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

Phase 2

Terminated

Conditions: Diffuse Large B-cell Lymphoma

Interventions: Drug: TAK-659

Registration Number: NCT03123393

Lead Sponsor: Calithera Biosciences, Inc

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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 49

Inclusion Criteria

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

a. High-grade B-cell lymphoma (BCL) with MYC and BCL-2 and/or BCL-6 translocations (double-hit DLBCL under DLBCL, not otherwise specified [NOS], based on the 2008 World Health Organization [WHO] classification criteria) is not eligible for this study.
Local pathology review for histological confirmation; A formalin-fixed, paraffin-embedded (FFPE) tumor block or appropriately stained slides from a fresh biopsy is required.
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.
Documented investigator-assessed relapse or progression after the last treatment is required if the participant responded and then progressed on the prior treatment.
Measurable disease per IWG 2007 criteria.
Eastern Cooperative Oncology Group (ECOG) performance status less than (<) 2.
Life expectancy of greater than (>) 3 months.
Adequate organ function, including the following:
1. Bone marrow reserve: absolute neutrophil count (ANC) >=1000/microliter (μL), platelet count >=75,000/μL (>=50,000/μL for participants with bone marrow involvement), and hemoglobin >=8 gram per deciliter (g/dL).
2. Hepatic: total bilirubin less than or equal to (<=) 1.5 times the upper limit of the normal range (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.5*ULN.
3. Renal: creatinine clearance >=60 milliliter per minute (mL/min).
4. Others:
  - Lipase <=1.5*ULN and amylase <=1.5*ULN with no clinical symptoms suggestive of pancreatitis or cholecystitis.
  - Blood pressure <=Grade 1 (hypertensive participants are permitted if their blood pressure is controlled to <=Grade 1 by hypertensive medications.
  - Glycosylated hemoglobin is <=6.5% hyperglycemic participants permitted if glucose is well controlled by antihyperglycemic medication).

Exclusion Criteria

Central nervous system (CNS) lymphoma; active brain or leptomeningeal metastases.
Known human immunodeficiency virus (HIV)-related malignancy.
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).
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.
Known HIV positive, hepatitis B surface antigen positive or known or suspected active hepatitis C infection.
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.
Participants with certain cardiovascular conditions are excluded.
Major surgery within 14 days before the first dose of study drug or incomplete recovery from any complications from surgery.
Systemic infection requiring parenteral antibiotic therapy or other serious infection (bacterial, fungal, or viral) within 21 days before the first dose of study drug.
Treatment with high-dose corticosteroids for anticancer purposes within 7 days before the first dose of TAK-659.
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.
Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-659.
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Trial Locations

Locations (41): Perelman Center for Advanced Medicine
🇺🇸
Philadelphia, Pennsylvania, United States
Azienda Ospedaliera Papa Giovanni XXIII
🇮🇹
Bergamo, Italy
Hopital Haut-Leveque
🇫🇷
Pessac Cedex, Aquitaine, France
Swedish Health Services
🇺🇸
Seattle, Washington, United States
Hopital Necker-Enfants Malades
🇫🇷
Paris, Ile-de-france, France
Swedish Medical Oncology - Edmonds
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Edmonds, Washington, United States
CHRU Clermont- Ferrand CHU Estaing
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Clermont-Ferrand, Auvergne, France
Hospital Universitari Vall d'Hebron
🇪🇸
Barcelona, Spain
CHU de Quebec -Universite Laval-Hopital de L'Enfant Jesus
🇨🇦
Quebec, Canada
Roswell Park Cancer Institute
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Buffalo, New York, United States
Swedish Cancer Institute - Issaquah
🇺🇸
Issaquah, Washington, United States
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
🇮🇹
Milano, Italy
Swedish First Hill Campus
🇺🇸
Seattle, Washington, United States
Hopital Saint Louis
🇫🇷
Paris Cedex 10, Ile-de-france, France
Azienda Ospedaliera Universitaria Citta della Salute e della Scienza di Torino
🇮🇹
Torino, Piemonte, Italy
Hospital Clinic de Barcelona
🇪🇸
Barcelona, Spain
Hospital Universitario La Paz
🇪🇸
Madrid, Spain
Azienda Ospedaliero Universitaria Santa Maria della Misericordia di Udine
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Udine, Italy
Centre Hospitalier Lyon Sud
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Pierre Benite Cedex, Rhone-alpes, France
University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital
🇬🇧
Birmingham, England, United Kingdom
Hospital General Universitario Gregorio Maranon
🇪🇸
Madrid, Spain
Hospital Universitario de Salamanca
🇪🇸
Salamanca, Spain
New York University Langone Medical Center
🇺🇸
New York, New York, United States
University of Washington, Hutchinson Cancer Research Center
🇺🇸
Seattle, Washington, United States
Centre Henri-Becquerel
🇫🇷
Rouen Cedex 1, Haute-normandie, France
Princess Margaret Cancer Center
🇨🇦
Toronto, Ontario, Canada
Groupe Hospitalier - Hopitaux Universitaires Pitie-Salpetriere - Charles-Foix - Pitie-Salpetriere
🇫🇷
Paris Cedex 13, Ile-de-france, France
Institut Gustave Roussy
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Villejuif Cedex, Ile-de-france, France
Hopital Dupuytren
🇫🇷
Limoges Cedex, Limousin, Lorraine, France
Institut Paoli Calmettes Departement de Recherche Clinique et de l'Innovation
🇫🇷
Marseille, Provence Alpes COTE D'azur, France
Ospedale Casa Sollievo della Sofferenza
🇮🇹
San Giovanni Rotondo, Foggia, Italy
University College London Hospitals NHS Foundation Trust
🇬🇧
London, England, United Kingdom
London North West Healthcare NHS Trust, Imperial College London
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Harrow, England, United Kingdom
The Christie NHS Foundation Trust
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Manchester, England, United Kingdom
Newcastle Hospitals NHS Foundation Trust
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Newcastle upon Tyne, England, United Kingdom
Centre Hospitalier Regional de Rimouski
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Rimouski, Quebec, Canada
Azienda Ospedaliero-Universitaria "Maggiore della Carita"
🇮🇹
Novara, Italy
Hospital Universitario Marques de Valdecilla
🇪🇸
Santander, Spain
Hospital Universitario La Fe
🇪🇸
Valencia, Spain
University of Kansas Medical Center
🇺🇸
Westwood, Kansas, United States