IACS-6274 With or Without Bevacizumab and Paclitaxel for the Treatment of Advanced Solid Tumors

Inclusion Criteria All Parts 1. Provision of written informed consent prior to any study related procedures and compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 2. Male or female patients ≥18 years of age at the time of study entry who agree to participate by giving written informed consent prior to participation in any study related activities. 3. Histologically or cytologically confirmed advanced solid tumors, specifically: Dose Escalation for Part A may include: Patients with tumors harboring actionable KEAP1/NFE2L2/STK11/NF1 mutations Patients with low ASNS expression levels (HGSOC or endometrial cancer) Patients who had immunotherapy (IO) melanoma (Minimum treatment duration of prior PD-1 or PD-L1-containing regimen of 12 weeks \[or equivalent of 2 response evaluations\]). Patients with post-platinum HNSCC Patients with chondrosarcoma Patients with ARID1A mutant clear cell ovarian cancer Dose Escalation for Part B may include: Confirmed recurrent high-grade non-mucinous ovarian cancer that is platinum-resistant, defined as disease relapse within a platinum-free interval (PFI, or the time elapsed from the last date of platinum dose until PD) of \< 6 months, and with less than 5 prior therapies Dose Expansion for Part B limited to: Confirmed recurrent high-grade non-mucinous ovarian cancer with low ASNS expression levels that is platinum-resistant, defined as disease relapse within a PFI of \< 6 months, and with less than 5 prior therapies. Dose Escalation for Part C may include: Patients with tumors harboring actionable KEAP1/NFE2L2 mutations Patients with tumors harboring PIK3CA hotspot mutations, activating AKT mutations, and inactivating PTEN mutations (irrespective of KEAP1/NFE2L2 mutations) Patients with low ASNS expression levels (HGSOC) Dose Expansion for Part C limited to: Patients with NSCLC with actionable KEAP1/NFE2L2 mutations Patients with HGSOClow ASNS expression levels (irrespective of biomarker status for KEAP1/NFE2L2) 4. Patients must have received at least one line of therapy for advanced stage disease and be refractory or ineligible to available existing therapy(ies) known to provide clinical benefit for their condition. 5. Prior treatment with chemotherapy, radiotherapy, immunotherapy or any investigational therapies must have been completed at least 3 weeks or at least five half lives, whichever is shorter, before the study drug administration, and all AEs (excluding alopecia and peripheral neuropathy) have either returned to ≤Grade 1 or stabilized. Patients with concurrent use of hormonal therapy for non-cancer related conditions (e.g., hormone replacement therapy) are allowed. 6. Fresh and/or archival tumor tissue from a biopsy obtained between the completion of the most recent line of treatment until study entry must be available for mutation and biomarker analysis. If available, archival tumor tissue from the time of initial diagnosis or the most recent biopsy (archival and/or fresh) will be collected. For ovarian cancer patients, a fresh biopsy must be collected in addition to archival tumor tissue. NOTE: No fresh tumor tissue will be required if a previous biopsy detected the selected mutations for each cohort. In all cases, procedures to obtain fresh tumor tissue should not put the patient at undue risk, and should only be performed if the risk is minimal (no greater than 2% risk of serious or severe complications). 7. Patients must have at least 1 lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessments. 8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing. 9. Adequate organ function as indicated by the following laboratory values: Absolute neutrophil count (ANC) ≥1.0×109/L Platelets ≥100×109/L Hemoglobin ≥9.0 g/dL (\>5.59 mmol/L) Creatinine clearance (CrCl) \>50 mL/min. Actual body weight should be used for calculating creatinine clearance using the Cockroft Gault equation (except for patients with body mass index \>30 kg/m2 when the lean body weight should be used, and without the need for chronic dialysis therapy). Serum total bilirubin ≤1.5×ULN (with the exception of patients with known thalassemia minor mutations or Gilbert's syndrome: serum total bilirubin must be \<3×ULN in these patients) Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine aminotransferase (serum glutamic pyruvic transaminase) ≤2.5×ULN or ≤5×ULN for patients with liver metastases) 10. Adequate cardiac function with a left ventricular ejection fraction ≥50% 11. Female patients of non childbearing potential, who are physiologically incapable of becoming pregnant, are eligible to enter and participate in the study if they: have had a hysterectomy, OR have had a bilateral oophorectomy, OR have had a bilateral salpingectomy, OR is postmenopausal (total cessation of menses for ≥2 years, or follicle stimulating hormone ≥50 IU/L). 12. Female patients of childbearing potential, who are not post-menopausal or surgically sterile and intent to be sexually active with a non-sterile male partner, are required to use one form of highly effective contraception combined with a barrier method (male condom, female condom, cervical cap, diaphragm with spermicide, or contraceptive sponge with spermicide) of contraception starting before entering the study and until 4 weeks after the last dose of treatment. Highly effective non-hormonal contraceptive methods that are acceptable include: Total/true abstinence\*\*\* for the total duration of the study treatment and for at least 1 month after the last dose of study treatment. Periodic abstinence using methods such as calendar ovulation, symptothermal, post ovulation methods, declaration of abstinence solely for th