A Study of TAK-659 in Combination With Nivolumab in Participants With Advanced Solid Tumors

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02834247
• Collaborator: (none)
• Enrollment: 41
• Locations: 22
• Arms: 5
• Actual Duration (Months): 27.6
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), safety and efficacy of TAK-659 in combination with nivolumab in participants with advanced solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Triple-Negative Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Head and Neck Carcinoma, Squamous Cell; Advanced Solid Tumors	Drug: TAK-659; Drug: Nivolumab	Phase 1

Detailed Description

The drug being tested is TAK-659.This study will look at the determination of the MTD/RP2D and efficacy measured by ORR in participants who take TAK-659 in combination with nivolumab. The study will include a dose escalation phase (Part 1), a potential nivolumab fixed dose cohort, and a dose expansion phase (Part 2).

The study will enroll approximately 120 participants, approximately 9-12 in the dose escalation phase and approximately 36 in each of the 3 dose expansion cohorts. Participants will be assigned to 1 of the 4 treatment groups:

• Part 1: Advanced Solid Tumors

• Potential Nivolumab Fixed Dose Cohort

• Part 2: Metastatic TNBC

• Part 2: Metastatic NSCLC

• Part 2: Metastatic HNSCC

All participants will be asked to take the tablets of TAK-659 at the same time each day throughout the study. Participants will also receive intravenous infusion of nivolumab (within 30 minutes after the TAK-650 dose) once every 2 weeks. This multi-center trial will be conducted globally. The overall time to receive treatment in this study is approximately 12 months. Participants will be assessed for disease response and PD during the PFS follow-up of 6 months (for participants who discontinue due to reasons other than PD) and OS follow-up of 12 months from the last dose of study drug.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 1b Study to Evaluate TAK-659 in Combination With Nivolumab in Patients With Advanced Solid Tumors
• Actual Study Start Date: Aug 12, 2016
• Actual Primary Completion Date: Nov 30, 2018
• Actual Study Completion Date: Nov 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: Advanced Solid Tumors TAK-659 60 milligram (mg), tablets, orally, once daily in each 28-day treatment cycle in combination with nivolumab 3 milligram per kilogram (mg/kg), infusion over 60 minutes, intravenously (IV), on Days 1 and 15 in each 28 day treatment cycle until PD or unacceptable toxicity. Dose escalation of TAK-659 to 100 mg may be done using a 3 + 3 dose escalation design to determine a maximum tolerated dose (MTD) and/or RP2D.	Drug: TAK-659; TAK-659 Tablets.; Drug: Nivolumab; Nivolumab intravenous infusion.
Experimental: Nivolumab Fixed Dose Cohort After RP2D of TAK-659 has been identified, based on evaluation of combination with weight-based dose of nivolumab (3 mg/kg), RP2D may be evaluated in combination with a fixed dose of 240 mg IV nivolumab after discussion between investigator and sponsor for all types of advanced solid tumors. For single-agent nivolumab, fixed dose is expected to have equal exposure, safety, and efficacy as weight-based (3 mg/kg) dose. If nivolumab fixed dose is evaluated with TAK-659 RP2D, 3 participants will be initially enrolled into cohort. Following evaluation of safety, efficacy, and any available PK data, along with discussions between investigator and sponsor, 3 additional participants may be enrolled into cohort for a total of 3 to 6 participants. If >=1 out of 6 participants experiences dose-limiting toxicity (DLT) in Cycle 1, or significant safety issues are seen in Cycle 2 and beyond, re-evaluation of TAK-659 RP2D when administered with a fixed dose of nivolumab is permitted.	Drug: TAK-659; TAK-659 Tablets.; Drug: Nivolumab; Nivolumab intravenous infusion.
Experimental: Part 2: Metastatic Triple-negative Breast Cancer (TNBC) Participants with metastatic TNBC will receive TAK-659 at the RP2D as determined in Part 1, tablets, orally, once daily in each 28-day treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Day 1 and Day 15 of each 28 day treatment cycle until PD or unacceptable toxicity. A subset of participants will receive two weeks of TAK-659 monotherapy during Cycle 1, and will receive nivolumab beginning on Day 15 of Cycle 1. The dose of nivolumab will be either 3 mg/kg or 240 mg IV, dependent on whether the 240 mg fixed-dose cohort is evaluated and deemed safe and tolerable. If so, the dosing regimen may switch to 240 mg, on the basis of change in clinical practice and discussion between the investigator and sponsor. If the nivolumab fixed-dose evaluation cohort is not run, the dose of nivolumab for all participants in the dose expansion phase will be 3 mg/kg.	Drug: TAK-659; TAK-659 Tablets.; Drug: Nivolumab; Nivolumab intravenous infusion.
Experimental: Part 2: Metastatic Non-small Cell Lung Cancer (NSCLC) Participants with metastatic NSCLC will receive TAK-659 at the RP2D as determined in Part 1, tablets, orally, once daily in each 28-day treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Day 1 and Day 15 of each 28 day treatment cycle until PD or unacceptable toxicity. A subset of participants will receive two weeks of TAK-659 monotherapy during Cycle 1, and will receive nivolumab beginning on Day 15 of Cycle 1.disease or unacceptable toxicity. The dose of nivolumab will be either 3 mg/kg or 240 mg IV, dependent on whether the 240 mg fixed-dose cohort is evaluated and deemed safe and tolerable. If so, the dosing regimen may switch to 240 mg, on the basis of change in clinical practice and discussion between the investigator and sponsor. If the nivolumab fixed-dose evaluation cohort is not run, the dose of nivolumab for all participants in the dose expansion phase will be 3 mg/kg.	Drug: TAK-659; TAK-659 Tablets.; Drug: Nivolumab; Nivolumab intravenous infusion.
Experimental: Part 2: Metastatic HNSCC Participants with Head and Neck Squamous Cell Carcinoma (HNSCC) will receive TAK-659 at the RP2D as determined in Part 1, tablets, orally, once daily in each 28-day treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Day 1 and Day 15 of each 28 day treatment cycle until PD or unacceptable toxicity. A subset of participants will receive two weeks of TAK-659 monotherapy during Cycle 1, and will receive nivolumab beginning on Day 15 of Cycle 1. The dose of nivolumab will be either 3 mg/kg or 240 mg IV, dependent on whether the 240 mg fixed-dose cohort is evaluated and deemed safe and tolerable. If so, the dosing regimen may switch to 240 mg, on the basis of change in clinical practice and discussion between the investigator and sponsor. If the nivolumab fixed-dose evaluation cohort is not run, the dose of nivolumab for all participants in the dose expansion phase will be 3 mg/kg.	Drug: TAK-659; TAK-659 Tablets.; Drug: Nivolumab; Nivolumab intravenous infusion.

Outcome Measures

Primary Outcome Measures

1. Part 1, Dose Escalation Phase: Maximum Tolerated Dose (MTD) [At end of Cycle 1 Day 28]

   The MTD was defined as the dose range at which less than or equal to (<=) 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1). Toxicities were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

2. Part 1, Dose Escalation Phase: Recommendation Phase 2 Dose (RP2D) [Up to Cycle 12 (each Cycle length is equal to [=] 28 days)]

   RP2D was evaluated from cumulative toxicities in Cycle 1 and beyond. Toxicities were evaluated according to NCI CTCAE version 4.03.

3. Part 2, Dose Expansion Phase: Overall Response Rate (ORR) [From the start of study treatment until the start of subsequent anticancer therapy (up to 28 months)]

   ORR was defined as the percentage of participants who's best overall response (BOR) was either complete response (CR) or partial response (PR). The ORR assessment was based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The BOR was defined as the best response recorded from the start of the study treatment until the start of subsequent anticancer therapy. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (<) 10 millimeter (mm). PR: was at least a 30 percent (%) decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.

Secondary Outcome Measures

1. Percentage of Participants Who Experienced at Least One Treatment-emergent Adverse Events (TEAEs), Grade 3 or 4 Adverse Events (AEs), Serious Adverse Events (SAEs), and TEAEs Leading to Discontinuation [From the first dose of the study drug up to 28 days after the last dose of the study drug or the start of subsequent anticancer therapy (up to 28 months)]

   AEs Grades were evaluated as per NCI CTCAE version 4.03.

2. Part 2, Dose Expansion Phase: Disease Control Rate (DCR) [From the start of study treatment until the start of subsequent anticancer therapy (up to 28 months)]

   DCR was the percentage of participants who had BOR with either CR, PR, or stable disease (SD). The DCR assessment was based on RECIST version 1.1. The BOR was defined as the best response recorded from the start of the study treatment until the start of subsequent anticancer therapy. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: was at least a 30% decrease in SOD of target lesions, taking as reference the baseline SOD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD.

3. Part 2, Dose Expansion Phase: Duration of Response (DOR) [From the date of first documentation of a response to the date of first documented PD (up to 28 months)]

   DOR was defined as the time from the date of first documentation of a response to the date of first documented progressive disease. DOR assessment was based on RECIST v1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. DOR was calculated using Kaplan-Meier analysis.

4. Part 2, Dose Expansion Phase: Percentage of Participants With PD at Month 6 [Month 6]

   PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. The PD assessment was based on RECIST v1.1.

5. Part 2, Dose Expansion Phase: Progression Free Survival (PFS) [From the date of first study drug administration up to date of first documented PD or death due to any cause, whichever occurred first (up to 28 months)]

   PFS was defined as the time from date of first study drug administration to the date of first documented PD or death due to any cause, whichever occurred first. The PFS assessment was based on RECIST v1.1. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was calculated using Kaplan-Meier estimate.

6. Part 2, Dose Expansion Phase: Overall Survival (OS) [Baseline up to the date of death due to any cause (up to 28 months)]

   OS was calculated from date of participant enrollment to the date of participant's death due to any cause. OS was assessed based on RECIST v 1.1. Participants without documentation of death at time of the analysis were censored as of the date the participant was last known to be alive, or the data cutoff date, whichever was earlier. OS was calculated using Kaplan-Meier estimate. Enrollment was defined as the time of the initiation of the first dose of study drug.

7. Part 1, Dose Escalation Phase, Cmax: Maximum Observed Plasma Concentration for TAK-659 [Cycle 1, Days 1 and 15: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)]

8. Part 1, Dose Escalation Phase, Tmax: Time to Reach the Cmax for TAK-659 [Cycle 1, Days 1 and 15: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)]

9. Part 1, Dose Escalation Phase, AUCtau: Area Under the Plasma Concentration-time Curve From Time 0 to Tau Over the Dosing Interval for Area Under the Plasma Concentration for TAK-659 [Cycle 1, Days 1 and 15: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Is a male or female participant aged 18 years or older.

2. Has eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

3. Female participants who:

• Are postmenopausal for at least 1 year before the Screening visit, or

• Are surgically sterile, or

• If childbearing potential, agree to practice 2 effective methods of contraception, 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 participants. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)

Male participants, 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 participants. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)

1. 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 participants at any time without prejudice to future medical care.

2. Suitable venous access for the study-required blood sampling, including PK and pharmacodynamic (PD) sampling.

3. Clinical laboratory values and other measures as specified below within 28 days before the first dose of study drug:

• Total bilirubin must be <=1.5*the upper limit of normal (ULN).

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be <=2.5*ULN.

• Creatinine clearance must be greater than or equal to (>=) 60 milliliter per (mL/) minute as estimated by the Cockcroft Gault equation or based on urine collection (12 or 24 hours).

• Hemoglobin must be >=8 gram per deciliter (g/dL), absolute neutrophil count (ANC) must be >=1500 per microliter (/mcL), and platelet count must be >=75,000/mcL.

• Lipase must be <=1.5ULN and amylase <=1.5ULN with no clinical symptoms suggestive of pancreatitis and cholecystitis.

• Blood pressure <=Grade 1 (hypertensive participants are permitted if their blood pressure is controlled to <=Grade 1 by hypotensive medications and glycosylated HbA1C <=6.5%).

1. Recovered (that is, <=Grade 1 toxicity) from the reversible effects of prior anticancer therapy.

2. To be enrolled in the dose escalation phase of the study, participants must have a radiographically or clinically evaluable tumor, but measurable disease as defined by RECIST version 1.1 is not required for participation in this study.

3. To be enrolled in the TNBC expansion cohort, participants must have:

• Histologically confirmed, metastatic TNBC with measurable disease per RECIST version 1.1.

• Triple-negative disease (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) negativity confirmed on a histological biopsy of a metastatic tumor lesion (receptor conversion not allowed).

• Safely accessible tumor lesions (based on investigator's assessment) for serial pre treatment and post treatment biopsies are required for participants receiving TAK-659 monotherapy run-in treatment for 2 weeks followed by TAK-659 plus nivolumab combination treatment [ approximately 10/30 response-evaluable participants]; adequate, newly obtained, core or excisional biopsy of a metastatic tumor lesion not previously irradiated is required. Mandatory biopsies will be taken before TAK-659 monotherapy, after the 2 weeks of TAK-659 monotherapy, and after 6 weeks of TAK-659 plus nivolumab combination therapy. An optional biopsy may be taken at PD with additional consent from the participants.

• One, 2, or 3 prior lines of chemotherapy for metastatic disease and with progression of disease on last treatment regimen.

• For the purposes of this study, neoadjuvant and/or adjuvant chemotherapy regimens do not count as a prior line of therapy.

• Prior treatment must include an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting with the exception for participants who are clinically contraindicated for these chemotherapies.

1. To be enrolled in the NSCLC expansion cohort, participants must have:

• Locally advanced or metastatic (stage IIIB, stage IV, or recurrent) NSCLC with measurable lesions per RECIST version 1.1.

• PD during or following at least 1 prior treatment. Participants should have received a prior platinum-based 2-drug regimen for locally advanced, unresectable/ inoperable or metastatic NSCLC or disease recurrence within 6 months of treatment with a platinum-based adjuvant/neoadjuvant regimen or combined modality (example, chemoradiation) regimen with curative intent.

• Participants with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic alternations should have PD on prior United States (US) Food and Drug Administration (FDA) approved therapy for these aberrations.

• Safely accessible tumor lesions (based on investigator's assessment) for serial pretreatment and posttreatment biopsies are required for participants receiving TAK-659 monotherapy run-in treatment for 2 weeks followed by TAK-659 plus nivolumab combination treatment (approximately10/30 response-evaluable participants); adequate, newly obtained, core or excisional biopsy of a metastatic tumor lesion not previously irradiated is required. Mandatory biopsies will be taken before TAK-659 monotherapy, after the 2 weeks of TAK-659 monotherapy, and after 6 weeks of TAK-659 plus nivolumab combination therapy. An optional biopsy may be taken at progression with additional consent from the participants.

1. To be enrolled in the HNSCC expansion cohort, participants must have:

• Histologically confirmed recurrent or metastatic HNSCC (oral cavity, pharynx, or larynx) that is stage III/IV and not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).

• Histologically confirmed recurrent or metastatic squamous cell carcinoma of unknown primary or nonsquamous histologies (example, mucosal melanoma) are not allowed.

• Histologically confirmed recurrent or metastatic carcinoma of the nasopharynx is allowed, but these participants will not be included as response-evaluable participants for efficacy analysis of HNSCC.

• Measurable disease per RECIST version 1.1.

• Tumor progression or recurrence within 6 months of the last dose of platinum-based therapy in the adjuvant (that is, with radiation after surgery), primary (that is, with radiation), recurrent, or metastatic setting.

• Safely accessible tumor lesions (based on investigator's assessment) for serial pretreatment and posttreatment biopsies are required for participants receiving TAK-659 monotherapy run-in treatment for 2 weeks followed by TAK-659 plus nivolumab combination treatment (approximately 10/30 response-evaluable participants); adequate, newly obtained, core or excisional biopsy of a metastatic tumor lesion not previously irradiated is required. Mandatory biopsies will be taken before TAK-659 monotherapy, after the 2 weeks of TAK-659 monotherapy, and TAK-659 after 6 weeks of TAK-659 plus nivolumab combination therapy. An optional biopsy may be taken at progression with additional consent from the participants.

Exclusion Criteria:

1. Has active brain metastases or leptomeningeal metastases.

2. Has active, or suspected autoimmune disease or a history of known autoimmune disease, with the exception of:

o Participants with vitiligo, type I diabetes mellitus, resolved childhood asthma/atopy, residual hypothyroidism due to autoimmune condition requiring only hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.

1. Any condition requiring systemic treatment with corticosteroids (less than [>]10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 before first dose of study drug.

o Corticosteroids for topical use or in nasal spray are allowed, as are inhaled steroids and adrenal replacement steroid doses >10 mg daily in the absence of active autoimmune disease.

1. Has history of pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on the Screening chest computed tomography scan (CT scan); history of radiation pneumonitis in the radiation field (fibrosis) is permitted.

2. Has history of interstitial lung disease.

3. Prior therapy with experimental antitumor vaccines; any T-cell co-stimulation agents or inhibitors of checkpoint pathways, such as anti- programmed cell death protein 1 (PD-1), anti- programmed cell death 1 ligand 1 (PD-L1), anti- programmed cell death 1 ligand 2 (PD-L2), anti-CD137, or anti-CTLA-4 antibody; or other agents specifically targeting T cells are prohibited. However, for dose escalation, prior treatment with the marketed inhibitors of the immune checkpoint pathway, such as nivolumab and pembrolizumab, is allowed. In addition, in each of the expansion cohorts, 6 response-evaluable participants with prior exposure to anti-PD-1 or anti-PD-L1 agents will be allowed to enroll.

4. Has 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.

5. Has life-threatening illness unrelated to cancer.

6. Is female participant 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.

7. Systemic anticancer treatment including investigational agents or radiotherapy <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) or have not recovered from acute toxic effects from prior chemotherapy and radiotherapy.

8. Prior treatment with investigational agents =<21 days or =<5*their half-lives (whichever is shorter) before the first dose of study treatment. A minimum of 10 days should elapse from prior therapy to initiating protocol therapy.

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

10. Systemic infection requiring intravenous antibiotic therapy or other serious infection within 14 days before the first dose of study drug.

11. Known human immunodeficiency virus (HIV) positive (testing not required).

12. Known hepatitis B surface antigen-positive or known or suspected active hepatitis C infection (testing not required).

13. 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.

14. Any clinically significant comorbidities, such as uncontrolled pulmonary disease, known impaired cardiac function or clinically significant cardiac disease (specified below), active central nervous system disease, active infection, or any other condition that could compromise the participant's participation in the study.

Participants with any of the following cardiovascular conditions are excluded:

• Acute myocardial infarction within 6 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.

• Fridericia 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.

1. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-659 including difficulty swallowing tablets; diarrhea

Grade 1 despite supportive therapy.

1. 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.

• Non-oncology vaccine therapies for prevention of infectious diseases (example, human papillomavirus [HPV] vaccine) within 4 weeks of study drug administration. The inactivated seasonal influenza vaccine can be given to participants before treatment and while on therapy without restriction. Influenza vaccines containing live virus or other clinically indicated vaccinations for infectious diseases (example, pneumovax, varicella) may be permitted but must be discussed with the sponsor's medical monitor and may require a washout period before and after administration of vaccine.

• 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.

• Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are prohibited during the study.

1. For dose expansion participants who will have tumor biopsies collected:

• ECOG performance status >1.

• Activated partial thromboplastin time (aPTT) or plasma thromboplastin (PT) outside the institution's standard of care.

• Platelet count <75,000/mcL.

• Known bleeding diathesis or history of abnormal bleeding, or any other known coagulation abnormalities that would contraindicate the tumor biopsy procedure.

• Ongoing therapy with any anticoagulant or antiplatelet agents (example, aspirin, clopidogrel, coumadin, heparin, or warfarin) that cannot be held to permit tumor biopsy).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSD	La Jolla	California	United States	92093
2	Emory	Atlanta	Georgia	United States	30322
3	Massachusetts General	Boston	Massachusetts	United States	2114
4	Barbara Ann Karmanos	Detroit	Michigan	United States	48201
5	Roswell Park	Buffalo	New York	United States	14263
6	Fox Chase	Philadelphia	Pennsylvania	United States	19111
7	Vanderbilt	Nashville	Tennessee	United States	37232
8	Mary Crowley Research Centers	Dallas	Texas	United States	75002
9	US Oncology	Fairfax	Virginia	United States	22031
10	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) S.r.l	Meldola		Italy	47014
11	Istituto di Ricovero e Cura a Carattere Scientifico - Istituto Clinico Humanitas (Humanitas Research	Milan		Italy	20089
12	Ospedale San Raffaele	Milan		Italy	20132
13	Azienda Ospedaliero - Universitaria di Modena Policlinico	Modena		Italy	41124
14	Azienda Ospedaliera Universitaria Senese - Policlinico Santa Maria Alle Scotte	Siena		Italy	53100
15	Hospital General Universitario Gregorio Maranon	Madrid		Spain	28007
16	Hospital Universitario Ramon y Cajal	Madrid		Spain	28034
17	Hospital Clinico Universitario Virgen de la Victoria	Malaga		Spain	29010
18	Consejo Superior de Investigaciones Cientificas (CSIC) - Centro de Investigacion del Cancer (CIC)	Salamanca		Spain	37007
19	Hospital Universitario La Fe	Valencia		Spain	46009
20	Hospital Clinico Universitario de Valencia (CHUV)	Valencia		Spain	46010
21	The Newcastle upon Tyne Hospitals NHS Foundation Trust - Freeman Hospital - Northern Centre for Canc	Newcastle upon Tyne		United Kingdom	NE7 7DN
22	University Hospital Southampton NHS Foundation Trust - Southampton General Hospital	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director Clinical Science, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Statistical Analysis Plan - Jan 22, 2019
• Study Protocol - Apr 27, 2017

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02834247
• Other Study ID Numbers: C34003; 2016-000853-10; U1111-1181-8312
• First Posted: Jul 15, 2016
• Last Update Posted: Mar 31, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug Therapy
• Additional relevant MeSH terms: Carcinoma; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Triple Negative Breast Neoplasms; Nivolumab

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 13 investigative sites in the United States, Spain and United Kingdom from 12 August 2016 to 30 November 2018.
Pre-assignment Detail	Participants with advanced solid tumors and metastatic TNBC were enrolled in Parts 1 and 2 respectively. Part 2 cohorts: TNBC cohort was discontinued due to insufficient efficacy of drug. Study was terminated before start of potential fixed dose cohort, non-small cell lung cancer cohort and head and neck squamous cell carcinoma cohort.

Arm/Group Title	Part 1: TAK-659 60 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 80 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 100 mg + Nivolumab 3 mg/kg	Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
Arm/Group Description	TAK-659 60 milligram (mg), tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 milligram per kilogram (mg/kg), infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until progressive disease (PD) or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 100 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 13) in Dose Expansion Phase in participants with metastatic triple negative breast cancer (TNBC).
Period Title: Dose Escalation Phase
STARTED	8	11	5	0
COMPLETED	0	0	0	0
NOT COMPLETED	8	11	5	0
Period Title: Dose Escalation Phase
STARTED	0	0	0	17
COMPLETED	0	0	0	0
NOT COMPLETED	0	0	0	17

Baseline Characteristics

Arm/Group Title	Part 1: TAK-659 60 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 80 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 100 mg + Nivolumab 3 mg/kg	Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)	Total
Arm/Group Description	TAK-659 60 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 100 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 13) in Dose Expansion Phase in participants with metastatic TNBC.	Total of all reporting groups
Overall Participants	8	11	5	17	41
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.8 (8.53)	51.2 (16.04)	56.8 (16.22)	49.2 (8.62)	52.3 (12.08)
Sex: Female, Male (Count of Participants)
Female	5 62.5%	8 72.7%	2 40%	17 100%	32 78%
Male	3 37.5%	3 27.3%	3 60%	0 0%	9 22%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	1 20%	0 0%	1 2.4%
Not Hispanic or Latino	8 100%	10 90.9%	4 80%	15 88.2%	37 90.2%
Unknown or Not Reported	0 0%	1 9.1%	0 0%	2 11.8%	3 7.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	2 18.2%	0 0%	1 5.9%	3 7.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 12.5%	0 0%	1 20%	2 11.8%	4 9.8%
White	7 87.5%	9 81.8%	4 80%	12 70.6%	32 78%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	2 11.8%	2 4.9%
Region of Enrollment (Count of Participants)
Spain	0 0%	0 0%	0 0%	9 52.9%	9 22%
United Kingdom	0 0%	0 0%	0 0%	2 11.8%	2 4.9%
United States	8 100%	11 100%	5 100%	6 35.3%	30 73.2%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	166.09 (11.473)	166.58 (11.360)	167.00 (5.523)	164.03 (8.245)	165.48 (9.334)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	71.75 (19.006)	60.11 (17.393)	73.62 (13.646)	69.50 (12.266)	67.92 (15.572)

Outcome Measures

1. Primary Outcome

Title	Part 1, Dose Escalation Phase: Maximum Tolerated Dose (MTD)
Description	The MTD was defined as the dose range at which less than or equal to (<=) 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1). Toxicities were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
Time Frame	At end of Cycle 1 Day 28

Outcome Measure Data

Analysis Population Description

The DLT-evaluable population was defined as participants who had met the minimum treatment and safety evaluation requirements of the study and/or who experienced a DLT during Cycle 1.

Arm/Group Title	Part 1: Dose Escalation Participants
Arm/Group Description	TAK-659 60 mg, 80 mg or 100 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48).
Measure Participants	19
Number [mg]	80

2. Primary Outcome

Title	Part 1, Dose Escalation Phase: Recommendation Phase 2 Dose (RP2D)
Description	RP2D was evaluated from cumulative toxicities in Cycle 1 and beyond. Toxicities were evaluated according to NCI CTCAE version 4.03.
Time Frame	Up to Cycle 12 (each Cycle length is equal to [=] 28 days)

Outcome Measure Data

Analysis Population Description

The DLT-evaluable population was defined as participants who had met the minimum treatment and safety evaluation requirements of the study and/or who experienced a DLT during Cycle 1.

Arm/Group Title	Part 1: Dose Escalation Participants
Arm/Group Description	TAK-659 60 mg, 80 mg or 100 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48).
Measure Participants	19
Number [mg]	80

3. Primary Outcome

Title	Part 2, Dose Expansion Phase: Overall Response Rate (ORR)
Description	ORR was defined as the percentage of participants who's best overall response (BOR) was either complete response (CR) or partial response (PR). The ORR assessment was based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The BOR was defined as the best response recorded from the start of the study treatment until the start of subsequent anticancer therapy. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (<) 10 millimeter (mm). PR: was at least a 30 percent (%) decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.
Time Frame	From the start of study treatment until the start of subsequent anticancer therapy (up to 28 months)

Outcome Measure Data

Analysis Population Description

The response-evaluable population was defined as participants who received at least 1 dose of study drug, had measurable disease at Baseline, and had at least 1 post-baseline disease assessment.

Arm/Group Title	Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
Arm/Group Description	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 13) in Dose Expansion Phase in participants with metastatic TNBC.
Measure Participants	15
Number [percentage of participants]	0 0%

4. Secondary Outcome

Title	Percentage of Participants Who Experienced at Least One Treatment-emergent Adverse Events (TEAEs), Grade 3 or 4 Adverse Events (AEs), Serious Adverse Events (SAEs), and TEAEs Leading to Discontinuation
Description	AEs Grades were evaluated as per NCI CTCAE version 4.03.
Time Frame	From the first dose of the study drug up to 28 days after the last dose of the study drug or the start of subsequent anticancer therapy (up to 28 months)

Outcome Measure Data

Analysis Population Description

The safety population was defined as all the participants who received at least 1 dose of study drug.

Arm/Group Title	Part 1: TAK-659 60 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 80 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 100 mg + Nivolumab 3 mg/kg	Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
Arm/Group Description	TAK-659 60 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 100 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 13) in Dose Expansion Phase in participants with metastatic TNBC.
Measure Participants	8	11	5	17
TEAEs	100 1250%	100 909.1%	100 2000%	100 588.2%
Grade 3 or 4 AEs	87.5 1093.8%	81.8 743.6%	100 2000%	76.5 450%
SAEs	75.0 937.5%	63.6 578.2%	80.0 1600%	70.6 415.3%
TEAEs Leading to Discontinuation	25.0 312.5%	27.3 248.2%	20.0 400%	23.5 138.2%

5. Secondary Outcome

Title	Part 2, Dose Expansion Phase: Disease Control Rate (DCR)
Description	DCR was the percentage of participants who had BOR with either CR, PR, or stable disease (SD). The DCR assessment was based on RECIST version 1.1. The BOR was defined as the best response recorded from the start of the study treatment until the start of subsequent anticancer therapy. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: was at least a 30% decrease in SOD of target lesions, taking as reference the baseline SOD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD.
Time Frame	From the start of study treatment until the start of subsequent anticancer therapy (up to 28 months)

Outcome Measure Data

Analysis Population Description

The response-evaluable population was defined as participants who received at least 1 dose of study drug, had measurable disease at Baseline, and had at least 1 post-baseline disease assessment.

Arm/Group Title	Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
Arm/Group Description	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 13) in Dose Expansion Phase in participants with metastatic TNBC.
Measure Participants	15
Number [percentage of participants]	26.7 333.8%

6. Secondary Outcome

Title	Part 2, Dose Expansion Phase: Duration of Response (DOR)
Description	DOR was defined as the time from the date of first documentation of a response to the date of first documented progressive disease. DOR assessment was based on RECIST v1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. DOR was calculated using Kaplan-Meier analysis.
Time Frame	From the date of first documentation of a response to the date of first documented PD (up to 28 months)

Outcome Measure Data

Analysis Population Description

The response-evaluable population was defined as participants who received at least 1 dose of study drug, had measurable disease at Baseline, and had at least 1 post-baseline disease assessment.

Arm/Group Title	Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
Arm/Group Description	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 13) in Dose Expansion Phase in participants with metastatic TNBC.
Measure Participants	15
Median (95% Confidence Interval) [months]	NA

7. Secondary Outcome

Title	Part 2, Dose Expansion Phase: Percentage of Participants With PD at Month 6
Description	PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. The PD assessment was based on RECIST v1.1.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

The response-evaluable population was defined as participants who received at least 1 dose of study drug, had measurable disease at Baseline, and had at least 1 post-baseline disease assessment.

Arm/Group Title	Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
Arm/Group Description	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 13) in Dose Expansion Phase in participants with metastatic TNBC.
Measure Participants	15
Number [percentage of participants]	86.7 1083.8%

8. Secondary Outcome

Title	Part 2, Dose Expansion Phase: Progression Free Survival (PFS)
Description	PFS was defined as the time from date of first study drug administration to the date of first documented PD or death due to any cause, whichever occurred first. The PFS assessment was based on RECIST v1.1. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was calculated using Kaplan-Meier estimate.
Time Frame	From the date of first study drug administration up to date of first documented PD or death due to any cause, whichever occurred first (up to 28 months)

Outcome Measure Data

Analysis Population Description

The safety population was defined as all the participants who received at least 1 dose of study drug.

Arm/Group Title	Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
Arm/Group Description	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 13) in Dose Expansion Phase in participants with metastatic TNBC.
Measure Participants	17
Median (95% Confidence Interval) [months]	1.7

9. Secondary Outcome

Title	Part 2, Dose Expansion Phase: Overall Survival (OS)
Description	OS was calculated from date of participant enrollment to the date of participant's death due to any cause. OS was assessed based on RECIST v 1.1. Participants without documentation of death at time of the analysis were censored as of the date the participant was last known to be alive, or the data cutoff date, whichever was earlier. OS was calculated using Kaplan-Meier estimate. Enrollment was defined as the time of the initiation of the first dose of study drug.
Time Frame	Baseline up to the date of death due to any cause (up to 28 months)

Outcome Measure Data

Analysis Population Description

The safety population was defined as all the participants who received at least 1 dose of study drug.

Arm/Group Title	Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
Arm/Group Description	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 13) in Dose Expansion Phase in participants with metastatic TNBC.
Measure Participants	17
Median (95% Confidence Interval) [months]	4.9

10. Secondary Outcome

Title	Part 1, Dose Escalation Phase, Cmax: Maximum Observed Plasma Concentration for TAK-659
Time Frame	Cycle 1, Days 1 and 15: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK)-evaluable population was defined as participants with sufficient concentration-time and dosing data to reliably estimate PK parameters. PK-evaluable population where data at specified time points was available.

Arm/Group Title	Part 1: TAK-659 60 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 80 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 100 mg + Nivolumab 3 mg/kg
Arm/Group Description	TAK-659 60 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 100 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.
Measure Participants	8	11	5
Cycle 1 Day 1	84.02 (56.11)	212.51 (64.69)	165.60 (55.53)
Cycle 1 Day 15	132.04 (67.98)	236.08 (58.99)	379.82 (26.66)

11. Secondary Outcome

Title	Part 1, Dose Escalation Phase, Tmax: Time to Reach the Cmax for TAK-659
Time Frame	Cycle 1, Days 1 and 15: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

Outcome Measure Data

Analysis Population Description

The PK-Evaluable population was defined as participants with sufficient concentration-time and dosing data to reliably estimate PK parameters. PK-evaluable population where data at specified time points was available.

Arm/Group Title	Part 1: TAK-659 60 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 80 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 100 mg + Nivolumab 3 mg/kg
Arm/Group Description	TAK-659 60 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 100 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.
Measure Participants	8	11	5
Cycle 1 Day 1	2.2000	2.0667	3.7000
Cycle 1 Day 15	1.9833	3.8583	3.8333

12. Secondary Outcome

Title	Part 1, Dose Escalation Phase, AUCtau: Area Under the Plasma Concentration-time Curve From Time 0 to Tau Over the Dosing Interval for Area Under the Plasma Concentration for TAK-659
Time Frame	Cycle 1, Days 1 and 15: pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

Outcome Measure Data

Analysis Population Description

The PK-evaluable population was defined as participants with sufficient concentration-time and dosing data to reliably estimate PK parameters. PK-evaluable population where data at specified time points was available.

Arm/Group Title	Part 1: TAK-659 60 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 80 mg + Nivolumab 3 mg/kg	Part 1: TAK-659 100 mg + Nivolumab 3 mg/kg
Arm/Group Description	TAK-659 60 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.	TAK-659 100 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.
Measure Participants	8	11	5
Cycle 1 Day 1	845.7076 (24.5906)	1867.3673 (59.4921)	1745.0750 (56.3522)
Cycle 1 Day 15	1906.1855 (28.4065)	2259.5453 (35.4104)	4515.3938 (37.5764)

Adverse Events

Time Frame	TEAEs are AEs that started after the first dose of study drug and no more than 28 days after the last dose of study drug (up to 28 months)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Reported AEs and deaths are TEAEs that occurred between the first dose of the study drug and 28 days after the last dose of the study drug.
Arm/Group Title	Part 1: TAK-659 60 mg + Nivolumab 3 mg/kg		Part 1: TAK-659 80 mg + Nivolumab 3 mg/kg		Part 1: TAK-659 100 mg + Nivolumab 3 mg/kg		Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
Arm/Group Description	TAK-659 60 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.		TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.		TAK-659 100 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 48) in Dose Escalation Phase.		TAK-659 80 mg, tablets, orally, once daily in each 28-days treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Days 1 and 15 in each 28-days treatment cycle until PD or unacceptable toxicity (up to Week 13) in Dose Expansion Phase in participants with metastatic TNBC.
All Cause Mortality
	Part 1: TAK-659 60 mg + Nivolumab 3 mg/kg		Part 1: TAK-659 80 mg + Nivolumab 3 mg/kg		Part 1: TAK-659 100 mg + Nivolumab 3 mg/kg		Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/8 (62.5%)		6/11 (54.5%)		5/5 (100%)		8/17 (47.1%)
Serious Adverse Events
	Part 1: TAK-659 60 mg + Nivolumab 3 mg/kg		Part 1: TAK-659 80 mg + Nivolumab 3 mg/kg		Part 1: TAK-659 100 mg + Nivolumab 3 mg/kg		Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/8 (75%)		7/11 (63.6%)		4/5 (80%)		12/17 (70.6%)
Blood and lymphatic system disorders
Febrile neutropenia	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Cardiac disorders
Cardiac arrest	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Left ventricular dysfunction	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Myocarditis	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Gastrointestinal disorders
Nausea	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Vomiting	1/8 (12.5%)	3	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
General disorders
Pyrexia	1/8 (12.5%)	1	1/11 (9.1%)	1	1/5 (20%)	1	4/17 (23.5%)	5
Fatigue	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Hepatobiliary disorders
Bile duct obstruction	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Infections and infestations
Sepsis	2/8 (25%)	3	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Anal abscess	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Bacteraemia	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Device related infection	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Lung infection	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Pneumocystis jirovecii pneumonia	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Investigations
Lipase increased	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Aspartate aminotransferase increased	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Platelet count decreased	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Metabolism and nutrition disorders
Hypercalcaemia	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Hyponatraemia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	2/17 (11.8%)	2
Metastases to liver	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Pancreatic carcinoma metastatic	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Triple negative breast cancer	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Nervous system disorders
Aphasia	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Headache	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Psychiatric disorders
Confusional state	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonitis	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	3/17 (17.6%)	3
Dyspnoea	1/8 (12.5%)	1	1/11 (9.1%)	2	0/5 (0%)	0	1/17 (5.9%)	1
Respiratory failure	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	1/17 (5.9%)	2
Acute respiratory failure	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	2	0/17 (0%)	0
Pleural effusion	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Other (Not Including Serious) Adverse Events
	Part 1: TAK-659 60 mg + Nivolumab 3 mg/kg		Part 1: TAK-659 80 mg + Nivolumab 3 mg/kg		Part 1: TAK-659 100 mg + Nivolumab 3 mg/kg		Part 2: TAK-659 80 mg + Nivolumab 3 mg/kg (TNBC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/8 (100%)		11/11 (100%)		5/5 (100%)		17/17 (100%)
Blood and lymphatic system disorders
Anaemia	3/8 (37.5%)	5	6/11 (54.5%)	9	2/5 (40%)	7	4/17 (23.5%)	4
Neutropenia	1/8 (12.5%)	1	0/11 (0%)	0	1/5 (20%)	1	1/17 (5.9%)	1
Thrombocytopenia	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	3	1/17 (5.9%)	1
Cardiac disorders
Tachycardia	3/8 (37.5%)	3	2/11 (18.2%)	2	0/5 (0%)	0	3/17 (17.6%)	4
Sinus tachycardia	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Acute myocardial infarction	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Atrial fibrillation	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Extrasystoles	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Left ventricular failure	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Left ventricular hypertrophy	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Supraventricular extrasystoles	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Ventricular hypokinesia	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Ear and labyrinth disorders
Tinnitus	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Ear pain	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Endocrine disorders
Adrenal insufficiency	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Eye disorders
Periorbital oedema	0/8 (0%)	0	3/11 (27.3%)	3	1/5 (20%)	1	0/17 (0%)	0
Dry eye	0/8 (0%)	0	1/11 (9.1%)	1	1/5 (20%)	1	0/17 (0%)	0
Vitreous floaters	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Cataract	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Exophthalmos	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Eye swelling	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Photophobia	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Photopsia	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Uveitis	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Vitreous degeneration	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Gastrointestinal disorders
Diarrhoea	4/8 (50%)	4	6/11 (54.5%)	9	2/5 (40%)	2	6/17 (35.3%)	6
Nausea	5/8 (62.5%)	7	2/11 (18.2%)	2	0/5 (0%)	0	4/17 (23.5%)	4
Constipation	2/8 (25%)	2	4/11 (36.4%)	5	0/5 (0%)	0	4/17 (23.5%)	4
Vomiting	4/8 (50%)	9	4/11 (36.4%)	6	1/5 (20%)	1	1/17 (5.9%)	2
Dry mouth	0/8 (0%)	0	1/11 (9.1%)	1	1/5 (20%)	1	2/17 (11.8%)	2
Stomatitis	1/8 (12.5%)	1	0/11 (0%)	0	2/5 (40%)	2	1/17 (5.9%)	1
Abdominal distension	2/8 (25%)	2	1/11 (9.1%)	2	0/5 (0%)	0	0/17 (0%)	0
Ascites	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	1/17 (5.9%)	2
Abdominal discomfort	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Abdominal pain	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	1/17 (5.9%)	1
Oral pain	2/8 (25%)	2	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Angular cheilitis	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Dyspepsia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Dysphagia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Gastric dilatation	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Gastrooesophageal reflux disease	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Glossodynia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Melaena	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Oesophagitis	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Tooth disorder	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Toothache	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
General disorders
Fatigue	5/8 (62.5%)	9	4/11 (36.4%)	4	3/5 (60%)	4	5/17 (29.4%)	7
Pyrexia	2/8 (25%)	4	3/11 (27.3%)	4	2/5 (40%)	6	6/17 (35.3%)	8
Oedema peripheral	3/8 (37.5%)	4	2/11 (18.2%)	5	0/5 (0%)	0	5/17 (29.4%)	6
Asthenia	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Chills	2/8 (25%)	2	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Early satiety	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Face oedema	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	2/17 (11.8%)	2
Pain	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Chest discomfort	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Chest pain	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Gait disturbance	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Generalised oedema	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Malaise	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Hepatobiliary disorders
Bile duct obstruction	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Hepatomegaly	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Hyperbilirubinaemia	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Hypertransaminasaemia	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Infections and infestations
Urinary tract infection	1/8 (12.5%)	1	2/11 (18.2%)	2	1/5 (20%)	1	1/17 (5.9%)	1
Candida infection	1/8 (12.5%)	2	0/11 (0%)	0	0/5 (0%)	0	2/17 (11.8%)	2
Oral candidiasis	1/8 (12.5%)	1	2/11 (18.2%)	2	0/5 (0%)	0	0/17 (0%)	0
Upper respiratory tract infection	1/8 (12.5%)	1	2/11 (18.2%)	2	0/5 (0%)	0	0/17 (0%)	0
Lower respiratory tract infection	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	2/17 (11.8%)	3
Pneumonia	2/8 (25%)	2	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Abscess	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Anal abscess	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Bacteriuria	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Clostridium difficile infection	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Conjunctivitis	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Device related infection	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Lymphangitis	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Oropharyngeal candidiasis	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Pneumocystis jirovecii pneumonia	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Pneumonia cytomegaloviral	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Respiratory tract infection	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Rhinitis	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Rhinovirus infection	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Tooth abscess	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Wound infection	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Injury, poisoning and procedural complications
Fall	3/8 (37.5%)	3	2/11 (18.2%)	2	1/5 (20%)	1	0/17 (0%)	0
Contusion	1/8 (12.5%)	1	2/11 (18.2%)	2	0/5 (0%)	0	1/17 (5.9%)	1
Allergic transfusion reaction	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Limb injury	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Skin abrasion	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Investigations
Aspartate aminotransferase increased	2/8 (25%)	3	6/11 (54.5%)	16	4/5 (80%)	5	7/17 (41.2%)	10
Alanine aminotransferase increased	2/8 (25%)	3	6/11 (54.5%)	10	3/5 (60%)	3	5/17 (29.4%)	6
Amylase increased	0/8 (0%)	0	6/11 (54.5%)	12	3/5 (60%)	4	4/17 (23.5%)	6
Lipase increased	0/8 (0%)	0	5/11 (45.5%)	9	3/5 (60%)	7	1/17 (5.9%)	2
Blood creatine phosphokinase increased	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	8/17 (47.1%)	13
Troponin increased	1/8 (12.5%)	1	3/11 (27.3%)	4	0/5 (0%)	0	1/17 (5.9%)	1
Weight decreased	2/8 (25%)	3	2/11 (18.2%)	2	0/5 (0%)	0	1/17 (5.9%)	1
Blood alkaline phosphatase increased	1/8 (12.5%)	1	2/11 (18.2%)	3	1/5 (20%)	1	0/17 (0%)	0
Lymphocyte count decreased	0/8 (0%)	0	2/11 (18.2%)	4	1/5 (20%)	1	1/17 (5.9%)	1
Platelet count decreased	0/8 (0%)	0	1/11 (9.1%)	1	2/5 (40%)	3	0/17 (0%)	0
Blood glucose increased	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	1/17 (5.9%)	1
Blood lactate dehydrogenase increased	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	2/17 (11.8%)	2
Blood thyroid stimulating hormone increased	0/8 (0%)	0	2/11 (18.2%)	2	0/5 (0%)	0	0/17 (0%)	0
Electrocardiogram QT prolonged	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Electrocardiogram ST-T segment abnormal	0/8 (0%)	0	2/11 (18.2%)	2	0/5 (0%)	0	0/17 (0%)	0
Gamma-glutamyltransferase increased	0/8 (0%)	0	1/11 (9.1%)	3	0/5 (0%)	0	1/17 (5.9%)	1
Weight increased	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Bacterial test positive	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Blood bilirubin increased	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Blood corticotrophin decreased	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Blood creatinine increased	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	2	0/17 (0%)	0
Cardiac murmur	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Electrocardiogram T wave abnormal	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Protein urine	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Respiratory syncytial virus test positive	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Transferrin saturation decreased	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Troponin T increased	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Metabolism and nutrition disorders
Hypophosphataemia	2/8 (25%)	2	7/11 (63.6%)	21	1/5 (20%)	1	4/17 (23.5%)	5
Hypokalaemia	2/8 (25%)	5	8/11 (72.7%)	13	0/5 (0%)	0	3/17 (17.6%)	3
Decreased appetite	4/8 (50%)	4	0/11 (0%)	0	0/5 (0%)	0	4/17 (23.5%)	6
Hypocalcaemia	2/8 (25%)	2	2/11 (18.2%)	3	1/5 (20%)	1	3/17 (17.6%)	5
Dehydration	2/8 (25%)	2	3/11 (27.3%)	3	0/5 (0%)	0	1/17 (5.9%)	2
Hypomagnesaemia	0/8 (0%)	0	3/11 (27.3%)	3	0/5 (0%)	0	2/17 (11.8%)	3
Hyponatraemia	2/8 (25%)	3	2/11 (18.2%)	4	0/5 (0%)	0	0/17 (0%)	0
Hypercalcaemia	0/8 (0%)	0	2/11 (18.2%)	4	0/5 (0%)	0	1/17 (5.9%)	1
Hypoalbuminaemia	0/8 (0%)	0	2/11 (18.2%)	5	0/5 (0%)	0	1/17 (5.9%)	1
Hyperglycaemia	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	1/17 (5.9%)	1
Hyperkalaemia	0/8 (0%)	0	0/11 (0%)	0	2/5 (40%)	2	0/17 (0%)	0
Cachexia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Hypernatraemia	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Hypovolaemia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Iron deficiency	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Lactic acidosis	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Malnutrition	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Polydipsia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	3/8 (37.5%)	6	2/11 (18.2%)	3	0/5 (0%)	0	3/17 (17.6%)	4
Myalgia	2/8 (25%)	6	0/11 (0%)	0	0/5 (0%)	0	3/17 (17.6%)	3
Pain in extremity	2/8 (25%)	2	1/11 (9.1%)	1	0/5 (0%)	0	2/17 (11.8%)	2
Musculoskeletal chest pain	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	2/17 (11.8%)	2
Arthralgia	1/8 (12.5%)	2	1/11 (9.1%)	1	0/5 (0%)	0	1/17 (5.9%)	1
Muscular weakness	2/8 (25%)	2	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	2
Musculoskeletal pain	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Flank pain	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Groin pain	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Intervertebral disc protrusion	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Lumbar spinal stenosis	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Muscle spasms	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Musculoskeletal stiffness	0/8 (0%)	0	1/11 (9.1%)	2	0/5 (0%)	0	0/17 (0%)	0
Neck pain	0/8 (0%)	0	1/11 (9.1%)	2	0/5 (0%)	0	0/17 (0%)	0
Pain in jaw	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Nervous system disorders
Headache	2/8 (25%)	3	2/11 (18.2%)	2	0/5 (0%)	0	4/17 (23.5%)	7
Dizziness	3/8 (37.5%)	3	0/11 (0%)	0	0/5 (0%)	0	3/17 (17.6%)	3
Dysgeusia	1/8 (12.5%)	1	1/11 (9.1%)	1	2/5 (40%)	2	0/17 (0%)	0
Hypoaesthesia	2/8 (25%)	2	1/11 (9.1%)	1	0/5 (0%)	0	1/17 (5.9%)	1
Balance disorder	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	1/17 (5.9%)	1
Neuropathy peripheral	2/8 (25%)	3	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Ataxia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Drooling	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Encephalopathy	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Migraine	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Motor dysfunction	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Paraesthesia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Peripheral motor neuropathy	1/8 (12.5%)	2	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Peripheral sensory neuropathy	1/8 (12.5%)	2	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Resting tremor	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Restless legs syndrome	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Sinus headache	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Somnolence	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Vocal cord paralysis	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Psychiatric disorders
Confusional state	2/8 (25%)	3	1/11 (9.1%)	1	1/5 (20%)	1	0/17 (0%)	0
Depression	0/8 (0%)	0	2/11 (18.2%)	2	0/5 (0%)	0	1/17 (5.9%)	1
Anxiety	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Insomnia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Irritability	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Mental status changes	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/8 (12.5%)	1	1/11 (9.1%)	1	1/5 (20%)	1	0/17 (0%)	0
Dysuria	2/8 (25%)	2	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Polyuria	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Proteinuria	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Urinary incontinence	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Reproductive system and breast disorders
Breast discomfort	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Breast pain	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	2
Testicular oedema	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Vulvovaginal pruritus	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/8 (37.5%)	3	5/11 (45.5%)	5	1/5 (20%)	1	9/17 (52.9%)	9
Cough	3/8 (37.5%)	5	6/11 (54.5%)	7	1/5 (20%)	1	3/17 (17.6%)	4
Pleural effusion	1/8 (12.5%)	1	2/11 (18.2%)	2	1/5 (20%)	1	0/17 (0%)	0
Dyspnoea exertional	2/8 (25%)	2	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Pulmonary embolism	0/8 (0%)	0	2/11 (18.2%)	2	0/5 (0%)	0	1/17 (5.9%)	1
Epistaxis	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	1/17 (5.9%)	1
Hypoxia	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Acute respiratory failure	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Aspiration	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Dysphonia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Haemoptysis	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Oropharyngeal pain	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Pleuritic pain	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Pneumonitis	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Pneumothorax	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Productive cough	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Respiratory tract oedema	0/8 (0%)	0	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Tachypnoea	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Skin and subcutaneous tissue disorders
Rash	2/8 (25%)	5	2/11 (18.2%)	3	2/5 (40%)	3	4/17 (23.5%)	12
Ecchymosis	2/8 (25%)	2	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Pruritus	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	2/17 (11.8%)	2
Rash maculo-papular	0/8 (0%)	0	1/11 (9.1%)	4	1/5 (20%)	1	0/17 (0%)	0
Rash pruritic	1/8 (12.5%)	1	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Swelling face	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Alopecia	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Decubitus ulcer	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Dry skin	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Hyperhidrosis	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Pain of skin	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Photosensitivity reaction	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	2
Rash erythematous	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Rash papular	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Vascular disorders
Hypotension	2/8 (25%)	2	1/11 (9.1%)	1	0/5 (0%)	0	1/17 (5.9%)	1
Flushing	1/8 (12.5%)	1	0/11 (0%)	0	1/5 (20%)	1	0/17 (0%)	0
Deep vein thrombosis	0/8 (0%)	0	1/11 (9.1%)	1	0/5 (0%)	0	0/17 (0%)	0
Hot flush	1/8 (12.5%)	1	0/11 (0%)	0	0/5 (0%)	0	0/17 (0%)	0
Hypertension	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1
Lymphoedema	0/8 (0%)	0	0/11 (0%)	0	0/5 (0%)	0	1/17 (5.9%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.