A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL
- Conditions
- Waldenstrom MacroglobulinemiaMantle Cell LymphomaSmall Lymphocytic LymphomaChronic Lymphocytic LeukemiaB-cell LymphomaMarginal Zone Lymphoma
- Interventions
- Registration Number
- NCT03740529
- Lead Sponsor
- Loxo Oncology, Inc.
- Brief Summary
This is an open-label, multi-center Phase 1/2 study of oral LOXO-305 (pirtobrutinib) in patients with CLL/SLL and NHL who have failed or are intolerant to standard of care.
- Detailed Description
This study includes 3 parts: Phase 1 (pirtobrutinib monotherapy dose escalation and dose expansion), Phase 1b (pirtobrutinib combination therapy dose expansion), and Phase 2 (pirtobrutinib monotherapy dose expansion). In Phase 1, patients will be enrolled using an accelerated titration design. The starting dose of pirtobrutinib in oral tablet form is 25 mg/day (e.g., 25 mg once daily \[QD\]). Once the MTD and/or RP2D is identified in Phase 1 dose escalation, enrollment will continue to Phase 1 dose expansion and can commence to Phase 1b (Arms A and B). For Phase 2, patients will be enrolled to one of seven Phase 2 dose expansion cohorts depending on tumor histology and prior treatment history. Cycle length will be 28 days.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 860
- 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.
- 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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 2 (Pirtobrutinib Monotherapy) Cohort 2 Pirtobrutinib CLL/SLL patients treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen. Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm B Pirtobrutinib Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax and rituximab Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm A Pirtobrutinib Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax Phase 1 Dose Expansion (Pirtobrutinib Monotherapy) Pirtobrutinib Patients to receive the recommended Phase 2 dose of pirtobrutinib Phase 2 (Pirtobrutinib Monotherapy) Cohort 3 Pirtobrutinib CLL/SLL patients with no prior therapy. Phase I Dose Escalation (Pirtobrutinib Monotherapy) Pirtobrutinib Dose Escalation and determination of MTD; multiple dose levels of pirtobrutinib to be evaluated Phase 2 (Pirtobrutinib Monotherapy) Cohort 1 Pirtobrutinib Non-blastoid MCL patients treated with a prior BTK-inhibitor containing regimen. Phase 2 (Pirtobrutinib Monotherapy) Cohort 4 Pirtobrutinib CLL/SLL patients treated with prior therapy, BTK inhibitor naïve. Phase 2 (Pirtobrutinib Monotherapy) Cohort 6 Pirtobrutinib MZL patients treated with a prior BTK inhibitor-containing regimen. Phase 2 (Pirtobrutinib Monotherapy) Cohort 5 Pirtobrutinib WM patients treated with a prior BTK inhibitor-containing regimen. Phase 2 (Pirtobrutinib Monotherapy) Cohort 7 Pirtobrutinib 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. Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm A Venetoclax Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm B Venetoclax Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax and rituximab Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm B Rituximab Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax and rituximab
- Primary Outcome Measures
Name Time Method To assess the preliminary anti-tumor activity of pirtobrutinib based on ORR as assessed by an Independent Review Committee (IRC). Up to 24 months Phase II
Maximum Tolerated Dose (MTD) Up to 24 Months Phase I
Recommended dose for further study Up to 24 Months Phase I
To evaluate the safety of pirtobrutinib in combination with venetoclax and rituximab (Arm B) by assessing incidence and severity of treatment-emergent adverse events as determined by CTCAE v5.0 Up to 24 Months For Phase 1b
To evaluate the safety of pirtobrutinib in combination with venetoclax (Arm A) by assessing incidence and severity of treatment-emergent adverse events as determined by CTCAE v5.0 Up to 24 Months For Phase 1b
- Secondary Outcome Measures
Name Time Method Overall survival (OS). Up to 24 Months Phase II
Functional Response: Change from Baseline in Physical Functioning as Measured by Physical Functioning Scale from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ) Baseline, End of Treatment (Estimated Up to 24 Months) EORTC physical function item scores range from 1 (not at all) to 4 (very much) with higher scores indicating poorer functioning.The total EORTC physical functioning score ranges from 0-100 where a higher score indicates higher/healthier level of functioning.
To determine the safety profile and tolerability of pirtobrutinib including acute and chronic toxicities by collecting and evaluating Adverse events and treatment emergent adverse events. Up to 24 Months Phase I
To assess the preliminary anti-tumor activity of pirtobrutinib based on overall response rate (ORR) as assessed by investigator. Up to 24 Months Phase I
ORR as assessed by the Investigator. Up to 24 Months Phase II
Progression free survival (PFS) as assessed by the Investigator and IRC. Up to 24 Months Phase II
Duration of response (DOR) as assessed by the Investigator and IRC. Up to 24 Months Phase II
To assess the preliminary anti-tumor activity of pirtobrutinib in combination based on overall response rate (ORR) as assessed by investigator. Up to 24 months For Phase 1b
To determine the safety profile and tolerability of pirtobrutinib including acute and chronic toxicities by collecting and evaluating Adverse events and treatment emergent adverse events Up to 24 Months Phase II
Symptomatic Response: Change from Baseline in Mantle Cell Lymphoma (MCL)-related symptoms selected from the European Organisation for Research and Treatment of Cancer (EORTC) Item Library Baseline, End of Treatment (Estimated Up to 24 Months) Individual EORTC symptom scores range from 1 (not at all) to 4 (very much) with higher scores representing more severe symptom severity.
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points. Up to 24 months For Phase 1b
Best overall response (BOR) as assessed by the Investigator and IRC. Up to 24 Months Phase II
Trial Locations
- Locations (56)
University of Pennsylvania Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Ohio State University Hospital
🇺🇸Columbus, Ohio, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Swedish Medical Center
🇺🇸Seattle, Washington, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Tokai University Hospital- Isehara Campus
🇯🇵Isehara, Kanagawa, Japan
Kyoto Furitsu Medical University Hospital
🇯🇵Kyoto, Japan
Kindai University Hospital
🇯🇵Osakasayama-Shi, Japan
Hokkaido University Hospital
🇯🇵Sapporo, Hokkaido, Japan
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Scripps Coastal Medical Center
🇺🇸San Diego, California, United States
Durham VA Medical Center
🇺🇸Durham, North Carolina, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Sarah Cannon Research Institute SCRI
🇺🇸Nashville, Tennessee, United States
Mayo Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
Florida Cancer Specialists ORLANDO/DDU
🇺🇸Lake Mary, Florida, United States
University of California San Francisco, Medical Center at Paranassus
🇺🇸San Francisco, California, United States
Emory Clinic
🇺🇸Atlanta, Georgia, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Northwell Health
🇺🇸New Hyde Park, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Instytut Hermatologii I Transfuzjologii
🇵🇱Warszawa, Poland
Mary Crowley Cancer Research Center
🇺🇸Dallas, Texas, United States
Flinders Medical Centre
🇦🇺Bedford Park, South Australia, Australia
Utah Cancer Specialists
🇺🇸Salt Lake City, Utah, United States
Linear Clinical Research
🇦🇺Nedlands, Western Australia, Australia
IRCCS - AOU di Bologna
🇮🇹Bologna, Italy
Nagoya Medical Center
🇯🇵Nagoya, Aichi, Japan
IRCCS Ospedale San Raffaele
🇮🇹Milano, Italy
Tohoku University Hospital
🇯🇵Sendai, Miyagi, Japan
Kochi Medical School Hospital
🇯🇵Nankoku, Kochi, Japan
National Hospital Organization Kyushu Cancer Center
🇯🇵Fukuoka, Japan
National Cancer Center Hospital
🇯🇵Chuo Ku, Tokyo, Japan
Okayama University Hospital
🇯🇵Okayama, Japan
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Pratia MCM Krakow
🇵🇱Krakow, Poland
Karolinska Institutet
🇸🇪Solna, AB, Sweden
Ospedale Regionale Bellinzona e Valli
🇨🇭Bellinzona, Ticino, Switzerland
St James's University Hospital
🇬🇧Leeds, United Kingdom
Churchill Hospital
🇬🇧Oxford, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Mayo Clinic of Scottsdale
🇺🇸Scottsdale, Arizona, United States
Florida Cancer Specialists
🇺🇸Sarasota, Florida, United States
Sylvester Comprehensive Cancer Center
🇺🇸Miami, Florida, United States
Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu
🇫🇷Nantes Cedex 1, France
Samsung Medical Center
🇰🇷Seoul, Seoul-teukbyeolsi [Seoul], Korea, Republic of
Smilow Cancer Hospital at Yale-New Haven
🇺🇸New Haven, Connecticut, United States
University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States