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

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ClinicalTrials.gov Identifier: NCT02954406
Recruitment Status : Recruiting
First Posted : November 3, 2016
Last Update Posted : September 7, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

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.

Condition or disease Intervention/treatment Phase
Lymphoma, Non-Hodgkin Drug: TAK-659 Drug: Bendamustine Drug: Rituximab Drug: Gemcitabine Drug: Lenalidomide Drug: Ibrutinib Phase 1

Detailed Description:

The drug being tested in this study is called TAK-659. TAK-659 is being tested to treat people who have advanced non-Hodgkin lymphoma. This study will determine the MTD or RP2D for TAK-659 in combination with bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, and ibrutinib. The study will enroll approximately 100 participants. Participants will be assigned to one of the 5 treatment groups:

  • TAK-659 + Bendamustine
  • TAK-659 + Bendamustine + Rituximab
  • TAK-659 + Gemcitabine
  • TAK-659 + Lenalidomide
  • TAK-659 + Ibrutinib

This multi-center trial will be conducted in North America and Europe. The overall time to participate in this study is approximately 27 months. Participants will make multiple visits to the clinic and will be followed up for safety for 28 days after the last dose of study drug.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b, Dose Escalation Study to Determine the Recommended Phase 2 Dose of TAK-659 in Combination With Bendamustine (±Rituximab), Gemcitabine, Lenalidomide, or Ibrutinib for the Treatment of Patients With Advanced Non-Hodgkin Lymphoma After At Least 1 Prior Line of Therapy
Actual Study Start Date : April 10, 2017
Estimated Primary Completion Date : April 26, 2019
Estimated Study Completion Date : April 26, 2019


Arm Intervention/treatment
Experimental: TAK-659 + Bendamustine
TAK-659 60 milligram (mg), immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 milligram per square meter (mg/m^2), infusion, intravenously, over 10 or 60 minutes (depending on formulation used) on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 will be escalated to 100 mg once daily after safety and tolerability of 60 mg dose is determined.
Drug: TAK-659
TAK-659 immediate release tablet

Drug: Bendamustine
Bendamustine intravenous infusion

Experimental: TAK-659 + Bendamustine + Rituximab
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 (depending on formulation used) 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 will be escalated to 100 mg once daily after safety and tolerability of 60 mg dose is determined.
Drug: TAK-659
TAK-659 immediate release tablet

Drug: Bendamustine
Bendamustine intravenous infusion

Drug: Rituximab
Rituximab intravenous infusion

Experimental: TAK-659 + Gemcitabine
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. The TAK-659 will be escalated to 100 mg once daily after safety and tolerability of 60 mg dose is determined.
Drug: TAK-659
TAK-659 immediate release tablet

Drug: Gemcitabine
Gemcitabine intravenous infusion

Experimental: TAK-659 + Lenalidomide
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. The TAK-659 will be escalated to 100 mg once daily after safety and tolerability of 60 mg dose is determined.
Drug: TAK-659
TAK-659 immediate release tablet

Drug: Lenalidomide
Lenalidomide capsule

Experimental: TAK-659 + Ibrutinib
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. The TAK-659 will be escalated to 100 mg once daily after safety and tolerability of 60 mg dose is determined.
Drug: TAK-659
TAK-659 immediate release tablet

Drug: Ibrutinib
Ibrutinib capsule




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of TAK-659 [ Time Frame: Up to 6 months ]
    Maximum dose that is determined to be safe and tolerable.

  2. Recommended Phase 2 Dose (RP2D) of TAK-659 [ Time Frame: Up to 6 months ]
    The dose recommended for use in phase 2 studies on the basis of the safety, tolerability, and preliminary pharmacokinetic (PK) and efficacy data obtained in phase 1 studies.


Secondary Outcome Measures :
  1. Summary Statistics of TAK-659 Maximum Observed Concentration (Cmax) on Cycle 1 Days 1, 8 and 15 by Dose Escalation Cohort [ Time Frame: Up to 16 days ]
    Geometric mean and coefficient of variation (CV) for Cmax for each dose escalation cohort of each study arm on Cycle 1 Days 1, 8 and 15 in the PK population.

  2. Summary Statistics of TAK-659 Time of First Occurrence of Cmax (Tmax) on Cycle 1 Days 1, 8 and 15 by Dose Escalation Cohort [ Time Frame: Up to 16 days ]
    Median (range) for Tmax for each dose escalation cohort of each study arm on Cycle 1 Days 1, 8 and 15 in the PK population.

  3. Summary Statistics of TAK-659 Area Under the Concentration-Time Curve During a Dosing Interval (AUCτ) on Cycle 1 Days 1, 8 and 15 by Dose Escalation Cohort [ Time Frame: Up to 16 days ]
    Geometric mean and CV for AUCτ for each dose escalation cohort of each study arm on Cycle 1 Days 1, 8 and 15 in the PK population.

  4. Overall Response Rate (ORR) [ Time Frame: Up to 6 months ]
    The proportion of participants in the response-evaluable population who achieved either complete response (CR), unconfirmed CR (CRu) or partial response (PR). CR is defined as the disappearance of all evidence of disease, CRu is defined as CR, except that bone marrow results are indeterminate or presence of residual nodal mass and PR is defined as regression of measurable disease and no new sites.

  5. Duration of Response (DOR) [ Time Frame: Up to 6 months ]
    The time from first CR or CRu or PR to progressive disease (PD) or relapse in the response-evaluable population. CR is defined as the disappearance of all evidence of disease, CRu is defined as CR, except that bone marrow results are indeterminate or presence of residual nodal mass. PR is defined as regression of measurable disease and no new sites. PD is defined as any new lesion or increase by >50% of previously involved sites from nadir.

  6. Time to Progression (TTP) [ Time Frame: Up to 6 months ]
    The time from first dose to PD or relapse in the response-evaluable population. PD is defined as any new lesion or increase by >50% of previously involved sites from nadir.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female participants aged 18 years or older.
  2. 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]).
  3. Radiographically or clinically measurable disease with at least 1 target lesion per International Working Group (IWG) criteria for malignant lymphoma.
  4. Participants who are refractory or relapsed after at least 1 prior line of therapy and for whom no effective standard therapy is available per the investigator's assessment.

    • 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).
    • Prior treatment with a regimen that includes the combination drug will not necessarily exclude a participant from that cohort if the investigator views treatment with that agent as appropriate. However, a participant who has a contraindication for a particular combination agent or who has been discontinued from prior therapy with a particular agent for toxicity will not be eligible for inclusion in that particular cohort.
  5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and life expectancy of greater than 3 months.
  6. 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 litre (/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 AST <=2.5*ULN.
    • Renal: serum creatinine >=60 milliliter per minute (mL/min) either as estimated by the Cockcroft-Gault equation or based on urine collection (12 or 24 hours).
    • 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 and glycosylated hemoglobin is ≤6.5%).
  7. Female participants who:

    • Are postmenopausal for at least 1 year before the screening visit, or
    • Are surgically sterile, or
    • If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method 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 participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)

    Male participant, 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 participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
  8. Both men and women in the rituximab combination arm (Cohort B) must practice contraception as described above from the time of signing of the informed consent form (ICF) through 12 months after the last dose of study drug.
  9. Both men and women in the lenalidomide combination arm (Cohort D) must adhere to the guidelines of the RevAssist program (United States participants) or, if not using commercial supplies, must adhere to the Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the Study Manual.
  10. 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 participant at any time without prejudice to future medical care.
  11. Recovered (that is, <= Grade 1 toxicity) from the reversible effects of prior anticancer therapy.

Exclusion Criteria:

  1. Central nervous system (CNS) lymphoma; active brain or leptomeningeal metastases, as indicated by positive cytology from lumbar puncture or computed tomography (CT) scan/magnetic resonance imaging (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).
  2. Known human immunodeficiency virus (HIV)-related malignancy.
  3. Known hypersensitivity (example, anaphylactic and anaphylactoid reactions) to any particular combination drug will result in a participant being ineligible for inclusion in that particular cohort.
  4. For participant in the lenalidomide combination arm, demonstrated hypersensitivity (example, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.
  5. History of drug-induced pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted.
  6. Life-threatening illness unrelated to cancer that could, in the investigator's opinion, make the participant not appropriate for this study.
  7. 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.
  8. 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.
  9. Known HIV positive.
  10. Known hepatitis B surface antigen positive, or known or suspected active hepatitis C infection.
  11. Systemic anticancer treatment (including investigational agents) or radiotherapy less than 2 weeks before the first dose of study treatment (<=4 weeks for large molecule agents).
  12. 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.
  13. Any clinically significant comorbidities, such as uncontrolled pulmonary disease, known impaired cardiac function or clinically significant cardiac disease (specified below), active CNS disease, active infection, or any other condition that could compromise the participant's participation in the study.
  14. 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.
    • Friderichia 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.
  15. Lack of suitable venous access for the study-required blood sampling for TAK-659.
  16. For participants in all combination arms (Cohorts A-E), 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 except in cases in which an AE must be managed. See a nonexhaustive list of prohibited strong CYP3A reversible inhibitors and/or P-gp inhibitors based on the US Food and Drug Administration (FDA) Draft Drug-Drug Interactions (DDI) Guidance.
    • 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. See a list of prohibited strong CYP3A mechanism-based inhibitors or strong CYP3A inducers and/or P-gp inducers based on the US FDA Draft DDI Guidance.
    • Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are not permitted during the study.
  17. Additionally, for participants in the ibrutinib combination arm (Cohort E), use or consumption of any of the following substances:

    • Medications or supplements that are known to be moderate reversible inhibitors of CYP3A 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 drugs. In general, the use of these agents is not permitted during the study for this combination except in cases in which an AE must be managed. See a list of nonexhaustive moderate CYP3A reversible inhibitors based on the US FDA Draft DDI Guidance.
    • Medications or supplements that are known to be moderate mechanism-based inhibitors or moderate inducers of CYP3A within 7 days or within 5 times the inhibitor or inducer half-life (whichever is longer) before the first dose of study drugs. In general, the use of these agents is not permitted during the study for this combination except in cases in which an AE must be managed. See a list of nonexhaustive moderate CYP3A mechanism-based inhibitors or moderate CYP3A inducers based on the US FDA Draft DDI Guidance.
    • Seville oranges within 5 days before the first dose of study drugs and during the study.
  18. Major surgery within 14 days before the first dose of study drug and not recovered fully from any complications from surgery.
  19. Systemic infection requiring IV antibiotic therapy or other serious infection within 14 days before the first dose of study drug.
  20. 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.
  21. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-659 including difficulty swallowing tablets or diarrhea >Grade 1 despite supportive therapy.
  22. Treatment with high-dose corticosteroids for anticancer purposes within 14 days before the first dose of TAK-659; daily dose equivalent to 10 mg oral prednisone or less is permitted. Corticosteroids for topical use or in nasal spray or inhalers are allowed.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02954406


Contacts
Contact: Takeda Study Registration Call Center +1-866-835-2233 GlobalOncologyMedinfo@takeda.com

Locations
United States, Arizona
University of Arizona Cancer Center, Tucson Recruiting
Tucson, Arizona, United States, 85724
United States, California
University of California San Diego (UCSD) - Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Cedars-Sinai Medical Center (CSMC) - Samuel Oschin Comprehensive Cancer Institute Not yet recruiting
West Hollywood, California, United States, 90048
United States, Kentucky
University of Louisville Kentucky James Graham Brown Cancer Center Recruiting
Louisville, Kentucky, United States, 40202
United States, Maryland
Center for Cancer and Blood Disorders Recruiting
Bethesda, Maryland, United States, 20817
United States, Massachusetts
Tufts Medical Center Not yet recruiting
Boston, Massachusetts, United States, 02111
United States, Michigan
Henry Ford Hospital Recruiting
Detroit, Michigan, United States, 48202-2608
United States, New York
NYU Langone Medical Center - NYU Medical Oncology Associates Recruiting
New York, New York, United States, 10016-4744
United States, North Carolina
University of North Carolina - Lineberger Comprehensive Cancer Center Recruiting
Chapel Hill, North Carolina, United States, 27514
United States, Ohio
University Hospitals of Cleveland Recruiting
Cleveland, Ohio, United States, 44106
United States, West Virginia
West Virginia University Recruiting
Morgantown, West Virginia, United States, 26506
Canada, Nova Scotia
Queen Elizabeth II Health Sciences Centre Recruiting
Halifax, Nova Scotia, Canada, B3H 2Y9
Canada, Quebec
McGill University - Jewish General Hospital Recruiting
Montreal, Quebec, Canada, H3T 1E2
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.

Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02954406     History of Changes
Other Study ID Numbers: C34005
U1111-1188-0891 ( Other Identifier: WHO )
2016-001426-34 ( EudraCT Number )
First Posted: November 3, 2016    Key Record Dates
Last Update Posted: September 7, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Drug Therapy

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Gemcitabine
Thalidomide
Lenalidomide
Rituximab
Bendamustine Hydrochloride
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Leprostatic Agents
Anti-Bacterial Agents