Pembrolizumab + Chemotherapy in Newly Diagnosed PCNSL

NCT06475235 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 24-246
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 2

Brief Summary

This research study is studying if the investigational drug, Pembrolizumab, in combination with chemotherapy helps primary central nervous system lymphoma with acceptable side effects. This research study involves a combination of the below drugs:

• Pembrolizumab (a type of monoclonal antibody)
• Methotrexate (a type of anti-metabolite)
• Temozolomide (a type of alkylating agent)
• Rituximab (a type of antibody)

Conditions

Lymphoma; Primary Central Nervous System Lymphoma

Keywords

Lymphoma; Primary Central Nervous System Lymphoma

Outcome Measures

Primary Outcomes (1)

• Number of Patients Experienced Dose Limiting Toxicity (DLT)

  Dose-limiting toxicities (DLTs) will be defined as any grade ≥3 non-hematologic toxicity (with exceptions), grade 4 neutropenia lasting \>7 days or febrile neutropenia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with clinically significant bleeding, any grade 5 toxicity or dose delays for \>14 consecutive days (related to AEs) with exceptions. Toxicities are to be assess according to the CTCAE v5.

  Up to 28 days

Secondary Outcomes (9)

• Complete Response Rate (CRR)

  Up to 16 weeks

• Objective Response Rate (ORR)

  Up to 106 weeks

• 2-Year Progression Free Survival (PFS2)

  Up to 2 years

• Duration of Response (DOR)

  Up to 106 weeks

• Median Progression Free Survival (PFS)

  Up to 106 weeks

Study Arms (2)

Induction Treatment:

EXPERIMENTAL

Participants will be enrolled and will complete procedures as follows, starting at Dose Level 0 for Methotrexate and Temozolomide: * Baseline visit with assessments and imaging. * Imaging on cycles 3 and 6 only. * Cycles 1 through 3: ---Days 3 and 10 of 14 day cycle: Predetermined dose of Rituximab 1x daily. * Cycles 1, 3, 5, and 7: ---Days 7 through 11 of 14 day cycle: Predetermined dose of Temozolomide 1x daily. * Cycles 1 through 8: ---Day 1 of 14 day cycle: Predetermined dose of Methotrexate 1x daily. * Cycles 1, 4, 7 * Day 10 of 14 day cycle: Predetermined dose of Pembrolizumab 1x daily. Treatment will de-escalate per protocol if greater than or equal to 2 out of 6 participants experience a dose-limiting toxicity.

Drug: Pembrolizumab; Drug: Methotrexate; Drug: Temozolomide; Drug: Rituximab

Consolidation Treatment:

EXPERIMENTAL

4-8 weeks after the completion of Induction Cycle 8, the study doctor will determine if it is appropriate to move on to consolidation therapy and participants will complete: * Imaging every other cycle. * Cycles 1 through 15: * Day 1 of 42 day cycle: Lumbar puncture * Day 1 of 42 day cycle: Predetermined dose of Pembrolizumab 1x daily. * End of treatment visit with lumbar puncture and imaging. * Follow up

Drug: Pembrolizumab

Interventions

Pembrolizumab DRUG

Humanized immunoglobin G4 monoclonal antibody, 4 mL vials, via intravenous infusion (into the vein) per protocol.

Also known as: Keytruda, MK-3475, Humanized X PD-1 mAb (H409A11) IgG4

Consolidation Treatment:; Induction Treatment:

Methotrexate DRUG

Anti-metabolite, 50 mL vials, via intravenous infusion per protocol.

Also known as: MTX

Induction Treatment:

Temozolomide DRUG

Alkylating agent, 5, 20, 100, 140, 180, or 250 mg capsules, taken orally per protocol.

Also known as: Temodar, Temodal

Induction Treatment:

Rituximab DRUG

Anti-CD20 antibody, 10 or 50 mL single-use vials, via intravenous infusion per standard of care.

Also known as: Riabni, Rituxan, Ruxience, Truxima

Induction Treatment:

Eligibility Criteria

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

You may qualify if:

• Subjects with pathologically confirmed newly diagnosed primary CNS diffuse large B-cell lymphoma (DLBCL) confirmed by one of the following:
• Brain biopsy or resection
• Cerebrospinal fluid
• Vitreous fluid
• Participants must not have any evidence or history of DLBCL outside of the CNS. Participants with prior history of isolated intraocular lymphoma (primary vitreoretinal lymphoma/PVRL) who have received only local therapy are allowed.
• Participants must not have received any systemic chemotherapy or whole brain radiation therapy directed to PCNSL.
• Age ≥18 years.
• ECOG performance status ≤2 (Karnofsky ≥70% will be considered if related to PCNSL, see Appendix A).
• Participants must have adequate organ function as defined below.
• Hematology
• Absolute neutrophil count (ANC) ≥1000/µL
• Platelets ≥100 000/µL
• Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks)
• Renal
• \-- Creatinine ≤1.5 x ULN OR Measured or calculated creatinine clearance ≥40 mL/min for participant with creatinine levels \>1.5 × institutional ULN (Creatinine clearance (CrCl) should be calculated per institutional standard.)

You may not qualify if:

• Participants who cannot undergo MRI
• Intraocular PCNSL without evidence of brain or spinal cord disease.
• Participants who are receiving any other investigational agents.
• History of allergic reactions or severe hypersensitivity reactions (≥grade 3) attributed to compounds of similar chemical or biologic composition to study agent and/or any of its excipients.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
• Has active autoimmune disease requiring immunosuppressives or steroids
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. COVID19 vaccines are allowed.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, transitional cell carcinoma of urothelial cancer, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Patient has poorly controlled diabetes mellitus with a glycosylated hemoglobin \>8% or poorly controlled steroid-induced diabetes mellitus with a glycosylated hemoglobin of \>8%.
• Unable to swallow capsules or disease significantly affecting gastrointestinal function, such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction.
• Enzyme-inducing antiepileptic drugs (EIAED) need to be discontinued and switched to a non-EIAED 2 weeks prior to starting on trial drugs
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection.
• Has a known history of active TB (Bacillus Tuberculosis)
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent)

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (2)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

RECRUITING

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

MeSH Terms

Conditions

Lymphoma

Interventions

pembrolizumab; Immunoglobulin G; Methotrexate; Temozolomide; Rituximab

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal

Study Officials

• Lakshmi Nayak, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lakshmi Nayak, MD

CONTACT

617-632-2166; Lakshmi_Nayak@DFCI.HARVARD.EDU

DFCI Clinical Trials Hotline

CONTACT

877-338-7425

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: June 20, 2024
• First Posted: June 26, 2024
• Study Start: October 18, 2024
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): June 30, 2027
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (2)