| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory CD20-Positive Non-Hodgkin Lymphoma |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10025320 |
| E.1.2 | Term | Lymphomas non-Hodgkin's B-cell |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1: To determine the safety and tolerability of TAK-981 in combination with rituximab in patients with r/r NHL.
To establish the recommended Phase 2 dose (RP2D) of TAK-981 in combination with rituximab.
Phase 2: To evaluate the efficacy of TAK-981 in combination with rituximab in select r/r NHL indications. |
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| E.2.2 | Secondary objectives of the trial |
To characterize the PK profile of TAK-981 in combination with rituximab.
Phase 1: To determine the MTD and/or pharmacologically active dose (PAD) of TAK-981 when administered in combination with rituximab.
To assess the preliminary antitumor activity of TAK-981-rituximab combination.
To assess target engagement of TAK-981 (SUMO-TAK-981 adduct formation) and SUMOylation pathway inhibition in blood and skin.
Phase 2: To evaluate the efficacy of TAK-981 in combination with rituximab in select r/r NHL as measured by disease control rate (DCR),
duration of response (DOR), time to progression (TTP), and progressionfree survival (PFS).
To evaluate the safety and tolerability of TAK-981 in combination with rituximab.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adults ≥18 years old.
2. For Phase 1 Dose Escalation: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; 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:Rituximab or antiCD20 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.
For Phase 2, the following CD20 positive: r/r 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 (Cohort A); 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 received prior cellular therapy. At least one prior line of therapy must have included a CD20-targeted therapy (Cohort B); 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).
3. Patients must be considered ineligible for, in the opinion of the investigator, or must have refused autologous stem cell transplantation.
4.Eastern Cooperative Oncology Group (ECOG) performance score of ≤2.
5. Adequate bone marrow function per local laboratory reference range at screening
6. Adequate renal and hepatic function, per local laboratory reference range at screening
7. Left ventricular ejection fraction (LVEF) ≥40%; as measured by echocardiogram or multiple gated acquisition (MUGA) scan.
8. Suitable venous access for safe drug administration and the studyrequired PK and pharmacodynamic sampling.
9. Have at least 1 bidimensionally measurable lesion per Lugano Classification (eg, measurable node >1.5 cm in its largest dimension; measureable extranodal lesion >1.0 cm in longest diameter) by computed tomography (CT). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
10. 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.
11. For patients enrolled in Phase 2, if available, mandatory submission of archival tumor tissue acquired ≤12 months prior to screening. Tumor tissue, including archival tissue, is not applicable to patients enrolled in China.
12. 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]).
13. Women of childbearing potential participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Nonsterilized female patients of reproductive age and male patients should use effective methods of contraception through defined periods during and after study treatment.
14. Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the following:Agree to practice effective barrier contraception during the entire study treatment period and through 12 months 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 subject. (Periodic abstinence [eg, 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.)
15. Subject has provided informed consent.
16. Must be willing and able to comply with clinic visits and procedures outlined in the study protocol.
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| E.4 | Principal exclusion criteria |
1. CNS lymphoma; active brain or leptomeningeal metastases, as indicated by positive cytology from lumbar puncture or CT scan/magnetic resonance imaging (MRI).
2. Hypersensitivity to TAK-981, rituximab, or any component of the drug product.
3. History of Grade ≥3 IRR that lead to permanent discontinuation of previous rituximab treatment.
4. Previous participation in the TAK-981-1002 clinical study.
5. Posttransplantation lymphoproliferative disease except relapsed NHL after ASCT.
6. Undergone ASCT or treatment with cellular therapy including CAR T within ≤12 weeks of TAK-981 dosing.
7. Prior allogeneic hematopoietic stem-cell transplantation.
8. Lymphomas with leukemic expression.
9. 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 RANKL (receptor activator of nuclear factor kappa-B ligand) inhibitors are allowed.
10. Major surgery within 14 days before the first dose of study drug and not recovered fully from any complications from surgery.
11. 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 noncompensated 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 (eg, pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy is allowed.
12. Known chronic hepatitis C and/or positive serology (unless due to vaccination or passive immunization due to Ig therapy) for chronic hepatitis B. Known HIV infection.
13. 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 patient is not on active anticancer therapy as defined in Exclusion Criterion 9.
14. Receipt of any live vaccine within 4 weeks of initiation of study treatment.
15. Active, uncontrolled autoimmune disease requiring >20 mg of prednisone or equivalent, cytotoxics, or biologicals.
16. 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. Patients 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.
17. History of medical or psychiatric illness likely to interfere with the ability to comply with protocol requirements or give informed consent.
18. Patients with baseline prolongation of the QT interval with Fridericia correction method (QTcF) (eg, >470 ms for women and >450 ms for men and a history of congenital long QT syndrome or torsades de pointes).
19. Receiving or requiring the continued use of medications that are known to be strong or moderate inhibitors and inducers of CYP3A4/5 and strong Pgp inhibitors. To participate in this study, such patients should discontinue use of such agents for at least 2 weeks (1 week forCYP3A4/5 and Pgp inhibitors) before receiving a dose of TAK-981.
20. Female patients who are lactating and breastfeeding or have a positive urine or serum pregnancy test during the screening period or on Day 1 before first dose of study drug.
21. Patients in Germany who are committed to an institution by virtue of an order issued either by judicial or administrative authorities as per German law.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1:
Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose groups according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0; except CRS which will be graded according to American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS.
Occurrence of DLTs within the first 21 days of treatment in Cycle 1.
Phase 2:
ORR (CR + PR) as defined by the investigator according to Lugano Classification for lymphomas. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
PK parameters after the first dose of TAK-981 on C1D1 and C1D8;
Phase 1:ORR, DCR, DOR, TTP, and PFS as assessed by the investigator according to Lugano Classification for lymphomas;
TAK-981-SUMO adduct formation and SUMO pathway inhibition in skin/blood.
Phase 2:Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose groups according to the NCI CTCAE, Version 5.0; except CRS which will be graded according to ASTCT Consensus
Grading for CRS. DCR, DOR, TTP, and PFS as assessed by the investigator according to Lugano Classification for lymphomas. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase 1 occurs only in Japan and NA |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| China |
| Japan |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The final data cutoff for the clinical study report will be conducted after all patients have been discontinued from treatment or transferred to a long-term safety study, a single-patient investigational new drug application, or a similar program. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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