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

NCT07220187 | Not Yet Recruiting Phase 3 DMC FDA Drug

• 3 other identifiers: S2504NCI-2025-06717U10CA180888
• Study Type: interventional
• Target: 102
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Richter Syndrome; Transformed Chronic Lymphocytic Leukemia to Diffuse Large B-Cell Lymphoma; Transformed Small Lymphocytic Lymphoma to Diffuse Large B-Cell Lymphoma

Outcome Measures

Primary Outcomes (2)

• Progression free survival (PFS)

  Progression free survival: is measured from date of randomization to the first of progression or death from any cause. Participants last known to be alive without progression will be censored at the date of last contact.

  Up to 7 years

• Overall free survival

  Overall free survival: is measured from date of randomization date of death from any cause. Participants last known to be alive will be censored at the date of last contact.

  Up to 7 years

Secondary Outcomes (3)

• Overall Response

  Up to 7 years

• Complete Remission

  Up to 7 years

• Incidence of adverse events

  Up to 7 years

Study Arms (2)

Arm I (pirtobrutinib and R-CHOP)

EXPERIMENTAL

Patients receive pirtobrutinib PO QD on days 1-21 of each cycle, 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. 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 MUGA scan and buccal swab collection during screening, as well as CT scan and/or PET/CT, and blood sample collection throughout the study.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Procedure: Echocardiography Test; Procedure: Multigated Acquisition Scan; Drug: Pirtobrutinib; Procedure: Positron Emission Tomography; Drug: Prednisone; Biological: Rituximab; Biological: Rituximab and Hyaluronidase Human; Other: Survey Administration; Drug: Vincristine

Arm II (R-CHOP)

ACTIVE COMPARATOR

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.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Procedure: Echocardiography Test; Procedure: Multigated Acquisition Scan; Procedure: Positron Emission Tomography; Drug: Prednisone; Biological: Rituximab; Biological: Rituximab and Hyaluronidase Human; Other: Survey Administration; Drug: Vincristine

Interventions

Biospecimen Collection PROCEDURE

Undergo blood and buccal swab sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Computed Tomography PROCEDURE

Undergo CT scan and/or PET/CT scan

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Asta B 518, B 518, B-518, B518, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR 138719, WR- 138719, WR-138719, WR138719

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Doxorubicin Hydrochloride DRUG

Given IV

Also known as: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, FI106, hydroxydaunorubicin, Rubex

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Echocardiography Test PROCEDURE

Undergo echocardiography

Also known as: EC, Echocardiography

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Multigated Acquisition Scan PROCEDURE

Undergo MUGA scan

Also known as: Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, MUGA Scan, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan, Radionuclide Ventriculography, RNV Scan, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Pirtobrutinib DRUG

Given PO

Also known as: 5-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((2S)-1,1,1-trifluoropropan-2-yl)-1h-pyrazole-4-carboxamide, BTK Inhibitor LOXO-305, Jaypirca, LOXO 305, LOXO-305, LOXO305, LY3527727

Arm I (pirtobrutinib and R-CHOP)

Positron Emission Tomography PROCEDURE

Undergo PET/CT scan

Also known as: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, PT

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Prednisone DRUG

Given PO

Also known as: .delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-Prednisone

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Rituximab BIOLOGICAL

Given IV

Also known as: ABP 798, ABP-798, ABP798, BI 695500, BI-695500, BI695500, Blitzima, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT P10, CT-P10, CTP10, GP 2013, GP-2013, GP2013, IDEC 102, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, IDEC102, Ikgdar, Mabtas, MabThera, Monoclonal Antibody IDEC-C2B8, PF 05280586, PF-05280586, PF05280586, Riabni, Ritemvia, Rituxan, Rituximab ABBS, Rituximab ARRX, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar GP2013, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, Rituximab Biosimilar SIBP-02, rituximab biosimilar TQB2303, Rituximab PVVR, Rituximab-abbs, Rituximab-arrx, Rituximab-blit, Rituximab-pvvr, Rituximab-rite, Rituximab-rixa, Rituximab-rixi, Rixathon, Riximyo, RTXM 83, RTXM-83, RTXM83, Ruxience, Truxima

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Rituximab and Hyaluronidase Human BIOLOGICAL

Given SC

Also known as: Rituxan Hycela, Rituximab Plus Hyaluronidase, Rituximab/Hyaluronidase, Rituximab/Hyaluronidase Human

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Survey Administration OTHER

Ancillary studies

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Vincristine DRUG

Given IV

Also known as: LCR, Leurocristine, VCR, Vincrystine

Arm I (pirtobrutinib and R-CHOP); Arm II (R-CHOP)

Eligibility Criteria

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

You may qualify if:

• Participants must have been diagnosed with Richter Transformation (RT) (CLL/small lymphocytic lymphoma \[SLL\] to LBCL)
• Participants must have histologically or cytologically confirmed LBCL
• Participants must have measurable disease determined by PET/CT or hematopathology (by morphology or flow cytometry) assessment within 42 days prior to registration
• Participants must have staging PET/CT imaging performed within 42 days prior to registration
• Participants are allowed prior treatments for CLL/SLL or its complications (autoimmune hemolytic anemia \[AIHA\], immune thrombocytopenic purpura \[ITP\]), with the exception of pirtobrutinib
• Participants must not have prior treatment for Richter transformation except for corticosteroids up to equivalent dose of prednisone 700 mg total for less than 7 days for disease control. Treatment for CLL/SLL with CLL/SLL directed drugs (including BTK inhibitors with the exception of pirtobrutinib) after the Richter transformation diagnosis is allowed for the purpose of disease control. CLL targeted therapies must be stopped within 3 days before initiation of therapy on protocol. Chemotherapy or anti-CD20 monoclonal antibody therapy must be stopped within 2 weeks before initiation of therapy on protocol
• Participants must not have contraindication for receiving anthracycline. Participants must not have received more than a cumulative dose of 100mg/m\^2 in those participants who will receive R-CHOP or not more than 250 mg/m\^2 in those participants who will receive R-mini-CHOP of prior doxorubicin (or equivalent dose of another anthracycline, such as epirubicin) therapy (at any time prior to registration)
• Patients requiring strong CYP3A inducers are not eligible and can only be enrolled if
• an alternative treatment to the strong CYP3A inducer is available for them and
• the last dose of the strong CYP3A inducer is administered at least 7 days before initiation of pirtobrutinib for patients in safety run-in and arm 1
• Participant must be ≥ 18 years old at the time of registration
• Participant must have Eastern Cooperative Oncology Group (ECOG)/Zubrod Performance Status of 0-2
• Participant must have a complete medical history and physical exam within 28 days prior to registration
• Absolute neutrophil count (ANC) ≥ 0.75 x 10\^3/µL or ≥ 0.50 x 10\^3/µL in participants with suspected marrow involvement considered to impair hematopoiesis (within 28 days prior to registration)
• Platelets ≥ 50 x 10\^3/µL or ≥ 30 x 10\^3/µL in participants with suspected marrow involvement considered to impair hematopoiesis (within 28 days prior to registration)

Sponsors & Collaborators

• SWOG Cancer Research Network: lead
• National Cancer Institute (NCI): collaborator

MeSH Terms

Interventions

Specimen Handling; Cyclophosphamide; Doxorubicin; pirtobrutinib; Magnetic Resonance Spectroscopy; Prednisone; deltacortene; prednylidene; Rituximab; CT-P10; Hyaluronoglucosaminidase; Vincristine

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Spectrum Analysis; Chemistry Techniques, Analytical; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Glycoside Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Polysaccharide-Lyases; Carbon-Oxygen Lyases; Lyases; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Study Officials

• Mazyar Shadman

  SWOG Cancer Research Network

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 6, 2025
• First Posted: October 23, 2025
• Study Start: May 2, 2026
• Primary Completion (Estimated): October 1, 2035
• Study Completion (Estimated): October 1, 2036
• Last Updated: October 23, 2025

Record last verified: 2025-10