MC# 19-12 - Phase I/II Study of Oral LOXO-305 in Patients with Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Non-Hodgkin Lymphoma (NHL)

  • Agent(s): LOXO-305
  • Disease Type(s): Non-Hodgkin Lymphoma, Esophageal, Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia
  • Phase(s): I, II
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): BTK

Mechanism of Action

LOXO-305 is a selective non-covalent Bruton’s tyrosine kinase (BTK) inhibitor and reversibly binds BTK, preserves activity in the presence of the C481 acquired resistance mutations, and avoids off-target kinases that have complicated the development of both covalent and investigational non-covalent BTK inhibitors.


In this study, the sponsor and investigators want to learn:

  • How much of LOXO-305 can be given with an acceptable level of side effects
  • The effects of LOXO-305 (good and bad)
  • How much of LOXO-305 is absorbed into the blood and how fast it is removed
  • If research tests can be used in the future to predict who will benefit from LOXO-305
Inclusion Criteria
  • Phase 1 dose escalation prior to PK trigger: Able to tolerate potentially subtherapeutic doses of LOXO-305 for the 28-day DLT window in the opinion of the Investigator and with documented Sponsor approval

All Patients

  • Histologically confirmed CLL/SLL or NHL failed or intolerant to standard of care therapies
  • ≥ 2 prior lines of therapy
  • Eastern Cooperative Oncology Group (ECOG) 0-2
  • At least 18 years of age
  • Confirmation of availability of tumor sample obtained after most recent treatment as described in the study protocol.
  • Adequate hematologic status, defined as the following on C1D1 prior to treatment:
    • Absolute neutrophil count (ANC) ≥ 0.75 x 109/L and not requiring growth factors; if there is documented bone marrow involvement, growth factors (pegfilgastrim preferred) may be used at any time prior to C1D1 to achieve this ANC threshold
    • Platelet count ≥ 50 x 109/L not requiring transfusion support; if there is documented bone marrow involvement, platelet transfusions or growth factors may be used prior to 7 days before C1D1 to achieve this platelet threshold
    • Hemoglobin (Hb) ≥ 8 mg/dL not requiring transfusion support or growth factors; if there is documented bone marrow involvement, growth factors (e.g., epoetin alpha) may be used at any time prior to C1D1 to achieve this Hb threshold
    • Adequate coagulation, defined as aPTT and PT (INR) not greater than 1.5 × upper limit of normal (ULN)
  • Adequate hepatic function, defined as:
    • ALT or AST ≤ 2.5 x the ULN or ≤ 5 x ULN with documented liver metastases
    • Total bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver metastases and/or Gilbert’s Disease
  • Adequate renal function defined as creatinine clearance ≥ 30 mL/ minute using Cockcroft/Gault Formula
  • Ability to swallow tablets and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
  • Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following the last dose of study treatment; this may include barrier methods such as condom or diaphragm with spermicidal gel. For male subjects with a non-pregnant female partner of child- bearing potential and a woman of child-bearing potential one of the following highly effective birth control methods with a failure rate of less than 1% per year when used consistently and correctly.
Exclusion Criteria
  • Transformation (e.g., Richter’s transformation, prolymphocytic leukemia, transformed NHL, blastoid lymphoma) prior to planned start of LOXO-305
  • Investigational agent or anticancer therapy within 2 weeks prior to planned start of LOXO-305. In addition, no concurrent investigational therapy is permitted.
    • Continuation of certain standard of care anticancer therapies, including hormonal therapy for localized breast and prostate cancer, is allowed, provided they are not on the list of prohibited concomitant medications. Refer to study protocol for permitted/not permitted drugs.
    • Therapeutic monoclonal antibody treatment must be discontinued a minimum of 4 weeks prior to the first dose of LOXO-305
    • LOXO-305 may be started sooner after prior investigational agent or anticancer therapy if considered by the Investigator to be safe and within the best interest of the patient (e.g., to avoid disease flare) and with documented Sponsor approval
  • Major surgery within 4 weeks prior to planned start of LOXO-305
  • Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment, except for patients receiving radiation to more than 30% of the bone marrow or receiving whole brain radiotherapy, which must be completed at least 4 weeks prior to the first dose of study treatment
  • Patients requiring therapeutic anticoagulation
  • Any unresolved toxicities from prior therapy greater than CTCAE (version 5.0) Grade 2 at the time of starting study treatment except for alopecia
  • History of allogeneic or autologous stem cell transplant (SCT) or CAR-T therapy within the last 100 days (180 days before the PK trigger) or with any of the following:
    • active graft versus host disease (GVHD);
    • cytopenias from incomplete blood cell count recovery post-transplant;
    • 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 central nervous system (CNS) involvement by lymphoma. Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided by the Investigator and with documented Sponsor approval.
  • Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP])
  • Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-305, or prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec on at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF > 470 msec on all 3 ECGs, during Screening.
    • Correction of suspected drug-induced QTcF prolongation can be attempted at the Investigator’s discretion and only if clinically safe to do so.
  • Active uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the Investigator and the Sponsor makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required.
  • Tested positive for Human Immunodeficiency Virus (HIV) is excluded (due to potential drug-drug interactions between anti-retroviral medications and LOXO-305 and risk of opportunistic infections with both HIV and irreversible BTK inhibitors). For patients with unknown HIV status, HIV testing will be performed at Screening.
  • Clinically significant active malabsorption syndrome or other condition likely to affect GI absorption of the study drug
  • Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong P-gp inhibitors
  • Treatment with PPIs within 7 days of starting LOXO-305
    • Refer to the study protocol for alternatives to PPIs if clinically required
  • Pregnancy or lactation
  • Active second malignancy unless in remission with life expectancy > 2 years and with documented Sponsor approval. Examples include:
    • Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
    • Adequately treated cervical carcinoma in situ without current evidence of disease
    • Localized (e.g. lymph node negative) breast cancer treated with curative intent with no evidence of active disease present for more than 3 years and receiving adjuvant hormonal therapy
    • Localized prostate cancer undergoing active surveillance


  • Dallas, TX - Mary Crowley Cancer Research - Medical City
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Re: MC# 19-12