Pirtobrutinib in Combination With Rituximab in Adults With Untreated Marginal Zone Lymphoma (PIONEER-MZL)

NCT06390956 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: HCI181739
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this clinical trial is to learn if the drugs Pirtobrutinib and Rituximab are effective for the treatment of newly diagnosed marginal zone lymphoma.

Conditions

Marginal Zone Lymphoma

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR) defined as the proportion of subjects achieving a partial response (PR) or complete response (CR) by Lugano Criteria at Cycle 7.

  To assess the ORR in the study population at Cycle 7.

  7 months

Secondary Outcomes (4)

• The proportion of subjects achieving a complete response (CR) by Lugano Criteria at Cycle 7.

  7 months

• Median and two year Progression-free survival (PFS). PFS will be as defined as the time from study drug initiation to the time of documented disease progression (as assessed by Lugano Criteria), or death from any cause.

  7 years

• Duration of response (DoR), defined as the interval of time from the date of initial documented response (PR or better per Lugano Criteria) to the time of progression from the best response, the start of a new therapy, or death from any cause.

  7 years

• Median and two year overall survival (OS). OS is defined as the time from registration until death from any cause.

  7 years

Study Arms (5)

Rituximab+Pirtobrutinib, Pirtobrutinib Alone

EXPERIMENTAL

This arm included participants who had a complete response to Rituximab and Pirtobrutinib in Stage 1. In Stage 1, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage 2, subjects who experience a complete response will discontinue rituximab and continue treatment with pirtobrutinib only for 6 additional cycles. Participants in this arm will not have Stage 3 treatment. After completing Stage II treatment, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits.

Drug: Pirtobrutinib; Drug: Rituximab

Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib, Pirtobrutinib Alone (6 Cycles)

EXPERIMENTAL

This arm included participants who had a Partial Response or Stable Disease response to Rituximab and Pirtobrutinib in Stage 1 and a Complete Response to continued Rituximab and Pirtobrutinib in Stage 2. In Stage 1, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage II, subjects who experienced a Partial Response or Stable Disease will continue Rituximab and Pirtobrutinib treatment for 6 additional cycles. In Stage III, subjects who experienced a Complete Response will discontinue rituximab and continue treatment with Pirtobrutinib only for 6 additional cycles. After completing Stage III treatment, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits.

Drug: Pirtobrutinib; Drug: Rituximab

Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib, Pirtobrutinib Alone (24 Cycles)

EXPERIMENTAL

This arm included participants who had a Partial Response or Stable Disease response to Rituximab and Pirtobrutinib in Stage 1 and a Progressive Disease after continued Rituximab and Pirtobrutinib in Stage 2. In Stage I, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage II, subjects who experience a Partial Response or Stable Disease will continue Rituximab and Pirtobrutinib treatment for 6 additional cycles. In Stage III, subjects who experience Progressive Disease will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits.

Drug: Pirtobrutinib; Drug: Rituximab

Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib

EXPERIMENTAL

This arm included participants who had a Partial Response or Stable Disease response to Rituximab and Pirtobrutinib in Stage 1 and a Partial Response or Stable Disease to continued Rituximab and Pirtobrutinib in Stage 2. In Stage I, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage II, subjects who experience a Partial Response or Stable Disease will continue Rituximab and Pirtobrutinib treatment for 6 additional cycles. In Stage III, subjects who experience a Partial Response or Stable Disease will discontinue rituximab and continue treatment with Pirtobrutinib only until progression or other treatment discontinuation criteria are met. After progression or other treatment discontinuation criteria are met, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits.

Drug: Pirtobrutinib; Drug: Rituximab

Rituximab+Pirtobrutinib Only

EXPERIMENTAL

This arm included participants who had Progressive Disease after Rituximab and Pirtobrutinib treatment in Stage 1. In Stage 1, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). If participants had Progressive Disease after Stage I, they will not have Stage II or Stage III of treatment. After completing Stage I treatment, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits.

Drug: Pirtobrutinib; Drug: Rituximab

Interventions

Pirtobrutinib DRUG

Administered once daily as an oral medication.

Also known as: LOXO-305, LY3527727

Rituximab+Pirtobrutinib Only; Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib; Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib, Pirtobrutinib Alone (24 Cycles); Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib, Pirtobrutinib Alone (6 Cycles); Rituximab+Pirtobrutinib, Pirtobrutinib Alone

Rituximab DRUG

Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV) administration. The product is formulated for intravenous administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for Injection.

Also known as: Rituxan

Rituximab+Pirtobrutinib Only; Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib; Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib, Pirtobrutinib Alone (24 Cycles); Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib, Pirtobrutinib Alone (6 Cycles); Rituximab+Pirtobrutinib, Pirtobrutinib Alone

Eligibility Criteria

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

You may qualify if:

• Subjects aged ≥ 18 years.
• ECOG Performance Status ≤ 2.
• Histologically confirmed marginal zone lymphoma, including splenic, nodal, and extranodal sub-types per the enrolling institution.
• Subjects must have an indication for treatment.
• No prior systemic therapy for MZL except for the following:
• Prior antibiotic therapy for H. pylori, C. psittaci, and B. burgdorferi
• Prior antiviral therapy for HCV
• Note: Subjects are eligible if they had a prior splenectomy or other local surgical treatment or local radiation therapy without systemic therapy and now require their first ever systemic therapy. In the event of the receipt of radiation therapy, the minimum washout period is 14 days
• Subjects with gastric MALT lymphoma must be H. pylori negative or have failed a trial of H. pylori eradication
• Subjects with localized MALT lymphoma must be ineligible for, have refused or failed radiation therapy (washout period of 14 days)
• Adequate organ function as defined as:
• Hematologic:
• Absolute neutrophil count ≥ 750 cells/mm3 (≥ 0.75 x 10\^9/L) independent of G-CSF support, unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case ANC of 500 cells/mm3 (0.5 x 10\^9/L) is permissible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow
• Platelet count ≥ 50,000/mm3 (≥50 x 10\^9/L) independent of transfusion support unless there is documented bone marrow involvement in which case platelet count of ≥30,000 cells/mm3 (≥30 x 10\^9/L) is permissible. Subjects must be responsive to transfusion support if given for thrombocytopenia and subjects refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
• Note: The platelet count threshold in the current study (≥50,000 cells/mm\^3 or ≥50 x 10\^9/L) is lower than normal threshold (≥75,000 cells/mm\^3 or ≥75 x 10\^9/L) as the majority of MZL subjects have lower than normal platelets due to splenomegaly and or autoimmune phenomena (which are related to the underlying lymphoma) and hence the lower than normal platelet count threshold for study entry

You may not qualify if:

• Subjects requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
• Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug.
• History of bleeding diathesis
• Major surgery 4 weeks prior to starting study drug or who have not fully recovered from major surgery.
• The diagnosis of another malignancy which is, in the opinion of the investigator, likely to negatively impact study participation or subject safety.
• Subjects with CNS involvement
• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
• Cardiovascular disorders:
• Grade 3 NYHA functional classification system of heart failure, uncontrolled or symptomatic arrhythmias ---Unstable angina pectoris or acute coronary syndrome within 2 months of first dose.
• History of myocardial infarction within 3 months prior to the first dose of study treatment
• Stroke or intracranial hemorrhage within 6 months prior to the first dose of study treatment.
• QTc prolongation defined as a QTcF \> 470 ms. ----Correction of suspected drug induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
• Correction for underlying bundle branch block (BBB) is allowed. .
• Left ventricular ejection fraction \< 40% within 12 months prior to the first dose of study treatment.

Sponsors & Collaborators

• University of Utah: lead
• Eli Lilly and Company: collaborator

Study Sites (2)

Washington University

St Louis, Missouri, 63130, United States

RECRUITING

Huntsman Cancer Institute at University of Utah

Salt Lake City, Utah, 84112, United States

RECRUITING

MeSH Terms

Conditions

Lymphoma, B-Cell, Marginal Zone

Interventions

pirtobrutinib; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

Rachel Kingsford

CONTACT

801-585-0115; rachel.kingsford@hci.utah.edu

Narendranath Epperla, MD, MS

CONTACT

801-585-0255; naren.epperla@hci.utah.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 17, 2024
• First Posted: April 30, 2024
• Study Start: February 20, 2025
• Primary Completion (Estimated): December 1, 2031
• Study Completion (Estimated): December 1, 2032
• Last Updated: December 4, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)