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

Chronic Lymphocytic Leukemia Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03740529
• Other study ID #: LOXO-BTK-18001 (BRUIN)
• Secondary ID: 2018-003340-24J2
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: November 16, 2018
• Est. completion date: January 2028

Study information

• Verified date: March 2024
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 860
• Est. completion date: January 2028
• Est. primary completion date: September 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• B-cell Lymphoma
• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, B-Cell, Marginal Zone
• Lymphoma, Mantle-Cell
• Mantle Cell Lymphoma
• Marginal Zone Lymphoma
• Small Lymphocytic Lymphoma
• Waldenstrom Macroglobulinemia

Intervention

Drug:
• Pirtobrutinib
Oral
• Venetoclax
Oral
• Rituximab
IV

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	Linear Clinical Research	Nedlands	Western Australia
France	Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu	Nantes Cedex 1
Italy	IRCCS - AOU di Bologna	Bologna
Italy	IRCCS Ospedale San Raffaele	Milano
Japan	National Cancer Center Hospital	Chuo Ku	Tokyo
Japan	National Hospital Organization Kyushu Cancer Center	Fukuoka
Japan	Tokai University Hospital- Isehara Campus	Isehara	Kanagawa
Japan	Kyoto Furitsu Medical University Hospital	Kyoto
Japan	Nagoya Medical Center	Nagoya	Aichi
Japan	Kochi Medical School Hospital	Nankoku	Kochi
Japan	Okayama University Hospital	Okayama
Japan	Kindai University Hospital	Osakasayama-Shi
Japan	Hokkaido University Hospital	Sapporo	Hokkaido
Japan	Tohoku University Hospital	Sendai	Miyagi
Korea, Republic of	Samsung Medical Center	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Seoul National University Hospital	Seoul
Poland	Pratia MCM Krakow	Krakow
Poland	Instytut Hermatologii I Transfuzjologii	Warszawa
Sweden	Karolinska Institutet	Solna	AB
Switzerland	Ospedale Regionale Bellinzona e Valli	Bellinzona	Ticino
United Kingdom	St James's University Hospital	Leeds
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Derriford Hospital	Plymouth
United States	Emory Clinic	Atlanta	Georgia
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Ohio State University Hospital	Columbus	Ohio
United States	Mary Crowley Cancer Research Center	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	Durham VA Medical Center	Durham	North Carolina
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic-Jacksonville	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Florida Cancer Specialists ORLANDO/DDU	Lake Mary	Florida
United States	Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Sarah Cannon Research Institute SCRI	Nashville	Tennessee
United States	Smilow Cancer Hospital at Yale-New Haven	New Haven	Connecticut
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 Nebraska Medical Center	Omaha	Nebraska
United States	University of Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	Utah Cancer Specialists	Salt Lake City	Utah
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	Florida Cancer Specialists	Sarasota	Florida
United States	Mayo Clinic of Scottsdale	Scottsdale	Arizona
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	Swedish Medical Center	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Loxo Oncology, Inc.	Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Australia,  France,  Italy,  Japan,  Korea, Republic of,  Poland,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose (MTD)	Phase I	Up to 24 Months
Primary	Recommended dose for further study	Phase I	Up to 24 Months
Primary	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
Primary	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
Primary	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	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
Secondary	To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.	Phase I	Up to 24 Months
Secondary	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
Secondary	ORR as assessed by the Investigator.	Phase II	Up to 24 Months
Secondary	Best overall response (BOR) as assessed by the Investigator and IRC.	Phase II	Up to 24 Months
Secondary	Duration of response (DOR) as assessed by the Investigator and IRC.	Phase II	Up to 24 Months
Secondary	Progression free survival (PFS) as assessed by the Investigator and IRC.	Phase II	Up to 24 Months
Secondary	Overall survival (OS).	Phase II	Up to 24 Months
Secondary	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
Secondary	To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.	Phase II	Up to 24 Months
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)