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

Primary Purpose

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

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
rHSC-DIPGVax
Balstilimab
Zalifrelimab
Sponsored by
Ann & Robert H Lurie Children's Hospital of Chicago
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Intrinsic Pontine Glioma focused on measuring Immunotherapy, Cancer vaccine, Checkpoint blockade, DIPG, Diffuse intrinsic pontine glioma, High grade glioma, DMG, Diffuse midline glioma, rHSC-DIPGVax, Balstilimab, Zalifrelimab

Eligibility Criteria

12 Months - 18 Years (Child, Adult)All SexesDoes not accept 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

Sites / Locations

  • Children's Health Orange County (CHOC)Recruiting
  • Ann and Robert H. Lurie Children's Hospital of ChicagoRecruiting
  • Dana-Farber Boston Children's Cancer and Blood Disorders CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

"Lead In": rHSC-DIPGVax Monotherapy

Part A: rHSC-DIPGVax in Combination with BALSTILIMAB (Anti-PD1)

Part B: Dose Escalation of ZALIFRELIMAB (Anti-CTLA4)

Part C: Dose Expansion

Arm Description

rHSC-DIPGVax for 8 total doses

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.

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.

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.

Outcomes

Primary Outcome Measures

Safety and Tolerability: Dose limiting toxicities of rHSC-DIPGVax
Number of DLT's per CTCAE version 5.0 and iRANO guidelines.
Safety and Tolerability: Dose limiting toxicities of rHSC-DIPGVax plus BALSTILIMAB
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
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
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
12 month overall survival
Overall survival at 1 year
Overall survival from time of diagnostic imaging to time of death
Time to progression
time to progression (from time of diagnostic imaging to time of disease progression)

Full Information

First Posted
May 24, 2021
Last Updated
September 7, 2023
Sponsor
Ann & Robert H Lurie Children's Hospital of Chicago
Collaborators
Dana-Farber Cancer Institute, Children's Hospital of Orange County, University of Calgary
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1. Study Identification

Unique Protocol Identification Number
NCT04943848
Brief Title
rHSC-DIPGVax Plus Checkpoint Blockade for the Treatment of Newly Diagnosed DIPG and DMG
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 10, 2022 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ann & Robert H Lurie Children's Hospital of Chicago
Collaborators
Dana-Farber Cancer Institute, Children's Hospital of Orange County, University of Calgary

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, H3 K27M-Mutant
Keywords
Immunotherapy, Cancer vaccine, Checkpoint blockade, DIPG, Diffuse intrinsic pontine glioma, High grade glioma, DMG, Diffuse midline glioma, rHSC-DIPGVax, Balstilimab, Zalifrelimab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Model Description
Phase I, open label, plus expansion clinical trial
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
"Lead In": rHSC-DIPGVax Monotherapy
Arm Type
Experimental
Arm Description
rHSC-DIPGVax for 8 total doses
Arm Title
Part A: rHSC-DIPGVax in Combination with BALSTILIMAB (Anti-PD1)
Arm Type
Experimental
Arm Description
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.
Arm Title
Part B: Dose Escalation of ZALIFRELIMAB (Anti-CTLA4)
Arm Type
Experimental
Arm Description
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.
Arm Title
Part C: Dose Expansion
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
rHSC-DIPGVax
Other Intervention Name(s)
vaccine
Intervention Description
Off-the-shelf, neoantigen heat shock protein vaccine
Intervention Type
Drug
Intervention Name(s)
Balstilimab
Other Intervention Name(s)
checkpoint blockade, anti-PD1
Intervention Description
BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1)
Intervention Type
Drug
Intervention Name(s)
Zalifrelimab
Other Intervention Name(s)
checkpoint blockade, anti-CTLA4
Intervention Description
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)
Primary Outcome Measure Information:
Title
Safety and Tolerability: Dose limiting toxicities of rHSC-DIPGVax
Description
Number of DLT's per CTCAE version 5.0 and iRANO guidelines.
Time Frame
DLT period of 28 days for rHSC-DIPGVax monotherapy
Title
Safety and Tolerability: Dose limiting toxicities of rHSC-DIPGVax plus BALSTILIMAB
Description
Number of DLT's per CTCAE version 5.0 and iRANO guidelines.
Time Frame
DLT period of 28 days for Part A
Title
Safety and Tolerability: Dose limiting toxicities of rHSC-DIPGVax plus BALSTILIMAB and ZALIFRELIMAB
Description
Number of DLT's per CTCAE version 5.0 and iRANO guidelines.
Time Frame
DLT period of 42 days for Part B
Secondary Outcome Measure Information:
Title
Total number of DLT's for ZALIFRELIMAB at RP2D in combination with rHSC-DIPGVax and BALSTILIMAB
Description
Number of DLT's using CTCAE version 5.0 and iRANO guidelines
Time Frame
On-going during 1 year of therapy plus 3 month follow up
Title
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
Description
12 month overall survival
Time Frame
On-going during 1 year of therapy plus 3 month follow up
Title
Overall survival at 1 year
Description
Overall survival from time of diagnostic imaging to time of death
Time Frame
On-going during 1 year of therapy
Title
Time to progression
Description
time to progression (from time of diagnostic imaging to time of disease progression)
Time Frame
On-going during 1 year of therapy plus up to 5 years off treatment
Other Pre-specified Outcome Measures:
Title
To evaluate biologic correlates for immune response in order to assess neo-antigen specific T cell responses
Description
PBMC immune subsets measured via flow cytometry from peripheral blood samples
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
Title
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
Description
peak plasma concentration (Cmax) of BALSTILIMAB AND ZALIFRELIMAB in the blood
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
Title
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
Description
Area under the plasma concentration versus time curve (AUC) of BALSTILIMAB AND ZALIFRELIMAB in the blood
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
Title
To evaluate the immunogenicity of BALSTILIMAB as mAb monotherapy with rHSC-DIPGVax and in mAb combination with ZALIFRELIMAB and rHSC-DIPGVax
Description
Assays to assess anti drug antibody levels in the blood
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Months
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
George Rafidi, BS
Phone
312-227-1099
Email
grafidi@luriechildrens.org
First Name & Middle Initial & Last Name or Official Title & Degree
Ashley Plant-Fox, MD
Phone
312-227-4858
Email
aplant@luriechildrens.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ashley Plant-Fox, MD
Organizational Affiliation
Ann and Robert H. Lurie Children's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Health Orange County (CHOC)
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mariko Sato, MD
Phone
714-509-8636
Email
mariko.sato@choc.org
First Name & Middle Initial & Last Name & Degree
Claudia Mousa
Phone
714-509-8724
Email
claudia.mousa@choc.org
First Name & Middle Initial & Last Name & Degree
Mariko Sato, MD
Facility Name
Ann and Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ashley S Plant, MD
Phone
312-227-4090
Email
aplant@luriechildrens.org
First Name & Middle Initial & Last Name & Degree
George Rafidi, BS
Phone
312-227-1099
Email
grafidi@luriechildrens.org
First Name & Middle Initial & Last Name & Degree
Ashley S Plant, MD
Facility Name
Dana-Farber Boston Children's Cancer and Blood Disorders Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alexa E Stathis
Phone
857-215-1558
Email
alexae_stathis@dfci.harvard.edu
First Name & Middle Initial & Last Name & Degree
Susan Chi, MD
Phone
617-632-4386
Email
susan_chi@dfci.harvard.edu
First Name & Middle Initial & Last Name & Degree
Susan Chi, MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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