Clinical trial NCT03604692: A Phase 1/2 Study to Evaluate Axatilimab in Participants With Active cGVHD
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Chronic Graft-versus-host-disease
Keywords: cGVHD
Lead sponsor: Syndax Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2018-07-27
Enrollment: 41
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Phase 1: Number of Participants With DLTs
timeFrame: 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)
measure: Phase 1: Recommended Phase 2 Dose (RP2D)
timeFrame: 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)
measure: 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)
timeFrame: Cycle 7 Day 1 (Day 168)
Secondary outcomes:
measure: Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration for SNDX-6352
timeFrame: Cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15
measure: Phase 1: Observed Maximum Plasma Concentration for SNDX-6352
timeFrame: Cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15
measure: Phase 1: Time to Observed Maximum Plasma Concentration
timeFrame: Cycle 1: predose, at 30 min (end of infusion), and at 1 hour and 8 hours on Day 1 and Day 15
measure: Phase 1: Changes From Baseline in Colony-Stimulating Factor-1 (CSF-1) and Interleukin (IL-34) Serum Concentrations
timeFrame: 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)
measure: Phase 1: Percent Change From Baseline in Nonclassical Monocytes (CD14+CD16++)
timeFrame: Baseline, Day 8, Day 15, predose at Cycle 2 Day 1, Cycle 4 Day 1, and EOT (median duration of treatment = 7 months)
measure: Phase 1: Number of Participants Positive for Anti-Drug Antibodies (ADA)
timeFrame: 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)
measure: Phase 2: Best Overall Response (BOR), as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD
timeFrame: Day 1 of each 28-Day cycle up to Cycle 7 Day 1
measure: Phase 2: Failure Free Survival (FFS)
timeFrame: From first dose of study intervention (Day 1) up to 27 months
measure: Phase 2: Duration of Response (DOR)
timeFrame: Day 1 of each 28-Day cycle for up to 12 cycles
measure: Phase 2: Sustained Response Rate (SRR)
timeFrame: Day 1 of each 28-Day cycle for up to 12 cycles
measure: Phase 2: Organ-specific Response Rate Based on 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD
timeFrame: Day 1 of each 28-Day cycle for up to 12 cycles
measure: Phase 2: Number of Participants With a Joint and Fascia Response Based on Refined NIH Response Algorithm for cGVHD
timeFrame: Day 1 of each 28-Day cycle for up to 12 cycles
measure: Phase 2: Number of Participants With A Lee Symptom Scale Summary Score Decrease of at Least 7 Points From Baseline
timeFrame: Day 1 of each 28-Day cycle for up to 12 cycles
measure: Phase 2: Number of Participants With a ≥50% Reduction in Prednisone Equivalent Dosage Lasting at Least 28 Days
timeFrame: Day 1 of each 28-Day cycle for up to 12 cycles
measure: Phase 2: Number of Participants Who Discontinued Calcineurin Inhibitor Use
timeFrame: Day 1 of each 28-Day cycle for up to 12 cycles
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Duarte
country: United States
facility: City of Hope
state: California
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Indianapolis
country: United States
facility: Indiana University Health Melvin and Bren Simon Cancer Center
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Salt Lake City
country: United States
facility: University of Utah Health Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Syndax Pharmaceuticals
name: Vedran Radojcic, M.D.
role: STUDY_DIRECTOR
References: