A Study to Evaluate Axatilimab Versus Best Available Therapy in Participants With Chronic Graft Versus Host Disease After at Least 2 Prior Lines of Systemic Therapy

• INCA034176 (Drug), also known as Axatilimab: IV infusion
• Best Available Therapy (BAT) (Drug), also known as BAT could include:, • Calcineurin inhibitor (cyclosporine or tacrolimus), • Extracorporeal photopheresis (ECP), • Mycophenolate mofetil (MMF), • A mammalian target of rapamycin (mTOR) inhibitor (everolimus or sirolimus), • Rituximab, • Pentostatin, • Proteasome inhibitors, • Imatinib, • Ibrutinib: Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.

Primary outcomes

• Objective Response (OR) at 6 months [6 months]: Defined for each treatment group as complete response (CR) or partial response (PR) at 6 months (Cycle 7 Day 1, 28-day cycles) in the absence of new systemic therapy for cGVHD. Responses defined by the 2014 NIH consensus criteria.

Secondary outcomes

• Failure-free survival (FFS) [Up to 5 years]: Defined as the time from the date of randomization to the date of addition or initiation of another systemic therapy for cGVHD, relapse of underlying disease, or death due to any cause.
• Proportion of participants with a ≥ 7-point improvement in modified Lee Symptom Scale (mLSS) total score [Up to 5 years]
• Overall Response at 12 months [12 months]: Defined as CR or PR at 12 months in the absence of new systemic therapy for cGVHD.
• Best Overall Response (BOR) [Up to 5 years]: Defined as the best response of CR or PR in the first 6 months (up to and including Cycle 7 Day 1), and at any timepoint up to the initiation of new therapy for cGVHD.
• DOR (in responders only) [Up to 5 years]: Defined as the time from the date of first response (PR or CR) to the date of progression of cGVHD from baseline scoring, start of new systemic treatment for cGVHD, or death from any cause, whichever comes first. An additional measure of response durability will consider DOR as the time from the date of first response to the date of new systemic therapy for cGVHD or death from any cause, whichever occurs first.
• Organ-specific response [Up to 5 years]: Organ-specific response as defined in the protocol.
• Overall Survival (OS) [Up to 5 years]: Defined as the time from the date of randomization to the date of death due to any cause.
• Nonrelapse mortality (NRM) [Up to 5 years]: Defined as the time from the date of randomization to the date of death not preceded by relapse of primary hematologic disease.
• Time to primary hematologic disease relapse [Up to 5 years]: Defined as the time from the date of randomization to the date of relapse.
• Percent reduction in daily corticosteroid dose at 6 months [6 months]
• Proportion of participants who tapered off all corticosteroids at 6 months [6 months]
• Number of participants with Treatment-emergent Adverse Events (TEAEs) [Up to 5 years and 30 days]: Defined as adverse events reported for the first time or worsening of a pre-existing event after the first dose of study treatment.

Sex: All, ages: 12 Years to any

Inclusion Criteria:

* Age ≥ 12 years at the time of signing the ICF.
* Active, moderate to severe cGVHD, requiring systemic immune suppression.
* Participants with refractory or recurrent cGVHD who have received at least 2 lines of systemic therapy, including corticosteroids and ruxolitinib.
* Concomitant use of systemic corticosteroids is allowed. Participants on systemic corticosteroids must be on a stable dose of corticosteroids for at least 2 weeks prior to C1D1. Topical and inhaled corticosteroid agents are allowed.
* Participants must accept to be treated with one of the following BAT options on C1D1: CNI (cyclosporine or tacrolimus), ECP, MMF, an mTOR inhibitor (everolimus or sirolimus), rituximab, pentostatin, proteasome inhibitors, imatinib, or ibrutinib.
* History of allo-HCT from any donor HLA type (related or unrelated donor with any degree of HLA matching) using any graft source (bone marrow, peripheral blood stem cells, or cord blood). Recipients of myeloablative, nonmyeloablative, or reduced-intensity conditioning are eligible.

Exclusion Criteria:

* Receipt of more than 1 prior allo-HCT. Prior autologous HCT is allowed.
* Evidence of relapse of hematologic disease or treatment for relapse after the allo-SCT was performed, including DLI for the treatment of molecular relapse. Note: Participants who have received a scheduled DLI as part of their transplant procedure and not for management of malignancy relapse are eligible.
* Systemic treatment with CNIs or mTOR inhibitors started within 2 weeks prior to C1D1.
* Severe renal impairment, that is, estimated creatinine clearance < 30 mL/min measured or calculated by Cockcroft-Gault equation in adults and Schwartz formula in pediatric participants, or end-stage renal disease on dialysis.
* Impaired liver function, defined as total bilirubin > 1.5 × ULN and/or ALT and AST > 3 × ULN in participants with no evidence of liver cGVHD.
* History of acute or chronic pancreatitis.
* Active, symptomatic myositis.
* Pregnant or breastfeeding.

Other protocol-defined Inclusion/Exclusion Criteria may apply.

30 more sites not listed.

• Incyte Medical Monitor, Study director, Incyte Corporation