TAK-659 in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

The drug being tested is TAK-659. This study will look at the OR in participants with
relapsed or refractory DLBCL who take TAK-659.

The study will enroll approximately 122 participants. Participants will be assigned to:

• TAK-659 60 mg to 100 mg

All participants will be asked to take the tablets of TAK-659 at the same time each day
throughout the study in 28-day cycle.

This multi-center trial will be conducted in United States, United Kingdom, Spain, Italy,
France, Canada, Germany. The overall time to participate in this study is approximately 48
months. Participants will be assessed for disease response and progression during the PFS
follow-up of every 3 months after end of treatment (for participants who discontinue due to
reasons other than disease progression) and OS follow-up of every 3 months from the last dose
of study drug until death or conclusion of the study, whichever occurs first.

Inclusion Criteria:

1. Must have histologically confirmed DLBCL, including de novo disease or transformed
disease from indolent NHL.

a. High-grade B-cell lymphoma (BCL) with MYC and BCL-2 and/or BCL-6 translocations
(double-hit DLBCL under DLBCL, not otherwise specified [NOS], based on the 2008 World
Health Organization [WHO] classification criteria) is not eligible for this study.

2. Local pathology review for histological confirmation; A formalin-fixed,
paraffin-embedded (FFPE) tumor block or appropriately stained slides from a fresh
biopsy is required.

3. Relapsed or refractory to greater than or equal to (>=) 2 prior lines of chemotherapy
based on standard of care with certain requirements for prior therapy.

4. Documented investigator-assessed relapse or progression after the last treatment is
required if the participant responded and then progressed on the prior treatment.

5. Measurable disease per IWG 2007 criteria.

6. Eastern Cooperative Oncology Group (ECOG) performance status less than (<) 2.

7. Life expectancy of greater than (>) 3 months.

8. Adequate organ function, including the following:

1. Bone marrow reserve: absolute neutrophil count (ANC) >=1000/microliter (μL),
platelet count >=75,000/μL (>=50,000/μL for participants with bone marrow
involvement), and hemoglobin >=8 gram per deciliter (g/dL).

2. Hepatic: total bilirubin less than or equal to (<=) 1.5 times the upper limit of
the normal range (ULN); alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) <=2.5*ULN.

3. Renal: creatinine clearance >=60 milliliter per minute (mL/min).

4. 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.

- Glycosylated hemoglobin is <=6.5% hyperglycemic participants permitted if
glucose is well controlled by hypoglycemic medication).

Exclusion Criteria:

1. Central nervous system (CNS) lymphoma; active brain or leptomeningeal metastases.

2. Known human immunodeficiency virus (HIV)-related malignancy.

3. 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 agents; <=8 weeks for cell-based therapy or anti-tumor vaccine).

4. Radiotherapy less than 3 weeks before the first dose of study treatment. If prior
radiotherapy occurred <4 to 6 weeks before study start, as radiated lesions cannot be
reliably assessed by fluorodeoxyglucose-positron emission tomography (FDG-PET),
nonradiated target lesions are required for eligibility, and prior radiotherapy
information must be submitted to the IRC.

5. Known HIV positive, hepatitis B surface antigen positive or known or suspected active
hepatitis C infection.

6. 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 any time.

7. Participants with certain cardiovascular conditions are excluded.

8. Major surgery within 14 days before the first dose of study drug or incomplete
recovery from any complications from surgery.

9. Systemic infection requiring parenteral antibiotic therapy or other serious infection
(bacterial, fungal, or viral) within 21 days before the first dose of study drug.

10. Treatment with high-dose corticosteroids for anticancer purposes within 7 days before
the first dose of TAK-659.

11. 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.

12. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of TAK-659.

13. 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 timeframe 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.