This phase I trial is trying to determine the recommended dose level, and understand how safe and effective, a new targeted therapy (ETH-155008) is in people with relapsed or refractory B-cell Non-Hodgkin's Lymphoma, chronic lymphocytic leukaemia, small lymphocytic lymphoma and acute myeloid leukaemiaA Phase 1a/1b Dose Escalation and Dose Expansion, First-in-human, Open-Labeled Study of ETH-155008 in Subjects With Relapsed or Refractory B-cell NHL, CLL/SLL and AML

Inclusion

• Each potential subject must fulfil all of the following criteria to be enrolled in the study.

  1. Be at least 18 years of age and < 80 years old.
  2. Must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the trial and are willing to participate in the trial prior to any other trial-related assessments or procedures. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard of care for the subject's disease.

  3. Has histologically or cytologically confirmed relapsed and/or refractory B-cell NHL, CLL/SLL or AML with no available standard therapy or is not a candidate for available standard therapy, and for whom, in the opinion of the investigator, experimental therapy with ETH-155008 may be beneficial.

     In addition, the following disease-specific criteria outlined below must be met.

     a. For all indolent NHL (FL, MZL and Waldenström Macroglobulinemia), previously treated with at least 2 prior lines of systemic therapy with at least 1 line being an anti-CD20 antibody-containing combination regimen.

     b. For aggressive NHL (DLBCL, HGBCL, and PMBCL), received, or not eligible for high-dose chemotherapy containing anti-CD20 monoclonal antibodies and autologous stem cell transplantation with curative intent.

     c. For MCL, previously treated with at least 1 prior line of systemic therapy including an anti-CD20 antibody combination regimen, with no other approved therapies that would be more appropriate in the investigator's judgement.

     d. For CLL/SLL, relapsed or refractory with at least 2 prior lines of systemic therapy using different treatment regimens including BTK inhibitors or venetoclax.

     e. For AML, AML diagnosis according to the 2016 World Health Organization (WHO) classification who have received no more than 3 prior lines of therapy and with no available therapy.

  4. Has one of the following RB POSITIVE B-cell NHL subtypes or AML for the Dose Expansion:

     1. Aggressive NHL (DLCBL, HGBCL and PMBCL)
     2. MCL,
     3. AML Note: at screening, archived or fresh tumor tissue will be assayed by local sites and may need to be confirmed by a central lab later to evaluate Rb expression. Rb IHC staining intensity will be deemed positive if a staining level of 1+ or greater above background is identified.
  5. Presence of measurable or evaluable disease.
  6. Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1 (dose escalation cohorts) or ≤2 (dose expansion cohorts) (Appendix 1).

  7. For B-NHL, hematology laboratory parameters must be within the following ranges. Values must be without transfusions or growth factors for at least 7 days prior to the first dose of study drug.

     1. Hemoglobin ≥8 g/dL
     2. Platelets ≥75×109 /L
     3. Absolute neutrophil count ≥1.0×109 /L
     4. If neutropenia or thrombocytopenia is believed to be due to marrow infiltration with malignant cells then the absolute neutrophil 0.75x10 9 /L (750/µL) or platelet count ≥ 50x10 9 /L (50,000/µL).
     5. For AML, WBC count, no upper limit at Screening, but must be <10 x109/L on Day 1 prior to the first dose of study drug. Note: Subjects with excessive blasts may be treated with hydroxyurea until 2 days prior to first dose of study drug to reduce WBC; Platelet count >10,000/µL; Platelet transfusion prior to first dose is permitted.
     6. INR/PT and aPTT ≤1.5 times institutional upper limit of normal (ULN).

  8. Clinical chemistry laboratory parameters must be within the following range:

     1. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), GGT, and alkaline phosphatase ≤2.5×upper limit of normal (ULN).
     2. Serum total bilirubin ≤1.5×the ULN.
     3. Creatinine clearance ≥60 mL/min (Cockcroft-Gault formula).
  9. Cardiac parameters within the following range: corrected QT interval (QTc intervals corrected using Fridericia's formula [QTcF]) ≤470 milliseconds based on the average of triplicate assessments performed no more than 5 minutes apart (±3 minutes).
  10. Life expectancy of at least 3 months.
  11. A woman of childbearing potential must have a negative serum beta-human chorionic gonadotropin (beta-hCG) at screening and prior to the first dose of study drug.
  12. Women must be (as defined in Appendix 3, Contraceptive Guidance and Pregnancy): a. Not of childbearing potential b. Of childbearing potential and - Practicing a highly effective, preferably user-independent method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study drug and until 90 days after last dose. Examples of highly effective methods of contraception are in Appendix 3, Contraceptive Guidance and Pregnancy.
  13. In addition to the user-independent, highly effective method of contraception, a male or female condom is required. Male condoms and female condoms should not be used together (due to risk of failure with friction).
  14. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control, e.g., either condom with or partner with occlusive cap (diaphragm or cervical/vault caps).
  15. Men or women must agree not to donate sperm or eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 3 months after the last study drug administration.
  16. For Part 2 (dose expansion): for B-cell NHL, tumor tissue availability is required at baseline unless clinically contraindicated.
  17. Must be willing and able to adhere to the requirements and restrictions specified in the ICF and this protocol.