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 | 20.1 |
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 | 20.1 |
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 |
Main Study (Phase Ib):
- Safety and tolerability of the combination of pola plus BR or BG
- Determination of Recommended Phase II Dose (RP2D) for pola plus BR or BG
Main Study (Phase II):
- Efficacy of the combination of pola plus BR compared to BR alone as measured by positron emission tomography (PET)-defined complete response (CR) rate using modified Lugano Response Criteria (PETcomputed tomography [CT] criteria) at primary response assessment (PRA, 6-8 weeks after cycle 6 day 1 or last dose of study drug) by IRC (independent review committee)
- NF Cohort (Phase II [R/R DLBCL]):
- Arm G: To evaluate the pharmacokinetics (PK) and safety of pola (lyophilized) plus BR
- Arm H: Efficacy of pola (lyophilized) plus BR measured by PET-CR at PRA by IRC |
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E.2.2 | Secondary objectives of the trial |
Main Study (Phase Ib/II):
Safety:
- Safety, tolerability of pola plus BR or BG (including Arm H)
- Immunogenicity of pola and G; potential relationships of ADA Formation with other measured outcomes (including NF Cohort)
PK:
- PK of pola with BR or BG (including Arm H)
- Potential PK interactions between pola and BR or BG; PK exposure response relationship
- Peripheral neuropathy symptom severity and interference on daily functioning to better understand treatment impact, tolerability, and reversibility
Efficacy:
- Investigator (INV) and IRC assessed CR, OR by PET-CT or CT only at PRA and BOR by PET-CT or CT only; IRC – BOR, DOR, PFS (DLBCL cohorts only)
- [NF Cohort] INV and IRC assessed CR and OR at PRA by PET-CT; BOR, DOR, PFS, EFS by PET-CT or CT only per INV (EFS only) and IRC; OS
- [Arm G]: INV and IRC assessed CR and OR at PRA by CT only |
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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, and agreement to refrain from donating eggs
- 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
- Treatment with chimeric antigen receptor T-cell therapy within 100 days prior to Cycle 1 Day 1
- 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 (Randomized Cohorts)
3. CR by IRC
Phase II (New Formulation [NF] Cohort)
4. PK parameters for polatuzumab vedotin (lyophilized) in combination with BR (Arm G)
5. Safety and tolerability of polatuzumab vedotin (lyophilized) in combination with BR (Arm G)
6. CR by IRC (Arm H) |
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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. PRA (6-8 weeks after Cycle 6 Day 1 or last dose of study medication)
4. Day 2, 8, 15 of Cycle 1; Day 1 of Cycle 2 and 4, Day 1, 8, 15 of Cycle 3 and at treatment completion/discontinuation and at Follow-up visit at
months 3, 6 and 12
5. Up to 50 months |
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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. CR
9. OR
10. DOR by IRC (DLBCL cohorts)
11. PFS by IRC (DLBCL cohorts)
12. BOR by IRC (DLBCL cohorts)
13. CR by IRC (Arm G of NF Cohort)
14. ORR by IRC for NF Cohort
15. EFS (NF Cohort only)
16. OS (NF Cohort only)
17. Formation of ADAs to polatuzumab vedotin (NF Cohort)
18. CR by PET-CT Responses at PRA as determined by IRC for expansion cohorts |
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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
10-12. Up to 50 months
13-14. PRA (6−8 weeks after Cycle 6 Day 1 or last dose of study medication)
15-16. Up to 50 months
17. Day 2, 8, 15 of Cycle 1, Day 1 of Cycle 2 and 4, Day 1, 8, 15 of Cycle 3, treatment discontinuation, and follow-up visits at months 3, 6, and 12 (Arm G); Day 2 of Cycle 1, Day 1 of Cycle 2 and 4, treatment discontinuation, and follow-up visit at month 3 (Arm H).
18. PRA (6−8 weeks after Cycle 6 Day 1 or last dose of study medication) |
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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
| 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 | 10 |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 2 |
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 |