LB-208: a new oral treatment for adults with advanced solid tumors or lymphoma

Inclusion Criteria:

1. Written informed consent obtained prior to performing any protocol related procedure.
2. Age ≥ 18 years at the time of signing the informed consent.
3. Histologically or cytologically confirmed diagnosis of advanced solid tumours or lymphoma who have failed, are intolerant to or are considered ineligible for standard of care anti-cancer treatments.
4. ECOG performance status of 0-1.
5. Participants must be able to take oral medications.
6. Participants must have adequate bone marrow function:

   Absolute neutrophil count (ANC) ≥ 1.5x 109/L. Platelets ≥ 100x 109/L. Haemoglobin ≥ 9 g/dL.
7. Participants must have adequate renal and liver function:

   Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5x upper limit normal (ULN) (≤ 5x ULN in case liver metastases).

   Total bilirubin ≤ 1.5x ULN. Creatinine clearance ≥ 50 mL/min (Cockroft-Gault formula).
8. Life expectancy ≥ 3months.

   Specific additional criteria for dose escalation:
9. Evaluable disease by RECIST 1.1 (that applies to patients with solid tumours) or according to Lugano (2014; patients with lymphoma).

   Specific additional criteria for PK/PD dedicated cohorts:
10. Measurable disease by RECIST 1.1 or Lugano (2014).
11. Participants must have disease amenable to undergo biopsies.

Exclusion Criteria:

1. Concomitant systemic chemotherapy, hormonal therapy, and immunotherapy for the treatment of cancer.

   Hormone-replacement therapy or oral contraceptives for hormone sensitive cancers.

   Gonadotropin-releasing hormone agonists or antagonists for prostate cancer. Bisphosphonates. Angiogenesis inhibitors.
2. Medications that are known to prolong the QT interval.
3. Participants with New York Heart Association (NYHA) Class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) \<40%.
4. Participants with heart-rate corrected QT (QTc) interval ≥450 msec or with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome).
5. Systemic anti-cancer therapy in the 3 prior weeks or 5 half-lives whichever is shorter.
6. Participants taking sensitive CYP 2B6 and CYP 2C8 substrate medications as defined by FDA drug- drug interaction (DDI) Website are excluded from the study.
7. Palliative radiotherapy for bone metastases in the 1 week prior to Cycle 1, Day 1.
8. Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study.
9. Uncontrolled intercurrent illness that according to the investigator might limit compliance with study requirements, might confound the assessment of the study endpoints, or might affect study compliance.
10. Untreated brain metastasis.
11. Leptomeningeal disease.
12. Spinal cord compression not treated with surgery and/or radiation.
13. Pregnant or breastfeeding women.
14. Female participants of childbearing potential not willing to take highly contraceptive methods during dosing and 6 months after stopping study treatment.
15. Female participants not willing to refrain from donating oocytes during dosing and 6 months after stopping study treatment.
16. Male participants with partners of childbearing potential not willing to use a highly effective contraceptive methods during dosing and 3 months after stopping study treatment.
17. Male participants not willing to refrain from donating sperm during dosing and 3 months after stopping study treatment.
18. Cancer history that according to the investigator might confound the assessment of the study endpoints.
19. Participants with known HIV infection who have a CD4+ count \<300/μL, a detectable viral load, or who are not receiving highly active antiretroviral therapy (HAART).
20. Active hepatitis B infection (hepatitis B surface antigen \[HbsAg\] positive) without receiving antiviral treatment.

    Participants who are HbsAg positive must receive antiviral treatment with lamivudine, tenofovir, entecavir, or other antiviral agents, starting at least ≥7 days before the initiation of study treatment, to be eligible.

    Participants with antecedents of hepatitis B (e.g., anti-hepatitis B core (anti-HBc) positive, HbsAg, and hepatitis B virus \[HBV\]-DNA negative) are eligible.
21. Positive test for hepatitis C virus (HCV) RNA. Participants in whom HCV infection resolved spontaneously (i.e., positive HCV antibodies without detectable HCV RNA), or who achieved a sustained response after antiviral treatment and show absence of detectable HCV RNA ≥6 months (with the use of interferon \[IFN\]-free regimens) or ≥12 months (with the use of IFN-based regimens) after cessation of antiviral treatment, are eligible.