Phase I Study of APX005M in Pediatric Central Nervous System Tumors

NCT03389802 | Active Not Recruiting Phase 1 Results DMC FDA Drug

• 3 other identifiers: PBTC-051UM1CA081457NCI-2017-01235
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 11

Brief Summary

This phase I trial studies the side effects and best dose of APX005M in treating younger patients with primary malignant central nervous system tumor that is growing, spreading, or getting worse (progressive), or newly diagnosed diffuse intrinsic pontine glioma. APX005M can trigger activation of B cells, monocytes, and dendritic cells and stimulate cytokine release from lymphocytes and monocytes. APX005M can mediate a direct cytotoxic effect on CD40+ tumor cells.

Conditions

Glioblastoma Multiforme; High-grade Astrocytoma Not Otherwise Specified (NOS); CNS Primary Tumor, Not Otherwise Specified (NOS); Ependymoma, Not Otherwise Specified (NOS); Diffuse Intrinsic Pontine Gliomas (DIPG); Medulloblastoma

Outcome Measures

Primary Outcomes (4)

• Number of Patients Who Experienced Dose-limiting Toxicities (DLTs)

  DLTs were defined as adverse events (AE) at least possibly attributed to APX005M that occurred during the first 2 courses (6 weeks) following APX005M administration. DLTs included any APX005M-related AE that led to dose reduction or permanent cessation of therapy or resulted in a treatment delay \>2 weeks. Hematologic DLTs included grade 3 neutropenia with fever, any grade 4 hematologic toxicity except lymphopenia, and grade 3 thrombocytopenia on 2 separate days or requiring platelet transfusion on 2 days within a 7-day period. Non-hematologic DLTs included any grade 4 non-hematologic toxicity, grade 3 or higher cytokine release syndrome, or any grade 3 non-hematologic toxicity with some exceptions such as grade 3 nausea/vomiting \<5 days or grade 3 diarrhea that responded to treatment within 5 days.

  6 weeks

• Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) of APX005M in Stratum 1

  Based on the 3+3 design, the MTD of APX005M was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a DLT, and the next higher dose level was determined to be too toxic. A total of 12 subjects were to be treated at the MTD/RP2D to further define the toxicity profile. Stratum 1 consisted of patients with recurrent or refractory primary malignant central nervous system tumors.

  6 weeks (first 2 courses of treatment)

• Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) of APX005M in Stratum 2

  The starting dose level for Stratum 2 was one dose level below the RP2D determined in Stratum 1. If there were no dose-limiting toxicities in the first 3 patients enrolled on Stratum 2, then we escalated to the Stratum 1 RP2D and could treat 6 diffuse intrinsic pontine glioma (DIPG) patients simultaneously. The RP2D was defined as the dose level at which 6 patients were treated with no more than one dose-limiting toxicity. Stratum 2 patients were those with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

  6 weeks (first 2 courses of treatment)

• Serum Concentration of APX005M

  Serial blood samples for APX005M pharmacokinetic studies were collected during courses 1 and 2 at pre-dose, at the end of infusion, and at 4, 24 ± 1 (Day 2), and 168 ± 4 hours (Day 8) from the start of infusion in that course and during courses 3 and 4 at pre-dose and end of induction.

  12 weeks

Secondary Outcomes (4)

• Overall Survival for Stratum 2 (DIPG) Patients

  1 year

• Progression-free Survival for Stratum 2 (DIPG) Patients

  1 year

• Overall Response Rate for Stratum 2 (DIPG) Patients

  Up to 2 years

• Duration of Response for Stratum 2 (DIPG) Patients

  Up to 2 years

Other Outcomes (7)

• Concentration of the Cytokine Tumor Necrosis Factor-alpha (TNF-alpha)

  Pre-treatment and up to 9 weeks post-treatment

• Concentration of the Cytokine Interleukin-8 (IL-8)

  Pre-treatment and up to 9 weeks post-treatment

• T Cell Phenotypes in Human PBMC

  Pre-treatment and up to 9 weeks post-treatment

Study Arms (2)

Stratum 1

EXPERIMENTAL

The recurrent, progressive, or refractory primary malignant non-brainstem CNS tumor patients will be treated with APX005M.

Biological: APX005M treatment for recurrent or refractory primary malignant CNS tumor patients

Stratum 2

EXPERIMENTAL

The newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) patients will be treated with APX005M.

Biological: APX005M treatment for newly diagnosed DIPG patients

Interventions

APX005M treatment for recurrent or refractory primary malignant CNS tumor patients BIOLOGICAL

APX005M dosing will begin at 0.1 mg/kg, the APX005M dose may be increased (0.3, 0.45, 0.6 mg/kg) or decreased (0.03 mg/kg) in subsequent cohorts until the maximum tolerated dose (MTD) is reached or until dose level 3 (0.6 mg/kg) is complete without the MTD being defined. APX005M will be administered at the assigned dose level every 21 days (3 weeks). Patients may continue to receive APX005M for 36 courses (approximately 2 years) or until disease progression, unacceptable toxicity or death, whichever occurs first.

Stratum 1

APX005M treatment for newly diagnosed DIPG patients BIOLOGICAL

The starting dose of APX005M for the DIPG patients will be one dose level below the recommended phase II dose (RP2D) determined in Stratum 1 patients. The dose may be decreased or increased to the RP2D established in Stratum 1. APX005M will be administered at the assigned dose level every 21 days (3 weeks). Patients may continue to receive APX005M for 36 courses (approximately 2 years) or until disease progression, unacceptable toxicity or death, whichever occurs first.

Stratum 2

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Diagnosis -- Stratum 1: Recurrent or refractory primary malignant CNS tumor patients Patients with a histologically confirmed diagnosis of a primary malignant non-brainstem CNS tumor (excluding DIPG patients) that is recurrent, progressive, or refractory. All tumors must have histologic verification at either the time of diagnosis or recurrence except patients with marker (+) CNS germ cell tumors.
• Stratum 2: Newly diagnosed DIPG patients (on-hold until pediatric RP2D has been established in Stratum 1) Patients with diffuse intrinsic pontine gliomas (DIPGs) will be eligible 6 to 14 weeks post-completion of radiation therapy if they do not have any evidence of progression. Patients with newly diagnosed DIPGs, defined as tumors with a pontine epicenter and diffuse involvement of 2/3 or more of the pons, are eligible without histologic confirmation. Patients with pontine tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors have been biopsied and (1) are proven to be an anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic mixed glioma or fibrillary astrocytoma or (2) have a histone mutation typically seen in DIPG. Patients with disseminated disease are not eligible, and MRI of spine must be performed if disseminated disease is suspected by the treating physician.
• Available Pre-trial Tumor Tissue -- Stratum 1: Recurrent or refractory primary malignant CNS tumor patients must have adequate pre-trial frozen or FFPE tumor material (minimum of 10 unstained slides) available for use in the tumor mutation burden studies (section 9.1.5).
• Stratum 2: Patients with DIPG who have pre-trial tumor tissue available are requested to submit tissue; however, this is not required for eligibility.
• Age -- Patient must be ≥ 1 and ≤ 21 years of age at the time of enrollment.
• Prior Therapy -- Newly Diagnosed DIPG patients Patients must have not received any prior therapy for treatment of their current CNS malignancy other than radiation therapy.
• Refractory/Recurrent patients Patients must have recovered from the acute treatment related toxicities (defined as \< grade 1) of all prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to entering this study.
• Myelosuppressive chemotherapy -- Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea.
• Biological agent: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the biologic agent ≥ 7 days prior to study enrollment.
• 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.
• Monoclonal antibody treatment and agents with known prolonged half-lives: At least three half-lives must have elapsed prior to enrollment.
• Radiation --
• Patients must have had their last fraction of:
• Craniospinal irradiation (\>24Gy) or total body irradiation or radiation to greater than 50% of pelvis \> 3 months prior to enrollment.
• Focal irradiation \>6 weeks prior to enrollment Local palliative irradiation (small port) ≥4 weeks

You may not qualify if:

• Concurrent Illness -- Patients with any clinically significant unrelated systemic illness (serious infections Grade ≥ 2 or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
• Patients with a history of any other malignancy, except patients with a secondary brain tumor if the patient's first malignancy has been in remission for at least 5 years from the end of treatment.
• Concurrent Therapy -- Patients who are receiving any other anticancer or investigational drug therapy.
• Patients requiring systemic treatment with either corticosteroids (greater than physiologic replacement, defined as dexamethasone 0.75 mg/m2/day) or other immunosuppressive medications within 14 days of study drug administration will be excluded. However, patients who require intermittent use of bronchodilators or local steroid injections will not be excluded from the study. Please see section 5.3 for a list of acceptable and unacceptable concomitant medications as well as reporting requirements.
• Presence of Bulky Tumor --
• Patients with bulky tumor on imaging are ineligible. Bulky tumor is defined as:
• Tumor with any evidence of uncal herniation or midline shift Tumor that in the opinion of the site investigator, shows significant mass effect
• Allergy -- Patients with a history of severe (Grade ≥ 3) hypersensitivity reaction to a monoclonal antibody are ineligible.
• Allogeneic Hematopoietic Stem Cell Transplantation -- Patients who have received allogeneic hematopoietic stem cell transplantation are ineligible.
• Autoimmune Diseases -- Patients with active autoimmune disease or documented history of autoimmune disease/syndrome that requires ongoing systemic steroids or systemic immunosuppressive agents, except Patients with vitiligo or well controlled asthma/atopy Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome
• Inability to Participate -- Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions.
• Bleeding Disorder -- Patients with a known coagulopathy or bleeding diathesis or require the use of systemic anticoagulant medication are not eligible.
• Pregnancy Status -- Female patients must not be pregnant or breast-feeding.

Sponsors & Collaborators

• Pediatric Brain Tumor Consortium: lead
• American Lebanese Syrian Associated Charities: collaborator
• Pyxis Oncology, Inc: collaborator
• Solving Kids' Cancer: collaborator
• Ty Louis Campbell Foundation: collaborator
• A Kids' Brain Tumor Cure Foundation: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (11)

Children's Hospital Los Angeles

Los Angeles, California, 90026, United States

Location

Lucile Packard Children Hospital Stanford University

Palo Alto, California, 94304, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Childrens National Medical Center

Washington D.C., District of Columbia, 20010-2970, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Lurie Childrens Hospital-Chicago

Chicago, Illinois, 60614, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cincinnati Children Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

St. Jude Children Research Hospital

Memphis, Tennessee, 38105, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Glioblastoma; Ependymoma; Medulloblastoma

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive

Results Point of Contact

• Title: Catherine Billups
• Organization: PediatricBTC

catherine.billups@stjude.org

901-595-3370

Study Officials

• Ira Dunkel

  Memorial Sloan Kettering Cancer Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: Stratum 1: Recurrent or refractory primary malignant CNS tumor patients; Stratum 2: Newly diagnosed DIPG patients

Study Record Dates

• First Submitted: December 15, 2017
• First Posted: January 4, 2018
• Study Start: March 1, 2018
• Primary Completion: September 30, 2023
• Study Completion (Estimated): June 30, 2026
• Last Updated: February 20, 2026
• Results First Posted: October 10, 2024

Record last verified: 2025-07

Locations

US (11)