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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)

NCT04074330

Description:

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.

Related Conditions:
  • Aggressive Non-Hodgkin Lymphoma
  • B-Cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma
  • Follicular Lymphoma
  • Marginal Zone Lymphoma
  • Transformed Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of TAK-981 in Combination With Rituximab in Participants With Relapsed/Refractory (r/r) CD20-positive (CD20+) Non-Hodgkin Lymphoma (NHL)
  • Official Title: Phase 1b/2 Study of TAK-981 in Combination With Rituximab in Patients With Relapsed/Refractory CD20-positive Non-Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: TAK-981-1501
  • SECONDARY ID: U1111-1236-0243
  • NCT ID: NCT04074330

Conditions

  • Lymphoma, Non-hodgkin

Interventions

DrugSynonymsArms
TAK-981Phase 1b: TAK-981 (From 3 mg to 160 mg) + Rituximab 375 mg/m^2
RituximabPhase 1b: TAK-981 (From 3 mg to 160 mg) + Rituximab 375 mg/m^2

Purpose

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.

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 2b 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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1b: TAK-981 (From 3 mg to 160 mg) + Rituximab 375 mg/m^2ExperimentalTAK-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.
  • TAK-981
  • Rituximab
Phase 2, iNHL: TAK-981 + Rituximab 375 mg/m^2ExperimentalTAK-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.
  • TAK-981
  • Rituximab
Phase 2, aNHL: TAK-981 + Rituximab 375 mg/m^2ExperimentalTAK-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.
  • TAK-981
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

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

          1. CD20+ aNHL include 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 ECG 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. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1b: Number of Participants With Overall and per Dose Level Treatment-emergent Adverse Events (TEAEs)
Time Frame:Up to 36 months
Safety Issue:
Description:DLTs will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure:ORR According to Lugano Classification With Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) Modification
Time Frame:Up to 36 months
Safety Issue:
Description:ORR is defined as the percentage of participants who achieve CR and PR, as defined by the investigator according to LYRIC during the study.
Measure:Duration of Response (DOR)
Time Frame:Up to 36 months
Safety Issue:
Description: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.
Measure:Progression-free Survival (PFS)
Time Frame:Up to 36 months
Safety Issue:
Description: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.
Measure:Time to Response (TTR)
Time Frame:Up to 36 months
Safety Issue:
Description:TTR will be assessed based on LYRIC criteria.
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Millennium Pharmaceuticals, Inc.

Trial Keywords

  • Drug Therapy

Last Updated

October 25, 2019