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

Primary Purpose

Chronic Lymphocytic Leukemia, Waldenstrom Macroglobulinemia, Mantle Cell Lymphoma

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Pirtobrutinib
Venetoclax
Rituximab
Sponsored by
Loxo Oncology, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

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

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

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)

Arm Description

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

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD)
Phase I
Recommended dose for further study
Phase I
To assess the preliminary anti-tumor activity of pirtobrutinib based on ORR as assessed by an Independent Review Committee (IRC).
Phase II
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
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

Secondary Outcome Measures

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
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
Phase I
To assess the preliminary anti-tumor activity of pirtobrutinib based on overall response rate (ORR) as assessed by investigator.
Phase I
ORR as assessed by the Investigator.
Phase II
Best overall response (BOR) as assessed by the Investigator and IRC.
Phase II
Duration of response (DOR) as assessed by the Investigator and IRC.
Phase II
Progression free survival (PFS) as assessed by the Investigator and IRC.
Phase II
Overall survival (OS).
Phase II
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
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
Phase II
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
For Phase 1b
To assess the preliminary anti-tumor activity of pirtobrutinib in combination based on overall response rate (ORR) as assessed by investigator.
For Phase 1b
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.
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.

Full Information

First Posted
November 6, 2018
Last Updated
March 7, 2023
Sponsor
Loxo Oncology, Inc.
Collaborators
Eli Lilly and Company
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1. Study Identification

Unique Protocol Identification Number
NCT03740529
Brief Title
A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
November 16, 2018 (Actual)
Primary Completion Date
April 2024 (Anticipated)
Study Completion Date
April 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Loxo Oncology, Inc.
Collaborators
Eli Lilly and Company

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia, Waldenstrom Macroglobulinemia, Mantle Cell Lymphoma, Marginal Zone Lymphoma, B-cell Lymphoma, Small Lymphocytic Lymphoma
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
860 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Phase I Dose Escalation (Pirtobrutinib Monotherapy)
Arm Type
Experimental
Arm Description
Dose Escalation and determination of MTD; multiple dose levels of pirtobrutinib to be evaluated
Arm Title
Phase 2 (Pirtobrutinib Monotherapy) Cohort 3
Arm Type
Experimental
Arm Description
CLL/SLL patients with no prior therapy.
Arm Title
Phase 2 (Pirtobrutinib Monotherapy) Cohort 1
Arm Type
Experimental
Arm Description
Non-blastoid MCL patients treated with a prior BTK-inhibitor containing regimen.
Arm Title
Phase 2 (Pirtobrutinib Monotherapy) Cohort 4
Arm Type
Experimental
Arm Description
CLL/SLL patients treated with prior therapy, BTK inhibitor naïve.
Arm Title
Phase 2 (Pirtobrutinib Monotherapy) Cohort 2
Arm Type
Experimental
Arm Description
CLL/SLL patients treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen.
Arm Title
Phase 2 (Pirtobrutinib Monotherapy) Cohort 5
Arm Type
Experimental
Arm Description
WM patients treated with a prior BTK inhibitor-containing regimen.
Arm Title
Phase 2 (Pirtobrutinib Monotherapy) Cohort 6
Arm Type
Experimental
Arm Description
MZL patients treated with a prior BTK inhibitor-containing regimen.
Arm Title
Phase 2 (Pirtobrutinib Monotherapy) Cohort 7
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm A
Arm Type
Experimental
Arm Description
Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax
Arm Title
Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm B
Arm Type
Experimental
Arm Description
Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax and rituximab
Arm Title
Phase 1 Dose Expansion (Pirtobrutinib Monotherapy)
Arm Type
Experimental
Arm Description
Patients to receive the recommended Phase 2 dose of pirtobrutinib
Intervention Type
Drug
Intervention Name(s)
Pirtobrutinib
Other Intervention Name(s)
LOXO-305, LY3527727
Intervention Description
Oral
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
Venclexta, Venclyxto
Intervention Description
Oral
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan, MabThera
Intervention Description
IV
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD)
Description
Phase I
Time Frame
Up to 24 Months
Title
Recommended dose for further study
Description
Phase I
Time Frame
Up to 24 Months
Title
To assess the preliminary anti-tumor activity of pirtobrutinib based on ORR as assessed by an Independent Review Committee (IRC).
Description
Phase II
Time Frame
Up to 24 months
Title
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
Description
For Phase 1b
Time Frame
Up to 24 Months
Title
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
Description
For Phase 1b
Time Frame
Up to 24 Months
Secondary Outcome Measure Information:
Title
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.
Description
Phase I
Time Frame
Up to 24 Months
Title
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
Description
Phase I
Time Frame
Up to 24 Months
Title
To assess the preliminary anti-tumor activity of pirtobrutinib based on overall response rate (ORR) as assessed by investigator.
Description
Phase I
Time Frame
Up to 24 Months
Title
ORR as assessed by the Investigator.
Description
Phase II
Time Frame
Up to 24 Months
Title
Best overall response (BOR) as assessed by the Investigator and IRC.
Description
Phase II
Time Frame
Up to 24 Months
Title
Duration of response (DOR) as assessed by the Investigator and IRC.
Description
Phase II
Time Frame
Up to 24 Months
Title
Progression free survival (PFS) as assessed by the Investigator and IRC.
Description
Phase II
Time Frame
Up to 24 Months
Title
Overall survival (OS).
Description
Phase II
Time Frame
Up to 24 Months
Title
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
Description
Phase II
Time Frame
Up to 24 Months
Title
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
Description
Phase II
Time Frame
Up to 24 Months
Title
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
Description
For Phase 1b
Time Frame
Up to 24 months
Title
To assess the preliminary anti-tumor activity of pirtobrutinib in combination based on overall response rate (ORR) as assessed by investigator.
Description
For Phase 1b
Time Frame
Up to 24 months
Title
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
Description
Individual EORTC symptom scores range from 1 (not at all) to 4 (very much) with higher scores representing more severe symptom severity.
Time Frame
Baseline, End of Treatment (Estimated Up to 24 Months)
Title
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)
Description
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.
Time Frame
Baseline, End of Treatment (Estimated Up to 24 Months)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Donald Tsai, MD, PhD
Organizational Affiliation
Loxo Oncology
Official's Role
Study Director
Facility Information:
Facility Name
Mayo Clinic of Scottsdale
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Facility Name
Scripps Coastal Medical Center
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States
Facility Name
University of California San Francisco, Medical Center at Paranassus
City
San Francisco
State/Province
California
ZIP/Postal Code
94117
Country
United States
Facility Name
Smilow Cancer Hospital at Yale-New Haven
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Facility Name
Mayo Clinic-Jacksonville
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
Florida Cancer Specialists ORLANDO/DDU
City
Lake Mary
State/Province
Florida
ZIP/Postal Code
32746
Country
United States
Facility Name
Sylvester Comprehensive Cancer Center
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Florida Cancer Specialists
City
Sarasota
State/Province
Florida
ZIP/Postal Code
34232
Country
United States
Facility Name
Emory Clinic
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905-0002
Country
United States
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68105
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Northwell Health
City
New Hyde Park
State/Province
New York
ZIP/Postal Code
11042
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Durham VA Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Ohio State University Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
University of Pennsylvania Hospital
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Sarah Cannon Research Institute SCRI
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Mary Crowley Cancer Research Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75230
Country
United States
Facility Name
University of Texas MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Utah Cancer Specialists
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84106
Country
United States
Facility Name
Swedish Medical Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
Facility Name
Seattle Cancer Care Alliance
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195
Country
United States
Facility Name
Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Facility Name
Flinders Medical Centre
City
Bedford Park
State/Province
South Australia
ZIP/Postal Code
5042
Country
Australia
Facility Name
Peter MacCallum Cancer Centre
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3000
Country
Australia
Facility Name
Linear Clinical Research
City
Nedlands
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia
Facility Name
Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu
City
Nantes Cedex 1
ZIP/Postal Code
44093
Country
France
Facility Name
IRCCS - AOU di Bologna
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Facility Name
IRCCS Ospedale San Raffaele
City
Milano
ZIP/Postal Code
20132
Country
Italy
Facility Name
Nagoya Medical Center
City
Nagoya
State/Province
Aichi
ZIP/Postal Code
460-0001
Country
Japan
Facility Name
Hokkaido University Hospital
City
Sapporo
State/Province
Hokkaido
ZIP/Postal Code
060-8648
Country
Japan
Facility Name
Tokai University Hospital- Isehara Campus
City
Isehara
State/Province
Kanagawa
ZIP/Postal Code
259-1193
Country
Japan
Facility Name
Kochi Medical School Hospital
City
Nankoku
State/Province
Kochi
ZIP/Postal Code
783-8505
Country
Japan
Facility Name
Tohoku University Hospital
City
Sendai
State/Province
Miyagi
ZIP/Postal Code
980-8574
Country
Japan
Facility Name
National Cancer Center Hospital
City
Chuo Ku
State/Province
Tokyo
ZIP/Postal Code
104-0045
Country
Japan
Facility Name
National Hospital Organization Kyushu Cancer Center
City
Fukuoka
ZIP/Postal Code
811-1395
Country
Japan
Facility Name
Kyoto Furitsu Medical University Hospital
City
Kyoto
ZIP/Postal Code
602-8566
Country
Japan
Facility Name
Okayama University Hospital
City
Okayama
ZIP/Postal Code
700-8558
Country
Japan
Facility Name
Kindai University Hospital
City
Osakasayama-Shi
ZIP/Postal Code
589-8511
Country
Japan
Facility Name
Samsung Medical Center
City
Seoul
State/Province
Seoul-teukbyeolsi [Seoul]
ZIP/Postal Code
06351
Country
Korea, Republic of
Facility Name
Seoul National University Hospital
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
Facility Name
Pratia MCM Krakow
City
Krakow
ZIP/Postal Code
30-510
Country
Poland
Facility Name
Instytut Hermatologii I Transfuzjologii
City
Warszawa
Country
Poland
Facility Name
Karolinska Institutet
City
Solna
State/Province
AB
ZIP/Postal Code
171 65
Country
Sweden
Facility Name
Ospedale Regionale Bellinzona e Valli
City
Bellinzona
State/Province
Ticino
ZIP/Postal Code
6500
Country
Switzerland
Facility Name
St James's University Hospital
City
Leeds
ZIP/Postal Code
LS9 7TF
Country
United Kingdom
Facility Name
Churchill Hospital
City
Oxford
ZIP/Postal Code
OX3 7LJ
Country
United Kingdom
Facility Name
Derriford Hospital
City
Plymouth
ZIP/Postal Code
Pl6 8DH
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
36164120
Citation
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.
Results Reference
derived
PubMed Identifier
35595730
Citation
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.
Results Reference
derived
PubMed Identifier
34398557
Citation
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.
Results Reference
derived
PubMed Identifier
33676628
Citation
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.
Results Reference
derived

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

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