Clinical Trials

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.