A Phase 1/2 Study to Evaluate Axatilimab in Participants With Active cGVHD

Syndax Pharmaceuticals41 enrolled

Overview

This is a Phase 1/2, Open-label, Dose Escalation study to investigate axatilimab in participants with active chronic graft versus host disease (cGVHD).

This is a dose escalation and dose expansion study in participants with active cGVHD who have received at least 2 lines of prior therapy.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Chronic Graft-versus-host-disease

Interventions

axatilimabDRUG

axatilimab is a high affinity antibody targeting the colony stimulating factor 1 receptor (CSF-1R). CSF-1R signaling has been demonstrated in nonclinical studies to be the key regulatory pathway involved in the expansion and infiltration of donor derived macrophages that mediate the disease processes involved in cGVHD.

Eligibility

Sex: ALLMin age: 6 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: 1. Participant must be 6 years of age or older, at the time of signing the informed consent. 2. Participants who are allogeneic hematopoietic stem cell transplant (HSCT) recipients with cGVHD requiring systemic immune suppression. 3. Participants with active cGVHD who have received at least 2 lines of therapy. Participants 18 or older with active cGVHD who have erythematous rash involving \>25% body surface area or a NIH mouth score of \>4 must have received prior ibrutinib therapy. a. Active cGVHD is defined as the presence of signs and symptoms of cGVHD per 2014 NIH Consensus Development Project on Criteria for Clinical trials in cGVHD. 4. Participants may have persistent active acute and cGVHD manifestations (overlap syndrome), as defined by 2014 NIH Consensus Development Project on Criteria for Clinical trials in cGVHD. 5. Karnofsky Performance Scale of ≥60 with a life expectancy of at least 3 months (if aged 16 years or older); Lansky Performance Score of ≥60 (if less than 16 years). 6. Adequate organ and bone marrow functions. 7. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 8. Capable of giving signed informed consent which includes compliance with the study requirements and restrictions. Key Exclusion Criteria: 1. Has acute GVHD without manifestations of cGVHD. 2. Any evidence (histologic, cytogenetic, molecular, hematologic, or mixed) of relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time of screening. 3. History or other evidence of severe illness, uncontrolled infection or any other conditions that would make the participant, in the opinion of the Investigator, unsuitable for the study. 4. Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV). 5. Diagnosed with another malignancy (other than malignancy for which transplant was performed) within 3 years of enrollment, unless previously treated with curative intent and must be approved by Sponsor medical monitor (for example, completely resected basal cell or squamous cell carcinoma of the skin, resected in situ cervical malignancy, resected breast ductal carcinoma in situ, or low-risk prostate cancer after curative resection). 6. Female participants who are pregnant or breastfeeding. 7. Previous exposure to study intervention or known allergy/sensitivity to study intervention. 8. Taking agents other than a corticosteroid and one calcineurin inhibitor (CNI) for treatment of cGVHD (This does not include agents being prescribed expressly for the treatment of acute GVHD). 9. Receiving an investigational treatment within 28 days of study entry.

Locations (11)

University of Alabama at Birmingham

Birmingham, Alabama, United States

City of Hope

Duarte, California, United States

University of Miami Miller School of Medicine

Miami, Florida, United States

Outcomes

Primary Outcomes

Phase 1: Number of Participants With DLTs

A DLT was defined as the occurrence of any protocol-specified event within the first 28 days from the first dose of SNDX-6352 or administration of the third dose (Cycle 2 Day 1), whichever is later (from Cycle 1 Day 1 to Cycle 2 Day 1) and assessed by the Investigator as not being definitely attributable to underlying disease, disease progression, inter-current illness, concomitant medications or any other alternative cause.

Time frame: Day 1 through the first 28 days from the first dose of SNDX-6352 or administration of the third dose (Cycle 2 Day 1), whichever is later (from Cycle 1 Day 1 to Cycle 2 Day 1)

Phase 1: Recommended Phase 2 Dose (RP2D)

The RP2D was determined in discussion with the Sponsor, Medical Monitor, and Dose Determination Phase Investigators and was based on observations from the Phase 1 of the study (clinical benefit in chronic graft versus host disease \[cGVHD\] and pharmacokinetic/pharmacodynamic effects).

Time frame: Day 1 through the first 28 days from the first dose of SNDX-6352 or administration of the third dose (Cycle 2 Day 1), whichever is later (from C1D1 to C2D1)

Phase 2: Overall Response Rate (ORR) as Assessed by the Number of Participants With Complete Response (CR) or Partial Response (PR) at Cycle 7 Day 1 (Day 168)

CR or PR was defined by the 2014 National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in cGVHD.CR was defined as resolution of all manifestations in each organ or site, and PR was defined as improvement in at least 1 organ or site without progression in any other organ or site. ORR was defined as the percentage of participants achieving a best overall response of CR or PR .ORR calculated as: (number of participants with best overall response as CR or PR)/total number of participants.

Time frame: Cycle 7 Day 1 (Day 168)

Secondary Outcomes

Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration for SNDX-6352

Data from ClinicalTrials.gov

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Indiana University Health Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Karmanos Cancer Institute

Detroit, Michigan, United States

University of Minnesota Medical Center

Minneapolis, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States

University of Utah Health Huntsman Cancer Institute

Salt Lake City, Utah, United States

...and 1 more locations

Blood samples were collected for determination of SNDX-6352 concentration.

Time frame: Cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15

Phase 1: Observed Maximum Plasma Concentration for SNDX-6352

Blood samples were collected for determination of SNDX-6352 concentration.

Time frame: Cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15

Phase 1: Time to Observed Maximum Plasma Concentration

Blood samples were collected for determination of SNDX-6352 concentration.

Time frame: Cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15

Phase 1: Changes From Baseline in Colony-Stimulating Factor-1 (CSF-1) and Interleukin (IL-34) Serum Concentrations

Blood samples were collected for determination of serum concentrations.

Time frame: Baseline, Cycle 1 Day 8, Day 15, predose at Cycle 2 Day 1, Cycle 4 Day 1 (28-day cycles), and end of treatment (EOT) (median duration of treatment = 7 months)

Phase 1: Percent Change From Baseline in Nonclassical Monocytes (CD14+CD16++)

Blood samples were collected for determination nonclassical monocytes levels.

Time frame: Baseline, Day 8, Day 15, predose at Cycle 2 Day 1, Cycle 4 Day 1, and EOT (median duration of treatment = 7 months)

Phase 1: Number of Participants Positive for Anti-Drug Antibodies (ADA)

Blood samples were collected for ADA assessment. A participant was considered ADA positive if at least 1 postbaseline sample was ADA positive.

Time frame: Predose on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, Day 1 of each subsequent cycle through EOT plus 30 days after last dose (safety follow-up) (median duration of treatment = 7 months)

Phase 2: Best Overall Response (BOR), as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD

Physician-reported global cGVHD activity assessment and cGVHD response determination. Best overall response was calculated as percent of participants with a response of CR or PR.

Time frame: Day 1 of each 28-Day cycle up to Cycle 7 Day 1

Phase 2: Failure Free Survival (FFS)

FFS was defined as the time from first dose of study intervention to unequivocal progression of cGVHD or relapse of underlying malignancy or addition of another systemic immune suppressive therapy or discontinuation of study treatment due to toxicity or death for any reason. Unequivocal progression of cGVHD is defined as treatment discontinuation due to clinical progression. The duration of FFS was evaluated using organ-specific cGVHD activity assessment form and and summarized descriptively using the Kaplan-Meier method.

Time frame: From first dose of study intervention (Day 1) up to 27 months

Phase 2: Duration of Response (DOR)

DOR was defined as the time of initial response until documented progression or start of another systemic treatment as assessed by the Kaplan-Meir method.