A Phase 1/2 Study to Evaluate SNDX- 6352 in Participants With Active cGVHD

• ClinicalTrials.gov Identifier: NCT03604692
• Recruitment Status: Active, not recruiting
• First Posted: July 27, 2018
• Last Update Posted: June 1, 2023
• Sponsor: Syndax Pharmaceuticals
• Information provided by (Responsible Party): Syndax Pharmaceuticals

Study Description

Brief Summary:

This is a Phase 1/2, Open-label, Dose Escalation study to investigate SNDX-6352 in participants with active chronic graft versus host disease (cGVHD).

Condition or disease	Intervention/treatment	Phase
Chronic Graft-versus-host-disease	Drug: SNDX-6352	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: The dose-escalation phase is a sequential group (dose-escalating) treatment study that is open-label. The dose-expansion phase is a parallel group treatment study with open-label cohorts.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 1, 2018
• Actual Primary Completion Date: August 12, 2022
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohorts of escalating dose levels of SNDX-6352; Escalating dose levels of SNDX-6352 to establish the optimal biologic dose (OBD) and recommended Phase 2 dose (RP2D). Intravenous (IV) infusion; SNDX-6352 at a dose of 0.15 milligrams (mg)/kilogram (kg) to 3 mg/kg.	Drug: SNDX-6352; SNDX-6352 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 Name: axatilimab
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; SNDX-6352 at a dose of 1 mg/kg.	Drug: SNDX-6352; SNDX-6352 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 Name: axatilimab

Outcome Measures

Primary Outcome Measures :

1. To characterize the OBD and determine the RP2D of SNDX-6352 in participants with cGVHD [Phase 1] [ Time Frame: Approximately 6 months ]
2. To evaluate the efficacy of SNDX 6352 in participants with cGVHD [Phase 2] [ Time Frame: Approximately 6 months ]
   Proportion of participants with CR or PR at Cycle 7 Day 1 (Day 168) as defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD

Secondary Outcome Measures :

1. To evaluate the safety and tolerability of axatilimab in participants with cGVHD by assessing the frequency and severity of adverse events and serious adverse events over the course of the participant's participation in the study from date of consent [ Time Frame: Approximately 16 months; From date of consent to 30 days after end of treatment for AEs and 90 days after last dose of study treatment for SAEs ]
   Frequency and severity of adverse events and serious adverse events as assessed by the NCI CTCAE version 5.0
2. Area under the plasma concentration-time curve from time 0 to time of last measurable concentration [Phase 1] [ Time Frame: Blood samples for determination of SNDX-6352 concentration will be collected at cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15; and at 168 hours on Day 8; and predose on Cycle 2 Day 1 (each cycle is 28 days) ]
   AUC0-t will be computed
3. Area under the plasma concentration-time curve from time 0 to infinity [Phase 1] [ Time Frame: Blood samples for determination of SNDX-6352 concentration will be collected at cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15; and at 168 hours on Day 8; and predose on Cycle 2 Day 1 (each cycle is 28 days) ]
   AUC0-inf will be computed
4. Observed maximum plasma concentration [Phase 1] [ Time Frame: Blood samples for determination of SNDX-6352 concentration will be collected at cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15; and at 168 hours on Day 8; and predose on Cycle 2 Day 1 (each cycle is 28 days) ]
   Cmax will be computed
5. Time to observed maximum plasma concentration [Phase 1] [ Time Frame: Blood samples for determination of SNDX-6352 concentration will be collected at cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15; and at 168 hours on Day 8; and predose on Cycle 2 Day 1 (each cycle is 28 days) ]
   Tmax will be computed
6. Changes in circulating factors related to SNDX-6352 mechanism (including CSF1, IL34) and their associated cGVHD response [Phase 1] [ Time Frame: Blood samples will be collected at baseline, Day 8, Day 15, predose at Cycle 2 Day 1, Cycle 4 Day 1, and end of treatment (each cycle is 28 days) ]
   To evaluate changes in circulating monocyte number and phenotype (CD14/16) after SNDX-6352 administration
7. Changes from baseline in inflammation biomarkers that may include monocyte chemoattractant protein 1 (MCP1), Chemokine (C-C motif) ligand 3 (CCL3) and CCL5 expression [Phase 1] [ Time Frame: Blood samples will be collected at baseline, Day 8, Day 15, predose at Cycle 2 Day 1, Cycle 4 Day 1, and end of treatment (each cycle is 28 days) ]
   To evaluate changes in biomarkers following SNDX-6352 administration
8. Presence of Anti-Drug Antibody [Phase 1] [ Time Frame: Blood samples will be collected at predose on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, Day 1 of each subsequent cycle, end of treatment, and 30-day follow-up visit. (each cycle is 28 days) ]
   To assess the immunogenicity of SNDX-6352
9. Best overall response (BOR), failure free survival (FFS), and duration of response (DOR) as defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD [Phase 2] [ Time Frame: Day 1 of each 28-Day cycle for up to 12 cycles ]
   Physician-reported global cGVHD activity assessment and cGVHD response determination
10. Sustained response rate (SRR) [Phase 2] [ Time Frame: Day 1 of each 28-Day cycle for up to 12 cycles ]
    CR or PR ≥20 weeks
11. Organ-specific response rate based on 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD [Phase 2] [ Time Frame: Day 1 of each 28-Day cycle for up to 12 cycles ]
    Physician-reported global cGVHD activity assessment and cGVHD response determination
12. NIH response algorithm score for cGVHD for joints and fascia [Phase 2] [ Time Frame: Day 1 of each 28-Day cycle for up to 12 cycles ]
    Based on the refined response on the physician reported global cGVHD activity assessment
13. Changes from baseline in subject-reported symptom activity using the Lee cGVHD symptom scale [Phase 2] [ Time Frame: Day 1 of each 28-Day cycle for up to 12 cycles ]
14. Number of participants with a ≥7-point improvement in normalized score [Phase 2] [ Time Frame: Day 1 of each 28-Day cycle for up to 12 cycles ]
15. Evaluate corticosteroid or calcineurin inhibitors use [Phase 2] [ Time Frame: Approximately 16 months; From date of consent to 30 days after end of treatment for AEs and 90 days after last dose of study treatment for SAEs ]
    Percent reduction in average daily dose (or equivalent) or discontinuation of corticosteroid or calcineurin inhibitor use, after study entry.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35294

United States, California

City of Hope

Duarte, California, United States, 91010

United States, Florida

University of Miami Miller School of Medicine

Miami, Florida, United States, 33136

United States, Indiana

Indiana University Health Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States, 46202

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Michigan

Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

United States, Minnesota

University of Minnesota Medical Center

Minneapolis, Minnesota, United States, 55455

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Tennessee

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States, 37212-3505

United States, Utah

University of Utah Health Huntsman Cancer Institute

Salt Lake City, Utah, United States, 84112

United States, Washington

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States, 98109

Sponsors and Collaborators

Syndax Pharmaceuticals

Investigators

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

More Information

• Responsible Party: Syndax Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03604692
• Other Study ID Numbers: SNDX-6352-0503
• First Posted: July 27, 2018
• Last Update Posted: June 1, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Syndax Pharmaceuticals:

cGVHD

Additional relevant MeSH terms:

Bronchiolitis Obliterans Syndrome; Graft vs Host Disease; Immune System Diseases; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases