Difluoromethylornithine (DFMO) and AMXT-1501 for Neuroblastoma, CNS Tumors, and Sarcomas

Phase 1

Not yet recruiting

• Conditions: Ewing Sarcoma; Osteosarcoma Recurrent; Atypical Teratoid/Rhabdoid Tumor; Neuroblastoma Recurrent; Embryonal Tumor With Multilayered Rosettes; DIPG Brain Tumor
• Interventions: Drug: Difluoromethylornithine (DFMO); Drug: AMXT-1501 Dicaprate

• Registration Number: NCT06465199
• Lead Sponsor: Milton S. Hershey Medical Center

Brief Summary

The purpose of this study is to evaluate the investigational drug AMXT 1501 (a pill taken by mouth) in combination with the drug difluoromethylornithine (DFMO) for infusion administered intravenously (IV; a liquid that continuously goes into your body through a tube that has been placed during a surgery into one of your veins). 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 for infusion

* Test the safety and tolerability of AMXT 1501 in combination with DFMO for infusion in patients 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

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-06-13
• Study First Submitted QC: 2024-06-13
• Study First Posted: 2024-06-18
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-05
• Last Update Posted: 2025-05-08
• Study Start: 2025-10-01
• Primary Completion: 2033-02
• Study Completion: 2035-02

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 253

Inclusion Criteria

1. Age: 0-21 years of age at diagnosis

2. Pathology

   All subjects must have a confirmed pathologic diagnosis of tumor type (except for DIPG):

   • Relapsed/Refractory Neuroblastoma
   • Embryonal tumor with multilayer rosettes (ETMR)
   • Atypical teratoid rhabdoid tumor (ATRT)
   • Diffuse Intrinsic Pontine Glioma (DIPG)- radiologic diagnosis
   • Relapsed/refractory Ewing Sarcoma
   • Relapsed/refractory Osteosarcoma

3. Tumor assessment:

   Disease staging must be performed. This disease assessment is required for eligibility and must be done within a maximum of 4 weeks before first dose of study drug.

4. Disease Status:

   Relapsed/Refractory Neuroblastoma Known high-risk neuroblastoma or previously intermediate-risk neuroblastoma that has relapsed or progressed to high-risk with failure to achieve CR with standard therapy (defined as 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 Known high-risk neuroblastoma or previously intermediate-risk neuroblastoma in a 2nd or greater remission

   Relapsed/refractory ETMR/ATRT Subjects 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.

   Diffuse Intrinsic Pontine Glioma (DIPG) Subjects with DIPG to start greater than 30 days, and no longer than 60 days, after standard of care radiation therapy. Subjects 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. Subjects with metastatic disease are not eligible. Subjects with a biopsy and no evidence of H3K27m mutations are eligible as long as they meet radiographic criteria. Subjects with H3K27m altered DMG outside of the brainstem are not eligible. Subjects with progression or recurrence after initial standard of care radiation are ineligible.

   Relapsed/refractory Ewing Sarcoma and Osteosarcoma Subjects that have relapsed following standard of care therapy or having progressed during standard of care therapy. Standard of care therapy for Ewing sarcoma includes multi-agent chemotherapy with local control consisting of either surgery or radiation therapy.

5. Subjects must be able to swallow capsules.

6. Subjects must not have progressed while taking any previous DFMO prior to this study.

7. Subjects 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.

8. Timing from prior therapy:

   Subjects must have fully recovered from the acute toxic effects of all prior anti- cancer chemotherapy and be within the following timelines:

   1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).

   2. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. 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.

   3. 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.

   4. XRT: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site.

      Note: Subjects with DIPG will be required to have had up front standard of care radiation. As above, subjects with DIPG must be between 30-60 days post initial up front radiation therapy.

   5. Stem Cell Transplant:

      1. Allogeneic: No evidence of active graft vs. host disease
      2. Allo/Auto: ≥ 2 months must have elapsed since transplant.

   6. MIBG Therapy: At least 6 weeks since treatment with MIBG therapy.

9. Subjects must have a Lansky or Karnofsky Performance Scale score of >/= 50

10. Subjects must have adequate organ function at the time of enrollment:

    • Hematological: Hematological recovery as defined by ANC ≥750/μL
    • Liver: Adequate liver function as defined by AST and ALT <10x upper limit of normal
    • Renal: Subjects must have adequate renal function defined as Creatinine clearance (in units ml/min) or radioisotope GFR ≥ 70 The formula to be used : Adjusted GFR=(Estimated GFR×BSA / 1.73)mL/min

11. Subjects of childbearing potential must have a negative pregnancy test. Subjects of childbearing potential must agree to use an effective birth control method. Subjects who are lactating must agree to stop breast-feeding.

12. Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or subjects' legal representative).

Exclusion Criteria

1. BSA of <0.25 m2
2. Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
3. 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.
4. 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.
5. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Phase I- Dose level 1	Difluoromethylornithine (DFMO)	Dose Level 1: AMXT-1501 400mg/m2 twice daily and DFMO 1 g/m2 IV (intravenous) daily. Each patient will receive DFMO by continuous infusion pump at the dose determined by their assigned dose level in addition to the AMXT-1501. At least three and up to six patients per dose level with an estimated three dose levels (based on safety), as well as a confirmation group of the final dose may be enrolled for a projected total of 12 to 24 patients in the Phase I. Subjects may continue to receive this combination until progression or twenty-four (24), 28-day cycles, whichever occurs first.
Phase I- Dose level 1	AMXT-1501 Dicaprate	Dose Level 1: AMXT-1501 400mg/m2 twice daily and DFMO 1 g/m2 IV (intravenous) daily. Each patient will receive DFMO by continuous infusion pump at the dose determined by their assigned dose level in addition to the AMXT-1501. At least three and up to six patients per dose level with an estimated three dose levels (based on safety), as well as a confirmation group of the final dose may be enrolled for a projected total of 12 to 24 patients in the Phase I. Subjects may continue to receive this combination until progression or twenty-four (24), 28-day cycles, whichever occurs first.
Phase I- Dose level 2	Difluoromethylornithine (DFMO)	Dose Level 2: AMXT-1501 600mg/m2 twice daily and DFMO 1 g/m2 IV (intravenous) daily. Each patient will receive DFMO by continuous infusion pump at the dose determined by their assigned dose level in addition to the AMXT-1501. At least three and up to six patients per dose level with an estimated three dose levels (based on safety), as well as a confirmation group of the final dose may be enrolled for a projected total of 12 to 24 patients in the Phase I. Subjects may continue to receive this combination until progression or twenty-four (24), 28-day cycles, whichever occurs first.
Phase I- Dose level 2	AMXT-1501 Dicaprate	Dose Level 2: AMXT-1501 600mg/m2 twice daily and DFMO 1 g/m2 IV (intravenous) daily. Each patient will receive DFMO by continuous infusion pump at the dose determined by their assigned dose level in addition to the AMXT-1501. At least three and up to six patients per dose level with an estimated three dose levels (based on safety), as well as a confirmation group of the final dose may be enrolled for a projected total of 12 to 24 patients in the Phase I. Subjects may continue to receive this combination until progression or twenty-four (24), 28-day cycles, whichever occurs first.
Phase I- Dose level 3	Difluoromethylornithine (DFMO)	Dose Level 3: AMXT-1501 RP2D and DFMO 1.5 g/m2 IV (intravenous) daily. Each patient will receive DFMO by continuous infusion pump at the dose determined by their assigned dose level in addition to the AMXT-1501. At least three and up to six patients per dose level with an estimated three dose levels (based on safety), as well as a confirmation group of the final dose may be enrolled for a projected total of 12 to 24 patients in the Phase I. Subjects may continue to receive this combination until progression or twenty-four (24), 28-day cycles, whichever occurs first.
Phase I- Dose level 3	AMXT-1501 Dicaprate	Dose Level 3: AMXT-1501 RP2D and DFMO 1.5 g/m2 IV (intravenous) daily. Each patient will receive DFMO by continuous infusion pump at the dose determined by their assigned dose level in addition to the AMXT-1501. At least three and up to six patients per dose level with an estimated three dose levels (based on safety), as well as a confirmation group of the final dose may be enrolled for a projected total of 12 to 24 patients in the Phase I. Subjects may continue to receive this combination until progression or twenty-four (24), 28-day cycles, whichever occurs first.
Phase II- Arm A: AMXT-1501 + DFMO	Difluoromethylornithine (DFMO)	In this portion of the study, cohort 1 will be randomized to either receive Arm A: oral AMXT-1501 at the RP2D found in the Phase I along with continuous infusion pump DFMO at the recommended phase 2 dose (RP2D) found in the Phase I on each day of study or Arm B: continuous infusion pump 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 (ATRT/ETMR), 3 (DIPG), and 4 (Sarcomas) will automatically be assigned to Arm A with AMXT-1501. Patients who progress on DFMO alone (and have met the primary PFS endpoint) may crossover to AMXT-1501 +DFMO.
Phase II- Arm A: AMXT-1501 + DFMO	AMXT-1501 Dicaprate	In this portion of the study, cohort 1 will be randomized to either receive Arm A: oral AMXT-1501 at the RP2D found in the Phase I along with continuous infusion pump DFMO at the recommended phase 2 dose (RP2D) found in the Phase I on each day of study or Arm B: continuous infusion pump 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 (ATRT/ETMR), 3 (DIPG), and 4 (Sarcomas) will automatically be assigned to Arm A with AMXT-1501. Patients who progress on DFMO alone (and have met the primary PFS endpoint) may crossover to AMXT-1501 +DFMO.
Phase II- Arm B: DFMO Alone	Difluoromethylornithine (DFMO)	In this portion of the study, cohort 1 will be randomized to either receive Arm A: oral AMXT-1501 at the RP2D found in the Phase I along with continuous infusion pump DFMO at the recommended phase 2 dose (RP2D) found in the Phase I on each day of study or Arm B: continuous infusion pump 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 (ATRT/ETMR), 3 (DIPG), and 4 (Sarcomas) will automatically be assigned to Arm A with AMXT-1501. Patients who progress on DFMO alone (and have met the primary PFS endpoint) may crossover to AMXT-1501 +DFMO.

Primary Outcome Measures

Name	Time	Method
Phase I- Number of Participants with Adverse Events as a Measure of Safety and Tolerability	28 days	To evaluate the safety, tolerability and recommended phase 2 dose (RP2D) of AMXT-1501 in combination with continuous infusion DFMO in pediatric and young adult subjects.
Phase II- Number of participants with progression free survival (PFS) during study	2 years plus 5 years follow up	To evaluate, in a prospective randomized clinical trial, the efficacy of difluoromethylornithine (DFMO) in combination with AMXT-1501 compared to DFMO alone in 4 separate disease cohorts based upon Progression Free Survival (PFS); 1. Relapsed/refractory neuroblastoma; 2. Relapsed/refractory ETMR/ATRT; 3. Diffuse Intrinsic Pontine Glioma (DIPG) at diagnosis after standard of care radiation therapy: Non-randomized cohort; 4. Sarcomas: Relapsed/refractory Ewing Sarcoma and Osteosarcoma: Non-randomized cohort

Secondary Outcome Measures

Name	Time	Method
Phase II-Number of Participants with Adverse Events as a Measure of Safety and Tolerability	2 years plus 30 days	To evaluate the safety and tolerability profile of difluoromethylornithine (DFMO) in combination with AMXT-1501 in pediatric and young adult subjects.
Phase II- Determine the Overall Response Rate (ORR) of Participants using INSS Response	2 years	To evaluate the efficacy of difluoromethylornithine (DFMO) in combination with AMXT-1501 compared to DFMO alone in disease cohorts outlined above, based upon Overall response rate (ORR)
Phase I- Number of participants with progression free survival (PFS) during study	2 years plus 5 years follow up	To evaluate the activity of AMXT-1501 in combination with DFMO based on Progression free survival (PFS)
Phase I- Determine the Overall Response Rate (ORR) of Participants using INSS Response	2 years	To evaluate the activity of AMXT-1501 in combination with DFMO based on Overall response rate (ORR)
Phase II- Length of time that participants experience Overall Survival (OS)	2 years plus 5 years follow up	To evaluate the efficacy of difluoromethylornithine (DFMO) in combination with AMXT-1501 compared to DFMO alone in disease cohorts outlined above, based upon Overall Survival (OS)