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

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ClinicalTrials.gov Identifier: NCT03604692
Recruitment Status : Not yet recruiting
First Posted : July 27, 2018
Last Update Posted : July 27, 2018
Sponsor:
Information provided by (Responsible Party):
Syndax Pharmaceuticals

Brief Summary:
This is a Phase 1, Open-label, Dose Escalation study to investigate SNDX-6352 in subjects with active cGVHD.

Condition or disease Intervention/treatment Phase
Chronic Graft-versus-host-disease Drug: SNDX-6352 Phase 1

Detailed Description:
This is dose escalation study in patients with active chronic graft versus host disease who have received at least 2 lines of prior therapy including ibrutinib.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Sequential Assignment
Intervention Model Description: A dose escalation study based on the use of a modified 3 + 3 design of up to 6 subjects in each of 5 SNDX-6352 dose levels to determine the optimal biologic dose (OBD) and recommended Phase 2 dose (RP2D).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Dose Escalation Study to Evaluate the Safety, Tolerability, PK and PD Activity of SNDX-6352 in Subjects With Active cGVHD Who Have Received at Least 2 Lines of Prior Therapy, Including Ibrutinib
Estimated Study Start Date : September 1, 2018
Estimated Primary Completion Date : October 1, 2019
Estimated Study Completion Date : March 1, 2020


Arm Intervention/treatment
Experimental: 5 cohorts of escalating dose levels of SNDX-6352

5 cohorts of 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.

Drug: SNDX-6352
SNDX-6352 is a high affinity antibody targeting the colony stimulating factor 1 receptor (CSF-1R). It has shown evidence of anti-tumor and anti-metastatic efficacy through its ability to limit the number and activity of immunosuppressive cells such as tumor associated macrophages.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subject must be 18 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 whose disease is unresponsive to ibrutinib in at least the second line setting (due to progression of disease, intolerability or toxicity).

    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.
  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 multiple other immune suppressive agents for treatment of cGVHD. This does not include agents for treatment of acute GVHD and prophylaxis for cGVHD.
  9. Receiving an investigational treatment within 28 days of study entry.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03604692


Contacts
Contact: Christine Quaranto 781-684-9824 cquaranto@syndax.com
Contact: Sue Fischer 781-795-9419 sfischer@syndax.com

Sponsors and Collaborators
Syndax Pharmaceuticals
Investigators
Study Director: Michael L Meyers, MD, PhD Syndax Pharmaceuticals

Responsible Party: Syndax Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03604692     History of Changes
Other Study ID Numbers: SNDX-6352-0503
First Posted: July 27, 2018    Key Record Dates
Last Update Posted: July 27, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Syndax Pharmaceuticals:
cGVHD

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases