Lymphoma, Non-Hodgkin
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of TAK-659 when administered in combination with bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, or ibrutinib.
Detailed description
The drug being tested in this study is called TAK-659. TAK-659 is being tested to treat people who have advanced non-Hodgkin lymphoma. This study will determine the MTD or RP2D for TAK-659 in combination with bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, and ibrutinib. The study will enroll approximately 96 participants. Participants will be assigned to one of the 5 combination cohorts: * Dose Escalation Phase Cohort A: TAK-659 + Bendamustine * Dose Escalation Phase Cohort B: TAK-659 + Bendamustine + Rituximab * Dose Escalation Phase Cohort C: TAK-659 + Gemcitabine * Dose Escalation Phase Cohort D: TAK-659 + Lenalidomide * Dose Escalation Phase Cohort E: TAK-659 + Ibrutinib This study comprises 2 phases: a dose escalation phase and a safety expansion phase. Participants in all 5 cohorts (Cohorts A-E) will participate in the dose escalation phase of the study. Approximately 12 additional participants with advanced follicular lymphoma (FL) or marginal zone lymphoma (MZL) will be added to Cohort B, in the safety expansion phase. This multi-center trial will be conducted in North America and Europe. The overall time to participate in this study is approximately 30 months. Participants will make multiple visits to the clinic and will be followed up for safety for 28 days after the last dose of study drug.
Interventions
DRUGTAK-659
TAK-659 immediate release tablet
DRUGBendamustine
Bendamustine intravenous infusion
DRUGRituximab
Rituximab intravenous infusion
DRUGGemcitabine
Gemcitabine intravenous infusion
DRUGLenalidomide
Lenalidomide capsule
DRUGIbrutinib
Ibrutinib capsule
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female participants aged 18 years or older. 2. In the dose escalation phase, histologically or cytologically confirmed diagnosis of advanced non-Hodgkin lymphoma (NHL) of any histology (with the exception of participants with Waldenström macroglobulinemia \[WM\] and chronic lymphocytic leukemia \[CLL\]). In the safety expansion phase for Cohort B, only participants with advanced FL or MZL will be included. 3. Radiographically or clinically measurable disease with at least 1 target lesion per International Working Group (IWG) criteria for malignant lymphoma. 4. In the dose escalation phase, participants who are refractory or relapsed after at least 1 prior line of therapy due to progression, intolerance, or physician/participant decision and for whom no effective standard therapy is available per the investigator's assessment. In the safety expansion phase for Cohort B in participants with FL or MZL, the prior line of therapy is limited to \<=1. * Either treatment naive to, relapsed/refractory to, or experienced treatment failure due to other reasons with ibrutinib, idelalisib, or any other investigational B-cell receptor (BCR) pathway inhibitors not directly targeting spleen tyrosine kinase (SYK). * Pre induction salvage chemotherapy and autologous stem cell transplant (ASCT) should be considered 1 therapy. * Any consolidation/maintenance therapy after a chemotherapy regimen (without intervening relapse) should be considered 1 line of therapy with the preceding combination therapy. Maintenance antibody therapy should not be considered a line of therapy. * For aggressive NHL (i.e., diffuse large B-cell lymphoma \[DLBCL\]), single-agent anti-CD20 monoclonal antibody therapy should not be considered a line of therapy. Antibody therapy in participants with indolent NHL (i.e., FL) given as a single agent after disease progression from a prior treatment should be considered a line of therapy. * For participants with DLBCL transformed from indolent lymphoma, any treatment received for the indolent disease before the transformation to DLBCL will, in general, not count toward the 2 to 3 prior lines of therapy required for DLBCL in this study. * Prior treatment with a regimen that includes the combination drug will not necessarily exclude a participant from that cohort if the investigator views treatment with that agent as appropriate. However, a participant who has a contraindication for a particular combination agent or who has been discontinued from prior therapy with a particular agent for toxicity will not be eligible for inclusion in that particular cohort. 5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and life expectancy of greater than 3 months. 6. Participants must have adequate organ function, including the following: * Adequate bone marrow reserve: absolute neutrophil count (ANC) greater than or equal to (\>=) 1000 per micro liter (/mcL), platelet count \>=75,000/mcL (\>=50,000/mcL 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). * Hepatic: total bilirubin less than or equal to (\<=) 1.5×the upper limit of the normal range (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<=2.5×ULN. * Renal: serum creatinine \>=60 milliliter per minute (mL/min) as estimated by the Cockcroft-Gault equation. * Others * Lipase \<=1.5×ULN and amylase \<=1.5×ULN with no clinical symptoms suggestive of pancreatitis or cholecystitis. * Blood pressure \<=Grade 1 (hypertensive participants are permitted if their blood pressure is controlled to \<= Grade 1 by hypertensive medications and glycosylated hemoglobin is \<=6.5%). * Fasting serum glucose level shall be controlled to 130 milligrams per deciliter (mg/dL) during the screening period. 7. Female participants who: * Are postmenopausal for at least 1 year before the screening visit, or * Are surgically sterile, or * If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 180 days after the last dose of study drug, or * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[example, calendar, ovulation, symptothermal, postovulation methods\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) Male participant, even if surgically sterilized (that is, status postvasectomy), who: * Agree to practice effective barrier contraception during the entire study treatment period and through 180 days after the last dose of study drug, or * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[example, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) * Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 international units per liter IU/L or equivalent units of human chorionic gonadotropin \[hCG\]) at screening. 8. Both men and women in the rituximab combination arm (Cohort B) must practice contraception as described above from the time of signing of the informed consent form (ICF) through 12 months after the last dose of study drug. 9. Female participants should not donate ova from the time of signing the informed consent through 180 days after the last dose of study drug. 10. Male participants should not donate sperm from the time of signing the informed consent through 180 days after the last dose of study drug. 11. Both men and women in the lenalidomide combination arm (Cohort D) must adhere to the guidelines of the RevAssist program (United States participants) or, if not using commercial supplies, must adhere to the Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the Study Manual. 12. Both men and women in the lenalidomide combination arm (Cohort D) must adhere to the guidelines of the RevAssist program (United States participants) or, if not using commercial supplies, must adhere to the Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the Study Manual. 13. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care. 14. Recovered (that is, \<= Grade 1 toxicity) from the reversible effects of prior anticancer therapy.
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) scan/magnetic resonance imaging (MRI). Exceptions include those participants who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 2 weeks after completion of the definitive therapy and steroids, and do not have neurologic dysfunction that would confound the evaluation of neurologic and other adverse events (AEs). 2. Known human immunodeficiency virus (HIV)-related malignancy. 3. Known hypersensitivity (example, anaphylactic and anaphylactoid reactions) to any particular combination drug will result in a participant being ineligible for inclusion in that particular cohort. 4. For participant in the lenalidomide combination arm, demonstrated hypersensitivity (example, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide. 5. History of drug-induced pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted. 6. Life-threatening illness unrelated to cancer that could, in the investigator's opinion, make the participant not appropriate for this study. 7. Female participants who are lactating and breast-feeding or a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before the first dose of study drug. 8. Any serious medical or psychiatric illness, including drug or alcohol abuse, that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. 9. Known human immunodeficiency virus (HIV) positive. 10. Known hepatitis B surface antigen positive, or known or suspected active hepatitis C infection. 11. Systemic anticancer treatment (including investigational agents) or radiotherapy less than 2 weeks before the first dose of study treatment (\<=4 weeks antibody-based therapy including unconjugated antibody, antibody-drug conjugate, and bi-specific T-cell engager agents; \<= 8 weeks for cell-based therapy or antitumor vaccine). 12. Prior ASCT within 6 months or prior ASCT at any time without adequate full hematopoietic recovery, defined by the entry criteria in the study, before Cycle 1 Day 1 or allogeneic stem cell transplant any time. 13. Any clinically significant comorbidities, such as uncontrolled pulmonary disease, known impaired cardiac function or clinically significant cardiac disease (specified below), active central nervous system (CNS) disease, active infection, or any other condition that could compromise the participant's participation in the study. 14. Participants with any of the following cardiovascular conditions are excluded: * Unstable angina or acute myocardial infarction within 12 months before starting study drug. * Current or history of New York Heart Association Class III or IV heart failure. * Evidence of current, uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. * Friderichia corrected QT interval (QTcF) \>450 milliseconds (msec) (men) or \>475 msec (women) on a 12-lead electrocardiogram (ECG) during the Screening period. * Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and intervals that, in the opinion of the investigator, are considered to be clinically significant. 15. Lack of suitable venous access for the study-required blood sampling for TAK-659. 16. For participants in all combination arms (Cohorts A-E), use or consumption of any of the following substances: * Medications or supplements that are known to be inhibitors of P-glycoprotein (P-gp) and/or strong reversible inhibitors of cytochrome P450 (CYP) 3A within 5 times the inhibitor half-life (if a reasonable half-life estimate is known) or within 7 days (if a reasonable half-life estimate is unknown) before the first dose of study drug. In general, the use of these agents is not permitted during the study except in cases in which an AE must be managed. See a nonexhaustive list of prohibited strong CYP3A reversible inhibitors and/or P-gp inhibitors based on the US Food and Drug Administration (FDA) Draft Drug-Drug Interactions (DDI) Guidance. * Medications or supplements that are known to be strong CYP3A mechanism-based inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 days or within 5 times the inhibitor or inducer half-life (whichever is longer) before the first dose of study drug. The use of these agents is not permitted during the study. See a list of prohibited strong CYP3A mechanism-based inhibitors or strong CYP3A inducers and/or P-glycoprotein (gp) inducers based on the United States (US) Food and Drug Administration (FDA) Draft Drug-drug Interaction (DDI) Guidance. * Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are not permitted during the study. 17. Additionally, for participants in the ibrutinib combination arm (Cohort E), use or consumption of any of the following substances: * Medications or supplements that are known to be moderate reversible inhibitors of CYP3A within 5 times the inhibitor half-life (if a reasonable half-life estimate is known) or within 7 days (if a reasonable half-life estimate is unknown) before the first dose of study drugs. In general, the use of these agents is not permitted during the study for this combination except in cases in which an adverse event (AE) must be managed. See a list of nonexhaustive moderate CYP3A reversible inhibitors based on the US FDA Draft DDI Guidance. * Medications or supplements that are known to be moderate mechanism-based inhibitors or moderate inducers of CYP3A within 7 days or within 5 times the inhibitor or inducer half-life (whichever is longer) before the first dose of study drugs. In general, the use of these agents is not permitted during the study for this combination except in cases in which an AE must be managed. See a list of non-exhaustive moderate CYP3A mechanism-based inhibitors or moderate CYP3A inducers based on the US FDA Draft DDI Guidance. * Seville oranges within 5 days before the first dose of study drugs and during the study. 18. Major surgery within 14 days before the first dose of study drug and not recovered fully from any complications from surgery. 19. Systemic infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before the first dose of study drug. 20. Participants with another malignancy within 2 years of study start. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection and are considered disease-free at the time of study entry. 21. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-659 including difficulty swallowing tablets or diarrhea \>Grade 1 despite supportive therapy. 22. Treatment with high-dose corticosteroids for anticancer purposes within 14 days before the first dose of TAK-659; daily dose equivalent to 10 mg oral prednisone or less is permitted. Corticosteroids for topical use or in nasal spray or inhalers are allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation Phase: Maximum Tolerated Dose (MTD) of TAK-659 | Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days) | MTD was defined as the maximum dose that is determined to be safe and tolerable in different cohorts. Each cohort (A, B, C, D and E) received different escalating doses of TAK-659 in combination with other drugs. For each cohort the maximum tolerated dose of TAK-659 in combination with the other drug/s from the selected dose range is reported. |
| Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of TAK-659 | Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E each cycle was of 28 days) | The RP2D was the MTD or less. The dose recommended for use in phase 2 studies was analyzed on the basis of the safety, tolerability, and preliminary pharmacokinetic (PK) and efficacy data obtained in phase 1 studies. Each cohort (A, B, C, D and E) received different escalating doses of TAK-659 in combination with other drugs. For each cohort the recommended Phase 2 dose of TAK-659 in combination with the other drug/s from the selected dose range is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Observed Plasma Concentration for TAK-659 | Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days) | — |
| Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days) | — |
| AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days) | — |
| Overall Response Rate (ORR) | Up to 123 weeks | ORR was defined as the percentage of participants in the response-evaluable population who achieved either complete response (CR), or partial response (PR). CR was defined as the disappearance of all evidence of disease, and PR was defined as regression of measurable disease and no new sites. |
| Duration of Response (DOR) | Up to 123 weeks | DOR was defined as the time from the date of first documented response to the date of first documented PD. PD was defined as any new lesion or increase by \> 50% of previously involved sites from nadir. |
| Time to Progression (TTP) | Up to 123 weeks | TTP was defined as the time from the date of first drug administration to the date of first documented PD. PD was defined as any new lesion or increase by \>50% of previously involved sites from nadir. |
| Safety Expansion Phase: Progression-free Survival (PFS) | Up to study completion (Up to 123 weeks) | PFS was defined as the time from the date of first study drug administration to the date of first documented PD or death due to any cause, whichever occurs first. PD was defined as any new lesion or increase by \>50% of previously involved sites from nadir. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants took part in the study at 9 investigative sites in Canada, Spain, and the United States from 05 March 2017 to 27 July 2020. The study was planned to be conducted in two Phases: Dose Escalation Phase and Safety Expansion Phase, however, per Sponsor's decision, the study was terminated prior to enrollment of participants in the Safety Expansion Phase.
Pre-assignment details
Participants with a diagnosis of advanced non-Hodgkin lymphoma were enrolled in Dose Escalation Phase Cohorts A, B, C, D and E of study to receive TAK-659 in combination with 1 of 5 combination drugs (bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, and ibrutinib) to determine the maximum tolerated dose (MTD)/ recommended phase 2 dose (RP2D).
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Phase Cohort A: TAK-659 60 mg + Bendamustine 90 mg/m^2 TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 39 cycles. | 3 |
| Dose Escalation Phase Cohort A: TAK-659 80 mg + Bendamustine 90 mg/m^2 TAK-659 80 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 80 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 39 cycles. | 6 |
| Dose Escalation Phase Cohort A: TAK-659 100 mg + Bendamustine 90 mg/m^2 TAK-659 100 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 100 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 39 cycles. | 6 |
| Dose Escalation Phase Cohort B: TAK-659 60 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles. | 6 |
| Dose Escalation Phase Cohort B: TAK-659 80 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 TAK-659 80 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 80 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles. | 7 |
| Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 TAK-659 100 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 100 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles. | 3 |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with gemcitabine 1000 mg/m\^2, infusion, intravenously, over 30 minutes on Days 1 and 8 in a 21-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 2 cycles. | 3 |
| Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg TAK-659 40 mg, immediate-release tablet, orally, once daily on Days 1 to 28 along with lenalidomide 25 mg, capsules orally, once daily on Days 1 to 21 in a 28-day treatment cycle. The TAK-659 60 mg dose was de-escalated to 40 mg in case of dose limiting toxicity or if the starting dose was determined to be not tolerable. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 26 cycles. | 2 |
| Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 28 along with lenalidomide 25 mg, capsules orally, once daily on Days 1 to 21 in a 28-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 26 cycles. | 4 |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg TAK-659 60 mg, immediate-release tablet, orally, once daily along with ibrutinib 560 mg capsules, orally, once daily on Days 1 to 28 in a 28-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 3 cycles. | 3 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Progressive Disease | 3 | 4 | 3 | 4 | 3 | 3 | 2 | 2 | 1 | 1 | 0 |
| Overall Study | Reason Not Specified | 0 | 0 | 3 | 2 | 2 | 0 | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Symptomatic Deterioration | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose Escalation Phase Cohort A: TAK-659 80 mg + Bendamustine 90 mg/m^2 | Dose Escalation Phase Cohort A: TAK-659 60 mg + Bendamustine 90 mg/m^2 | Total | Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg | Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg | Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Dose Escalation Phase Cohort B: TAK-659 80 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Dose Escalation Phase Cohort B: TAK-659 60 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Dose Escalation Phase Cohort A: TAK-659 100 mg + Bendamustine 90 mg/m^2 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 61.8 years | 58.7 years | 64.52 years | 71.0 years | 61.0 years | 58.5 years | 72.7 years | 72.7 years | 57.0 years | 61.3 years | 70.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 40 Participants | 3 Participants | 4 Participants | 2 Participants | 3 Participants | 3 Participants | 5 Participants | 6 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Height | 171.7 cm | 171.5 cm | 167.5 cm | 164.7 cm | 169.8 cm | 167.5 cm | 154.3 cm | 169.3 cm | 172.7 cm | 170.3 cm | 163.0 cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 1 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 | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 37 Participants | 2 Participants | 4 Participants | 2 Participants | 2 Participants | 3 Participants | 6 Participants | 5 Participants | 6 Participants |
| Region of Enrollment Canada | 4 Participants | 3 Participants | 26 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 2 Participants | 3 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Spain | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 2 Participants | 0 Participants | 13 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 15 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 1 Participants | 28 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 2 Participants | 5 Participants | 5 Participants | 3 Participants |
| Weight | 94.3 kg | 88.0 kg | 80.5 kg | 70.0 kg | 90.8 kg | 85.5 kg | 60.0 kg | 87.3 kg | 86.1 kg | 66.7 kg | 76.3 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 2 / 6 | 0 / 6 | 0 / 6 | 1 / 7 | 0 / 3 | 0 / 3 | 1 / 2 | 1 / 4 | 3 / 3 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 6 / 6 | 6 / 6 | 7 / 7 | 3 / 3 | 3 / 3 | 2 / 2 | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 3 / 3 | 4 / 6 | 4 / 6 | 2 / 6 | 6 / 7 | 2 / 3 | 1 / 3 | 1 / 2 | 0 / 4 | 2 / 3 |
Outcome results
Primary
Dose Escalation Phase: Maximum Tolerated Dose (MTD) of TAK-659
MTD was defined as the maximum dose that is determined to be safe and tolerable in different cohorts. Each cohort (A, B, C, D and E) received different escalating doses of TAK-659 in combination with other drugs. For each cohort the maximum tolerated dose of TAK-659 in combination with the other drug/s from the selected dose range is reported.
Time frame: Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days)
Population: Dose-limiting toxicity (DLT)-evaluable analysis set: participants who have met the minimum treatment and safety evaluation requirements of the study or who experience a DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase Cohort A: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 | Dose Escalation Phase: Maximum Tolerated Dose (MTD) of TAK-659 | NA mg |
| Dose Escalation Phase Cohort B: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Dose Escalation Phase: Maximum Tolerated Dose (MTD) of TAK-659 | NA mg |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Dose Escalation Phase: Maximum Tolerated Dose (MTD) of TAK-659 | NA mg |
| Dose Escalation Phase Cohort D: TAK-659 40-60 mg + Lenalidomide 25 mg | Dose Escalation Phase: Maximum Tolerated Dose (MTD) of TAK-659 | NA mg |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Dose Escalation Phase: Maximum Tolerated Dose (MTD) of TAK-659 | NA mg |
Primary
Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of TAK-659
The RP2D was the MTD or less. The dose recommended for use in phase 2 studies was analyzed on the basis of the safety, tolerability, and preliminary pharmacokinetic (PK) and efficacy data obtained in phase 1 studies. Each cohort (A, B, C, D and E) received different escalating doses of TAK-659 in combination with other drugs. For each cohort the recommended Phase 2 dose of TAK-659 in combination with the other drug/s from the selected dose range is reported.
Time frame: Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E each cycle was of 28 days)
Population: DLT-evaluable analysis set: participants who have met the minimum treatment and safety evaluation requirements of the study or who experience a DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase Cohort A: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 | Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of TAK-659 | NA mg |
| Dose Escalation Phase Cohort B: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of TAK-659 | 60 mg |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of TAK-659 | NA mg |
| Dose Escalation Phase Cohort D: TAK-659 40-60 mg + Lenalidomide 25 mg | Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of TAK-659 | NA mg |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of TAK-659 | NA mg |
Secondary
AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval
Time frame: Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days)
Population: PK Analysis Set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Number analyzed is the number of participants with data available for analyses at the given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort A: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 1 | 1094.51 h×ng/mL | Geometric Coefficient of Variation 52.35 |
| Dose Escalation Phase Cohort A: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 15 | 1845.21 h×ng/mL | Geometric Coefficient of Variation 74.17 |
| Dose Escalation Phase Cohort B: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 1 | 1011.49 h×ng/mL | Geometric Coefficient of Variation 53.85 |
| Dose Escalation Phase Cohort B: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 15 | 1675.91 h×ng/mL | Geometric Coefficient of Variation 90.89 |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 1 | 1532.34 h×ng/mL | Geometric Coefficient of Variation 65.52 |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 15 | 3050.97 h×ng/mL | Geometric Coefficient of Variation 54.46 |
| Dose Escalation Phase Cohort D: TAK-659 40-60 mg + Lenalidomide 25 mg | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 1 | 852.36 h×ng/mL | Geometric Coefficient of Variation 40.94 |
| Dose Escalation Phase Cohort D: TAK-659 40-60 mg + Lenalidomide 25 mg | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 15 | 1896.76 h×ng/mL | Geometric Coefficient of Variation 43.15 |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 15 | 2788.61 h×ng/mL | Geometric Coefficient of Variation 17.61 |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 1 | 1455.92 h×ng/mL | Geometric Coefficient of Variation 44.57 |
| Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 15 | 2662.16 h×ng/mL | Geometric Coefficient of Variation 21.31 |
| Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 1 | 1444.89 h×ng/mL | Geometric Coefficient of Variation 19.43 |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 15 | 3251.29 h×ng/mL | — |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 1 | 387.54 h×ng/mL | — |
| Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 1 | 1456.03 h×ng/mL | — |
| Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 15 | 2536.48 h×ng/mL | — |
| Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 1 | 758.76 h×ng/mL | Geometric Coefficient of Variation 76.63 |
| Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 15 | 2578.30 h×ng/mL | Geometric Coefficient of Variation 24.56 |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 1 | 968.82 h×ng/mL | Geometric Coefficient of Variation 36.59 |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval | Cycle 1 Day 15 | 4218.90 h×ng/mL | Geometric Coefficient of Variation 46.77 |
Secondary
Cmax: Maximum Observed Plasma Concentration for TAK-659
Time frame: Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days)
Population: Pharmacokinetic (PK) Analysis Set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Number analyzed is the number of participants with data available for analyses at the given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort A: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 83.61 nanograms(ng)/mL | Geometric Coefficient of Variation 92.17 |
| Dose Escalation Phase Cohort A: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 126.49 nanograms(ng)/mL | Geometric Coefficient of Variation 105.13 |
| Dose Escalation Phase Cohort B: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 89.74 nanograms(ng)/mL | Geometric Coefficient of Variation 59.03 |
| Dose Escalation Phase Cohort B: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 145.03 nanograms(ng)/mL | Geometric Coefficient of Variation 96.78 |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 118.10 nanograms(ng)/mL | Geometric Coefficient of Variation 63.83 |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 187.73 nanograms(ng)/mL | Geometric Coefficient of Variation 47.29 |
| Dose Escalation Phase Cohort D: TAK-659 40-60 mg + Lenalidomide 25 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 128.58 nanograms(ng)/mL | Geometric Coefficient of Variation 27.19 |
| Dose Escalation Phase Cohort D: TAK-659 40-60 mg + Lenalidomide 25 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 158.28 nanograms(ng)/mL | Geometric Coefficient of Variation 43.71 |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 222.96 nanograms(ng)/mL | Geometric Coefficient of Variation 31.1 |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 142.84 nanograms(ng)/mL | Geometric Coefficient of Variation 57.58 |
| Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 223.53 nanograms(ng)/mL | Geometric Coefficient of Variation 44.02 |
| Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 180.10 nanograms(ng)/mL | Geometric Coefficient of Variation 17.93 |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 303.34 nanograms(ng)/mL | Geometric Coefficient of Variation 12.39 |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 141.27 nanograms(ng)/mL | Geometric Coefficient of Variation 296.57 |
| Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 139.00 nanograms(ng)/mL | — |
| Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 188.00 nanograms(ng)/mL | — |
| Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 65.03 nanograms(ng)/mL | Geometric Coefficient of Variation 80.98 |
| Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 202.90 nanograms(ng)/mL | Geometric Coefficient of Variation 69.27 |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 120.23 nanograms(ng)/mL | Geometric Coefficient of Variation 42.42 |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Cmax: Maximum Observed Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 306.59 nanograms(ng)/mL | Geometric Coefficient of Variation 66.37 |
Secondary
Duration of Response (DOR)
DOR was defined as the time from the date of first documented response to the date of first documented PD. PD was defined as any new lesion or increase by \> 50% of previously involved sites from nadir.
Time frame: Up to 123 weeks
Population: Response-evaluable Analysis Set included participants who received at least 1 dose of study drug, had sites of measurable disease at Baseline, and 1 post-baseline disease assessment. Only responders were analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase Cohort A: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 | Duration of Response (DOR) | 2.3 months |
| Dose Escalation Phase Cohort B: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Duration of Response (DOR) | 2.8 months |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Duration of Response (DOR) | NA months |
| Dose Escalation Phase Cohort D: TAK-659 40-60 mg + Lenalidomide 25 mg | Duration of Response (DOR) | NA months |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Duration of Response (DOR) | 3.9 months |
| Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg | Duration of Response (DOR) | 1.8 months |
| Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg | Duration of Response (DOR) | NA months |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Duration of Response (DOR) | NA months |
Secondary
Overall Response Rate (ORR)
ORR was defined as the percentage of participants in the response-evaluable population who achieved either complete response (CR), or partial response (PR). CR was defined as the disappearance of all evidence of disease, and PR was defined as regression of measurable disease and no new sites.
Time frame: Up to 123 weeks
Population: Response-evaluable Analysis Set included participants who received at least 1 dose of study drug, had sites of measurable disease at Baseline, and 1 post-baseline disease assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase Cohort A: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 | Overall Response Rate (ORR) | 33.3 percentage of participants |
| Dose Escalation Phase Cohort B: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Overall Response Rate (ORR) | 75.0 percentage of participants |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Overall Response Rate (ORR) | 50.0 percentage of participants |
| Dose Escalation Phase Cohort D: TAK-659 40-60 mg + Lenalidomide 25 mg | Overall Response Rate (ORR) | 40.0 percentage of participants |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Overall Response Rate (ORR) | 80.0 percentage of participants |
| Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Overall Response Rate (ORR) | 0.0 percentage of participants |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Overall Response Rate (ORR) | 0.0 percentage of participants |
| Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg | Overall Response Rate (ORR) | 100.0 percentage of participants |
| Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg | Overall Response Rate (ORR) | 33.3 percentage of participants |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Overall Response Rate (ORR) | 50.0 percentage of participants |
Secondary
Safety Expansion Phase: Progression-free Survival (PFS)
PFS was defined as the time from the date of first study drug administration to the date of first documented PD or death due to any cause, whichever occurs first. PD was defined as any new lesion or increase by \>50% of previously involved sites from nadir.
Time frame: Up to study completion (Up to 123 weeks)
Population: Data is not available for this outcome measure as the study was terminated prior to start of safety expansion phase.
Secondary
Time to Progression (TTP)
TTP was defined as the time from the date of first drug administration to the date of first documented PD. PD was defined as any new lesion or increase by \>50% of previously involved sites from nadir.
Time frame: Up to 123 weeks
Population: Response-evaluable Analysis Set included participants who received at least 1 dose of study drug, had sites of measurable disease at Baseline, and 1 post-baseline disease assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase Cohort A: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 | Time to Progression (TTP) | 4.2 months |
| Dose Escalation Phase Cohort B: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Time to Progression (TTP) | 2.7 months |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Time to Progression (TTP) | 9.6 months |
| Dose Escalation Phase Cohort D: TAK-659 40-60 mg + Lenalidomide 25 mg | Time to Progression (TTP) | 2.6 months |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Time to Progression (TTP) | 4.2 months |
| Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Time to Progression (TTP) | 1.3 months |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Time to Progression (TTP) | 1.4 months |
| Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg | Time to Progression (TTP) | 3.4 months |
| Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg | Time to Progression (TTP) | NA months |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Time to Progression (TTP) | 2.7 months |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659
Time frame: Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days)
Population: PK Analysis Set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Number analyzed is the number of participants with data available for analyses at the given time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation Phase Cohort A: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 4.00 hours (h) |
| Dose Escalation Phase Cohort A: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 4.00 hours (h) |
| Dose Escalation Phase Cohort B: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 2.03 hours (h) |
| Dose Escalation Phase Cohort B: TAK-659 60-100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 1.09 hours (h) |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 4.00 hours (h) |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 3.83 hours (h) |
| Dose Escalation Phase Cohort D: TAK-659 40-60 mg + Lenalidomide 25 mg | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 1.10 hours (h) |
| Dose Escalation Phase Cohort D: TAK-659 40-60 mg + Lenalidomide 25 mg | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 1.17 hours (h) |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 1.93 hours (h) |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 2.00 hours (h) |
| Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 2.47 hours (h) |
| Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 2.00 hours (h) |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 2.76 hours (h) |
| Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 4.13 hours (h) |
| Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 0.6 hours (h) |
| Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 1.9 hours (h) |
| Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 2.12 hours (h) |
| Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 2.08 hours (h) |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 1 | 1.00 hours (h) |
| Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg | Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659 | Cycle 1 Day 15 | 1.01 hours (h) |