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

Sponsor

Ann & Robert H Lurie Children's Hospital of Chicago (Other)

Overall Status

Recruiting

CT.gov ID

NCT04943848

Collaborator

Dana-Farber Cancer Institute (Other), Children's Hospital of Orange County (Other), University of Calgary (Other)

Enrollment

Locations

Arms

25.7

Anticipated Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant	Biological: rHSC-DIPGVax Drug: Balstilimab Drug: Zalifrelimab	Phase 1

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 Design

Study Type:

Interventional

Anticipated Enrollment :

36 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Phase I, open label, plus expansion clinical trialPhase I, open label, plus expansion clinical trial

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 10, 2022

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Mar 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: "Lead In": rHSC-DIPGVax Monotherapy rHSC-DIPGVax for 8 total doses	Biological: rHSC-DIPGVax 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 12 years or older. 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.	Biological: rHSC-DIPGVax Off-the-shelf, neoantigen heat shock protein vaccine Other Names: vaccine Drug: Balstilimab 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 12 years or older. 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.	Biological: rHSC-DIPGVax Off-the-shelf, neoantigen heat shock protein vaccine Other Names: vaccine Drug: Balstilimab BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1) Other Names: checkpoint blockade anti-PD1 Drug: Zalifrelimab 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.	Biological: rHSC-DIPGVax Off-the-shelf, neoantigen heat shock protein vaccine Other Names: vaccine Drug: Balstilimab BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1) Other Names: checkpoint blockade anti-PD1 Drug: Zalifrelimab 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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Total number of DLT's for ZALIFRELIMAB at RP2D in combination with rHSC-DIPGVax and BALSTILIMAB [On-going during 1 year of therapy plus 3 month follow up]
Number of DLT's using CTCAE version 5.0 and iRANO guidelines
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 [On-going during 1 year of therapy plus 3 month follow up]
12 month overall survival
Overall survival at 1 year [On-going during 1 year of therapy]
Overall survival from time of diagnostic imaging to time of death
Time to progression [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)

Other Outcome Measures

To evaluate biologic correlates for immune response in order to assess neo-antigen specific T cell responses [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
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 [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
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 [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
To evaluate the immunogenicity of BALSTILIMAB as mAb monotherapy with rHSC-DIPGVax and in mAb combination with ZALIFRELIMAB and rHSC-DIPGVax [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Months to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Health Orange County (CHOC)	Orange	California	United States	92868
2	Ann and Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
3	Dana-Farber Boston Children's Cancer and Blood Disorders Center	Boston	Massachusetts	United States	02215