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Trace Elements

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.

Off-the-shelf, neoantigen heat shock protein vaccine

rHSC-DIPGVax

BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1)

Balstilimab

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)

Zalifrelimab

George Rafidi, BS

Ashley Plant-Fox, MD

Mariko Sato, MD

Claudia Mousa

Ashley S Plant, MD

Alexa E Stathis

Susan Chi, MD

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.

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.

Phase I, open label, plus expansion clinical trial

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

PBMC immune subsets measured via flow cytometry from peripheral blood samples

peak plasma concentration (Cmax) of BALSTILIMAB AND ZALIFRELIMAB in the blood

Area under the plasma concentration versus time curve (AUC) of BALSTILIMAB AND ZALIFRELIMAB in the blood

Assays to assess anti drug antibody levels in the blood

Number of DLT's per CTCAE version 5.0 and iRANO guidelines.

Number of DLT's using CTCAE version 5.0 and iRANO guidelines

Overall survival from time of diagnostic imaging to time of death

time to progression (from time of diagnostic imaging to time of disease progression)

Dana-Farber Cancer Institute

Children's Hospital of Orange County

University of Calgary

Ann & Robert H Lurie Children's Hospital of Chicago

Digestive System Diseases

Gland and Hormone Related Diseases

Adenocarcinoma

Pancreatic Neoplasms

Pancreatic Cancer

Antineoplastic Agents

Gemcitabine

Paclitaxel

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

Antimetabolites

Conventional Chemotherapy (Gemcitabine + nab-paclitaxel) plus NLM-001 plus Zalifrelimab

Gemcitabine 1000 mg/m2 IV on days 1, 8 and 15 (conventional chemotherapy).

Nab-Paclitaxel 125 mg/m2 IV on days 1, 8 and 15 (conventional chemotherapy).

Nab paclitaxel

NLM-001 will be administered three cycles consecutively followed by two rest cycles.

NLM-001

Zalifrelimab administration each 6 weeks.

Teresa Macarulla, MD

In order to improve the survival rates and decrease progression of pancreatic advanced cancer, this study aims to evaluate the first line treatment approved for this disease (gemcitabine plus nab-paclitaxel) in combination with two experimental drugs, an inhibitor of the signaling pathway of Hedgehog and an immunotherapy drug able of blocking the CTLA-4 receptor.

Pancreatic cancer is one of the leading neoplasms in the world in terms of mortality, with very low survival rates mainly due to its rapid progression and diagnosis in advanced stages, which makes its treatment extremely difficult.

Gemcitabine plus nab-paclitaxel is currently considered the first-line standard treatment for advanced pancreatic cancer due to this superiority against other treatments.

In order to find an alternative to improve survival of advanced pancreatic cancer, this study aims to evaluate the efficacy with first-line treatment in combination of two experimental drugs, a Hedgehog pathway inhibitor (NLM-001) and a CTLA-4 blocker (zalifrelimab) in previously untreated patients with advanced pancreatic cancer.

Study to Evaluate the Safety and Efficacy of Treatment With NLM-001 and Standard Chemotherapy Plus Zalifrelimab in Patients With Advanced Pancreatic Cancer

Phase Ib/IIa Study to Evaluate Safety and Efficacy of Treatment With the Hedgehog Inhibitor NLM-001 and Chemotherapy (Gemcitabine and Nab-Paclitaxel) Plus Zalifrelimab as First Line Treatment in Patients With Advanced Pancreatic Cancer

Objective Response Rate (ORR): Complete Response (CR) + Partial Response (PR) according to RECIST 1.1 criteria

Frequency of occurrence of adverse events according to NCI-CTCAE v5.0 criteria

Disease Control Rate (DCR): Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) evaluated by RECIST 1.1 criteria

Time in months from the patient's study enrolment until patient progression according to RECIST 1.1 criteria or death.

Time between the date of first confirmed response to the date of the first documented tumor progression (per RECIST 1.1), or death due to any cause, whichever occurs first

Time in months since the patient's study enrolment until death.

Correlation between change in Gli mRNA and SMA + CAF expression and Objective Response Rate (ORR).

Correlation between change in Gli mRNA and SMA + CAF expression and Progression Free Survival (PFS).

Correlation between change in Collagen structure and Objective Response Rate (ORR)

Correlation between change in Collagen structure and Progression Free Survival (PFS).

Correlation between change in lymphocyte infiltration and Objective Response Rate (ORR).

Correlation between change in lymphocyte infiltration and Progression Free Survival (PFS).

Apices Soluciones S.L.

Agenus Inc.

Nelum Corp

An anti-programmed death 1 (PD-1) monoclonal antibody.

An anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody.

Agenus, Inc.

Medical Director

This is an expanded access study for cancer treatment with balstilimab alone or in combination with zalifrelimab for an intermediate-size participant population. This study addresses the treatment needs of participants who have been previously and specifically treated with balstilimab alone or in combination with zalifrelimab in a clinical study, who have experienced a benefit from this treatment and/or wish to continue treatment, and who are eligible for treatment under this expanded access study.

This study will not exceed 100 participants. Participants will be reevaluated annually to assess the treatment benefit of zalifrelimab and/or balstilimab and thereby, continued eligibility for treatment. Under this program, treatment will be continued with balstilimab, as either monotherapy or as used in combination therapy with zalifrelimab, for participants that have previously received one or both of these investigational medicinal products in a clinical study.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
rHSC-DIPGVax Plus Checkpoint Blockade for the Treatment of Newly Diagnosed DIPG and DMG	NCT04943848	Diffuse Intrins... Diffuse Midline...	rHSC-DIPGVax Balstilimab Zalifrelimab	12 Months - 18 Years	Ann & Robert H Lurie Children's Hospital of Chicago
Study to Evaluate the Safety and Efficacy of Treatment With NLM-001 and Standard Chemotherapy Plus Zalifrelimab in Patients With Advanced Pancreatic Cancer	NCT04827953	Pancreatic Duct...	Gemcitabine Nab paclitaxel NLM-001 Zalifrelimab	18 Years - 90 Years	Nelum Corp
Expanded Access for Cancer Treatment With Balstilimab (AGEN2034) and Zalifrelimab (AGEN1884)	NCT05572970	Cancer	Balstilimab Zalifrelimab	18 Years -	Agenus Inc.
Study to Evaluate the Safety and Efficacy of Treatment With NLM-001 and Standard Chemotherapy Plus Zalifrelimab in Patients With Advanced Pancreatic Cancer	NCT04827953	Pancreatic Duct...	Gemcitabine Nab paclitaxel NLM-001 Zalifrelimab	18 Years - 90 Years	Nelum Corp

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