AVA6103 in Subjects With Locally Advanced or Metastatic Selected Solid Tumors

You may be eligible if

• 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. -
• 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.