Lymphoma, Follicular, Marginal Zone, Lymphoma, Non-Hodgkin
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to determine the safety, tolerability, maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of TAK-659 when administered in East Asian participants with NHL who do not have an effective standard treatment available and to characterize the plasma and urine pharmacokinetic (PK) of TAK-659 in East Asian participants with NHL.
Detailed description
The drug being tested in this study is called TAK-659. TAK-659 is being tested to treat people who have NHL or people who have relapsed and/or refractory NHL. This study will assess the safety, tolerability, PK, and preliminary efficacy of single-agent TAK-659 in East Asian participants with NHL. The study will enroll approximately 33 to 47 participants, including at least 6 Japanese at RP2D dose level. Participants will be assigned to one of the following treatment groups: Dose Escalation Part: TAK-659 Expansion Part: TAK-659 RP2D This multi-center trial will be conducted in Japan and Republic of Korea. The maximum duration of participation in dose escalation part of the study is up to 12 months, unless in the opinion of the investigator and sponsor the participant would derive benefit from continued therapy beyond 12 months. In expansion part, participants who stop treatment for any other reason other than PD will continue to have PFS follow-up at the site every 2 months from the last dose of study drug up to 6 months or until PD. Participants will be followed 28 days after last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurs first, for a follow up assessment.
Interventions
DRUGTAK-659
TAK-659 Tablets.
Sponsors
Calithera Biosciences, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. To be enrolled to the dose escalation part, participants must have histologically or cytologically confirmed diagnosis of NHL for which no effective standard treatment is available. 2. To be enrolled in the expansion part, participants must meet the following criteria: 1. Must have pathologically confirmed FL (Grade 1, 2, or 3A) or MZL. 2. Relapsed and/or refractory to \>=2 prior lines of chemotherapy based on standard of care that include at least 1 anti-CD20-based regimen, as well as alkylating agents (example cyclophosphamide or bendamustine). 3. Participants must be ineligible for or refusal to hematopoietic stem cell transplant. 4. If the participants have relapsed or progressed after achieving a response (defined as CR or PR), documented, investigator-assessed relapse or progression after the last treatment is required. 3. Measurable disease per IWG 2007 criteria. 4. Eastern Cooperative Oncology Group performance status score of 0 or 1. 5. Life expectancy of longer than 3 months. 6. Adequate organ function, including the following: 1. Bone marrow reserve: absolute neutrophil count \>=1,000 per cubic millimeter (/mm\^3), platelet count \>=75,000/mm\^3 (\>=50,000/mm\^3 for participants with bone marrow involvement), and hemoglobin \>=8 gram per deciliter (g/dL) (red blood cell \[RBC\] and platelet transfusion allowed \>=14 days before assessment). 2. Hepatic function: total bilirubin less than or equal to (\<=) 1.5\*the upper limit of the normal range (ULN); alanine aminotransferase and aspartate aminotransferase \<=2.5\*ULN. 3. Renal function: creatinine clearance \>=60 milliliter per minute (mL/min) either as estimated by the Cockcroft-Gault equation.
Exclusion criteria
1. Central nervous system (CNS) lymphoma; active brain or leptomeningeal metastases as indicated by positive cytology from lumbar puncture or computed tomography (CT)/magnetic resonance imaging (MRI) by local assessment. 2. Systemic anticancer treatment (including investigational agents) less than 3 weeks before the first dose of study treatment (\<=4 weeks for antibody-based therapy including unconjugated antibody, antibody-drug conjugate, and bi-specific T-cell engager agent; \<=8 weeks for cell-based therapy or anti-tumor vaccine). 3. Radiotherapy less than (\<) 3 weeks before the first dose of study treatment. If prior radiotherapy occurred \<4 to 6 weeks before the study start, as radiated lesions cannot be reliably assessed by fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET), nonradiated target lesions are required for eligibility. 4. Prior autologous stem cell transplant (ASCT) within 6 months or prior ASCT at any time without full hematopoietic recovery before Cycle 1 Day 1, or allogeneic stem cell transplant at any time. 5. Any clinically significant comorbidities, such as uncontrolled pulmonary disease (example, severe chronic obstructive pulmonary disease with hypoxemia, interstitial lung disease, radiation induced lung injury), known impaired cardiac function or clinically significant cardiac disease, active CNS disease, or any other condition that could, in the opinion of the investigator, compromise the participant's safety and participation in the study per protocol. 6. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-659. 7. Use or consumption of any of the following substances: Received medications, supplements, or food/beverages that are P-glycoprotein (P-gp) inhibitors or inducers or strong cytochrome P450 (CYP) 3A inhibitors or inducers within a certain time frame prior to the first dose of study drug. Depending on the substance, the washout period for P-gp inhibitors or inducers or strong CYP3A inhibitors or inducers will be either 7 days or 5 times the half-life (half-life is related to the time required for elimination from the body). The washout period for grapefruit containing food or beverages is 5 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | From first dose of study drug up to 28 days after the last dose of study drug or before the start of subsequent anticancer therapy (up to Cycle 31) (Cycle length =28 days) | — |
| Percentage of Participants With Grade 3 or Higher TEAEs | From first dose of study drug up to 28 days after the last dose of study drug or before the start of subsequent anticancer therapy (up to Cycle 31) (Cycle length =28 days) | TEAEs were graded as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. As per the NCI-CTCAE, Grade 1 (mild, asymptomatic or mild symptoms); Grade 2 (moderate, minimal, local or noninvasive intervention indicated); Grade 3 (severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated); Grade 4 (life-threatening consequences, urgent intervention indicated); Grade 5 (death related to adverse event \[AE\]). |
| Percentage of Participants With Serious TEAEs | From first dose of study drug up to 28 days after the last dose of study drug or before the start of subsequent anticancer therapy (up to Cycle 31) (Cycle length =28 days) | — |
| Dose Escalation Part: Percentage of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 | Cycle 1 (Cycle length =28 days) | DLT was evaluated as per NCI-CTCAE, v4.03 and defined as any of the following events occurring during Cycle 1 that were considered by the investigator to be possibly related to therapy: Grade 4 neutropenia unresolved to less than or equal to (\<=) Grade 1 or baseline for more than 7 days in the absence of growth factor support; greater than or equal to (\>=) Grade 3 neutropenia with fever and/or infection;Grade 4 thrombocytopenia unresolved to \<=Grade 1 or baseline for more than 7 days; \>=Grade 3 thrombocytopenia with clinically significant bleeding; Grade \>=3 nonhematologic toxicity except for treated \>=Grade 3 nausea and/or emesis and diarrhea resolved to less than (\<) Grade 3 within 3 days, Grade 3 fatigue \<=72 hours, isolated asymptomatic \>=Grade 3 laboratory abnormalities resolved to \<=Grade 1 or baseline in \<=7 days;received \<75% of planned doses of study drug in Cycle 1;TAK-659-related \>=Grade 2 nonhematologic toxicities that required dose reduction or discontinuation of therapy. |
| Percentage of Participants Who Discontinued Study Drug Due to TEAEs | From first dose of study drug up to 28 days after the last dose of study drug or before the start of subsequent anticancer therapy (up to Cycle 31) (Cycle length =28 days) | — |
| Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 1 | Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | — |
| Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A): pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 1 | Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A): pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | — |
| AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 1 | Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | — |
| AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A) | Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A): pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | — |
| CLR: Renal Clearance for TAK-659 on Cycle 1 Day 15 | Cycle 1 Day 15: pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days) | — |
Countries
Japan, South Korea
Participant flow
Recruitment details
Participants took part in the study at 5 investigative sites in Japan and South Korea from 1 August 2017 to 17 August 2020.
Pre-assignment details
Participants with non-Hodgkin lymphoma (NHL) were enrolled in 1 of the 2 treatment schedules in the Dose Escalation Part to receive TAK-659: Dosing Schedule A and Dosing Schedule B. Dose Expansion part was not initiated and the data for secondary outcome measures was not analyzed due to early termination of the study by the sponsor due to business decision.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Part, Dosing Schedule A: TAK-659 40 mg TAK-659 40 mg, tablet, orally, once daily, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or withdrawal due to other reasons. | 3 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg TAK-659 60 mg, tablet, orally, once daily, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or withdrawal due to other reasons. | 6 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg TAK-659 80 mg, tablet, orally, once daily, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or withdrawal due to other reasons. | 4 |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg TAK-659 80 mg, tablet, orally, once daily as 7 days on and 7 days off treatment (dosing on 7 days followed by 7 days of rest) in each 28-days treatment cycle until disease progression, unacceptable toxicity, or withdrawal due to other reasons. | 3 |
| Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg TAK-659 100 mg, tablet, orally, once daily as 7 days on and 7 days off treatment (dosing on 7 days followed by 7 days of rest) in each 28-days treatment cycle until disease progression, unacceptable toxicity, or withdrawal due to other reasons. | 1 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 | 2 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Progressive Disease | 2 | 2 | 2 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Dose Escalation Part, Dosing Schedule A: TAK-659 40 mg | Total | Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg | Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 66.7 years STANDARD_DEVIATION 8.5 | 64.9 years STANDARD_DEVIATION 12.04 | 67.0 years | 65.7 years STANDARD_DEVIATION 2.89 | 63.3 years STANDARD_DEVIATION 8.92 | 64.5 years STANDARD_DEVIATION 19.46 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 17 Participants | 1 Participants | 3 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 17 Participants | 1 Participants | 3 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 1 Participants | 8 Participants | 0 Participants | 1 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Korea, Republic Of | 2 Participants | 9 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 0 Participants | 5 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 12 Participants | 0 Participants | 2 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 6 | 0 / 4 | 0 / 3 | 0 / 1 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 4 / 4 | 3 / 3 | 1 / 1 |
| serious Total, serious adverse events | 0 / 3 | 6 / 6 | 3 / 4 | 1 / 3 | 1 / 1 |
Outcome results
Primary
AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 1
Time frame: Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 1 | 587.2534 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 22.2886 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 1 | 1207.6554 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 26.3167 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 1 | 1742.7394 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 39.3327 |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 1 | 1899.2508 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 15.1827 |
| Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 1 | 1828.4544 hour*nanogram per milliliter (h*ng/mL) | — |
Primary
AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A)
Time frame: Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A): pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A) | 1114.2391 h*ng/mL | Geometric Coefficient of Variation 1.1927 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A) | 2016.8000 h*ng/mL | Geometric Coefficient of Variation 21.3348 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A) | 3502.3513 h*ng/mL | Geometric Coefficient of Variation 25.098 |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A) | 3349.4133 h*ng/mL | Geometric Coefficient of Variation 12.2891 |
Primary
CLR: Renal Clearance for TAK-659 on Cycle 1 Day 15
Time frame: Cycle 1 Day 15: pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Here overall number of participants analyzed were participants who were evaluable for this outcome measure. CLR data was planned to be collected and analyzed for both of the Dosing Schedule A and B arms. However, urine sample was not collected in Dosing Schedule B due to administrative reasons. Therefore, data was not analyzed and reported for schedule B arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | CLR: Renal Clearance for TAK-659 on Cycle 1 Day 15 | 6.7303 liter per hour (L/h) | Geometric Coefficient of Variation 49.0441 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | CLR: Renal Clearance for TAK-659 on Cycle 1 Day 15 | 8.4185 liter per hour (L/h) | Geometric Coefficient of Variation 114.6567 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | CLR: Renal Clearance for TAK-659 on Cycle 1 Day 15 | 9.4059 liter per hour (L/h) | Geometric Coefficient of Variation 22.3501 |
Primary
Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 1
Time frame: Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: The pharmacokinetic (PK) analysis set included participants who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 1 | 93.86 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 62.88 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 1 | 127.65 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 22.39 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 1 | 214.50 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 74.67 |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 1 | 216.00 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 18.01 |
| Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 1 | 297.00 nanogram per milliliter (ng/mL) | — |
Primary
Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A)
Time frame: Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A): pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | 121.18 ng/mL | Geometric Coefficient of Variation 39.57 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | 130.23 ng/mL | Geometric Coefficient of Variation 62.95 |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | 308.29 ng/mL | Geometric Coefficient of Variation 53.67 |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | 339.42 ng/mL | Geometric Coefficient of Variation 29.96 |
| Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | 329.00 ng/mL | — |
Primary
Dose Escalation Part: Percentage of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1
DLT was evaluated as per NCI-CTCAE, v4.03 and defined as any of the following events occurring during Cycle 1 that were considered by the investigator to be possibly related to therapy: Grade 4 neutropenia unresolved to less than or equal to (\<=) Grade 1 or baseline for more than 7 days in the absence of growth factor support; greater than or equal to (\>=) Grade 3 neutropenia with fever and/or infection;Grade 4 thrombocytopenia unresolved to \<=Grade 1 or baseline for more than 7 days; \>=Grade 3 thrombocytopenia with clinically significant bleeding; Grade \>=3 nonhematologic toxicity except for treated \>=Grade 3 nausea and/or emesis and diarrhea resolved to less than (\<) Grade 3 within 3 days, Grade 3 fatigue \<=72 hours, isolated asymptomatic \>=Grade 3 laboratory abnormalities resolved to \<=Grade 1 or baseline in \<=7 days;received \<75% of planned doses of study drug in Cycle 1;TAK-659-related \>=Grade 2 nonhematologic toxicities that required dose reduction or discontinuation of therapy.
Time frame: Cycle 1 (Cycle length =28 days)
Population: DLT-evaluable analysis set included participants who met the minimum treatment and safety evaluation requirements of the study or who experienced a DLT during Cycle 1. As planned, this outcome measure was analyzed and reported for dose escalation part only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | Dose Escalation Part: Percentage of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 | 0 percentage of participants |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | Dose Escalation Part: Percentage of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 | 16.7 percentage of participants |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | Dose Escalation Part: Percentage of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 | 50 percentage of participants |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | Dose Escalation Part: Percentage of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 | 0 percentage of participants |
| Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg | Dose Escalation Part: Percentage of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 | 0 percentage of participants |
Primary
Percentage of Participants Who Discontinued Study Drug Due to TEAEs
Time frame: From first dose of study drug up to 28 days after the last dose of study drug or before the start of subsequent anticancer therapy (up to Cycle 31) (Cycle length =28 days)
Population: The safety analysis set included participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | Percentage of Participants Who Discontinued Study Drug Due to TEAEs | 33.3 percentage of participants |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | Percentage of Participants Who Discontinued Study Drug Due to TEAEs | 50 percentage of participants |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | Percentage of Participants Who Discontinued Study Drug Due to TEAEs | 50 percentage of participants |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | Percentage of Participants Who Discontinued Study Drug Due to TEAEs | 0 percentage of participants |
| Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg | Percentage of Participants Who Discontinued Study Drug Due to TEAEs | 0 percentage of participants |
Primary
Percentage of Participants With Grade 3 or Higher TEAEs
TEAEs were graded as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. As per the NCI-CTCAE, Grade 1 (mild, asymptomatic or mild symptoms); Grade 2 (moderate, minimal, local or noninvasive intervention indicated); Grade 3 (severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated); Grade 4 (life-threatening consequences, urgent intervention indicated); Grade 5 (death related to adverse event \[AE\]).
Time frame: From first dose of study drug up to 28 days after the last dose of study drug or before the start of subsequent anticancer therapy (up to Cycle 31) (Cycle length =28 days)
Population: The safety analysis set included participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | Percentage of Participants With Grade 3 or Higher TEAEs | 66.7 percentage of participants |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | Percentage of Participants With Grade 3 or Higher TEAEs | 100 percentage of participants |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | Percentage of Participants With Grade 3 or Higher TEAEs | 100 percentage of participants |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | Percentage of Participants With Grade 3 or Higher TEAEs | 100 percentage of participants |
| Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg | Percentage of Participants With Grade 3 or Higher TEAEs | 0 percentage of participants |
Primary
Percentage of Participants With Serious TEAEs
Time frame: From first dose of study drug up to 28 days after the last dose of study drug or before the start of subsequent anticancer therapy (up to Cycle 31) (Cycle length =28 days)
Population: The safety analysis set included participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | Percentage of Participants With Serious TEAEs | 0 percentage of participants |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | Percentage of Participants With Serious TEAEs | 100 percentage of participants |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | Percentage of Participants With Serious TEAEs | 75 percentage of participants |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | Percentage of Participants With Serious TEAEs | 33.3 percentage of participants |
| Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg | Percentage of Participants With Serious TEAEs | 100 percentage of participants |
Primary
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
Time frame: From first dose of study drug up to 28 days after the last dose of study drug or before the start of subsequent anticancer therapy (up to Cycle 31) (Cycle length =28 days)
Population: The safety analysis set included participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 100 percentage of participants |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 1
Time frame: Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 1 | 1.97 hours |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 1 | 3.01 hours |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 1 | 2.00 hours |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 1 | 2.05 hours |
| Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 1 | 2.00 hours |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A)
Time frame: Cycle 1 Day 7 (Dosing Schedule B) and Day 15 (Dosing Schedule A): pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Part, Schedule Dosing A: TAK-659 40 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | 3.00 hours |
| Dose Escalation Part, Dosing Schedule A: TAK-659 60 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | 3.01 hours |
| Dose Escalation Part, Dosing Schedule A: TAK-659 80 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | 2.25 hours |
| Dose Escalation Part, Dosing Schedule B: TAK-659 80 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | 2.00 hours |
| Dose Escalation Part, Dosing Schedule B: TAK-659 100 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 on Cycle 1 Day 7 (Dosing Schedule B) and Cycle 1 Day 15 (Dosing Schedule A) | 1.00 hours |