A Study of TAK-659 in Combination With NKTR-214 in Participants With Advanced Non-Hodgkin Lymphoma (NHL)

The drugs that are being tested in this study are TAK-659 and NKTR-214. TAK-659 in
combination with NKTR-214 is being tested for participants with advanced NHL after 2 but no
more than 3 prior lines of therapy. The study will determine the MTD or the RP2D of TAK-659
when administered with NKTR-214.

The study will enroll approximately 40 participants, approximately 18 to 24 participants in a
dose escalation phase, and approximately 12 participants will be added after determination of
MTD/RP2D/MAD in the safety expansion phase. This study consists of 2 phases: a dose
escalation phase and a safety expansion phase.

TAK-659 and NKTR-214 doses will be escalated according to a standard 3+3 dose escalation
schema. TAK-659 60 mg + NKTR-214 0.003 mg/kg is the starting dose. Participants could also
receive 40 mg, 80 mg or 100 mg QD TAK-659 during dose escalation and .003mg/kg or .006mg/kg
of NKTR-214. Alternative regimens or schedules of TAK-659 are permissible following
discussion between sponsor and investigators. In dose escalation phase, dose levels will be
escalated based on available safety and tolerability data to determine the MTD or MAD or
RP2D. Dose for safety expansion phase will be based on available safety, pharmacodynamics,
and preliminary efficacy data.

For participants enrolled in either the dose escalation or safety expansion phases, the
maximum duration of treatment will be 12 months unless, in the opinion of the investigator
and with the agreement of the sponsor, the participant would derive benefit from continued
therapy beyond 12 months. Participants will make multiple visits to the clinic, and will have
an end of treatment visit 30 days after the last dose of TAK-659 or NKTR-214 or the start of
subsequent alternative anticancer therapy, whichever occurs first. Participants will be
followed for 90 days after the last dose to permit the detection of any delayed
treatment-related adverse events (AEs).

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of advanced NHL of any histology
(with the exception of participants with Waldenstrom macroglobulinemia [WM] and
chronic lymphocytic leukemia [CLL]).

2. Radiographically or clinically measurable disease with at least 1 target lesion per
Lugano 2014 criteria for malignant lymphoma.

3. Participants who are refractory or relapsed after at least 2 prior lines of therapy
but no more than 3 prior lines of therapy due to progression, intolerance, or
physician/participant decision, and for whom no effective standard therapy is
available per the investigator's assessment. Requirements for prior therapy depending
on disease type are outlined in the protocol, however all patients must be ineligible
for hematopoietic stem cell transplant.

4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and life
expectancy of >3 months.

5. Must have adequate organ function.

6. Recovered (that is, less than or equal to [<=] Grade 1 toxicity) from the clinically
significant 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. 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
AEs.

2. Known HIV infection or HIV-related malignancy, hepatitis B surface antigen positive,
or known or suspected active hepatitis C infection.

3. 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.

4. Systemic anticancer treatment (including investigational agents) or radiotherapy less
than 2 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 antitumor vaccine).

5. Prior chimeric antigen receptor T-cell (CAR-T) therapy.

6. Participants in need of immediate cytoreductive therapy.

7. Prior autologous stem cell transplant (ASCT) within 12 months or prior ASCT at any
time without full hematopoietic recovery before Cycle 1 Day 1 or allogeneic stem cell
transplant any time.

8. Prior treatment with a SYK inhibitor or interleukin-2 (IL-2) therapy.

9. Active, known, or suspected autoimmune disease. Participants requiring systemic
treatment within the past 3 months or with a documented history of clinically severe
autoimmune disease that requires systemic steroids or immunosuppressive agents.
(Exceptions include any patient taking 10 mg or less of prednisone or equivalent,
participants with vitiligo, hypothyroidism stable on hormone replacement, type 1
diabetes, Graves disease, Hashimoto disease, alopecia areata, eczema, or with medical
monitor approval.)

10. History of organ or tissue transplant that requires systemic use of immunosuppressive
agents.

11. Major surgery within 14 days before the first dose of study drug and not recovered
fully from any complications from surgery or systemic infection requiring intravenous
antibiotic therapy or other serious infection within 14 days before the first dose of
study drug.

12. Use of >2 antihypertensive medications for management of hypertension (including
diuretics).

13. 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.

14. 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.

15. Use or consumption of:

- Medications or supplements that are known to be inhibitors of P-gp and/or strong
reversible inhibitors of cytochrome (CYP3A), strong CYP3A mechanism-based
inhibitors, strong CYP3A inducers or P-gp inducers within 5 times the inhibitor
half-life or within 7 days 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.

- 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.