A Study of TAK-981 in Combination With Rituximab in Participants With Relapsed/Refractory (r/r) CD20-positive (CD20+) Non-Hodgkin Lymphoma (NHL)
A Study of TAK-981 in Combination With Rituximab in Participants With Relapsed/Refractory (r/r) CD20-positive (CD20+) Non-Hodgkin Lymphoma (NHL)
The purpose of this study is to determine the safety, tolerability and to establish the
 recommended Phase 2 dose (RP2D) of TAK-981 in combination with rituximab in participants with
 r/r CD20+ NHL in Phase 1, and to evaluate the efficacy of TAK-981 in combination with
 rituximab in select r/r CD20+ NHL indications in Phase 2.
The drug being tested in this study is called TAK-981 in combination with rituximab. The
 study will include a dose escalation phase (Phase 1) and an expansion phase in select NHL
 indications (Phase 2).

 The study will enroll approximately 130 participants, approximately 35 participants in Phase
 1 and approximately 95 participants in Phase 2. The participants with indolent or aggressive
 relapsed or refractory (r/r) NHL in Phase 1 will identify the maximum tolerated dose (MTD)
 and/or pharmacologically active dose (PAD). PAD can be defined retrospectively once MTD is
 reached and it can below MTD or coincide with it. In the dose escalation phase, the starting
 dose of TAK-981 will be 10 mg. The RP2D will be determined based on the available safety,
 preliminary pharmacokinetic (PK), pharmacodynamic information data, and after any early
 antitumor activity observed along with the statistical inference from the Bayesian Logistic
 Regression Modeling (BLRM).

 Participants in the Phase 2 will be enrolled once the Phase 1 of the study is completed, and
 MTD and/or PAD is determined. Phase 2 will explore the efficacy and safety of TAK-981 in
 combination with rituximab in participants with select r/r NHL types and indications.
 Participants in Phase 2 will be enrolled in one of the three treatment arms based on Cohorts:

 -  Cohort A: r/r DLBCL Progressed to CAR T-cell therapy

 -  Cohort B: r/r DLBCL with no CAR T-cell Prior Therapy

 -  Cohort C: r/r FL Progressed to Systemic Therapies

 This multi-center trial will be conducted in the United States and Canada. The overall time
 to participate in this study is approximately 48 months. Participants will make multiple
 visits to the clinic, and will attend the end of treatment (EOT) visit 30 days after
 receiving their last dose of drug or before the start of subsequent systemic anticancer
 therapy, whichever occurs first for a follow-up assessment.
Inclusion Criteria:

 Each participant must meet all the following inclusion criteria to be enrolled in the
 study:

 1. Participant Population:

 o. For Phase 1 Dose Escalation: o. aNHL including mantle cell lymphoma and DLBCL
 histologies such as transformed DLBCL from low-grade lymphoma (follicular or others),
 DLBCL associated with small-cell infiltration in bone marrow, B-cell lymphoma with
 intermediate features between DLBCL and Burkitt's lymphoma or with intermediate
 features between DLBCL and Hodgkin lymphoma, FL grade 3B, and aggressive B-cell
 lymphoma unclassifiable who must have previously received rituximab, cyclophosphamide,
 doxorubicin (hydroxydaunorubicin), vincristine, (Oncovin) and prednisone (R-CHOP) (or
 equivalent anti-CD20 containing therapy) and 1 additional line of therapy in the r/r
 setting.

 o. iNHL (including FL of grades 1-3A and marginal zone lymphoma) refractory to
 rituximab or to any other anti-CD20 monoclonal antibodies, who have received at least
 1 prior systemic therapy for r/r iNHL:

 o Rituximab or anti-CD20 refractoriness is defined as failure to respond to, or
 progression during, any previous rituximab/anti-CD20-containing regimen (monotherapy
 or combined with chemotherapy), or progression within 6 months of the last rituximab
 or anti-CD20 dose.

 Note: The minimum qualifying rituximab/anti-CD20 dose is 1 full cycle (that is,
 weekly*4 doses monotherapy or 1 complete dose if combined with chemotherapy). Prior
 anti-CD20 antibody or cytotoxic drugs may have been administered as single agents or
 as components of combination therapies. Each repeated course of the same single-agent
 or combination is considered an independent regimen.

 o. For Phase 2: o. r/r DLBCL progressed or relapsed after a prior CAR T-cells therapy
 that has received approval by a health authority for the treatment of DLBCL (Cohort
 A).

 o. r/r DLBCL that has progressed or relapsed after at least 2 but no more than 3 prior
 lines of systemic therapy and has not I prior cellular therapy. At least one prior
 line of therapy must have included a CD20-targeted therapy (Cohort B).

 o. r/r FL that has progressed or relapsed after at least 2 but no more than 3 prior
 lines of systemic therapy. At least one prior line of therapy must have included a
 CD20-targeted therapy (Cohort C).

 2. Must be considered ineligible in the opinion of the investigator, or refused
 autologous stem-cell transplantation.

 3. Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to
 (<=) 2.

 4. Adequate bone marrow function per local laboratory reference range at screening as
 follows:

 o Platelet count greater than or equal to (>=) 75.0*10^9/L, Grade 2 thrombocytopenia
 (platelet count >=50.0*10^9 per liter [/L]) is allowed if it is clearly due to marrow
 involvement with no evidence of myelodysplastic syndrome or hypoplastic bone marrow if
 found. Absolute neutrophil count (ANC) >=1.0*10^9/L. Hemoglobin >=85 gram per liter
 (g/L) (red blood cell [RBC] transfusion allowed >=14 days before assessment).

 5. Adequate renal and hepatic function, per local laboratory reference range at screening
 as follows:

 -  Calculated creatinine clearance >=45 milliliter per minute (mL/min) calculated
 with Cockcroft-Gault formula.

 -  Aspartate aminotransferase and alanine aminotransferase <=3.0*the upper limit of
 normal (ULN) of the institution's normal range; bilirubin <=1.5*ULN. Participants
 with Gilbert's syndrome may have a bilirubin level >1.5*ULN, per discussion
 between the investigator and the medical monitor.

 6. Left ventricular ejection fraction (LVEF) >=40 percent (%); as measured by
 echocardiogram or multiple gated acquisition scan (MUGA).

 7. Suitable venous access for safe drug administration and the study-required PK and
 pharmacodynamic sampling.

 8. Have at least 1 bidimensionally measurable lesion per Lugano Classification (>1.5
 centimeter [cm] in its largest dimension) by computed tomography (CT). Tumor lesions
 situated in a previously irradiated area are considered measurable if progression has
 been demonstrated in such lesions. In the Phase 2, Stage 1 portion of the study >1
 measurable lesions are required, 1 for biopsy, and 1 for response.

 9. Willing to consent to 1 mandatory pretreatment and 1 on-treatment skin biopsy during
 Phase 1. The skin biopsy entry requirement may be discontinued by the sponsor once
 there is enough pharmacodynamic evidence of target engagement.

 10. For participants enrolled in Phase 2, Stage, willing to consent to one mandatory
 pretreatment and 1 on-treatment tumor biopsy. For fresh tumor biopsies, the lesion
 must be accessible for a low risk biopsy procedure (those occurring outside the brain,
 lung/mediastinum, and intra-abdominal, or obtained with endoscopic procedures beyond
 the stomach or bowel). The skin biopsy entry requirement may be discontinued by the
 sponsor once there is enough pharmacodynamic evidence of target engagement. Outside of
 Phase 2 Stage 1, paired tumor biopsies are optional.

 11. Recovered to Grade 1, baseline or established as sequela, from all toxic effects of
 previous therapy (except alopecia, neuropathy, autoimmune endocrinopathies with stable
 endocrine replacement therapy, neurotoxicity [Grade 1 or 2 permitted], or bone marrow
 parameters [any of Grade 1, 2, permitted if directly related to bone marrow
 involvement]).

 Exclusion Criteria:

 Participants meeting any of the following exclusion criteria are not to be enrolled in the
 study:

 1. Central nervous system lymphoma; active brain or leptomeningeal metastases, as
 indicated by positive cytology from lumbar puncture or CT scan/magnetic resonance
 imaging (MRI).

 2. History of Grade >=3 infusion-related reaction (IRR) that lead to permanent
 discontinuation of previous rituximab treatment.

 3. Post transplantation lymphoproliferative disease except relapsed NHL after autologous
 stem cell transplantation.

 4. Undergone ASCT or treatment with cellular therapy including CAR T within <=3 months of
 TAK-981 dosing.

 5. Prior allogeneic hematopoietic stem-cell transplantation.

 6. Lymphomas with leukemic expression.

 7. Prior anticancer therapy including chemotherapy, hormonal therapy, or investigational
 agents within 2 weeks or within at least 5 half-lives before TAK-981 dosing (up to a
 maximum of 4 weeks), whichever is shorter. Low dose steroids (oral prednisone or
 equivalent <=20 mg per day), hormonal therapy for prostate cancer or breast cancer (in
 adjuvant situation), and treatment with bisphosphonates and receptor activator of
 nuclear factor kappa-B ligand (RANKL) inhibitors are allowed.

 8. Major surgery within 14 days before the first dose of study drug and not recovered
 fully from any complications from surgery.

 9. Significant medical diseases or conditions, as assessed by the Investigators and
 Sponsor that would substantially increase the risk-benefit ratio of participating in
 the study. This includes but is not limited to acute myocardial infarction or unstable
 angina within the last 6 months, uncontrolled diabetes mellitus, significant active
 bacterial, viral or fungal infections, severely immunocompromised state, severe
 non-compensated hypertension and congestive heart failure New York Heart Association
 Class III or IV, ongoing symptomatic cardiac arrhythmias of >Grade 2, pulmonary
 embolism, or symptomatic cerebrovascular events, or any other serious cardiac
 condition (example, pericardial effusion or restrictive cardiomyopathy). Chronic
 atrial fibrillation on stable anticoagulant therapy is allowed.

 10. Known chronic hepatitis C and/or positive serology (unless due to vaccination or
 passive immunization due to immunoglobulin (Ig) therapy) for chronic hepatitis B.
 Known Human Immunodeficiency Virus (HIV) infection.

 11. Second malignancy within the previous 3 years, except treated basal cell or localized
 squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ,
 resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for
 which the participant is not on active anticancer therapy.

 12. Receipt of any live vaccine (example, varicella, pneumococcus) within 4 weeks of
 initiation of study treatment.

 13. Active, uncontrolled autoimmune disease requiring >20 mg of prednisone or equivalent,
 cytotoxics or biologicals.

 14. Corticosteroid use within 1 week before the first dose of study drug, except as
 indicated for other medical conditions such as inhaled steroid for asthma, topical
 steroid use, or as premedication for administration of study drug or contrast.
 Participants requiring steroids at daily doses >20 mg prednisone equivalent systemic
 exposure daily, or those who are administered steroids for lymphoma control or white
 blood cell count lowering are not eligible.

 15. With baseline prolongation of the Fridericia-corrected QT interval (QTc) (QT interval
 with Fridericia correction method (example, repeated demonstration of QTcT interval
 >480 millisecond (ms), history of congenital long QT syndrome, or torsades de
 pointes).

 16. Receiving or requiring the continued use of medications that are known to be strong or
 moderate inhibitors and inducers of Cytochrome P450 3A4/5b (CYP3A4/5 b) and strong
 P-glycoprotein (Pgp) inhibitors. To participate in this study, such participants
 should discontinue use of such agents for at least 2 weeks (1 week washout for
 CYP3A4/5 inhibitors, and 2 weeks washout if using CYP3A4/5 inducers) before receiving
 a dose of TAK-981.