Clinical Trial 18772

Cancer Type: Malignant Hematology
Interventions:AMP-514 (Durvalumab); Durvalumab; MEDI4736 (Durvalumab); azacitidine (5-azacitidine)

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

  • Jeffrey Lancet

Overview

Study Title

A Randomized Multicenter, Open-label, Phase 2 Study Evaluating the Efficacy and Safety of Azacitidine Subcutaneous in Combination With Durvalumab (MEDI4736) in Previously Untreated Subjects with Higher-Risk Myelodysplastic Syndromes (MDS) or in Elderly (>= 65 years) Acute Myeloid Leukemia (AML) Subjects Not Eligible for Hematopoietic Stem Cell Transplantation (HSCT)

Summary

The purpose of this study is to look at the safety and effectiveness of the addition of a study drug (durvalumab, also referenced as MEDI4736), to the standard of care treatment azacitidine.

Objective

Primary Objective: Efficacy: - Evaluate the efficacy of subcutaneous (sc) azacitidine in combination with durvalumab as compared with subcutaneous azacitidine alone in the defined study population. Secondary Objectives: Safety: - Assess the safety and tolerability of subcutaneous (sc) azacitidine in combination with durvalumab compared with subcutaneous azacitidine alone in the defined study population. Pharmacokinetics: - To assess the pharmacokinetics (PK) of durvalumab when given in combination with subcutaneous azacitidine in the defined study population.

Inclusion Criteria

  • FOR BOTH COHORTS:
  • Understand and voluntarily sign informed consent form (ICF) prior to any study-related assessments/procedures being conducted.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  • Females of childbearing potential may participate, providing they meet the following conditions: Have pregnancy tests according to protocol guidelines; Practice birth control according to protocol guidelines; Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of investigational product (IP); Refrain from egg cell donation while taking durvalumab and for at least 90 days after the last dose of durvalumab.
  • Males must: Practice birth control according to protocol guidelines; Refrain from semen or sperm donation while taking investigational product (IP) and for at least 90 days after the last dose of IP.
  • Understand and voluntarily sign a biomarker-specific component of the informed consent form prior to any study-related procedures conducted.
  • Willing and able to adhere to study visit schedule and other protocol requirements.
  • FOR MYELODYSPLASTIC SNYDROME (MDS) COHORT:
  • Age ≥ 18 years at the time of signing the informed consent form.
  • Central confirmation of diagnosis of previously untreated primary or secondary Myelodysplastic syndromes (MDS) as per World Health Organization (WHO) classification. Results of central pathology review are required prior to receiving the first dose of IP.
  • Central confirmation of the categorization of the MDS risk classification, as per the Revised - International prognostic scoring system (IPSS-R) Intermediate risk with >10% blasts or poor or very poor cytogenetics, or IPSS-R High or Very High risk (Results of central pathology review required prior to receiving the first dose of IP).
  • Age ≥ 65 years at time of signing informed consent form (ICF).
  • Central confirmation of diagnosis of one of following untreated AML as per WHO classification: Newly diagnosed, histologically confirmed de novo AML (bone marrow blasts ≥ 20%), or AML secondary to prior MDS, or AML secondary to exposure to potentially leukemogenic therapies or agents (e.g., radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 2 years.
  • Central confirmation of intermediate or poor risk status, based on Cytogenetics for Acute Myeloid Leukemia.

  • Exclusion Criteria

  • Prior hematopoietic stem cell transplant.
  • Eligible for hematopoietic stem cell transplant.
  • Prior exposure to azacitidine, decitabine, or investigational oral formulation of decitabine, or other oral azacitidine derivative.
  • Inaspirable bone marrow.
  • Use of any of following within 28 days prior to first dose of IP: Thrombopoiesis-stimulating agents; Any hematopoietic growth factors; Any investigational agents within 28 days or 5 half-lives (whichever is longer).
  • History of malignancies, (except MDS for AML cohorts), unless free of disease for ≥ 2 years. Conditions allowed: Basal or squamous cell carcinoma of the skin; Carcinoma in situ of the cervix or breast; Incidental histologic finding of prostate cancer.
  • Females who are pregnant; breast-feeding; intend to become pregnant during study participation.
  • Active or prior documented autoimmune or inflammatory disorders within past 3 years. Exceptions: Vitiligo or alopecia; Hypothyroidism stable on hormone replacement for ≥ 3 months prior to signing ICF; Psoriasis not requiring systemic treatment.
  • Significant active cardiac disease within previous 6 months.
  • Uncontrolled intercurrent illness that would limit compliance with protocol.
  • Known HIV or Hepatitis C infection; or evidence of active Hepatitis B Virus infection.
  • Known or suspected hypersensitivity to azacitidine, mannitol, or durvalumab, its constituents, or any other humanized monoclonal antibody.
  • Significant medical condition, laboratory abnormality, or psychiatric illness that would prevent participation.
  • Any condition including presence of laboratory abnormalities, placing participants at unacceptable risk.
  • Prior anti-CTLA-4, PD-1, or PD-L1 or other immune checkpoint mAb exposure.
  • Other investigational mAbs within 6 months.
  • Current/prior use of immunosuppressive medication within 14 days prior to first dose of IP. 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.
  • History of primary immunodeficiency.
  • Receipt of live, attenuated vaccine within 30 days prior to first dose of IP.
  • Unwilling/unable to complete participant reported outcome assessments without assistance or with minimal assistance from trained site personnel and/or caregiver.
  • CNS or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia.
  • Presence of advanced malignant hepatic tumors.
  • Laboratory abnormalities as outlined in the protocol.
  • Previous cytotoxic, cytostatic, hormonal, biological or immunological treatment for MDS (with few specific exceptions).
  • Investigational therapy within 28 days prior to the first dose of IP.
  • Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology sample.
  • Absolute WBC count ≥ 15 × 10^9/L.
  • Previous cytotoxic, cytostatic, hormonal, biological or immunological treatment (with few specific exceptions), biologic treatment for AML.
  • Investigational therapy within 28 days prior to first dose of IP.
  • Use of hydroxyurea within 2 weeks prior to screening hematology sample.
  • Prior use of targeted therapy agents.
  • Suspected/proven acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype; AML associated with t karyotype, biphenotypic acute leukemia; AML with previous hematologic disorder.
  • AML associated with inv(16), t(8;21), t(16;16), t(15;17) karyotypes or molecular evidence of such translocations if not associated with mutation defining intermediate or poor risk cytogenetics.
  • Absolute WBC count ≥ 15 × 10^9/L.