Oral Azacitidine (CC-486) Epigenetic Priming and Maintenance for Adult Acute Myeloid Leukemia (AML) Patients

NCT06180863 | Withdrawn Phase 2 DMC FDA Drug

• 2 other identifiers: 20000310651T32CA233414-01A1
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

To investigate the feasibility of delivering oral azacitidine (CC-486) as a consolidation regimen from the time of first complete remission (CR1), in patients with acute myelogenous leukemia (AML) eligible for curative intent Allogeneic Stem Cell Transplant (ASCT).

Conditions

Acute Myeloid Leukemia

Keywords

Azacitidine; Reduced Intensity Allogeneic Stem Cell Transplant; Epigenetic priming; Complete remission

Outcome Measures

Primary Outcomes (2)

• Number of patients receiving oral azacitidine (CC 486) as post-remission consolidation therapy that are able to proceed to reduced intensity conditioning (RIC) allogeneic stem cell transplant (ASCT)

  To identify the number of participants able to receive a minimum of 1 and a maximum of 3 cycles of CC-486 consolidation therapy as a bridge to Reduced Intensity Conditioning (RIC) ASCT while maintaining first complete remission- CR1.

  With each cycle (1 cycle is equivalent to 28 days) of CC-486 pre-transplant, up to 3 months

• Total number of participants that experience any adverse events with oral azacitidine (CC 486) use prior to RIC ASCT for patients with (AML) in first complete remission (CR1).

  Adverse events (AEs) occurring in the participants will be graded according to NCI CTCAE v 5.0 with each cycle of CC\_486 administered pre-transplant.

  For a maximum of 3 cycles (1 cycle is equivalent to 28 days) and or up to 3 months from the start of CC-486

Secondary Outcomes (8)

• Disease status and response to each cycle of pre-transplant CC-486 administration as per European Leukemia Net (ELN) AML 2017 guidelines

  With each cycle (1 cycle is equivalent to 28 days) of CC-486 pre-transplant

• Number of participants retaining remission post-transplant

  Up to 720 days

• Total number of maintenance cycles administered post-transplant to assess compliance

  Up to 2 years post transplant

• Overall Survival

  Up to 2 years from the time of starting CC-486

• Incidence of graft versus host disease (GVHD)

  up to 2 years post-transplant

Study Arms (1)

Oral azacitidine (CC-486)

EXPERIMENTAL

Patients on study will receive 300 mg CC-486 for 14 out of 28 days per cycle with dose modification according to the Onureg United States Prescribing Information (USPI). Up to 3 cycles of CC-486 will be allowed, and a minimum of 1 cycle is to be given prior to transplant. Multiple cycles will be allowed only if donor-specific or logistical issues prevent transplantation after the first cycle. CC-486 will be dispensed on day 1 of each treatment cycle and only 1 cycle equivalent is to be dispensed at the beginning of each cycle. Post-transplant maintenance with CC-486 can be started 60 days (range 60-120 days) after hematopoietic progenitor cell infusion which should allow time for count and graft recovery after post-transplant cyclophosphamide (PTCY). The CC-486 maximum preferred pre-emptive dose post-ASCT is 200 mg daily, which will be administered for 14 of 28 days per cycle (max 12 cycles).

Drug: oral azacitidine (CC-486)

Interventions

oral azacitidine (CC-486) DRUG

Oral azacitidine is indicated for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.

Also known as: Onureg

Oral azacitidine (CC-486)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have acute myeloid leukemia (AML) of Intermediate or High risk (IR or HR per National Comprehensive Cancer \[NCCN\] Criteria) in first CR/CRi achieved with 1 or 2 cycles of cytarabine based induction therapy. Zero to 1 cycle of cytarabine based consolidation will be allowed post CR1. OR Nucleophosmin 1(NPM 1) positive AML ((in the absence of FMS like tyrosine kinase 3 (FLT3) mutation)) at diagnosis with positive NPM1 PCR (measurable residual disease \[MRD\]) after at least 1 cycle of cytarabine-based consolidation chemotherapy OR Secondary AML(s-AML) based on prior MDS or CMML in first CR/CRi. OR Therapy-related AML (t-AML) with IR or HR criteria
• Vyxeos induction (up to 2 cycles to reach CR1) and 0-1 cycle of vyxeos consolidation will be allowed.
• Eligible to receive RIC or Non myeloablative (NMA) transplant preparative regimen with post-transplant cyclophosphamide (PTCY) based GVHD prophylaxis, at the discretion of study investigator.
• Patients must have a calculated creatinine clearance (Cockcroft-Gault equation) \> 50 mL/min.
• Patients must have a related or unrelated donor. Sibling donor must be a 6/6 match for human leukocyte antigen A (HLA-A) and HLA-B at intermediate or higher resolution, and DRB1 at high resolution using DNA-based typing; must be willing to donate peripheral blood stem cells; and meet institutional criteria for donation. Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C, and -DRB1 at high resolution using DNA-based typing; must be willing to donate peripheral blood mononuclear cells (PBSCs); and be medically eligible to donate stem cells according to National Marrow Donor Program (NMDP) criteria.
• Patients must be willing to have peripheral blood stem cells as the graft source.
• Patients must have adequate hepatic function (i.e., serum bilirubin level ≤1.5 times the upper limit of normal \[ULN\], aspartate aminotransferase (AST), and alanine aminotransferase (ALT), defined as ≤2.5 × ULN). Higher levels of bilirubin are acceptable in the setting of Gilbert's disease with no other provable etiologies for altered liver function.
• Patients must have a Karnofsky performance score (KPS) ≥70 and/or ECOG score of ≤2.
• Patients must have recovered from the toxicities of the most recent induction/consolidation chemotherapy. Recovery is defined by the absence of persistent treatment-related AE of grade 2 or above. Persistent cytopenia meeting the criteria for a CRi and controlled infections on antimicrobials is acceptable.
• Women of childbearing potential must be surgically sterile or agree to practice abstinence or utilize acceptable contraception (intrauterine, injectable, transdermal, or combination oral contraceptive) during the period while receiving study medication and for at least 6 months after the last dose of CC-486. Males who are sexually active with women of childbearing potential must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) from time of screening through at least 3 months after the last dose of CC-486.
• Patients must be able to understand the study procedures, agree to participate in the study program, and voluntarily provide written Informed Consent
• Patients must have no active COVID-19 infection symptoms at the time of enrollment. Those who tested positive in the past or made recovery post infection must be symptom free for at least 2 weeks prior to enrollment.
• Patients must be able to start transplant preparative regimens no later than 35 days from Day 1 of the most recent CC-486 cycle administration.

You may not qualify if:

• Patients may not have Acute Promyelocytic leukemia
• Patients may not have favorable risk AML per National Comprehensive Cancer Network (NCCN) guidelines ((Core binding factor leukemias, CCAAT/enhancer-binding protein-alpha (CEBPA) double mutant, AML with concomitant mutations in Nucleophosmin 1 (NPM1) and FLT3))
• Patients must not have received more than two rounds of chemotherapy to achieve first CR or CRi
• Patients may not have had exposure to hypomethylating agent (HMA) to treat the leukemia or prior hematologic malignancy ((i.e., myelodysplastic syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML)) in the 6 months prior to study enrollment.
• Patients may not be, per investigator evaluation, currently in need of other leukemia-directed therapy such as FLT3- or Isocitrate dehydrogenase (IDH)-directed therapy.
• Patients may not have myeloproliferative neoplasm progressing to AML (except for CMML)
• With related and unrelated donors, patients may not have high pre-transplant donor-specific HLA antibodies warranting need for desensitization or other maneuvers per discretion of the treating physician.
• Patients may not have previously received radiation to maximum tolerable limits to any critical normal organ.
• Patients with prior Central Nervous System (CNS) involvement or extramedullary disease will be excluded.
• Patients may not have previously received allogeneic Hematopoietic Cell Transplantation (HCT).
• Patients may not have clinically significant cardiac disease ((New York Heart Association (NYHA) Class III or IV)); clinically significant arrhythmia i.e., ventricular tachycardia, ventricular fibrillation, or "Torsade de Pointes." Significant active cardiac disease within the previous 6 months including NYHA class 4 Congestive Heart Failure (CHF), Unstable angina, and Myocardial Infarction
• Patients may not have positive test results for human immunodeficiency virus (HIV) or hepatitis B (HBV) or C (HCV). Subjects with a past positive HBV test results due to previous exposure but who have cleared the virus or are vaccinated against hepatitis B, as evidenced by negative hepatitis B surface antigen (HbsAg), negative HBV viral load, and positive antibody to the HbsAg (anti-HBs) are not excluded. Subjects who have positive hepatitis test results with adequate organ function as defined in the protocol are not excluded.
• Patients may not have uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
• Patients may not be currently receiving any other investigational agents for relapse reduction.
• Patients seeking umbilical cord blood transplants, or bone marrow graft, or mismatched unrelated donor (MMUD) with \<9/10 HLA match are ineligible.

Sponsors & Collaborators

• Yale University: lead
• Bristol-Myers Squibb: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Yale Comprehensive Cancer Center

New Haven, Connecticut, 06520, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Pathologic Complete Response

Interventions

Azacitidine; cc-486

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Progression; Disease Attributes; 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

• Lohith Gowda, MD

  Yale University

  PRINCIPAL INVESTIGATOR

• Marcos de Lima, MD

  Ohio State University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A single-arm non-randomized pilot study

Study Record Dates

• First Submitted: November 17, 2023
• First Posted: December 26, 2023
• Study Start: November 1, 2023
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): April 1, 2029
• Last Updated: December 26, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)