| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients whose cancer of the lymph nodes has returned or not responded to treatment |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 | 10003901 |
| E.1.2 | Term | B-cell lymphoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012820 |
| E.1.2 | Term | Diffuse large B-cell lymphoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023769 |
| E.1.2 | Term | Large cell immunoblastic lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) refractory |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| 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 |
|
| 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 |
Primary objective
The primary objective of this study is to investigate the following question in patients with relapsed or primary refractory DLBCL:
Does salvage therapy with Pola-R-ICE improve event-free survival (EFS) compared to R-ICE alone?
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary efficacy objectives
• enhances the rate of metabolic complete response (CR) at the end of study treatment;
• enhances the partial response (PR) rate and overall response rate (ORR) and decreases the progression rate and relapse rate;
• enhances the duration of response, progression-free survival (PFS) and overall survival (OS);
• impacts the mobilization of autologous CD34+ stem cells;
• enhances the rate of patients proceeding to transplantation;
• impacts the non-relapse mortality.
Further secondary objectives of the study regarding safety, protocol adherence, quality of life (QoL) and biology are to collect data in order to evaluate adverse and serious adverse events, incidence and duration of neutropenia and thrombocytopenia Grade 4 CTC, rate of treatment-related deaths, number of second malignancies, cumulative and relative doses, and QoL, as well as to provide samples for translational research. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Blood and tissue sampling for translational research is planned prior to and after end of study treatment (see visit schedule Table 10). Providing blood samples for translational research is not mandatory for study participation but encouraged. A separate written informed consent of the patient is to be obtained before sampling.
To gain insights into molecular signatures that predict response and resistance to polatuzumab and polatuzumab-containing salvage therapies, an extensive correlative science program will be initiated that includes assessment of the molecular composition of the tumor itself and its interaction to the tumor microenvironment at relapse and/or after failed treatment aiming to eventually develop a predictive biomarker. As it is increasingly clear that dynamic changes to the tumor under therapy are an additional important response criterion, circulating tumor DNA (ctDNA) as a minimal residual disease (MRD) maker with and without correlation to clinical and imaging-based response assessment will be evaluated. |
|
| E.3 | Principal inclusion criteria |
(1) The informed consent form must be signed before any study specific tests or procedures are done
(2) Adult male and female patients ≥18 years (≥16 years in the UK*) at the time of inclusion in the study
* In the UK an “adult” means a person who has attained the age of 16 years, according to The Medicines for Human Use (Clinical Trials) Regulations 2004, Part 1 Point 2.
(3) Ability to understand and follow study-related instructions
(4) Risk group: All patients with one of the following histologically defined entities: Histological diagnosis of primary refractory or relapsed aggressive B-cell non-Hodgkin lymphoma (B-NHL), confirmed by a biopsy of involved nodal or extranodal site. Patients with any of the following histologies can be included:
• DLBCL not otherwise specified (NOS)
• T-cell/histiocyte-rich large B-cell lymphoma
• Primary cutaneous DLBCL, leg type
• Epstein-Barr virus (EBV)-positive DLBCL, NOS
• DLBCL associated with chronic inflammation
• Primary mediastinal (thymic) large B-cell lymphoma
• High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
• High-grade B-cell lymphoma, NOS
Refractory disease is defined as no complete remission to first line therapy; subjects who are intolerant to first line therapy are excluded. Three groups of patients are eligible:
• Progressive disease (PD) as best response to first line therapy (biopsy not mandatory if diagnostic sample available).
• Stable disease (SD) as best response after at least 4 cycles of first line therapy (e.g., 4 cycles of R-CHOP) (biopsy not mandatory if diagnostic sample available).
• Partial response (PR) as best response after at least 6 cycles, and biopsy-proven residual disease or disease progression after the partial response.
Relapsed disease is defined as complete remission to first line therapy followed by biopsy proven disease relapse.
(5) Performance Status ECOG 0-2 at time of randomization or ECOG 3 at screening if this is DLBCL-related and has improved to ECOG 2 or less with a 7-day steroid treatment during the screening phase (e.g. 1 mg/kg prednisone).
(6) Information on all 5 International Prognostic Index (IPI) factors
(7) Staging (PET-CT based-staging according to Lugano criteria 2014). Patients must have PET-positive lesions.
(8) Subjects must have received adequate first line therapy including at a minimum: i) anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and ii) an anthracycline containing chemotherapy regimen
(9) Intent to proceed to high-dose therapy (HDT) and stem cell transplantation (SCT) if response to second line therapy
(10) Adequate hematological function, as defined by: hemoglobin ≥ 8 g/dL, if anemia is attributable to underlying disease and transfusions result to an increase ≥ 8 g/dL, patients can be included, absolute neutrophil count (ANC) ≥ 1.0 x 109/L OR ≥ 0.5 x 109/L if neutropenia is attributable to underlying disease and before the administration of steroids, and platelet count ≥ 75 x 109/L OR ≥ 50 x 109/L if thrombocytopenia is attributable to underlying disease
(11) Women of childbearing potential must have a negative pregnancy test result within 7 days prior to the first study drug administration
(12) For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs
(13) For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm |
|
| E.4 | Principal exclusion criteria |
(1) Serious accompanying disorder leading to impaired organ function causing significant clinical problems and reduced life expectancy of less than 3 months. In particular, patients with the following organ dysfunction caused by accompanying disorders are to be excluded:
• Heart failure with left ventricular ejection fraction (LVEF) < 45%
• Impaired pulmonary function with vital capacity (VC) or forced expiratory volume (FEV1) < 50% of normal (only in case of history of significant pulmonary disease)
• Impaired renal function with glomerular filtration rate (GFR) < 50 mL/min (calculated)
• Impaired liver function with alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) or bilirubin > 1.5 x upper limit of normal (ULN). If elevation is caused by the disease, threshold of 2.5 x ULN is accepted
• Peripheral neuropathy > Grade II
(2) Human immunodeficiency virus (HIV)-positivity with detectable viral load and/or a CD4+ count below 0.3/nL
(3) Hepatitis B and C are defined by seropositivity (HBsAg and anti HBc; anti-HCV). Patients with occult or prior HBV infection (defined as negative HBsAg and positive hepatitis B core antibody [Anti-HBc]) or HCV infection (defined as undetectable HCV RNA and positive anti-HCV) may be included if HBV DNA or HCV RNA is undetectable, provided that they are willing to undergo DNA testing on Day 1 of every cycle and monthly for at least 12 months after the last cycle of study treatment. In case of false positive serology (transfused antibodies) negative PCR-results will allow patient inclusion.
(4) Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study inclusion or any unresolved major episode of infection (as evaluated by the investigator) within 1 week prior to Cycle 1 Day 1
(5) Patients with suspected or latent tuberculosis. Latent tuberculosis needs to be confirmed by positive interferon-gamma release assay
(6) Primary or secondary central nervous system (CNS) lymphoma at the time of recruitment
(7) Richter’s transformation or prior chronic lymphocytic leukemia (CLL)
(8) Vaccination with a live vaccine within 4 weeks prior to treatment
(9) Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis
(10) 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
(11) Received more than one line of therapy for DLBCL
(12) Received polatuzumab vedotin as part of the first line therapy
(13) 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
(14) Ongoing treatment or study procedures within any other Investigational Medicinal Product (IMP) clinical trial with the exception of follow-up. In case of a preceding clinical trial, last application of the respective IMP(s) must have been done more than five elimination half-lives before start of study medication in this trial.
(15) History of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine monoclonal antibodies
(16) History of hypersensitivity to any of the study drugs or their ingredients or to drugs with similar structure
(17) Contraindications according to the Investigator´s Brochure (IB) of polatuzumab vedotin or the local Summary of Product Characteristics (SmPCs) of the used rituximab, ifosfamide, carboplatin or etoposide products
(18) Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the subject’s safety
(19) Pregnancy or breastfeeding, or intending to become pregnant during the study or within 12 months after the last dose of study drug
(20) Close affiliation with the investigator (e.g. a close relative) or persons working at the study site
(21) Subject is an employee of the sponsor or involved Contract Research Organization
At study inclusion, any organ impairment due to lymphoma infiltration is NOT regarded as an exclusion criterion.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is EFS of patients with DLBCL at first progression or relapse. EFS is defined as the time between the day of randomization and the occurrence of any of the following events:
• Failure to achieve sufficient response in PET-CT (Deauville score 3 or less) at end of study treatment (metabolic CR)
• Disease progression (PD)
• Start of additional unplanned anti-tumor treatment (radiation therapy allowed)
• Relapse after achieving CR
• Death due to any cause
Patients who have not experienced any of these events by the time of analysis will be censored at the most recent date of disease assessment.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints
Secondary endpoints for efficacy are rate of metabolic CR after end of study treatment, PR rate, ORR, duration of response, progression rate, relapse rate, PFS, OS, number of CD34+ cells, mobilization failure rate, rate of patients proceeding to transplantation, and non-relapse mortality.
Secondary safety endpoints
• Adverse events (AE)
• Serious adverse events (SAE)
• Incidence and duration of neutropenia and thrombocytopenia Grade 4 CTC
• Rate of treatment-related deaths
• Second malignancies
Secondary endpoints for protocol adherence
• Number of chemotherapy cycles
• Duration of chemotherapy cycles
• Cumulative dose and relative dose of ifosfamide, carboplatin and etoposide
• Cumulative dose and relative dose of rituximab
• Cumulative dose and relative dose of the polatuzumab vedotin
Secondary endpoints for QoL
Secondary endpoint is evaluation of generic health-related QoL as assessed by different questionnaires. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | 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) | 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 | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
|
| 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
|
|
| 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 | 0 |
| 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
