Safety and Efficacy of Efavaleukin Alfa in Subjects With Steroid Refractory Chronic Graft Versus Host Disease

Inclusion Criteria Subjects are eligible to be included in the study only if all of the following criteria apply:

• Subject has provided informed consent prior to initiation of any study specific activities/procedures.
• Subject is an adult ≥ 18 years old at the time of signing the informed consent.
• Subject is a recipient of an allogeneic HSCT.
• Subject has moderate to severe steroid-refractory cGVHD as defined by all of the following criteria:
• Diagnosed with cGVHD per the 2014 cGVHD NIH Consensus Criteria
• Steroid refractory cGVHD, defined as having persistent signs and symptoms of cGVHD despite ≥ 4 weeks of prednisone (or equivalent) dosed at ≥ 0.25 mg/kg/day (or ≥ 0.5 mg/kg every other day).
• Moderate to severe cGVHD (in accordance with 2014 cGVHD NIH Consensus Criteria at screening with involvement of at least one of the following organs at the screening and baseline visits: skin, mouth, eyes, gastrointestinal (GI) tract, liver, lungs, and joint and fascia.
• Subject has received no more than 3 previous treatments for cGVHD, excluding topical agents.
• Treatment with corticosteroids is considered a treatment for cGVHD and should be included in determining the number of previous treatments.
• Lines of therapy consisting of concurrent medications or interventions (eg, tacrolimus and corticosteroids; ECP and corticosteroids) count as 2 separate treatments.
• If cGVHD has worsened during a taper of immunosuppressive agents, restoring the agents to therapeutic level is permitted and does not count as an additional treatment.
• Subject may be receiving corticosteroid therapy provided that the dose is ≤ 1 mg/kg/day of systemic prednisone or equivalent and has been stable for at least 2 weeks prior to first dose of efavaleukin alfa.
• Subject may be receiving other non-corticosteroid immunosuppressive therapies provided that the immunosuppressant dose is stable for at least 2 weeks prior to first dose of efavaleukin alfa. Adjustments to dose of calcineurin inhibitor or sirolimus are allowed only to maintain drug levels within therapeutic range.
• Subject has a Karnofsky performance status score ≥ 50%.
• Subject has an estimated life expectancy of > 3 months.
• Subject must have adequate hepatic function, defined below, unless the treating physician documents the abnormal LFTs as consistent with hepatic cGVHD:
• total bilirubin < 2.0 mg/dL (34.2 mol/L) [elevated values due to Gilbert's Syndrome or of non- hepatic origin are excluded].
• aspartate transaminase [AST; SGOT]/Alanine transaminase [ALT; SGPT] ≤ 2x upper limit of normal (ULN).
• If LFT abnormalities are deemed consistent with hepatic cGVHD by the investigator, a liver biopsy will not be mandated.
• Subject must have adequate pulmonary function defined as: forced expiratory volume in 1 second (FEV1) ≥ 50% or hemoglobin-adjusted diffusion capacity for carbon monoxide (DLCO Hb) ≥ 40% of predicted, unless pulmonary dysfunction is deemed to be due to cGVHD.
• Subject must have adequate renal function defined as: a calculated glomerular filtration rate of > 50 mL/min/1.73 m2 using the MDRD formula.
• Subject must have adequate cardiac function defined as: no history within 6 months prior to screening of myocardial infarction, unstable angina, New York Heart Associate Class III or IV heart failure, or stroke. No findings on the screening electrocardiogram (ECG) that in the opinion of the investigator requires further cardiovascular evaluation, including severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
• Subject must have adequate bone marrow function indicated by ANC > 1.00 x 109/L and platelets > 50 x 109/L without growth factors or transfusions within the 4 weeks prior to starting efavaleukin alfa.

Exclusion Criteria Subjects are excluded from the study if any of the following criteria apply.

• Subject is concurrently receiving treatment with calcineurin-inhibitor plus sirolimus (either agent alone is acceptable).
• Subject has received ibrutinib, imatinib, bortezomib, entospletinib, ruxolitinib or other JAK inhibitor, or treatment with any investigational drug or device within 4 weeks prior to starting efavaleukin alfa.
• Subject has received treatment with T-cell depleting, B-cell depleting or IL-2 signaling targeted medication (eg, ATG, alemtuzumab, basiliximab, denileukin diftitox, IL-2, rituximab) within 12 weeks prior to starting efavaleukin alfa.
• Subject has received treatment with T regulatory cell expanding therapies (ie PUVA, UVB, adoptively transferred T regulatory cells) within 4 weeks prior to starting efavaleukin alfa.
• Subject has received a donor lymphocyte infusion within 12 weeks prior to starting dose of efavaleukin alfa.
• Subject with active morphologic relapse/progression of hematologic malignancy post transplantation. Persistent CLL early after transplantation that subsequently entered remission will not be excluded.
• Subject has a history of malignancy, other than the indication for hematopoietic cell transplantation, with the following exceptions:
• adequately treated nonmelanoma skin cancers without current evidence of disease
• adequately treated cervical carcinoma in situ without current evidence of disease
• adequately treated breast ductal cancer in situ without current evidence of disease
• any malignancy treated with curative intent and with no evidence of active disease present for more than 5 years prior to screening and felt to be at low risk for recurrence by the treating physician
• Subject has a history of thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura.
• Subject has an active infection requiring treatment with IV antibiotics or has been hospitalized for treatment of an active infection in the 4 weeks prior to starting dose of efavaleukin alfa.
• Subject has known history of active tuberculosis.
• Positive test for tuberculosis during screening defined as either:
• positive purified derivative (PPD) (≥ 5 mm of induration at 48 to 72 hours after test is placed) OR
• positive Quantiferon or T-SPOT test o a positive PPD and a history of Bacillus Calmette-Guérin vaccination are allowed with a negative Quantiferon or T-SPOT test and negative chest x-ray
• a positive PPD test (without a history of Bacillus Calmette-Guérin vaccination) or a positive

Quantiferon or T-SPOT test are allowed if they have ALL of the following at screening:

• no symptoms per tuberculosis worksheet provided by Amgen
• document history of a completed course of adequate prophylaxis (completed treatment for latent tuberculosis per local standard of care prior to the start of investigational product
• no known exposure to a case of active tuberculosis after most recent prophylaxis
• negative chest X-ray o an indeterminate Quantiferon or T-SPOT test is allowed if they have ALL of the following at screening:
• no symptoms per tuberculosis worksheet provided by Amgen
• no known recent exposure to a case of active tuberculosis
• no history of a positive Quantiferon or T-SPOT test without documented history of a completed course of adequate prophylaxis (completed treatment for latent tuberculosis per local standard of care prior to the start of investigational product)
• negative chest X-ray
• are deemed to be at low risk for tuberculosis exposure in the opinion of the principle investigator
• Subject is positive for hepatitis B surface antigen, hepatitis B core antibody (confirmed by hepatitis B deoxyribonucleic acid [DNA] polymerase chain reaction [PCR] test) or detectable hepatitis C virus ribonucleic acid (RNA) by PCR (screening is generally done by hepatitis C antibody [HepCAb], followed by hepatitis C virus RNA by PCR if HepCAb is positive). Subjects with a history of hepatitis B vaccination without history of hepatitis B are allowed.
• Subject has positive test results for Human Immunodeficiency Virus (HIV) or known to be HIV-positive.
• Phase 1b subject has a drug or alcohol urine test positive for illicit drugs at the screening visit. Prescription medications detected by the drug test are allowed if they are being taken under the direction of a physician or if permitted for recreational purposes as per country regulations..
• Phase 1b subject cannot be a current smoker, nor have used any nicotine or tobacco containing products within the last 6 months prior to screening. These types of products include but are not limited to: snuff, chewing tobacco, cigars, cigarettes, pipes, or nicotine patches.
• Phase 1b subject is unable to avoid alcohol during the 4-week DLT evaluation period or tobacco consumption for the duration of the study.
• Subject has known sensitivity to efavaleukin alfa or its excipients to be administered during dosing.
• Subject likely to be unable to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments [COAs]) to the best of the subject and investigator's knowledge.
• History or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
• Females who are pregnant or breastfeeding, or planning to become pregnant or breastfeed during treatment and for an additional 6 weeks after the last dose of efavaleukin alfa.
• Females of child-bearing potential with a positive pregnancy test (assessed by a serum pregnancy test at screening and a urine pregnancy test at baseline).
• Females of childbearing potential who are unwilling to use 1 highly effective method of contraception during treatment and for an additional 6 weeks after receiving the last dose of efavaleukin alfa.
• Subject has previously entered the study