3004 - A Phase 2 Study of Minimal Residual Disease-Guided, Time-Limited, First-Line Therapy of Chronic Lymphocytic Leukemia with Pirtobrutinib and Venetoclax (MIRACLE)

Background and Significance: The current standard of care for first-line therapy of chronic lymphocytic leukemia (CLL) is continuous therapy with a covalent Bruton’s tyrosine kinase inhibitor (BTKi), with or without an anti-CD20 monoclonal antibody, or fixed-duration therapy with venetoclax plus obinutuzumab. Indefinite therapy with a BTKi comes with long-term toxicities and inevitable development of resistance, while fixed-duration venetoclax-based therapy might be insufficient for a subset of high-risk diseases (e.g., with TP53 deletion or mutation). Combination therapy with a covalent BTKi and venetoclax is being studied in several clinical trials, but the optimal strategy, especially the optimal duration of therapy, remains unclear.

We developed an investigator-initiated study to evaluate time-limited first-line CLL therapy with pirtobrutinib and venetoclax, in which the duration of therapy will be guided by minimal residual disease (MRD) status. Pirtobrutinib is an orally available, highly selective, noncovalent, reversible inhibitor of BTK, which has demonstrated excellent efficacy and safety in CLL and mantle cell lymphoma, including in patients with prior covalent BTKi exposure and BTK C481 mutation, a key mechanism of resistance to covalent BTKi in CLL. The rationale for combining pirtobrutinib and venetoclax include their distinct mechanisms of action, potential synergy, significant single-agent activities, and the potential for achieving undetectable MRD (uMRD) with time-limited therapy. The rationale for MRD-guided therapy include (1) MRD status is prognostic for progression-free survival (PFS) and overall survival (OS) in CLL and achieving uMRD is an important milestone in CLL treatment; and (2) the MRD-guided approach can tailor individualized duration of therapy based on the depth of response and may result in less toxicities and longer remissions.

Study Design and

Methods: This is a single center, open label, phase 2 study. A total of 45 patients will be enrolled at Mayo Clinic (Rochester, MN). The main inclusion criteria include confirmed diagnosis of CLL or small lymphocytic lymphoma (SLL), presence of an indication for treatment according to iwCLL 2018 guidelines, ECOG performance status 0-2, adequate blood counts and hepatorenal function (e.g., CrCl ≥ 40 ml/min). The main exclusion criteria include prior CLL/SLL-directed therapy, Richter transformation, CNS involvement, major comorbidities (e.g., cardiac, pulmonary, infectious), a bleeding disorder, major surgery within 4 weeks, and other active primary malignancy requiring treatment or limiting expected survival to ≤ 2 years.

Eligible patients will receive time-limited combination therapy with pirtobrutinib and venetoclax, and the duration of therapy will be guided by MRD results. Treatment consists of a 3-cycle lead-in with pirtobrutinib alone, followed by 12-24 cycles of pirtobrutinib-venetoclax combination therapy (with standard venetoclax dose ramp-up in Cycle 4). MRD status in peripheral blood (PB) and bone marrow (BM) will be monitored using the ClonoSEQ assay at key timepoints (Fig 1). Patients can discontinue therapy if they achieve uMRD ( < 1/10^4) in both PB and BM after Cycle 15 or Cycle 21. Patients who do not achieve uMRD by Cycle 21 will continue therapy for 6 more cycles and discontinue therapy after Cycle 27, regardless of MRD results (Fig 2). After completion of therapy, PB MRD will be monitored by ClonoSEQ every 6 months for 3 years. Research samples will be collected at key clinical response assessment timepoints for correlative research.

The primary endpoint is the rate of uMRD in both PB and BM after Cycle 15. The secondary endpoints include PB uMRD rate, BM uMRD rate, complete response (CR) rate, objective response rate (ORR), duration of response (DOR), PFS, time to next treatment, OS, and adverse event incidences (measured per NCI-CTCAE version 5.0).

With a one-stage binomial design, a sample size of 41 evaluable patients will have 10% Type I error and 90% power to detect an effective treatment, if the true proportion of patients who achieve uMRD in both PB and BM after Cycle 15 is at least 60% versus the null hypothesis that the true proportion is at most 40%. Four additional patients will be enrolled to account for ineligibility or drop out, for a total sample size of 45.

This study is registered with ClinicalTrial.gov (NCT05677919). The trial is currently open to accrual at Mayo Clinic in Rochester, MN, and we anticipate to complete accrual by early 2024.