The purpose of this study is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of TAK-659 and venetoclax when administered in combination in participants with non-Hodgkin lymphoma (NHL) relapsed and/or refractory after at least 1 prior line of therapy and to evaluate safety and tolerability of TAK-659 and venetoclax when administered in combination.
The drugs being tested in this study are called TAK-659 and venetoclax. TAK-659 in combination with venetoclax is being tested to treat people who have advanced NHL after at least 1 prior line of therapy. This study will look at the safety data, pharmacokinetic (PK) data and any early anti-tumor activity observed. The study will enroll approximately 53 participants. • TAK-659 and venetoclax doses will be escalated according to a Bayesian logistic regression model (BLRM) with overdose control escalation schema. TAK-659 60 mg + Venetoclax 400 mg is the starting dose. Participants could also receive 40 mg, 60 mg, 80 mg or 100 mg TAK-659 during dose escalation and 200 mg, 400 mg, 800 mg, or 1200 mg of venetoclax. Following dose escalation the safety and tolerability of the MTD/RP2D of the TAK-659+venetoclax combination will be further explored in two dose-safety expansion cohorts, Cohort A in participants with DLBCL and Cohort B in participants with FL. All participants will be asked to take one tablet of TAK-659 on an empty stomach at least 1 hour before and no sooner than 2 hours after eating food and/or drinking fluids other than water. Venetoclax will be taken with a meal and water 2 hours after TAK-659 has been taken. No food or drink (except water) are allowed between TAK-659 and venetoclax. TAK-659 and venetoclax should be taken at the same time each day throughout the study. This multi-center trial will be conducted in the United States, Canada and Europe. The overall time to participate in this study is 20 months or until disease progression, unacceptable toxicities, or withdrawal from study by participant. Participants will make multiple visits to the clinic, and will be followed for 28 days (+10) days after the last dose of TAK-659 or venetoclax or the start of subsequent alternative anticancer therapy to permit the detection of any delayed treatment-related AEs. For participants enrolled in either the dose escalation or safety expansion phases, the maximum duration of treatment will be 12 months unless, in the opinion of the investigator and with the agreement of the sponsor, the participant would derive benefit from continued therapy beyond 12 months. Participants enrolled in the safety expansion part who stop treatment for any reason other than disease progression will continue PFS follow-up every 2 months after the last dose of study drug for up to 6 months or until disease progression or the start of alternative therapy, whichever occurs first.
TAK-659 tablets.
Venetoclax tablets.
University of Alabama at Birmingham
Birmingham, Alabama, United States
Emory University
Atlanta, Georgia, United States
Number of Participants with a Dose Limiting Toxicity (DLT)
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), Version 5.0 DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications and that occur within the first cycle.
Time frame: Baseline up to 5 weeks
Percentage of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs), Grade 3 or Higher Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation
AE Grades will be evaluated as per NCI CTCAE, version 5.0.
Time frame: Baseline up to 13 months
Cmax: Maximum Observed Plasma Concentration for TAK-659 and Venetoclax
Time frame: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length is equal to [=] 35 days)
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 and Venetoclax
Time frame: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)
AUCτ: Area Under the Plasma Concentration-time Curve from Time 0 to Time Over the Dosing Interval for TAK-659 and Venetoclax
Time frame: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)
Oral Clearance (CL/F) for TAK-659 and Venetoclax
Time frame: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)
Peak-trough Ratio (PTR) for TAK-659 and Venetoclax
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Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
43
NorthShore Medical Group - Evanston
Evanston, Illinois, United States
Ingalls Memorial Hospital
Harvey, Illinois, United States
Norton Cancer Institute - Shelbyville
Shelbyville, Kentucky, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Icahn School of Medicine at Mount Sinai
New York, New York, United States
Baylor Scott & White Research Institute
Dallas, Texas, United States
Hopital Maisonneuve-Rosemont
Montreal, Quebec, Canada
Jewish General Hospital
Montreal, Quebec, Canada
...and 5 more locations
Time frame: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)
Accumulation Ratio (Rac) for TAK-659 and Venetoclax
Time frame: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)
Trough Concentration (C trough) for TAK-659 and Venetoclax
Time frame: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)
Overall Response Rate (ORR)
ORR is calculated as percentage of participants with complete response (CR) + percentage of participants with partial response (PR) as assessed by International Working Group (IWG) criteria for malignant lymphoma.
Time frame: Up to 12 months
Duration of Overall Response
Time frame: Up to 12 months
CR Rate
CR rate is calculated as percentage of participants with CR as assessed by IWG criteria for malignant lymphoma.
Time frame: Up to 12 months
Duration of CR
Time frame: Up to 12 months
Time to Progression (TTP)
TTP will be measured as the time in months from the first dose of study treatment to the date of the first documented disease progression as assessed using IWG criteria.
Time frame: Up to 13 months
Progression-free Survival (PFS)
PFS is defined as the time from date of first study drug administration to the day of first documented disease progression or death due to any cause, whichever occurs first.
Time frame: Up to 18 months