Clinical Trials

Inclusion Criteria:

• B-cell malignancy defined as either:
  • histologically confirmed CLL or SLL according to the 2018 international workshop CLL (iwCLL) criteria; OR
  • histologically confirmed NHL patients according to WHO criteria;
  • multiple myeloma according to International Myeloma Working Group (IMWG) criteria (Rajkumar et al. 2014).
• Prior therapy:
  • CLL/SLL, MCL, or WM: received at least 2 prior lines of therapy;
  • Other NHL or MM: have failed standard therapy and, in the opinion of the investigator, have no options available known to provide benefit for the patient’s condition;
  • Regardless of diagnosis, must not have progressed while receiving a prior BCL-2 inhibitor.
• Patients must have an objective indication for therapy, including any of the following:
  • For CLL: as defined by iwCLL criteria, such as escalating lymphocytes count increasing > 50% over a period of 2 months or doubling time of less than 6 months;
  • Regardless of diagnosis, any of the following:
    • enlarging adenopathy at least 2 cm in one dimension if palpable and/or worsening splenomegaly;
    • increasing cytopenias due to disease;
    • threatened end-organ function;
    • steady progression over at least 6 months;
  • For WM: Symptoms such as hyperviscosity, neuropathy, organomegaly, amyloidosis, cold agglutinins, cryoglobulinemia.
• Age 18 and older at time of enrollment.
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2.
• Anticipated life expectancy of ≥ 12 weeks.
• Must have adequate bone marrow function, as defined below:
  • Absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L; if marrow is known to be infiltrated with underlying disease, granulocyte-colony stimulating factor (G-CSF) support may be used to achieve eligibility criteria;
  • Platelets ≥ 50 × 10^9/L not requiring transfusion support or growth factors within 14 days of C1D1;
  • Hemoglobin ≥ 8 g/dL not requiring transfusion support or growth factors within 14 days of C1D1.
• Normal hepatic function defined as:
  • Total bilirubin ≤ 1.5 × upper limit of normal (ULN) patients with known Gilberts can enroll provided direct bilirubin is within the normal range.
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN or baseline if baseline abnormal.
• Creatinine clearance of ≥ 60 mL/minute using Cockcroft/Gault Formula.
• Ability to swallow tablets.
• Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
• Patients are required to have had the following washout periods prior to planned start of any study therapy:
  • Targeted agents or cytotoxic chemotherapy: 5 half-lives or 14 days, whichever is shorter;
  • Therapeutic monoclonal antibodies: 4 weeks;
  • Palliative limited field radiation: 7 days;
  • Broad field radiation (≥ 30% of bone marrow or whole brain radiotherapy): 28 days.
• Prior treatment-related AEs must have recovered to Grade ≤ 1 or pretreatment baseline with the exception of alopecia.
• Men with partners of childbearing potential or women with childbearing potential must agree to use a highly effective contraceptive method of birth control during study treatment and for at least 6 months following the last dose of study drug. Sperm donation is prohibited during the duration of participation on this protocol and for 6 months after the last dose of study drug.
  Acceptable methods of birth control are:
  • Total abstinence from intercourse; periodic abstinence is not acceptable;
  • Surgical sterilization as appropriate by vasectomy, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;
  • Intrauterine device;
  • Double-barrier method including contraceptive sponge, diaphragm, or cervical cap with spermicidal jellies or cream AND a condom;
  • Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal); the specific contraceptive must have been used for at least 3 months prior to study drug administration.
• Women of childbearing potential (WOCBP) (defined as not postmenopausal for at least 2 years or surgically sterile) must have a negative serum pregnancy test documented within 14 days prior to initiation of treatment and a negative urine pregnancy test obtained on C1D1 if theserum pregnancy test was obtained more than 7 days from C1D1.
• The patient or his/her legally authorized representative must be capable of demonstrating an understanding of the nature, significance, and implications of participation in the trial and giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

• Prior to identification of the 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;
  • 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 symptomsof neurotoxicity Grade > 1 from CAR-T therapy;
  • Ongoing immunosuppressive therapy;
  • Known Human Immunodeficiency Virus (HIV) positive, regardless of 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. Also, because of their effect as irreversible inhibitors on CYP3A4 and potential impact on LOXO-338 or LOXO-305metabolism, any of the following within 7 days of start of study therapy or planned use while taking study therapy is prohibited:
  • Grapefruit or products from grapefruit;
  • Seville oranges or products from Seville oranges;
  • Star fruit or products from star fruit.
• Use of ≥ 20 mg prednisone QD or equivalent dose of steroid per day within 7 days of start of study treatment. Patients may not be on prednisone of any dose intended for antineoplasticus.
• Vaccination with a live vaccine within 28 days prior to start of study therapy, with the exception of vaccinations for coronavirus disease 2019 (COVID-19), as applicable. Live vaccination for COVID-19 should occur at least two weeks prior to C1D1.
• Major surgery within 4 weeks of planned start of study therapy.
• Prolongation of the QT interval corrected by Fridericia’s Formula for heart rate (QTcF) > 470 msec. QTcF is calculated using Fridericia’s Formula: QTcF=QT/(RR1/3).
• Manual correction for underlying bundle branch block (BBB) allowed if approved by the sponsor.
• Clinically significant cardiovascular disease defined as any of the following:
  • Unstable angina;
  • History of myocardial infarction within 6 months prior to planned start of study treatment;
  • Any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
• Female patient who is pregnant or lactating.
• Active second malignancy which may preclude assessment of DLT as defined in this protocol.
• Clinically significant active malabsorption syndrome including surgical resection of small intestine or other condition likely to affect gastrointestinal (GI) absorption of the oral administered study drugs.
• Active hepatitis B or C infection documented during screening and defined as:
  • Hepatitis B virus (HBV): positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc). If anti-HBc positive with surface antigen negative, patient will need to have a negative result for hepatitis B DNA before start of study therapy. Patients who are anti-HBc positive and hepatitis B polymerase chain reaction (PCR) positive will be excluded;
  • Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C RNA beforestart of study therapy. Patients who are hepatitis C RNA positive will be excluded.
• 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 which in the opinion of the investigator and Medical Monitor maypose a risk for patient participation. Screening for chronic conditions is not required.
• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) where new therapy is introduced, or concomitant medication escalated within the 4 weeks prior to study enrollment is required to maintainadequate blood counts.

Additional Exclusion Criteria for patients enrolled to Part 2: LOXO-338 and LOXO-305 Combination:

• Prior progression or intolerance to LOXO-305.
• Patients requiring therapeutic anticoagulation with warfarin.
• Known hypersensitivity to any component or excipient of LOXO-305..
• In patients with history of myocardial infarction or congestive heart failure, documented left ventricular ejection fraction (LVEF) by any method of ≤ 45% 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.
  • NOTE: Major bleeding is defined as bleeding having 1 or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2 g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome).
  • Current treatment with strong P-gp inhibitors.

Eligibility last updated 9/24/21. Questions regarding updates should be directed to the study team contact.