Pirtobrutinib + Rituximab for Lymphoma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: M.D. Anderson Cancer Center
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?To learn if the chemotherapy-free combination of pirtobrutinib (also called LOXO-305) and rituximab can help provide long term remission in low and intermediate risk MCL.
What is known about the safety of Pirtobrutinib and Rituximab for lymphoma?
Pirtobrutinib, approved for certain types of lymphoma, has been associated with side effects like fatigue, muscle pain, diarrhea, and bruising. Serious warnings include risks of infection, bleeding, and heart rhythm problems. Rituximab, often used in combination therapies, can cause side effects such as fatigue, diarrhea, and nausea, with rare but serious risks of blood and heart issues.
6791011What makes the drug combination of Pirtobrutinib and Rituximab unique for treating lymphoma?
The combination of Pirtobrutinib and Rituximab is unique because Pirtobrutinib is a newer Bruton's tyrosine kinase (BTK) inhibitor, which may offer a different mechanism of action compared to other BTK inhibitors like Ibrutinib, potentially leading to improved outcomes or reduced side effects when used with Rituximab, a well-established monoclonal antibody targeting CD20 on B-cells.
23568Will I have to stop taking my current medications?
The trial does not specify if you must stop taking your current medications, but it does prohibit certain medications like warfarin, vitamin K antagonists, and strong CYP3A4 inhibitors or inducers. It's best to discuss your current medications with the study team to see if any adjustments are needed.
What data supports the effectiveness of the drug combination Pirtobrutinib and Rituximab for treating lymphoma?
Rituximab, when combined with other treatments, has shown effectiveness in treating various types of lymphoma, including follicular lymphoma, by improving response rates and survival. Additionally, similar combinations like ibrutinib (a drug similar to pirtobrutinib) with rituximab have demonstrated high response rates and tolerability in patients with follicular lymphoma.
14568Eligibility Criteria
This trial is for people newly diagnosed with a type of cancer called Mantle Cell Lymphoma (MCL), specifically those who are considered low or intermediate risk and have not yet been treated. The specific eligibility criteria to join the study were not provided.Inclusion Criteria
My lymphoma is confirmed to be mantle cell type and tests positive for CD20.
My cancer is low risk with a small tumor size and no high-risk features.
I am a woman who cannot become pregnant due to surgery, menopause, or a negative pregnancy test.
My doctor expects me to live more than 12 weeks with my lymphoma.
I am 18 years old or older.
I am over 18 and have just been diagnosed with mantle cell lymphoma without any prior treatment.
I can walk and take care of myself without help.
Exclusion Criteria
I am using steroids for cancer-related pain.
I have severe ongoing health or mental health issues.
I have a history of unusual bleeding.
I have an active CMV infection.
I have a condition that affects how my body absorbs nutrients.
I am HIV positive or have an active hepatitis B/C infection.
I have had a transplant or graft-versus-host disease.
I have not been cancer-free for at least a year from any other cancer.
I have a serious heart condition.
I do not have uncontrolled immune-related blood disorders.
My lymphoma has spread to my brain or I might have a brain infection.
I do not have any uncontrolled health conditions.
I am currently taking specific medications.
I had severe bleeding or heart rhythm problems with a previous BTK inhibitor treatment.
Participant Groups
The study is testing a combination of two drugs, Pirtobrutinib and Rituximab, in patients with MCL. It aims to find out if this chemotherapy-free treatment can control the disease effectively.
2Treatment groups
Experimental Treatment
Group I: Cohort BExperimental Treatment2 Interventions
If participants test positive for MRD at the 24 month time point, participants will be in Cohort B and the participant will continue taking pirtobrutinib.
Group II: Cohort AExperimental Treatment2 Interventions
If participants show that they have no MRD, participants will be in Cohort A and will stop taking pirtobrutinib. Participants will continue to be observed and tested for MRD, and participants will be able to continue receiving the drug if you test positive.
Pirtobrutinib is already approved in United States for the following indications:
🇺🇸 Approved in United States as Jaypirca for:
- Mantle Cell Lymphoma
- Chronic Lymphocytic Leukemia
- Small Lymphocytic Lymphoma
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
MD Anderson Cancer CenterHouston, TX
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Who is running the clinical trial?
M.D. Anderson Cancer CenterLead Sponsor
References
Rituximab: clinical development and future directions. [2019]The availability of effective monoclonal antibodies (mAbs) has revolutionised the management of patients with B-cell malignancies. The most widely studied of these agents is rituximab (Rituxan, IDEC Pharmaceuticals, San Diego, CA), a chimeric anti-CD20 antibody. Using the standard 4-weekly administration schedule, rituximab induces responses in almost half of patients with relapsed follicular/low-grade (F/LG) non-Hodgkin's lymphoma (NHL) with complete remissions in 6%. Lower response rates (RRs) have been noted in chronic lymphocytic leukaemia (CLL) using the standard dose and schedule. The drug has been well tolerated in most patients with common adverse events including mild to moderate fevers and chills and rare occurrences of a serious syndrome related to cytokine release and rapid tumour clearance. This antibody is also active against aggressive NHL, mantle cell NHL, post-transplant lymphoproliferative disorder (PTLD), lymphoplasmacytic NHL and hairy cell leukaemia and is also being evaluated in autoimmune disorders. Combinations of rituximab with chemotherapy regimens such as CHOP (cyclophosphamide, adriamycin, vincristine, predinisone) may alter the therapeutic paradigm for these diseases. The future promise of this antibody is a foundation on which to develop new strategies to increase the cure of patients with lymphoid malignancies.
Rituximab therapy in malignant lymphoma. [2022]Rituximab is the first monoclonal antibody to have been registered for the treatment of B-cell lymphomas. Randomized studies have demonstrated its activity in follicular lymphoma (FL), mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL) in untreated or relapsing patients. Non-comparative studies have shown an activity in all other lymphomas. Because of its high activity and low toxicity ratio, rituximab has transformed the outcome of patients with B-cell lymphoma. A combination of rituximab plus chemotherapy, rituximab+cyclophosphamide+doxorubicin+vincristine+prednisolone (R-CHOP), has the highest efficacy ever described with any chemotherapy in DLBCL and FL. Some patients are refractory to rituximab but the precise mechanisms of this refractoriness are not understood.
Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. [2016]Radioimmunotherapy has been approved for relapsed follicular lymphoma (FL), including rituximab-refractory FL. This study was designed to determine the CR rate with short-course chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) followed by 90-Y ibritumomab tiuxetan (RIT) with extended rituximab as first-line treatment.
Review of the safety and feasibility of rapid infusion of rituximab. [2022]Added to standard chemotherapy, rituximab improved survival in patients with non-Hodgkin's lymphoma; added to fludarabine-based regimens, it improved response and survival in patients with chronic B-cell lymphocytic leukemia.
Biological therapy doublets: pairing rituximab with interferon, lenalidomide, and other biological agents in patients with follicular lymphoma. [2021]Rituximab (R) is a monoclonal antibody with high therapeutic efficacy in low-grade CD20+ lymphoma. The combination of R with chemotherapy is the most common treatment option for patients with follicular lymphoma (FL). The efficacy of R has also been shown to be augmented, when used in combinations with biologicals such as interferon-alpha-2a (IFN), bortezomib, or lenalidomide. The best combination of these drugs are not well defined and a better understanding of pharmacokinetics and timing of drugs relative to the rituximab infusion is crucial. Other new targeted agents, such as inhibitors of BTK and PI3Kdelta, have also been promising in FL. Translational research questions should be added to clinical trial protocols to increase the knowledge on how the tumor microenvironment and the host immune system affect the response to the different drugs and combinations with the aim of a more individualized therapy.
The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma. [2021]This phase 2 study evaluated the activity and safety of ibrutinib, a Bruton's tyrosine kinase inhibitor, plus rituximab in adults with previously untreated follicular lymphoma. Patients received once-daily ibrutinib 560 mg continuously plus once-weekly rituximab 375 mg/m2 for 4 weeks beginning Week 1 (Arm 1, n = 60) or Week 9 (following an 8-week ibrutinib lead-in) to explore biomarkers (Arm 2, n = 20). The primary endpoint was the best overall response rate (ORR). The median age was 58 years; most had an Eastern Cooperative Oncology Group Performance Status of 0 (74%) and Stage III/IV disease (84%). At a median study follow-up of 34 months in Arm 1 and 29 months in Arm 2, ORRs were 85% [95% confidence interval (CI) 73-93] and 75% (95% CI 51-91), respectively, with complete responses in 40% and 50%. The median duration of response was not reached in either arm; 30-month progression-free and overall survival rates were 67% and 97% (Arm 1) and 65% and 100% (Arm 2). The most common adverse events were fatigue, diarrhoea and nausea. Higher grade (Grade 3/4) haematological, haemorrhagic and cardiac events occurred infrequently. Ibrutinib plus rituximab was active and tolerable in first-line follicular lymphoma.
PI3K Inhibitors and Their Role as Novel Agents for Targeted Therapy in Lymphoma. [2021]Phosphatidylinositol 3-kinase (PI3K) inhibitors represent a novel class of agents targeting the key cellular regulatory PI3K/AKT/mTOR pathway involved in crucial functions such as cellular proliferation, cell cycle regulation, protein synthesis, and cell motility. This review starts with an overview of the PI3K pathway and the rationale for its targeting in lymphoma and potential on-target side effects of PI3K inhibition. With three agents now FDA approved for the treatment of relapsed and refractory (R/R) indolent non-Hodgkin lymphoma (iNHL), idelalisib, copanlisib, and duvelisib, we aim to review the pivotal trials leading to their approval as well as their clinical applications according to lymphoma subtypes. Important treatment-related adverse events are also reviewed and a perspective on the clinical role of these agents is provided, as well as some practical guidance on how to prevent, monitor, and manage potential adverse events in the clinic. PI3K inhibitors have an established role in the management of R/R iNHL, but their use and development are hampered by adverse events, particularly when used in combination with other anti-lymphoma therapies. Finally, this review highlights areas in need of more research in order to optimally use these agents in the care of patients with lymphoma.
Life-threatening disseminated enterovirus infection during combined rituximab and ibrutinib maintenance treatment for mantle cell lymphoma: a case report. [2021]Rituximab is a well-established component of treatment regimens for B-cell non-Hodgkin lymphoma. Rituximab binds the CD20 antigen on the surface of B lymphocytes, causing an enhanced clearance of malignant and benign B cells. Thus, rituximab leads to depletion of normal B lymphocytes as well, which can cause substantial immunodeficiency. Ibrutinib inhibits the Bruton tyrosine kinase and thereby B-cell activity. It is used for the treatment of different B-lymphocyte malignancies, such as mantle cell lymphoma. Recently, the combination of both drugs has been tested in various clinical scenarios.
Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors. [2022]Limited information is available regarding the drug-drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown.
Pirtobrutinib: First Approval. [2023]Pirtobrutinib (JaypircaTM), a highly selective, non-covalent, reversible Bruton's tyrosine kinase (BTK) inhibitor, is being developed by Eli Lilly and Company (Lilly) for the treatment of B-cell leukemias and lymphomas. In January 2023, pirtobrutinib was approved in the USA under the Accelerated Approval pathway for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. This article summarizes the milestones in the development of pirtobrutinib leading to this first approval for the treatment of adult patients with relapsed or refractory MCL.
FDA Approval Summary: Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma. [2023]In January 2023, the U.S. Food and Drug Administration granted accelerated approval to pirtobrutinib for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor. Approval was based on BRUIN, a single-arm study of pirtobrutinib monotherapy in patients with B-cell malignancies. Efficacy was based on independent review committee- assessed overall response rate (ORR) supported by durability of response in 120 patients with relapsed or refractory MCL who had received a prior BTK inhibitor and received the approved pirtobrutinib dosage of 200 mg once daily. The ORR was 50% (95% confidence interval [CI]: 41, 59) and the complete response rate was 13% (95% CI: 7, 20), with an estimated median duration of response of 8.3 months. The most common non-hematologic adverse reactions were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Warnings and Precautions in labeling include infection, hemorrhage, cytopenias, atrial arrhythmias, and second primary malignancies. Postmarketing studies were required to evaluate longer-term safety of pirtobrutinib and to verify the clinical benefit of pirtobrutinib. This article summarizes key aspects of the regulatory review, including the indication statement, efficacy and safety considerations, and postmarketing requirements.