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

To find the highest tolerable dose of IACS-6274 that can be given alone, in combination with bevacizumab and paclitaxel, or in combination with capivasertib to patients who have solid tumors. The safety and tolerability of the study drug(s) will also be studied.

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 \450 ms for males and \>470 ms for females 3. History of any of the following cardiovascular conditions within 6 months of enrolment: * cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association. 4. Major surgical intervention within 28 days before study drug administration, or an anticipated need for major surgery during the study. 5. Significant acute or chronic infections. 6. Any psychiatric condition that would prohibit the understanding or rendering of informed consent. 7. Treatment with strong cytochrome P450 subtype 3A4 (CYP3A4) inducers and inhibitors (including grapefruit juice) within 2 weeks of the first dose of study drug NOTE: patients must have stopped taking St. John's Wort 3 weeks prior to the start of treatment and stopped taking enzalutamide 4 weeks prior to the start of treatment. 8. Treatment with strong CYP450 subtype 2D6 (CYP2D6) inhibitors or sensitive CYP3A4 substrates within 7 days of the first dose of study drug. 9. Radiotherapy within 4 weeks prior to the start of study drug. Palliative radiotherapy for symptomatic control is acceptable if completed at least 2 weeks prior to study drug administration and no additional radiotherapy for the same lesion is planned. 10. Underlying medical conditions (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant and active bleeding diseases), for which in the investigator's opinion will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or AEs. 11. History of allergic reactions attributed to compounds of similar chemical or biological composition to any of the compounds in the study. 12. Known history of alcohol or drug abuse. 13. Legal incapacity or limited legal capacity. 14. Inability to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation. Patients should not have gastrointestinal illnesses (such as refractory nausea and vomiting, chronic gastrointestinal disease or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretionof IACS-6274 and capivasertib, which are oral agents. 15. Patients unwilling to comply with protocol requirements related to the assigned part. 16. Any other disease, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent. Part B Specific Exclusion Criteria (B1) Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (that is, three or more features of partially controlled asthma). (B2) Patient has a known hypersensitivity to paclitaxel or bevacizumab components or excipients. (B3) Patient has a history of bowel obstruction, including sub-occlusive disease, related to the underlying disease and history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscesses. Evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. (B4) Patient has proteinuria as demonstrated by urine protein:creatinine ratio ≥1.0 at screening or urine dipstick for proteinuria ≥2 (patients discovered to have ≥2 proteinuria on dipstick at baseline should undergo 24-hour urine collection and must demonstrate \8% (64 mmol/mol) (C4) Patients with evidence of severe or uncontrolled systemic liver disease including severe hepatic impairment, or abnormal liver enzymes at screening (AST or ALT \>2.5 x ULN; total bilirubin \>1.5 x ULN). (C5) Patients with elevated alkaline phosphatase (ALP) can be enrolled if the abnormal value is due to the presence of bone metastasis, but liver function is considered adequate according to the principal investigator. (C6) Patients with persistent toxicities (Grade ≥2 by Common Terminology Criteria for Adverse Events (CTCAE) version 4) caused by previous anticancer therapy, excluding alopecia. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study treatment may be included after consultation with the sponsor and the study physician. (C7) Patients with spinal cord compression or leptomeningeal disease not requiring steroids for at least 4 weeks prior to start of study intervention. (C8) Patients with clinically significant cardiovascular disease including, but not limited to, significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial infarction, cardiac arrhythmia or unstable angina, New York Heart Association Grade 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or greater peripheral vascular disease, and history of cerebrovascular accident \[CVA\]) within 6 months of enrollment. In addition, patients will be excluded based on the study physician's judgment of the following criteria: * Mean resting corrected QT interval \>470ms, obtained from triplicate ECGs performed at screening. * Medical history significant for arrhythmia that is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation regardless of treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be included based on the study physician's judgment. * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia of Grade ≥1, potential for Torsades de Pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first-degree relative, history of QT prolongation associated with other medications that required discontinuation of the medication. * Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association Grade ≥2. * Uncontrolled hypotension: SBP \