E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Follicular Lymphoma and Diffuse Large B-Cell Lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Lymphoma is a cancer that affects the lymphatic system, a network of vessels and glands spread throughout the body |
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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 | LLT |
E.1.2 | Classification code | 10012857 |
E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) refractory |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012855 |
E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012856 |
E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) recurrent |
E.1.2 | System Organ Class | 100000004864 |
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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 1b: Safety and tolerability of the combination of polatuzumab vedotin with bendamustine and rituximab (BR) or bendamustine and obinutuzumab (BG) when administered to patients with relapsed or refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL)
- Phase 1b: Determination of the Recommended Phase II Dose (RP2D) for polatuzumab vedotin given in combination with BR or with BG in patients with R/R FL or DLBCL
- Phase II: Efficacy of the combination of polatuzumab vedotin plus BR compared with BR alone in patients with R/R FL or DLBCL as assessed by the independent review committee at primary response assessment (PRA, 6-8 weeks after cycle 6 day 1 or last dose of study treatment)
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E.2.2 | Secondary objectives of the trial |
- Safety and tolerability of the combination of polatuzumab vedotin with BR or BG when administered to patients with R/R FL or DLBCL during the Phase II portion of the study
- Immunogenicity of polatuzumab vedotin and obinutuzumab, as measured by the formation ATAs
- Potential relationships of such anti-therapeutic antibody formation with other outcome measures
- PK of polatuzumab vedotin in combination with BR or BG in patients with R/R FL or DLBCL
- Potential PK interactions between polatuzumab vedotin and BR or BG
- PK exposure response relationship
- Efficacy: Investigator assessed CR and ORR using PET/CT and CT alone at PRA and best objective response (CR or PR) either by PET/CT or CT alone, DOR, PFS, EFS, OS
- Peripheral neuropathy symptom severity and interference on daily functioning and to better understand treatment impact, tolerability, and reversibility, as measured by the Therapy Induced Neuropathy Assessment Scale (TINAS)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >= 18 years
- Histologically confirmed FL (Grade 1, 2, or 3a) or DLBCL
- Must have received at least one prior therapy for FL or DLBCL. Patients must have either relapsed or have become refractory to a prior regimen as defined in the protocol.
- If the patient has received prior bendamustine, response duration must have been > 1 year (for patients who have relapse disease after a prior regimen)
- At least one bi-dimensionally measurable lesion on imaging scan defined as > 1.5 cm in its longest dimension
- Confirmed availability of archival or freshly collected tumor tissue prior to study enrollment
- Life expectancy of at least 24 weeks
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- Adequate hematologic function unless inadequate function is due to underlying disease.
- For women who are not postmenopausal (>=12 months of non−therapy−induced amenorrhea and age >45 years) or surgically sterile: agreement to remain abstinent or to use single highly effective or combined contraceptive methods that result in a failure rate of <1% per year during the treatment period and for >=12 months after the last dose of rituximab or for >=18 months after the last dose of obinutuzumab
- For women of childbearing potential, a negative serum pregnancy test result within 7 days prior to commencement of dosing.
- For men, agreement to remain abstinent or to use a condom plus an additional contraceptive method that together result in a failure rate of <1% per year during the treatment period and for at least 6 months after the last dose of study drug and agreement to refrain from donating sperm during this same period
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E.4 | Principal exclusion criteria |
- History of severe allergic or anaphylactic reactions to humanized or murine MAbs (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products
- Contraindication to bendamustine, rituximab, or obinutuzumab
- History of sensitivity to mannitol (mannitol is an excipient in bendamustine)
- Prior use of any MAb, radioimmunoconjugate, or ADC within 5 half-lives or 4 weeks (whichever is longer) of study start before Cycle 1 Day 1
- Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 2 weeks prior to Cycle 1 Day 1
- Ongoing corticosteroid use >30 mg/day prednisone or equivalent, for purposes other than lymphoma symptom control
- Completion of autologous stem cell transplant within 100 days prior to Cycle 1 Day 1
- Prior allogeneic stem cell transplant
- Eligibility for autologous SCT (patients with R/R DLBCL)
- Grade 3b follicular lymphoma
- History of transformation of indolent disease to DLBCL
- Primary or secondary CNS lymphoma
- Current Grade >1 peripheral neuropathy
- History of other malignancy that could affect compliance with the protocol or interpretation of results.
- Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or significant pulmonary disease
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment or any major episode of infection requiring treatment with intravenous (IV) antibiotics or hospitalization within 4 weeks prior to Cycle 1 Day 1
- Patients with suspected or latent tuberculosis,
- Positive test results for chronic hepatitis B virus infection or for hepatitis C virus antibody
- Known infection with HIV or human T-cell leukemia virus 1 virus
- Vaccination with a live vaccine within 28 days prior to treatment
- Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis
- Women who are pregnant or lactating or who intend to become pregnant within a year of the last dose of study treatment in the rituximab cohorts or within 18 months of the last dose of study treatment in the obinutuzumab cohort
- Any abnormal laboratory values as defined in the protocol, unless abnormal laboratory values are due to underlying lymphoma per the investigator
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase Ib
1. Safety: Incidence and nature of dose-limiting toxicities (DLTs)
2. Safety: Incidence of adverse events
Phase II
3. Responses at primary response assessment as detetermined by IRC
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. 21-28 days
2. 2.5 years, indefinitely for secondary malignancies in obinutuzumab cohort
3. Primary response assessment (PRA): 6− 8 weeks after Cycle 6 Day 1 or last dose of study medication
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E.5.2 | Secondary end point(s) |
1. Safety: Incidence of adverse events during phase II
2. Safety: Incidence of antibody formation to study drugs
3. Pharmacokinetics: Area under the concentration-time curve
4. Pharmacokinetics: Maximum concentration (Cmax)
5. Pharmacokinetics: Clearance (CL)
6. Pharmacokinetics: Terminal half-life (t1/2)
7. Pharmacokinetics: Steady-state volume of distribution (Vss)
8. Complete response rate
9. Objective response rate
10. Duration of response
11. Progression-free survival
12. Event-free survival
13. Overall survival |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 2.5 years, indefinitely for secondary malignancies in obinutuzumab cohort
2. 2 years
3-7. Participants will be followed through four cycles of treatment, then in follow up at month 3, 6, 12, 18, 24
8-9. Approximately at 8-10 weeks (Cycle 3 Day
10-13. approximately 2.5 years
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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 | 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 |
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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 | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Phase II randomized for R-containing cohorts but non-randomized for G-containing cohorts |
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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 | Yes |
E.8.2.3.1 | Comparator description |
Polatuzumab vedotin + BR versus BR and polatuzumab vedotin + BG |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
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 |
Australia |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Korea, Republic of |
Netherlands |
Spain |
Turkey |
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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The end of the study is defined as the timepoint at which all patients enrolled in the study have had either at least 2 years of follow-up from the time of the Treatment Completion Visit or have discontinued the study. |
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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 | |
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 | 2 |