A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL
Chronic Lymphocytic Leukemia, Waldenstrom Macroglobulinemia, Mantle Cell Lymphoma
About this trial
This is an interventional treatment trial for Chronic Lymphocytic Leukemia focused on measuring Loxo, LOXO-305, BTK, Bruton's tyrosine kinase, CLL, SLL, NHL, Chronic Lymphocytic Leukemia, C481S, C481, Ibrutinib, Acalabrutinib, Zanubrutinib, BGB-3111, GS-4059, ONO-4059, Tirabrutinib, Small Lymphocytic Lymphoma, Mantle Cell Lymphoma, Waldenstrom macroglobulinemia, Non-Hodgkin Lymphoma, BTK Intolerant, C481S Mutation, Marginal zone lymphoma, DLBCL (Diffuse Large B-cell lymphoma), Follicular Lymphoma, PI3KD, Idelalisib, Umbralisib, BCL2, Venetoclax, Rituximab, Primary CNS Lymphoma, Richter's Transformation
Eligibility Criteria
Inclusion Criteria:
- Histologically confirmed CLL/SLL, WM, or NHL intolerant to either ≥ 2 prior standard of care regimens given in combination or sequentially OR have received 1 prior BTK inhibitor-containing regimen when a BTK inhibitor is approved as first line therapy (Phase 1) OR with prior treatment defined by phase 2 cohort (Phase 2 Patients only).
- Adequate hematologic function (Phase 1 and 1b Patients only).
- Responsive to transfusion support if given for thrombocytopenia or anemia (Phase 1 and 1b Patients only).
- Histologically confirmed relapsed/recurrent CLL in whom venetoclax is appropriate standard salvage treatment; no prior venetoclax is permitted (Phase 1b Arm A Patients only).
- Histologically confirmed relapsed/refractory CLL in whom venetoclax + rituximab is appropriate standard salvage treatment; no prior venetoclax is permitted (Phase 1b Arm B Patients only).
- Eastern Cooperative Oncology Group (ECOG) 0-2.
- Adequate hepatic and renal function.
- Ability to receive study drug therapy orally.
- Willingness of men and women of reproductive potential (defined as following menarche and not postmenopausal [and 2 years of non-therapy-induced amenorrhea] or surgically sterile) to observe conventional and effective birth control.
Exclusion Criteria:
- Investigational agent or anticancer therapy within 5 half-lives or 14 days, whichever is shorter, prior to planned start of specified study therapy except antineoplastic and immunosuppressant monoclonal antibody treatment must be discontinued a minimum of 4 weeks prior to the first dose of pirtobrutinib. In addition, no concurrent systemic anticancer therapy is permitted.
- Major surgery within 4 weeks prior to planned start of specified study therapy.
- Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment.
- Pregnancy or lactation.
- Patients requiring therapeutic anticoagulation with warfarin.
- Any unresolved toxicities from prior therapy greater than CTCAE (version 5.0) Grade 2 or greater at the time of starting study treatment except for alopecia.
- History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T-cell (CAR-T) therapy within the past 60 days (180 days before the PK trigger) prior to planned start of specified study therapy.
- Known central nervous system (CNS) involvement by systemic lymphoma. Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible and enrolled to phase 2 Cohort 7 if a compelling clinical rationale is provided by the Investigator and with documented Sponsor approval.
- Active uncontrolled auto-immune cytopenia where new therapy introduced or concomitant therapy escalated within the 4 weeks prior to study enrollment is required to maintain adequate blood counts.
- Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of pirtobrutinib.
- Active uncontrolled systemic bacterial, viral, fungal or parasitic infection.
- Patients who have tested positive for human immunodeficiency virus (HIV) are excluded. For patients with unknown HIV status, HIV testing will be performed at Screening and result should be negative for enrollment.
- Clinically significant active malabsorption syndrome.
- Current treatment with certain strong CYP3A4 inhibitors or inducers and/or strong P-gp inhibitors.
- For patients enrolled to phase 1b Arm A or B: Patients with prior treatment with venetoclax or other BCL-2 inhibitors.
- Prior treatment with pirtobrutinib.
- Active second malignancy unless in remission and with life expectancy > 2 years.
- Known hypersensitivity to any component or excipient of pirtobrutinib.
- For patients enrolled to phase 1b Arm B: Patients with prior significant hypersensitivity, allergy, or anaphylactic reaction to rituximab/biosimilar requiring discontinuation.
- Patients with prior significant hypersensitivity to rituximab requiring discontinuation, prior allergic or anaphylactic reaction to rituximab (Phase 1b Arm B Patients only).
Sites / Locations
- Mayo Clinic of Scottsdale
- Scripps Coastal Medical Center
- University of California San Francisco, Medical Center at Paranassus
- Smilow Cancer Hospital at Yale-New Haven
- Mayo Clinic-Jacksonville
- Florida Cancer Specialists ORLANDO/DDU
- Sylvester Comprehensive Cancer Center
- Florida Cancer Specialists
- Emory Clinic
- Northwestern University
- University of Kansas Medical Center
- Dana-Farber Cancer Institute
- Mayo Clinic
- University of Nebraska Medical Center
- Roswell Park Cancer Institute
- Northwell Health
- Columbia University Medical Center
- Memorial Sloan Kettering Cancer Center
- University of North Carolina at Chapel Hill
- Durham VA Medical Center
- Duke University Medical Center
- Cleveland Clinic Foundation
- Ohio State University Hospital
- University of Pennsylvania Hospital
- Sarah Cannon Research Institute SCRI
- Mary Crowley Cancer Research Center
- University of Texas MD Anderson Cancer Center
- Utah Cancer Specialists
- Swedish Medical Center
- Seattle Cancer Care Alliance
- Medical College of Wisconsin
- Flinders Medical Centre
- Peter MacCallum Cancer Centre
- Linear Clinical Research
- Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu
- IRCCS - AOU di Bologna
- IRCCS Ospedale San Raffaele
- Nagoya Medical Center
- Hokkaido University Hospital
- Tokai University Hospital- Isehara Campus
- Kochi Medical School Hospital
- Tohoku University Hospital
- National Cancer Center Hospital
- National Hospital Organization Kyushu Cancer Center
- Kyoto Furitsu Medical University Hospital
- Okayama University Hospital
- Kindai University Hospital
- Samsung Medical Center
- Seoul National University Hospital
- Pratia MCM Krakow
- Instytut Hermatologii I Transfuzjologii
- Karolinska Institutet
- Ospedale Regionale Bellinzona e Valli
- St James's University Hospital
- Churchill Hospital
- Derriford Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm 9
Arm 10
Arm 11
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Phase I Dose Escalation (Pirtobrutinib Monotherapy)
Phase 2 (Pirtobrutinib Monotherapy) Cohort 3
Phase 2 (Pirtobrutinib Monotherapy) Cohort 1
Phase 2 (Pirtobrutinib Monotherapy) Cohort 4
Phase 2 (Pirtobrutinib Monotherapy) Cohort 2
Phase 2 (Pirtobrutinib Monotherapy) Cohort 5
Phase 2 (Pirtobrutinib Monotherapy) Cohort 6
Phase 2 (Pirtobrutinib Monotherapy) Cohort 7
Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm A
Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm B
Phase 1 Dose Expansion (Pirtobrutinib Monotherapy)
Dose Escalation and determination of MTD; multiple dose levels of pirtobrutinib to be evaluated
CLL/SLL patients with no prior therapy.
Non-blastoid MCL patients treated with a prior BTK-inhibitor containing regimen.
CLL/SLL patients treated with prior therapy, BTK inhibitor naïve.
CLL/SLL patients treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen.
WM patients treated with a prior BTK inhibitor-containing regimen.
MZL patients treated with a prior BTK inhibitor-containing regimen.
Defined as CLL/SLL or NHL not otherwise specified in Cohorts 1 through 6, inclusive of CLL/SLL, Richter's transformation, or low grade NHL with transformation, blastoid MCL, and patients with history of CNS involvement or primary CNS lymphoma. In the event the Sponsor electively closes Cohorts 2-4 prior to completion, patients with CLL/SLL who are ineligible to participate in or unable to access late phase studies of pirtobrutinib may be eligible to enroll in this cohort Diffuse large B-cell lymphoma (DLBCL) is excluded. MCL without prior BTK inhibitor treatment is excluded. Patients enrolling to Cohort 7 must have received one or more prior therapies or have no available approved therapy with demonstrated clinical benefit with the exception of untreated Richter's transformation, which is allowed.
Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax
Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax and rituximab
Patients to receive the recommended Phase 2 dose of pirtobrutinib