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

A Phase 1/2, Open-Label, Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamic Activity, and Efficacy of SNDX- 6352 in Subjects With Active Chronic Graft Versus Host Disease Who Have Received at Least 2 Lines of Prior Therapy

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

Study Overview

• Status: Completed
• Conditions: Chronic Graft-versus-host-disease
• Intervention / Treatment: Drug: axatilimab

Detailed Description

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
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Duarte, California, United States, 91010
      • City of Hope
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Melvin and Bren Simon Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Tennessee
    • Nashville, Tennessee, United States, 37212-3505
      • Vanderbilt-Ingram Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah Health Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohorts of escalating dose levels of axatilimab; Escalating dose levels of axatilimab to establish the optimal biologic dose (OBD) and recommended Phase 2 dose (RP2D). Intravenous (IV) infusion; axatilimab at a dose of 0.15 milligrams (mg)/kilogram (kg) to 3 mg/kg.	Drug: axatilimab; 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.; Other Names: SNDX-6352; Niktimvo
Experimental: Phase 2 Dose Expansion; Phase 2, dose expansion, is an open-label design, evaluating the 1 mg/kg dose in a larger sample size. IV infusion; axatilimab at a dose of 1 mg/kg.	Drug: axatilimab; 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.; Other Names: SNDX-6352; Niktimvo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).	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.	Cycle 7 Day 1 (Day 168)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration for SNDX-6352	Blood samples were collected for determination of SNDX-6352 concentration.	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.	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.	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.	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.	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.	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.	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.	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.	Day 1 of each 28-Day cycle for up to 12 cycles
Phase 2: Sustained Response Rate (SRR)	SSR of CR or PR ≥20 weeks was defined as rate of CR or PR lasting for at least 20 weeks from the time of initial response.	Day 1 of each 28-Day cycle for up to 12 cycles
Phase 2: Organ-specific Response Rate Based on 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD	The percentage of participants with a response (CR/PR) in the skin, eyes, mouth, esophagus, upper gastrointestinal (GI), lower GI, liver, lungs, or joints and fascia were assessed using the NIH Consensus Development Project on Clinical Trials.	Day 1 of each 28-Day cycle for up to 12 cycles
Phase 2: Number of Participants With a Joint and Fascia Response Based on Refined NIH Response Algorithm for cGVHD		Day 1 of each 28-Day cycle for up to 12 cycles
Phase 2: Number of Participants With A Lee Symptom Scale Summary Score Decrease of at Least 7 Points From Baseline	The Lee cGVHD symptom questionnaire asked participants to indicate the degree of "bother" that they experienced during the past 7 days due to symptoms in 7 domains potentially affected by chronic GVHD (skin, eyes and mouth, breathing, eating and digestion, muscles and joints, energy, emotional distress) using a 5-point Likert scale from 0 "not at all" to 4 "extremely." Scores were normalized (0 to 100 scale) and the number of participants with a ≥ 7-point decrease in normalized score was calculated. A decrease in score indicated improvement in symptoms.	Day 1 of each 28-Day cycle for up to 12 cycles
Phase 2: Number of Participants With a ≥50% Reduction in Prednisone Equivalent Dosage Lasting at Least 28 Days		Day 1 of each 28-Day cycle for up to 12 cycles
Phase 2: Number of Participants Who Discontinued Calcineurin Inhibitor Use		Day 1 of each 28-Day cycle for up to 12 cycles

Collaborators and Investigators

• Sponsor: Syndax Pharmaceuticals
• Investigators: Study Director: Vedran Radojcic, M.D., Syndax Pharmaceuticals

Publications and helpful links

General Publications

• Kitko CL, Arora M, DeFilipp Z, Zaid MA, Di Stasi A, Radojcic V, Betts CB, Coussens LM, Meyers ML, Qamoos H, Ordentlich P, Kumar V, Quaranto C, Schmitt A, Gu Y, Blazar BR, Wang TP, Salhotra A, Pusic I, Jagasia M, Lee SJ. Axatilimab for Chronic Graft-Versus-Host Disease After Failure of at Least Two Prior Systemic Therapies: Results of a Phase I/II Study. J Clin Oncol. 2023 Apr 1;41(10):1864-1875. doi: 10.1200/JCO.22.00958. Epub 2022 Dec 2.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2018
• Primary Completion (Actual): August 12, 2022
• Study Completion (Actual): October 18, 2024

Study Registration Dates

• First Submitted: July 10, 2018
• First Submitted That Met QC Criteria: July 20, 2018
• First Posted (Actual): July 27, 2018

Study Record Updates

• Last Update Posted (Estimated): September 15, 2025
• Last Update Submitted That Met QC Criteria: August 25, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: cGVHD
• Additional Relevant MeSH Terms: Organizing Pneumonia; Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Graft vs Host Disease; Bronchiolitis Obliterans Syndrome; axatilimab
• Other Study ID Numbers: SNDX-6352-0503

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No