Steroid Refractory Chronic Graft versus Host Disease
Conditions
Interventions
Product Name: Efavaleukin Alfa
Product Code: AMG592
Pharmaceutical Form: Solution for injection
Current Sponsor code: AMG 592
Other descriptive name: RECOMBINANT FACTOR FC FUSION PROTEIN
Concentrati
Sponsors
Amgen, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subject or legally acceptable representative 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 hematopoietic stem cell transplant (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 (Jagasia, 2015; Appendix 8) within the past 2 years prior to screening. • 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) within the 12 months prior to screening. • Moderate to severe cGVHD (in accordance with 2014 cGVHD NIH Consensus Criteria [Jagasia, 2015; Appendix 9]) 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. Subjects must have adequate hepatic function: • total bilirubin 50 mL/min/1.73 m2 using the MDRD formula. Subjects must have adequate cardiac function defined as:: no history within 6 months prior to screening of myocardial infarction, unstable angina, New York Heart
Exclusion criteria
Exclusion criteria: Subject is concurrently receiving treatment with calcineurin-inhibitor plus sirolimus 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 the following therapies considered investigational for treament of cGVHD: imatinib, ibrutinib, bortezomib, ruxolitnib, entospletinib, within 4 weeks prior to enrollment or is currently receiving treatment in another investigational drug or device study. Subject has received treatment with T-cell depleting, B-cell depleting or IL-2 signaling targeted medication Subject has received treatment with T regulatory cell expanding therapies (ie ECP, 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 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 efavaleukin alfa. Subject has known history of active tuberculosis. Subject has a 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 • subjects with a positive PPD and a history of Bacillus Calmette-Guérin vaccination are allowed with a negative Quantiferon test and negative chest x ray • subjects with a positive PPD test (without a history of Bacillus Calmette-Guérin vaccination) or subjects with a positive or indeterminate Quantiferon test are allowed if they have ALL of the following at screening: o no symptoms per tuberculosis worksheet provided by Amgen o document history of a completed course of adequate prophylaxis (completed treatment for latent tuberculosis [TB] per local standard of care prior to the start of investigational product o no known exposure to a case of active tuberculosis after most recent prophylaxis o negative chest X-ray 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 hep
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • (Phase 1b) To evaluate the safety and tolerability of multiple ascending doses of efavaleukin alfa in subjects with steroid refractory cGVHD in order to estimate the MTD and establish the RP2D • (Phase 2) To evaluate the efficacy of efavaleukin alfa in subjects with steroid refractory cGVHD as measured by the best overall response rate (ORR) during the study according to the 2014 cGVHD National Institutes of Health (NIH) Consensus Criteria;Secondary Objective: • (Phase 1b)To evaluate the immunologic effects of efavaleukin alfa including fold change from baseline in regulatory T cell (Treg), conventional T cell (Tcon), and natural killer (NK) cell numbers (cells/µL) and the Treg/Tcon ratio . • (Phase 1b) To characterize the pharmacokinetic (PK) profile following multiple ascending subcutaneous dose administrations of efavaleukin alfa. • (Phase 1b) To evaluate the incidence of anti efavaleukin alfa antibody formation and cross reactivity to native human IL 2. • (Phase 2) To evaluate the safety and tolerability of efavaleukin alfa as measured by the occurrence of treatment emergent adverse events • (Phase 2) To evaluate ORR, as defined by cGVHD NIH Consensus Criteria at various timepoints in efavaleukin alfa-treated subjects • (Phase 2) To evaluate failure free survival (FFS), defined as absence of relapse, death, or need for additional systemic immunosuppressant cGVHD therapy • (Phase 2)To evaluate changes in steroid use over time ;Primary end point(s): Phase 1b - Incidence of dose limiting toxicities (DLTs) at first 4 weeks - Incidence of dose limiting toxicities (DLTs) at first 4 weeks - Incidence of all treatment related and treatment emergent adverse events and serious adverse events Phase 2 - Best ORR defined as the proportion of subjects achieving a Complete Response (CR) or Partial Response (PR) at any visit during the study according to the 2014 cGVHD NIH Consensus Criteria;Timepoint(s) of evaluation of this end point: Throughout study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1b - Fold changes from baseline of Treg absolute cell counts (cells/µL), after efavaleukin alfa administration. - Fold changes from baseline of Tcon and NK absolute cell counts (cells/µL), after efavaleukin alfa administration. - Efavaleukin alfa serum concentration and PK parameters including, but not limited to, maximum observed concentration (Cmax), the time of maximum observed concentration (Tmax), and the area under the concentration-time curve over a dosing interval (AUCtau) after the first and week 4 doses - Subject incidence of anti efavaleukin alfa binding antibodies and cross reactivity to IL 2 - Subject incidence of anti efavaleukin alfa and anti IL 2 neutralizing antibodies Phase 2 - Treatment-emergent and treatment-related adverse events and serious adverse events throughout the study - ORR at 8, 16, 24, 36, and 52 weeks - Time to first response - Duration of response - FFS at 52 weeks - Steroid use over time as compared to baseline - Changes in Lee Symptom Score over time - Changes in SF36v over time - Changes in Karnofsky performance status over time - Efavaleukin alfa plasma concentration and PK parameters including, but not limited to, maximum observed concentration (Cmax), the time of maximum observed concentration (Tmax), and AUCtau after the first and last doses and AUC from time 0 to the time of the last quantifiable sample (AUClast). - Subject incidence of anti efavaleukin alfa binding antobidies and cross-reactivity to IL 2 - Subject incidence of anti efavaleukin alfa and anti IL 2 neutralizing antibodies;Timepoint(s) of evaluation of this end point: Throughout study | — |
Countries
Belgium, France, United States
Contacts
Public ContactMedical Information
Amgen NV
Outcome results
None listed