Overview

Conditions acute myelogenous leukemia, aml
Treatments venetoclax, cytarabine
Phase phase 1
Target BCL-2
Sponsor AbbVie
Collaborator Genentech, Inc.
Start date January 2015
End date September 2018
Trial size 91 participants
Trial identifier NCT02287233, 2014-002610-23, M14-387

Summary

This study consists of three portions: The first portion- Phase 1, or dose-escalation portion, that will evaluate the safety and pharmacokinetic profile of venetoclax in combination with low-dose cytarabine (LDC), define the maximum tolerated dose (MTD), and generate data to support a recommended Phase 2 dose (RPTD) in treatment-naïve subjects with Acute Myelogenous Leukemia (AML). Second portion, initial Phase 2 that will evaluate if the RPTD has sufficient efficacy and acceptable toxicity to warrant further development of the combination therapy. Subsequently, Phase 2 Cohort C, will evaluate the overall response rate (ORR) for subjects allowed additional supportive medications (strong CYP3A inhibitors) if medically indicated.

Recruiting in the following locations…

United States Kansas and New York
Other countries Australia, Germany, and Italy

Study Design

Intervention model single group assignment
Primary purpose treatment
Masking no masking
Arm
(Experimental)
Treatment Naive Acute Myelogenous Leukemia
venetoclax GDC-0199
Venetoclax will be taken orally once daily on Days 1 through 28 of each cycle. This is a dose escalation study, therefore the dose of venetoclax will change.
cytarabine
Cytarabine will be administered subcutaneously on Days 1 to 10 of each 28-day cycle.

Primary Outcomes

Measure
Number of participants with adverse events
time frame: From participant's first dose until 30 days after participant's last dose of study drug; up to 2 years following last participant first dose
Maximum observed plasma concentration (Cmax) of venetoclax
time frame: Blood samples will be taken at 0 (pre-dose), 2, 4, 6, 8 and 24 hours post-dose on Days 10 and 18.
Time to maximum observed plasma concentration (Tmax) of venetoclax
time frame: Blood samples will be taken at 0 (pre-dose), 2, 4, 6 ,8 and 24 hours post-dose on Days 10 and 18.
Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC24) of venetoclax
time frame: Blood samples will be taken at 0 (pre-dose), 2, 4, 6, 8, and 24 hours post-dose on Days 10 and 18.
Maximum tolerated dose (MTD) of venetoclax in combination with cytarabine
time frame: Minimum first cycle of dosing (28 days)
Recommended phase two dose (RPTD) of venetoclax in combination with cytarabine
time frame: Minimum first cycle of dosing (28 days)
Overall Response Rate- In Cohort C, overall response rate (ORR) will be evaluated for subjects allowed additional supportive meds (e.g strong CYP3A inhibitor) if medically indicated.
time frame: Measured up to 2 years after the last participant has enrolled in the study.
Time to progression (TTP)
time frame: Measured up to 2 years after the last participant has enrolled in the study.
Maximum observed plasma concentration (Cmax) of cytarabine
time frame: Blood samples will be taken 0 (pre-dose); 15 and 30 minutes; and 1, 3, and 6 hours after subcutaneous injection on Days 1 and 10.
Time to maximum observed plasma concentration (Tmax) of cytarabine.
time frame: Blood samples will be taken 0 (pre-dose); 15 and 30 minutes; and 1, 3, and 6 hours after subcutaneous injection on Days 1 and 10.
Area under the plasma concentration-time curve from time 0 to 6 hours post-dose (AUC6) of cytarabine.
time frame: Blood samples will be taken 0 (pre-dose); 15 and 30 minutes; and 1, 3, and 6 hours after subcutaneous injection on Days 1 and 10.

Secondary Outcomes

Measure
Duration of response (DOR)
time frame: Measured up to 2 years after the last participant has enrolled in the study.
Progression-free survival
time frame: Measured up to 2 years after the last participant has enrolled in the study.
Overall survival (OS)
time frame: Measured up to 2 years after the last participant has enrolled in the study.
The percentage of participants with minimal residual disease (MRD) negativity
time frame: Measured up to 2 years after the last participant has enrolled in the study.
The number of participants who undergo transplant
time frame: Measured up to 2 years after the last participant has enrolled in the study.
Leukemia response rates to venetoclax/cytarabine combination therapy
time frame: Measured up to 2 years after the last participant has enrolled in the study.

Eligibility Criteria

All participants from 60 years up to 99 years old.

Inclusion Criteria: - Subject must be greater than or equal to 65 years of age in Phase 1 and 2. Subjects enrolled in Cohort C must be either: - greater than or equal to 75 years of age; OR - greater than or equal to 60 to 74 years will be eligible if the subjects has at least one of the following co-morbidities, which make the subject unfit for intensive chemotherapy: - ECOG Performance Status of 2 - 3; - Cardiac history of CHF requiring treatment or Ejection Fraction less than or equal to 50% or chronic stable angina; - DLCO less than or equal to 65% or FEV1 less than or equal to 65%; - Creatinine clearance greater than or equal to 30 mL/min to less than 45 ml/min (calculated by Cockcroft-Gault formula) - Moderate hepatic impairment with total bilirubin greater than 1.5 to less than or equal to 3.0 × ULN - Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the study medical monitor before study enrollment - Subject must have a projected life expectancy of at least 12 weeks. - Subject must have histological confirmation of AML and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to co-morbidity or other factors. - Subject must have received no prior treatment for AML with the exception of hydroxyurea, allowed through the first cycle of study treatment. Note: Subject may have been treated for prior Myelodysplastic Syndrome. - Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status; - of 0 to 2 for subjects greater than equal to 75 years of age - of 0 to 3 for subjects greater than equal to 60 to 74 years of age, if 0 - 1 another co-morbidity is required to make subject eligible. - Subject must have adequate renal function as demonstrated by a creatinine clearance greater than or equal to 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula. Note: Investigators should consider measuring a 24-hour creatinine clearance for subjects who are morbidly obese, have fluctuating renal function, or who in the investigator's clinical judgment may yield a more accurate clearance when measured than when calculated. - Subject must have adequate liver function as demonstrated by: - aspartate aminotransferase (AST) less than or equal to 2.5 × upper limit of normal (ULN)* - alanine aminotransferase (ALT) less than or equal to 2.5 × ULN* - bilirubin less than or equal to 1.5 × ULN for all subjects age 75 and older* Subjects who are less than 75 years of age must have a bilirubin of less than 3.0 × ULN * Unless considered due to leukemic organ involvement. Note: Subjects with Gilbert's Syndrome may have a bilirubin greater than 1.5 × ULN per discussion between the investigator and AbbVie medical monitor. - Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 180 days after the last dose of study drug. - Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures. - If female, subject must be either: - Postmenopausal defined as no menses for 12 or more months without an alternative medical cause OR - Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). Exclusion Criteria: - Participant has received treatment with cytarabine for a pre-existing myeloid disorder. - Participant has acute promyelocytic leukemia (French-American-British Class M3 AML). - Participant has known active central nervous system (CNS) involvement with AML. - Participant has tested positive for human immunodeficiency virus (HIV). - Participant has received the following within 7 days prior to the initiation of study treatment: strong and moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort. - Participant has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment. - Participant has a cardiovascular disability status of New York Heart Association Class greater than 2. - Participant has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study. - Participant has chronic respiratory disease that requires continuous oxygen use. - Participant has a malabsorption syndrome or other condition that precludes enteral route of administration. - Participant exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to: uncontrolled systemic infection requiring IV therapy (viral, bacterial or fungal). - Participant 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; or previous malignancy confined and surgically resected (or treated with other modalities) with curative intent. - Participant has a white blood cell count greater than 25 × 10^9/L. Hydroxyurea is permitted to meet this criterion. - Participant is a candidate for a bone marrow or stem cell transplant within 12 weeks after study enrollment. - Subject has a history of myeloproliferative neoplasm (MPN) including polycythemia vera, myelofibrosis, essential thrombocythemia, or chronic myelogenous leukemia.

Additional Information

Official title A Phase 1/2 Study of Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia Who Are ≥ 60 Years of Age and Who Are Not Eligible for Standard Anthracycline-Based Induction Therapy
Trial information was received from ClinicalTrials.gov and was last updated in February 2017.
Information provided to ClinicalTrials.gov by AbbVie.