Clinical trial NCT04074330: A Study of TAK-981 Given With Rituximab in Adults With Relapsed or Refractory CD20-Positive Non-Hodgkin Lymphoma
Official title: Phase 1/2 Study of TAK-981 in Combination With Rituximab in Patients With Relapsed/Refractory CD20-Positive Non-Hodgkin Lymphoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Lymphoma, Non-Hodgkin
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2019-08-30
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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 non-Hodgkin lymphoma (NHL) indications (Phase 2).

The study will enroll approximately 180 participants, approximately 35 participants in Phase 1 and approximately 145 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 NHL types and indications. Participants in Phase 2 will be enrolled in one of the three treatment arms based on Cohorts:

* Phase 2, Cohort A r/r DLBCL Progressed after CAR T-cell therapy:TAK-981+Rituximab
* Phase 2, Cohort B:r/r DLBCL;no CAR T-cell Therapy;2-3 Prior Lines: Two Dose Levels of TAK-981+Rituximab
* Phase 2, Cohort C:r/r FL;no CAR T-cell Therapy;2-3 Prior Lines: Two Dose Levels of TAK-981+Rituximab

This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 72 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.

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 confirmed 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 1 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 (ASCT).
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.
   * Potassium levels \>=lower limit of normal (LLN). For potassium \>upper limit of normal (ULN) discussion with Takeda medical monitor (MM)/designee recommended.
   * Aspartate aminotransferase and alanine aminotransferase \<=3.0\*the 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 (MUGA) scan.
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 by computed tomography (CT). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
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, if available, mandatory submission of archival tumor tissue acquired ≤12 months prior to screening.
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 ASCT.
4. Undergone ASCT or treatment with cellular therapy including CAR T within \<=12 weeks 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 QT interval with Fridericia correction method (QTcF) (example, \>470 milliseconds (ms) for women and \>450 ms for men and a 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.
17. Participants in Germany who are committed to an institution by virtue of an order issued either by judicial or administrative authorities as per German law.

Primary outcomes:
measure: Phase 1: Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
measure: Phase 1: Number of Participants With Grade 3 or Higher TEAEs
timeFrame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
measure: Phase 1: Duration of TEAEs
timeFrame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
measure: Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) Per Dose Level
timeFrame: Up to 42 months
measure: Phase 2: Overall Response Rate (ORR)
timeFrame: Up to 42 months
Secondary outcomes:
measure: Cmax: Maximum Observed Plasma Concentration for TAK-981
timeFrame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
measure: Tmax: Time of First Occurrence of the Maximum Plasma Concentration (Cmax) for TAK-981
timeFrame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
measure: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981
timeFrame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
measure: AUC0-∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981
timeFrame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
measure: t1/2z: Terminal Disposition Phase Half-life for TAK-981
timeFrame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
measure: CL: Total Clearance After Intravenous Administration for TAK-981
timeFrame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
measure: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981
timeFrame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
measure: Phase 1: Overall Response Rate (ORR)
timeFrame: Up to 42 months
measure: Phase 1: Disease Control Rate (DCR)
timeFrame: Up to 42 months
measure: Phase 1: Duration of Response (DOR)
timeFrame: Up to 42 months
measure: Phase 1: Time to Progression (TTP)
timeFrame: Up to 42 months
measure: Phase 1: Progression-Free Survival (PFS)
timeFrame: Up to 42 months
measure: Phase 1: Fold Change From Baseline in Levels of TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation in Blood as Assessed by Flow Cytometry During Phase 1
timeFrame: Cycle 1 Day 1 (1 hour, 4 hours, 8 hours) and Day 8 (Pre-dose, 1 hour, 4 hours and 8 hours) (Cycle length = 21 days)
measure: Phase 1: Levels of TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation in Skin as Assessed by Immunohistochemistry (IHC) During Phase 1
timeFrame: Cycle 1 Days 1 and 8 (Cycle length = 21 days)
measure: Phase 1: Fold Change From Baseline in SUMO Pathway Inhibition in Blood as Assessed by Flow Cytometry During Phase 1
timeFrame: Cycle 1 Day 1 (1 hour, 4 hours, 8 hours) and Day 8 (Pre-dose, 1 hour, 4 hours and 8 hours) (Cycle length = 21 days)
measure: Phase 1: SUMO Pathway Inhibition in Skin as Assessed by Immunohistochemistry (IHC) During Phase 1
timeFrame: Cycle 1 Days 1 and 8 (Cycle length = 21 days)
measure: Phase 2: Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
measure: Phase 2: Number of Participants With Grade 3 or Higher TEAEs
timeFrame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
measure: Phase 2: Duration of TEAEs
timeFrame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
measure: Phase 2: Disease Control Rate (DCR)
timeFrame: Up to 42 months
measure: Phase 2: Duration of Response (DOR)
timeFrame: Up to 42 months
measure: Phase 2: Time to Progression (TTP)
timeFrame: Up to 42 months
measure: Phase 2: Progression-Free Survival (PFS)
timeFrame: Up to 42 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Cancer Center - Rochester - PPDS
state: Minnesota
city: Chapel Hill
country: United States
facility: Levine Cancer Institute - Charlotte
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: City of Hope - Comprehensive Cancer Center (CCC)
state: Oregon
city: Pittsburgh
country: United States
facility: Western Pennsylvania Hospital
state: Pennsylvania
city: Dallas
country: United States
facility: Texas Oncology (Medical City) - USOR
state: Texas
city: Tyler
country: United States
facility: Texas Oncology (Tyler) - USOR
state: Texas
city: Montreal
country: Canada
facility: Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Pointe-Claire
country: Canada
facility: Sir Mortimer B Davis Jewish General Hospital
state: Quebec
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Shanghai
country: China
facility: Shanghai East Hospital
state: Shanghai
city: Marseille
country: France
facility: Institut Paoli Calmettes
state: Bouches-du-Rhone
city: Dijon
country: France
facility: Hopital Francois Mitterand
state: Cote-d'Or
city: Montpellier
country: France
facility: CHU Montpellier - Hopital St Eloi
state: Herault
city: Rennes
country: France
facility: Hopital Prive Sevigne
state: Ille-et-Vilaine
city: Nantes
country: France
facility: Hotel Dieu - Nantes
state: Loire-Atlantique
city: Rouen
country: France
facility: Centre Henri Becquerel
state: Seine-Maritime
city: Paris
country: France
facility: Hopital Saint Antoine
city: Paris
country: France
facility: Hopital Universitaire Pitie Salpetriere
city: Freiburg
country: Germany
facility: Universitatsklinikum Freiburg
state: Baden-Wurttemberg
city: Tubingen
country: Germany
facility: Universitatsklinikum Tubingen
state: Baden-Wurttemberg
city: Munchen
country: Germany
facility: Klinikum rechts der Isa der Technischen Universitaet Muenchen
state: Bayern
city: Wurzburg
country: Germany
facility: Universitatsklinikum Wurzburg
state: Bayern
city: Essen
country: Germany
facility: Universitatsklinikum Essen
state: Nordrhein-Westfalen
city: Magdeburg
country: Germany
facility: Otto-von-Guericke-Universitat Magdeburg
state: Sachsen-Anhalt
city: Leipzig
country: Germany
facility: Universitatsklinikum Leipzig
state: Sachsen
city: Berlin
country: Germany
facility: Charite - Universitatsmedizin Berlin
city: Ravenna
country: Italy
facility: Azienda Sanitaria Locale di Ravenna
state: Emilia-Romagna
city: Roma
country: Italy
facility: Azienda Ospedaliera San Camillo Forlanini
state: Lazio
city: Milano
country: Italy
facility: Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
state: Lombardia
city: Milano
country: Italy
facility: Istituto Nazionale Dei Tumori
state: Lombardia
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda - Presidio Ospedaliero Ospedale Niguarda
state: Lombardia
city: Novara
country: Italy
facility: A.O.U. Maggiore della Carita
state: Piemonte
city: Torino
country: Italy
facility: Azienda Ospedaliera Citta della Salute e della Scienza di Torino
state: Piemonte
city: Tricase
country: Italy
facility: Azienda Ospedaliera Cardinale G Panico
state: Puglia
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo di Pavia
city: Nagoya-Shi
country: Japan
facility: National Hospital Organization Nagoya Medical Center
state: Aiti
city: Sendai-Shi
country: Japan
facility: National University Corporation Tohoku University Tohoku University Hospital
state: Miyagi
city: Osakasayama-Shi
country: Japan
facility: Kindai University Hospital
state: Osaka
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Tiba
city: Koto-Ku
country: Japan
facility: The Cancer Institute Hospital of Japanese Foundation For Cancer Research
state: Tokyo
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario La Paz - PPDS
city: Salamanca
country: Spain
facility: Complejo Asistencial Universitario de Salamanca H. Clinico
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio - PPDS
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: Devon
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre - PPDS
state: Lanarkshire
city: London
country: United Kingdom
facility: University College London
state: London, City Of
city: London
country: United Kingdom
facility: Royal Marsden Hospital - Downs Road
state: London, City Of
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust
state: Oxfordshire
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Nakamura A, Grossman S, Song K, Xega K, Zhang Y, Cvet D, Berger A, Shapiro G, Huszar D. The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation. Blood. 2022 May 5;139(18):2770-2781. doi: 10.1182/blood.2021014267.