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

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03123393
• Collaborator: (none)
• Enrollment: 49
• Locations: 41
• Arms: 2
• Actual Duration (Months): 26.2
• Patients Per Site: 1.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy of TAK-659 measured by independent radiologic review committee (IRC)-assessed overall response rate (ORR) in participants with relapsed or refractory DLBCL.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-cell Lymphoma	Drug: TAK-659	Phase 2

Detailed Description

The drug being tested is TAK-659. This study will evaluate overall response rate (ORR) in participants with relapsed or refractory DLBCL who take TAK-659.

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

• TAK-659 60 mg to 100 mg

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

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of TAK-659 in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma After at Least 2 Prior Lines of Chemotherapy
• Actual Study Start Date: Oct 10, 2017
• Actual Primary Completion Date: Dec 17, 2019
• Actual Study Completion Date: Dec 17, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A: TAK-659 100 mg TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	Drug: TAK-659; TAK-659 Tablets
Experimental: Cohort B: TAK-659 Ramp-up Dosing TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).	Drug: TAK-659; TAK-659 Tablets

Outcome Measures

Primary Outcome Measures

1. Stage 2: ORR as Assessed by Independent Radiologic Review Committee (IRRC) Based on Modified 2007 International Working Group (IWG) Criteria [Up to 12 months]

   ORR was defined as the percentage of participants with complete response (CR), or partial response (PR) as assessed by IRRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.

Secondary Outcome Measures

1. Stage 2: CR Rate as Assessed by IRC Based on Modified 2007 IWG Criteria [Up to 12 months]

   CR rate was defined as percentage of participants with complete response as assessed by IRC according to the modified 2007 IWG. CR was defined as disappearance of all evidence of disease.

2. Stage 2: ORR as Assessed by IRRC Based on 2014 IWG-Lugano Criteria [Up to 12 months]

   ORR was defined as the percentage of participants with CR or PR as assessed by IRRC according to the 2014 Lugano classification, IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.

3. Stage 2: CR Rate as Assessed by IRRC Based on 2014 IWG-Lugano Criteria [Up to 12 months]

   CR rate was defined as percentage of participants with complete response as assessed by IRC according to the 2014 Lugano classification, IWG criteria. CR was defined as disappearance of all evidence of disease.

4. Stage 2: Duration of Response (DOR) [Up to 12 months]

   DOR was defined as the time from the date of first documentation of a CR/PR to the date of first documentation of tumor progression or progressive disease (PD) per IRRC assessment according to IWG criteria. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. PD was defined as presence of any new lesion or increase by >=50% of previously involved sites from nadir.

5. Stage 2: Duration of CR [Up to 12 months]

   Duration of CR was defined as the time from the date of first documentation of a CR/PR to the date of first documentation of tumor progression or PD per IRRC assessment according to IWG criteria. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. PD was defined as presence of any new lesion or increase by >=50% of previously involved sites from nadir.

6. Stage 2: ORR as Assessed by IRRC in Participants With Germinal Center B-cell (GCB) DLBCL [Up to 12 months]

   ORR was defined as the percentage of participants with CR or PR as assessed by IRRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.

7. Stage 2: ORR as Assessed by IRC in Participants With DLBCL Transformed From Indolent Non-Hodgkin's Lymphoma (NHL) [Up to 12 months]

   ORR was defined as the percentage of participants with CR or PR as assessed by IRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.

8. Stage 2: Progression Free Survival (PFS) as Assessed by IRC [Up to 18 months]

   PFS was defined as time from start of study treatment to first documentation of PD per IRC assessment or up to death due to any cause, whichever occurs first based on IWG criteria. PD was defined as presence of any new lesion or increase by >=50% of previously involved sites from nadir.

9. Stage 2: Overall Survival (OS) [Up to 24 months]

   OS was defined as the time from start of study treatment to date of death due to any cause.

10. Stage 1: ORR as Assessed by IRRC to Select Stage 2 Dose Regimen of TAK-659 From the Lead-in Dose Exploration Phase [Up to 12 months]

    ORR was defined as the percentage of participants with CR or PR as assessed by IRC. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.

11. Stage 2: ORR as Assessed by IRC at 3, 6, and 9 Cycles in Participants With DLBCL [At Cycles 3, 6 and 9 (Up to 12 months) (Each cycle of 28 days)]

    ORR was defined as the percentage of participants with CR or PR as assessed by IRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

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

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

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

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

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

4. Measurable disease per IWG 2007 criteria.

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

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

7. Adequate organ function, including the following:

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

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

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

11. Others:

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

• Blood pressure <=Grade 1 (hypertensive participants are permitted if their blood pressure is controlled to <=Grade 1 by hypertensive medications.

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

Exclusion Criteria:

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

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

3. Systemic anticancer treatment (including investigational agents) less than 3 weeks before the first dose of study treatment (<=4 weeks for antibody-based therapy including unconjugated antibody, antibody-drug conjugate, and bi-specific T-cell engager agents; <=8 weeks for cell-based therapy or anti-tumor vaccine).

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

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

6. Prior autologous stem cell transplant (ASCT) within 6 months or prior ASCT at any time without full hematopoietic recovery before Cycle 1 Day 1, or allogeneic stem cell transplant any time.

7. Participants with certain cardiovascular conditions are excluded.

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

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

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

11. Participants with another malignancy within 2 years of study start. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection and are considered disease-free at the time of study entry.

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

13. Received medications, supplements, or food/beverages that are P-glycoprotein (P-gp) inhibitors or inducers or strong cytochrome P450 (CYP) 3A inhibitors or inducers within a certain timeframe prior to the first dose of study drug. Depending on the substance, the washout period for P-gp inhibitors or inducers or strong CYP3A inhibitors or inducers will be either 7 days or 5 times the half-life (half-life is related to the time required for elimination from the body). The washout period for grapefruit containing food or beverages is 5 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Kansas Medical Center	Westwood	Kansas	United States	66205
2	University of Michigan	Ann Arbor	Michigan	United States	48109-1274
3	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
4	New York University Langone Medical Center	New York	New York	United States	10016
5	Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania	United States	19104
6	Swedish Medical Oncology - Edmonds	Edmonds	Washington	United States	98026
7	Swedish Cancer Institute - Issaquah	Issaquah	Washington	United States	98029
8	Swedish Health Services	Seattle	Washington	United States	98104
9	University of Washington, Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
10	Swedish First Hill Campus	Seattle	Washington	United States	98122
11	Princess Margaret Cancer Center	Toronto	Ontario	Canada	M5G2M9
12	Centre Hospitalier Regional de Rimouski	Rimouski	Quebec	Canada	G5L 5T1
13	CHU de Quebec -Universite Laval-Hopital de L'Enfant Jesus	Quebec		Canada	G1J 1Z4
14	Hopital Haut-Leveque	Pessac Cedex	Aquitaine	France	33604
15	CHRU Clermont- Ferrand CHU Estaing	Clermont-Ferrand	Auvergne	France	63000
16	Centre Henri-Becquerel	Rouen Cedex 1	Haute-normandie	France	76038
17	Hopital Saint Louis	Paris Cedex 10	Ile-de-france	France	75475
18	Groupe Hospitalier - Hopitaux Universitaires Pitie-Salpetriere - Charles-Foix - Pitie-Salpetriere	Paris Cedex 13	Ile-de-france	France	75651
19	Hopital Necker-Enfants Malades	Paris	Ile-de-france	France	75015
20	Institut Gustave Roussy	Villejuif Cedex	Ile-de-france	France	94805
21	Hopital Dupuytren	Limoges Cedex	Limousin, Lorraine	France	87042
22	Institut Paoli Calmettes Departement de Recherche Clinique et de l'Innovation	Marseille	Provence Alpes COTE D'azur	France	13009
23	Centre Hospitalier Lyon Sud	Pierre Benite Cedex	Rhone-alpes	France	69495
24	Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo	Foggia	Italy	71013
25	Azienda Ospedaliera Universitaria Citta della Salute e della Scienza di Torino	Torino	Piemonte	Italy	10126
26	Azienda Ospedaliera Papa Giovanni XXIII	Bergamo		Italy	24127
27	Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda	Milano		Italy	20162
28	Azienda Ospedaliero-Universitaria "Maggiore della Carita"	Novara		Italy	28100
29	Azienda Ospedaliero Universitaria Santa Maria della Misericordia di Udine	Udine		Italy	33100
30	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
31	Hospital Clinic de Barcelona	Barcelona		Spain	08036
32	Hospital General Universitario Gregorio Maranon	Madrid		Spain	28009
33	Hospital Universitario La Paz	Madrid		Spain	28046
34	Hospital Universitario de Salamanca	Salamanca		Spain	37007
35	Hospital Universitario Marques de Valdecilla	Santander		Spain	39008
36	Hospital Universitario La Fe	Valencia		Spain	46026
37	University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital	Birmingham	England	United Kingdom	B15 2GW
38	London North West Healthcare NHS Trust, Imperial College London	Harrow	England	United Kingdom	HA1 3UJ
39	University College London Hospitals NHS Foundation Trust	London	England	United Kingdom	NW1 2BU
40	The Christie NHS Foundation Trust	Manchester	England	United Kingdom	M20 4BX
41	Newcastle Hospitals NHS Foundation Trust	Newcastle upon Tyne	England	United Kingdom	NE7 7DN

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Apr 24, 2018
• Statistical Analysis Plan - Apr 1, 2019

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03123393
• Other Study ID Numbers: C34004; U1111-1187-6208; 2016-003716-12; 17/YH/0181
• First Posted: Apr 21, 2017
• Last Update Posted: Sep 16, 2020
• Last Verified: Sep 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: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 26 investigative sites in France, Great Britain, Italy, Spain, Canada, United States from 10 October 2017 to 17 December 2019. The study was terminated by the sponsor before the initiation of the stage 2 efficacy evaluation.
Pre-assignment Detail	Participants with a diagnosis of relapsed or refractory diffuse large B-cell lymphoma who had at least 2 prior lines of chemotherapy were enrolled in Cohorts A and B. Cohort A received a single dose and Cohort B received ramp-up doses of TAK-659 in Stage 1 of the study.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Period Title: Overall Study
STARTED	24	25
COMPLETED	3	2
NOT COMPLETED	21	23

Baseline Characteristics

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing	Total
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).	Total of all reporting groups
Overall Participants	24	25	49
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.2 (9.01)	64.6 (11.37)	64.4 (10.18)
Sex: Female, Male (Count of Participants)
Female	6 25%	14 56%	20 40.8%
Male	18 75%	11 44%	29 59.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 4.2%	0 0%	1 2%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	21 87.5%	19 76%	40 81.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 8.3%	6 24%	8 16.3%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	1 4.2%	4 16%	5 10.2%
Non-Hispanic and Latino	21 87.5%	13 52%	34 69.4%
Not Reported	2 8.3%	7 28%	9 18.4%
Unknown	0 0%	1 4%	1 2%
Region of Enrollment (Count of Participants)
France	3 12.5%	11 44%	14 28.6%
United Kingdom	3 12.5%	3 12%	6 12.2%
Italy	4 16.7%	4 16%	8 16.3%
Spain	3 12.5%	3 12%	6 12.2%
Canada	1 4.2%	0 0%	1 2%
United States	10 41.7%	4 16%	14 28.6%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	172.8 (9.55)	167.5 (9.52)	170.1 (9.81)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	92.88 (21.132)	72.81 (18.388)	82.64 (22.040)

Outcome Measures

1. Primary Outcome

Title	Stage 2: ORR as Assessed by Independent Radiologic Review Committee (IRRC) Based on Modified 2007 International Working Group (IWG) Criteria
Description	ORR was defined as the percentage of participants with complete response (CR), or partial response (PR) as assessed by IRRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

2. Secondary Outcome

Title	Stage 2: CR Rate as Assessed by IRC Based on Modified 2007 IWG Criteria
Description	CR rate was defined as percentage of participants with complete response as assessed by IRC according to the modified 2007 IWG. CR was defined as disappearance of all evidence of disease.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

3. Secondary Outcome

Title	Stage 2: ORR as Assessed by IRRC Based on 2014 IWG-Lugano Criteria
Description	ORR was defined as the percentage of participants with CR or PR as assessed by IRRC according to the 2014 Lugano classification, IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

4. Secondary Outcome

Title	Stage 2: CR Rate as Assessed by IRRC Based on 2014 IWG-Lugano Criteria
Description	CR rate was defined as percentage of participants with complete response as assessed by IRC according to the 2014 Lugano classification, IWG criteria. CR was defined as disappearance of all evidence of disease.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

5. Secondary Outcome

Title	Stage 2: Duration of Response (DOR)
Description	DOR was defined as the time from the date of first documentation of a CR/PR to the date of first documentation of tumor progression or progressive disease (PD) per IRRC assessment according to IWG criteria. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. PD was defined as presence of any new lesion or increase by >=50% of previously involved sites from nadir.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

6. Secondary Outcome

Title	Stage 2: Duration of CR
Description	Duration of CR was defined as the time from the date of first documentation of a CR/PR to the date of first documentation of tumor progression or PD per IRRC assessment according to IWG criteria. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. PD was defined as presence of any new lesion or increase by >=50% of previously involved sites from nadir.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

7. Secondary Outcome

Title	Stage 2: ORR as Assessed by IRRC in Participants With Germinal Center B-cell (GCB) DLBCL
Description	ORR was defined as the percentage of participants with CR or PR as assessed by IRRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

8. Secondary Outcome

Title	Stage 2: ORR as Assessed by IRC in Participants With DLBCL Transformed From Indolent Non-Hodgkin's Lymphoma (NHL)
Description	ORR was defined as the percentage of participants with CR or PR as assessed by IRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

9. Secondary Outcome

Title	Stage 2: Progression Free Survival (PFS) as Assessed by IRC
Description	PFS was defined as time from start of study treatment to first documentation of PD per IRC assessment or up to death due to any cause, whichever occurs first based on IWG criteria. PD was defined as presence of any new lesion or increase by >=50% of previously involved sites from nadir.
Time Frame	Up to 18 months

Outcome Measure Data

Analysis Population Description

As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

10. Secondary Outcome

Title	Stage 2: Overall Survival (OS)
Description	OS was defined as the time from start of study treatment to date of death due to any cause.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

11. Secondary Outcome

Title	Stage 1: ORR as Assessed by IRRC to Select Stage 2 Dose Regimen of TAK-659 From the Lead-in Dose Exploration Phase
Description	ORR was defined as the percentage of participants with CR or PR as assessed by IRC. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Data were not reported for this outcome measure because ORR was only assessed by the investigator on this study and not by IRRC as the study was terminated and the selection of dose for Stage 2 was not applicable.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

12. Secondary Outcome

Title	Stage 2: ORR as Assessed by IRC at 3, 6, and 9 Cycles in Participants With DLBCL
Description	ORR was defined as the percentage of participants with CR or PR as assessed by IRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time Frame	At Cycles 3, 6 and 9 (Up to 12 months) (Each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.

Arm/Group Title	Cohort A: TAK-659 100 mg	Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).	TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
Measure Participants	0	0

Adverse Events

Time Frame	From the signing of the informed consent form (ICF) through 28 days after administration of the last dose of study drug or until the start of subsequent anticancer therapy, whichever occurs first (Up to approximately 14 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.
Arm/Group Title	Cohort A: TAK-659 100 mg		Cohort B: TAK-659 Ramp-up Dosing
Arm/Group Description	TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days).		TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).
All Cause Mortality
	Cohort A: TAK-659 100 mg		Cohort B: TAK-659 Ramp-up Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/24 (12.5%)		3/25 (12%)
Serious Adverse Events
	Cohort A: TAK-659 100 mg		Cohort B: TAK-659 Ramp-up Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/24 (58.3%)		13/25 (52%)
Blood and lymphatic system disorders
Anaemia	0/24 (0%)		2/25 (8%)
Bone marrow failure	1/24 (4.2%)		0/25 (0%)
Lymphocytic infiltration	0/24 (0%)		1/25 (4%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	0/24 (0%)		1/25 (4%)
Rectal haemorrhage	0/24 (0%)		1/25 (4%)
Upper gastrointestinal haemorrhage	1/24 (4.2%)		0/25 (0%)
General disorders
Pyrexia	3/24 (12.5%)		2/25 (8%)
Asthenia	1/24 (4.2%)		0/25 (0%)
General physical health deterioration	1/24 (4.2%)		0/25 (0%)
Multiple organ dysfunction syndrome	0/24 (0%)		1/25 (4%)
Pain	1/24 (4.2%)		0/25 (0%)
Infections and infestations
Pneumonia	1/24 (4.2%)		1/25 (4%)
Sepsis	1/24 (4.2%)		1/25 (4%)
Asymptomatic bacteriuria	0/24 (0%)		1/25 (4%)
Candida sepsis	0/24 (0%)		1/25 (4%)
Cellulitis	1/24 (4.2%)		0/25 (0%)
Enterococcal bacteraemia	0/24 (0%)		1/25 (4%)
Enterovirus infection	1/24 (4.2%)		0/25 (0%)
Influenza	1/24 (4.2%)		0/25 (0%)
Lung infection	1/24 (4.2%)		0/25 (0%)
Pulmonary nocardiosis	1/24 (4.2%)		0/25 (0%)
Rhinovirus infection	1/24 (4.2%)		0/25 (0%)
Upper respiratory tract infection	1/24 (4.2%)		0/25 (0%)
Urinary tract infection	1/24 (4.2%)		0/25 (0%)
Injury, poisoning and procedural complications
Animal bite	1/24 (4.2%)		0/25 (0%)
Post procedural fever	0/24 (0%)		1/25 (4%)
Investigations
Aspartate aminotransferase increased	1/24 (4.2%)		0/25 (0%)
Electrocardiogram QT prolonged	0/24 (0%)		1/25 (4%)
Metabolism and nutrition disorders
Dehydration	0/24 (0%)		1/25 (4%)
Musculoskeletal and connective tissue disorders
Back pain	1/24 (4.2%)		0/25 (0%)
Flank pain	1/24 (4.2%)		0/25 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphoma	1/24 (4.2%)		3/25 (12%)
Gastrointestinal adenocarcinoma	0/24 (0%)		1/25 (4%)
Non-Hodgkin's lymphoma	1/24 (4.2%)		0/25 (0%)
Tumour associated fever	1/24 (4.2%)		0/25 (0%)
Nervous system disorders
Encephalopathy	0/24 (0%)		1/25 (4%)
Psychiatric disorders
Confusional state	1/24 (4.2%)		0/25 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/24 (4.2%)		1/25 (4%)
Interstitial lung disease	0/24 (0%)		1/25 (4%)
Pneumonitis	0/24 (0%)		1/25 (4%)
Other (Not Including Serious) Adverse Events
	Cohort A: TAK-659 100 mg		Cohort B: TAK-659 Ramp-up Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/24 (100%)		20/25 (80%)
Blood and lymphatic system disorders
Anaemia	7/24 (29.2%)		5/25 (20%)
Neutropenia	2/24 (8.3%)		4/25 (16%)
Thrombocytopenia	3/24 (12.5%)		1/25 (4%)
Increased tendency to bruise	2/24 (8.3%)		0/25 (0%)
Cardiac disorders
Tachycardia	0/24 (0%)		2/25 (8%)
Eye disorders
Periorbital oedema	5/24 (20.8%)		3/25 (12%)
Vision blurred	2/24 (8.3%)		0/25 (0%)
Gastrointestinal disorders
Diarrhoea	4/24 (16.7%)		2/25 (8%)
Abdominal pain	4/24 (16.7%)		1/25 (4%)
Constipation	3/24 (12.5%)		1/25 (4%)
Nausea	2/24 (8.3%)		2/25 (8%)
Dry mouth	1/24 (4.2%)		2/25 (8%)
Vomiting	1/24 (4.2%)		2/25 (8%)
Abdominal distension	2/24 (8.3%)		0/25 (0%)
General disorders
Fatigue	6/24 (25%)		8/25 (32%)
Oedema peripheral	7/24 (29.2%)		2/25 (8%)
Asthenia	3/24 (12.5%)		1/25 (4%)
Oedema	2/24 (8.3%)		0/25 (0%)
Pyrexia	9/24 (37.5%)		10/25 (40%)
Infections and infestations
Oral candidiasis	2/24 (8.3%)		4/25 (16%)
Injury, poisoning and procedural complications
Contusion	3/24 (12.5%)		0/25 (0%)
Investigations
Aspartate aminotransferase increased	9/24 (37.5%)		5/25 (20%)
Alanine aminotransferase increased	7/24 (29.2%)		4/25 (16%)
Amylase increased	6/24 (25%)		4/25 (16%)
Blood creatine phosphokinase increased	6/24 (25%)		2/25 (8%)
Lipase increased	4/24 (16.7%)		3/25 (12%)
Gamma-glutamyltransferase increased	1/24 (4.2%)		4/25 (16%)
Blood alkaline phosphatase increased	4/24 (16.7%)		0/25 (0%)
Blood lactate dehydrogenase increased	2/24 (8.3%)		2/25 (8%)
C-reactive protein increased	1/24 (4.2%)		2/25 (8%)
Neutrophil count decreased	2/24 (8.3%)		0/25 (0%)
Platelet count decreased	2/24 (8.3%)		0/25 (0%)
Metabolism and nutrition disorders
Hypophosphataemia	7/24 (29.2%)		1/25 (4%)
Decreased appetite	1/24 (4.2%)		2/25 (8%)
Hypokalaemia	0/24 (0%)		2/25 (8%)
Musculoskeletal and connective tissue disorders
Back pain	4/24 (16.7%)		1/25 (4%)
Arthralgia	3/24 (12.5%)		0/25 (0%)
Myalgia	2/24 (8.3%)		0/25 (0%)
Nervous system disorders
Headache	3/24 (12.5%)		2/25 (8%)
Dizziness	3/24 (12.5%)		0/25 (0%)
Neuropathy peripheral	2/24 (8.3%)		1/25 (4%)
Hypoaesthesia	2/24 (8.3%)		0/25 (0%)
Renal and urinary disorders
Acute kidney injury	2/24 (8.3%)		0/25 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	9/24 (37.5%)		3/25 (12%)
Dyspnoea	4/24 (16.7%)		3/25 (12%)
Pleural effusion	2/24 (8.3%)		1/25 (4%)
Oropharyngeal pain	2/24 (8.3%)		0/25 (0%)
Sputum discoloured	2/24 (8.3%)		0/25 (0%)
Skin and subcutaneous tissue disorders
Rash	5/24 (20.8%)		1/25 (4%)
Pruritus	2/24 (8.3%)		1/25 (4%)
Vascular disorders
Hypertension	1/24 (4.2%)		2/25 (8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.