Fixed Duration Pirtobrutinib and Obinutuzumab in Chronic Lymphocytic Leukemia

A Phase 2 Study of Fixed Duration Therapy With Pirtobrutinib and Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia (POP)

This study will evaluate fixed-duration therapy with pirtobrutinib and obinutuzumab given over 12 cycles (approximately 1 year) as first-line treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL or SLL).

Study Overview

• Status: Recruiting
• Conditions: Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
• Intervention / Treatment: Drug: Pirtobrutinib; Drug: Obinutuzumab

Detailed Description

This is an open-label, multicenter, single-arm phase 2 study of pirtobrutinib with obinutuzumab for participants with CLL or SLL. Eligible participants will receive 6 cycles of pirtobrutinib alone followed by an additional 6 cycles of pirtobrutinib-obinutuzumab combination therapy. All participants will stop treatment after 12 cycles in total (approximately 1 year).

If CLL progresses and requires treatment after 1-year of therapy, participants will receive retreatment with pirtobrutinib only. Participants will be followed for up to a total of 10 years. Up to 60 participants will take part in this study.

The U.S. Food and Drug Administration (FDA) has approved pirtobrutinib for continuous treatment of CLL that has relapsed or become refractory to other treatments. Pirtobrutinib is not approved for the first-line treatment of CLL/SLL nor for fixed-duration therapy. The FDA has approved obinutuzumab for the treatment of CLL.

The research study procedures include screening for eligibility, study treatment visits, electrocardiograms, imaging (e.g. computerized tomography or CT scans), blood tests, saliva tests, bone marrow biopsies, and/or lymph node biopsies (if feasible).

Loxo Oncology at Eli Lilly and Company is supporting this study by providing pirtobrutinib and research funding.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Megan Forsyth; Phone Number: 857-215-1405; Email: megan_forsyth@dfci.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute
      • Principal Investigator: Inhye Ahn, MD
      • Contact: Megan Forsyth; Phone Number: 857-215-1405; Email: megan_forsyth@dfci.harvard.edu
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Beth Israel Deaconess Medical Center
      • Principal Investigator: Jon Arnason, MD
      • Contact: Jon Arnason, MD
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Brigham & Women's Hospital
      • Principal Investigator: Inhye Ahn, MD
      • Contact: Inhye Ahn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Meet 2018 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines for the diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
• Presence of measurable disease (absolute lymphocyte count > 5,000/µL, palpable or measurable lymph nodes ≥1.5cm on imaging, or bone marrow involvement of CLL ≥ 30%).
• No prior systemic therapy for CLL or SLL.
• Currently have an indication for treatment as defined by the following 2018 IWCLL guidelines
• Age ≥ 18 years
• Eastern Cooperative Oncology Group performance status ≤ 2
• Adequate organ and bone marrow function as defined by the study protocol
• Ability to take oral medications.
• Ability to understand and the willingness to sign a written informed consent document.

Key Exclusion Criteria:

• Known or suspected Richter's transformation or known central nervous system involvement.
• History of bleeding disorders
• History of stroke or intracranial hemorrhage within 6 months of starting study therapy.
• Significant cardiovascular disease such as uncontrolled arrhythmia, Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or left ventricular ejection fraction < 40% by any methods in the 12 months prior to study therapy.
• History of other malignancies with life expectancy of < 2 years.
• Receiving any other investigational agents.
• Concurrent systemic immunosuppression < 28 days of study therapy or administration of > 20 mg of prednisone or equivalent daily < 7 days of study therapy.
• Vaccinated with live vaccine within 4 weeks of starting study therapy.
• Major surgery within 4 weeks of starting study therapy.
• Ongoing or recent infection requiring intravenous antimicrobials at time of screening. Prophylactic antibiotics are allowed if there is no evidence of active infection and the antibiotics is not included on the list of the prohibited medications.
• Patients who have tested positive for HIV are excluded due to potential drug-drug interactions between anti-retroviral medications and pirtobrutinib and risk of opportunistic infections with both HIV and irreversible BTK inhibitors. For patients with unknown HIV status, HIV testing will be performed at Screening and result should be negative for enrollment.
• Active human T cell leukemia virus infection or active hepatitis B or C virus infection
• Known active cytomegalovirus infection
• Pregnancy, lactation or plan to breastfeed during the study or within 6 months of the last dose of study treatment.
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug
• Active uncontrolled auto-immune cytopenia.
• Significant co-morbid condition or disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Pirtobrutinib-Obinutuzumab; Eligible participants will receive initial treatment with pirtobrutinib and obinutuzumab for 12 cycles. Participants with progressive chronic lymphocytuc leukemia or small lymphocytic lymphoma during the off-treatment follow-up will receive continuous pirtobrutinib monotherapy.

Drug: Pirtobrutinib; Initial treatment: - Pirtobrutinib 200 mg by mouth (PO) daily from Cycle 1 Day 1 until the end of Cycle 12. Each cycle is 28 days. Re-treatment: -Pirtobrutinib 200 mg PO daily continuously; Drug: Obinutuzumab; Obinutuzumab is given intravenously from Cycle 7 to Cycle 12, for total 6 cycles during initial treatment only. Initial treatment: - Obinutuzumab intravenous (IV) following the standard schedule from Cycle 6 through Cycle 12 (total 6 cycles: 100 mg on Cycle 6 Day 1, 900 mg on Cycle 6 Day 2, 1000 mg on Cycle 6 Day 8 and Cycle 6 Day 15, 1000 mg on Day 1 of Cycle 7 through Cycle 12).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of complete response after initial therapy	Defined by the 2018 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines	1 year since treatment initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	Defined by the 2018 IWCLL guidelines	1 year since treatment initiation
Rate of partial response	Defined by the 2018 IWCLL guidelines	1 year since treatment initiation
Time to next line of therapy	Time from the initiation of study therapy until the next line of therapy (excluding pirtobrutinib re-treatment)	5 years after the last enrollment
Event-free survival	Time from the initiation of study therapy until pre-defined events (progression, death, or start of a new treatment)	5 years after the last enrollment
Progression-free survival	Time from the initiation of study therapy until disease progression or death	5 years after the last enrollment
Overall survival	Time from the initiation of study therapy until death	5 years after the last enrollment
Rate of re-treatment with pirtobrutinib	Rate of re-treatment with pirtobrutinib on study	5 years after the last enrollment

Collaborators and Investigators

• Sponsor: Inhye Ahn
• Collaborators: Loxo Oncology, Inc.
• Investigators: Principal Investigator: Inhye E Ahn, MD, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2024
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: March 20, 2024
• First Submitted That Met QC Criteria: March 26, 2024
• First Posted (Actual): March 27, 2024

Study Record Updates

• Last Update Posted (Actual): May 7, 2024
• Last Update Submitted That Met QC Criteria: May 6, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Obinutuzumab; Chronic Lymphocytic Leukemia; Bruton's tyrosine kinase inhibitor; Small Lymphocytic Lymphoma; Pirtobrutinib; Fixed-duration
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Obinutuzumab; Pirtobrutinib
• Other Study ID Numbers: 24-017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication.
• IPD Sharing Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No