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A Study of Axatilimab at 3 Different Doses in Patients With Chronic Graft Versus Host Disease (cGVHD) (AGAVE-201)

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ClinicalTrials.gov Identifier: NCT04710576
Recruitment Status : Recruiting
First Posted : January 14, 2021
Last Update Posted : January 14, 2021
Sponsor:
Information provided by (Responsible Party):
Syndax Pharmaceuticals

Brief Summary:
AGAVE-201 is a Phase 2 study to evaluate the efficacy, safety, and tolerability of axatilimab at 3 different dose levels in patients with recurrent or refractory active chronic graft versus host disease (cGVHD) who have received at least 2 prior lines of systemic therapy due to progression of disease, intolerability or toxicity.

Condition or disease Intervention/treatment Phase
Chronic Graft-versus-host-disease Drug: axatilimab Phase 2

Detailed Description:
AGAVE-201 is a Phase 2, open-label, randomized, multicenter study to evaluate the efficacy, safety, and tolerability of axatilimab at 3 different dose levels in patients with recurrent or refractory active cGVHD who have received at least 2 prior lines of systemic therapy due to progression of disease, intolerability or toxicity. Disease progression is defined 1) by the NIH 2014 consensus criteria, either in terms of organ specific algorithm or global assessment or 2) as active, symptomatic cGVHD for whom the physician believes that a new line of systemic therapy is required.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: AGAVE-201, A Phase 2, Open-label, Randomized, Multicenter Study to Evaluate the Efficacy, Safety and Tolerability of Axatilimab at 3 Different Doses in Patients With Recurrent or Refractory Active Chronic Graft Versus Host Disease Who Have Received at Least 2 Lines of Systemic Therapy
Estimated Study Start Date : January 2021
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : July 2023


Arm Intervention/treatment
Active Comparator: Axatilimab (SNDX-6352) Dose Cohort 1 - 0.3 mg/kg IV Q2W
IV infusion; Axatilimab (SNDX-6352) 0.3 mg/kg Q2W
Drug: axatilimab
Axatilimab (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: SNDX-6352

Active Comparator: Axatilimab (SNDX-6352) Dose Cohort 2 - 1 mg/kg IV Q2W
IV infusion; Axatilimab (SNDX-6352) 1 mg/kg Q2W
Drug: axatilimab
Axatilimab (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: SNDX-6352

Active Comparator: Axatilimab (SNDX-6352) Dose Cohort 3 - 3 mg/kg IV Q4W
IV infusion; Axatilimab (SNDX-6352) 3 mg/kg Q4W
Drug: axatilimab
Axatilimab (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: SNDX-6352




Primary Outcome Measures :
  1. Overall response rate in the first 6 cycles [ Time Frame: Approximately 6 Months ]
    The proportion of patients with objective response during the first 6 cycles, where the first 6 cycles is defined as the time from randomization up to Day 169 or the beginning of Cycle 7


Secondary Outcome Measures :
  1. Duration of Response [ Time Frame: Day 1 of each 28-Day cycle for up to 12 cycles ]
    The time from best response of partial response or complete response until documented progression of cGVHD, start of new therapy, or death for any reason.

  2. To evaluate key secondary measures of clinical benefit for patients with cGVHD [ Time Frame: Approximately 6 Months ]
    Proportion of patients with a >5-point improvement in normalized score on the modified Lee Symptom Scale.

  3. To evaluate the safety and tolerability of axatilimab in patients with cGVHD [ Time Frame: Approximately 30 months; from date of consent to 90 days after last dose of study treatment for AEs and SAEs ]
    Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) as assessed by the NCI CTCAE version 5.0

  4. Sustained Response Rate [ Time Frame: at least 20 weeks ]
    Proportion of patients with objective response lasting for at least 20 weeks (140 days) from the time of initial response. Responses by organ system will be assessed based on the 2014 NIH Consensus Development Project on Clinical Trials in cGVHD

  5. Organ-specific Response Rate [ Time Frame: approximately 30 Months ]
    Proportion of patients with objective response for the nine individual organs based on 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD (Skin, Eyes, Mouth, Esophagus, Upper GI, Lower GI, Liver, Lungs and Joints and Fascia)

  6. Corticosteroid reduction [ Time Frame: approximately 30 Months ]
    Percent reductions in average daily doses (or equivalent) of corticosteroid after study entry.

  7. Corticosteroid discontinuation [ Time Frame: approximately 30 Months ]
    Proportion of patients who discontinue corticosteroid use after study entry.

  8. Calcineurin inhibitor reduction [ Time Frame: approximately 30 Months ]
    Percent reductions in average daily doses (or equivalent) of calcineurin inhibitors after study entry .

  9. Calcineurin inhibitor discontinuation [ Time Frame: approximately 30 Months ]
    Proportion of patients who discontinue calcineurin inhibitors after study entry.

  10. To determine or assess the changes in monocyte level with response [ Time Frame: approximately 12 months ]
    Change from baseline in circulating monocyte number and phenotype (CD14/16)

  11. To determine or assess the baseline in monocyte level with response [ Time Frame: approximately 12 months ]
    Baseline circulating monocyte number and phenotype (CD14/16)

  12. Presence of Anti-Drug Antibody [ Time Frame: approximately 12 months ]
    To assess the immunogenicity of SNDX-6352

  13. Area under the plasma concentration-time curve from time 0 to time of last measurable concentration [Phase 1] [ Time Frame: approximately 12 months ]
    AUC0-t will be computed

  14. Area under the plasma concentration-time curve from time 0 to infinity [Phase 1] [ Time Frame: approximately 12 months ]
    AUC0-inf will be computed

  15. Percentage of estimated part for the calculation of AUC0-inf [ Time Frame: approximately 12 months ]
    %AUCextra will be computed

  16. Observed maximum plasma concentration [ Time Frame: approximately 12 months ]
    Cmax will be computed

  17. Time to observed maximum plasma concentration [ Time Frame: approximately 12 months ]
    Tmax will be computed

  18. Terminal disposition phase rate constant [ Time Frame: approximately 12 months ]
    terminal disposition phase rate constant will be computed

  19. Terminal phase half-life [ Time Frame: approximately 12 months ]
    t1/2 will be computed

  20. Clearance [ Time Frame: approximately 12 months ]
    CL will be computed

  21. Terminal phase volume of distribution [ Time Frame: approximately 12 months ]
    Vz will be computed



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient must be 6 years of age or older, at the time of signing the informed consent.
  2. Patients who are allogeneic HSCT recipients with active cGVHD requiring systemic immune suppression.

    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 (Jagasia 2015).

  3. Patients with refractory or recurrent active cGVHD despite at least 2 lines of systemic therapy.

    • Refractory disease defined as meeting any of the following criteria:

      • The development of 1 or more new sites of disease while being treated for cGVHD.
      • Progression of existing sites of disease despite at least 1 month of standard or investigation therapy for cGVHD.
      • Patients who have not achieved a response within 3 months on their prior therapy for cGVHD and for whom the treating physician believes a new systemic therapy is required.
    • Recurrent cGVHD is active, symptomatic disease (after an initial response to prior therapy) as defined, based on the NIH 2014 consensus criteria, by organ-specific or global assessment or for which the physician believes that a new line of systemic therapy is required.
  4. Patients 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 (if aged 16 years or older); Lansky Performance Score of ≥60 (if aged <16 years)
  6. Adequate organ and bone marrow functions evaluated during the 14 days prior to randomization.
  7. Creatinine clearance (CrCl) ≥30 mL/min/1.73 m2 based on the Cockcroft-Gault formula in adult patients and Schwartz formula in pediatric patients.
  8. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  9. Concomitant use a of systemic corticosteroid is allowed but not required. Topical and inhaled corticosteroid agents are allowed. If a patient is taking corticosteroids at study randomization, they must be on a stable dose of corticosteroids for at least 2 weeks prior to Cycle 1 Day 1.
  10. Concomitant use of CNI or sirolimus is allowed but not required.
  11. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. A parent/guardian should provide consent for pediatric patients unable to provide consent themselves; in addition, where applicable pediatric patients should sign their own assent form.

Exclusion Criteria:

Patients are excluded from the study if any of the following criteria apply:

  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 of acute or chronic pancreatitis
  4. History of myositis
  5. History or other evidence of severe illness, uncontrolled infection or any other conditions that would make the patient, in the opinion of the Investigator, unsuitable for the study.
  6. Patients with acquired immune deficiency syndrome (AIDS).
  7. Hepatitis B (defined as hepatitis B virus [HBV] surface antigen positive and HBV core antibody positive, with positive HBV deoxyribonucleic acid [DNA], or HBV positive core antibody alone with positive HBV DNA. Hepatitis C (defined as positive hepatitis C [HCV] antibody with positive HCV ribonucleic acid [RNA]).
  8. Diagnosed with another malignancy (other than malignancy for which transplant was performed) within 3 years of randomization, unless previously treated with curative intent and approved by Sponsor's Medical Monitor (eg, 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).
  9. Female patient who is pregnant or breastfeeding.
  10. Previous exposure to CSF1-R targeted therapies.
  11. Taking agents for treatment of cGVHD other than corticosteroids and either a CNI or sirolimus is prohibited. See Inclusion Criteria 9 and 9 for guidelines regarding the appropriate use of corticosteroids, CNI, and sirolimus in combination with study treatment.
  12. For approved or commonly used agents, other than corticosteroids, CNI and sirolimus, a washout of 2 weeks or 5 half-lives, whichever is shorter, is required at study enrollment.
  13. Receiving another investigational treatment within 28 days of randomization.
  14. Patients should not be participating in any other interventional study. Pediatric patients are encouraged to also participate in the ongoing developmental studies of the Pediatric cGVHD Symptom Scale (PCSS).

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): NCT04710576


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

Locations
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United States, Indiana
Indiana University Health Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Mohammed Abu Zaid, MD       mabuzaid@iu.edu   
Sponsors and Collaborators
Syndax Pharmaceuticals
Investigators
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Study Director: Michael Meyers, M.D., Ph.D. Syndax Pharmaceuticals, Inc.
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Responsible Party: Syndax Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04710576    
Other Study ID Numbers: SNDX-6352-0504
First Posted: January 14, 2021    Key Record Dates
Last Update Posted: January 14, 2021
Last Verified: January 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Syndax Pharmaceuticals:
cGVHD
AGAVE-201
GVHD
graft versus host disease
graft-versus-host-disease
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases