Safety and Clinical Activity Study of Combination Azacitidine and Avelumab in Patients With Acute Myeloid Leukemia (AML) and Minimal Residual Disease (MRD)

NCT03699384 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: 18-012
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase I / II study. The purposes of this study are to: 1) find out what effects, good and/or bad, the combination of the experimental drug avelumab and the drug azacitidine has on people with AML and MRD, and 2) test if the two drugs, avelumab and azacitidine, are effective in getting rid of AML MRD when the drugs are given together in combination.

Conditions

Acute Myeloid Leukemia (AML); Minimal Residual Disease

Keywords

Azacitidine; Avelumab; 18-012

Outcome Measures

Primary Outcomes (2)

• Number of patients with dose limiting toxicities as assessed by CTCAE v4.0

  Up to 6 pre-allo SCT patients who are evaluable for DLT will be enrolled, with the first 3 patients enrolled in a sequential manner with a 1-week interval between the start of dosing for each patient. If the regimen appears tolerable in the first 3 patients (i.e., ≤ 1 of the first 3 patients enrolled experiences a DLT), then the next 3 patients will be enrolled concurrently. If more than 1 out of 6 in the pre-alloSCT group has a DLT, the trial will stop accrual. The combination will be considered safe in pre-allo SCT patients if one or no patient has a DLT out of the six patients. If the combination is safe in pre-alloSCT patients, additional pre-alloSCT patients will begin enrollment for the expanded phase II portion of the study, and accrual of 6 post-alloSCT patients for separate safety evaluation will begin. Toxicity will be graded on a scale of 1 to 5 as described by the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

  1 year

• sustained MRD negativity (Phase II)

  This is defined as the time from the first dose of azacitidine to a patient"s confirmed MRD negativity on the second bone marrow.

  1 year

Study Arms (1)

Azacitidine and Avelumab

EXPERIMENTAL

All enrolled patients will receive 1 cycle of AZA followed by cycles of combination AZA+Avelumab.

Drug: Azacitidine; Drug: Avelumab

Interventions

Azacitidine DRUG

AZA 75 mg/m\^2 SC or IV D 1-7 28 day cycle x 1

Azacitidine and Avelumab

Avelumab DRUG

Avelumab 10mg/kg IV D1, D15, 28d cycle Until progression or MRD If MRD-, tx x 1 yr or go to allo SCT

Azacitidine and Avelumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must be ≥18 years of age.
• Subjects must have a history of AML as defined by WHO criteria. AML patients with any cytogenetic abnormalities are eligible except for patients with t (15;17) (acute promyelocytic leukemia). AML patients who have never undergone allogeneic stem cell transplant must have adverse-risk AML by ELN criteria77 to be eligible. Patients with a history of therapy related AML, myeloid sarcoma, or patients whose AML evolved from an antecedent MDS or MPN are also eligible. Patients with any molecular mutations are eligible.
• Subjects must have received therapy for AML and have a bone marrow biopsy within 28 days prior to registration that demonstrates a morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) as defined by European Leukemia Net (ELN) criteria. Patients with prior myeloid sarcoma must have no residual evidence of extramedullary leukemia.
• Subjects may have received any prior therapy for AML including cytotoxic agents, hypomethylating agents, or other therapeutics to achieve morphologic CR or CRi.
• Subjects must have MRD in a bone marrow aspirate within 28 days prior to registration from the same bone marrow sample which demonstrates morphologic CR. MRD is identified by multiparameter flow cytometry as a cell population showing deviation from normal antigen-expression patterns seen in specific cell lineages at specific stages of maturation. Any level of residual flow cytometric disease is considered MRD positive.
• Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling, and urine sampling during the study.
• Subjects or their legal representatives must be able to understand and sign an informed consent.
• Subjects must have ECOG PS of 0 to 2. 9. Subjects must have adequate hematological function defined by absolute neutrophil count (ANC) ≥ 1.0 × 10\^9/L, platelet count ≥ 50 × 10\^9/L, and hemoglobin ≥ 9 g/dL (may have been transfused)
• Subjects must have adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN
• Subjects must have adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula
• Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer. (Subjects with residual Grade 1-2 toxicity, for example Grade 1-2 peripheral neuropathy or residual alopecia, are allowed with approval of the principal investigator.)
• Negative serum pregnancy test at screening for women of childbearing potential.
• Subjects must use highly effective contraception for both male and female subjects if the risk of conception exists. (Note: The effects of the trial drug on the developing human fetus are unknown; thus, women of childbearing potential and men able to father a child must agree to use 2 highly effective contraception, defined as methods with a failure rate of less than 1% per year. Highly effective contraception is required at least 28 days prior, throughout and for at least 60 days after avelumab treatment.)

You may not qualify if:

• Patients with prior allogeneic stem cell transplantation (SCT) who have had:
• allo-SCT performed \<3 months prior to enrollment; or
• immunosuppressive treatment for acute or chronic graft-versus-host disease (GVHD) within 3 months prior to enrollment (with the exception of those patients who required ≤15 mg/day oral prednisone or equivalent); or
• acute Grade 3 or Grade 4 GVHD at any time in the past (as defined by the modified Seattle Glucksberg Criteria); or
• prior chronic GVHD (as defined by the NIH Consensus Development Project), persisting for \>6 months, which required systemic immunosuppression (with the exception of those patients who required ≤15 mg/day oral prednisone or equivalent); or
• a donor lymphocyte infusion (DLI) within 6 months prior to enrollment; or
• is currently on treatment with GVHD prophylaxis medications tacrolimus, sirolimus, or cyclosporine
• Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
• Significant acute or chronic infections including, among others:
• Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV antibody tested positive)
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
• Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
• Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day
• Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• Pfizer: collaborator

Study Sites (1)

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Neoplasm, Residual

Interventions

Azacitidine; avelumab

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Aaron Goldberg, MD, PhD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is an open label, phase I/II prospective clinical trial.

Study Record Dates

• First Submitted: October 4, 2018
• First Posted: October 9, 2018
• Study Start: October 3, 2018
• Primary Completion: February 18, 2019
• Study Completion: February 18, 2019
• Last Updated: February 20, 2019

Record last verified: 2019-02

Locations

US (1)