Clinical Trial 18599

Cancer Type: Malignant Hematology
Interventions:AMP-514 (Durvalumab); Azacitidine (Oral); CC-486 (Azacitidine (Oral)); Durvalumab; MEDI4736 (Durvalumab)

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

  • Rami Komrokji

Overview

Study Title

A Phase 2, International, Multicenter,Randomized, Open-Label, Parallel Group Study to Evaluate the Efficacy and Safety of CC-486 (Oral Azacitidine) Alone and in Combination with Durvalumab (Medi4736) in Subjects with Myelodysplastic Syndromes who Fail to Achieve an Objective Response to Treatment with Azacitidine for Injection or Decitabine

Summary

The purpose of this study is to evaluate the safety and efficacy of CC-486 and Durvalumab in participants with Myelodysplastic Syndromes who failed to achieve an objective response post iHMA treatment.

Objective

Primary Objective: The primary objective of this study is to investigate the efficacy of CC-486 as monotherapy and in combination with anti-PD-L1 monoclonal antibody, durvalumab (MEDI4736), in subjects with MDS that did not respond to prior treatment with an injectable hypomethylating agent (HMA azacitidine for injection or decitabine), or were unable to tolerate treatment with an injectable HMA. Secondary Objectives: The secondary objectives of the study are to: - Assess the safety and tolerability of CC-486 alone and in combination with durvalumab, as treatment for MDS. - Describe the clinical relevance of objective hematologic and/or biologic responses associated with treatment with CC-486 alone and in combination with durvalumab. - Evaluate the impact (if any) of durvalumab on the pharmacokinetics of CC-486 and CC-486 on durvalumab in subjects with MDS. Exploratory Objectives: - Determine the immunogenicity of durvalumab when given in combination with CC-486 in subjects with MDS. - Evaluate molecular and cellular markers in bone marrow and/or peripheral blood that may impact azacitidine efficacy (resistance to azacitidine for injection and/or CC-486 resistance or sensitivity). - Establish PK/pharmacodynamic relationship, explore pharmacodynamic mechanistic, and predictive biomarkers of CC-486 as a single agent and when given in combination with durvalumab in subjects with MDS. - Evaluate additional measures of efficacy of monotherapy and combination therapy in subjects with MDS.

Inclusion Criteria

  • Male or female, ≥ 18 years of age at the time of signing the informed consent document
  • Documented diagnosis of MDS (MYELODYSPLASTIC SYNDROMES), classified according to FAB (FRENCH-AMERICAN BRITISH) classification criteria.
  • Adequate course of treatment with an injectable hypomethylating agent (azacitidine for injection or decitabine) as the last therapeutic intervention for MDS (MYELODYSPLASTIC SYNDROMES) prior to beginning screening for this study.
  • Documented disease progression or stable disease as best response to treatment (or attempted treatment) with azacitidine for injection or decitabine. Those achieving an objective response to treatment regimen with an injectable Hypomethylating agent (HMA) are excluded from participation in this study. Definitions of disease progression are modified from IWG (INTERNATIONAL WORKING GROUP) 2006 criteria.
  • Have the last dose of the prior treatment regimen (injectable HMA (HYPOMETHYLATING AGENT) - azacitidine for injection or decitabine) not more than 16 weeks prior to screening for this study (date of informed consent signature).
  • No less than 3 weeks between the last dose of the prior treatment regimen (injectable HMA (HYPOMETHYLATING AGENT) - azacitidine for injection or decitabine) and the planned date of first dose of IP (INVESTIGATIONAL PRODUCT).
  • An ECOG (EASTERN COOPERATIVE ONCOLOGY GROUP) performance status of 0, 1, or 2.
  • Females of childbearing potential (FCBP) may participate, providing they adhere to all of the pregnancy test, contraception or abstinence guidelines outlined in the study protocol documentation. Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of IP. Refrain from egg cell donation while taking durvalumab and for at least 90 days after the last dose of durvalumab.
  • Male participants must adhere to all of the pregnancy test, contraception or abstinence guidelines outlined in the study protocol documentation. Refrain from semen or sperm donation while taking IP and for at least 90 days after the last dose of IP.
  • Understand and voluntarily sign an informed consent document prior to any study-related assessments or procedures conducted.
  • Be able to adhere to the study visit schedule and other protocol requirements.
  • Understand and voluntarily sign a biomarker-specific component of the informed consent document prior to any study-related procedures conducted.
  • Additional criteria may apply.

  • Exclusion Criteria

  • Rapidly-progressing MDS (MYELODYSPLASTIC SYNDROMES).
  • Acute myelogenous leukemia (AML (ACUTE MYELOID LEUKEMIA) - FAB (FRENCH-AMERICAN-BRITISH) classification: ≥ 30% blasts in bone marrow).
  • Prior allogeneic stem cell transplant.
  • Prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative.
  • Prior or ongoing response to treatment with azacitidine for injection or decitabine, at any time, includes relapsed disease.
  • Ongoing medically significant adverse events from previous treatment, regardless of the time period.
  • Use of any of the following within 28 days prior to the first dose of IP (INVESTIGATIONAL PRODUCT): Thrombopoiesis-stimulating agents ([TSAs]; e.g., Romiplostim, Eltrombopag, Interleukin-11); ESAs (Erythropoiesis stimulating agent) and other RBC (Red blood cell) hematopoietic growth factors (e.g., interleukin-3); Hhydroxyurea.
  • Concurrent use of corticosteroids unless on a stable or decreasing dose for ≥ 1 week prior to enrollment for medical conditions other than MDS.
  • History of inflammatory bowel disease, celiac disease, prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the IP and/or predispose the participant to an increased risk of gastrointestinal toxicity.
  • Prior history of malignancies, other than MDS, unless have been free of the disease for ≥ 3 years. Conditions allowed: Basal or squamous cell carcinoma of the skin; Carcinoma in situ of the cervix; Carcinoma in situ of the breast; Incidental histologic finding of prostate cancer (T1a or T1b).
  • Significant active cardiac disease within the previous 6 months.
  • Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
  • Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection.
  • Any of the following laboratory abnormalities: Serum AST/SGOT or ALT/SGPT > 2.5 x ULN; Serum total bilirubin > 1.5 ULN (some exceptions may apply); Serum creatinine > 2.5 ULN; Absolute WBC count >/= 20 x 10^9/L.
  • Known or suspected hypersensitivity to azacitidine, mannitol, or durvalumab, its constituents, or to any other humanized monoclonal antibody.
  • Any condition including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study.
  • Any condition that confounds the ability to interpret data from the study, including known or suspected conditions other than MDS, associated with anemia.
  • Have received any prior MAb (monoclonal antibodies) against CTLA-4 (cytotoxic T lymphocyte-associated antigen), PD-1, or PD-L1 or have received other investigational MAbs (monoclonalantibodies) within 6 months.
  • Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, or CNS leukemia.
  • Current or prior use of immunosuppressive medication within 14 days prior to the first dose of durvalumab. Exclusion exceptions:Intranasal, inhaled, topical or local steroid injections; Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent; Steroids as premedication for hypersensitivity reactions.
  • Active or prior documented autoimmune or inflammatory disorders within 3 years prior to the start of treatment. Some exceptions may apply.
  • History of primary immunodeficiency.
  • Active myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML).
  • Additional criteria may apply.