Phase III Study of Polatuzumab Vedotin with Rituximab, Ifosfamide, Carboplatin, and Etoposide in Relapsed/Refractory Diffuse Large B-Cell Lymphoma
- Trial ID
- 2023-508259-38-00
- Protocol
- MO40599/GLA 2017-R2
- Sponsor
- GWT-Tud GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine whether salvage therapy with Pola-R-ICE improves **event-free survival (EFS)** in patients with relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL) compared to R-ICE alone. This is clinically relevant as improving EFS could potentially lead to better long-term outcomes and quality of life for patients with this aggressive form of lymphoma.
Secondary objectives include evaluating whether the addition of polatuzumab vedotin to standard therapy R-ICE enhances the rate of metabolic complete response (CR) at the end of study treatment, improves the partial response (PR) rate and overall response rate (ORR), and decreases the progression and relapse rates. Additionally, the study aims to assess the impact on the duration of response, progression-free survival (PFS), overall survival (OS), and the mobilization of autologous CD34+ stem cells. The study will also evaluate the rate of patients proceeding to transplantation and the impact on non-relapse mortality. Further secondary objectives involve collecting data on safety, protocol adherence, quality of life (QoL), and biology, including adverse and serious adverse events, incidence and duration of neutropenia and thrombocytopenia Grade 4 CTC, treatment-related deaths, second malignancies, cumulative and relative doses, and QoL, as well as providing samples for translational research.
Participants
The clinical trial involves a total of **32 participants** who are adult patients with **relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL)**. The study population includes both male and female subjects aged 18 years and older, with the inclusion of individuals as young as 16 years in the UK, in accordance with local regulations. Participants were selected based on their diagnosis of aggressive B-cell non-Hodgkin lymphoma, confirmed through biopsy, and must have received adequate first-line therapy. The trial population is characterized by a requirement for adequate hematological function and a performance status of ECOG 0-2, or ECOG 3 if related to DLBCL and improved with steroid treatment. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use contraceptive measures if of childbearing potential. The trial includes a vulnerable population, indicating additional ethical considerations in the study design.
Plans and Procedures
The clinical trial is designed as a **randomized**, **open-label**, Phase III study to evaluate the efficacy of polatuzumab vedotin in combination with rituximab, ifosfamide, carboplatin, and etoposide (Pola-R-ICE) compared to rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) alone in patients with relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL). The primary objective is to assess whether the Pola-R-ICE regimen improves event-free survival (EFS) compared to R-ICE alone. The trial is expected to conclude by June 30, 2025, with recruitment having commenced on April 30, 2021.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as adequate hematological function and performance status. The inclusion criteria require participants to have a histological diagnosis of primary refractory or relapsed aggressive B-cell non-Hodgkin lymphoma, among other conditions. Women of childbearing potential must have a negative pregnancy test, and all participants must agree to use contraceptive measures. The trial will include follow-up visits to monitor treatment response and safety, with the end-of-study visit marking the completion of the trial for each participant.
The expected duration of participant involvement is contingent upon the treatment response and the trial's overall timeline, with the maximum treatment period for certain drugs being up to three cycles. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or failure to adhere to protocol requirements. The primary endpoint is the EFS at first progression or relapse, while secondary endpoints include metabolic complete response rate, progression-free survival, overall survival, and safety assessments such as adverse events and treatment-related mortality.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Carboplatin**, marketed as "Carboplatin onkovis 10 mg/ml Infusionslösung," is provided as a solution for infusion. The maximum daily and total dose is 800 mg, administered via intravenous use over a maximum treatment period of 1 day. This medication is produced by ONKOVIS GMBH and is chemically derived.
**Ifosfamide** is included in the trial under multiple formulations. "Holoxan 1 g - Trockensubstanz zur Injektionsbereitung" and "Holoxan 2 g - Trockensubstanz zur Injektionsbereitung" are both solutions for infusion, with a maximum daily and total dose of 5000 mg/m². "Ifosfamide Injection 1g" and "Holoxan" are also administered intravenously with the same dosing parameters. These formulations are produced by BAXTER HEALTHCARE GMBH and BAXTER ONCOLOGY GMBH, respectively, and are chemically derived.
**Etoposide** is administered as "Etoposid Accord 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung" and "Etopósido Sandoz 20 mg/ml concentrado para solución para perfusión EFG," both solutions for infusion. The maximum daily dose is 100 mg/m², with a total dose of 300 mg/m² over a treatment period of 3 days. These products are manufactured by ACCORD HEALTHCARE B.V. and SANDOZ FARMACÉUTICA, S.A., respectively, and are chemically derived.
**Etoposide phosphate** is provided as "ETOPOPHOS® 100 mg, Pulver zur Herstellung einer Infusionslösung," a solution for infusion with the same dosing schedule as etoposide. This product is manufactured by CHEPLAPHARM ARZNEIMITTEL GMBH and is chemically derived.
**Polatuzumab vedotin**, marketed as "Polivy 140 mg powder for concentrate for solution for infusion," is administered intravenously with a maximum dose of 1.80 mg/kg. This protein-derived medication is produced by ROCHE REGISTRATION GMBH and is designated as an orphan drug with study-specific labeling.
**Rituximab** is included as "MabThera 500 mg concentrate for solution for infusion," administered intravenously with a maximum dose of 375 mg/m². This protein-derived medication is also produced by ROCHE REGISTRATION GMBH and features study-specific labeling.
All medications are administered via intravenous use, and participant compliance is monitored throughout the trial. The trial aims to compare the efficacy of the Pola-R-ICE regimen, which includes polatuzumab vedotin, with the R-ICE regimen in patients with primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL).
Efficacy
The efficacy of the clinical trial will be assessed using several endpoints. The primary endpoint is event-free survival (EFS) of patients with diffuse large B-cell lymphoma (DLBCL) at first progression or relapse. Secondary efficacy endpoints include the rate of metabolic complete response (CR) after the end of study treatment, partial response (PR) rate, overall response rate (ORR), duration of response, progression rate, relapse rate, progression-free survival (PFS), overall survival (OS), number of CD34+ cells, mobilization failure rate, rate of patients proceeding to transplantation, and non-relapse mortality.
These efficacy parameters will be measured and collected at various timepoints throughout the study. The methods for assessing these endpoints include imaging techniques such as PET-CT based-staging according to Lugano criteria 2014, which requires patients to have PET-positive lesions. The trial will also evaluate the cumulative dose and relative dose of the drugs involved, including ifosfamide, carboplatin, etoposide, rituximab, and **polatuzumab vedotin**. Additionally, the study will assess protocol adherence through the number and duration of chemotherapy cycles.
Quality of life (QoL) will be evaluated as a secondary endpoint using different questionnaires to assess generic health-related QoL. The trial is designed to provide comprehensive data on the efficacy of the treatment regimen, with the estimated end date set for June 30, 2025.
Inclusion and Exclusion Criteria
Inclusion Criteria
- The informed consent form must be signed before any study specific tests or procedures are done
- 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
- Ability to understand and follow study-related instructions
- 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
- 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)
- Information on all 5 International Prognostic Index (IPI) factors
- Staging (PET-CT based-staging according to Lugano criteria 2014). Patients must have PET-positive lesions
- 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
- Intent to proceed to high-dose therapy (HDT) and stem cell transplantation (SCT) if response to second line therapy
- 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
- Women of childbearing potential must have a negative pregnancy test result within 7 days prior to the first study drug administration
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
Exclusion Criteria
- 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
- 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
- Received more than one line of therapy for DLBCL
- Received polatuzumab vedotin as part of the first line therapy
- 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
- 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
- Human immunodeficiency virus (HIV)-positivity with detectable viral load and/or a CD4+ count below 0.3/nL
- 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
- 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
- Patients with suspected or latent tuberculosis. Latent tuberculosis needs to be confirmed by positive interferon-gamma release assay
- Primary or secondary central nervous system (CNS) lymphoma at the time of recruitment
- Richter’s transformation or prior chronic lymphocytic leukemia (CLL)
- Vaccination with a live vaccine within 4 weeks prior to treatment
- Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis
- History of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine monoclonal antibodies
- History of hypersensitivity to any of the study drugs or their ingredients or to drugs with similar structure
- 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
- 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
- Pregnancy or breastfeeding, or intending to become pregnant during the study or within 12 months after the last dose of study drug
- Close affiliation with the investigator (e.g. a close relative) or persons working at the study site
- Subject is an employee of the sponsor or involved Contract Research Organization
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 30 Apr 2021 | 13 |
 Germany | Not Recruiting | 30 Apr 2021 | 140 |
 Spain | Not Recruiting | 30 Apr 2021 | 149 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ETOPOPHOS® 100 mg, Pulver zur Herstellung einer Infusionslösung | Test | PULVER ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 100 | 3 | PRD7449651 |
MabThera 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 375 | 1 | PRD2154043 |
Carboplatino Pharmacia 10 mg/ml concentrado para solución para perfusión EFG | Test | CONCENTRADO PARA SOLUCIÓN PARA PERFUSIÓN | INTRAVENOUS USE | 800 | 1 | PRD7814588 |
Holoxan | Test | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS USE | 5000 | 1 | PRD624993 |
Etoposid Accord 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 100 | 3 | PRD1800145 |
Carboplatin onkovis 10 mg/ml Infusionslösung | Test | INFUSIONSLÖSUNG | INTRAVENOUS USE | 800 | 1 | PRD805680 |
Holoxan 2 g - Trockensubstanz zur Injektionsbereitung | Test | TROCKENSUBSTANZ ZUR INJEKTIONSBEREITUNG | INTRAVENOUS USE | 5000 | 1 | PRD612049 |
Ifosfamide Injection 1g | Test | INJECTION | INTRAVENOUS USE | 5000 | 1 | PRD633031 |
Etopósido Sandoz 20 mg/ml concentrado para solución para perfusión EFG | Test | CONCENTRADO PARA SOLUCIÓN PARA PERFUSIÓN | INTRAVENOUS USE | 100 | 3 | PRD1804535 |
Polivy 140 mg powder for concentrate for solution for infusion. | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1.80 | 1 | PRD7856215 |