A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL

A Phase 1/2 Study of Oral LOXO-305 in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Non-Hodgkin Lymphoma (NHL)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: B-cell Lymphoma; Waldenstrom Macroglobulinemia; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
• Intervention / Treatment: Drug: Rituximab; Drug: Pirtobrutinib; Drug: Venetoclax

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.

• Study Type: Interventional
• Enrollment (Estimated): 860
• Phase: Phase 2; Phase 1

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

• Study Contact: Name: Patient Advocacy; Phone Number: 1-855-569-6305; Email: clinicaltrials@loxooncology.com

Study Locations

• Australia
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Linear Clinical Research
• France
  • Nantes Cedex 1, France, 44093
    • Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu
• Italy
  • Bologna, Italy, 40138
    • IRCCS - AOU di Bologna
  • Milano, Italy, 20132
    • IRCCS Ospedale San Raffaele
• Japan
  • Fukuoka, Japan, 811-1395
    • National Hospital Organization Kyushu Cancer Center
  • Kyoto, Japan, 602-8566
    • Kyoto Furitsu Medical University Hospital
  • Okayama, Japan, 700-8558
    • Okayama University Hospital
  • Osakasayama-Shi, Japan, 589-8511
    • Kindai University Hospital
  • Aichi
    • Nagoya, Aichi, Japan, 460-0001
      • Nagoya Medical Center
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8648
      • Hokkaido University Hospital
  • Kanagawa
    • Isehara, Kanagawa, Japan, 259-1193
      • Tokai University Hospital- Isehara Campus
  • Kochi
    • Nankoku, Kochi, Japan, 783-8505
      • Kochi Medical School Hospital
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
      • Tohoku University Hospital
  • Tokyo
    • Chuo Ku, Tokyo, Japan, 104-0045
      • National Cancer Center Hospital
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul-teukbyeolsi [Seoul]
    • Seoul, Seoul-teukbyeolsi [Seoul], Korea, Republic of, 06351
      • Samsung Medical Center
• Poland
  • Krakow, Poland, 30-510
    • Pratia McM Kraków
  • Warszawa, Poland
    • Instytut Hermatologii I Transfuzjologii
• Sweden
  • AB
    • Solna, AB, Sweden, 171 65
      • Karolinska Institutet
• Switzerland
  • Ticino
    • Bellinzona, Ticino, Switzerland, 6500
      • Ospedale Regionale Bellinzona e Valli
• United Kingdom
  • Leeds, United Kingdom, LS9 7TF
    • St James's University Hospital
  • Oxford, United Kingdom, OX3 7LJ
    • Churchill Hospital
  • Plymouth, United Kingdom, PL6 8DH
    • Derriford Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic of Scottsdale
  • California
    • San Diego, California, United States, 92103
      • Scripps Coastal Medical Center
    • San Francisco, California, United States, 94117
      • University of California San Francisco, Medical Center at Paranassus
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Smilow Cancer Hospital at Yale-New Haven
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic-Jacksonville
    • Lake Mary, Florida, United States, 32746
      • Florida Cancer Specialists ORLANDO/DDU
    • Miami, Florida, United States, 33136
      • Sylvester Comprehensive Cancer Center
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Clinic
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905-0002
      • Mayo Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68105
      • University of Nebraska Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New Hyde Park, New York, United States, 11042
      • Northwell Health
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Durham, North Carolina, United States, 27705
      • Durham VA Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • Ohio State University Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute SCRI
  • Texas
    • Dallas, Texas, United States, 75230
      • Mary Crowley Cancer Research Center
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Medical Center
    • Seattle, Washington, United States, 98195
      • Seattle Cancer Care Alliance
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I Dose Escalation (Pirtobrutinib Monotherapy); Dose Escalation and determination of MTD; multiple dose levels of pirtobrutinib to be evaluated	Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 3; CLL/SLL patients with no prior therapy.	Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 1; Non-blastoid MCL patients treated with a prior BTK-inhibitor containing regimen.	Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 4; CLL/SLL patients treated with prior therapy, BTK inhibitor naïve.	Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 2; CLL/SLL patients treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen.	Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 5; WM patients treated with a prior BTK inhibitor-containing regimen.	Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 6; MZL patients treated with a prior BTK inhibitor-containing regimen.	Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 7; 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.	Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727
Experimental: Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm A; Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax	Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727; Drug: Venetoclax; Oral; Other Names: Venclexta, Venclyxto
Experimental: Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm B; Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax and rituximab	Drug: Rituximab; IV; Other Names: Rituxan; MabThera; Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727; Drug: Venetoclax; Oral; Other Names: Venclexta, Venclyxto
Experimental: Phase 1 Dose Expansion (Pirtobrutinib Monotherapy); Patients to receive the recommended Phase 2 dose of pirtobrutinib	Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD)	Phase I	Up to 24 Months
Recommended dose for further study	Phase I	Up to 24 Months
To assess the preliminary anti-tumor activity of pirtobrutinib based on ORR as assessed by an Independent Review Committee (IRC).	Phase II	Up to 24 months
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	For Phase 1b	Up to 24 Months
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	For Phase 1b	Up to 24 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Phase I	Up to 24 Months
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.	Phase I	Up to 24 Months
To assess the preliminary anti-tumor activity of pirtobrutinib based on overall response rate (ORR) as assessed by investigator.	Phase I	Up to 24 Months
ORR as assessed by the Investigator.	Phase II	Up to 24 Months
Best overall response (BOR) as assessed by the Investigator and IRC.	Phase II	Up to 24 Months
Duration of response (DOR) as assessed by the Investigator and IRC.	Phase II	Up to 24 Months
Progression free survival (PFS) as assessed by the Investigator and IRC.	Phase II	Up to 24 Months
Overall survival (OS).	Phase II	Up to 24 Months
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	Phase II	Up to 24 Months
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.	Phase II	Up to 24 Months
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.	For Phase 1b	Up to 24 months
To assess the preliminary anti-tumor activity of pirtobrutinib in combination based on overall response rate (ORR) as assessed by investigator.	For Phase 1b	Up to 24 months
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	Individual EORTC symptom scores range from 1 (not at all) to 4 (very much) with higher scores representing more severe symptom severity.	Baseline, End of Treatment (Estimated Up to 24 Months)
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)	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.	Baseline, End of Treatment (Estimated Up to 24 Months)

Collaborators and Investigators

• Sponsor: Loxo Oncology, Inc.
• Collaborators: Eli Lilly and Company
• Investigators: Study Director: Donald Tsai, MD, PhD, Loxo Oncology

Publications and helpful links

General Publications

• Kipps TJ. Mining the Microenvironment for Therapeutic Targets in Chronic Lymphocytic Leukemia. Cancer J. 2021 Jul-Aug 01;27(4):306-313. doi: 10.1097/PPO.0000000000000536.
• Cohen JB, Shah NN, Alencar AJ, Gerson JN, Patel MR, Fakhri B, Jurczak W, Tan XN, Lewis KL, Fenske T, Coombs CC, Flinn IW, Lewis DJ, Gouill SL, Palomba ML, Woyach JA, Pagel JM, Lamanna N, Barve MA, Ghia P, Eyre TA, Zinzani PL, Ujjani CS, Koh Y, Izutsu K, Lech-Maranda E, Tam CS, Sundaram S, Yin M, Nair B, Tsai DE, Balbas M, Mato AR, Cheah CY, Wang ML. MCL-133 Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results From the Phase 1/2 BRUIN Study. Clin Lymphoma Myeloma Leuk. 2022 Oct;22 Suppl 2:S394-S395. doi: 10.1016/S2152-2650(22)01569-5.
• Aslan B, Kismali G, Iles LR, Manyam GC, Ayres ML, Chen LS, Gagea M, Bertilaccio MTS, Wierda WG, Gandhi V. Pirtobrutinib inhibits wild-type and mutant Bruton's tyrosine kinase-mediated signaling in chronic lymphocytic leukemia. Blood Cancer J. 2022 May 20;12(5):80. doi: 10.1038/s41408-022-00675-9.
• Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, Fakhri B, Eyre TA, Lamanna N, Patel MR, Alencar A, Lech-Maranda E, Wierda WG, Coombs CC, Gerson JN, Ghia P, Le Gouill S, Lewis DJ, Sundaram S, Cohen JB, Flinn IW, Tam CS, Barve MA, Kuss B, Taylor J, Abdel-Wahab O, Schuster SJ, Palomba ML, Lewis KL, Roeker LE, Davids MS, Tan XN, Fenske TS, Wallin J, Tsai DE, Ku NC, Zhu E, Chen J, Yin M, Nair B, Ebata K, Marella N, Brown JR, Wang M. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021 Mar 6;397(10277):892-901. doi: 10.1016/S0140-6736(21)00224-5.

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2018
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: November 6, 2018
• First Submitted That Met QC Criteria: November 12, 2018
• First Posted (Actual): November 14, 2018

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Rituximab; NHL; Follicular Lymphoma; Ibrutinib; Venetoclax; CLL; Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Waldenstrom macroglobulinemia; Mantle Cell Lymphoma; SLL; BTK; C481S; BCL2; Acalabrutinib; Zanubrutinib; LOXO-305; Marginal zone lymphoma; Small Lymphocytic Lymphoma; BGB-3111; Loxo; Primary CNS Lymphoma; Bruton's tyrosine kinase; Richter's Transformation; C481; GS-4059; ONO-4059; Tirabrutinib; BTK Intolerant; C481S Mutation; DLBCL (Diffuse Large B-cell lymphoma); PI3KD; Idelalisib; Umbralisib
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Disease Attributes; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia, B-Cell; Chronic Disease; Lymphoma; Lymphoma, B-Cell; Leukemia; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Venetoclax; Rituximab; Pirtobrutinib
• Other Study ID Numbers: LOXO-BTK-18001 (BRUIN); 2018-003340-24 (EudraCT Number); J2N-OX-JZNA (Other Identifier: Eli Lilly and Company)

Drug and device information, study documents

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