study of oral loxo-338 in patients with advanced blood cancers

Conditions: Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-cell Marginal Zone; Lymphoma, Non-Hodgkin; Multiple Myeloma; B-cell Lymphoma; Waldenstrom Macroglobulinemia; Lymphoma, Mantle-Cell

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.

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).

Eligibility criteria:
inclusion criteria: * b-cell malignancy. * patients must have received prior therapy. * patients must have an objective indication for therapy. * eastern cooperative oncology group performance status (ecog ps) of 0-1. * anticipated life expectancy of greater than or equal to (≥) 12 weeks. * adequate bone marrow function. * adequate hepatic function. * creatinine clearance of ≥ 60 milliliters (ml)/minute. * ability to swallow tablets. * ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. * 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. * men with partners of childbearing potential or women of childbearing potential (wocbp) must agree to use highly effective birth control. * wocbp must not be pregnant. * 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. exclusion criteria: * 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 * known or suspected history of central nervous system (cns) involvement. * 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 * known human immunodeficiency virus (hiv) positive, regardless of cluster of differentiation 4 (cd4) count. unknown or negative status eligible. * inability to take necessary uric acid lowering agents (i.e., allopurinol, rasburicase, orfebuxostat). * concurrent anticancer therapy. * concurrent treatment with strong cytochrome p450 3a4 (cyp3a4) inhibitors or inducers that can include antifungals. * 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. * vaccination with a live vaccine within 28 days prior to start of study therapy. * 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). * clinically significant cardiovascular disease. * female patient who is pregnant or lactating. * active second malignancy which may preclude assessment of dlt. * 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. * active hepatitis b or c infection. * 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. * active uncontrolled auto-immune cytopenia. * 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). * 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.

Keywords: btki hematologic disease small lymphocytic lymphoma bcl-2 inhibitor cll sll nhl