Phase II Study of Combined Pirtobrutinib, Venetoclax and Obinutuzumab (PVO) Time-limited Treatment for Patients With Recurrent Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL).

Phase 2

Not yet recruiting

• Conditions: Chronic Lymphocytic Leukemia; Small Lymphocytic Leukemia (SLL)
• Interventions: Drug: Pirtobrutinib; Drug: Venetoclax; Drug: Obinutuzumab

• Registration Number: NCT06967610
• Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary

To learn if the drug combination pirtobrutinib, venetoclax, and obinutuzumab can help to control relapsed CLL/SLL.

Detailed Description

Primary Objective:

- Rate of bone marrow undetectable Measurable Residual Disease (10-4 sensitivity; uMRD4) at end of Cycle 13.

Secondary Objectives:

* Blood uMRD6 rate at end of cycles 9, 13, 19, 25.

* 2018 iwCLL response rates defined as complete response (CR), CR with incomplete count recovery (CRi), partial response (PR), overall response (OR), stable disease (SD), and progressive disease (PD) at cycle 13.

* Progression-free (PFS) and overall survival (OS); time to blood uMRD6 relapse; safety and tolerability.

Study Timeline

• Status Verified: 2025-05
• Study First Submitted: 2025-05-05
• Study First Submitted QC: 2025-05-05
• Last Update Submitted: 2025-05-05
• Study First Posted: 2025-05-13
• Last Update Posted: 2025-05-13
• Study Start: 2025-10-30
• Primary Completion: 2031-06-01
• Study Completion: 2033-06-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

Not provided

Exclusion Criteria

1. Participants who experienced progression of disease according to 2018 iwCLL criteria while on venetoclax will be excluded.

2. Patient with prior history of Richter's syndrome or current Richter's Syndrome.

3. Participants with known hypersensitivity to any of the excipients of pirtobrutinib, venetoclax,obinutuzumab or to any intended study medications.

4. Known or suspected history of central nervous system (CNS) involvement by CLL/SLL.

5. History of bleeding diathesis.

6. Participants who experienced a major bleeding event on a prior BTK inhibitor.• NOTE: Major bleeding is defined as bleeding having one or more of the following features: life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2 g/dL; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome).

7. History of stroke or intracranial hemorrhage within 6 months of enrollment.

8. Participants requiring therapeutic anticoagulation with warfarin or another vitamin K antagonists.

9. Major surgery within 4 weeks of planned start of study therapy.

10. A significant history of renal, neurologic, psychiatric, endocrine, metabolic or immunologic disorder, that, in the opinion of the Investigator, would adversely affect the participant's participation in this study or interpretation of study outcomes.

11. History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified Tcell (CAR-T) therapy within 60 days of enrollment or presence of any of the following, regardless of prior SCT and/or CAR-T therapy timing:

    • active graft versus host disease (GVHD);
    • cytopenia from incomplete blood cell count recovery post-transplant;
    • need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy;
    • ongoing immunosuppressive therapy (> 20 mg prednisone or equivalent daily).

12. Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts.

13. Participants who experienced grade >3 arrhythmia on prior treatment with BTK inhibitor.

14. Significant cardiovascular disease, defined as any of the following:

    1. Unstable angina or acute coronary syndrome within the past 2 months.
    2. History of myocardial infarction within 6 months prior to planned start of study treatment.
    3. Documented left ventricular ejection fraction (LVEF) by any method of ≤ 45% in the 12 months prior to planned start of study treatment.
    4. ≥ Grade 3 New York Heart Association (NYHA) functional classification system of heart failure.
    5. uncontrolled or symptomatic arrhythmias

15. Prolongation of the QT interval corrected (QTc - see Appendix 3) for heart rate using Fredericia's Formula (QTcF) > 470 msec on an EKG during screening.

    1. QTcF is calculated using Fredericia's Formula (QTcF = QT/(RR^0.33)
    2. Correction of suspected drug-induced QTcF prolongation or prolongation due to electrolyte abnormalities 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 or electrolyte supplementation.
    3. Correction of QTc for underlying bundle branch block (BBB) permissible. Participants with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker

16. Hepatitis B or hepatitis C testing indicating active/ongoing infection based on screening laboratory tests as defined as:

    1. Hepatitis B virus (HBV): Participants with positive hepatitis B surface antigen (HBsAg) are excluded. Participants with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation. Participants who are hepatitis B PCR positive will be excluded.
    2. Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, participant will need to have a negative result for hepatitis C ribonucleic acid (RNA) . Participants who are hepatitis C RNA positive will be excluded.

17. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, parasitic or fungal) or other clinically significant active disease process which in the opinion of the Principal Investigator may pose a risk for patient participation. Screening for chronic conditions is not required.

18. Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. For participants with unknown HIV status, HIV testing will be performed at screening and result must be negative for enrollment.

19. Known active CMV infection. Participants with unknown or negative status are eligible.

20. Vaccination with live vaccine within 28 days prior to enrollment

21. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the oral administered study treatments.

22. Active other malignancy unless in remission and with life expectancy > 2 years. with exception of participants diagnosed with basal cell or squamous cell carcinoma of the skin or carcinoma "in situ" of the cervix or breast who are eligible even if diagnosed within 2 years. If Participants have another malignancy that was treated within the last 2 years, such participants may be enrolled, if the likelihood of requiring systemic therapy for this other malignancy within 2 years is less than 10%, as determined by an expert in that particular malignancy at MD Anderson Cancer Center, and after consultation with the Principal Investigator.

23. Current treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers. A washout period of at least 5 half-lives of these agents following discontinuation before study entry is required (treatment with moderate CYP3A4 inhibitors or inducers is not excluded). Because of their effect on CYP3A4, use of any of the following within 7 days of study therapy start or planned use during study participation is prohibited i. Grapefruit or grapefruit products ii. Seville oranges or products from Seville oranges iii. Star fruit.

24. Current treatment with the following P-gp inhibitors: amiodarone, clarithromycin, cyclosporine, erythromycin, ketoconazole, and verapamil. A washout period of at least 5 half-lives of the inhibitor before study entry is required.

25. Participants that are pregnant or plan to become pregnant during the study or within 1 month of the last dose of study treatment.

25. Participants that are lactating or plan to breastfeed during the study or within 1 week of the last dose of study treatment.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
V-Exposed	Pirtobrutinib	Venetoclax Exposed: Treatment with Pirtobrutinib+Venetoclax+Obinutuzumab Q4W
V-Exposed	Venetoclax	Venetoclax Exposed: Treatment with Pirtobrutinib+Venetoclax+Obinutuzumab Q4W
V-Exposed	Obinutuzumab	Venetoclax Exposed: Treatment with Pirtobrutinib+Venetoclax+Obinutuzumab Q4W
V-Naive	Pirtobrutinib	Venetoclax Naive: Treatment with Pirtobrutinib+Venetoclax+Obinutuzumab Q4W
V-Naive	Venetoclax	Venetoclax Naive: Treatment with Pirtobrutinib+Venetoclax+Obinutuzumab Q4W
V-Naive	Obinutuzumab	Venetoclax Naive: Treatment with Pirtobrutinib+Venetoclax+Obinutuzumab Q4W

Primary Outcome Measures

Name	Time	Method
Safety and adverse events	Through study completion; an average of 1 year.	Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5

Trial Locations

Locations (1)

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States