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

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ClinicalTrials.gov Identifier: NCT03604692
Recruitment Status : Active, not recruiting
First Posted : July 27, 2018
Last Update Posted : May 14, 2021
Sponsor:
Information provided by (Responsible Party):
Syndax Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE July 10, 2018
First Posted Date  ICMJE July 27, 2018
Last Update Posted Date May 14, 2021
Actual Study Start Date  ICMJE November 1, 2018
Estimated Primary Completion Date November 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 4, 2020)
  • To characterize the optimal biologic dose (OBD) and determine the recommended Phase 2 dose (RP2D) of SNDX-6352 in subjects with cGVHD [Phase 1] [ Time Frame: Approximately 6 months ]
    Up to 30 patients will be enrolled in a modified 3+3 design, where 6 patients must be treated in a dose level and have safety assessed in order to determine the OBD/RP2D.
  • To evaluate the efficacy of SNDX 6352 in subjects with cGVHD [Phase 2] [ Time Frame: Approximately 6 months ]
    Proportion of subjects 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
Original Primary Outcome Measures  ICMJE
 (submitted: July 20, 2018)
To characterize the optimal biologic dose (OBD) and determine the recommended Phase 2 dose (RP2D) of SNDX-6352 in subjects with cGVHD [ Time Frame: Approximately 6 months ]
Up to 30 patients will be enrolled in a modified 3+3 design, where 6 patients must be treated in a dose level and have safety assessed in order to determine the OBD/RP2D.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 12, 2021)
  • To evaluate the safety and tolerability of axatilimab in patients with cGVHD [ 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 (AEs) and serious adverse events (SAEs) 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] [ 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
  • 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
  • Percentage of estimated part for the calculation of AUC0-inf [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) ]
    %AUCextra will be computed
  • 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
  • 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
  • Terminal disposition phase rate constant [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) ]
    terminal disposition phase rate constant will be computed [Phase 1]
  • Terminal phase half-life [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) ]
    t1/2 will be computed
  • Clearance [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) ]
    CL will be computed
  • Terminal phase volume of distribution [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) ]
    Vz will be computed
  • 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
  • Changes from baseline in inflammation biomarkers that may include monocyte chemoattranct 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
  • 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
  • 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
  • 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
  • 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
  • Duration of Response [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
  • 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 calcineurin inhibitor use, after study entry.
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2018)
  • Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) [ 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 ]
    Assessed by the NCI CTCAE version 5.0
  • Area under the plasma concentration-time curve from time 0 to time of last measurable concentration [ 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
  • Area under the plasma concentration-time curve from time 0 to infinity [ 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
  • Percentage of estimated part for the calculation of AUC0-inf [ 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) ]
    %AUCextra will be computed
  • Observed maximum plasma concentration [ 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
  • Time to observed maximum plasma concentration [ 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
  • Terminal disposition phase rate constant [ 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) ]
    terminal disposition phase rate constant will be computed
  • Terminal phase half-life [ 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) ]
    t1/2 will be computed
  • Clearance [ 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) ]
    CL will be computed
  • Terminal phase volume of distribution [ 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) ]
    Vz will be computed
  • Changes in circulating factors related to SNDX-6352 mechanism (including CSF1, IL34) and associated with cGVHD response and inflammation (including MCP1, CCL3 and CCL5 expression) [ 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 the change from baseline in CSF1 and IL34 and after treatment
  • Circulating monocyte number and phenotype (CD14/16) [ 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
  • Presence of Anti-Drug Antibody [ 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 as measured by presence of ADA
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 1/2 Study to Evaluate SNDX- 6352 in Subjects With Active cGVHD
Official Title  ICMJE 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 Chronic Graft Versus Host Disease Who Have Received at Least 2 Lines of Prior Therapy
Brief Summary This is a Phase 1/2, Open-label, Dose Escalation study to investigate SNDX-6352 in subjects with active cGVHD.
Detailed Description This is dose escalation and dose expansion study in patients with active chronic graft versus host disease (cGVHD) who have received at least 2 lines of prior therapy.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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
Condition  ICMJE Chronic Graft-versus-host-disease
Intervention  ICMJE 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
Study Arms  ICMJE
  • 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).

    IV infusion; SNDX-6352 at a dose of 0.15 mg/kg to 3 mg/kg.

    Intervention: Drug: SNDX-6352
  • 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.

    Intervention: Drug: SNDX-6352
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 12, 2021)
37
Original Estimated Enrollment  ICMJE
 (submitted: July 20, 2018)
30
Estimated Study Completion Date  ICMJE May 1, 2022
Estimated Primary Completion Date November 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Subject must be 6 years of age or older, at the time of signing the informed consent.
  2. Subjects who are allogeneic HSCT recipients with cGVHD requiring systemic immune suppression.
  3. Subjects with active cGVHD who have received at least 2 lines of therapy. Subjects 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. Subjects 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 requirements and restrictions listed in the informed consent form (ICF) and in the study protocol.

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 subject, 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 (e.g., 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 subjects who is 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03604692
Other Study ID Numbers  ICMJE SNDX-6352-0503
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Syndax Pharmaceuticals
Study Sponsor  ICMJE Syndax Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Michael L Meyers, MD, PhD Syndax Pharmaceuticals
PRS Account Syndax Pharmaceuticals
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP