Study of Oral LOXO-338 in Patients With Advanced Blood Cancers
- Conditions
- Multiple MyelomaWaldenstrom MacroglobulinemiaLeukemia, Lymphocytic, Chronic, B-CellLymphoma, Non-HodgkinLymphoma, Mantle-CellLymphoma, B-cell Marginal ZoneB-cell Lymphoma
- Interventions
- Registration Number
- NCT05024045
- Lead Sponsor
- Eli Lilly and Company
- Brief Summary
The purpose of this study is to find out whether the study drug, LOXO-338, is safe and effective in patients with advanced blood cancer. Patients must have already received standard therapy. The study may last up to approximately 3 years.
- Detailed Description
This study will be conducted in 2 parts. Part 1 will evaluate LOXO-338 as monotherapy. If safety and initial evidence of efficacy of LOXO-338 monotherapy are confirmed, part 2 will evaluate the combination of LOXO-338 with the highly selective, noncovalent Bruton's tyrosine kinase (BTK) inhibitor, pirtobrutinib (LOXO-305).
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 316
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B-cell malignancy.
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Patients must have received prior therapy.
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Patients must have an objective indication for therapy.
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Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1.
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Anticipated life expectancy of greater than or equal to (≥) 12 weeks.
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Adequate bone marrow function.
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Adequate hepatic function.
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Creatinine clearance of ≥ 60 milliliters (mL)/minute.
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Ability to swallow tablets.
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Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
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Prior treatment-related adverse events (AEs) must have recovered to grade less than or equal to (≤) 1 or pretreatment baseline, with the exception of alopecia.
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Men with partners of childbearing potential or women of childbearing potential (WOCBP) must agree to use highly effective birth control.
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WOCBP must not be pregnant.
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Additional Inclusion Criteria for Patients with AL Amyloidosis
- In Part 1 Dose Expansion, patients with AL amyloidosis are eligible based on prior detection of primary systemic light-chain amyloidosis.
- Must have measurable disease of AL amyloidosis.
- Prior local fluorescence in-situ hybridization (FISH) testing results for t(11;14) are required to be submitted prior to enrollment.
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Prior to identification of an appropriate RP2D (Dose Expansion) of LOXO-338, a history of known, active or suspected:
- Richter's transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocyticleukemia, or Hodgkin lymphoma
- Transformed low grade lymphoma
- Burkitt or Burkitt-like lymphoma
- Diffuse large B-cell lymphoma
- AL amyloidosis
- Multiple myeloma
- Lymphoblastic lymphoma or leukemia
- Posttransplant lymphoproliferative disorder
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Known or suspected history of central nervous system (CNS) involvement.
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History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T cell (CAR-T) therapy within the past 60 days and with any of the following:
- Active graft versus host disease (GVHD)
- Cytopenias from incomplete blood cell count recovery post-transplant or CAR-T therapy
- Need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity Grade > 1 from CAR-T therapy
- Ongoing immunosuppressive therapy
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Known human immunodeficiency virus (HIV) positive, regardless of cluster of differentiation 4 (CD4) count. Unknown or negative status eligible.
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Inability to take necessary uric acid lowering agents (i.e., allopurinol, rasburicase, orfebuxostat).
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Concurrent anticancer therapy.
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Concurrent treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers that can include antifungals.
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Use of ≥ 20 milligrams (mg) prednisone once a day (QD) or equivalent dose of steroid per day, within 7 days of start of study treatment. Patients may not be on any dose of prednisone intended for antineoplastic use.
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Vaccination with a live vaccine within 28 days prior to start of study therapy.
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Major surgery within four weeks of planned start of study therapy Prolongation of the QT interval corrected by Fridericia's Formula for heart rate (QTcF) greater than (>) 470 milliseconds (msec).
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Clinically significant cardiovascular disease.
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Female patient who is pregnant or lactating.
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Active second malignancy which may preclude assessment of DLT.
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Clinically significant active malabsorption syndrome including surgical resection of small intestine or other condition likely to affect gastrointestinal (GI) absorption of the orally administered study drugs.
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Active hepatitis B or C infection.
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Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal) or other clinically significant active disease process.
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Active uncontrolled auto-immune cytopenia.
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Additional Exclusion Criteria for Patients with AL Amyloidosis (Part 1 Dose-Expansion)
- Previous or current diagnosis of symptomatic MM.
- Heart failure that, in the opinion of the Investigator, is on the basis of ischemic heart disease.
- Supine systolic blood pressure < 90 mmHg, or symptomatic orthostatic hypotension in the absence of volume depletion.
- N-terminal pro hormone natriuretic peptide (NT-proBNP) > 8500 ng/L (or BNP > 700 ng/L if NT-proBNP is not available by local or central testing).
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Additional exclusion criteria for patients enrolled to part 2: LOXO-338 and pirtobrutinib combination
- Prior progression or intolerance to pirtobrutinib.
- Patients requiring therapeutic anticoagulation with warfarin.
- Known hypersensitivity to any component or excipient of pirtobrutinib.
- In patients with history of myocardial infarction or congestive heart failure, documented left ventricular ejection fraction (LVEF) by any method of ≤ 45 percent (%) in the 12 months prior to planned start of study treatment.
- History of uncontrolled or symptomatic arrhythmias including grade ≥ 3 arrhythmia on a prior BTK inhibitor.
- History of major bleeding on a prior BTK inhibitor.
- Current treatment with strong permeability glycoprotein (P-gp) inhibitors.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description LOXO-338 (Monotherapy) LOXO-338 LOXO-338 administered orally. LOXO-338 + Pirtobrutinib (Combination) LOXO-338 LOXO-338 administered orally in combination with pirtobrutinib LOXO-338 + Pirtobrutinib (Combination) Pirtobrutinib LOXO-338 administered orally in combination with pirtobrutinib
- Primary Outcome Measures
Name Time Method Part 1 - To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of oral LOXO-338 Cycle 1 (28 Days) Measured by the number of patients with dose-limiting toxicities (DLTs)
Part 1 - To determine the effect of LOXO-338 on response rates Estimated up to 2 years Measured by the appropriate disease specified response criteria as appropriate to tumor type
Part 2 - To determine the safety and tolerability of LOXO-338 when given in combination with pirtobrutinib Cycle 2 (28 Days) Measured by the number of patients with dose-limiting toxicities (DLTs)
- Secondary Outcome Measures
Name Time Method Part 1 - To assess preliminary antitumor activity of LOXO-338 based on progression-free survival (PFS) Estimated up to 2 years PFS
Part 1 - To assess preliminary antitumor activity of LOXO-338 based on overall response rate (ORR) Estimated up to 2 years ORR
Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on progression-free survival (PFS) Estimated up to 2 years PFS
Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on time-to-progression (TTP) Estimated up to 2 years TTP
Part 1 - To characterize the pharmacokinetics (PK) properties of LOXO-338: Area under the plasma concentration versus time curve (AUC) Predose up to 24 hours postdose PK: AUC of LOXO-338
Part 1 - To characterize the PK properties of LOXO-338: Maximum drug concentration (Cmax) Predose up to 24 hours postdose PK: Cmax of LOXO-338
Part 1 - To assess preliminary antitumor activity of LOXO-338 based on duration of response (DOR) Estimated up to 2 years DOR
Part 2 - To characterize the PK properties of LOXO-338 and in combination with pirtobrutinib: Maximum drug concentration (Cmax) Predose up to 24 hours postdose PK: Cmax of LOXO-338 alone and in combination with pirtobrutinib
Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on overall response rate (ORR) Estimated up to 2 years ORR
Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on duration of response (DOR) Estimated up to 2 years DOR
Part 1 - To assess preliminary antitumor activity of LOXO-338 based on time-to-progression (TTP) Estimated up to 2 years TTP
Part 2 - To characterize the pharmacokinetics (PK) properties of LOXO-338 in combination with pirtobrutinib: Area under the plasma concentration versus time curve (AUC) Predose up to 24 hours postdose PK: AUC of LOXO-338 alone and in combination with pirtobrutinib
Trial Locations
- Locations (23)
The University of Arizona Cancer Center
🇺🇸Tucson, Arizona, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
Mayo Clinic in Florida
🇺🇸Jacksonville, Florida, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Centre Hospitalier Lyon Sud
🇫🇷Pierre-Bénite, Cedex, France
CHRU de Montpellier-Hopital St Eloi
🇫🇷Montpellier Cedex 5, France
Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu
🇫🇷Nantes, France
Institut Curie
🇫🇷Paris, France
Centre hospitalier universitaire de Haut Leveque
🇫🇷Pessac Cedex, France
Emory University
🇺🇸Atlanta, Georgia, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Swedish Medical Center
🇺🇸Seattle, Washington, United States
University of California San Francisco, Medical Center at Paranassus
🇺🇸San Francisco, California, United States
IRCCS - AOU di Bologna
🇮🇹Bologna, Italy
Indiana Blood & Marrow Transplantation (IBMT)
🇺🇸Indianapolis, Indiana, United States
L'Institut Universitaire du Cancer de Toulouse Oncopole
🇫🇷Toulouse, Cedex 9, France
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy
🇵🇱Warszawa, Poland
Centrum Medyczne Pratia Poznan
🇵🇱Skorzewo, Poznan, Poland
Pratia MCM Krakow
🇵🇱Krakow, Poland
Sylvester Comprehensive Cancer Center
🇺🇸Miami, Florida, United States
University of Kansas Medical Center
🇺🇸Westwood, Kansas, United States