Study of Oral LOXO-338 in Patients With Advanced Blood Cancers

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 requiredclinic visits for the duration of study participation.

• Prior treatment-related adverse events (AEs) must have recovered to grade less thanor 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 onprior detection of primary systemic light-chain amyloidosis.

• Must have measurable disease of AL amyloidosis.

• Prior local fluorescence in-situ hybridization (FISH) testing results fort(11;14) are required to be submitted prior to enrollment.

Exclusion Criteria:

• Prior to identification of an appropriate RP2D (Dose Expansion) of LOXO-338, ahistory 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 antigenreceptor-modified T cell (CAR-T) therapy within the past 60 days and with any of thefollowing:

• Active graft versus host disease (GVHD)

• Cytopenias from incomplete blood cell count recovery post-transplant or CAR-Ttherapy

• Need for anti-cytokine therapy for toxicity from CAR-T therapy; residualsymptoms of neurotoxicity Grade > 1 from CAR-T therapy

• Ongoing immunosuppressive therapy

• Known human immunodeficiency virus (HIV) positive, regardless of cluster ofdifferentiation 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 inducersthat can include antifungals.

• Use of ≥ 20 milligrams (mg) prednisone once a day (QD) or equivalent dose of steroidper day, within 7 days of start of study treatment. Patients may not be on any doseof 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 ofthe 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 ofsmall intestine or other condition likely to affect gastrointestinal (GI) absorptionof the orally administered study drugs.

• Active hepatitis B or C infection.

• Evidence of other clinically significant uncontrolled condition(s) including, butnot limited to, uncontrolled systemic infection (viral, bacterial, or fungal) orother clinically significant active disease process.

• Active uncontrolled auto-immune cytopenia.

• Additional Exclusion Criteria for Patients with AL Amyloidosis (Part 1Dose-Expansion)

• Previous or current diagnosis of symptomatic MM.

• Heart failure that, in the opinion of the Investigator, is on the basis ofischemic heart disease.

• Supine systolic blood pressure < 90 mmHg, or symptomatic orthostatichypotension 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 andpirtobrutinib 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 ≤ 45percent (%) in the 12 months prior to planned start of study treatment.

• History of uncontrolled or symptomatic arrhythmias including grade ≥ 3arrhythmia on a prior BTK inhibitor.

• History of major bleeding on a prior BTK inhibitor.

• Current treatment with strong permeability glycoprotein (P-gp) inhibitors.