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 OR HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)
The goal of this clinical research study is to learn if adding durvalumab to azacitidine can help to control AML and/or MDS. The safety of this drug combination will also be studied.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: Azacitidine,MEDI4736
Treatment Location: Both at MD Anderson & Other Sites
Sponsor: Celgene International II Sàrl
Primary Objectives The primary objective of the study is to evaluate the efficacy of subcutaneous azacitidine in combination with durvalumab as compared with subcutaneous azacitidine alone in the defined study population. Secondary Objectives The secondary objectives are to: Assess the safety and tolerability of subcutaneous azacitidine in combination with durvalumab as compared with subcutaneous azacitidine alone in the defined study population Assess the pharmacokinetics (PK) of durvalumab when given in combination with subcutaneous azacitidine in the defined study population. Exploratory Objectives The exploratory objectives are: Evaluate the effect of subcutaneous azacitidine in combination with durvalumab on health-related quality-of-life (HRQoL) and healthcare resource utilization (HRU) as compared to subcutaneous azacitidine alone, Describe the immunogenicity of durvalumab in combination with subcutaneous azacitidine in the defined study population, Establish PK/pharmacodynamic (PD) relationship, explore pharmacodynamic, mechanistic, and predictive biomarkers of durvalumab when given in combination with subcutaneous azacitidine in the defined study population.
IRB Review and Approval Date: 12/14/2016
Recruitment Status: Open
Projected Accrual: 182
1) For both cohorts:
2) Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
3) Have an ECOG performance status of 0, 1, or 2
4) Female subjects of childbearing potential may participate, providing they meet the following conditions: a. Have 2 negative pregnancy tests as verified by the investigator prior to starting any investigational product (IP) therapy: serum pregnancy test at screening and negative serum or urine pregnancy test (investigator’s discretion) within 72 hours prior to starting treatment with IP (Cycle 1, Day 1). They must agree to ongoing pregnancy testing during the course of the study (before beginning each subsequent cycle of treatment), and after the last dose of any IP. This applies even if the subject practices complete abstinence from heterosexual contact.
5) Continued from #4: b. Agree to practice true abstinence (which must be reviewed on a monthly basis and source documented) or agree to use at least two effective methods of contraception (eg, oral, injectable, or implantable hormonal contraceptive; tubal ligation; intrauterine device; barrier contraceptive with spermicide; true abstinence; or vasectomized partner) from 28 days prior to starting durvalumab or azacitidine, and must agree to continue using such precautions while taking durvalumab or azacitidine (including dose interruptions) and for 90 days after the last dose of durvalumab or azacitidine.
6) Continued from #5: c. Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of IP. d. Refrain from egg cell donation while taking durvalumab and for at least 90 days after the last dose of durvalumab.
7) Male subject must: a. Either practice true abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use male condom plus spermicide during sexual contact with a pregnant female or a female of childbearing potential (even if he has undergone a successful vasectomy) from starting dose of IP (Cycle 1 Day 1), including dose interruptions through 90 days after receipt of the last dose of durvalumab or azacitidine. b. Refrain from semen or sperm donation while taking IP and for at least 90 days after the last dose of IP.
8) Understand and voluntarily sign a biomarker-specific component of the informed consent form prior to any study-related procedures conducted.
9) Willing and able to adhere to the study visit schedule and other protocol requirements.
10) MDS Cohort:
11) Age >/= 18 years at the time of signing the informed consent form.
12) Central confirmation of diagnosis of previously untreated primary or secondary MDS as per WHO classification. Results of central pathology review are required prior to receiving the first dose of IP.
13) Central confirmation of the categorization of the MDS risk classification, as per the IPSSR 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).
14) AML Cohort:
15) Age >/= 65 years at the time of signing the informed consent form (ICF).
16) Central confirmation of diagnosis of one of the 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 (eg, radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 2 years.
17) Central confirmation of intermediate or poor risk status, based on Cytogenetics for Acute Myeloid Leukemia.
1) For both cohorts:
2) Prior hematopoietic stem cell transplant.
3) Considered eligible for hematopoietic stem cell transplant (allogeneic or autologous) at the time of signing the ICF.
4) Prior exposure to azacitidine, decitabine or prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative.
5) Inaspirable bone marrow.
6) Use of any of the following within 28 days prior to the first dose of IP: Thrombopoiesis-stimulating agents (eg, romiplostim, eltrombopag, Interleukin-11); Any hematopoietic growth factors (ESAs and other RBC hematopoietic growth factors (eg, Interleukin-3); Any investigational agents within 28 days or 5 half-lives (whichever is longer) of initiating study treatment
7) Prior history of malignancies, (except MDS for AML subjects), unless the subject has been free of the disease for = 2 years. However, subjects with the following history/concurrent conditions are 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 using the tumor, nodes, metastasis [TNM] clinical staging system).
8) Pregnant or breast-feeding females or females who intend to become pregnant during study participation.
9) Subject has active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease [exclude only if active within the last 6 months prior to signing the ICF], or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener’s syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis; hypophysitis, uveitis; etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: Subjects with vitiligo or alopecia; Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement for >/= 3 months prior to signing the ICF; or Subjects with psoriasis not requiring systemic treatment
10) Significant active cardiac disease within the previous 6 months prior to signing the ICF, including: New York Heart Association (NYHA) Class III or IV congestive heart failure (see Appendix F); Unstable angina or angina requiring surgical or medical intervention; and/or Significant cardiac arrhythmia; Myocardial infarction
11) Uncontrolled intercurrent illness including, but not limited to, ongoing or active systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment), uncontrolled hypertension, cardiac arrhythmia, pneumonitis, interstitial lung disease, active peptic ulcer disease or gastritis that would limit compliance with study requirement.
12) Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection.
13) Known or suspected hypersensitivity to azacitidine, mannitol, or durvalumab, its constituents, or to any other humanized monoclonal antibody.
14) Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
15) Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
16) Prior anti-CTLA-4, PD-1, or PD-L1 or other immune checkpoint mAb exposure.
17) Other investigational mAbs within 6 months prior to first dose of IP.
18) Current or prior use of immunosuppressive medication within 14 days prior to the first dose of IP. The following are exceptions to this criterion: Intranasal, inhaled, topical, or local steroid injections (eg, intra-articular injection); Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent; Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication)
19) History of primary immunodeficiency.
20) Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP (NOTE: Subjects, if enrolled, should not receive live vaccine during the study and for 30 days after the last dose of durvalumab).
21) Unwilling or unable to complete subject reported outcome assessments without assistance or with minimal assistance from trained site personnel and/or caregiver.
22) Subjects who have had clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia.
23) Presence of advanced malignant hepatic tumors.
24) Any of the following laboratory abnormalities: Serum aspartate aminotransferase (AST/SGOT) or alanine aminotransferase (ALT/SGPT) > 2.5 × upper limit of normal (ULN); Serum total bilirubin > 1.5 × ULN. Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis). Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive Coombs’ test or over 50% of indirect bilirubin; Serum creatinine > 2.5 × ULN.
25) MDS Cohort:
26) Any previous cytotoxic, cytostatic, hormonal, biological or immunological treatment for MDS (ESA with or without granulocyte colony stimulating factor (G-CSF) are allowed under certain conditions, see exclusion criterion # 5).
27) Any investigational therapy within 28 days prior to the first dose of IP.
28) Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology sample.
29) Absolute WBC count >/=15 × 10^9/L.
30) AML Cohort:
31) Previous cytotoxic, cytostatic, hormonal, biological or immunological treatment (ESA with or without G-CSF and iron chelating therapy and hydroxyurea are allowed under certain conditions, see exclusion criterion #5) or biologic treatment for AML.
32) Any investigational therapy within 28 days prior to the first dose of IP.
33) Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology sample.
34) Prior use of targeted therapy agents (eg, FLT3 inhibitors, other kinase inhibitors).
35) Suspected or proven acute promyelocytic leukemia (FAB M3) based on morphology, immunophenotype, molecular assay, or karyotype; AML associated with t(9;22) karyotype, biphenotypic acute leukemia or AML with previous hematologic disorder such as chronic myelogenous leukemia or myeloproliferative neoplasms.
36) Acute myeloid leukemia 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.
37) Absolute WBC count >/= 15 × 10^9/L (NOTE: Hydroxyurea is not allowed to attain a WBC count </= 15 x 10^9/L).
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
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