Triple Therapy for Central Nervous System Lymphoma
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Dana-Farber Cancer Institute
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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)
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, you must discontinue any medications that are moderate or strong inhibitors or inducers of CYP3A4/5 two weeks before starting the study treatment. Additionally, enzyme-inducing antiepileptic drugs need to be switched to a non-inducing alternative two weeks prior to the trial.
What makes the triple drug therapy for CNS lymphoma unique?
The triple drug therapy for CNS lymphoma is unique because it combines ibrutinib, pembrolizumab, and rituximab, which target different aspects of the cancer cells and immune system. Ibrutinib crosses the blood-brain barrier to inhibit a specific protein in cancer cells, pembrolizumab helps the immune system recognize and attack cancer cells, and rituximab targets a protein on the surface of cancer cells, making this combination potentially more effective than traditional treatments.
124511Is the triple therapy for CNS lymphoma generally safe in humans?
The treatments involved in the triple therapy, such as Pembrolizumab (also known as KEYTRUDA), have been studied for safety in various conditions. Pembrolizumab has shown acceptable safety in patients with Hodgkin lymphoma, though it can cause immune-related side effects, including neurological symptoms. In another study, Pembrolizumab had manageable safety in patients with myelodysplastic syndromes, with some experiencing treatment-related adverse events.
378910What data supports the effectiveness of the drugs Ibrutinib, Imbruvica, Pembrolizumab, KEYTRUDA, MK-3475, Rituximab, Rituxan, Riabni, Ruxience, Truxima for treating central nervous system lymphoma?
Research shows that Ibrutinib, when used alone or in combination with other drugs like rituximab, has shown positive responses in treating central nervous system lymphoma, with some patients experiencing sustained remission. Additionally, rituximab has been associated with improved survival in aggressive B cell CNS lymphoma.
125611Eligibility Criteria
This trial is for adults with recurrent primary central nervous system lymphoma (PCNSL) who've had at least one prior CNS-directed therapy. They should be in good physical condition (ECOG 0-1), have a life expectancy over three months, and recovered from previous treatments to ≤ Grade 1 toxicity. Participants must understand and consent to the study's procedures, agree to use effective contraception, and not have certain health conditions or recent treatments that could interfere.Inclusion Criteria
I am fully active or restricted in physically strenuous activity but can do light work.
I am 18 years old or older.
I can undergo spinal fluid tests.
Exclusion Criteria
I do not have serious heart problems like recent heart attacks or uncontrolled heart failure.
I have a history of Hepatitis B or active Hepatitis C.
I have had pneumonitis treated with steroids or have it now.
I am taking immunosuppressants or steroids for an autoimmune disease.
I have an immune system disorder or take more than 10 mg of steroids daily.
I have been treated with specific immune therapy drugs before.
I have a wound, ulcer, or bone fracture that hasn't healed.
I have a bleeding disorder such as von Willebrand's disease or hemophilia.
I cannot swallow pills or have serious digestive issues.
I need treatment for brain lymphoma and have been on high dose steroids recently.
I have recovered from any side effects of radiation, don't need steroids, and haven't had lung inflammation from radiation. I haven't had brain radiation in the last 2 weeks.
My diabetes is not well-managed, with a HbA1c level over 8%.
I have a known history of HIV/AIDS.
I have an active tuberculosis infection.
I haven't needed systemic treatment for an autoimmune disease in the last 2 years.
I have not had major surgery in the last 2 weeks and am not planning any within the next 2 weeks.
I have had a serious brain bleed.
I have had a stem cell transplant from a donor.
I have not received a live vaccine in the last 30 days.
Participant Groups
The study tests a combination of three drugs: Pembrolizumab, Ibrutinib, and Rituximab as potential treatments for PCNSL. The goal is to evaluate their effectiveness together in patients who have seen their cancer return after initial treatment.
1Treatment groups
Experimental Treatment
Group I: Pembrolizumab + Ibrutinib + RituximabExperimental Treatment3 Interventions
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).
Ibrutinib is already approved in European Union, United States, Canada, Japan for the following indications:
🇪🇺 Approved in European Union as Imbruvica for:
- Chronic lymphocytic leukemia
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
- Marginal zone lymphoma
- Graft-versus-host disease
🇺🇸 Approved in United States as Imbruvica for:
- Chronic lymphocytic leukemia/small lymphocytic lymphoma
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
- Marginal zone lymphoma
- Graft-versus-host disease
🇨🇦 Approved in Canada as Imbruvica for:
- Chronic lymphocytic leukemia
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
- Marginal zone lymphoma
🇯🇵 Approved in Japan as Imbruvica for:
- Chronic lymphocytic leukemia
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Dana Farber Cancer InstituteBoston, MA
Beth Israel Deaconess Medical CenterBoston, MA
Loading ...
Who is running the clinical trial?
Dana-Farber Cancer InstituteLead Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
References
Rituximab is associated with improved survival for aggressive B cell CNS lymphoma. [2022]The optimal treatment strategy in patients with aggressive B cell central nervous system lymphoma suitable to receive intensive therapy is unknown. The benefit of incorporating rituximab in systemic therapy remains unclear. We performed a retrospective study examining the impact of rituximab in the context of concomitant therapies, including methotrexate, cytarabine, and radiotherapy, in patients treated with curative intent at 4 university teaching hospitals during 1996-2011.
Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. [2018]In this issue of Cancer Cell, Lionakis et al. demonstrate that the combination of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib induced frequent responses in patients with primary central nervous system lymphoma but was associated with significant toxicity, including pulmonary and cerebral aspergillosis infections.
Immune-related Neurological Symptoms in an Adolescent Patient Receiving the Checkpoint Inhibitor Nivolumab. [2018]Immune checkpoint inhibitors are a novel group of immunotherapeutic agents for the treatment of cancer. Immune-related adverse events, including neurological symptoms, have been associated with these agents. We present the case of an adolescent with refractory Hodgkin lymphoma treated with nivolumab, a PD1 inhibitor, who developed Hashimoto thyroiditis, posterior reversible encephalopathy syndrome causing seizures, as well as urinary retention, truncal/appendicular spasticity, dysphagia, and a progressive encephalopathy that was clinically consistent with a diagnosis of progressive encephalopathy with rigidity and myoclonus, a stiff-person-syndrome spectrum disorder. He showed response and ultimately full recovery to a combination of intravenous steroids, intravenous immunoglobulin, and plasma exchange. To our knowledge, this is the first documented report of an immune-related neurological reaction to nivolumab in an adolescent patient and expands the spectrum of known nivolumab-associated toxicities.
Spotlight on Ibrutinib in PCNSL: Adding Another Feather to Its Cap. [2021]<b/> In this issue Grommes and colleagues elegantly show that the irreversible inhibitor of Bruton tyrosine kinase, ibrutinib, promotes a high proportion of durable responses in primary central nervous system lymphoma, a type of diffuse large B-cell lymphoma (DLBCL), and also in secondary DLBCL relapsing to the central nervous system. Mutations in the B-cell antigen receptor-associated protein CD79B with upregulation of the MTOR pathway were associated with diminished response, but preclinical combination of PIK3CA and PIK3CD inhibitors synergized with ibrutinib to overcome this resistance mechanism, providing opportunity for further targeted therapy of this difficult-to-treat disease. Cancer Discov; 7(9); 940-2. ©2017 AACRSee related article by Grommes et al., p. 1018.
Therapy of primary CNS lymphoma: role of intensity, radiation, and novel agents. [2018]Primary central nervous system (CNS) lymphomas represent a subgroup of malignancies with specific characteristics, an aggressive course, and unsatisfactory outcome in contrast with other lymphomas comparable for tumor burden and histological type. Despite the high sensitivity to conventional chemotherapy and radiotherapy, remissions are frequently short lasting. Treatment efficacy is limited by several factors, including the biology and microenvironment of this malignancy and the "protective" effect of the blood-brain barrier, which limits the access of most drugs to the CNS. Patients who survive are at high risk of developing treatment-related toxicity, mainly disabling neurotoxicity, raising the question of how to balance therapy intensification with the control of side effects. Recent therapeutic progress and effective international cooperation have resulted in a significantly improved outcome over the past 2 decades, with a higher proportion of patients receiving treatment with curative intent. Actual front-line therapy consists of high-dose methotrexate-based polychemotherapy. Evidence supporting the addition of an alkylating agent and rituximab is growing, and a recent randomized trial demonstrated that the combination of methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) is associated with a significantly better overall survival. Whole-brain irradiation and high-dose chemotherapy supported by autologous stem cell transplantation are 2 effective consolidation strategies in patients with a disease responsive to induction chemotherapy. Different strategies such as alkylating maintenance, conservative radiotherapy, and nonmyeloablative consolidation are being addressed in large randomized trials and a more accurate knowledge of the molecular and biological characteristics of this malignancy are leading to the development of target therapies in refractory/relapsing patients, with the overall aim to incorporate new active agents as part of first-line treatment. The pros and cons of these approaches together with the best candidates for each therapy are outlined in this article.
Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. [2021]Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.
Patient-reported outcomes in KEYNOTE-087, a phase 2 study of pembrolizumab in patients with classical Hodgkin lymphoma. [2020]In KEYNOTE-087, pembrolizumab had a 69% overall response rate and acceptable safety in patients with relapsed/refractory classical Hodgkin lymphoma (rrHL). We assessed health-related quality of life (HRQoL) in KEYNOTE-087. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire 3-level version (EQ-5D) were administered to 206 patients across three cohorts defined by lymphoma progression after: (1) autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV) (n = 69); (2) salvage chemotherapy and BV (n = 79); and (3) ASCT without post-transplantation BV (n = 58). Compliance/completion rates were ≥90% at week 12 and ≥70% at week 24. QLQ-C30 global health status/QoL and EQ-5D visual analog scale scores showed mean increases from baseline in overall health at all assessed timepoints. With few exceptions, mean improvements from baseline to weeks 12 and 24 in QLQ-C30 functional and symptom scores occurred in all cohorts.Clinicaltrials.gov identifier: NCT02453594.
Inflammatory Myeloradiculitis Secondary to Pembrolizumab: A Case Report and Literature Review. [2020]Immune checkpoint inhibitors are the most important new medications in oncology and include inhibitors of programmed cell death protein-1 (PD-1) such as Pembrolizumab, Nivolumab, and Cemiplimab. These anticancer agents prevent tumour immune evasion and have been associated with a range of immune-related adverse events (irAEs) including those involving the nervous system. In this case report and literature review, we present the first case of inflammatory myeloradiculitis secondary to Pembrolizumab. We also summarise the characteristics, treatment, and outcomes of other cases reported in the literature which include a component of myelitis. Finally, we make general recommendations on management.
Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. [2021]Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.
Pembrolizumab for myelodysplastic syndromes after failure of hypomethylating agents in the phase 1b KEYNOTE-013 study. [2022]The phase 1b multicohort KEYNOTE-013 study assessed the safety and antitumor activity of pembrolizumab given at 10 mg/kg/day every 2 weeks for up to 2 years in hematologic malignancies, including myelodysplastic syndromes (MDS) refractory to a hypomethylating agent (HMA). Primary outcomes were safety and objective response rate per International Working Group 2006 criteria. By June 26, 2020, 28 patients were enrolled; median duration of follow-up was 5.6 months (range, 1-78), and 25 patients (89%) had died. Treatment-related adverse events occurred in 10 patients (36%), including 2 (7%) treatment-related discontinuations. No patient achieved complete or partial response. Five patients (19%) had bone marrow complete response, 12 (44%) stable disease, 10 (37%) progressive disease, 6 (22%) cytogenetic response, and 5 (19%) hematologic improvement. Median overall survival (OS) was 6.0 months (95% CI, 4-12); the overall 2-year OS rate was 17%. Pembrolizumab had manageable safety and clinical activity in patients with HMA-refractory MDS.This trial was registered at www.clinicaltrials.gov as #NCT01953692.
Successful Consolidation/Maintenance Therapy with Single Agent Ibrutinib for Primary CNS Lymphoma after Initial Induction Therapy. [2022]Primary central nervous system lymphoma (PCNSL) is a rare and aggressive disease that originates from lymphocytes and develops in the central nervous system. There is no standard consolidation/maintenance therapy for PCNSL. While there exists a variety of options, the high chance of inferior outcomes for elderly patients and the risk of neurotoxicity requires exploration of alternative options for consolidation/maintenance therapy for PCNSL in the elderly population with CNS lymphoma. We treated one 77-year-old patient with single agent ibrutinib, a Bruton's tyrosine kinase inhibitor that crosses the blood-brain-barrier, as consolidation/maintenance therapy after induction therapy with high-dose methotrexate (HD-MTX) and rituximab plus temozolomide. This treatment resulted in good tolerance, further resolution of a small residue lymphoma, and sustained remission. The patient has completed one year of consolidation/maintenance therapy and is currently under clinical and imaging surveillance. She has survived 27 months without recurrence since diagnosis. This case shows the potential effectiveness of single agent ibrutinib as consolidation/maintenance therapy for PCNSL after induction therapy. More cases are needed to confirm the findings.