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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03740529




Registration number
NCT03740529
Ethics application status
Date submitted
6/11/2018
Date registered
14/11/2018
Date last updated
2/10/2024

Titles & IDs
Public title
A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL
Scientific 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)
Secondary ID [1] 0 0
2018-003340-24
Secondary ID [2] 0 0
LOXO-BTK-18001 (BRUIN)
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Lymphocytic Leukemia 0 0
Waldenstrom Macroglobulinemia 0 0
Mantle Cell Lymphoma 0 0
Marginal Zone Lymphoma 0 0
B-cell Lymphoma 0 0
Small Lymphocytic Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - Pirtobrutinib
Treatment: Drugs - Venetoclax
Treatment: Drugs - Rituximab

Experimental: Phase I Dose Escalation (Pirtobrutinib Monotherapy) - Dose Escalation and determination of MTD; multiple dose levels of pirtobrutinib to be evaluated

Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 3 - CLL/SLL patients with no prior therapy.

Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 1 - Non-blastoid MCL patients treated with a prior BTK-inhibitor containing regimen.

Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 4 - CLL/SLL patients treated with prior therapy, BTK inhibitor naïve.

Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 2 - CLL/SLL patients treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen.

Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 5 - WM patients treated with a prior BTK inhibitor-containing regimen.

Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 6 - MZL patients treated with a prior BTK inhibitor-containing regimen.

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.

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

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

Experimental: Phase 1 Dose Expansion (Pirtobrutinib Monotherapy) - Patients to receive the recommended Phase 2 dose of pirtobrutinib


Treatment: Drugs: Pirtobrutinib
Oral

Treatment: Drugs: Venetoclax
Oral

Treatment: Drugs: Rituximab
IV
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Maximum Tolerated Dose (MTD)
Timepoint [1] 0 0
Up to 24 Months
Primary outcome [2] 0 0
Recommended dose for further study
Timepoint [2] 0 0
Up to 24 Months
Primary outcome [3] 0 0
To assess the preliminary anti-tumor activity of pirtobrutinib based on ORR as assessed by an Independent Review Committee (IRC).
Timepoint [3] 0 0
Up to 24 months
Primary outcome [4] 0 0
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
Timepoint [4] 0 0
Up to 24 Months
Primary outcome [5] 0 0
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
Timepoint [5] 0 0
Up to 24 Months
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
Up to 24 Months
Secondary outcome [2] 0 0
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
Timepoint [2] 0 0
Up to 24 Months
Secondary outcome [3] 0 0
To assess the preliminary anti-tumor activity of pirtobrutinib based on overall response rate (ORR) as assessed by investigator.
Timepoint [3] 0 0
Up to 24 Months
Secondary outcome [4] 0 0
ORR as assessed by the Investigator.
Timepoint [4] 0 0
Up to 24 Months
Secondary outcome [5] 0 0
Best overall response (BOR) as assessed by the Investigator and IRC.
Timepoint [5] 0 0
Up to 24 Months
Secondary outcome [6] 0 0
Duration of response (DOR) as assessed by the Investigator and IRC.
Timepoint [6] 0 0
Up to 24 Months
Secondary outcome [7] 0 0
Progression free survival (PFS) as assessed by the Investigator and IRC.
Timepoint [7] 0 0
Up to 24 Months
Secondary outcome [8] 0 0
Overall survival (OS).
Timepoint [8] 0 0
Up to 24 Months
Secondary outcome [9] 0 0
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
Timepoint [9] 0 0
Up to 24 Months
Secondary outcome [10] 0 0
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
Timepoint [10] 0 0
Up to 24 Months
Secondary outcome [11] 0 0
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
Timepoint [11] 0 0
Up to 24 months
Secondary outcome [12] 0 0
To assess the preliminary anti-tumor activity of pirtobrutinib in combination based on overall response rate (ORR) as assessed by investigator.
Timepoint [12] 0 0
Up to 24 months
Secondary outcome [13] 0 0
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
Timepoint [13] 0 0
Baseline, End of Treatment (Estimated Up to 24 Months)
Secondary outcome [14] 0 0
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)
Timepoint [14] 0 0
Baseline, End of Treatment (Estimated Up to 24 Months)

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
16/11/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/01/2028
Actual
Sample size
Target
860
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC,WA
Recruitment hospital [1] 0 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 0 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 0 0
5042 - Bedford Park
Recruitment postcode(s) [2] 0 0
3000 - Melbourne
Recruitment postcode(s) [3] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Connecticut
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Georgia
Country [6] 0 0
United States of America
State/province [6] 0 0
Illinois
Country [7] 0 0
United States of America
State/province [7] 0 0
Kansas
Country [8] 0 0
United States of America
State/province [8] 0 0
Massachusetts
Country [9] 0 0
United States of America
State/province [9] 0 0
Minnesota
Country [10] 0 0
United States of America
State/province [10] 0 0
Nebraska
Country [11] 0 0
United States of America
State/province [11] 0 0
New York
Country [12] 0 0
United States of America
State/province [12] 0 0
North Carolina
Country [13] 0 0
United States of America
State/province [13] 0 0
Ohio
Country [14] 0 0
United States of America
State/province [14] 0 0
Pennsylvania
Country [15] 0 0
United States of America
State/province [15] 0 0
Tennessee
Country [16] 0 0
United States of America
State/province [16] 0 0
Texas
Country [17] 0 0
United States of America
State/province [17] 0 0
Utah
Country [18] 0 0
United States of America
State/province [18] 0 0
Washington
Country [19] 0 0
United States of America
State/province [19] 0 0
Wisconsin
Country [20] 0 0
France
State/province [20] 0 0
Nantes Cedex 1
Country [21] 0 0
Italy
State/province [21] 0 0
Bologna
Country [22] 0 0
Italy
State/province [22] 0 0
Milano
Country [23] 0 0
Japan
State/province [23] 0 0
Aichi
Country [24] 0 0
Japan
State/province [24] 0 0
Hokkaido
Country [25] 0 0
Japan
State/province [25] 0 0
Kanagawa
Country [26] 0 0
Japan
State/province [26] 0 0
Kochi
Country [27] 0 0
Japan
State/province [27] 0 0
Miyagi
Country [28] 0 0
Japan
State/province [28] 0 0
Tokyo
Country [29] 0 0
Japan
State/province [29] 0 0
Fukuoka
Country [30] 0 0
Japan
State/province [30] 0 0
Kyoto
Country [31] 0 0
Japan
State/province [31] 0 0
Okayama
Country [32] 0 0
Japan
State/province [32] 0 0
Osakasayama-Shi
Country [33] 0 0
Korea, Republic of
State/province [33] 0 0
Seoul-teukbyeolsi [Seoul]
Country [34] 0 0
Korea, Republic of
State/province [34] 0 0
Seoul
Country [35] 0 0
Poland
State/province [35] 0 0
Krakow
Country [36] 0 0
Poland
State/province [36] 0 0
Warszawa
Country [37] 0 0
Sweden
State/province [37] 0 0
AB
Country [38] 0 0
Switzerland
State/province [38] 0 0
Ticino
Country [39] 0 0
United Kingdom
State/province [39] 0 0
Leeds
Country [40] 0 0
United Kingdom
State/province [40] 0 0
Oxford
Country [41] 0 0
United Kingdom
State/province [41] 0 0
Plymouth

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Loxo Oncology, Inc.
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Eli Lilly and Company
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Donald Tsai, MD, PhD
Address 0 0
Loxo Oncology
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results not provided in https://clinicaltrials.gov/study/NCT03740529