rHSC-DIPGVax Plus Checkpoint Blockade for the Treatment of Newly Diagnosed DIPG and DMG

A Phase I Clinical Trial of Neo-antigen Heat Shock Protein Vaccine (rHSC-DIPGVax) in Combination With Checkpoint Blockade for the Treatment of Diffuse Intrinsic Pontine Glioma (DIPG) and Diffuse Midline Glioma in Childhood

This is a phase I, open label, plus expansion clinical trial evaluating the safety and tolerability of rHSC-DIPGVax in combination with BALSTILIMAB and ZALIFRELIMAB. rHSC-DIPGVax is an off-the-shelf neo-antigen heat shock protein containing 16 peptides reflecting neo-epitopes found in the majority of DIPG and DMG tumors. Newly diagnosed patients with DIPG and DMG who have completed radiation six to ten weeks prior to enrollment are eligible.

Study Overview

Detailed Description

This is a phase I, open label, plus expansion clinical trial evaluating the safety and tolerability of rHSC-DIPGVax in combination with BALSTILIMAB and ZALIFRELIMAB using a 3+3 design for subjects with newly diagnosed DIPG or DMG following completion of radiation therapy. Given this is a first in-human study of rHSC-DIPGVax, an initial study "Lead In" will assess the tolerability of vaccine monotherapy first in older children (ages 5 to 18 years of age) followed by younger children (12 months to 18 years of age).

Sequential Parts A and B of this study will also first enroll patients ages 5 to 18 years of age before enrolling younger children. The rationale for the combination of vaccine and anti-PD1 therapy includes evidence of a more profound intra-tumoral response with addition of inhibition of negative co-regulatory pathways, such as, PD1/PDL1 and the need to overcome potentially immunosuppressive or immune "cold" microenvironment of gliomas. Anti-CLTA4 therapy will also be combined with rHSC-DIPGVax in the dose escalation portion of this study because of the ability of anti-CTLA4 therapy to induce T cell priming to promote T memory formation. Given the lack of standard treatment options for DIPG and DMG patients, this clinical trial will use combinatorial immunotherapy in upfront treatment of these patients in hopes of maximizing potential efficacy in this at-risk population while still assessing safety throughout.

Part A will evaluate rHSC-DIPGVax plus BALSTILIMAB. Pharmacokinetics (PK) of BALSTILIMAB will also be evaluated to assess exposure. If the rHSC-DIPGVax plus BALSTILIMAB is well tolerated in Part A for 28-days, this study will then move to enrolling Part B to evaluate the safety and tolerability of rHSC-DIPGVax and BALSTILIMAB in combination with ZALIFRELIMAB at two dose levels for a total therapy duration of one year or twenty-seven cycles, whichever occurs first.

Advancement from Part A to Part B and dose escalation in Part B will follow a conservative 3+3 design. The dose limiting toxicity (DLT) monitoring period will last 28 days (2 cycles) for Part A subjects and 42 days (1 cycle) for Part B. Subjects will be allowed to continue on in Part A for twenty-seven 14-day cycles or nine 42-day cycles in Part B or 1 year of total therapy, whichever comes first.

After the RP2D of ZALIFRELIMAB is determined, Part C, the expansion arm, will enroll further subjects at this dose level to assess futility versus efficacy. All subjects in trial Part C will be monitored for dose limiting toxicities for the duration of their participation in the study to monitor for excess toxicity.

Study Type

Interventional

Enrollment (Estimated)

36

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • California
      • Orange, California, United States, 92868
        • Recruiting
        • Children's Health Orange County (CHOC)
        • Contact:
        • Contact:
        • Principal Investigator:
          • Mariko Sato, MD
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Recruiting
        • Ann and Robert H. Lurie Children's Hospital of Chicago
        • Contact:
        • Contact:
        • Principal Investigator:
          • Ashley S Plant, MD
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Recruiting
        • Dana-Farber Boston Children's Cancer and Blood Disorders Center
        • Contact:
        • Principal Investigator:
          • Susan Chi, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Subjects with newly diagnosed typical or non-typical, biopsy-proven DIPG or DMG are eligible for study enrollment. Biopsy is not required for subjects with radiographically typical DIPG meeting imaging criteria. Biopsy is required for DMG's and non-radiographically typical DIPG. Histone mutation must be confirmed by pathology report. Radiographically typical DIPG defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons.

    = Subjects ages > or = to 12 months and < or = 18 years ("Lead In", Part A, and Part B require first three patients be > or = to 12 years of age)

  • BSA > or = 0.35m2 at the time of study enrollment
  • Performance score: Karnofsky >50% of subjects >16 years of age and Lansky > or = 50 for subjects < or = 16 years of age. Subjects who are unable to walk because of paralysis but are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score.
  • Must start radiation therapy within 42 days from date of diagnostic imaging. C1D1 must be within 42 days to 70 days post radiation (6-10 weeks). Patients CANNOT receive temozolomide during radiation
  • Corticosteroids should be weaned as tolerated after radiation therapy with the goal of < or = 0.5mg/kg/day for a minimum of 7 days prior to enrollment.
  • Subjects must have measurable disease

Exclusion Criteria:

  • Patients cannot receive temozolomide during radiation
  • Disseminated disease
  • Subjects who have received any cancer therapy except for radiation
  • Autoimmune or immune disorders
  • Active respiratory disorder or infection
  • Active viral infection

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: "Lead In": rHSC-DIPGVax Monotherapy
rHSC-DIPGVax for 8 total doses
Off-the-shelf, neoantigen heat shock protein vaccine
Other Names:
  • vaccine
Experimental: Part A: rHSC-DIPGVax in Combination with BALSTILIMAB (Anti-PD1)

rHSC-DIPGVax (8 total doses) + BALSTILIMAB (1 year of therapy or 27 cycles, whichever comes first)

Patients will enroll 6-10 weeks post standard of care (SOC) radiation completion. Steroid dose must be at or below 0.5mg/kg/day for a minimum of 7 days. The first 3 patients must be 5 years or older to 18. Subsequently, subjects ages 12 months to 18 years can be enrolled. Up to six patients will be enrolled on Part A. Once safety is established for rHSC-DIPGVax plus anti-PD1 (BALSTILIMAB), the study will proceed to Part B.

Off-the-shelf, neoantigen heat shock protein vaccine
Other Names:
  • vaccine
BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1)
Other Names:
  • checkpoint blockade
  • anti-PD1
Experimental: Part B: Dose Escalation of ZALIFRELIMAB (Anti-CTLA4)

rHSC-DIPGVax (8 total doses) + BALSTILIMAB + ZALIFRELIMAB (1 year of therapy or 9 cycles, whichever comes first)

Patients will enroll 6-10 weeks post standard of care (SOC) radiation therapy. Steroid dose must be at or below 0.5mg/kg/day for a minimum of 7 days. The first 3 patients must be 5 years or older to 18. Subsequently, subjects ages 12 months to 18 years can be enrolled. Up to 12 patients will be enrolled on Part B. Once safety is established for rHSC-DIPGVax plus anti-PD1 (BALSTILIMAB) plus anti-CTLA4 (ZALIFRELIMAB), the study will proceed to Part C.

Off-the-shelf, neoantigen heat shock protein vaccine
Other Names:
  • vaccine
BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1)
Other Names:
  • checkpoint blockade
  • anti-PD1
ZALIFRELIMAB is a human monoclonal immunoglobulin G1k subclass (IgG1k) antibody that specifically recognizes cytotoxic T lymphocyte-associated protein 4 (CTLA-4, also known as CD152)
Other Names:
  • checkpoint blockade
  • anti-CTLA4
Experimental: Part C: Dose Expansion

rHSC-DIPGVax (8 total doses) + BALSTILIMAB + ZALIFRELIMAB (at RP2D from Part B) (1 year of therapy or 9 cycles, whichever comes first)

Patients will enroll 6-10 weeks post standard of care (SOC) radiation therapy. Steroid dose must be at or below 0.5mg/kg/day for a minimum of 7 days. Up to 12 patients will be enrolled on Part C. All subjects in Part C will be monitored for DLT's for the duration of their participation in the study to monitor for excess toxicity.

Off-the-shelf, neoantigen heat shock protein vaccine
Other Names:
  • vaccine
BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1)
Other Names:
  • checkpoint blockade
  • anti-PD1
ZALIFRELIMAB is a human monoclonal immunoglobulin G1k subclass (IgG1k) antibody that specifically recognizes cytotoxic T lymphocyte-associated protein 4 (CTLA-4, also known as CD152)
Other Names:
  • checkpoint blockade
  • anti-CTLA4

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety and Tolerability: Dose limiting toxicities of rHSC-DIPGVax
Time Frame: DLT period of 28 days for rHSC-DIPGVax monotherapy
Number of DLT's per CTCAE version 5.0 and iRANO guidelines.
DLT period of 28 days for rHSC-DIPGVax monotherapy
Safety and Tolerability: Dose limiting toxicities of rHSC-DIPGVax plus BALSTILIMAB
Time Frame: DLT period of 28 days for Part A
Number of DLT's per CTCAE version 5.0 and iRANO guidelines.
DLT period of 28 days for Part A
Safety and Tolerability: Dose limiting toxicities of rHSC-DIPGVax plus BALSTILIMAB and ZALIFRELIMAB
Time Frame: DLT period of 42 days for Part B
Number of DLT's per CTCAE version 5.0 and iRANO guidelines.
DLT period of 42 days for Part B

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Total number of DLT's for ZALIFRELIMAB at RP2D in combination with rHSC-DIPGVax and BALSTILIMAB
Time Frame: On-going during 1 year of therapy plus 3 month follow up
Number of DLT's using CTCAE version 5.0 and iRANO guidelines
On-going during 1 year of therapy plus 3 month follow up
To evaluate the efficacy of the combination of rHSC-DIPGVax, BALSTILIMAB, and ZALIFRELIMB in pediatric subjects with DIPG and DMG as measured by overall survival at 12 months and time-to-progression as measured from time of diagnostic imaging
Time Frame: On-going during 1 year of therapy plus 3 month follow up
12 month overall survival
On-going during 1 year of therapy plus 3 month follow up
Overall survival at 1 year
Time Frame: On-going during 1 year of therapy
Overall survival from time of diagnostic imaging to time of death
On-going during 1 year of therapy
Time to progression
Time Frame: On-going during 1 year of therapy plus up to 5 years off treatment
time to progression (from time of diagnostic imaging to time of disease progression)
On-going during 1 year of therapy plus up to 5 years off treatment

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
To evaluate biologic correlates for immune response in order to assess neo-antigen specific T cell responses
Time Frame: At the end of each cycle (1 cycle = 28 days) fore the first 3 cycles, on day 1 of cycle 6, and at 3 month post treatment follow up
PBMC immune subsets measured via flow cytometry from peripheral blood samples
At the end of each cycle (1 cycle = 28 days) fore the first 3 cycles, on day 1 of cycle 6, and at 3 month post treatment follow up
To characterize PK profile (Cmax) of BALSTILIMAB as a mAb monotherapy with rHSC-DIPGVax and in mAb combination with ZALIFRELIMAB and rHSC-DIPGVax to assess potential impact on PK exposure and biologic activity in pediatrics
Time Frame: 1 cycle = 28 days; Predose Cycle 1 day 1, 2 hours post dose 1, cycle 1 day 2, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 predose and 2 hours post dose, cycle 4 day 2, cycle 4 day 8, cycle 5 day 1, cycle 10 day 1, cycle 15 day 1, and end of treatment
peak plasma concentration (Cmax) of BALSTILIMAB AND ZALIFRELIMAB in the blood
1 cycle = 28 days; Predose Cycle 1 day 1, 2 hours post dose 1, cycle 1 day 2, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 predose and 2 hours post dose, cycle 4 day 2, cycle 4 day 8, cycle 5 day 1, cycle 10 day 1, cycle 15 day 1, and end of treatment
To characterize PK profile (AUC) of BALSTILIMAB as a mAb monotherapy with rHSC-DIPGVax and in mAb combination with ZALIFRELIMAB and rHSC-DIPGVax to assess potential impact on PK exposure and biologic activity in pediatrics
Time Frame: 1 cycle = 28 days; Predose Cycle 1 day 1, 2 hours post dose 1, cycle 1 day 2, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 predose and 2 hours post dose, cycle 4 day 2, cycle 4 day 8, cycle 5 day 1, cycle 10 day 1, cycle 15 day 1, and end of treatment
Area under the plasma concentration versus time curve (AUC) of BALSTILIMAB AND ZALIFRELIMAB in the blood
1 cycle = 28 days; Predose Cycle 1 day 1, 2 hours post dose 1, cycle 1 day 2, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 predose and 2 hours post dose, cycle 4 day 2, cycle 4 day 8, cycle 5 day 1, cycle 10 day 1, cycle 15 day 1, and end of treatment
To evaluate the immunogenicity of BALSTILIMAB as mAb monotherapy with rHSC-DIPGVax and in mAb combination with ZALIFRELIMAB and rHSC-DIPGVax
Time Frame: 1 cycle = 42 days; Predose on cycle 1 day 1, 2 hours post dose 1, cycle 1 day 2, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 predose and 2 hours post dose, cycle 4 day 2, cycle 4 day 8, cycle 5 day 1, cycle 10 day 1, cycle 15 day 1, and end of treatment
Assays to assess anti drug antibody levels in the blood
1 cycle = 42 days; Predose on cycle 1 day 1, 2 hours post dose 1, cycle 1 day 2, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 predose and 2 hours post dose, cycle 4 day 2, cycle 4 day 8, cycle 5 day 1, cycle 10 day 1, cycle 15 day 1, and end of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Ashley Plant-Fox, MD, Ann and Robert H. Lurie Children's Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 10, 2022

Primary Completion (Estimated)

December 1, 2024

Study Completion (Estimated)

March 1, 2025

Study Registration Dates

First Submitted

May 24, 2021

First Submitted That Met QC Criteria

June 21, 2021

First Posted (Actual)

June 29, 2021

Study Record Updates

Last Update Posted (Actual)

September 11, 2023

Last Update Submitted That Met QC Criteria

September 7, 2023

Last Verified

January 1, 2023

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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