A Study of TAK-981 Given With Rituximab in Adults With Relapsed or Refractory CD20-Positive Non-Hodgkin Lymphoma

Phase 1/2 Study of TAK-981 in Combination With Rituximab in Patients With Relapsed/Refractory CD20-Positive Non-Hodgkin Lymphoma

Sponsors

Lead Sponsor: Takeda

Source Takeda
Brief Summary

This study is about a medicine called TAK-981 given with rituximab, used to treat adults with relapsed or refractory CD20-positive Non-Hodgkin lymphoma. This study has 2 parts. The main aims of the study are: - To check for side effects from treatment with TAK-981 given with rituximab. - To check how much TAK-981 participants can tolerate. - To check if participants with diffuse large B-cell lymphoma or follicular lymphoma respond well to treatment. Participants will receive TAK-981 and rituximab in 21-day cycles. They will continue treatment for about 12 months unless their condition gets worse (disease progression), they cannot tolerate the treatment, or they leave the study for certain reasons.

Detailed Description

The drug being tested in this study is called TAK-981 in combination with rituximab. The study will include a dose escalation phase (Phase 1) and an expansion phase in select NHL indications (Phase 2). The study will enroll approximately 130 participants, approximately 35 participants in Phase 1 and approximately 95 participants in Phase 2. The participants with indolent or aggressive relapsed or refractory (r/r) NHL in Phase 1 will identify the maximum tolerated dose (MTD) and/or pharmacologically active dose (PAD). PAD can be defined retrospectively once MTD is reached and it can below MTD or coincide with it. In the dose escalation phase, the starting dose of TAK-981 will be 10 mg. The RP2D will be determined based on the available safety, preliminary pharmacokinetic (PK), pharmacodynamic information data, and after any early antitumor activity observed along with the statistical inference from the Bayesian Logistic Regression Modeling (BLRM). Participants in the Phase 2 will be enrolled once the Phase 1 of the study is completed, and MTD and/or PAD is determined. Phase 2 will explore the efficacy and safety of TAK-981 in combination with rituximab in participants with select r/r NHL types and indications. Participants in Phase 2 will be enrolled in one of the three treatment arms based on Cohorts: - Cohort A: r/r DLBCL Progressed to CAR T-cell therapy - Cohort B: r/r DLBCL with no CAR T-cell Prior Therapy - Cohort C: r/r FL Progressed to Systemic Therapies This multi-center trial will be conducted in the United States and Canada. The overall time to participate in this study is approximately 48 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.

Overall Status Recruiting
Start Date 2019-10-15
Completion Date 2023-07-15
Primary Completion Date 2023-07-15
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Phase 1: Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs) Up to 48 months
Phase 1: Number of Participants With Grade 3 or Higher TEAEs Up to 48 months
Phase 1: Duration of TEAEs Up to 48 months
Phase 1: Number of Participants With Clinically Significant Laboratory Values Up to 48 months
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) per Dose Level Up to 48 months
Phase 2: Overall Response Rate (ORR) Assessed by Investigator According to Lugano Classification for Lymphomas Up to 48 months
Secondary Outcome
Measure Time Frame
Cmax: Maximum Observed Plasma Concentration for TAK-981 Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days)
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days)
AUCt: Area Under the Plasma Concentration-time Curve from Time 0 to Time t Over the Dosing Interval for TAK-981 Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days)
AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981 Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days)
t1/2z: Terminal Disposition Phase Half-life for TAK-981 Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days)
CL: Total Clearance After Intravenous Administration for TAK-981 Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days)
Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 Cycle 1 Days 1 and 8 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 21 days)
Phase 1: Overall Response Rate (ORR) Assessed by Investigator According to Lugano Classification for Lymphomas Up to 48 months
Disease Control Rate (DCR) Assessed by Investigator According to Lugano Classification for Lymphomas Up to 48 months
Duration of Response (DOR) Assessed by Investigator According to Lugano Classification for Lymphoma Up to 48 months
Progression-Free Survival (PFS) Assessed by Investigator According to Lugano Classification for Lymphoma Up to 48 months
Time to Progression (TTP) Assessed by Investigator According to Lugano Classification for Lymphoma Up to 48 months
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 1 and in Tumor Tissues During Phase 2 Up to 48 months
Enrollment 130
Condition
Intervention

Intervention Type: Drug

Intervention Name: TAK-981

Description: TAK-981 intravenous infusion.

Intervention Type: Drug

Intervention Name: Rituximab

Description: Rituximab intravenous infusion.

Eligibility

Criteria:

Inclusion Criteria: Each participant must meet all the following inclusion criteria to be enrolled in the study: 1. Participant Population: o. For Phase 1 Dose Escalation: o. aNHL including mantle cell lymphoma and DLBCL histologies such as transformed DLBCL from low-grade lymphoma (follicular or others), DLBCL associated with small-cell infiltration in bone marrow, B-cell lymphoma with intermediate features between DLBCL and Burkitt's lymphoma or with intermediate features between DLBCL and Hodgkin lymphoma, FL grade 3B, and 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. o. iNHL (including FL 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. Note: 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. o. For Phase 2, the following CD20 +: o. r/r DLBCL progressed or relapsed after a prior CAR T-cells therapy that has received approval by a health authority for the treatment of DLBCL (Cohort A). o. r/r DLBCL that has progressed or relapsed after at least 2 but no more than 3 prior lines of systemic therapy and has not I prior cellular therapy. At least one prior line of therapy must have included a CD20-targeted therapy (Cohort B). o. r/r FL that has progressed or relapsed after at least 2 but no more than 3 prior lines of systemic therapy. At least one prior line of therapy must have included a CD20-targeted therapy (Cohort C). 2. Must be considered ineligible in the opinion of the investigator, or refused autologous stem-cell transplantation. 3. Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (<=) 2. 4. Adequate bone marrow function per local laboratory reference range at screening as follows: o Platelet count greater than or equal to (>=) 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). 5. Adequate renal and hepatic function, per local laboratory reference range at screening as follows: - Calculated creatinine clearance >=30 milliliter per minute (mL/min) calculated with Cockcroft-Gault formula. - 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. 6. Left ventricular ejection fraction (LVEF) >=40 percent (%); as measured by echocardiogram or multiple gated acquisition scan (MUGA). 7. Suitable venous access for safe drug administration and the study-required PK and pharmacodynamic sampling. 8. Have at least 1 bidimensionally measurable lesion per Lugano Classification (>1.5 centimeter [cm] in its largest dimension) by computed tomography (CT). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. In the Phase 2, Stage 1 portion of the study >1 measurable lesions are required, 1 for biopsy, and 1 for response. 9. Willing to consent to 1 mandatory pretreatment and 1 on-treatment skin biopsy during Phase 1. The skin biopsy entry requirement may be discontinued by the sponsor once there is enough pharmacodynamic evidence of target engagement. 10. For participants enrolled in Phase 2, Stage 1, willing to consent to one mandatory pretreatment and 1 on-treatment tumor biopsy. 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). Outside of Phase 2 Stage 1, paired tumor biopsies are optional. 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. Central nervous system 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. Post transplantation lymphoproliferative disease except relapsed NHL after autologous stem cell transplantation. 4. Undergone ASCT or treatment with cellular therapy including CAR T within <=3 months of TAK-981 dosing. 5. Prior allogeneic hematopoietic stem-cell transplantation. 6. Lymphomas with leukemic expression. 7. Prior anticancer therapy including chemotherapy, hormonal therapy, or investigational agents within 2 weeks or within at least 5 half-lives before TAK-981 dosing, 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. 8. Major surgery within 14 days before the first dose of study drug and not recovered fully from any complications from surgery. 9. 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. 10. 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. 11. 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. 12. Receipt of any live vaccine within 4 weeks of initiation of study treatment. 13. Active, uncontrolled autoimmune disease requiring >20 mg of prednisone or equivalent, cytotoxics or biologicals. 14. 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. 15. With baseline prolongation of the Fridericia-corrected QT interval (QTcF) (example, repeated demonstration of corrected QT interval [QTc] >480 millisecond (ms), history of congenital long QT syndrome, or torsades de pointes). 16. Receiving or requiring the continued use of medications that are known to be strong or moderate inhibitors and inducers of Cytochrome P450 3A4/5 (CYP3A4/5) 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 for CYP3A4/5 and Pgp inhibitors) before receiving a dose of TAK-981.

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Study Director Study Director Takeda
Overall Contact

Last Name: Takeda Contact

Phone: +1-877-825-3327

Email: [email protected]

Location
Facility: Status:
Henry Ford Hospital | Detroit, Michigan, 48202, United States Recruiting
Case Western Reserve University Seidman Cancer Center | Cleveland, Ohio, 44106, United States Recruiting
Jewish General Hospital | Montreal, Quebec, H3T 1E2, Canada Recruiting
Location Countries

Canada

United States

Verification Date

2021-05-01

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 4
Arm Group

Label: Phase 1, aNHL/iNHL: TAK-981 (10-160 mg) + Rituximab 375 mg/m^2

Type: Experimental

Description: TAK-981 (at increasing dose levels from 10 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.

Label: Phase 2, Cohort A: r/r DLBCL Progressed to CAR T-cell therapy

Type: Experimental

Description: 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 in participants with r/r diffuse large B-cell lymphoma (DLBCL) progressed or relapsed after a prior chimeric antigen receptor (CAR) T-cells therapy that has received approval by a health authority for the treatment of DLBCL.

Label: Phase 2, Cohort B: r/r DLBCL with no CAR T-cell Prior Therapy

Type: Experimental

Description: 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 in participants with r/r DLBCL that has progressed or relapsed after at least 2 but no more than 3 prior lines of systemic therapy and no prior therapy with CAR T-cells.

Label: Phase 2, Cohort C: r/r FL Progressed to Systemic Therapies

Type: Experimental

Description: 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 in participants with r/r follicular lymphoma (FL) that has progressed or relapsed after at least 2 but no more than 3 prior lines of systemic therapy.

Patient Data Yes
Study Design Info

Allocation: Non-Randomized

Intervention Model: Sequential Assignment

Primary Purpose: Other

Masking: None (Open Label)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact [email protected]. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Research News