Clinical Trial 19377

Cancer Type:
Interventions:AMG 592

Study Type: Treatment
Phase of Study: Phase I/II
Investigators:

  • Joseph Pidala

Overview

Study Title

A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 592 in Adult Subjects With Steroid Refractory Chronic Graft versus Host Disease

Summary

The purpose of Phase 1b is to evaluate the safety and tolerability of multiple ascending doses of AMG 592 in participants with steroid refractory cGVHD. The purpose of Phase 2 is to evaluate the efficacy of AMG 592 in participants with steroid refractory cGVHD as measured by ORR at 16 weeks according to the 2014 cGVHD NIH Consensus Criteria.

Objective

Primary: Phase 1b : To evaluate the safety and tolerability of multiple ascending doses of AMG 592 in subjects with steroid refractory cGVHD in order to estimate the MTD and establish the RP2D. Phase 2 :To evaluate the efficacy of AMG 592 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: Phase 1b :To evaluate the immunologic effects of AMG 592 including fold change from baseline in regulatory T cell (Treg), conventional T cell (Tcon), and NK cell numbers (cells/ìL) and the Treg/Tcon ratio. To characterize the PK profile following multiple ascending subcutaneous (SC) dose administrations of AMG 592. To evaluate the incidence of anti-AMG 592 antibody formation and cross-reactivity to native human interleukin-2 (IL-2). Phase 2: To evaluate the safety and tolerability of AMG 592 as measured by the occurrence of treatment-emergent adverse events. To evaluate ORR, as defined by 2014 cGVHD NIH Consensus Criteria at various timepoints in AMG 592- treated subjects. To evaluate failure free survival (FFS), defined as absence of relapse, death, or need for additional systemic immunosuppressant cGVHD therapy. To evaluate systemic steroid use. To evaluate changes in symptom burden as measured by the Lee Symptom Scale. To measure changes in quality of life as measured by Short Form Health Survey 36 version 2 (SF36v2) and Karnofsky performance status. To evaluate the PK of AMG 592. To evaluate the incidence of anti-AMG 592 antibody formation and cross reactivity to human IL-2.

Inclusion Criteria

  • Male or Female ≥ 18 years old at the time of signing the informed consent.
  • Recipient of an allogeneic HSCT.
  • Moderate to severe steroid-refractory cGVHD as defined by all following criteria: A.) Diagnosed with cGVHD per the 2014 cGVHD NIH Consensus Criteria within the past 2 years prior to screening. B.) 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. C.) 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.
  • No more than 3 previous treatments for cGVHD, excluding topical agents.
  • Stable dose of ≤ 1 mg/kg/day of systemic prednisone or equivalent for at least 2 weeks prior to first dose of AMG 592.
  • Stable dose of non-corticosteroid immunosuppressants for the 2 weeks prior to first dose of AMG 592.
  • Karnofsky performance status score ≥ 50%.
  • Adequate bone marrow function indicated by ANC > 1.00 x 10^9/L and platelets > 50 x 10^9/L without growth factors or transfusions within the 4 weeks prior to starting AMG 592.

  • Exclusion Criteria

  • Concurrently receiving treatment with calcineurin-inhibitor plus sirolimus (either agent alone is acceptable).
  • Received ibrutinib or following therapies considered investigational for treatment of cGVHD including imatinib, bortezomib, ruxolitnib, or entospletinib, within 4 weeks prior to starting AMG 592 or is currently receiving treatment in another investigational drug or device study.
  • Treatment with T-cell depleting, B-cell depleting or IL-2 signaling targeted medication (e.g., ATG, alemtuzumab, basiliximab, denileukin diftitox, IL-2, rituximab within 12 weeks prior to starting AMG 592.
  • Treatment with T regulatory cell expanding therapies (i.e., ECP, PUVA, UVB, adoptively transferred T regulatory cells) within 4 weeks prior to starting dose of AMG 592.
  • Donor lymphocyte infusion within 12 weeks prior to starting dose of AMG 592.
  • Active morphologic relapse/progression of hematologic malignancy post transplantation.
  • History of thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura.
  • Active infection requiring treatment with IV antibiotics or hospitalized for treatment of an active infection in 4 weeks prior to starting dose of AMG 592.
  • History of active tuberculosis.
  • Hepatitis B and Hepatitis C.
  • HIV-positive.
  • Phase 1b: has a positive drug or alcohol urine test at screening visit.
  • Phase 1b: is unable to avoid alcohol or tobacco consumption for the duration of the study.