Chronic Graft-versus-host-disease
Conditions
Keywords
cGVHD, AGAVE-201, GVHD, graft versus host disease, graft-versus-host-disease
Brief summary
This is a Phase 2 study to evaluate the efficacy, safety, and tolerability of axatilimab at 3 different dose levels in participants with recurrent or refractory active chronic graft versus host disease (cGVHD) who have received at least 2 prior lines of systemic therapy.
Detailed description
AGAVE-201 is a Phase 2, open-label, randomized, multicenter study to evaluate the efficacy, safety, and tolerability of axatilimab in participants with recurrent or refractory active cGVHD after failure of at least 2 prior lines of systemic therapy due to progression of disease, intolerability, or toxicity. Participants will be randomized to receive 1 of 3 different axatilimab treatment regimens in 28-day treatment cycles for up to 2 years.
Interventions
DRUGAxatilimab
Axatilimab 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.
Sponsors
Syndax Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants must be 2 years of age or older, at the time of signing the informed consent. 2. Participants who are allogeneic hematopoietic stem cell transplantation (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. 3. Participants 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. * Participants 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. 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. 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 milliliter/minute based on the Cockcroft-Gault formula in adult participants and Schwartz formula in pediatric participants. 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 participant 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 mammalian target of repamycin (mTOR) inhibitors (sirolimus or everolimus) 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 protocol. A parent/guardian should provide consent for pediatric participants unable to provide consent themselves; in addition, where applicable pediatric participants should sign their own assent form.
Exclusion criteria
Participants 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 participant, in the opinion of the Investigator, unsuitable for the study. 6. Participants 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 (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). 9. Female participant who is pregnant or breastfeeding. 10. Previous exposure to CSF1-R targeted therapies. 11. Taking agents for treatment of cGVHD other than corticosteroids or either a CNI or mTOR inhibitor is prohibited. 12. For approved or commonly used agents, other than corticosteroids, CNI and mTOR inhibitor, 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. Participants should not be participating in any other interventional study. Pediatric participants are encouraged to also participate in the ongoing developmental studies of the Pediatric cGVHD Symptom Scale (PCSS).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) in the First 6 Cycles as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease (cGVHD) | First 6 cycles (up to Cycle 7 Day 1; each cycle = 4 weeks) | The ORR was defined as the percentage of participants with objective response (complete response \[CR\] or partial response \[PR\]). CR was defined as resolution of all manifestations in each organ or site, and PR was defined as improvement in at least 1 organ or site without progression in any other organ or site. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORR on Study as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD | Up to 2 years | — |
| Number of Participants With a Clinically Significant Improvement in Normalized Score on the Modified Lee Symptom Scale | Up to 2 years | — |
| Duration of Response | Up to 2 years | Duration of response is defined as the time from initial partial response or complete response until documented progression of cGVHD, start of new therapy, or death for any reason. |
| Sustained Response Rate | Up to 2 years | Sustained response rate is defined as the number of participants with objective response lasting for at least 20 weeks (140 days) from the time of initial response. Responses will be assessed based on the 2014 NIH Consensus Development Project on Clinical Trials in cGVHD. |
| Organ-specific Response Rate | Up to 2 years | Organ-specific response is defined as the number of participants 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 gastrointestinal \[GI\], lower GI, liver, lungs and joints and fascia). |
| Joints and Fascia Response Rate Based on Refined NIH Response Algorithm for cGVHD | Up to 2 years | — |
| Percent Reductions in Average Daily Doses (or Equivalent) of Corticosteroid | Up to 2 years | — |
| Number of Participants Who Discontinue Corticosteroid Use | Up to 2 years | — |
| Percent Reductions in Average Daily Doses (or Equivalent) of Calcineurin Inhibitors (CNI) | Up to 2 years | — |
| Number of Participants Who Discontinue CNIs | Up to 2 years | — |
| Change From Baseline in Circulating Monocyte Number and Phenotype (CD14/16) | Baseline, up to 2 years | — |
| Number of Participants With Anti-Drug Antibody | Up to 2 years | — |
| Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Measurable Concentration (AUC0-t) | Approximately 12 months | — |
| Number of Participants With Treatment-emergent Adverse Events | Up to 2 years | — |
| Change From Baseline in Bone Turnover Markers | Baseline, up to 2 years | — |
| Change From Baseline in Bone Density | Baseline, up to 2 years | — |
| Change From Baseline in Colony Stimulating Factor 1 (CSF-1) and Interleukin 34 (IL-34) Levels | Baseline, up to 2 years | — |
Countries
Australia, Belgium, Canada, France, Germany, Greece, Israel, Italy, Poland, Portugal, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
CONTACTSyndax Pharmaceuticals
STUDY_DIRECTOREllen Hooper, M.D.
Syndax Pharmaceuticals
Participant flow
Recruitment details
Data collection for the primary outcome measure is complete for all participants and new participants are only being recruited for secondary outcome measures. That is, the primary outcome measure reported will not be revised and additional primary outcome measures will not be added.
Pre-assignment details
The primary analysis results are reported. The final results will be posted after completion of the study.
Participants by arm
| Arm | Count |
|---|---|
| Axatilimab 0.3 mg/kg Q2W Participants received axatilimab 0.3 mg/kg IV Q2W (Days 1 and 15 of each 4-week cycle) for up to 2 years. | 80 |
| Axatilimab 1 mg/kg Q2W Participants received axatilimab 1 mg/kg IV Q2W (Days 1 and 15 of each 4-week cycle) for up to 2 years. | 81 |
| Axatilimab 3 mg/kg Q4W Participants received axatilimab 3 mg/kg IV Q4W (Day 1 of each 4-week cycle) for up to 2 years. | 80 |
| Total | 241 |
Baseline characteristics
| Characteristic | Axatilimab 0.3 mg/kg Q2W | Axatilimab 1 mg/kg Q2W | Axatilimab 3 mg/kg Q4W | Total |
|---|---|---|---|---|
| Age, Continuous | 49.4 years STANDARD_DEVIATION 16.88 | 54.0 years STANDARD_DEVIATION 12.65 | 50.8 years STANDARD_DEVIATION 16.02 | 51.4 years STANDARD_DEVIATION 15.34 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 9 Participants | 5 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 73 Participants | 69 Participants | 73 Participants | 215 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 4 Participants | 8 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 4 Participants | 8 Participants | 18 Participants |
| Race (NIH/OMB) White | 68 Participants | 70 Participants | 62 Participants | 200 Participants |
| Sex: Female, Male Female | 33 Participants | 30 Participants | 27 Participants | 90 Participants |
| Sex: Female, Male Male | 47 Participants | 51 Participants | 53 Participants | 151 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 80 | 7 / 81 | 12 / 80 |
| other Total, other adverse events | 74 / 79 | 78 / 81 | 78 / 79 |
| serious Total, serious adverse events | 30 / 79 | 33 / 81 | 38 / 79 |
Outcome results
Primary
Overall Response Rate (ORR) in the First 6 Cycles as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease (cGVHD)
The ORR was defined as the percentage of participants with objective response (complete response \[CR\] or partial response \[PR\]). CR was defined as resolution of all manifestations in each organ or site, and PR was defined as improvement in at least 1 organ or site without progression in any other organ or site.
Time frame: First 6 cycles (up to Cycle 7 Day 1; each cycle = 4 weeks)
Population: The ITT analysis set for each dose level included all participants randomized to the dose level.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Axatilimab 0.3 mg/kg Q2W | Overall Response Rate (ORR) in the First 6 Cycles as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease (cGVHD) | 73.8 percentage of participants |
| Axatilimab 1 mg/kg Q2W | Overall Response Rate (ORR) in the First 6 Cycles as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease (cGVHD) | 66.7 percentage of participants |
| Axatilimab 3 mg/kg Q4W | Overall Response Rate (ORR) in the First 6 Cycles as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease (cGVHD) | 50.0 percentage of participants |
Secondary
Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Measurable Concentration (AUC0-t)
Time frame: Approximately 12 months
Secondary
Change From Baseline in Bone Density
Time frame: Baseline, up to 2 years
Secondary
Change From Baseline in Bone Turnover Markers
Time frame: Baseline, up to 2 years
Secondary
Change From Baseline in Circulating Monocyte Number and Phenotype (CD14/16)
Time frame: Baseline, up to 2 years
Secondary
Change From Baseline in Colony Stimulating Factor 1 (CSF-1) and Interleukin 34 (IL-34) Levels
Time frame: Baseline, up to 2 years
Secondary
Duration of Response
Duration of response is defined as the time from initial partial response or complete response until documented progression of cGVHD, start of new therapy, or death for any reason.
Time frame: Up to 2 years
Secondary
Joints and Fascia Response Rate Based on Refined NIH Response Algorithm for cGVHD
Time frame: Up to 2 years
Secondary
Number of Participants Who Discontinue CNIs
Time frame: Up to 2 years
Secondary
Number of Participants Who Discontinue Corticosteroid Use
Time frame: Up to 2 years
Secondary
Number of Participants With a Clinically Significant Improvement in Normalized Score on the Modified Lee Symptom Scale
Time frame: Up to 2 years
Secondary
Number of Participants With Anti-Drug Antibody
Time frame: Up to 2 years
Secondary
Number of Participants With Treatment-emergent Adverse Events
Time frame: Up to 2 years
Secondary
Organ-specific Response Rate
Organ-specific response is defined as the number of participants 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 gastrointestinal \[GI\], lower GI, liver, lungs and joints and fascia).
Time frame: Up to 2 years
Secondary
ORR on Study as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD
Time frame: Up to 2 years
Secondary
Percent Reductions in Average Daily Doses (or Equivalent) of Calcineurin Inhibitors (CNI)
Time frame: Up to 2 years
Secondary
Percent Reductions in Average Daily Doses (or Equivalent) of Corticosteroid
Time frame: Up to 2 years
Secondary
Sustained Response Rate
Sustained response rate is defined as the number of participants with objective response lasting for at least 20 weeks (140 days) from the time of initial response. Responses will be assessed based on the 2014 NIH Consensus Development Project on Clinical Trials in cGVHD.
Time frame: Up to 2 years