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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05024045
Recruitment Status : Recruiting
First Posted : August 27, 2021
Last Update Posted : October 12, 2022
Sponsor:
Collaborator:
Loxo Oncology, Inc.
Information provided by (Responsible Party):
Eli Lilly and Company

Brief 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.

Condition or disease Intervention/treatment Phase
Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, B-cell Marginal Zone Lymphoma, Non-Hodgkin Multiple Myeloma B-cell Lymphoma Waldenstrom Macroglobulinemia Lymphoma, Mantle-Cell Drug: LOXO-338 Drug: Pirtobrutinib Phase 1

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 316 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of Oral LOXO-338, a Selective BCL-2 Inhibitor, in Patients With Advanced Hematologic Malignancies
Actual Study Start Date : September 30, 2021
Estimated Primary Completion Date : April 2024
Estimated Study Completion Date : April 2024


Arm Intervention/treatment
Experimental: LOXO-338 (Monotherapy)
LOXO-338 administered orally.
Drug: LOXO-338
Oral
Other Name: LY3847429

Experimental: LOXO-338 + Pirtobrutinib (Combination)
LOXO-338 administered orally in combination with pirtobrutinib
Drug: LOXO-338
Oral
Other Name: LY3847429

Drug: Pirtobrutinib
Oral
Other Names:
  • LOXO-305
  • LY3527727




Primary Outcome Measures :
  1. Part 1 - To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of oral LOXO-338 [ Time Frame: Cycle 1 (28 Days) ]
    Measured by the number of patients with dose-limiting toxicities (DLTs)

  2. Part 1 - To determine the effect of LOXO-338 on response rates [ Time Frame: Estimated up to 2 years ]
    Measured by the appropriate disease specified response criteria as appropriate to tumor type

  3. Part 2 - To determine the safety and tolerability of LOXO-338 when given in combination with pirtobrutinib [ Time Frame: Cycle 2 (28 Days) ]
    Measured by the number of patients with dose-limiting toxicities (DLTs)


Secondary Outcome Measures :
  1. Part 1 - To characterize the pharmacokinetics (PK) properties of LOXO-338: Area under the plasma concentration versus time curve (AUC) [ Time Frame: Predose up to 24 hours postdose ]
    PK: AUC of LOXO-338

  2. Part 1 - To characterize the PK properties of LOXO-338: Maximum drug concentration (Cmax) [ Time Frame: Predose up to 24 hours postdose ]
    PK: Cmax of LOXO-338

  3. Part 1 - To assess preliminary antitumor activity of LOXO-338 based on overall response rate (ORR) [ Time Frame: Estimated up to 2 years ]
    ORR

  4. Part 1 - To assess preliminary antitumor activity of LOXO-338 based on progression-free survival (PFS) [ Time Frame: Estimated up to 2 years ]
    PFS

  5. Part 1 - To assess preliminary antitumor activity of LOXO-338 based on time-to-progression (TTP) [ Time Frame: Estimated up to 2 years ]
    TTP

  6. Part 1 - To assess preliminary antitumor activity of LOXO-338 based on duration of response (DOR) [ Time Frame: Estimated up to 2 years ]
    DOR

  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) [ Time Frame: Predose up to 24 hours postdose ]
    PK: AUC of LOXO-338 alone and in combination with pirtobrutinib

  8. Part 2 - To characterize the PK properties of LOXO-338 and in combination with pirtobrutinib: Maximum drug concentration (Cmax) [ Time Frame: Predose up to 24 hours postdose ]
    PK: Cmax of LOXO-338 alone and in combination with pirtobrutinib

  9. Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on overall response rate (ORR) [ Time Frame: Estimated up to 2 years ]
    ORR

  10. Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on progression-free survival (PFS) [ Time Frame: Estimated up to 2 years ]
    PFS

  11. Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on time-to-progression (TTP) [ Time Frame: Estimated up to 2 years ]
    TTP

  12. Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on duration of response (DOR) [ Time Frame: Estimated up to 2 years ]
    DOR



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05024045


Contacts
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Contact: Patient Advocacy 1-855-LOXO-305 clinicaltrials@loxooncology.com

Locations
Show Show 21 study locations
Sponsors and Collaborators
Eli Lilly and Company
Loxo Oncology, Inc.
Investigators
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Study Director: James Pauff, MD; PhD Loxo Oncology, Inc.
Additional Information:
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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT05024045    
Other Study ID Numbers: LOXO-BCL-20001
2021-000060-30 ( EudraCT Number )
J3N-OX-JZRA ( Other Identifier: Eli Lilly and Company )
First Posted: August 27, 2021    Key Record Dates
Last Update Posted: October 12, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eli Lilly and Company:
BTKi
Hematologic disease
Small lymphocytic lymphoma
BCL-2 inhibitor
CLL
SLL
NHL
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Multiple Myeloma
Lymphoma, B-Cell
Waldenstrom Macroglobulinemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Leukemia
Leukemia, B-Cell