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

Study Overview
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Brief Summary
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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
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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).

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

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

Intervention / Treatment
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* Drug: LOXO-338
* Drug: Pirtobrutinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LOXO-338 (Monotherapy)<br>LOXO-338 administered orally. | Drug: LOXO-338<br>* Oral<br>* Other names: LY3847429;|
| Experimental: LOXO-338 + Pirtobrutinib (Combination)<br>LOXO-338 administered orally in combination with pirtobrutinib | Drug: LOXO-338<br>* Oral<br>* Other names: LY3847429;Drug: Pirtobrutinib<br>* Oral<br>* Other names: LY3527727;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 - To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of oral LOXO-338 | Measured by the number of patients with dose-limiting toxicities (DLTs) | Cycle 1 (28 Days) | 
| Part 1 - To determine the effect of LOXO-338 on response rates | Measured by the appropriate disease specified response criteria as appropriate to tumor type | Estimated up to 2 years | 
| Part 2 - To determine the safety and tolerability of LOXO-338 when given in combination with pirtobrutinib | Measured by the number of patients with dose-limiting toxicities (DLTs) | Cycle 2 (28 Days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 - To characterize the pharmacokinetics (PK) properties of LOXO-338: Area under the plasma concentration versus time curve (AUC) | PK: AUC of LOXO-338 | Predose up to 24 hours postdose | 
| Part 1 - To characterize the PK properties of LOXO-338: Maximum drug concentration (Cmax) | PK: Cmax of LOXO-338 | Predose up to 24 hours postdose | 
| Part 1 - To assess preliminary antitumor activity of LOXO-338 based on overall response rate (ORR) | ORR | Estimated up to 2 years | 
| Part 1 - To assess preliminary antitumor activity of LOXO-338 based on progression-free survival (PFS) | PFS | Estimated up to 2 years | 
| Part 1 - To assess preliminary antitumor activity of LOXO-338 based on time-to-progression (TTP) | TTP | Estimated up to 2 years | 
| Part 1 - To assess preliminary antitumor activity of LOXO-338 based on duration of response (DOR) | DOR | Estimated up to 2 years | 
| Part 2 - To characterize the pharmacokinetics (PK) properties of LOXO-338 in combination with pirtobrutinib: Area under the plasma concentration versus time curve (AUC) | PK: AUC of LOXO-338 alone and in combination with pirtobrutinib | Predose up to 24 hours postdose | 
| Part 2 - To characterize the PK properties of LOXO-338 and in combination with pirtobrutinib: Maximum drug concentration (Cmax) | PK: Cmax of LOXO-338 alone and in combination with pirtobrutinib | Predose up to 24 hours postdose | 
| Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on overall response rate (ORR) | ORR | Estimated up to 2 years | 
| Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on progression-free survival (PFS) | PFS | Estimated up to 2 years | 
| Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on time-to-progression (TTP) | TTP | Estimated up to 2 years | 
| Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on duration of response (DOR) | DOR | Estimated up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL, Hematologic disease, Small lymphocytic lymphoma, BCL-2 inhibitor, SLL, NHL, BTKi