Clinical trial NCT03740529: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
Collaborators: name: Eli Lilly and Company
First posted: 2018-11-14
Enrollment: 860
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: Up to 24 Months
measure: Recommended dose for further study
timeFrame: Up to 24 Months
measure: To assess the preliminary anti-tumor activity of pirtobrutinib based on ORR as assessed by an Independent Review Committee (IRC).
timeFrame: Up to 24 months
measure: 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
timeFrame: Up to 24 Months
measure: 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
timeFrame: Up to 24 Months
Secondary outcomes:
measure: 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.
timeFrame: Up to 24 Months
measure: To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
timeFrame: Up to 24 Months
measure: To assess the preliminary anti-tumor activity of pirtobrutinib based on overall response rate (ORR) as assessed by investigator.
timeFrame: Up to 24 Months
measure: ORR as assessed by the Investigator.
timeFrame: Up to 24 Months
measure: Best overall response (BOR) as assessed by the Investigator and IRC.
timeFrame: Up to 24 Months
measure: Duration of response (DOR) as assessed by the Investigator and IRC.
timeFrame: Up to 24 Months
measure: Progression free survival (PFS) as assessed by the Investigator and IRC.
timeFrame: Up to 24 Months
measure: Overall survival (OS).
timeFrame: Up to 24 Months
measure: 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
timeFrame: Up to 24 Months
measure: To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
timeFrame: Up to 24 Months
measure: To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points.
timeFrame: Up to 24 months
measure: To assess the preliminary anti-tumor activity of pirtobrutinib in combination based on overall response rate (ORR) as assessed by investigator.
timeFrame: Up to 24 months
measure: 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
timeFrame: Baseline, End of Treatment (Estimated Up to 24 Months)
measure: 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)
timeFrame: Baseline, End of Treatment (Estimated Up to 24 Months)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic of Scottsdale
state: Arizona
city: San Diego
country: United States
facility: Scripps Coastal Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco, Medical Center at Paranassus
state: California
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale-New Haven
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic-Jacksonville
state: Florida
city: Lake Mary
country: United States
facility: Florida Cancer Specialists ORLANDO/DDU
state: Florida
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Atlanta
country: United States
facility: Emory Clinic
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New Hyde Park
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Durham VA Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Hospital
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute SCRI
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists
state: Utah
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Nedlands
country: Australia
facility: Linear Clinical Research
state: Western Australia
city: Nantes Cedex 1
country: France
facility: Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu
city: Bologna
country: Italy
facility: IRCCS - AOU di Bologna
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Nagoya
country: Japan
facility: Nagoya Medical Center
state: Aichi
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Isehara
country: Japan
facility: Tokai University Hospital- Isehara Campus
state: Kanagawa
city: Nankoku
country: Japan
facility: Kochi Medical School Hospital
state: Kochi
city: Sendai
country: Japan
facility: Tohoku University Hospital
state: Miyagi
city: Chuo Ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Cancer Center
city: Kyoto
country: Japan
facility: Kyoto Furitsu Medical University Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osakasayama-Shi
country: Japan
facility: Kindai University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Krakow
country: Poland
facility: Pratia MCM Krakow
city: Warszawa
country: Poland
facility: Instytut Hermatologii I Transfuzjologii
city: Solna
country: Sweden
facility: Karolinska Institutet
state: AB
city: Bellinzona
country: Switzerland
facility: Ospedale Regionale Bellinzona e Valli
state: Ticino
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
Study officials:
affiliation: Loxo Oncology
name: Donald Tsai, MD, PhD
role: STUDY_DIRECTOR
References:
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.
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.
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.
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.