Clinical trial NCT04833114: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Relapsed Diffuse Large B-cell Lymphoma
Refractory Diffuse Large B-Cell Lymphoma
Lead sponsor: GWT-TUD GmbH
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2021-04-06
Enrollment: 306
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Primary outcomes:
measure: Assessment of the event-free survival of patients with DLBCL at first progression and the occurrence of any of the following events:
timeFrame: Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)
Secondary outcomes:
measure: Assessment of the rate of metabolic complete response.
timeFrame: Day of randomization until end weeks 12 treatment.
measure: Evaluation of the partial response rate.
timeFrame: Day of randomization until end of 12 weeks treatment.
measure: Assessment of the overall response rate.
timeFrame: Day of randomization until end of 12 weeks treatment.
measure: Assessment duration of response.
timeFrame: Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)
measure: Assessment of the rate of progressive disease.
timeFrame: Day of randomization until end of 12 weeks treatment.
measure: Assessment of disease relapse.
timeFrame: Day of randomization until end of 12 weeks treatment.
measure: Assessment of progression free survival.
timeFrame: Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)
measure: Assessment of overall survival.
timeFrame: Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)
measure: Assessment of the rate of patients proceeding to transplantation.
timeFrame: Day of randomization until week 12.
measure: Assessment of the rate of patients with non-relapse mortality.
timeFrame: Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)
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.
timeFrame: Day of Randomization until 28 days after start of last cycle or start of further therapy
measure: Assessment of the number of patients with treatment-related death.
timeFrame: Day of Randomization until up week 12 or 2 months after week 12 but before start of further therapy
measure: To determine the number of patients with occurence of second malignancies
timeFrame: Day of Randomization until Day of randomization until end of follow up (at least 21 months follow up)
measure: Assessment of the protocol adherence by the rate and duration of chemotherapy cycles patients received.
timeFrame: Day of Randomizaton until week 12.
measure: Assessment of the cumulative and relative dose of each IMP( ifosfamide, carboplatin and etoposide, rituximab and of the polatuzumab vedotin) by quantitative measurement.
timeFrame: Day of Randomizaton until week 12.
measure: Assessment of the change in health related quality of life by generic questionnaire.
timeFrame: Day of Randomization until weeks 12 and months 3 and 12 in follow up.
measure: Assessment of the change in health related quality of life by five-item questionnaire.
timeFrame: Day of Randomization until weeks 12 and months 3 and 12 in follow up
measure: Assessment visual analogue scale to measure health state.
timeFrame: Day of Randomization until weeks 12 and months 3 and 12 in follow up
measure: Functional assessment of the cancer therapy-lymphoma by general questions and specific questions for lymphoma.
timeFrame: Day of Randomization until weeks 12 and months 3 and 12 in follow up.
Other outcomes:
Locations:
city: Graz
country: Austria
facility: UK Graz Universitätsklinik für Innere Medizin Klinische Abteilung für Hämatologie
city: Leoben
country: Austria
facility: LKH Hochsteiermark Standort Leoben Abteilung für Innere Medizin Department für Hämato-Onkologie
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH- Elisabethinen: I. Interne Abteilung Hämato-Onkologie
city: Linz
country: Austria
facility: Kepler Universitätsklinikum Med Campus III, Univ.-Klinik für Hämatologie und Internistische Onkologie
city: Salzburg
country: Austria
facility: Landeskrankenhaus Salzburg
city: Vienna
country: Austria
facility: AKH Meduni Wien Universitätsklinik für Innere Medizin I:
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen Abteilung für Innere Medizin IV
city: Wien
country: Austria
facility: Hanusch Krankenhaus
city: Aachen
country: Germany
facility: Universitätsklinikum RWTH-Aachen
city: Berlin
country: Germany
facility: HELIOS Klinik Berlin-Buch, Klinik für Hämatologie und Stammzelltransplantation
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig
city: Bremen
country: Germany
facility: DIAKO Ev.Diakonie-Krankenhaus gemeinnützige GmbH
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Dortmund
country: Germany
facility: St. Johannes Hospital Dortmund
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden
city: Duisburg
country: Germany
facility: Helios St. Johannes Klinik
city: Düsseldorf
country: Germany
facility: Klinik für Onkologie, Hämatologie und Palliativmedizin
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
city: Göttingen
country: Germany
facility: Georg-August-Universität Göttingen Universitätsmedizin Göttingen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH
city: Kiel
country: Germany
facility: Städtisches Krankenhaus Kiel
city: Ludwigshafen
country: Germany
facility: Klinikum Ludwigshafen
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
city: Marburg
country: Germany
facility: Philipps-Universität Marburg
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Rostock
country: Germany
facility: Unversitätsmedizin Rostock
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart
city: Trier
country: Germany
facility: Klinikum Mutterhaus
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Wuppertal
country: Germany
facility: Helios Universitätsklinikum Wuppertal
city: Palma
country: Spain
facility: Hospital Universitario Son Espases
state: Islas Baleares
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Badalona
country: Spain
facility: Hospital Germans Trias I Pujol
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Donostia
country: Spain
facility: Hospital Universitario de Donostia
city: Gijón
country: Spain
facility: Hospital Universitario de Cabueñes
city: Hospitalet de Llobregat
country: Spain
facility: Institut Català d'oncologia de L'Hospitalet (ICO-L'Hospitalet)
city: Las Palmas De Gran Canaria
country: Spain
facility: Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín
city: Madrid
country: Spain
facility: Clínica Universidad de Navarra (Madrid location)
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jimenez Díaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra (Pamplona location)
city: Salamanca
country: Spain
facility: Complejo Asistencial Universitario de Salamanca
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Vigo
country: Spain
facility: Complejo Hospitalario Universitario de Vigo
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Cornwell
country: United Kingdom
facility: Royal Cornwall Hospital
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: London
country: United Kingdom
facility: University London College Hospitals
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital, Plymouth
city: Romford
country: United Kingdom
facility: Queens Hospital, Romford
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS
Study officials:
affiliation: HELIOS Klinik Berlin-Buch, Klinik für Hämatologie und Stammzelltransplantation
name: Bertram Glaß, Prof.
role: PRINCIPAL_INVESTIGATOR
References: