Pembrolizumab in Combination With R-ICE Chemotherapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma

NCT05221645 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: RHMCAN1402
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 2

Brief Summary

This is an open-label, multicentre, randomised phase II trial in relapsed or refractory diffuse large B-cell lymphoma.

Conditions

Diffuse Large B Cell Lymphoma

Outcome Measures

Primary Outcomes (1)

• To establish the event-free survival at 1 year in patients treated with P+R-ICE

  Event free survival at 1 year (binary) - the proportion of patients alive and event free at 1 year. An event is defined as any of the following: * Progression / relapse of lymphoma * Stable disease at 3 cycles of therapy * Commencement of any unplanned non-protocol treatment for lymphoma * Death from any cause

  12 months

Secondary Outcomes (11)

• Event free survival (EFS) (time to event outcome) - median and at 1 and 2 years from Kaplan-meier curve

  12 months to 24 months

• Progression-free survival (PFS) (time to event outcome) - median and at 1 and 2 years from Kaplan-meier curve

  12 months to 24 months

• Overall Survival (OS) (time to event outcome) - median and at 1 and 2 years from Kaplan-meier curve

  12 months to 24 months

• Number of patients achieving 2 x 106 CD34 positive cells per kg stem cells on harvest

  12 months

• The number and proportion of patients achieving CR at the end of induction

  12 months

Study Arms (2)

Control Arm A

ACTIVE COMPARATOR

Patients will receive three cycles of R-ICE. Each cycle is 21 days +/- 3 days Rituximab 375mg/m2 Ifosfamide 5,000mg/m2 Carboplatin AUC = 5 (max dose 800mg) Etoposide 100mg/m2 All patients who are deemed to be in CR or PR on the post treatment PET-CT scan will undergo autologous stem cell transplant (ASCT) within 4 weeks of completing R-ICE treatment. BEAM (carmustine, etoposide, cytarabine and melphalan) conditioning will be employed according to institutional protocol.

Drug: Rituximab; Drug: Ifosfamide; Drug: Carboplatin; Drug: Etoposide

Experimental Arm B

EXPERIMENTAL

Pembrolizumab 200mg Rituximab 375mg/m2 Ifosfamide 5,000mg/m2 Carboplatin AUC = 5 (max dose 800mg) Etoposide 100mg/m2 Patients will receive up to 3 cycles of: P+R-ICE, where each cycle is 21 days long +/-\_3 days. All patients who are deemed to be in CR or PR on the post treatment PET-CT scan will undergo autologous stem cell transplant (ASCT) within 4 weeks of completing P+R-ICE treatment. BEAM (carmustine, etoposide, cytarabine and melphalan) conditioning will be employed according to institutional protocol. These patients will then be offered maintenance pembrolizumab every 3 weeks for one year.

Drug: Pembrolizumab; Drug: Rituximab; Drug: Ifosfamide; Drug: Carboplatin; Drug: Etoposide

Interventions

Pembrolizumab DRUG

Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD 1. Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an intravenous (IV) immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of indications because of its mechanism of action to bind the PD-1 receptor on the T cell.

Also known as: KEYTRUDA

Experimental Arm B

Rituximab DRUG

Rituximab is a chimeric mouse/human monoclonal antibody that binds to CD20, on pre-B and mature B lymphocytes and eliminates these cells potentially via a number of different mechanisms. Anti-CD20 mAbs, like rituximab, are classified by their CD20-binding characteristics, ability to induce complement-dependent cytotoxicity (CDC), and immune effector cell effects.

Also known as: MabThera

Control Arm A; Experimental Arm B

Ifosfamide DRUG

Ifosfamide, Carboplatin and Etoposide (ICE) is proven to be an effective regimen in the relapsed refractory NHL population. In a study of 163 transplant eligible patients with relapsed/refractory disease, 66.3% of patients obtained CR/PR after 3 cycles of ICE chemotherapy at two weekly intervals.

Control Arm A; Experimental Arm B

Carboplatin DRUG

Ifosfamide, Carboplatin and Etoposide (ICE) is proven to be an effective regimen in the relapsed refractory NHL population. In a study of 163 transplant eligible patients with relapsed/refractory disease, 66.3% of patients obtained CR/PR after 3 cycles of ICE chemotherapy at two weekly intervals.

Control Arm A; Experimental Arm B

Etoposide DRUG

Ifosfamide, Carboplatin and Etoposide (ICE) is proven to be an effective regimen in the relapsed refractory NHL population. In a study of 163 transplant eligible patients with relapsed/refractory disease, 66.3% of patients obtained CR/PR after 3 cycles of ICE chemotherapy at two weekly intervals.

Control Arm A; Experimental Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically proven CD20 +ve diffuse large B-cell lymphoma, preferably with sufficient diagnostic material, obtained either at diagnosis or relapse (the latter is preferable) that is available to forward to the Haematological Malignancies Diagnostic Service (HMDS) for gene expression profiling and central pathology review
• Refractory to, or relapsed following, first-line or second-line treatments with rituximab concurrently with anthracycline or anthracenedione-based chemotherapy or similar (etoposide allowed if comorbid).
• Refractory disease must fulfil one of the following:
• Continuing partial response (PR) from termination of first-line treatment. It is strongly recommended the lymphoma be reconfirmed by biopsy however, if these procedures are deemed to be inappropriate, the CI may determine eligibility following review of the imaging results and disease history.
• Continuing stable disease (SD) from termination of first-line treatment. Reconfirmation of the lymphoma by biopsy (preferred) is recommended but not mandatory.
• Progressive disease (PD). Biopsy or reconfirmation of the lymphoma is recommended but not mandatory.
• Potentially eligible for high-dose therapy and peripheral blood progenitor cell rescue in the event of response
• Positive lesions shown on baseline PET-CT must be compatible with CT defined anatomical tumour sites.
• At least 2 demarcated lesions/nodes with a long axis \>1.5 cm and a short axis equal to 1.0cm or 1 clearly demarcated lesion/node with a long axis \>2.0cm and short axis of 1.0cm
• Previous therapy related toxicity should have resolved to a grade that the investigator deems appropriate to commence further treatment
• ECOG Performance Status 0 - 1
• Has provided written informed consent
• Willing to use acceptable contraception (see Section 4.6)
• Aged 18 or over

You may not qualify if:

• Previous lymphoma cancer treatment beyond third line
• Radiotherapy or cytotoxic drugs within two weeks of trial treatment
• Major surgery within 4 weeks of trial registration. If a subject had major surgery, more than 4 weeks ago, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
• Treatment with any unlicensed drug within 4 weeks of trial treatment
• History of stroke or intracranial haemorrhage within 6 months prior to registration
• Pre-existing peripheral neuropathy grade \>2
• Clinically significant cardiac disease (inc. unstable angina, acute myocardial infarction, congestive heart failure, a current LVEF of \<40%) within 6 months of registration
• Any significant uncontrolled medical condition or known hypersensitivity to the study drugs
• Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis and tuberculosis.
• Other past or current malignancy within 2 years prior to registration unless in the opinion of the investigator it does not contraindicate participation in the study. Subjects who have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma, are eligible
• Known CNS involvement
• Serological positivity for Hepatitis B, C, or known HIV infection. As per standard of care, prior to initiation of immunochemotherapy, the results of hepatitis serology should be known prior to commencement of therapy.
• Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible.
• Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible.
• Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible.

Sponsors & Collaborators

• University of Southampton: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (2)

The Beatson West of Scotland Cancer Centre

Glasgow, Glasgow, G12 0YN, United Kingdom

Location

Oxford Cancer & Haematology Centre, The Churchill Hospital

Headington, Oxford, OX3 7LE, United Kingdom

Location

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

pembrolizumab; Rituximab; Ifosfamide; Carboplatin; Etoposide

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cyclophosphamide; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Coordination Complexes; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The study has two treatment arms to which participants will be randomised on a 3:1 basis to the experimental arm. The control arm (Arm A) will be R-ICE for 3 cycles followed by an autologous stem cell transplant (for patients in a CR or PR on the post treatment PET-CT scan). The experimental arm (Arm B) will consist of P+R-ICE for 3 cycles followed by an autologous stem cell transplant (for patients in a CR or PR on the post treatment PET-CT scan) and maintenance Pembrolizumab every 3 weeks for one year. All patients will be randomised at study entry and will be stratified by relapse within 12 months or \> 12 months of first line therapy.

Study Record Dates

• First Submitted: October 14, 2021
• First Posted: February 3, 2022
• Study Start: June 27, 2022
• Primary Completion (Estimated): May 30, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: May 15, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)