Venetoclax and Azacitidine for Non-Elderly Adult Patients With Acute Myeloid Leukemia

• ClinicalTrials.gov Identifier: NCT03573024
• Recruitment Status: Recruiting
• First Posted: June 28, 2018
• Last Update Posted: November 21, 2019
• Sponsor: University of Colorado, Denver
• Information provided by (Responsible Party): University of Colorado, Denver

Tracking Information

• First Submitted Date: June 19, 2018
• First Posted Date: June 28, 2018
• Last Update Posted Date: November 21, 2019
• Actual Study Start Date: November 14, 2018
• Estimated Primary Completion Date: June 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 19, 2018)

Response Rate, measured by the European Leukemia Net definition: (CRMRD-+CR+CRi+MLFS) [ Time Frame: Study start date to study end date, or death, whichever comes first, up to 4 years ]

The (CRMRD-+CR+CRi+MLFS) shows non-inferiority of venetoclax with azacitidine when compared with historical controls who received induction chemotherapy.

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT03573024 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: June 19, 2018)

• Incidence of Minimal Residual Disease (MRD) Negative Responses [ Time Frame: Study start date to study end date, or death, whichever comes first, up to 4 years ]
  Number of new cases of Complete Remission, Complete Remission with Incomplete Blood Count Recovery, or Morphologic Leukemia Free State. This will be measure by multi-dimensional flow cytometry with a sensitivity to 0.1%.
• Remission Duration [ Time Frame: Study start date to study end date, or death, whichever comes first, up to 4 years ]
  Remission Duration will be defined as the length of time a patient does not display leukemic blasts or extramedullary disease
• One Year Event Free Survival [ Time Frame: Study start date to study end date, or death, whichever comes first, up to 4 years ]
  Determined using Kaplan Meier survival analysis methods with 95% confidence intervals.
• Overall Survival [ Time Frame: Study start date to study end date, or death, whichever comes first, up to 4 years ]
  Overall Survival will be defined as the time from administration of the initial doses until death from any cause. Determined using Kaplan Meier survival analysis methods with 95% confidence intervals.
• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Study start date to study end date, or death, whichever comes first, up to 4 years ]
  Safety and tolerability analysis of azacitidine and venetoclax will be summarized by dose and severity as assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 and relationship to study drug.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Venetoclax and Azacitidine for Non-Elderly Adult Patients With Acute Myeloid Leukemia
• Official Title: Safety and Efficacy of Venetoclax and Azacitidine for Newly Diagnosed Non-Elderly Adult Patients (Aged 18-59) With Acute Myeloid Leukemia
• Brief Summary: This study aims to treat non-elderly adult patients, who were previously untreated for acute myeloid leukemia, using venetoclax and azacitidine.
• Detailed Description: This is a phase II study that seeks to treat patients ages 18-59 who have acute myeloid leukemia but have never been treated before. It will use venetoclax and azacitidine, and patients can receive up to four cycles of this medication. Depending on the level of recovery, patients will either be forced to come off study or have the option to continue the medication, receive maintenance therapy, or pursue an allogeneic stem cell transplant.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Acute Myeloid Leukemia

Intervention

• Drug: Azacitidine
  On day 1 of cycle 1, azacitidine 75 mg/m2 SC or IV will be given, and will continue for 7 days.
• Drug: Venetoclax
  Starting on day 1 of cycle 1, venetoclax will be initiated. It will be dose escalated to a target dose of 600 mg in the following manner: 100 mg on day 2, 200 mg on day 3, 400 mg on day 4 and 600 mg on day 5. The patient then continues to take the 600mg dose for the remainder of the 28 day cycle. Each dose of venetoclax will be self-administered with approximately 240 mL of water within 30 minutes after the completion of a meal, preferably breakfast. The dose should be administered at the same time each day. On days the subject is given azacitidine, venetoclax must be given first.

Study Arms

Experimental: Azacitidine and Venetoclax

Azacitidine will be given intravenously for 7 days. Venetoclax will be given orally. The patient will start out with 100mg and progress to 600mg. Once 600mg is reached, the patient will stay at this dose until the 28 day cycle is finished.

Interventions:

• Drug: Azacitidine
• Drug: Venetoclax

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 19, 2019): 36
• Original Estimated Enrollment (submitted: June 19, 2018): 30
• Estimated Study Completion Date: June 2023
• Estimated Primary Completion Date: June 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

A subject will be eligible for study participation if he/she meets the following criteria within 28 days prior to the first day of therapy (bone marrow biopsy can be performed 28 days prior to the first day of therapy). Historical records are permitted per Investigator discretion.

1. Subject must have confirmation of non-APL and AML by WHO criteria45
2. Subject must have received no prior treatment for AML
3. Age ≥18 years, ≤59 years
4. Without clinical signs of active central nervous system disease
5. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of ≤2
6. Subject must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula

7. Subject must have adequate liver function as demonstrated by:

   • aspartate aminotransferase (AST) ≤ 3.0 × ULN*
   • alanine aminotransferase (ALT) ≤ 3.0 × ULN*
   • bilirubin ≤ 3.0 × ULN, unless due to Gilbert's syndrome* * Unless considered due to leukemic organ involvement
8. Non-sterile male subjects must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 90 days after the last dose of study drug. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug.
9. Female subjects who are pre-menopausal and have not had a hysterectomy or oophorectomy must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting therapy; 2) throughout the entire duration of treatment; 3) during dose interruptions; and 4) for at least 90 days after discontinuation of therapy (last dose of study drug).
10. Subject must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any research directed screening procedures.
11. Subject must have adverse risk disease as defined by the European LeukemiaNet46 (Appendix B) 5.3.2 Exclusion Criteria

A subject will not be eligible for study participation if he/she meets any of the following criteria:

1. Subject has received disease modifying treatment for myelodysplastic syndrome (MDS) or AML. ATRA given for clinical suspicion of APL will not be exclusionary and no washout will be required in this scenario.
2. Subject is known to be positive for HIV. HIV testing is not required.
3. Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Hepatitis B or C testing is not required and subjects with serologic evidence of prior vaccination to HBV (i.e., HBs Ag-, anti-HBs+ and anti-HBc-) may participate
4. Subject has received within 7 days prior to the first dose of study drug:steroid therapy for anti-neoplastic intent; strong and moderate CYP3A inhibitors; strong and moderate CYP3A inducers.
5. Subject is informed that consumption of the following fruits is prohibited 3 days prior to the initiation of study treatment and throughout participation: grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit.

6. Subject has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to:

   • New York Heart Association heart failure > class 2
   • Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia
7. Subject has a malabsorption syndrome or other condition that precludes enteral route of administration
8. Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal)

9. Subject has a history of other malignancies prior to study entry, with the exception of:

   • Adequately treated in situ carcinoma of the breast or cervix uteri
   • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
   • Prostate cancer with no plans for therapy of any kind
   • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
10. Subject has a white blood cell count >25 × 10^9/L or absolute blast count of >50 10^9/L. Hydroxyurea and leukapheresis are permitted, if clinically indicated.
11. Patients willing to receive intensive induction chemotherapy
12. Pregnant and breastfeeding females.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 59 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Emily Berrens; 720-848-8031; emily.berrens@cuanschutz.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03573024
• Other Study ID Numbers: 18-0709.cc
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: University of Colorado, Denver
• Study Sponsor: University of Colorado, Denver
• Collaborators: Not Provided

Investigators

• Principal Investigator: Daniel Pollyea, MD; University of Colorado, Denver

• PRS Account: University of Colorado, Denver
• Verification Date: November 2019