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

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 FL or 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.

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/patient
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 (ie, diffuse large B-cell lymphoma [DLBCL]), single-agent
anti-CD20 monoclonal antibody therapy should not be considered a line of therapy.
Antibody therapy in patients with indolent NHL (ie, 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 patients 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 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 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 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-gp inducers based on the US FDA Draft 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 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 nonexhaustive 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 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.