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

Primary Purpose

Chronic Graft-versus-host-disease

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

SNDX-6352

About this trial

This is an interventional treatment trial for Chronic Graft-versus-host-disease focused on measuring cGVHD

Eligibility Criteria

6 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

Participant must be 6 years of age or older, at the time of signing the informed consent.
Participants who are allogeneic hematopoietic stem cell transplant (HSCT) recipients with cGVHD requiring systemic immune suppression.
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.
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.
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).
Adequate organ and bone marrow functions.
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Capable of giving signed informed consent which includes compliance with the study requirements and restrictions.

Key Exclusion Criteria:

Has acute GVHD without manifestations of cGVHD.
Any evidence (histologic, cytogenetic, molecular, hematologic, or mixed) of relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time of screening.
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.
Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV).
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).
Female participants who are pregnant or breastfeeding.
Previous exposure to study intervention or known allergy/sensitivity to study intervention.
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).
Receiving an investigational treatment within 28 days of study entry.

Sites / Locations

University of Alabama at Birmingham
City of Hope
University of Miami Miller School of Medicine
Indiana University Health Melvin and Bren Simon Cancer Center
Massachusetts General Hospital
Karmanos Cancer Institute
University of Minnesota Medical Center
Washington University School of Medicine
Vanderbilt-Ingram Cancer Center
University of Utah Health Huntsman Cancer Institute
Fred Hutchinson Cancer Research Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Cohorts of escalating dose levels of SNDX-6352

Phase 2 Dose Expansion

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

To characterize the OBD and determine the RP2D of SNDX-6352 in participants with cGVHD [Phase 1]

To evaluate the efficacy of SNDX 6352 in participants with cGVHD [Phase 2]

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

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

Frequency and severity of adverse events and serious adverse events as assessed by the NCI CTCAE version 5.0

Area under the plasma concentration-time curve from time 0 to time of last measurable concentration [Phase 1]

AUC0-t will be computed

Area under the plasma concentration-time curve from time 0 to infinity [Phase 1]

AUC0-inf will be computed

Observed maximum plasma concentration [Phase 1]

Cmax will be computed

Time to observed maximum plasma concentration [Phase 1]

Tmax will be computed

Changes in circulating factors related to SNDX-6352 mechanism (including CSF1, IL34) and their associated cGVHD response [Phase 1]

To evaluate changes in circulating monocyte number and phenotype (CD14/16) after SNDX-6352 administration

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]

To evaluate changes in biomarkers following SNDX-6352 administration

Presence of Anti-Drug Antibody [Phase 1]

To assess the immunogenicity of SNDX-6352

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]

Physician-reported global cGVHD activity assessment and cGVHD response determination

Sustained response rate (SRR) [Phase 2]

CR or PR ≥20 weeks

Organ-specific response rate based on 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD [Phase 2]

Physician-reported global cGVHD activity assessment and cGVHD response determination

NIH response algorithm score for cGVHD for joints and fascia [Phase 2]

Based on the refined response on the physician reported global cGVHD activity assessment

Changes from baseline in subject-reported symptom activity using the Lee cGVHD symptom scale [Phase 2]

Number of participants with a ≥7-point improvement in normalized score [Phase 2]

Evaluate corticosteroid or calcineurin inhibitors use [Phase 2]

Percent reduction in average daily dose (or equivalent) or discontinuation of corticosteroid or calcineurin inhibitor use, after study entry.

Full Information

NCT ID

NCT03604692

First Posted

July 10, 2018

Last Updated

August 1, 2023

Sponsor

Syndax Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT03604692

Brief Title

A Phase 1/2 Study to Evaluate SNDX- 6352 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

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

November 1, 2018 (Actual)

Primary Completion Date

August 12, 2022 (Actual)

Study Completion Date

December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Syndax Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Graft-versus-host-disease

Keywords

cGVHD

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

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)

Allocation

Non-Randomized

Enrollment

41 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohorts of escalating dose levels of SNDX-6352

Arm Type

Experimental

Arm Description

Arm Title

Phase 2 Dose Expansion

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

SNDX-6352

Other Intervention Name(s)

axatilimab

Intervention Description

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.

Primary Outcome Measure Information:

Title

To characterize the OBD and determine the RP2D of SNDX-6352 in participants with cGVHD [Phase 1]

Time Frame

Approximately 6 months

Title

To evaluate the efficacy of SNDX 6352 in participants with cGVHD [Phase 2]

Description

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

Time Frame

Approximately 6 months

Secondary Outcome Measure Information:

Title

Description

Frequency and severity of adverse events and serious adverse events as assessed by the NCI CTCAE version 5.0

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

Title

Area under the plasma concentration-time curve from time 0 to time of last measurable concentration [Phase 1]

Description

AUC0-t will be computed

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)

Title

Area under the plasma concentration-time curve from time 0 to infinity [Phase 1]

Description

AUC0-inf will be computed

Time Frame

Title

Observed maximum plasma concentration [Phase 1]

Description

Cmax will be computed

Time Frame

Title

Time to observed maximum plasma concentration [Phase 1]

Description

Tmax will be computed

Time Frame

Title

Changes in circulating factors related to SNDX-6352 mechanism (including CSF1, IL34) and their associated cGVHD response [Phase 1]

Description

To evaluate changes in circulating monocyte number and phenotype (CD14/16) after SNDX-6352 administration

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)

Title

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]

Description

To evaluate changes in biomarkers following SNDX-6352 administration

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)

Title

Presence of Anti-Drug Antibody [Phase 1]

Description

To assess the immunogenicity of SNDX-6352

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)

Title

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]

Description

Physician-reported global cGVHD activity assessment and cGVHD response determination

Time Frame