A Pilot Study of Pembrolizumab in Combination With Chemotherapy in Newly Diagnosed Primary Central Nervous System Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Pembrolizumab
- Conditions
- Lymphoma
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 15
- Locations
- 4
- Primary Endpoint
- Number of Patients Experienced Dose Limiting Toxicity (DLT)
- Status
- Recruiting
- Last Updated
- 2 months ago
Overview
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)
Detailed Description
This is an open label, pilot trial of Pembrolizumab in combination with chemotherapy in participants with newly diagnosed Primary Central Nervous System Lymphoma (PCNSL). The U.S. Food and Drug Administration (FDA) has not approved Pembrolizumab for Primary Central Nervous System Lymphoma (PCNSL) but it has been approved for other uses. The FDA has approved Rituximab for PCNSL. The FDA has not approved Temozolomide for PCNSL but it has been approved for other uses. The FDA has not approved Methotrexate for PCNSL but it has been approved for other uses. The research study procedures include screening for eligibility, blood and urine tests, Computerized Tomography (CT) scans, Magnetic Resonance Imaging (MRI) scans, Positron Emission Tomography (PET) scans, testicular ultrasounds, electrocardiograms (ECG), and eye exams. It is expected that about 15 people will take part in this research study. Merck \& Co. is supporting this research study by providing the study drug pembrolizumab.
Investigators
Lakshmi Nayak, MD
Sponsor Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •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
Exclusion Criteria
- •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%.
Arms & Interventions
Induction Treatment:
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.
Intervention: Pembrolizumab
Induction Treatment:
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.
Intervention: Methotrexate
Induction Treatment:
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.
Intervention: Temozolomide
Induction Treatment:
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.
Intervention: Rituximab
Consolidation Treatment:
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
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Number of Patients Experienced Dose Limiting Toxicity (DLT)
Time Frame: Up to 28 days
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.
Secondary Outcomes
- Complete Response Rate (CRR)(Up to 16 weeks)
- Median Overall Survival (OS)(Up to 3 years)
- Objective Response Rate (ORR)(Up to 106 weeks)
- Median Progression Free Survival (PFS)(Up to 106 weeks)
- Frequency of Missed or Delayed doses(Up to 106 weeks)
- Percentage of actual planned dosage administration(Up to 106 weeks)
- Percentage of patients that discontinue study drugs due to treatment-related toxicity.(Up to 106 weeks)
- 2-Year Progression Free Survival (PFS2)(Up to 2 years)
- Duration of Response (DOR)(Up to 106 weeks)