Combination of Serabelisib and Insulin Suppressing Diet With or Without Nab-paclitaxel in Subjects With Advanced Solid Tumors With PIK3CA Mutations

Inclusion Criteria

• Able to provide written informed consent.
• Age ≥18 at Visit -1 (screening).
• Histologically or cytologically confirmed recurrent solid tumors.
• Cohort 1a: any extracranial solid tumor (may include EC, ovarian clear cell, or ovarian endometrioid carcinoma if subject is not eligible for nab-paclitaxel in Cohort 1b)
• Cohort 1b: either recurrent or persistent endometrial adenocarcinoma (EC) with the following histologic epithelial cell types: endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.), mucinous adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, and carcinosarcoma or; ovarian cancer (OC) with the primary tumor having ≥ 50% clear cell histomorphology or ovarian clear cell or ovarian endometrioid carcinoma.
• Cohort 2: adenocarcinoma of the colon or rectum.
• Cohort 3: recurrent or persistent endometrial adenocarcinoma with the following histologic epithelial cell types as described for Cohort 1b
• Cohort 4: OC primary tumor carcinomas as described for Cohort 1b
• Tumor must harbor an activating mutation in the PIK3CA gene with or without PTEN loss, either previously documented or determined during screening.
• Fresh or archival tumor biopsy with sufficient material to be sent to the designated laboratory for PD analyses. For subjects who consent to future research, an additional 5 slides from a surgical specimen or biopsy is required.
• Cohort 1a - Dose Modification (subjects with any solid tumor): failed, were intolerant of, or ineligible for no more than three prior lines of therapy (LOT) for advanced/metastatic disease or refused SOC therapy.
• For all cohorts, in the unlikely scenario that a subject refused all available SOC they may proceed with trial. These subjects would be regarded as having 0 prior LOT.
• Cohorts 1b, 2, 3, and 4 - failed, were intolerant of, ineligible for, or have refused SOC therapy for advanced/metastatic disease (AJCC stage III and IV) and:
• Cohort 2 (subjects with colorectal cancer): Have failed no more than two prior LOT for metastatic CRC.
• Cohort 1b, and Cohort 3 (subjects with EC): Have no more than three prior chemotherapeutic regimens for management of endometrial carcinoma (neo-adjuvant and/or adjuvant chemotherapy will be counted as one prior LOT). Prior hormonal therapy will not count as a systemic regimen.
• Cohort 1b, and Cohort 4 (subjects with clear cell or endometrioid OC): Subjects must have had no more than three prior chemotherapeutic regimens for management of ovarian carcinoma. Prior hormonal therapy will not count as a systemic regimen.
• Life expectancy of at least 3 months.
• At least one measurable lesion (as defined by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1).
• ECOG PS of 0 to 1.
• Adequate organ function
• Absolute neutrophil count (ANC) ≥1.0 × 10^9/L or ≥1.5 x 10^9/L if planned to be treated with nab-paclitaxel, platelet count ≥75 × 10^9/L, and hemoglobin ≥8.5 gm/dL (may be transfused to reach this hemoglobin level unless due to blood loss).
• Liver transaminases (AST and ALT) ≤2.5 × upper limit of normal (ULN) (<5 × ULN if liver metastases are present), and total bilirubin ≤1.5 × ULN (<3 x ULN if subject has Gilbert Syndrome).
• INR ≤1.5 x ULN unless subject is on anticoagulants that would affect the INR, then INR must be in the desired therapeutic range as judged by the Investigator.
• Albumin level ≥3.0 mg/dL or ≥ the lower limit of normal.
• Renal: Serum creatinine ≤2 x ULN
• Ability to take PO medication, be willing to adhere to study procedures and Study Intervention administration, and receive, consume, and comply with Study ISD.
• For women of child-bearing potential, a negative serum pregnancy test collected at screening (Visit-1) and negative urine pregnancy test collected at baseline (Visit-1) and use of physician-approved method of birth control from the time of the pregnancy test performed at screening to 90 days following the last administration of Study Drug or, if applicable, 6 months following the last administration of nab-paclitaxel.
• Male subjects must be surgically sterile or must agree to use physician-approved contraception during the study and for 90 days following the last administration of Study Drug.

Exclusion Criteria

• Diagnosis of primary malignant brain tumor.
• Has had serabelisib, alpelisib, or other PI3K inhibitor.
• Leptomeningeal disease and symptomatic or untreated brain metastases.
• Diagnosis of, or requiring treatment for, another malignancy within the past 2 years (excluding a history of carcinoma in situ of the cervix, superficial non-melanoma skin cancer, or superficial bladder cancer that has been adequately treated, or stage 1 prostate cancer that does not require treatment or requires only treatment with luteinizing hormone-releasing hormone agonists or antagonists if initiated at least 90 days prior to the first dose of Study Drug).
• Is less than 21 days from therapeutic radiation or chemotherapy prior to the first day of dosing with Study Drug and has not recovered to Grade ≤ 1 from all clinically significant toxicities related to prior therapies.
• For subjects receiving nitrosoureas or mitomycin C, the subject is < 6 weeks from last dose. For monoclonal antibody therapy, the subject is < 1 half-life or <4 weeks from the last dose.
• Chronic, systemically administered glucocorticoids in doses equivalent to >5 mg prednisone daily. Replacement corticosteroids for adrenal insufficiency are permitted.
• Diabetes mellitus requiring insulin or insulin secretagogue therapy.
• Poorly controlled diabetes mellitus defined as glycosylated hemoglobin A1c (HbA1c) >7.5% or fasting blood sugar >160 mg/ dL.
• Known impaired cardiac function or clinically significant cardiac disease.
• QTcF interval >470 msec found at screening.
• Myocardial infarction, cardiac stent placement, or unstable angina within 6 months before the first administration of Study Drug.
• Have clinically significant peripheral vascular disease.
• Manifestations of malabsorption
• Other clinically significant comorbidities.
• Pregnant (positive serum pregnancy test), planning to become pregnant during the study, or breastfeeding/planning to breastfeed during the study.
• Have taken strong CYP3A4 inducers/inhibitors within 7 days before the first administration of serabelisib or have conditions that require the concomitant use of CYP3A4 inducers/inhibitors.
• Untreated or poorly controlled, gastro-esophageal reflux disease.
• Have taken histamine-H2 receptor antagonists within 12 hours before the first administration of serabelisib.
• Have taken PPI within 7 days or 5 half-lives (whichever is the shorter duration) before the first administration of serabelisib or are anticipated to need PPI during the study.
• Have taken neutralizing antacids within 4 hours before the first administration of serabelisib or are anticipated to need frequent antacid use during the study.
• Subjects with poorly controlled human immunodeficiency virus, hepatitis B virus, and/or hepatitis C virus infections.
• Known allergies to nab-paclitaxel or excipients, serabelisib or excipients or the ISD
• Severe, uncontrolled gout.
• A BMI <18.5 kg/m2, or serious or refractive cachexia or anorexia that, in the Investigator's opinion, realistically prohibits subjects from having energy or appetite sufficient to reliably engage in a strict ISD regimen for an extended time.
• Any condition that renders the subject unable to satisfactorily chew, swallow, digest, or tolerate (i.e., persistent diarrhea) the majority of foods and liquids of the Study ISD.
• History of severe nephrolithiasis requiring urologic intervention.
• Participation in a diet or weight loss plan within 10 days prior to the first administration of Study Drug.
• Severe constipation or condition where exacerbation of constipation is not advisable (eg, small bowel obstruction history).
• History of anaphylaxis from food allergy or other disease state requiring avoidance of a particular food, such as celiac disease.
• Diagnosed eating disorder in the past 10 years.
• Unwilling to take a non-vegan or non-vegetarian diet.
• Peripheral neuropathy ≥ CTC Grade 2