| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of white blood cell responsible for producing antibodies. |
|
| 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 | PT |
| E.1.2 | Classification code | 10012822 |
| E.1.2 | Term | Diffuse large B-cell lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 Primary Objective: To asses safety, efficacy, and potentially select the most active treatment regimen
among 3 treatment arms to advance to the Phase 3 component of the study.
Phase 3 Primary Objective: To demonstrate superiority in PFS as assessed by the Blinded Independent Central
Review (BICR) of the selected Phase 1b avelumab-based combination regimen over
Investigator’s Choice chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
Ph1b: evaluate PK & assess immunogenicity of treatments; evaluate PD-L1 expression levels in tumor cells and cells of the tumor microenvironment with their relationship to clinical response parameters; evaluate relationship between minimal residual disease burden as assessed using serial blood samples with clinical response parameters
Ph3: compare overall survival between the selected Ph1b avelumab combination regimen to Investigator’s Choice chemotherapy; evaluate efficacy & safety profile of treatments; evaluate PK & assess immunogenicity of Ph1b avelumab combination regimen; evaluate reported outcomes in Ph1b avelumab combination regimen vs Investigator’s Choice chemotherapy; evaluate PD-L1 expression levels in tumor cells and cells of the tumor microenvironment with their relation to clinical response parameters; evaluate relationship between minimal residual disease burden as assessed using serial blood samples with clinical response parameters |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Any of the following as defined by the WHO, 2016 lymphoid neoplasm classification and histologically confirmed:
- Discussed large B-cell lymphoma (DLBCL), Non Otherwise Specified (NOS)
- Germinal center B-cell type (GCB)
- Activated B-cell type (ABC)
- High-grade B-cell lymphoma (HGBCL)
- HGBCL with MYC and BCL2 and/or BCL6 rearrangements
- T-cell histocyte-rich large B-cell lymphoma
- EBV+ DLBCL, NOS
- HHV8+ DLBCL, NOS
2. Documentation that the disease is relapsed or refractory following at least 2 lines (and a maximum of 4 lines) of prior rituximab containing multi-agent chemotherapy which may include an autologous stem cell transplantation unless patients are not considered suitable for intensive second-line chemotherapy or autologous stem cell transplantation. Patients who are ineligible for intensive second line chemotherapy, must have received at least one prior rituximab-containing combination
chemotherapy regimen.
3. Patients previously treated with bendamustine must have experienced a response duration ≥6 months.
4. Documentation of baseline measurable disease with at least 1 bi-dimensional lesion with longest diameter (LDi) >1.5 cm on CT scan which is fluorodeoxyglucose (FDG) avid on PET scan.
5. A biopsy (archived or Screening/recent) will be collected at Screening.
6. Estimated life expectancy ≥3 months.
7. At least 18 years of age (or ≥20 years in Japan).
8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
9. All adverse events must have resolved to NCI CTCAE v.4.03 Grade ≤1 (with the exception of alopecia and other Grade ≤2 AEs not considered medically relevant in the judgment of the Investigator).
10. Patients must have an adequate bone marrow function, including: a. Absolute neutrophil count (ANC) ≥1.5 x 10(9)/L; b. Platelet count ≥100 x 10(9)/L; c. Hemoglobin ≥8 g/dL.
11. Patients must have adequate liver function, including: a. Total bilirubin level ≤1.5 × upper limit of normal (ULN); b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN.
12. Patients must have an adequate renal function as evidenced by a creatinine clearance ≥40 mL/min as calculated using the Cockcroft-Gault equation.
13. Serum or urine pregnancy test (for females of childbearing potential) must be negative.
14. Female patients of non-childbearing potential must meet at least 1 of the following
criteria: Achieved postmenopausal status, defined as follows: cessation of regular menses
for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the post-menopausal state; Have undergone a documented hysterectomy and/or bilateral oophorectomy; Have medically confirmed ovarian failure. All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential.
15. Must be willing to receive prophylactic granulocyte colony stimulating factor (G-CSF) in all cycles, for patients ≥60 years old randomized to arm C (and arm D in Phase 3, if arm C is selected to advance to the Phase 3 component). |
|
| E.4 | Principal exclusion criteria |
1. Active central nervous system (CNS) lymphoma.
2. Prior organ transplantation including prior allogeneic SCT.
3. Prior therapy with an anti PD-1, anti PD-L1, anti PD-L2, anti CD137, or anti-cytotoxic T lymphocyte associated antigen 4 (CTLA-4) antibody (including ipilimumab, tremelimumab or any other antibody, or drug specifically targeting T-cell co-stimulatory or immune checkpoint pathways).
4. Use of any standard or experimental anti-cancer therapy within 2 weeks to first dose of study treatment, including cytoreductive therapy and radiotherapy, immunotherapy, or cytokine therapy (except for erythropoietin).
5. Use of any non-drug anti-cancer therapy including chimeric antigen receptor (CAR) T-Cell (CAR-T-Cell) therapy.
6. Major surgery within 28 days prior to first dose of study treatment.
7. Diagnosis of any other malignancy ≤3 years prior to first dose of study treatment, with the exception of: (i) adequately treated basal cell or squamous cell skin cancer, (ii) carcinoma in situ of the breast or cervix, or (iii) low-grade (Gleason ≤6) prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration).
8. Known history of testing positive for human immunodeficiency virus ( HIV) or known acquired immunodeficiency syndrome.
9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen, positive HBV core antibody or HCV ribonucleic acid (RNA) if anti-HCV antibody screening test positive).
10. Active infection requiring systemic therapy.
11. Vaccination within 4 weeks prior to randomization and while on trial is prohibited except for administration of inactivated vaccines.
12. Peripheral neuropathy with functional impairment (for the Phase 3 component only due to oxaliplatin).
13. Current use of immunosuppressive medication, EXCEPT for the following: a.) intranasal, inhaled, eye drops, topical steroids, or local steroid injection (eg, intra-articular injection); b.) Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent; c.) Steroids as premedication for hypersensitivity reactions
(eg, CT scan premedication).
14. Active autoimmune disease that might deteriorate when receiving an
immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo-hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
15. Known anaphylaxis or severe hypersensitivity to rituximab or other monoclonal
antibodies, mannitol, or any of the compounds used in this study or to compounds
with a similar chemical or biological composition.
16. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke/transient ischemic attack [TIA]/symptomatic pulmonary embolism (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (≥New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication, other severe acute or chronic medical (including colitis, inflammatory bowel disease, pneumonitis, uncontrolled asthma, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
17. Pregnant female patients; breastfeeding female patients; fertile male patients and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception for a defined timeframe dependent on study treament assigned per protocol and, where applicable, in agreement with local prescribing information for individual drugs.
18. Current use or anticipated need for treatment with drugs that are known strong CYP1A2 inhibitors, including their administration within 10 days prior to patient randomization (ie ciprofloxacin, fluvoxamine, clinafloxacin, exoxacin, oltipraz, propranolol, rofecoxib, thiabendole and zafirlukast).
19. Current use or anticipated need for treament with drugs that are known CYP1A2 inducers, including their administration within 10 days prior to patient randomization (ie omeprazole, phenytoin). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b Primary Endpoint: Dose Limiting Toxicity (DLT); Objective Response (OR) as assessed by the Investigator per Lugano Response Classification Criteria.
Phase 3 - Primary Endpoint: Progression-Free Survival (PFS) as determined by Blinded Independent Central Review (BICR) per Lugano Response Classification Criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b:
18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET) imaging will be used with Computerized Tomography (CT) imaging. It will be performed ≤6 weeks prior to randomization then every 12 weeks (±1 week) from randomization and at EOT (unless performed ≤6 weeks before EOT). After 12-months from randomization, 18F-FDG PET-CT is performed every 24 weeks (±1 week) until PD.
Phase 3:
Tumor assessments must continue until confirmation of disease progression by BICR (Blinded Independent Central Review), regardless of the Investigator’s assessment of PD.
Baseline prior to first day of first cycle and at Cycles 3, 6, 9, 12 (and EOT unless performed ≤4 weeks before EOT). After 12-months, 18F-FDG PET-CT is performed every 6 months until PD. |
|
| E.5.2 | Secondary end point(s) |
Phase 1b Secondary Endpoints:
Safety: AEs and laboratory abnormalities as graded by National Cancer Institute (NCI) Common Terminology -Critera for Adverse Events (CTCAE) v.4.03; vital signs (blood pressure, heart rate); electrocardiograms (ECGs); -Duration of Response (DR), Time to Tumor Response (TTR), Disease Control (DC); Progression-Free Survival (PFS), as assessed by the Investigator per Lugano Response Classification Criteria and Overall Survival (OS); -Pharmacokinetics: PK parameters of avelumab, rituximab, utomilumab, azacitidine and bendamustine as data permit: maximum plasma concentration C(max), time to maximum plasma concentration T(max), area under the plasma concentration time curve from time 0 to T hours post dose apparent plasma clearance (CL/F), and apparent volume of distribution (V/F) of each analyte following single and multiple dosing.
- Immunogenicity: Anti-drug antibodies (ADA); neutralizing antibodies (Nab) against avelumab, rituximab, and utomilumab.
-PD-L1 expression levels in tumor cells and cells of the tumor microenvironment at baseline.
- Minimal residual disease burden (MRD) as assessed using serial blood samples.
Phase 3 - Secondary Endpoints:
- Overall Survival (OS).
- PFS by Investigator assessment.
- Objective Response (OR), Time to Tumor Response (TTR), Duration of Response (DR), and Disease Control (DC) by BICR and Investigator assessment.
- Safety: AEs and laboratory abnormalities as graded by National Cancer Institute (NCI) Common Terminology Critera for Adverse Events (CTCAE) v.4.03; vital signs (blood pressure, heart rate); electrocardiogram (ECG).
- Pharmacokinetics: PK parameters of avelumab, rituximab, utomilumab, azacitidine, and bendamustine (depending on the treatment being tested in Phase 3) will be determined as data permit: maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma concentration time curve from time 0 to T hours post dose apparent plasma clearance (CL/F), and apparent volume of distribution (V/F) of each analyte following single and multiple dosing.
- Immunogenicity: anti-drug antibodies (ADA) and neutralizing antibodies (Nab) against avelumab, rituximab, and utomilumab.
- Patient-Reported Outcomes: Fatigue measured via Brief Fatigue Inventory (BFI) questionnaire, disease symptoms and quality of life (QoL) measured via the NCCNFACT FLymSI-18 questionnaire, and QoL measured via the EQ-5D-5L questionnaire.
- PD-L1 expression levels in tumor cells and cells of the tumor microenvironment at baseline.
- Minimal residual disease burden as assessed using serial blood samples. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1b
*PK
Avelumab Arm A, B, C: pre-dose & after dose day 2, 8, 16 of cycle 1. Pre-dose day 1 of cycles 4, 6
Rituximab Arm A, C: pre-dose & after dose day 1, 7, 15, 22 of cycle 1. Pre-dose day 1 of cycles 4, 6
Utomilumab Arm A, B: pre-dose & after dose day 2, 16 of cycle 1. Pre-dose day 1 of cycles 4, 6
Azacitidine Arm B: pre-dose & after dose day 1, 5 of cycle 1, and day 1 of cycles 4, 6
Bendamustine/M3 metabolite, Arm C: Pre-dose & after dose cycles 1, 4, 6
*Immunogenicity
Avelumab, All Arms and Rituximab Arm A, C: pre-dose day 1 of cycle 1, and day 1 of cycles 4, 6. Day 30 after end of therapy & at early withdrawal
Utomilumab, Arm A, B: pre-dose day 2 of cycle 1 and day 1 cycles 4, 6. Day 30 after end of therapy & at early withdrawal
*Biomarkers (PD-L1): day 1 on cycle 1 |
|
| 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 | Yes |
| 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 |
| Assessment of safety and efficacy for each combination regimen |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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
|
| End of trial (EoT) in a Member State of the EU is the time at which it is deemed that a sufficient number of patients have been recruited and completed the study as stated in the regulatory and ethics applications in the Member State. Poor recruitment by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State. EoT in all other participating countries is defined as last patient last visit (LPLV). |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
