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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

GWT-Tud GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

29 Apr 2021 → 19 Dec 2025

Decision date (initial)

2024-02-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffman-La Roche Ltd (Switzerland)

External identifiers

EU CT number

2023-508259-38-00

EudraCT number

2019-002962-10

WHO UTN

U1111-1299-4165

ClinicalTrials.gov

NCT04833114

ISRCTN

ISRCTN13438605

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

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?

Secondary objectives 7

1. Evaluation 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
2. Evaluation whether the addition of polatuzumab vedotin to standard therapy R-ICE enhances the partial response (PR) rate and overall response rate (ORR) and decreases the progression rate and relapse rate
3. Evaluation whether the addition of polatuzumab vedotin to standard therapy R-ICE enhances the duration of response, progression-free survival (PFS) and overall survival (OS)
4. Evaluation whether the addition of polatuzumab vedotin to standard therapy R-ICE impacts the mobilization of autologous CD34+ stem cells
5. Evaluation whether the addition of polatuzumab vedotin to standard therapy R-ICE enhances the rate of patients proceeding to transplantation
6. Evaluation whether the addition of polatuzumab vedotin to standard therapy R-ICE impacts the non-relapse mortality
7. 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

Conditions and MedDRA coding

Adult patients with relapsed or primary refractory DLBCL

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

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
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

Exclusion criteria 21

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. 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
3. Received more than one line of therapy for DLBCL
4. Received polatuzumab vedotin as part of the first line therapy
5. 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
6. 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
7. Human immunodeficiency virus (HIV)-positivity with detectable viral load and/or a CD4+ count below 0.3/nL
8. 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
9. 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
10. Patients with suspected or latent tuberculosis. Latent tuberculosis needs to be confirmed by positive interferon-gamma release assay
11. Primary or secondary central nervous system (CNS) lymphoma at the time of recruitment
12. Richter’s transformation or prior chronic lymphocytic leukemia (CLL)
13. Vaccination with a live vaccine within 4 weeks prior to treatment
14. Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis
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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is EFS of patients with DLBCL at first progression or relapse.

Secondary endpoints 4

1. 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
2. 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
3. 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
4. Secondary endpoints for QoL: Secondary endpoint is evaluation of generic health-related QoL as assessed by different questionnaires

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 13

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

GWT-Tud GmbH

Sponsor organisation

GWT-Tud GmbH

Address

Freiberger Strasse 33, Wilsdruffer Vorstadt/seevorstadt-West Wilsdruffer Vorstadt/seevorstadt-West

City

Dresden

Postcode

01067

Country

Germany

Scientific contact point

Organisation

GWT-Tud GmbH

Contact name

FB MEDIZIN

Public contact point

Organisation

GWT-Tud GmbH

Contact name

FB MEDIZIN

Third parties 6

Locations

3 EU/EEA countries · 48 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 46 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications