Study of Chemotherapy Plus Ipatasertib for People With Solid Tumors With PTEN/AKT Mutations, A ComboMATCH Treatment Trial

Inclusion Criteria:

• Patient must have enrolled onto EAY191 and must have been given a treatmentassignment to ComboMATCH to EAY191-S3 based on the presence of an actionablemutation as defined in EAY191

• GENERAL COMBOMATCH EAY191 REGISTRATION INCLUSION CRITERIA:

• Participants must be enrolled on the ComboMATCH Master Registration Trial EAY191

• Participants must have an activating AKT mutation (a known mutation in AKT1, AKT2,or AKT3, a single nucleotide variant, insertion, or deletion), PTEN mutation (aknown mutation in PTEN, a single nucleotide variant, insertion, or deletion), orgenomic deletion loss of PTEN as determined by the ComboMATCH screening assessment

• GENERAL COMBOMATCH EAY191 REGISTRATION EXCLUSION CRITERIA:

• Participants must not have an activating KRAS, NRAS, HRAS, or BRAF mutation (asingle nucleotide variant, insertion, or deletion) as determined by the ComboMATCHscreening assessment

• Participants must have disease that can be safely biopsied and agree to apre-treatment biopsy or have archival tissue available from within 12 months priorto the date of registration on the ComboMATCH Registration Trial (EAY191)

• Participants must have a histologically confirmed non-breast solid malignancy

• Participants must have locally advanced, unresectable, or metastatic disease in theopinion of the treating investigator

• Participants must have measurable disease documented by CT or MRI. Measurabledisease must be assessed within 28 days prior to registration. Non-measurabledisease must be assessed within 42 days prior to registration. The CT from acombined positron emission tomography (PET)/CT may be used only if it is ofdiagnostic quality. All known sites of disease must be assessed and documented onthe Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). Participants whose only measurable disease is within a previousradiation therapy port must demonstrate clearly progressive disease (in the opinionof the treating investigator) prior to registration

• Participants with known brain metastases must have a CT/MRI scan to evaluate forcentral nervous system (CNS) disease and show no evidence of progression within 42days prior to registration

• Participants must have completed any CNS-directed therapy and/or local therapy forspinal cord compression at least 28 days prior to registration

• Participants must not have spinal cord compression or brain metastases unless: (1)metastases have been locally treated and have remained clinically controlled andasymptomatic for at least 14 days prior to registration, AND (2) participant has noresidual neurological dysfunction and has been off corticosteroids for at least 24hours prior to registration

• Participants must not have leptomeningeal disease

• Participants must have progressed on or within 6 months of taxane-based therapy inthe neoadjuvant/adjuvant or metastatic setting prior to registration

• Participants must not have received any prior AKT inhibitor (e.g., capivasertib oripatasertib); prior PI3K/mTOR inhibitor is acceptable

• Participants must not have received cancer-directed therapy prior for at least 14days prior to initiation of treatment on study

• Participants must not be planning to receive any concurrent chemotherapy,immunotherapy, biologic, radiation, or hormonal therapy for cancer treatment whilereceiving treatment on this study

• Participants must be >= 18 years of age

• Participants must be able to swallow oral medications whole

• Participants must have a pre-study history and physical exam done within 28 daysprior to registration

• Participants must have a Zubrod performance status of 0-2 within 28 days prior toregistration

• Participants must have adverse events resolved =< grade 1 related to any priortherapy, except alopecia within 14 days prior to registration

• Participants with neuropathy must have resolved to < grade 2 within 14 days prior toregistration

• Leukocytes >= 3 x 10^3/uL (within 28 days prior to registration)

• Absolute neutrophil count >= 1.5 x 10^3/uL (within 28 days prior to registration)

• Platelets >= 100 x 10^3/uL (within 28 days prior to registration)

• Total bilirubin =< institutional upper limit of normal (ULN) unless history ofGilbert's disease. Participants with history of Gilbert's disease must have totalbilirubin =< 5 x institutional ULN (within 28 days prior to registration)

• Aspartate aminotransferase (AST) & alanine aminotransferase (ALT) =< 3 xinstitutional ULN (within 28 days prior to registration)

• Participants must have adequate cardiac function, class IIB (2B) or better.Participants with known history or current symptoms of cardiac disease, or historyof treatment with cardiotoxic agents, must have a clinical risk assessment ofcardiac function using the New York Heart Association Functional Classification

• Participants must have a measured OR calculated creatinine clearance >= 50 mL/minusing the following Cockcroft-Gault formula. This specimen must have been drawnwithin 28 days prior to registration

• Participants with known human immunodeficiency virus (HIV)-infection must bereceiving anti-retroviral therapy and have an undetectable viral load test on themost recent test results obtained within 6 months prior to registration

• Participants with evidence of chronic hepatitis B virus (HBV) infection must haveundetectable HBV viral load on suppressive therapy within 28 days prior toregistration

• Participants with a history of hepatitis C virus (HCV) infection must have beentreated and cured. Participants with HCV infection who are currently on treatmentmust have an undetectable HCV viral load within 28 days prior to registration

• Participants must have an electrocardiography (ECG) performed (if clinicallyindicated with a corrected QTc interval of =< 470 msec) within 28 days prior toregistration

• Participants must not have a history of allergic reactions attributed to compoundsof similar chemical or biologic composition to ipatasertib and/or paclitaxel

• Participants must not have an active small/large bowel inflammation such asulcerative colitis or Crohn's disease

• Participants must not have grade 2 or higher uncontrolled intercurrent illness

• NOTE: To receive an agent, participant must not have any uncontrolledintercurrent illness requiring antibiotic/antiviral/antifungal therapy orinterventional procedures. Participants with infections unlikely to be resolvedwithin 2 weeks following registration should not be considered for the trial

• Participants must not have a known grade 2 or higher uncontrolled or untreatedhypercholesterolemia or hypertriglyceridemia

• Participants must not have any of the following:

• Cirrhosis at a level of Child-Pugh B (or worse),

• Cirrhosis (any degree) and a history of hepatic encephalopathy, or

• Clinically meaningful ascites resulting from cirrhosis. Clinically meaningfulascites is defined as ascites from cirrhosis requiring diuretics orparacentesis

• Participants must not be receiving any medications or substances that are inhibitorsor inducers of CYP3A. Treatment with strong CYP3A inhibitors or strong CYP3Ainducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, priorto initiation of study drug is prohibited.

• NOTE: Because the lists of these agents are constantly changing, it isimportant to regularly consult a frequently updated medical reference. As partof the enrollment/informed consent procedures, the participant will becounseled on the risk of interactions with other agents, and what to do if newmedications need to be prescribed or if the participant is considering a newover-the-counter medicine or herbal product. The participant wallet card shouldbe presented to the participant

• Participants must not have baseline fasting glucose (after 8-hour fast) > 160 mg/dL (8.9 mmol/L) within 28 days prior to registration

• Participants with known diabetes mellitus must not require insulin therapy or have abaseline fasting glucose >150 mg/dL (8.3 mmol/L) or high glycosylated hemoglobin (Hb)A1c, (>= 8.0%), suggesting poorly controlled diabetes

• Participants who are on a stable dose of oral diabetes medication >= 2 weeks priorto initiation of study drug treatment are eligible for enrollment

• Participants with a prior or concurrent malignancy whose natural history ortreatment (in the opinion of the treating physician) must not have a potential tointerfere with the safety or efficacy assessment of the investigational regimen

• Participants must not have lung disease requiring active systemic therapy or placingparticipants at increased risk of toxicity related to study-directed therapyincluding, but not limited to pneumonitis, interstitial lung disease, idiopathicpulmonary fibrosis, cystic fibrosis, aspergillosis, active tuberculosis, or historyof opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia)

• Participants must not be pregnant or nursing. Individuals who are of reproductivepotential must have agreed to use an effective contraceptive method with detailsprovided as a part of the consent process. A person who has had menses at any timein the preceding 12 consecutive months or who has semen likely to contain sperm isof "reproductive potential". In addition to routine contraceptive methods, "effective contraception" also includes surgery intended to prevent pregnancy (orwith a side-effect of pregnancy prevention) including hysterectomy, bilateraloophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showingno sperm in the semen

• Participants must not have psychiatric illness/social situations that would limitcompliance with study requirements