A Study of TAK-659 in Combination With Bendamustine (+/-Rituximab), Gemcitabine, Lenalidomide, or Ibrutinib for the Treatment of Participants With Advanced Non-Hodgkin Lymphoma

NCT02954406 | Terminated Phase 1 Results FDA Drug

• 3 other identifiers: C34005U1111-1188-08912016-001426-34
• Study Type: interventional
• Target: 43
• Locations: 2 countries
• Sites: 13

Brief Summary

The purpose of this study is to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of TAK-659 when administered in combination with bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, or ibrutinib.

Conditions

Lymphoma, Non-Hodgkin

Keywords

Drug Therapy

Outcome Measures

Primary Outcomes (2)

• Dose Escalation Phase: Maximum Tolerated Dose (MTD) of TAK-659

  MTD was defined as the maximum dose that is determined to be safe and tolerable in different cohorts. Each cohort (A, B, C, D and E) received different escalating doses of TAK-659 in combination with other drugs. For each cohort the maximum tolerated dose of TAK-659 in combination with the other drug/s from the selected dose range is reported.

  Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days)

• Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of TAK-659

  The RP2D was the MTD or less. The dose recommended for use in phase 2 studies was analyzed on the basis of the safety, tolerability, and preliminary pharmacokinetic (PK) and efficacy data obtained in phase 1 studies. Each cohort (A, B, C, D and E) received different escalating doses of TAK-659 in combination with other drugs. For each cohort the recommended Phase 2 dose of TAK-659 in combination with the other drug/s from the selected dose range is reported.

  Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E each cycle was of 28 days)

Secondary Outcomes (7)

• Cmax: Maximum Observed Plasma Concentration for TAK-659

  Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days)

• Tmax: Time to Reach the Maximum Plasma Concentration for TAK-659

  Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days)

• AUCtau: Area Under the Plasma Concentration-time Curve During Dosing Interval

  Days 1 and 15: Pre-dose and at multiple time points (up to 24 hours) post-dose in Cycle 1 (Cohorts A, B and C - each cycle was of 21 days and Cohorts D and E - each cycle was of 28 days)

• Overall Response Rate (ORR)

  Up to 123 weeks

• Duration of Response (DOR)

  Up to 123 weeks

Study Arms (11)

Dose Escalation Phase Cohort A: TAK-659 60 mg + Bendamustine 90 mg/m^2

EXPERIMENTAL

TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. Participants continued to receive TAK-659 monotherapy until they experienced progressive disease (PD) or unacceptable toxicities or up to 39 cycles.

Drug: TAK-659; Drug: Bendamustine

Dose Escalation Phase Cohort A: TAK-659 80 mg + Bendamustine 90 mg/m^2

EXPERIMENTAL

TAK-659 80 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 80 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 39 cycles.

Drug: TAK-659; Drug: Bendamustine

Dose Escalation Phase Cohort A: TAK-659 100 mg + Bendamustine 90 mg/m^2

EXPERIMENTAL

TAK-659 100 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 100 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 39 cycles.

Drug: TAK-659; Drug: Bendamustine

Dose Escalation Phase Cohort B: TAK-659 60 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2

EXPERIMENTAL

TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.

Drug: TAK-659; Drug: Bendamustine; Drug: Rituximab

Dose Escalation Phase Cohort B: TAK-659 80 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2

EXPERIMENTAL

TAK-659 80 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 80 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.

Drug: TAK-659; Drug: Bendamustine; Drug: Rituximab

Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2

EXPERIMENTAL

TAK-659 100 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 100 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles.

Drug: TAK-659; Drug: Bendamustine; Drug: Rituximab

Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2

EXPERIMENTAL

TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with gemcitabine 1000 mg/m\^2, infusion, intravenously, over 30 minutes on Days 1 and 8 in a 21-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 2 cycles.

Drug: TAK-659; Drug: Gemcitabine

Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg

EXPERIMENTAL

TAK-659 40 mg, immediate-release tablet, orally, once daily on Days 1 to 28 along with lenalidomide 25 mg, capsules orally, once daily on Days 1 to 21 in a 28-day treatment cycle. The TAK-659 60 mg dose was de-escalated to 40 mg in case of dose limiting toxicity or if the starting dose was determined to be not tolerable. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 26 cycles.

Drug: TAK-659; Drug: Lenalidomide

Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg

EXPERIMENTAL

TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 28 along with lenalidomide 25 mg, capsules orally, once daily on Days 1 to 21 in a 28-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 26 cycles.

Drug: TAK-659; Drug: Lenalidomide

Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg

EXPERIMENTAL

TAK-659 60 mg, immediate-release tablet, orally, once daily along with ibrutinib 560 mg capsules, orally, once daily on Days 1 to 28 in a 28-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 3 cycles.

Drug: TAK-659; Drug: Ibrutinib

Safety Expansion Phase Cohort B: TAK-659 + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2

EXPERIMENTAL

TAK-659 immediate-release tablet, at the MTD/maximally administered dose (MAD)/RP2D determined from Dose Escalation Phase, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles in participants (who were to be entered in Phase 2) with advanced FL or MZL. Treatment could then be continued until they experienced PD or unacceptable toxicities or up to 12 cycles in participants who were to be enrolled in the Safety Expansion Phase Cohort.

Drug: TAK-659; Drug: Bendamustine; Drug: Rituximab

Interventions

TAK-659 DRUG

TAK-659 immediate release tablet

Dose Escalation Phase Cohort A: TAK-659 100 mg + Bendamustine 90 mg/m^2; Dose Escalation Phase Cohort A: TAK-659 60 mg + Bendamustine 90 mg/m^2; Dose Escalation Phase Cohort A: TAK-659 80 mg + Bendamustine 90 mg/m^2; Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2; Dose Escalation Phase Cohort B: TAK-659 60 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2; Dose Escalation Phase Cohort B: TAK-659 80 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2; Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2; Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg; Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg; Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg; Safety Expansion Phase Cohort B: TAK-659 + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2

Bendamustine DRUG

Bendamustine intravenous infusion

Dose Escalation Phase Cohort A: TAK-659 100 mg + Bendamustine 90 mg/m^2; Dose Escalation Phase Cohort A: TAK-659 60 mg + Bendamustine 90 mg/m^2; Dose Escalation Phase Cohort A: TAK-659 80 mg + Bendamustine 90 mg/m^2; Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2; Dose Escalation Phase Cohort B: TAK-659 60 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2; Dose Escalation Phase Cohort B: TAK-659 80 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2; Safety Expansion Phase Cohort B: TAK-659 + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2

Rituximab DRUG

Rituximab intravenous infusion

Dose Escalation Phase Cohort B: TAK-659 100 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2; Dose Escalation Phase Cohort B: TAK-659 60 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2; Dose Escalation Phase Cohort B: TAK-659 80 mg + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2; Safety Expansion Phase Cohort B: TAK-659 + Bendamustine 90 mg/m^2 + Rituximab 375 mg/m^2

Gemcitabine DRUG

Gemcitabine intravenous infusion

Dose Escalation Phase Cohort C: TAK-659 60 mg + Gemcitabine 1000 mg/m^2

Lenalidomide DRUG

Lenalidomide capsule

Dose Escalation Phase Cohort D: TAK-659 40 mg + Lenalidomide 25 mg; Dose Escalation Phase Cohort D: TAK-659 60 mg + Lenalidomide 25 mg

Ibrutinib DRUG

Ibrutinib capsule

Dose Escalation Phase Cohort E: TAK-659 60 mg + Ibrutinib 560 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female participants aged 18 years or older.
• In the dose escalation phase, histologically or cytologically confirmed diagnosis of advanced non-Hodgkin lymphoma (NHL) of any histology (with the exception of participants with Waldenström macroglobulinemia \[WM\] and chronic lymphocytic leukemia \[CLL\]). In the safety expansion phase for Cohort B, only participants with advanced FL or MZL will be included.
• Radiographically or clinically measurable disease with at least 1 target lesion per International Working Group (IWG) criteria for malignant lymphoma.
• In the dose escalation phase, participants who are refractory or relapsed after at least 1 prior line of therapy due to progression, intolerance, or physician/participant decision and for whom no effective standard therapy is available per the investigator's assessment. In the safety expansion phase for Cohort B in participants with FL or MZL, the prior line of therapy is limited to \<=1.
• Either treatment naive to, relapsed/refractory to, or experienced treatment failure due to other reasons with ibrutinib, idelalisib, or any other investigational B-cell receptor (BCR) pathway inhibitors not directly targeting spleen tyrosine kinase (SYK).
• Pre induction salvage chemotherapy and autologous stem cell transplant (ASCT) should be considered 1 therapy.
• Any consolidation/maintenance therapy after a chemotherapy regimen (without intervening relapse) should be considered 1 line of therapy with the preceding combination therapy. Maintenance antibody therapy should not be considered a line of therapy.
• For aggressive NHL (i.e., diffuse large B-cell lymphoma \[DLBCL\]), single-agent anti-CD20 monoclonal antibody therapy should not be considered a line of therapy. Antibody therapy in participants with indolent NHL (i.e., FL) given as a single agent after disease progression from a prior treatment should be considered a line of therapy.
• For participants with DLBCL transformed from indolent lymphoma, any treatment received for the indolent disease before the transformation to DLBCL will, in general, not count toward the 2 to 3 prior lines of therapy required for DLBCL in this study.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and life expectancy of greater than 3 months.
• Participants must have adequate organ function, including the following:
• Adequate bone marrow reserve: absolute neutrophil count (ANC) greater than or equal to (\>=) 1000 per micro liter (/mcL), platelet count \>=75,000/mcL (\>=50,000/mcL for participants with bone marrow involvement), and hemoglobin \>=8 gram per deciliter (g/dL) (red blood cell \[RBC\] and platelet transfusion allowed \>=14 days before assessment).
• Hepatic: total bilirubin less than or equal to (\<=) 1.5×the upper limit of the normal range (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<=2.5×ULN.
• Renal: serum creatinine \>=60 milliliter per minute (mL/min) as estimated by the Cockcroft-Gault equation.
• Others

You may not qualify if:

• Central nervous system (CNS) lymphoma; active brain or leptomeningeal metastases, as indicated by positive cytology from lumbar puncture or computed tomography (CT) scan/magnetic resonance imaging (MRI). Exceptions include those participants who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 2 weeks after completion of the definitive therapy and steroids, and do not have neurologic dysfunction that would confound the evaluation of neurologic and other adverse events (AEs).
• Known human immunodeficiency virus (HIV)-related malignancy.
• For participant in the lenalidomide combination arm, demonstrated hypersensitivity (example, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.
• History of drug-induced pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Life-threatening illness unrelated to cancer that could, in the investigator's opinion, make the participant not appropriate for this study.
• Female participants 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.
• 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.
• Known human immunodeficiency virus (HIV) positive.
• Known hepatitis B surface antigen positive, or known or suspected active hepatitis C infection.
• Systemic anticancer treatment (including investigational agents) or radiotherapy less than 2 weeks before the first dose of study treatment (\<=4 weeks 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).
• Prior ASCT within 6 months or prior ASCT at any time without adequate full hematopoietic recovery, defined by the entry criteria in the study, before Cycle 1 Day 1 or allogeneic stem cell transplant any time.
• Any clinically significant comorbidities, such as uncontrolled pulmonary disease, known impaired cardiac function or clinically significant cardiac disease (specified below), active central nervous system (CNS) 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:
• Unstable angina or acute myocardial infarction within 12 months before starting study drug.
• Current or history of New York Heart Association Class III or IV heart failure.

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (13)

University of Arizona Cancer Center, Tucson

Tucson, Arizona, 85724, United States

Location

University of California San Diego (UCSD) - Moores Cancer Center

La Jolla, California, 92093, United States

Location

Cedars-Sinai Medical Center (CSMC) - Samuel Oschin Comprehensive Cancer Institute

West Hollywood, California, 90048, United States

Location

University of Louisville Kentucky James Graham Brown Cancer Center

Louisville, Kentucky, 40202, United States

Location

Center for Cancer and Blood Disorders

Bethesda, Maryland, 20817, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202-2608, United States

Location

NYU Langone Medical Center - NYU Medical Oncology Associates

New York, New York, 10016-4744, United States

Location

University of North Carolina - Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27514, United States

Location

University Hospitals of Cleveland

Cleveland, Ohio, 44106, United States

Location

West Virginia University

Morgantown, West Virginia, 26506, United States

Location

Queen Elizabeth II Health Sciences Centre

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

McGill University - Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

TAK-659; Bendamustine Hydrochloride; Rituximab; Gemcitabine; Lenalidomide; ibrutinib

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Piperidines; Isoindoles

Results Point of Contact

• Title: Study Director
• Organization: Takeda

TrialDisclosures@takeda.com

+1-877-825-3327

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2016
• First Posted: November 3, 2016
• Study Start: March 5, 2017
• Primary Completion: July 27, 2020
• Study Completion: July 27, 2020
• Last Updated: February 18, 2022
• Results First Posted: February 18, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

Locations

US (11); CA (2)