AVA6103 in soggetti con tumori solidi selezionati localmente avanzati o metastatici (FOCUS-01)

Inclusion Criteria:

1. The subject is fully informed about the study and is willing and able to sign the informed consent form (ICF).

2. Male or female subjects, ≥18 years of age.

3. Subjects with the following tumors reported to be FAP positive, with histological or cytological confirmation of a locally advanced (unresectable) and/or metastatic progressing disease that have received all standard-of-care or Food and Drug Administration (FDA) approved treatments, or are ineligible for those treatments, or decline those treatments

   1. Cervical/vulvar cancer
   2. SCLC
   3. Gastric/GEJ cancer
   4. PDAC
   5. CRC
   6. HR+ breast cancer

4. Has a life expectancy of ≥3 months, in the opinion of the investigator.

5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Has recovered from all acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure (must have resolved to CTCAE Grade ≤1 or returned to baseline, whichever is greater. Exceptions include alopecia and peripheral neuropathy, which can be up to CTCAE Grade 2).

7. Has adequate hematological function (applies only to subjects not receiving therapeutic anticoagulation; subjects receiving therapeutic anticoagulation should be on a stable dose):

   1. Absolute neutrophil count of ≥1.5 × 109 cells/L. Subjects with documented benign ethnic neutropenia may be enrolled with an absolute neutrophil count of ≥1.0 × 109 cells/L
   2. Hemoglobin ≥9.0 g/dL.
   3. Platelet count of ≥100,000/µL.
   4. International normalized ratio and activated partial thromboplastin time ≤1.5 times the ULN, except for subjects on direct acting anticoagulation.

8. Has adequate liver function:

   1. Total bilirubin 1.5 × ULN (except for subjects with documented Gilbert's Syndrome or liver metastases who must have a total bilirubin <3 × ULN).
   2. AST and ALT ≤2.5 × ULN (in subjects with liver metastases, <5 × ULN is allowed).

9. Has adequate renal function as defined by creatinine clearance ≥ 60 mL/min by the Cockcroft-Gault equation.

10. Women of childbearing potential and women who have ≤2 years amenorrhea after start of menopause, must have a negative serum or urine pregnancy test within 7 days prior to Cycle 1 Day 1.

11. Contraception requirements:

    1. Female subjects of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use a highly effective contraceptive method (Pearl Index failure rate < 1% per year) during the treatment period and for at least 6 months after the last dose of study drug.
    2. Male subjects with female partners of childbearing potential must agree to using 2 acceptable methods of contraception (Pearl Index failure rate <1% per year), including a barrier method (with or without spermicide) during the treatment period and for at least 6 months after the last dose of study drug.
    3. Male subjects must agree to refrain from sperm donation during the treatment period and for at least 6 months after the last dose of study drug.

12. The subject is willing and able to comply with the protocol, including any PK blood sampling and tumor biopsy requirements and agrees to return to clinic for follow-up visits and examinations.

    1. For subjects in Phase 1a or 1b, on treatment tumor biopsy is optional, except for patients assigned to backfill slots, where biopsies are mandatory.

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Exclusion Criteria:

1. Has active or suspected central nervous system (CNS) metastases as determined by the Investigator. Subjects may still be eligible if CNS metastases are definitively treated with radiotherapy, the subject is asymptomatic, not requiring corticosteroids (prednisone or equivalent must be 10 mg/day or less), and have had repeat imaging no less than 4 weeks after completing radiotherapy to document stability.

2. Subjects who have any history of an active (requiring treatment) other malignancy (except any in-situ carcinoma, non-melanoma skin carcinoma and early prostate cancer with a normal prostate-specific antigen) within 2 years of study entry.

3. Has a significant, uncontrolled, concomitant disease that could affect compliance with the protocol.

4. History or evidence of any other clinically unstable/uncontrolled disorder, condition, or disease (including, but not limited to, cardiopulmonary, renal, metabolic, hematologic or psychiatric) other than their primary malignancy, that in the opinion of the Investigator would pose a risk to subject safety or interfere with study evaluations, procedures, or completion.

5. History of known infection is defined as:

   1. HIV infection defined as: An AIDS-defining infection within 12 months of planned study Day 1. Subjects on anti-retroviral treatment who are not established on anti-retroviral treatment for ≥4 weeks and who have a viral load >400 copies/mL prior to study Day 1.
   2. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection defined as: a positive hepatitis B surface antigen (HBsAG) test at screening. Subjects with a past or resolved HBV infection (defined as having a negative HBsAG test and a positive antibody to hepatitis B core antigen antibody test) are eligible. Subjects positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
   3. Chronic HBV (HBsAg positive, undetectable or low HBV DNA and normal ALT).
   4. Subjects with active disease who are not on/have not initiated anti-retroviral treatment prior to study Day 1.
   5. Subjects with untreated HCV infection or have not completed treatment for HCV infection.
   6. Subjects with treated HCV infection but with an HCV viral load above the level of quantification.
   7. Has a severe infection (requiring IV antibiotic treatment) within 21 days prior to Cycle 1, Day 1 including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.

6. Has any other clinically significant active disease, metabolic dysfunction, physical examination finding, altered mental status, clinical laboratory finding, or reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug in the opinion of the investigator.

7. Has had major surgery within 21 days prior to Cycle 1, Day 1 (excluding biopsies) or anticipates the need for major surgery during study treatment.

8. Is a pregnant or breastfeeding woman.

9. Has a known hypersensitivity to any of the components of AVA6103 or any excipient of the product or to other topoisomerase 1 (TOP1) inhibitors.

10. Has received prior investigational therapy (defined as a treatment for which there is no Regulatory Authority-approved indication) within 5 half-lives or 28 days (whichever is shorter) of Cycle 1 Day 1.

11. Has received any approved anticancer therapy, including chemotherapy or hormonal therapy, within 14 days (or 5 half-lives, whichever is shorter) prior to Cycle 1 Day 1, with the following exception:

    1. Is planned for on-study treatment or has received within 14 days (or 5 half-lives, whichever is shorter) prior to Cycle 1 Day 1.
    2. Subjects who have received a monoclonal antibody.

12. Is currently taking St John's Wort, any drugs that are a strong inhibitor or inducer of cytochrome P450 (CYP)3A4, CYP1A2, CYP2D6, or P-glycoprotein (P-gp) such as ketoconazole, Nifedipine, erythromycin and fentanyl.

13. Drugs which are strong inhibitors of multidrug resistance protein (MRP)2, MRP3 or MRP4.

14. Is planned for on study treatment with any drugs that are sensitive CYP3A4 or organic anion transporting polypeptide (OATP)1B3 substrates, and/or where these drugs will be in the systemic circulation at the start of Cycle 1, Day 1. For this protocol, it means that the drug must not be used within 5 half-lives (or 5 days, whichever is longer) prior to AVA6103 Cycle 1 Day 1 and during study treatment.

15. Has received granulocyte-colony stimulating factor (G-CSF), or red blood cell or platelet transfusion within 14 days prior to Cycle 1 Day 1.

16. Has received radiotherapy within 28 days prior to Cycle 1 Day 1, except for limited field palliative radiotherapy, which requires at least a 7-day washout period.

17. Has received live attenuated vaccine within 30 days prior to Cycle 1 Day 1. Note: If a COVID-19 vaccine is administered it should be done >96 hours prior to AVA6103 administration. For the dose escalation phase, it should be administered after completion of the DLT period.

18. QT interval corrected through use of Fridericia's formula (QTcF) > 470 ms demonstrated by at least two single ECGs ≥ 30 minutes apart.