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A Study of TAK-981 in Combination With Rituximab in Participants With Relapsed/Refractory (r/r) CD20-positive (CD20+) Non-Hodgkin Lymphoma (NHL)

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ClinicalTrials.gov Identifier: NCT04074330
Recruitment Status : Recruiting
First Posted : August 30, 2019
Last Update Posted : May 21, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
The purpose of this study is to determine the safety and tolerability of TAK-981 in combination with rituximab in participants with r/r CD20+ NHL in Phase 1b, and to evaluate the efficacy of TAK-981 in combination with rituximab in r/r CD20+ NHL in Phase 2.

Condition or disease Intervention/treatment Phase
Lymphoma, Non-Hodgkin Drug: TAK-981 Drug: Rituximab Phase 1 Phase 2

Detailed Description:

The drug being tested in this study is called TAK-981 in combination with rituximab. The study will determine the safety, tolerability and efficacy of TAK-981 in combination with rituximab in participants with r/r CD20+ NHL. The study will include a dose escalation phase (Phase 1b) and an open label study (Phase 2).

The study will enroll approximately 90 participants, approximately 34 participants in Phase 1b and approximately 56 participants in Phase 2. The phase 1b will identify the maximum tolerated dose (MTD) and/or pharmacologically active dose (PAD). In the dose escalation phase, the starting dose of TAK-981 will be 3 mg, however, a starting dose of TAK-981 that is greater than (>) 3 mg may be considered if emerging preliminary safety experience from the ongoing TAK-981-1002 single agent study supports it. The starting dose level will be escalated based on available safety, PK and pharmacodynamic data, and after any early antitumor activity is observed.

Participants in the Phase 2 will be enrolled once the Phase 1b of the study is completed, and MTD and/or PAD is determined. Participants in Phase 2 will be enrolled in 2 treatment arms: indolent non-Hodgkin lymphoma (iNHL) and aggressive non-Hodgkin lymphoma (aNHL).

This multi-center trial will be conducted in the United States and Canada. The overall time to participate in this study is approximately 36 months. Participants will make multiple visits to the clinic, and will attend the end of treatment (EOT) visit 30 days after receiving their last dose of drug or before the start of subsequent systemic anticancer therapy, whichever occurs first for a follow-up assessment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Phase 1b/2 Study of TAK-981 in Combination With Rituximab in Patients With Relapsed/Refractory CD20-Positive Non-Hodgkin Lymphoma
Actual Study Start Date : October 15, 2019
Estimated Primary Completion Date : August 19, 2023
Estimated Study Completion Date : August 19, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Rituximab

Arm Intervention/treatment
Experimental: Phase 1b: TAK-981 (From 3 mg to 160 mg) + Rituximab 375 mg/m^2
TAK-981 (at increasing dose levels from 3 milligram [mg] to 160 mg), infusion, intravenously, once on Days 1 and 8 of each 21 day treatment cycle in combination with rituximab 375 milligram per square meter (mg/m^2), infusion, intravenously, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to disease progression (PD) or unacceptable toxicity. Dose levels will be escalated based on available safety, pharmacokinetic (PK) and pharmacodynamic data.
Drug: TAK-981
TAK-981 intravenous infusion.

Drug: Rituximab
Rituximab intravenous infusion.

Experimental: Phase 2, iNHL: TAK-981 + Rituximab 375 mg/m^2
TAK-981 TBD, infusion, intravenously, once on Days 1 and 8 of each 21 day treatment cycle in combination with rituximab 375 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to PD or unacceptable toxicity.
Drug: TAK-981
TAK-981 intravenous infusion.

Drug: Rituximab
Rituximab intravenous infusion.

Experimental: Phase 2, aNHL: TAK-981 + Rituximab 375 mg/m^2
TAK-981 TBD, infusion, intravenously, once on Days 1 and 8 of each 21 day treatment cycle in combination with rituximab 375 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to PD or unacceptable toxicity.
Drug: TAK-981
TAK-981 intravenous infusion.

Drug: Rituximab
Rituximab intravenous infusion.




Primary Outcome Measures :
  1. Phase 1b: Number of Participants With Overall and per Dose Level Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to 36 months ]
  2. Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs) per Dose Level [ Time Frame: Up to 36 months ]
    DLTs will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.

  3. Phase 1b: Number of Participants With Greater Than or Equal to (>=) Grade 3 TEAEs [ Time Frame: Up to 36 months ]
    Adverse event (AE) Grades will be evaluated as per NCI CTCAE, version 5.

  4. Phase 1b: Number of Participants With one or More Serious Adverse Events (SAEs) [ Time Frame: Up to 36 months ]
  5. Phase 1b: Number of Participants With Treatment Related Dose Modifications Including Dose Delays, Dose interruption and Dose Reductions, and Who Discontinued Due to TEAEs [ Time Frame: Up to 36 months ]
  6. Phase 1b: Number of Participants With Clinically Significant Laboratory Values [ Time Frame: Up to 36 months ]
  7. Phase 2: Overall Response Rate (ORR) Assessed by Investigator According to Lugano Classification for Lymphomas [ Time Frame: Up to 36 months ]
    ORR is defined as the percentage of participants who achieve complete response (CR) and partial response (PR), as defined by the investigator according to Lugano classification for lymphomas during the study.


Secondary Outcome Measures :
  1. Cmax: Maximum Observed Plasma Concentration for TAK-981 [ Time Frame: Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length is equal to [=] 21 days) ]
  2. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 [ Time Frame: Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days) ]
  3. AUCt: Area Under the Plasma Concentration-time Curve from Time 0 to Time t Over the Dosing Interval for TAK-981 [ Time Frame: Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days) ]
  4. AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981 [ Time Frame: Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days) ]
  5. t1/2z: Terminal Disposition Phase Half-life for TAK-981 [ Time Frame: Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days) ]
  6. CL: Total Clearance After Intravenous Administration for TAK-981 [ Time Frame: Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days) ]
  7. Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 [ Time Frame: Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days) ]
  8. ORR According to Lugano Classification With Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) Modification [ Time Frame: Up to 36 months ]
    ORR is defined as the percentage of participants who achieve CR and PR, as defined by the investigator according to LYRIC during the study.

  9. Duration of Response (DOR) [ Time Frame: Up to 36 months ]
    DOR is the time from the date of first documentation of a PR or better to the date of first documentation of PD for responders (PR or better). DOR will be assessed by the investigator according to LYRIC.

  10. Progression-free Survival (PFS) [ Time Frame: Up to 36 months ]
    PFS is defined as the time from the date of the first dose administration to the date of first documentation of PD or death due to any cause, whichever occurs first. PD will be determined by Response Evaluation Criteria in Lymphoma. PFS will be assessed by the investigator according to LYRIC.

  11. Time to Response (TTR) [ Time Frame: Up to 36 months ]
    TTR will be assessed based on LYRIC criteria.

  12. Number of Participants With TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation and SUMO Pathway Inhibition in Skin and Blood During Phase 1b and in Skin, Blood and Tumor Tissues During Phase 2 [ Time Frame: Up to 36 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

Each participant must meet all the following inclusion criteria to be enrolled in the study:

  1. CD20+ aNHL including mantle cell lymphoma (phase 1b only) and diffuse large B-cell lymphoma (DLBCL) histologies such as transformed DLBCL from low-grade lymphoma (follicular or others), DLBCL associated with small-cell infiltration in bone marrow, CD20+ B-cell lymphoma with intermediate features between DLBCL and Burkitt's lymphoma or with intermediate features between DLBCL and Hodgkin lymphoma, follicular lymphoma grade 3B, and CD20+ aggressive B-cell lymphoma unclassifiable who must have previously received rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine, (Oncovin) and prednisone (R-CHOP) (or equivalent anti-CD20 containing therapy) and 1 additional line of therapy in the r/r setting.
  2. CD20+ iNHL (including follicular lymphoma of grades 1-3A and marginal zone lymphoma) refractory to rituximab or to any other anti-CD20 monoclonal antibodies, who have received at least 1 prior systemic therapy for r/r iNHL:

    o Rituximab or anti-CD20 refractoriness is defined as failure to respond to, or progression during, any previous rituximab/anti-CD20-containing regimen (monotherapy or combined with chemotherapy), or progression within 6 months of the last rituximab or anti-CD20 dose.

    • The minimum qualifying rituximab/anti-CD20 dose is 1 full cycle (that is, weekly*4 doses monotherapy or 1 complete dose if combined with chemotherapy).
    • Prior anti-CD20 antibody or cytotoxic drugs may have been administered as single agents or as components of combination therapies. Each repeated course of the same single-agent or combination is considered an independent regimen.
  3. Must be ineligible or refused autologous or allogenic hematopoietic stem cell transplantation or Chimeric Antigen Receptor (CAR) T-cell therapy.
  4. Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (<=) 2.
  5. Adequate bone marrow function per local laboratory reference range at screening as follows:

    o Platelet count >=75.0*10^9/L, Grade 2 thrombocytopenia (platelet count >=50.0*10^9 per liter [/L]) is allowed if it is clearly due to marrow involvement with no evidence of myelodysplastic syndrome or hypoplastic bone marrow if found. Absolute neutrophil count (ANC) >=1.0*10^9/L. Hemoglobin >=85 gram per liter (g/L) (red blood cell [RBC] transfusion allowed >=14 days before assessment).

  6. Adequate renal and hepatic function, per local laboratory reference range at screening as follows:

    • Calculated creatinine clearance >=45 milliliter per minute (mL/min) using measured 24-hour creatinine clearance or calculated with modified Cockcroft-Gault formula. Participants can be enrolled based only on calculated glomerular filtration rate; however, if creatinine clearance is measured, this value must be used for inclusion.
    • Aspartate aminotransferase and alanine aminotransferase <=3.0*the upper limit of normal (ULN) of the institution's normal range; bilirubin <=1.5*ULN. Participants with Gilbert's syndrome may have a bilirubin level >1.5*ULN, per discussion between the investigator and the medical monitor.
  7. Left ventricular ejection fraction (LVEF) >=40 percent (%); as measured by echocardiogram or multiple gated acquisition scan (MUGA).
  8. Suitable venous access for safe drug administration and the study-required PK and pharmacodynamic sampling.
  9. Have at least 1 bidimensionally measurable lesion per Lugano Classification (>1.5 centimeter [cm] in its largest dimension) by computed tomography (CT) that has not been previously irradiated. In the phase 2 portion of the study >1 measurable lesions are required, 1 for biopsy, and 1 for response.
  10. Willing to consent to 1 mandatory pretreatment and 1 on-treatment skin biopsy during phase 1b and 1 mandatory pretreatment and 1 on-treatment skin and tumor biopsies during phase 2. For fresh tumor biopsies, the lesion must be accessible for a low risk biopsy procedure (those occurring outside the brain, lung/mediastinum, and intra-abdominal, or obtained with endoscopic procedures beyond the stomach or bowel). The skin biopsy entry requirement may be discontinued by the sponsor once there is enough pharmacodynamic evidence of target engagement.
  11. Recovered to Grade 1, baseline or established as sequela, from all toxic effects of previous therapy (except alopecia, neuropathy, autoimmune endocrinopathies with stable endocrine replacement therapy, neurotoxicity [Grade 1 or 2 permitted], or bone marrow parameters [any of Grade 1, 2, permitted if directly related to bone marrow involvement]).

Exclusion Criteria:

Participants meeting any of the following exclusion criteria are not to be enrolled in the study:

  1. CNS lymphoma; active brain or leptomeningeal metastases, as indicated by positive cytology from lumbar puncture or CT scan/magnetic resonance imaging (MRI).
  2. History of Grade >=3 infusion-related reaction (IRR) that lead to permanent discontinuation of previous rituximab treatment.
  3. Posttransplantation lymphoproliferative disease except relapsed NHL after autologous stem cell transplantation.
  4. Prior allogeneic hematopoietic stem-cell transplantation.
  5. Lymphomas with leukemic expression.
  6. Prior anticancer therapy including chemotherapy, hormonal therapy, or investigational agents within 2 weeks or within at least 5 half-lives before TAK-981 dosing (up to a maximum of 4 weeks), whichever is shorter. Low dose steroids (oral prednisone or equivalent <=20 mg per day), hormonal therapy for prostate cancer or breast cancer (in adjuvant situation), and treatment with bisphosphonates and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors are allowed.
  7. Major surgery within 14 days before the first dose of study drug and not recovered fully from any complications from surgery.
  8. Significant medical diseases or conditions, as assessed by the Investigators and Sponsor that would substantially increase the risk-benefit ratio of participating in the study. This includes but is not limited to acute myocardial infarction or unstable angina within the last 6 months, uncontrolled diabetes mellitus, significant active bacterial, viral or fungal infections, severely immunocompromised state, severe non-compensated hypertension and congestive heart failure New York Heart Association Class III or IV, ongoing symptomatic cardiac arrhythmias of >Grade 2, pulmonary embolism, or symptomatic cerebrovascular events, or any other serious cardiac condition (example, pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy is allowed.
  9. Known chronic hepatitis C and/or positive serology (unless due to vaccination or passive immunization due to immunoglobulin (Ig) therapy) for chronic hepatitis B. Known Human Immunodeficiency Virus (HIV) infection.
  10. Second malignancy within the previous 3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the participant is not on active anticancer therapy.
  11. Receipt of any live vaccine (example, varicella, pneumococcus) within 4 weeks of initiation of study treatment.
  12. Active, uncontrolled autoimmune disease requiring >20 mg of prednisone or equivalent, cytotoxics or biologicals.
  13. Corticosteroid use within 1 week before the first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. Participants requiring steroids at daily doses >20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for lymphoma control or white blood cell count lowering are not eligible.
  14. Participants with baseline prolongation of the Fridericia-corrected QT interval (example, repeated demonstration of QTc interval >480 millisecond (ms), history of congenital long QT syndrome, or torsades de pointes).
  15. Receiving or requiring the continued use of medications that are known to be strong or moderate inhibitors and inducers of Cytochrome P450 3A4/5b (CYP3A4/5 b) and strong P-glycoprotein (Pgp) inhibitors. To participate in this study, such participants should discontinue use of such agents for at least 2 weeks (1 week washout for CYP3A4/5 inhibitors, and 2 weeks washout if using CYP3A4/5 inducers) before receiving a dose of TAK-981.

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): NCT04074330


Contacts
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Contact: Takeda Study Registration Call Center +1-844-662-8532 globaloncologymedinfo@takeda.com

Locations
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United States, Michigan
Henry Ford Hospital Recruiting
Detroit, Michigan, United States, 48202
United States, Ohio
Case Western Reserve University Seidman Cancer Center Recruiting
Cleveland, Ohio, United States, 44106
Canada, Quebec
Jewish General Hospital Recruiting
Montreal, Quebec, Canada, H3T 1E2
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Director Millennium Pharmaceuticals, Inc.
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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04074330    
Other Study ID Numbers: TAK-981-1501
U1111-1236-0243 ( Registry Identifier: WHO )
First Posted: August 30, 2019    Key Record Dates
Last Update Posted: May 21, 2020
Last Verified: May 2020
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 for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com 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.

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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:
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Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents