E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or Refractory Diffuse Large B-Cell Lymphoma
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E.1.1.1 | Medical condition in easily understood language |
Relapsed or Refractory Diffuse Large B-Cell Lymphoma |
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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 | HLT |
E.1.2 | Classification code | 10012819 |
E.1.2 | Term | Diffuse large B-cell lymphomas |
E.1.2 | System Organ Class | 100000004851 |
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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 |
To assess the efficacy of TAK-659 as measured by independent radiologic review committee (IRC)-assessed overall response rate (ORR) in patients with diffuse large B-cell lymphoma (DLBCL) - (Stage 2). |
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E.2.2 | Secondary objectives of the trial |
• To assess complete response (CR) rate per IRC in patients with DLBCL - (Stage 2)
• To select the Stage 2 dose regimen of TAK-659 from the lead-in dose exploration phase (Stage 1) and assess efficacy using ORR per IRC (Stage 2).
• To assess ORR per IRC at 3, 6, and 9 cycles in patients with DLBCL - (Stage 2).
• To assess duration of response (DOR) and duration of CR per IRC in patients with DLBCL - (Stage 2).
• To assess overall response rate (ORR) per IRC in the subgroup of patients with germinal center B-cell (GCB) DLBCL - (Stage 2).
• To assess ORR per IRC in the subgroup of patients with DLBCL transformed from indolent lymphoma - (Stage 2).
• To assess progression-free survival (PFS) per IRC in patients with DLBCL - (Stage 2).
• To assess overall survival (OS) in patients with DLBCL - (Stage 2).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients aged 18 years or older.
2. Patients must have histologically confirmed DLBCL, including de novo disease or transformed disease from indolent NHL. High-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 translocations (double-hit
DLBCL under DLBCL, NOS, based on the 2008 WHO classification criteria) is not eligible for this study.
a. Local pathology review for histological confirmation:
- A formalin-fixed, paraffin-embedded (FFPE) tumor block or appropriately stained slides from a fresh biopsy is required.
3. Relapsed or refractory to ≥2 prior lines of chemotherapy based on standard of care with certain requirements for prior therapy.
4. For patients who have relapsed or progressed after achieving a response, documented, investigator-assessed relapse or progression after the last treatment is required.
5. Must have FDG-PET–avid measurable disease that meets the size criteria per IWG as assessed on cross-sectional imaging by CT/MRI.
6. ECOG performance status score of 0 or 1.
7. Life expectancy of >3 months
8. Patients must have adequate organ function, including the following:
a. Bone marrow reserve: absolute neutrophil count (ANC) ≥1000/μL, platelet count ≥75,000/μL (≥50,000/μL for patients with bone marrow involvement), and hemoglobin ≥8 g/dL (red blood cell [RBC] and
platelet transfusion allowed ≥14 days before assessment).
b. Hepatic: total bilirubin ≤1.5 times the upper limit of the normal range (ULN); ALT and AST ≤2.5xULN.
c. Renal: creatinine clearance ≥60 mL/min either as estimated by the Cockcroft-Gault equation or based on urine collection (12 or 24 hours).
d. Others:
•Lipase ≤1.5xULN and amylase ≤1.5xULN with no clinical symptoms suggestive of pancreatitis or cholecystitis.
•Blood pressure ≤Grade 1 (hypertensive patients are permitted if their blood pressure is controlled to ≤Grade 1 by hypertensive medications and glycosylated hemoglobin is ≤6.5%). |
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E.4 | Principal exclusion criteria |
1. CNS lymphoma; active brain or leptomeningeal metastases.
2. Known human immunodeficiency virus (HIV)–related malignancy.
3. Systemic anticancer treatment (including investigational agents) less than 3 weeks before the first dose of study treatment.
4. Radiotherapy less than 3 weeks before the first dose of study treatment.
5. Known HIV positive (testing not required).
6. Known hepatitis B surface antigen positive or known or suspected active hepatitis C infection.
7. Prior ASCT within 6 months or prior ASCT at any time without full hematopoietic recovery before Cycle 1 Day 1, or allogeneic stem cell transplant any time.
8. Participants with certain cardiovascular conditions are excluded.
9. Major surgery within 14 days before the first dose of study drug or incomplete recovery from any complications from surgery.
10. Systemic infection requiring parenteral antibiotic therapy or other serious infection (bacterial, fungal, or viral) within 21 days before the first dose of study drug.
11. Treatment with high-dose corticosteroids for anticancer purposes within 7 days before the first dose of TAK-659.
12. Patients with another malignancy within 2 years of study start. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection and are
considered disease-free at the time of study entry.
13. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-659.
14. Certain wash-out restrictions before the first dose of study drug on inhibitors of P-gp and/or strong reversible inhibitors of CYP3A, strong CYP3A mechanism-based inhibitors or strong CYP3A inducers and/or Pgp inducers, grapefruit containing food or beverages.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is ORR as assessed by IRC according to the modified 2007 International Working Group (IWG) criteria for malignant lymphoma - (Stage 2). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary analysis - after all patients enrolled in the study have had the opportunity to complete 6 cycles of treatment with study drug.
Conclusion of the study - when OS events have occurred in 70% of patients, or 24 months after last patient in, whichever occurs earlier.
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E.5.2 | Secondary end point(s) |
• CR rate as assessed by IRC according to the modified 2007 IWG criteria (Stage 2)
• ORR per IRC according to the 2014 IWG (Lugano) criteria (Stage 2).
• CR rate per IRC according to the 2014 IWG (Lugano) criteria (Stage 2).
• ORR per IRC to select the Stage 2 dose regimen of TAK-659 from the lead-in dose exploration phase (Stage 1).
• ORR per IRC at 3, 6, and 9 cycles, respectively (Stage 2).
• DOR and duration of CR per IRC (Stage 2).
• ORR per IRC in patients with GCB DLBCL (Stage 2).
• ORR per IRC in patients with DLBCL transformed from indolent NHL (Stage 2).
• PFS per IRC (Stage 2).
• OS (Stage 2).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Primary analysis - after all patients enrolled in the study have had the opportunity to complete 6 cycles of treatment with study drug.
Conclusion of the study - when OS events have occurred in 70% of patients, or 24 months after last patient in, whichever occurs earlier.
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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 | No |
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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
France |
Germany |
Italy |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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Conclusion of the study will be considered when OS events have occurred in 70% of patients, or 24 months after last patient in, whichever occurs earlier. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |