Clinical Trials /

Polatuzumab Vedotin Plus Rituximab, Ifosfamide, Carboplatin and Etoposide (Pola-R-ICE) Versus R-ICE Alone in Second Line Treatment of Diffuse Large B-cell Lymphoma (DLBCL)

NCT04833114

Description:

An open-label, prospective Phase III clinical study to compare polatuzumab vedotin plus rituximab, ifosfamide, carboplatin and etoposide (Pola-R-ICE) with rituximab, ifosfamide, carboplatin and etoposide (R-ICE) alone as salvage therapy in patients with primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL)

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma Associated with Chronic Inflammation
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • High Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements
  • High Grade B-Cell Lymphoma, Not Otherwise Specified
  • Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
  • Primary Mediastinal B-Cell Lymphoma
  • T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Polatuzumab Vedotin Plus Rituximab, Ifosfamide, Carboplatin and Etoposide (Pola-R-ICE) Versus R-ICE Alone in Second Line Treatment of Diffuse Large B-cell Lymphoma (DLBCL)
  • Official Title: Open-label, Prospective Phase III Clinical Study to Compare Polatuzumab Vedotin Plus Rituximab, Ifosfamide, Carboplatin and Etoposide (Pola-R-ICE) With Rituximab, Ifosfamide, Carboplatin and Etoposide (R-ICE) Alone as Salvage Therapy in Patients With Primary Refractory or Relapsed Diffuse Large B-cell Lymphoma (DLBCL)

Clinical Trial IDs

  • ORG STUDY ID: Pola-R-ICE
  • SECONDARY ID: MO40599 / GLA 2017-R2
  • NCT ID: NCT04833114

Conditions

  • Relapsed Diffuse Large B-cell Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
Polatuzumab VedotinExperimental Arm: Pola-R-ICE
MabtheraExperimental Arm: Pola-R-ICE
IfosfamideExperimental Arm: Pola-R-ICE
CarboplatinExperimental Arm: Pola-R-ICE
EtoposideExperimental Arm: Pola-R-ICE

Purpose

An open-label, prospective Phase III clinical study to compare polatuzumab vedotin plus rituximab, ifosfamide, carboplatin and etoposide (Pola-R-ICE) with rituximab, ifosfamide, carboplatin and etoposide (R-ICE) alone as salvage therapy in patients with primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL)

Detailed Description

      The study is designed as an international, multicenter, open-label, two-arm, prospective
      phase III study to compare the treatment of polatuzumab vedotin plus rituximab, ifosfamide,
      carboplatin and etoposide (Pola-R-ICE) with the combination of rituximab, ifosfamide,
      carboplatin and etoposide (R-ICE) alone as salvage therapy in patients with primary
      refractory or relapsed DLBCL.

      The study will involve study sites in Germany, UK, Spain, and Austria. It is planned to
      include 324 patients who will be randomized 1:1 to receive either treatment in the
      experimental arm (Pola-R-ICE) or in the standard arm (R-ICE) to end up with 308 evaluable
      subjects for the randomized part of the trial. Further 10 patients will be treated with
      Pola-R-ICE during the safety run-in phase.

      The study consists of a screening/inclusion visit, three chemotherapy cycles, an end-of -
      treatment visit (EoT), and follow-up visits. For each subject, the total duration of the
      study will be approximately 3 months of treatment plus at least 21 months follow-up. The
      study will end when the last included patient will have passed the last follow-up visit
      (LPLFU). For the study as a whole, the primary outcome will be evaluated when the last
      included patient will have completed the 21 months follow-up period or has left the study
      prematurely.

      For the study as a whole, the primary outcome will be evaluated when the last included
      patient will have completed the 21 months follow-up period or has left the study prematurely.
    

Trial Arms

NameTypeDescriptionInterventions
Experimental Arm: Pola-R-ICEExperimentalcombination of standard chemotherapy with polatuzumab vedotin (Pola-R-ICE) Application
  • Polatuzumab Vedotin
  • Mabthera
  • Ifosfamide
  • Carboplatin
  • Etoposide
Standard Arm: R-ICEActive Comparatorconventional treatment with rituximab, ifosfamide, carboplatin and etoposide (R-ICE)
  • Mabthera
  • Ifosfamide
  • Carboplatin
  • Etoposide

Eligibility Criteria

        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, 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

        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 as defined by seropositivity (HBsAG and anti HBe/ anti HBc;
             anti-Hc); in case of false positive serology (transfused antibodies) negative
             PCR-results will allow patient inclusion. Patients with occult or prior HBV infection
             (defined as negative HBsAg and positive hepatitis B core antibody [HBcAb]) may be
             included if HBV DNA 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

             (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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Assessment of the event-free survival of patients with DLBCL at first progression and the occurrence of any of the following events:
Time Frame:Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Assessment of the rate of metabolic complete response.
Time Frame:Day of randomization until end weeks 12 treatment.
Safety Issue:
Description:Number of complete remissions.
Measure:Evaluation of the partial response rate.
Time Frame:Day of randomization until end of 12 weeks treatment.
Safety Issue:
Description:Number of partial responses.
Measure:Assessment of the overall response rate.
Time Frame:Day of randomization until end of 12 weeks treatment.
Safety Issue:
Description:Number of complete and partial responses.
Measure:Assessment duration of response.
Time Frame:Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)
Safety Issue:
Description:Time from documentation of tumor response to disease progression or relapse.
Measure:Assessment of the rate of progressive disease.
Time Frame:Day of randomization until end of 12 weeks treatment.
Safety Issue:
Description:Number of progressive diseases.
Measure:Assessment of disease relapse.
Time Frame:Day of randomization until end of 12 weeks treatment.
Safety Issue:
Description:Number of relapses.
Measure:Assessment of progression free survival.
Time Frame:Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)
Safety Issue:
Description:Occurence of disease progression, relapse or death due to any cause.
Measure:Assessment of overall survival.
Time Frame:Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)
Safety Issue:
Description:
Measure:Assessment of the rate of patients proceeding to transplantation.
Time Frame:Day of randomization until week 12.
Safety Issue:
Description:
Measure:Assessment of the rate of patients with non-relapse mortality.
Time Frame:Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)
Safety Issue:
Description:
Measure:Evaluation of the frequency of adverse and serious adverse events including the incidence and duration of the adverse events neutropenia and thrombocytopenia with grade 4.
Time Frame:Day of Randomization until 28 days after start of last cycle or start of further therapy
Safety Issue:
Description:
Measure:Assessment of the number of patients with treatment-related death.
Time Frame:Day of Randomization until up week 12 or 2 months after week 12 but before start of further therapy
Safety Issue:
Description:
Measure:To determine the number of patients with occurence of second malignancies
Time Frame:Day of Randomization until Day of randomization until end of follow up (at least 21 months follow up)
Safety Issue:
Description:
Measure:Assessment of the protocol adherence by the rate and duration of chemotherapy cycles patients received.
Time Frame:Day of Randomizaton until week 12.
Safety Issue:
Description:
Measure:Assessment of the cumulative and relative dose of each IMP( ifosfamide, carboplatin and etoposide, rituximab and of the polatuzumab vedotin) by quantitative measurement.
Time Frame:Day of Randomizaton until week 12.
Safety Issue:
Description:
Measure:Assessment of the change in health related quality of life by generic questionnaire.
Time Frame:Day of Randomization until weeks 12 and months 3 and 12 in follow up.
Safety Issue:
Description:Scale scores to be obtained for the multi-items scales. Range in score from 0 to 100. A high scale score represents a higher response level.
Measure:Assessment of the change in health related quality of life by five-item questionnaire.
Time Frame:Day of Randomization until weeks 12 and months 3 and 12 in follow up
Safety Issue:
Description:
Measure:Assessment visual analogue scale to measure health state.
Time Frame:Day of Randomization until weeks 12 and months 3 and 12 in follow up
Safety Issue:
Description:This scale is provided with numbers from 0 to 100.100 is the best health state and 0 (zero) is the worst health state.
Measure:Functional assessment of the cancer therapy-lymphoma by general questions and specific questions for lymphoma.
Time Frame:Day of Randomization until weeks 12 and months 3 and 12 in follow up.
Safety Issue:
Description:Assessment how lymphoma-specific symptoms impact quality of life.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:GWT-TUD GmbH

Last Updated

July 13, 2021