Phase 1/2 Study of TP-0903 (an Inhibitor of AXL Kinase) in Patients With Previously Treated CLL

Inclusion Criteria:

1. Be ≥18 years old
2. Have an established, pathologically confirmed diagnoses of CLL/ Small Lymphocytic Lymphoma (SLL) requiring therapy according to the 2018 IWCLL guidelines
3. Have received at least one prior therapy for CLL/SLL and can be classified in one of two patient groups:

   * Group 1 (TP-0903 monotherapy): Patients with CLL/SLL who are intolerant to, or have progressed on B-cell receptor antagonists and/or BCL-2 antagonists or other investigational treatments for CLL/SLL
   * Group 2 (TP-0903 and ibrutinib combination therapy): Patients with CLL/SLL who have progressed on ibrutinib, yet the treating provider considers continuation of ibrutinib therapy to be in the best interest of the patient
4. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2
5. Have adequate hematologic function:

   * Absolute neutrophil count (ANC) ≥500/µL
   * Platelet count ≥30,000/µL
   * Hemoglobin ≥8 g/dL in the absence of transfusions within the previous 2 weeks
6. Have adequate organ function:

   * Creatinine clearance ≥30 mL/min
   * Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level ≤2.5 × upper limit of normal (ULN)
   * Have a total bilirubin level ≤1.5 × ULN (unless secondary to Gilbert syndrome, hemolysis, or leukemia)
7. Have acceptable coagulation status:

   • Activated partial thromboplastin (aPTT) and prothrombin time (PT) ≤1.5 × ULN
8. Have a negative pregnancy test (if female of childbearing potential)
9. Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception (hormonal or barrier method of birth control, or abstinence) prior to study entry and for the duration of study participation and for at least 30 days after the last study drug dose. Should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately.
10. Have read and signed the Institutional Review Board (IRB) approved informed consent form (ICF) prior to any study related procedure. (In the event that the patient is rescreened for study participation or a protocol amendment alters the care of an ongoing patient, a new ICF must be signed.)
11. Are able to comply with the requirements of the entire study

Exclusion Criteria:

1. Have undergone prior autologous or allogeneic stem cell transplant within ≤3 months, have not recovered from transplant associated toxicities, or requires graft versus host immunosuppressive therapy
2. Have known central nervous system (CNS) involvement
3. Have Richter's transformation of CLL
4. Have received any monoclonal antibody therapy directed at treatment of the patient's malignancy within 2 weeks prior to anticipated first dose
5. Have received any anticancer therapy including chemotherapy, radiotherapy, or an investigational anticancer drug within less than 5 half lives of the last dose of that treatment

   • This exclusion criterion is not applicable to patients requiring continuation on ibrutinib. (Note: Certain patients with a rapidly rising white blood cell count while on ibrutinib may need to remain on this drug for medical reasons. These patients will need to be approved by the Medical Monitor and treated in accordance with the protocol.)
6. Have received \>20 mg/day of prednisone and 0.1 mg/day of mineralocorticoids within 7 days prior to anticipated first dose
7. Have a corrected QT interval of \>450 msec (males) and \>470 msec (females) using Fridericia's correction formula
8. Have a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, or cardiovascular disease or any other medical condition that, in the opinion of the Investigator, would adversely affect his/her participation in the study
9. Are pregnant and/or nursing, or refuse to use appropriate contraceptives during the course of the study and for at least 30 days after the last dose of study drug
10. History of another malignancy in the last 5 years except for the following adequately treated:

    * Local basal cell or squamous cell carcinoma of the skin
    * Carcinoma in situ of the cervix or breast
    * Papillary, noninvasive bladder cancer
    * Early stage prostate cancer for which observation is clinically indicated
    * Other Stage 1 or 2 cancers currently in complete remission
    * Any other cancer that has been in complete remission for 2 years or surgically cured. Medical Monitor may be contacted for additional determination of acceptable prior cancer history
11. Have known gastrointestinal disorders (eg, malabsorption syndrome), complications (eg, dysphagia), or surgery that could make consumption or absorption of oral medications problematic
12. Have an uncontrolled systemic infection (viral, bacterial, or fungal) or fever and neutropenia within 7 days prior to anticipated first dose
13. Have active and uncontrolled autoimmune cytopenias for 2 or more weeks including autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP)
14. Have received prior therapy with an AXL inhibitor
15. Have exhibited allergic reactions to a similar structural compound, biological agent, or formulation
16. Are unwilling or unable to comply with procedures required in this protocol
17. Have a history of severe adverse reaction (eg. hypersensitivity reaction, anaphylaxis) to sulfonamides