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)

Sponsor

GWT-TUD GmbH (Other)

Overall Status

Recruiting

CT.gov ID

NCT04833114

Collaborator

Hoffmann-La Roche (Industry)

334

Enrollment

Locations

Arms

Anticipated Duration (Months)

5.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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)

Condition or Disease	Intervention/Treatment	Phase
Relapsed Diffuse Large B-cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma	Drug: Polatuzumab Vedotin Drug: Mabthera Drug: Ifosfamide Drug: Carboplatin Drug: Etoposide	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

334 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Apr 30, 2021

Anticipated Primary Completion Date :

Oct 31, 2024

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental Arm: Pola-R-ICE combination of standard chemotherapy with polatuzumab vedotin (Pola-R-ICE) Application	Drug: Polatuzumab Vedotin Polatuzumab vedotin 1.8 mg/kg will be administered intravenously on Day 1 of each 21-day cycle for up to 3 cycles. Drug: Mabthera Rituximab (Mabthera/Rituxan®) will be administered as per local practice at a dose of 375 mg/m2 intravenously on Day 1 of each 21-day cycle for up to 3 cycles. Drug: Ifosfamide Ifosfamide 5000 mg/m² will be administered i.v. over a 24 hr period starting on cycle Day 2. Drug: Carboplatin Carboplatin AUC 5 max 800 mg will be administered i.v. on cycle Day 2. Drug: Etoposide Etoposide 100 mg/m² will be administered i.v. on cycle Days 1, 2 and 3.
Active Comparator: Standard Arm: R-ICE conventional treatment with rituximab, ifosfamide, carboplatin and etoposide (R-ICE)	Drug: Mabthera Rituximab (Mabthera/Rituxan®) will be administered as per local practice at a dose of 375 mg/m2 intravenously on Day 1 of each 21-day cycle for up to 3 cycles. Drug: Ifosfamide Ifosfamide 5000 mg/m² will be administered i.v. over a 24 hr period starting on cycle Day 2. Drug: Carboplatin Carboplatin AUC 5 max 800 mg will be administered i.v. on cycle Day 2. Drug: Etoposide Etoposide 100 mg/m² will be administered i.v. on cycle Days 1, 2 and 3.

Arm

Intervention/Treatment

Experimental: Experimental Arm: Pola-R-ICE

combination of standard chemotherapy with polatuzumab vedotin (Pola-R-ICE) Application

Drug: Polatuzumab Vedotin

Polatuzumab vedotin 1.8 mg/kg will be administered intravenously on Day 1 of each 21-day cycle for up to 3 cycles.

Drug: Mabthera

Rituximab (Mabthera/Rituxan®) will be administered as per local practice at a dose of 375 mg/m2 intravenously on Day 1 of each 21-day cycle for up to 3 cycles.

Drug: Ifosfamide

Ifosfamide 5000 mg/m² will be administered i.v. over a 24 hr period starting on cycle Day 2.

Drug: Carboplatin

Carboplatin AUC 5 max 800 mg will be administered i.v. on cycle Day 2.

Drug: Etoposide

Etoposide 100 mg/m² will be administered i.v. on cycle Days 1, 2 and 3.

Active Comparator: Standard Arm: R-ICE

conventional treatment with rituximab, ifosfamide, carboplatin and etoposide (R-ICE)

Drug: Mabthera

Rituximab (Mabthera/Rituxan®) will be administered as per local practice at a dose of 375 mg/m2 intravenously on Day 1 of each 21-day cycle for up to 3 cycles.

Drug: Ifosfamide

Ifosfamide 5000 mg/m² will be administered i.v. over a 24 hr period starting on cycle Day 2.

Drug: Carboplatin

Carboplatin AUC 5 max 800 mg will be administered i.v. on cycle Day 2.

Drug: Etoposide

Etoposide 100 mg/m² will be administered i.v. on cycle Days 1, 2 and 3.

Outcome Measures

Primary Outcome Measures

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

Assessment of the rate of metabolic complete response. [Day of randomization until end weeks 12 treatment.]
Number of complete remissions.
Evaluation of the partial response rate. [Day of randomization until end of 12 weeks treatment.]
Number of partial responses.
Assessment of the overall response rate. [Day of randomization until end of 12 weeks treatment.]
Number of complete and partial responses.
Assessment duration of response. [Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)]
Time from documentation of tumor response to disease progression or relapse.
Assessment of the rate of progressive disease. [Day of randomization until end of 12 weeks treatment.]
Number of progressive diseases.
Assessment of disease relapse. [Day of randomization until end of 12 weeks treatment.]
Number of relapses.
Assessment of progression free survival. [Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)]
Occurence of disease progression, relapse or death due to any cause.
Assessment of overall survival. [Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)]
Assessment of the rate of patients proceeding to transplantation. [Day of randomization until week 12.]
Assessment of the rate of patients with non-relapse mortality. [Day of randomization until end of follow up (12 weeks treatment and at least 21 months follow up)]
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. [Day of Randomization until 28 days after start of last cycle or start of further therapy]
Assessment of the number of patients with treatment-related death. [Day of Randomization until up week 12 or 2 months after week 12 but before start of further therapy]
To determine the number of patients with occurence of second malignancies [Day of Randomization until Day of randomization until end of follow up (at least 21 months follow up)]
Assessment of the protocol adherence by the rate and duration of chemotherapy cycles patients received. [Day of Randomizaton until week 12.]
Assessment of the cumulative and relative dose of each IMP( ifosfamide, carboplatin and etoposide, rituximab and of the polatuzumab vedotin) by quantitative measurement. [Day of Randomizaton until week 12.]
Assessment of the change in health related quality of life by generic questionnaire. [Day of Randomization until weeks 12 and months 3 and 12 in follow up.]
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.
Assessment of the change in health related quality of life by five-item questionnaire. [Day of Randomization until weeks 12 and months 3 and 12 in follow up]
Assessment visual analogue scale to measure health state. [Day of Randomization until weeks 12 and months 3 and 12 in follow up]
This scale is provided with numbers from 0 to 100.100 is the best health state and 0 (zero) is the worst health state.
Functional assessment of the cancer therapy-lymphoma by general questions and specific questions for lymphoma. [Day of Randomization until weeks 12 and months 3 and 12 in follow up.]
Assessment how lymphoma-specific symptoms impact quality of life.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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.

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, 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:

(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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UK Graz Universitätsklinik für Innere Medizin Klinische Abteilung für Hämatologie	Graz		Austria	8036
2	LKH Hochsteiermark Standort Leoben Abteilung für Innere Medizin Department für Hämato-Onkologie	Leoben		Austria	8700
3	Ordensklinikum Linz GmbH- Elisabethinen: I. Interne Abteilung Hämato-Onkologie	Linz		Austria	4020
4	Kepler Universitätsklinikum Med Campus III, Univ.-Klinik für Hämatologie und Internistische Onkologie	Linz		Austria	4021
5	Landeskrankenhaus Salzburg	Salzburg		Austria	5020
6	AKH Meduni Wien Universitätsklinik für Innere Medizin I:	Vienna		Austria	1090
7	Klinikum Wels-Grieskirchen Abteilung für Innere Medizin IV	Wels		Austria	4600
8	Hanusch Krankenhaus	Wien		Austria	1140
9	Universitätsklinikum RWTH-Aachen	Aachen		Germany
10	HELIOS Klinik Berlin-Buch, Klinik für Hämatologie und Stammzelltransplantation	Berlin		Germany	13125
11	Städtisches Klinikum Braunschweig	Braunschweig		Germany
12	DIAKO Ev.Diakonie-Krankenhaus gemeinnützige GmbH	Bremen		Germany
13	Klinikum Chemnitz gGmbH	Chemnitz		Germany
14	St. Johannes Hospital Dortmund	Dortmund		Germany
15	Universitätsklinikum Dresden	Dresden		Germany
16	Helios St. Johannes Klinik	Duisburg		Germany
17	Klinik für Onkologie, Hämatologie und Palliativmedizin	Düsseldorf		Germany	40479
18	Universitätsklinikum Frankfurt	Frankfurt		Germany
19	Georg-August-Universität Göttingen Universitätsmedizin Göttingen	Göttingen		Germany
20	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany
21	Universitätsklinikum Jena	Jena		Germany
22	Westpfalz-Klinikum GmbH	Kaiserslautern		Germany
23	Städtisches Krankenhaus Kiel	Kiel		Germany
24	Klinikum Ludwigshafen	Ludwigshafen		Germany
25	Universitätsklinikum Magdeburg	Magdeburg		Germany
26	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz		Germany
27	Philipps-Universität Marburg	Marburg		Germany
28	Universitätsklinikum Münster	Münster		Germany
29	Klinikum Nürnberg	Nürnberg		Germany
30	Klinikum Oldenburg	Oldenburg		Germany
31	Universitätsklinikum Regensburg	Regensburg		Germany
32	Unversitätsmedizin Rostock	Rostock		Germany
33	Klinikum Stuttgart	Stuttgart		Germany
34	Klinikum Mutterhaus	Trier		Germany
35	Universitätsklinikum Ulm	Ulm		Germany
36	Helios Universitätsklinikum Wuppertal	Wuppertal		Germany
37	Hospital Universitario Son Espases	Palma	Islas Baleares	Spain	07120
38	Hospital Germans Trias I Pujol	Badalona		Spain	08916
39	Hospital Universitari Vall d'Hebron	Barcelona		Spain	8035
40	Hospital Universitario de Donostia	Donostia		Spain	20014
41	Hospital Universitario de Cabueñes	Gijón		Spain	33394
42	Institut Català d'oncologia de L'Hospitalet (ICO-L'Hospitalet)	Hospitalet de Llobregat		Spain	08908
43	Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín	Las Palmas De Gran Canaria		Spain	35012
44	Hospital Universitario Fundación Jimenez Díaz	Madrid		Spain	28040
45	Hospital Universitario La Paz	Madrid		Spain	28046
46	Hospital Universitario Ramón y Cajal	Madrid		Spain
47	Hospital Universitario Virgen de la Arrixaca	Murcia		Spain	30003
48	Complejo Asistencial Universitario de Salamanca	Salamanca		Spain	37007
49	Hospital Universitario Marqués de Valdecilla	Santander		Spain	39908
50	Hospital Universitario Virgen del Rocío	Sevilla		Spain	41013
51	Hospital Clínico Universitario de Valencia	Valencia		Spain	46010
52	Belfast City Hospital	Belfast		United Kingdom	BT9 7AB
53	Blackpool Victoria Hopsital	Blackpool		United Kingdom	FY3 8NR
54	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN
55	St James University Hospital	Leeds		United Kingdom	LS9 7TF
56	Aintree University Hospital	Liverpool		United Kingdom	L9 7AL
57	University London College Hospitals	London		United Kingdom	NW1 2PG
58	The James Cook University Hospital	Middlesbrough		United Kingdom	TS4 3BW
59	Freeman Hospital	Newcastle upon Tyne		United Kingdom	NE7 7DN
60	Nottingham City Hospital	Nottingham		United Kingdom	NG5 1PB
61	Churchill Hospital	Oxford		United Kingdom	OX3 7LE
62	Royal Hallamshire Hospital	Sheffield		United Kingdom	S10 2JF
63	Royal Cornwall Hospital	Truro		United Kingdom	TR1 3LQ