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Leukemia, Lymphocytic, Chronic, B-CellPhase 1NCT05024045

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

A Phase 1 study testing LOXO-338 and Pirtobrutinib in people with Leukemia, Lymphocytic, Chronic, B-Cell and Lymphoma, B-cell Marginal Zone, run by Eli Lilly and Company at 23 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
LOXO-338 and Pirtobrutinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
27 participants
Where
23 sitesin 4 countries
Study dates
30 Sep 2021to 2 Mar 2026
Phase
Phase 1

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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
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  • 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.

Trial locations and contacts

23 sites in 4 countries.

23 sites in 4 countries

United States13 sites

  • Emory University

    Atlanta, Georgia, 30322

  • Tufts Medical Center

    Boston, Massachusetts, 02111

  • City of Hope National Medical Center

    Duarte, California, 91010-0269

  • Indiana Blood & Marrow Transplantation (IBMT)

    Indianapolis, Indiana, 46237

  • Mayo Clinic in Florida

    Jacksonville, Florida, 32224

  • Sylvester Comprehensive Cancer Center

    Miami, Florida, 33136

  • Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

  • Mayo Clinic

    Rochester, Minnesota, 55905-0002

  • University of California San Francisco, Medical Center at Paranassus

    San Francisco, California, 94117

  • Swedish Medical Center

    Seattle, Washington, 98104

  • The University of Arizona Cancer Center

    Tucson, Arizona, 85724

  • University of Kansas Medical Center

    Westwood, Kansas, 66205

Other trials in United States

France6 sites

  • CHRU de Montpellier-Hopital St Eloi

    Montpellier, 34295

  • Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu

    Nantes, 44093

  • Institut Curie

    Paris, 75248

  • Centre hospitalier universitaire de Haut Leveque

    Pessac, 33604

  • Centre Hospitalier Lyon Sud

    Pierre-Bénite, Cedex, 69495

  • L'Institut Universitaire du Cancer de Toulouse Oncopole

    Toulouse, Cedex 9, 31100

Other trials in France

Poland3 sites

  • Pratia MCM Krakow

    Krakow, 30-510

  • Centrum Medyczne Pratia Poznan

    Skorzewo, Poznan, 60 185

  • Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy

    Warsaw, 02-781

Other trials in Poland

Italy1 site

  • IRCCS - AOU di Bologna

    Bologna, 40138

Other trials in Italy

About this study

Official title: 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.

Read the 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).

Being tested
LOXO-338, Pirtobrutinib
Keywords
BTKi, Hematologic disease, Small lymphocytic lymphoma, BCL-2 inhibitor, CLL, SLL, NHL
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, B-Cell, Marginal Zone, Lymphoma, Non-Hodgkin, Multiple Myeloma, Lymphoma, B-Cell, Waldenstrom Macroglobulinemia, Lymphoma, Mantle-Cell, Hematologic Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LOXO-338Drug

    Also called LY3847429

    Oral

  • PirtobrutinibDrug

    Also called LOXO-305, LY3527727

    Oral

Study groups in NCT05024045
Study groupRoleWhat they receive
LOXO-338 (Monotherapy)ExperimentalLOXO-338 administered orally.
Receives: Drug: LOXO-338
LOXO-338 + Pirtobrutinib (Combination)ExperimentalLOXO-338 administered orally in combination with pirtobrutinib
Receives: Drug: LOXO-338; Drug: Pirtobrutinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    Measured: Cycle 1 (28 Days)

  2. 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

    Measured: Estimated up to 2 years

  3. 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)

    Measured: Cycle 2 (28 Days)

Secondary outcomes (12)

  1. 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

    Measured: Predose up to 24 hours postdose

  2. Part 1 - To characterize the PK properties of LOXO-338: Maximum drug concentration (Cmax)

    PK: Cmax of LOXO-338

    Measured: Predose up to 24 hours postdose

  3. Part 1 - To assess preliminary antitumor activity of LOXO-338 based on overall response rate (ORR)

    ORR

    Measured: Estimated up to 2 years

  4. Part 1 - To assess preliminary antitumor activity of LOXO-338 based on progression-free survival (PFS)

    PFS

    Measured: Estimated up to 2 years

  5. Part 1 - To assess preliminary antitumor activity of LOXO-338 based on time-to-progression (TTP)

    TTP

    Measured: Estimated up to 2 years

  6. Part 1 - To assess preliminary antitumor activity of LOXO-338 based on duration of response (DOR)

    DOR

    Measured: Estimated up to 2 years

  7. 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

    Measured: Predose up to 24 hours postdose

  8. 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

    Measured: Predose up to 24 hours postdose

  9. Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on overall response rate (ORR)

    ORR

    Measured: Estimated up to 2 years

  10. Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on progression-free survival (PFS)

    PFS

    Measured: Estimated up to 2 years

  11. Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on time-to-progression (TTP)

    TTP

    Measured: Estimated up to 2 years

  12. Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on duration of response (DOR)

    DOR

    Measured: Estimated up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Aug 2021
  2. Study start30 Sep 2021
  3. Primary completion14 Jun 2023
  4. Study completion2 Mar 2026

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
27 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05024045
Sponsor's protocol ID
18258
Other IDs
2021-000060-30, J3N-OX-JZRA, LOXO-BCL-20001
Status last verified
Oct 2026
First submitted
25 Aug 2021
Last updated
6 Oct 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Kwiatek M, Murthy GSG, Hoffmann M, Tessoulin B, Danilov A, Alencar AJ, Shah NN, Ghesquieres H, Le Gouill S, Jurczak W, Han H, Yuen E, Patel V, Guo-Avrutin Y, Pauff JM, Roeker LE. A First-in-Human Phase I Study of LOXO-338, an Oral Selective Bcl-2 Inhibitor, in Patients With Advanced Hematologic Malignancies. Clin Lymphoma Myeloma Leuk. 2025 Jul;25(7):512-519. doi: 10.1016/j.clml.2025.01.018. Epub 2025 Jan 28.

    PubMed 40000354

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