Phase 1  | 
 | Investigational Drug


Advanced Hematologic Malignancies

BCL-2 Inhibitor

A Phase 1 Study of Oral LOXO-338, a Selective BCL-2 Inhibitor, in Patients With Advanced Hematologic Malignancies*

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Key Inclusion Criteria
  • B-cell malignancy
  • Prior therapy in which treatment-related adverse events recovered to grade ≤1 or pretreatment baseline, except for alopecia 
  • Patients must have an objective indication for therapy
  • Anticipated life expectancy of ≥12 weeks
  • Creatinine clearance of ≥60 mL/min
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Adequate bone marrow and hepatic function
  • 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
  • Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
  • Ability to swallow tablets
  • 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
Key Exclusion Criteria
  • Prior to identification of an appropriate recommended phase 2 dose (Dose Expansion) of LOXO-338, a history of known, active, or suspected:
    • Richter’s transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocytic leukemia, 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
    • Post-transplant lymphoproliferative disorder
  • Known or suspected history of central nervous system involvement
  • History of allogeneic or autologous stem cell transplant or chimeric antigen receptor–modified T-cell (CAR-T) therapy within the past 60 days and with any of the following:
    • Active graft vs host disease
    • Cytopenias from incomplete blood cell count recovery posttransplant or CAR-T therapy
    • Need for anticytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity grade >1 from CAR-T therapy
    • Ongoing immunosuppressive therapy
  • Known HIV positive, regardless of cluster of differentiation 4 (CD4) count. Unknown or negative status eligible
  • Inability to take necessary uric acid lowering agents (ie, allopurinol, rasburicase, or febuxostat)
  • Concurrent anticancer therapy or treatment with strong cytochrome P450 3A4 inhibitors or inducers that can include antifungals
  • Use of ≥20 mg prednisone 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 4 weeks of planned start of study
  • Prolonged QT interval corrected using Fridericia’s formula (QTcF) >470 ms
  • Clinically significant cardiovascular disease
  • Female patient who is pregnant or lactating
  • Active second malignancy which may preclude assessment of dose-limiting toxicities
  • Clinically significant active malabsorption syndrome including surgical resection of small intestine or other condition likely to affect gastrointestinal absorption of the orally administered study drugs
  • Active hepatitis B or C
  • Evidence of other clinically significant uncontrolled condition(s) (eg, uncontrolled systemic infection [viral, bacterial, or fungal] or other clinically significant active disease process)
  • Active uncontrolled autoimmune 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 + pirtobrutinib
    • 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 by any method of ≤45% 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 P-gp inhibitors
This clinical trial is being conducted globally.
LOXO-338 is administered PO.
Pirtobrutinib is administered PO.
An additional primary outcome measure for part 1 (Dose Expansion) is to determine the effect of LOXO-338 on response rates, as measured by the appropriate disease specified response criteria as appropriate to tumor type.
Contact the Loxo Oncology at Lilly Clinical Trial Team

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The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.