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Not Yet RecruitingNCT07220187

Adding Pirtobrutinib to the Usual Treatment for People With Newly Diagnosed Richter Transformation, The PIRAMID Trial

A Randomized Phase III Study of Pirtobrutinib Plus R-CHOP vs. R-CHOP for Participants With Previously Untreated Richter Transformation (PIRAMID)

Status
Not Yet Recruiting
Phase
Phase 3
Study type
Interventional
Enrollment
102 (estimated)
Sponsor
SWOG Cancer Research Network · Network
Sex
All
Age
18 Years
Healthy volunteers
Not accepted

Summary

This phase III trial compares the effect of adding pirtobrutinib to the usual treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) to R-CHOP alone for the treatment of Richter transformation, which is when chronic lymphocytic leukemia or small lymphocytic lymphoma turns into large B-cell lymphoma, a more aggressive (faster-growing) form of lymphoma. Pirtobrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill cancer cells. It also blocks a certain enzyme needed for cell division and DNA repair. Vincristine is in a class of medications called vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill them. Prednisone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Adding pirtobrutinib to R-CHOP may kill more cancer cells than R-CHOP alone in patients with Richter transformation.

Detailed description

PRIMARY OBJECTIVES: I. In participants aged 74 and younger, to evaluate the safety of the addition of pirtobrutinib to R-CHOP before initiating randomization in participants with untreated Richter Transformation to large B-cell lymphoma (LBCL). (Safety run-in) II. In participants aged 75 and older, to evaluate the safety of the addition of pirtobrutinib to R-mini-CHOP before initiating randomization in this patient population. (Safety run-in) III. To evaluate whether the addition of pirtobrutinib to R-CHOP improves investigator-assessed progression-free survival (PFS) compared to R-CHOP alone in this patient population. (Randomized comparison) IV. If investigator-assessed PFS is improved with the addition of pirtobrutinib, then to evaluate whether the addition of pirtobrutinib improves overall survival (OS) in this patient population. (Randomized comparison-hierarchical testing) TRANSLATIONAL MEDICINE PRIMARY OBJECTIVE: I. To evaluate the association between high-risk Richter-associated mutations (presence vs. absence of at least one of: TP53, CDK2NA, or MYC pathway alterations as assessed by targeted next generation sequencing (NGS) panel and whole exome sequencing of baseline tumor tissue) and overall survival (OS) within treatment arms in this patient population. SECONDARY OBJECTIVES: I. To estimate and compare the rate of investigator-assessed complete response (CR) after treatment between the randomized arms. II. To estimate the frequency and severity of adverse events in both arms. TRANSLATIONAL MEDICINE SECONDARY OBJECTIVES: I. To evaluate the association between high-risk Richter-associated mutations and overall response rate (ORR \[complete and partial response\], PFS and complete response \[CR\]) across treatment arms in this patient population. II. To descriptively report the interaction between high-risk Richter-associated mutations and randomized arm and the outcomes CR, ORR, PFS, and OS. III. To descriptively report the mutational landscape (as assessed by targeted NGS panel and whole exome sequencing of baseline tumor tissue and at the time of progression) in this patient population. IV. In mutations present in at least 5 patients, to descriptively report CR, ORR, PFS, and OS by mutation status across treatment arms. V. To evaluate associations between minimal residual disease (MRD) status (as assessed by circulating tumor deoxyribonucleic acid \[ctDNA\]) and OS and PFS. VI. To evaluate associations between clonal relatedness and OS and PFS across treatment arms. ADDITIONAL OBJECTIVES: I. To compare OS of participants receiving stem cell transplant versus those who did not receive transplant. II. To compare the OS of participants receiving chimeric antigen receptor t cell (CAR-T) therapy versus those who did not receive CAR-T therapy. III. To evaluate the association between Bruton Tyrosine Kinase (BTK) resistance mutations on clinical outcomes (PFS and OS). IV. To evaluate the association of clonal relatedness between chronic lymphocytic leukemia (CLL) and LBCL and clinical outcomes (PFS and OS). PATIENT-REPORTED OUTCOMES OBJECTIVE: I. To compare participant-reported symptoms (PROs) between arms as measured by PRO-Common Terminology Criteria for Adverse Events (CTCAE) items and the Functional Assessment of Chronic Illness Therapy (FACIT) single-item GP5 question. BANKING OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive pirtobrutinib orally (PO) once daily (QD) on days 1-21 of each cycle, rituximab intravenously (IV) or rituximab and hyaluronidase human (rituximab hyaluronidase) subcutaneously (SC) (starting with cycle 2), cyclophosphamide IV on day 1 of each cycle, doxorubicin IV on day 1 of each cycle, vincristine IV on day 1 of each cycle, and prednisone PO QD on days 1-5 of each cycle. Cycles repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 6, patients continue to receive pirtobrutinib PO QD on days 1-21 of each cycle for up to 5 years in the absence of disease progression or unacceptable toxicity. Patients with progressive disease or symptomatic deterioration may receive 1 additional cycle as long as the participant is continuing to clinically benefit from treatment in the opinion of the treating investigator. Patients undergo echocardiography or multigated acquisition (MUGA) scan and buccal swab collection during screening, as well as computed tomography (CT) scan and/or positron emission tomography (PET)/CT, and blood sample collection throughout the study. ARM 2: Patients receive rituximab IV or rituximab hyaluronidase SC (starting with cycle 2), cyclophosphamide IV on day 1 of each cycle, doxorubicin IV on day 1 of each cycle, vincristine IV on day 1 of each cycle, and prednisone PO QD on days 1-5 of each cycle. Cycles repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or MUGA scan and buccal swab collection during screening, as well as CT scan and/or PET, and blood sample collection throughout the study. After completion of study treatment, patients are followed up periodically for until 7 years after registration.

Conditions

Interventions

TypeNameDescription
PROCEDUREBiospecimen CollectionUndergo blood and buccal swab sample collection
PROCEDUREComputed TomographyUndergo CT scan and/or PET/CT scan
DRUGCyclophosphamideGiven IV
DRUGDoxorubicin HydrochlorideGiven IV
PROCEDUREEchocardiography TestUndergo echocardiography
PROCEDUREMultigated Acquisition ScanUndergo MUGA scan
DRUGPirtobrutinibGiven PO
PROCEDUREPositron Emission TomographyUndergo PET/CT scan
DRUGPrednisoneGiven PO
BIOLOGICALRituximabGiven IV
BIOLOGICALRituximab and Hyaluronidase HumanGiven SC
OTHERSurvey AdministrationAncillary studies
DRUGVincristineGiven IV

Timeline

Start date
2026-05-02
Primary completion
2035-10-01
Completion
2036-10-01
First posted
2025-10-23
Last updated
2025-10-23

Regulatory

Source: ClinicalTrials.gov record NCT07220187. Inclusion in this directory is not an endorsement.