Overview

Conditions acute myelogenous leukemia, aml
Treatments abt-199, cytarabine
Phase phase 1
Target BCL-2
Sponsor AbbVie
Collaborator Genentech, Inc.
Start date January 2015
End date October 2017
Trial size 91 participants
Trial identifier NCT02287233, 2014-002610-23, M14-387

Summary

This study consists of two phases: a Phase 1, or dose-escalation portion, that will evaluate the safety and pharmacokinetic profile of ABT-199 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); and a subsequent Phase 2 that will evaluate if the RPTD has sufficient efficacy and acceptable toxicity to warrant further development of the combination therapy.

Recruiting in the following locations…

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

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Treatment Naive Acute Myelogenous Leukemia
abt-199 GDC-0199
ABT-199 will be taken orally once daily on Days 2 through 28 of Cycle 1 and Days 1 through 28 of each subsequent cycle. This is a dose escalation study, therefore the dose of ABT-199 will change.
cytarabine
Cytarabine will be taken orally 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 ABT-199
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 ABT-199
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 ABT-199
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 ABT-199 in combination with cytarabine
time frame: Minimum first cycle of dosing (28 days)
Recommended phase two dose (RPTD) of ABT-199 in combination with cytarabine
time frame: Minimum first cycle of dosing (28 days)
Overall response rate (ORR)
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 ABT-199/cytarabine combination therapy
time frame: Measured up to 2 years after the last participant has enrolled in the study.

Eligibility Criteria

Male or female participants from 65 years up to 99 years old.

Inclusion Criteria: - Participant must have a projected life expectancy of at least 12 weeks. - Participant must have histological confirmation of Acute Myelogenous Leukemia (AML) and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to co-morbidity or other factors. - Participant must not have received prior treatment for AML with the exception of hydroxyurea, allowed through the first cycle of study treatment. Participant may have been treated for prior Myelodysplastic Syndrome. - Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. - Participant must have adequate renal and liver function. - Male participants 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. 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 received the following within 5 days prior to the initiation of study treatment: strong and moderate CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin. - 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 ≥ 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 > 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.

Additional Information

Official title A Phase 1/2 Study of ABT-199 in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia Who Are ≥ 65 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 November 2016.
Information provided to ClinicalTrials.gov by AbbVie.