A Study of TAK-659 in Combination With Bendamustine (+/-Rituximab), Gemcitabine, Lenalidomide, or Ibrutinib for the Treatment of Participants With Advanced Non-Hodgkin Lymphoma

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.

What this study is about