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

Diffuse Intrinsic Pontine Glioma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04943848
• Other study ID #: LCH 20C05
• Status: Recruiting
• Phase: Phase 1
• Start date: January 10, 2022
• Est. completion date: March 2025

Study information

• Verified date: January 2023
• Source: Ann & Robert H Lurie Children's Hospital of Chicago
• Contact: George Rafidi, BS
• Phone: 312-227-1099
• Email: grafidi[@]luriechildrens.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: March 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Months to 18 Years

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Biological:
• rHSC-DIPGVax
Off-the-shelf, neoantigen heat shock protein vaccine

Drug:
• Balstilimab
BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1)
• 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)

Locations

Country	Name	City	State
United States	Dana-Farber Boston Children's Cancer and Blood Disorders Center	Boston	Massachusetts
United States	Ann and Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Children's Health Orange County (CHOC)	Orange	California

Sponsors (4)

Lead Sponsor	Collaborator
Ann & Robert H Lurie Children's Hospital of Chicago	Children's Hospital of Orange County, Dana-Farber Cancer Institute, University of Calgary

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	To evaluate biologic correlates for immune response in order to assess neo-antigen specific T cell responses	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
Other	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	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
Other	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	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
Other	To evaluate the immunogenicity of BALSTILIMAB as mAb monotherapy with rHSC-DIPGVax and in mAb combination with ZALIFRELIMAB and rHSC-DIPGVax	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	Overall survival at 1 year	Overall survival from time of diagnostic imaging to time of death	On-going during 1 year of therapy
Secondary	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