Adverse Events as a Measure of Safety and Tolerability(2 years plus 30 days)
研究者
Giselle Sholler
Beat Childhood Cancer Chair
Milton S. Hershey Medical Center