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

Phase 1

Active, not recruiting

• Conditions: Chronic Graft-versus-host-disease
• Interventions: Drug: axatilimab

• Registration Number: NCT03604692
• Lead Sponsor: Syndax Pharmaceuticals

Brief Summary

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

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 Timeline

• Study First Submitted: 2018-07-10
• Study First Submitted QC: 2018-07-20
• Study First Posted: 2018-07-27
• Study Start: 2018-11-01
• Primary Completion: 2022-08-12
• Disposition First Submitted: 2023-08-01
• Results First Submitted: 2024-09-12
• Status Verified: 2024-11
• Results First Submitted QC: 2024-11-20
• Last Update Submitted: 2024-11-20
• Results First Posted: 2024-11-27
• Disposition First Posted: 2024-11-27
• Last Update Posted: 2024-11-27
• Study Completion: 2024-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 41

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 2 Dose Expansion	axatilimab	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.
Cohorts of escalating dose levels of axatilimab	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.

Primary Outcome Measures

Name	Time	Method
Phase 1: Number of Participants With DLTs	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)	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.
Phase 1: Recommended Phase 2 Dose (RP2D)	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)	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).
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)	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.

Secondary Outcome Measures

Name	Time	Method
Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration for SNDX-6352	Cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15	Blood samples were collected for determination of SNDX-6352 concentration.
Phase 1: Observed Maximum Plasma Concentration for SNDX-6352	Cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15	Blood samples were collected for determination of SNDX-6352 concentration.
Phase 1: Time to Observed Maximum Plasma Concentration	Cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15	Blood samples were collected for determination of SNDX-6352 concentration.
Phase 1: Changes From Baseline in Colony-Stimulating Factor-1 (CSF-1) and Interleukin (IL-34) 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)	Blood samples were collected for determination of serum concentrations.
Phase 1: Percent Change From Baseline in Nonclassical Monocytes (CD14+CD16++)	Baseline, Day 8, Day 15, predose at Cycle 2 Day 1, Cycle 4 Day 1, and EOT (median duration of treatment = 7 months)	Blood samples were collected for determination nonclassical monocytes levels.
Phase 1: Number of Participants Positive for Anti-Drug Antibodies (ADA)	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)	Blood samples were collected for ADA assessment. A participant was considered ADA positive if at least 1 postbaseline sample was ADA positive.
Phase 2: Best Overall Response (BOR), as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD	Day 1 of each 28-Day cycle up to Cycle 7 Day 1	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.
Phase 2: Failure Free Survival (FFS)	From first dose of study intervention (Day 1) up to 27 months	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.
Phase 2: Duration of Response (DOR)	Day 1 of each 28-Day cycle for up to 12 cycles	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.
Phase 2: Sustained Response Rate (SRR)	Day 1 of each 28-Day cycle for up to 12 cycles	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.
Phase 2: Organ-specific Response Rate Based on 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD	Day 1 of each 28-Day cycle for up to 12 cycles	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.
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	Day 1 of each 28-Day cycle for up to 12 cycles	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.
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

Trial Locations

Locations (11)

City of Hope; 🇺🇸 Duarte, California, United States

University of Minnesota Medical Center; 🇺🇸 Minneapolis, Minnesota, United States

University of Miami Miller School of Medicine; 🇺🇸 Miami, Florida, United States

Indiana University Health Melvin and Bren Simon Cancer Center; 🇺🇸 Indianapolis, Indiana, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

University of Utah Health Huntsman Cancer Institute; 🇺🇸 Salt Lake City, Utah, United States

Vanderbilt-Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States