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Phase I Study of APX005M in Pediatric CNS Tumors

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ClinicalTrials.gov Identifier: NCT03389802
Recruitment Status : Recruiting
First Posted : January 4, 2018
Last Update Posted : February 6, 2018
Sponsor:
Collaborators:
St. Jude Children's Research Hospital
American Lebanese Syrian Associated Charities
The Cancer Therapy Evaluation Program of the National Cancer Institute
Apexigen, Inc.
Solving Kids’ Cancer
Ty Louis Campbell Foundation
A Kids Brain Tumor Cure
Information provided by (Responsible Party):
Pediatric Brain Tumor Consortium

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 stimulat cytokine release from lymphocytes and monocytes. APX005M can mediate a direct cytotoxic effect on CD40+ tumor cells.

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme High-grade Astrocytoma NOS CNS Primary Tumor, Nos Ependymoma, NOS Diffuse Intrinsic Pontine Gliomas (DIPG) Medulloblastoma Biological: APX005M treatment for recurrent or refractory primary malignant CNS tumor patients Biological: APX005M treatment for newly diagnosed DIPG patients Phase 1

Detailed Description:

This is a multicenter phase I trial of APX005M in patients with recurrent or refractory primary malignant central nervous system tumor, or newly diagnosed diffuse intrinsic pontine glioma.

APX005M is a humanized IgG1κ mAb that binds to CD40. APX005M binds to both human and cynomolgus monkey CD40 with high affinity, triggering activation of B cells, monocytes, and dendritic cells and stimulating cytokine release from both human and monkey lymphocytes and monocytes. APX005M does not bind to mouse or rat CD40. CD40 is also expressed on many human tumor cells, and APX005M can mediate a direct cytotoxic effect on CD40+ tumor cells.

Activation of CD40 on tumor cells results in tumor cell apoptosis and inhibition of tumor growth. CD40 agonistic antibodies have demonstrated potent antitumor immune response stimulation in both animal models and cancer patients. Due to its action on both immune and tumor cells, CD40 has been studied as a target for novel cancer immunotherapy.

Apexigen has declared the adult recommended phase 2 dose to be 0.3 mg/kg because no dose limiting toxicities were encountered at that dose and the pharmacodynamic profile was similar to the 1 mg/kg maximally tolerated dose. This phase 1 clinical trial is to study APX005M in children with central nervous system tumors.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Stratum 1: Recurrent or refractory primary malignant CNS tumor patients; Stratum 2: Newly diagnosed DIPG patients
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study to Evaluate the Safety and Tolerability of the CD40 Agonistic Monoclonal Antibody APX005M in Pediatric Subjects With Recurrent/Refractory Brain Tumors and Newly Diagnosed Brain Stem Glioma
Actual Study Start Date : February 2, 2018
Estimated Primary Completion Date : September 30, 2019
Estimated Study Completion Date : September 30, 2022


Arm Intervention/treatment
Experimental: Stratum 1
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

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 MTD is reached or until dose level 3 (0.6 mg/kg) is complete without 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.


Experimental: Stratum 2
The newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) patients will be treated with APX005M.
Biological: APX005M treatment for newly diagnosed DIPG patients

The starting dose of APX005M for the DIPG patients will be one dose level below the 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.





Primary Outcome Measures :
  1. The incidence of APX005M treatment-emergent adverse events in children with central nervous system tumors. [ Time Frame: 36 courses (approximately 2 years) ]
    Adverse Events

  2. The maximum tolerated dose and/or the recommended phase II dose of APX005M. [ Time Frame: Course 1 and Course 2 (the first 6 weeks of treatment) ]
    Dose Finding

  3. The pharmacokinetics of APX005M. [ Time Frame: Course 1 - 2: at 4, 24, and 168 hours from the start of the infusion; Course 3 - 4 pre-dose and at the end of infusion. ]
    Plasma APX005M concentration


Secondary Outcome Measures :
  1. The overall response rate. [ Time Frame: 36 courses (approximately 2 years) ]
    Evaluated the overall response rate per imaging or clinical progression

  2. The duration of response. [ Time Frame: 36 courses (approximately 2 years) ]
    Evaluated the Duration of Response per imaging or clinical progression

  3. The progression-free survival. [ Time Frame: 36 courses (approximately 2 years) ]
    Evaluated the progression-free survival per imaging or clinical progression

  4. The overall survival for DIPG patients. [ Time Frame: approximately 3 years ]
    Evaluated the overall survival for DIPG patients.


Other Outcome Measures:
  1. The incidence of anti-drug antibodies. [ Time Frame: 36 courses (approximately 2 years) ]
    Plasma anti-drug-antibodies (ADA)

  2. The circulating cytokines in human plasma [ Time Frame: 0, 2 weeks, 3 weeks, 6 weeks, and 9 weeks post-treatment ]
    Measurement of circulating cytokines in human plasma

  3. T cell phenotypes in human PBMC [ Time Frame: 0, 2 weeks, 3 weeks, 6 weeks, and 9 weeks post-treatment ]
    Characterization of T cell phenotypes in human PBMC

  4. The exome sequencing of tumor tissue and PBMC [ Time Frame: Day 0 of treatment ]
    The mutations detected by comparing the exome sequencing of tumor tissue and PBMC

  5. The RNAseq of tumor tissue and PBMC [ Time Frame: Day 0 of treatment ]
    The mutations detected by comparing the RNA sequencing of tumor tissue and PBMC

  6. The TCR sequencing of tumor tissue and PBMC [ Time Frame: Day 0 of treatment ]
    The mutations detected by comparing the TCR sequencing of tumor tissue and PBMC



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Autologous Stem Cell Transplant -- Patient must be ≥ 6 months since autologous bone marrow/stem cell transplant prior to enrollment and have CD4 counts above 200/mm3.

Surgery -- Patients must be at least 4 weeks (28 days) from major surgery and fully recovered from all acute effects of prior surgical intervention.

  • Inclusion of Women and Minorities -- Both males and females of all races and ethnic groups are eligible for this study
  • Neurologic Status -- Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment.

Patients with seizure disorders may be enrolled if seizures are well controlled.

• Performance Status -- Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within two weeks of enrollment must be ≥ 60. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

• Organ Function --

Patients must have adequate organ and bone marrow function as defined below:

Absolute Neutrophil Count (ANC) ≥ 1.0 x 109 cells/ L Platelets ≥ 100 x 109 cells/L (unsupported, defined as no platelet transfusion within 7 days) Hemoglobin ≥ 8 g/dL (may receive transfusions) Total bilirubin ≤1.5 times institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤ 3 x institutional upper limit of normal (ULN) Albumin ≥ 3 g/dl Serum creatinine based on age/gender as noted below. Patients that do not meet the criteria below but have a 24 hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2 are eligible.

Age Maximum Serum Creatinine (mg/dL) 1 to < 2 years 0.6, 0.6 (M, F); 2 to < 6 years 0.8, 0.8 (M, F); 6 to < 10 years 1, 1 (M, F); 10 to < 13 years 1.2, 1.2 (M, F); 13 to < 16 years 1.5, 1.4 (M, F); ≥ 16 years 1.7, 1.4 (M, F).

• Cardiac Function: Left Ventricular Ejection Fraction (LVEF) > 50% ECG QTc ≤ 450 msec

• Pulmonary Function: Oxygen saturation as measured by pulse oximetry is > 93% on room air and no evidence of dyspnea at rest

• Growth Factors -- Patients must be off all colony- forming growth factor(s) for at least 1 week prior to enrollment (i.e., filgrastim, sargramostim or erythropoietin). 2 weeks must have elapsed if patients received PEG formulations.

  • Pregnancy Status -- Female patients of childbearing potential must have a negative serum or urine pregnancy test.
  • Pregnancy Prevention -- Female subjects with childbearing potential and male subjects should use effective contraception methods (or abstain from sexual activity) while being treated with APX005M and for 30 days following treatment.
  • Informed Consent -- The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines.

Exclusion Criteria:

• 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03389802


Contacts
Contact: Shujie Han 901-595-4877 shujie.han@stjude.org

Locations
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90026
Contact: Girish Dhall, MD    323-361-4629    gdhall@chla.usc.edu   
Principal Investigator: Girish Dhall, MD         
Lucile Packard Children Hospital Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Michelle Monje    650-721-5750    mmonje@stanford.edu   
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Kathleen Dorris    720-777-1234    kathleen.dorris@childrenscolorado.org   
United States, District of Columbia
Childrens National Medical Center Recruiting
Washington, District of Columbia, United States, 20010-2970
Contact: Eugene Hwang, MD    202-476-5046    ehwang@childrensnational.org   
Principal Investigator: Lindsay B Kilburn, MD         
Sub-Investigator: Roger Packer, MD         
Sub-Investigator: Brain Rood, MD         
United States, Georgia
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Tobey MacDonald    404-727-1447    tobey.macdonald@emory.edu   
United States, Illinois
Lurie Childrens Hospital-Chicago Recruiting
Chicago, Illinois, United States, 60614
Contact: Stewart Goldman    312-227-4874    sgoldman@luriechildrens.org   
Principal Investigator: Stewart Goldman, MD         
Sub-Investigator: Jason Fangusaro, MD         
Sub-Investigator: Rishi Lulla, MD         
Sub-Investigator: Natasha Pillay-Smiley, MD         
United States, Maryland
National Cancer Institute Pediatric Oncology Branch Recruiting
Bethesda, Maryland, United States, 20892
Contact: Katherine E. Warren    301-435-4683    warrenk@mail.nih.gov   
Principal Investigator: Katherine E. Warren         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Ira Dunkel    212-639-2153    dunkeli@mskcc.org   
Principal Investigator: Ira Dunkel         
United States, Ohio
Cincinnati Children Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Maryam Fouladi    513-803-0721    maryam.fouladi@cchmc.org   
Principal Investigator: Maryam Fouladi         
United States, Pennsylvania
Children Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Ian Pollack    412-692-5881    Pollaci@chp.edu   
Sub-Investigator: Ian Pollack, MD         
United States, Tennessee
St. Jude Children Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Giles Robinson, MD    901-595-2907    giles.robinson@stjude.org   
Sub-Investigator: Amar Gajjar, MD         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Patricia Baxter, MD    832-824-4681    pabaxter@txch.org   
Contact: Susan Burlingame, CCRP    832-824-1532    sxburlin@txch.org   
Principal Investigator: Patricia Baxter, MD         
Sponsors and Collaborators
Pediatric Brain Tumor Consortium
St. Jude Children's Research Hospital
American Lebanese Syrian Associated Charities
The Cancer Therapy Evaluation Program of the National Cancer Institute
Apexigen, Inc.
Solving Kids’ Cancer
Ty Louis Campbell Foundation
A Kids Brain Tumor Cure
Investigators
Study Chair: Ira Dunkel Memorial Sloan Kettering Cancer Center

Responsible Party: Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier: NCT03389802     History of Changes
Other Study ID Numbers: PBTC-051
First Posted: January 4, 2018    Key Record Dates
Last Update Posted: February 6, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Glioblastoma
Glioma
Astrocytoma
Ependymoma
Medulloblastoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neuroectodermal Tumors, Primitive