Pembrolizumab, Ibrutinib and Rituximab in PCNSL

NCT04421560 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 20-144
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 4

Brief Summary

This research study is evaluating a combination therapy of 3 drugs as possible treatments for recurrent primary central nervous system lymphoma (PCNSL). The three drugs being used in the study are:

• Pembrolizumab (MK3475)
• Ibrutinib
• Rituximab (or biosimilar)

Conditions

Primary Central Nervous System Lymphoma; Recurrent Cancer; Refractory Cancer; Relapsed Cancer

Keywords

Primary Central Nervous System Lymphoma; Recurrent Cancer; Refractory Cancer; Relapsed Cancer

Outcome Measures

Primary Outcomes (1)

• Progression-free survival rate 6 months (PFS6)

  The primary endpoint of PFS6 will be estimated as a binomial response proportion. The efficacy analysis population will include all evaluable patients (subjects will be considered evaluable for efficacy as long as they have received at least 75% of the planned doses for the 1st 6 weeks of treatment). Patients missing 6 months progression evaluation (for any reason) will be counted as progressors. For the primary analysis, the proportion of progression free patients at 6 months will be evaluated and 95% exact binomial CI will be provided. The Kaplan-Meier method will be used as a secondary approach to evaluate the PFS6 based on the recorded times to progression for each patient, with patients without progression or lost to follow-up being censored at their last follow-up date.

  6 months

Secondary Outcomes (5)

• Number of Participants With Treatment-Related Adverse Events CTCAE version 5.0.

  24 Months

• Objective response rate (ORR)

  24 months

• Duration of response rate

  24 Months

• Progression-free survival (PFS) Rate

  24 Months

• Overall survival (OS) Rate

  24 Months

Study Arms (1)

Pembrolizumab + Ibrutinib + Rituximab

EXPERIMENTAL

Phase 1b Dose escalation will occur using a standard 3+3 dose-escalation approach, beginning at dose level I (560 mg daily) and potentially escalating to dose level 2 (840mg) with rules for escalation and de-escalation. * Ibrutinib: orally 2x daily * Pembrolizumab: 200 mg intravenously every 3 weeks * Rituximab/biosimilar: 375mg/m\^2 intravenously once per week for 4 weeks (4 total doses). Phase 2 Participants will receive Pembrolizumab, Rituximab and Ibrutinib at the pre-determined dosage level established in Phase 1b. * Ibrutinib: orally maximum tolerated dose from phase 1 daily (560 mg or 840mg) * Pembrolizumab: 200 mg intravenously every 3 weeks * Rituximab/biosimilar: 375 mg/m\^2 intravenously once per week for 4 weeks (4 total doses).

Drug: Ibrutinib; Drug: Pembrolizumab; Drug: Rituximab

Interventions

Ibrutinib DRUG

Capsule, taken by mouth daily

Also known as: Imbruvica

Pembrolizumab + Ibrutinib + Rituximab

Pembrolizumab DRUG

Given as an intravenous injection through a vein (IV) every 3 weeks

Also known as: Keytruda

Pembrolizumab + Ibrutinib + Rituximab

Rituximab DRUG

Given as infusion into a vein (intravenous, IV)

Also known as: Rituxan, Truxima

Pembrolizumab + Ibrutinib + Rituximab

Eligibility Criteria

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

You may qualify if:

• Participant must be able to understand and willing to sign a written informed consent document.
• Participant must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care.
• Participant must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study.
• Participant must be at least 18 years old on day of signing informed consent.
• Subjects with pathologically confirmed PCNSL who progressed after CNS-directed therapy, primary refractory disease and relapsed disease are allowed. Participants should have evidence of R/R disease on MRI or CSF cytology. Ocular only recurrences are allowed.
• Subjects must have a Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Life expectancy of \>3 months (in the opinion of the investigator)
• Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1
• Must be able to tolerate lumbar puncture and/or Ommaya taps
• Demonstrate adequate organ function as defined below, all screening labs should be performed within 28 days of treatment initiation.
• Hematology
• White Blood Count (WBC) ≥ 2 K/μL
• Platelet count ≥ 100 K/μL
• Absolute Neutrophil Count ≥ 1.5 K/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)

You may not qualify if:

• Participants who meet any of the following criteria will not be eligible for admission into the study.
• Patients who cannot undergo MRI brain
• 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)
• Previously progressed on ibrutinib or other BTK inhibitor use (patient who have previously received BTK inhibitor but not progressed while on it are allowed)
• Patients with \> Grade 2 intracranial hemorrhage
• Concomitant warfarin, any other warfarin-derivative anticoagulant, vitamin K antagonists, within 7 days before starting treatment. Note: novel oral anticoagulants (NOACs, e.g., Apixaban, Dabigatran, Edoxaban, Rivaroxaban), low molecular weight heparin (LMWH) are allowed
• Arterial thromboembolic events such as cerebrovascular accident within 3 months before the start of study treatment
• Active autoimmune disease requiring immunosuppressive agents or steroids (prednisone \>10mg or equivalent)
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Requires treatment for PCNSL with high dose systemic corticosteroids defined as dexamethasone \> 4 mg/day or bioequivalent for \>3 consecutive days within 2 weeks of registration
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks \[could consider shorter interval for kinase inhibitors or other short half-life drugs\] prior to dosing. OR 5 half-lives, whichever is shorter --- Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with≤Grade 2 neuropathy may be eligible.
• Patients who underwent major surgery ≤ 2 weeks before starting study treatment are excluded. If participant underwent major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. Patients who plan to undergo surgery within 2 weeks of first dose of study treatment are excluded.
• Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. Has received prior radiotherapy to CNS disease within 2 weeks of start of study treatment.
• 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.
• 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.

Sponsors & Collaborators

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

Study Sites (4)

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

RECRUITING

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

RECRUITING

Columbia University Medical Center

New York, New York, 10032, United States

WITHDRAWN

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

RECRUITING

MeSH Terms

Conditions

Recurrence; Neoplasms

Interventions

ibrutinib; pembrolizumab; Rituximab

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Lakshmi Nayak, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lakshmi Nayak, MD

CONTACT

(617) 632-2166; lnayak2@partners.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 4, 2020
• First Posted: June 9, 2020
• Study Start: August 1, 2020
• Primary Completion (Estimated): December 5, 2026
• Study Completion (Estimated): January 5, 2027
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• 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 (4)