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

NCT ID: NCT03740529

Last Updated: 2025-09-25

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 860 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-15
• Study Completion Date: 2027-09-30

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.

Conditions

Chronic Lymphocytic Leukemia; Waldenstrom Macroglobulinemia; Mantle Cell Lymphoma; Marginal Zone Lymphoma; B-cell Lymphoma; Small Lymphocytic Lymphoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase I Dose Escalation (Pirtobrutinib Monotherapy)

Dose Escalation and determination of MTD; multiple dose levels of pirtobrutinib to be evaluated

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

Oral

Phase 2 (Pirtobrutinib Monotherapy) Cohort 3

CLL/SLL patients with no prior therapy.

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

Oral

Phase 2 (Pirtobrutinib Monotherapy) Cohort 1

Non-blastoid MCL patients treated with a prior BTK-inhibitor containing regimen.

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

Oral

Phase 2 (Pirtobrutinib Monotherapy) Cohort 4

CLL/SLL patients treated with prior therapy, BTK inhibitor naïve.

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

Oral

Phase 2 (Pirtobrutinib Monotherapy) Cohort 2

CLL/SLL patients treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen.

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

Oral

Phase 2 (Pirtobrutinib Monotherapy) Cohort 5

WM patients treated with a prior BTK inhibitor-containing regimen.

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

Oral

Phase 2 (Pirtobrutinib Monotherapy) Cohort 6

MZL patients treated with a prior BTK inhibitor-containing regimen.

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

Oral

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.

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

Oral

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

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

Oral

Venetoclax

Intervention Type: DRUG

Oral

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

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

Oral

Venetoclax

Intervention Type: DRUG

Oral

Rituximab

Intervention Type: DRUG

IV

Phase 1 Dose Expansion (Pirtobrutinib Monotherapy)

Patients to receive the recommended Phase 2 dose of pirtobrutinib

Group Type: EXPERIMENTAL

Pirtobrutinib

Intervention Type: DRUG

Oral

Interventions

Pirtobrutinib

Oral

Intervention Type: DRUG

Venetoclax

Oral

Intervention Type: DRUG

Rituximab

IV

Intervention Type: DRUG

Other Intervention Names

LOXO-305; LY3527727; Venclexta, Venclyxto; Rituxan; MabThera

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eli Lilly and Company

INDUSTRY

Sponsor Role: collaborator

Loxo Oncology, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Donald Tsai, MD, PhD

Role: STUDY_DIRECTOR

Loxo Oncology

Locations

Mayo Clinic of Scottsdale

Scottsdale, Arizona, United States

Scripps Coastal Medical Center

San Diego, California, United States

University of California San Francisco, Medical Center at Paranassus

San Francisco, California, United States

Smilow Cancer Hospital at Yale-New Haven

New Haven, Connecticut, United States

Mayo Clinic-Jacksonville

Jacksonville, Florida, United States

Florida Cancer Specialists ORLANDO/DDU

Lake Mary, Florida, United States

Sylvester Comprehensive Cancer Center

Miami, Florida, United States

Florida Cancer Specialists

Sarasota, Florida, United States

Emory Clinic

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Mayo Clinic

Rochester, Minnesota, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Roswell Park Cancer Institute

Buffalo, New York, 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

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Durham VA Medical Center

Durham, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Ohio State University Hospital

Columbus, Ohio, United States

University of Pennsylvania Hospital

Philadelphia, Pennsylvania, United States

Sarah Cannon Research Institute SCRI

Nashville, Tennessee, United States

Mary Crowley Cancer Research Center

Dallas, Texas, United States

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Utah Cancer Specialists

Salt Lake City, Utah, United States

Swedish Medical Center

Seattle, Washington, United States

Seattle Cancer Care Alliance

Seattle, Washington, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Flinders Medical Centre

Bedford Park, South Australia, Australia

Peter MacCallum Cancer Centre

Melbourne, Victoria, Australia

Linear Clinical Research

Nedlands, Western Australia, Australia

Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu

Nantes, , France

IRCCS - AOU di Bologna

Bologna, , Italy

IRCCS Ospedale San Raffaele

Milan, , Italy

Nagoya Medical Center

Nagoya, Aichi-ken, Japan

Hokkaido University Hospital

Sapporo, Hokkaido, Japan

Tokai University Hospital- Isehara Campus

Isehara, Kanagawa, Japan

Kochi Medical School Hospital

Nankoku, Kochi, Japan

Tohoku University Hospital

Sendai, Miyagi, Japan

National Cancer Center Hospital

Chuo Ku, Tokyo, Japan

National Hospital Organization Kyushu Cancer Center

Fukuoka, , Japan

Kyoto Furitsu Medical University Hospital

Kyoto, , Japan

Okayama University Hospital

Okayama, , Japan

Kindai University Hospital

Osakasayama-Shi, , Japan

Pratia MCM Krakow

Krakow, , Poland

Instytut Hermatologii I Transfuzjologii

Warsaw, , Poland

Samsung Medical Center

Seoul, Seoul-teukbyeolsi [Seoul], South Korea

Seoul National University Hospital

Seoul, , South Korea

Karolinska Institutet

Solna, AB, Sweden

Ospedale Regionale Bellinzona e Valli

Bellinzona, Canton Ticino, Switzerland

St James's University Hospital

Leeds, , United Kingdom

Churchill Hospital

Oxford, , United Kingdom

Derriford Hospital

Plymouth, , United Kingdom

Countries

United States; Australia; France; Italy; Japan; Poland; South Korea; Sweden; Switzerland; United Kingdom

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Other Identifiers

2018-003340-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

J2N-OX-JZNA

Identifier Type: OTHER

Identifier Source: secondary_id

LOXO-BTK-18001 (BRUIN)

Identifier Type: OTHER

Identifier Source: secondary_id

17539

Identifier Type: -

Identifier Source: org_study_id