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

Study Overview
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Brief Summary
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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
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This is a dose escalation and dose expansion study in participants with active cGVHD who have received at least 2 lines of prior therapy.

Official Title
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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

Conditions
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Chronic Graft-versus-host-disease

Intervention / Treatment
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* Drug: SNDX-6352


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohorts of escalating dose levels of SNDX-6352<br>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<br>* 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.<br>* Other names: axatilimab;|
| Experimental: Phase 2 Dose Expansion<br>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<br>* 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.<br>* Other names: axatilimab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the OBD and determine the RP2D of SNDX-6352 in participants with cGVHD [Phase 1] |  | Approximately 6 months | 
| 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 | Approximately 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 
| Area under the plasma concentration-time curve from time 0 to time of last measurable concentration [Phase 1] | AUC0-t will be computed | 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) | 
| Area under the plasma concentration-time curve from time 0 to infinity [Phase 1] | AUC0-inf will be computed | 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) | 
| Observed maximum plasma concentration [Phase 1] | Cmax will be computed | 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) | 
| Time to observed maximum plasma concentration [Phase 1] | Tmax will be computed | 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) | 
| 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 | 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) | 
| 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 | 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) | 
| Presence of Anti-Drug Antibody [Phase 1] | To assess the immunogenicity of SNDX-6352 | 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) | 
| 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 | Day 1 of each 28-Day cycle for up to 12 cycles | 
| Sustained response rate (SRR) [Phase 2] | CR or PR ≥20 weeks | Day 1 of each 28-Day cycle for up to 12 cycles | 
| 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 | Day 1 of each 28-Day cycle for up to 12 cycles | 
| 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 | Day 1 of each 28-Day cycle for up to 12 cycles | 
| Changes from baseline in subject-reported symptom activity using the Lee cGVHD symptom scale [Phase 2] |  | Day 1 of each 28-Day cycle for up to 12 cycles | 
| Number of participants with a ≥7-point improvement in normalized score [Phase 2] |  | Day 1 of each 28-Day cycle for up to 12 cycles | 
| 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cGVHD