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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, H3 K27M-Mutant

Intervention / Treatment
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* Biological: rHSC-DIPGVax
* Drug: Balstilimab
* Drug: Zalifrelimab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase I, open label, plus expansion clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lead In: rHSC-DIPGVax Monotherapy<br>rHSC-DIPGVax for 8 total doses | Biological: rHSC-DIPGVax<br>* Off-the-shelf, neoantigen heat shock protein vaccine<br>* Other names: vaccine;|
| Experimental: Part A: rHSC-DIPGVax in Combination with BALSTILIMAB (Anti-PD1)<br>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. | Biological: rHSC-DIPGVax<br>* Off-the-shelf, neoantigen heat shock protein vaccine<br>* Other names: vaccine;Drug: Balstilimab<br>* BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1)<br>* Other names: anti-PD1;|
| Experimental: Part B: Dose Escalation of ZALIFRELIMAB (Anti-CTLA4)<br>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. | Biological: rHSC-DIPGVax<br>* Off-the-shelf, neoantigen heat shock protein vaccine<br>* Other names: vaccine;Drug: Balstilimab<br>* BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1)<br>* Other names: anti-PD1;Drug: Zalifrelimab<br>* 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)<br>* Other names: anti-CTLA4;|
| Experimental: Part C: Dose Expansion<br>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<br>* Off-the-shelf, neoantigen heat shock protein vaccine<br>* Other names: vaccine;Drug: Balstilimab<br>* BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1)<br>* Other names: anti-PD1;Drug: Zalifrelimab<br>* 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)<br>* Other names: anti-CTLA4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability: Dose limiting toxicities of rHSC-DIPGVax | 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 | 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 | 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 | 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 | 12 month overall survival | On-going during 1 year of therapy plus 3 month follow up | 
| Overall survival at 1 year | Overall survival from time of diagnostic imaging to time of death | On-going during 1 year of therapy | 
| Time to progression | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Cancer vaccine, Checkpoint blockade, DIPG, Diffuse intrinsic pontine glioma, High grade glioma, DMG, Diffuse midline glioma, rHSC-DIPGVax, Balstilimab, Zalifrelimab