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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Lymphoma, Non-Hodgkin; B-cell Lymphoma; Multiple Myeloma; Lymphoma, Mantle-Cell; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-cell Marginal Zone
• Intervention / Treatment: Drug: Pirtobrutinib; Drug: LOXO-338

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Estimated): 316
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Montpellier Cedex 5, France, 34295
    • CHRU de Montpellier-Hopital St Eloi
  • Nantes, France, 44093
    • Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu
  • Paris, France, 75248
    • Institut Curie
  • Pessac Cedex, France, 33604
    • Centre hospitalier universitaire de Haut Leveque
  • Cedex
    • Pierre-Bénite, Cedex, France, 69495
      • Centre Hospitalier Lyon Sud
  • Cedex 9
    • Toulouse, Cedex 9, France, 31100
      • L'Institut Universitaire du Cancer de Toulouse Oncopole
• Italy
  • Bologna, Italy, 40138
    • IRCCS - AOU di Bologna
• Poland
  • Krakow, Poland, 30-510
    • Pratia MCM Krakow
  • Warszawa, Poland, 02-781
    • Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy
  • Poznan
    • Skorzewo, Poznan, Poland, 60 185
      • Centrum Medyczne Pratia Poznan
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • The University of Arizona Cancer Center
  • California
    • Duarte, California, United States, 91010-0269
      • City of Hope National Medical Center
    • San Francisco, California, United States, 94117
      • University of California San Francisco, Medical Center at Paranassus
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic in Florida
    • Miami, Florida, United States, 33136
      • Sylvester Comprehensive Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Indiana Blood & Marrow Transplantation (IBMT)
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905-0002
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College Of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LOXO-338 (Monotherapy); LOXO-338 administered orally.	Drug: LOXO-338; Oral; Other Names: LY3847429
Experimental: LOXO-338 + Pirtobrutinib (Combination); LOXO-338 administered orally in combination with pirtobrutinib	Drug: Pirtobrutinib; Oral; Other Names: LOXO-305; LY3527727; Drug: LOXO-338; Oral; Other Names: LY3847429

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Collaborators: Loxo Oncology, Inc.
• Investigators: Study Director: James Pauff, MD; PhD, Loxo Oncology, Inc.

Publications and helpful links

Helpful Links

• Study of Oral LOXO-338 in Patients with Advanced Blood Cancers

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2021
• Primary Completion (Estimated): May 1, 2023
• Study Completion (Estimated): December 1, 2023

Study Registration Dates

• First Submitted: August 25, 2021
• First Submitted That Met QC Criteria: August 25, 2021
• First Posted (Actual): August 27, 2021

Study Record Updates

• Last Update Posted (Actual): June 1, 2023
• Last Update Submitted That Met QC Criteria: May 30, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: NHL; CLL; SLL; BTKi; Hematologic disease; Small lymphocytic lymphoma; BCL-2 inhibitor
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia; Leukemia, B-Cell; Chronic Disease; Lymphoma; Lymphoma, B-Cell; Multiple Myeloma; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Pirtobrutinib
• Other Study ID Numbers: LOXO-BCL-20001; 2021-000060-30 (EudraCT Number); J3N-OX-JZRA (Other Identifier: Eli Lilly and Company)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No