A study to evaluate the safety, tolerability, processing by the body, and antitumor activity of inavolisib and paclitaxel

• Signed Informed Consent Form
• Aged over 18 years and over
• Evaluable or measurable disease per RECIST, v1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of >12 weeks
• Adequate hematologic and organ function within 14 days prior to initiation of study treatment, defined by the following:
  • Absolute neutrophil count 1500/μl
  • Hemoglobin ≥9 g/dl
  • Platelet count ≥100,000/l
  • Fasting glucose <126 mg/dL or <7 mmol/l and glycosylated hemoglobin (HbA1C) 5.7% or <39 millimoles per mole (mmol/mol)
  • Total bilirubin <1.5 upper limit of normal (ULN)
  • Serum albumin ≥2.5 g/dl or 25 g/l
  • AST and ALT ≤2.5 ULN with the following exception: patients with documented liver metastases may have AST and ALT ≤5.0 ULN.
  • Serum creatinine 1.5 ULN or creatinine clearance ≥50 ml/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation
  • International normalized ratio (INR) <1.5 x upper limit of normal (ULN) and activated partial thromboplastin time (aPTT) <1.5 x ULN
• Consent to provide fresh (preferred) or archival tumor tissue specimen. It is preferred that the specimen be from the most recently collected and available tumor tissue, and whenever possible, from a metastatic site of disease.
• Consent to provide a freshly collected pre-treatment blood sample.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective form of contraceptive method with a failure rate of 1% per year in combination with use of male condom with spermicide (for male partners), unless male sterilization has been confirmed.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive measures, and agreement to refrain from donating sperm.

Inclusion Criteria Specific to Patients Enrolling in Part 1, Arm A:

• Histologically documented, locally advanced, recurrent, or metastatic, incurable solid tumor malignancy that has progressed after available standard systemic therapies; or for whom standard therapy has proven to be ineffective or intolerable; or for whom a clinical trial of an investigational agent is a recognized standard of care. If there are other available SOC therapies, these will be discussed with the patient and documented before informed consent is obtained.

Inclusion Criteria Specific to Patients Enrolling in Part 2, Arm A Expansion Cohorts:

• Histologically documented, locally advanced, recurrent, or metastatic, incurable solid tumor malignancy with a known PIK3CA mutation that has progressed after at least one available standard systemic therapy in the metastatic setting.
  - Cohort 1 (HNSCC): Histologically or cytologically confirmed recurrent and/or metastatic HNSCC that has been previously treated with systemic therapy in the recurrent and/or metastatic setting, which may include immunotherapy and/or chemotherapy with or without cetuximab.
  - Cohort 2 (ovarian cancer): Persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal tumors that have been previously treated with up to 4 prior regimens in the recurrent and/or metastatic setting, being at least one platinum-based. Patients may have received bevacizumab and/or poly-ADP ribose polymerase (PARP) inhibitors.
  - Cohort 3 (TNBC): Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic, not amenable to surgical or radiation therapy with curative intent, which has progressed after all available standard therapies, or for which standard therapy has proven to be ineffective or intolerable.
  - Cohort 4 (endocrine resistant/refractory HR-positive, HER2 negative breast cancer):
  Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to surgical or radiation therapy with curative intent and has progressed after all available endocrine-based standard therapies in the locally advanced/metastatic setting or for which endocrine-based standard therapy has proven to be ineffective or intolerable.

• Confirmation of biomarker eligibility: valid results from central testing of blood or local testing of blood or tumor tissue documenting PIK3CA-mutated tumor status is required for patients enrolling to Part 2, Arm A, expansion cohorts.

• Metaplastic breast cancer
• Any history of leptomeningeal disease
• Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes
• Inability or unwillingness to swallow pills
• Malabsorption syndrome or other condition that would interfere with enteral absorption
• Known and untreated, or active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control).
• Uncontrolled pleural effusion or ascites requiring recurrent drainage procedures twice per month or more frequently
• Any active infection that, in the opinion of the investigator, could impact patient safety; or, serious infection requiring IV antibiotics within 7 days prior to Day 1 of Cycle 1
• Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in the opinion of the investigator or study ophthalmologist, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition
• Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or autoimmuneassociated uveitis in either eye
• Patients requiring any daily supplemental oxygen
• History of or active inflammatory disease (e.g., Crohn’s disease or ulcerative colitis), or any active bowel inflammation (including diverticulitis). Patients currently receiving immunosuppressants (e.g., sulfasalazines) are considered to have active disease; therefore, they are ineligible.
• Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy
• Clinically significant history of liver disease, including severe liver impairment (Child-Pugh Class B/C), viral or other hepatitis, current alcohol abuse, or cirrhosis
• Known HIV infection
• Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or renders the patients at high risk from treatment complications
• Significant traumatic injury or major surgical procedure within 4 weeks prior to initiation of study treatment
• Radiation therapy (other than palliative radiation to bony metastases) as cancer therapy within 4 weeks prior to initiation of study treatment
• Palliative radiation to bony metastases within 2 weeks prior to initiation of study treatment
• Unresolved toxicity from prior therapy, except for the following: Alopecia Grade 1 and peripheral neuropathy
• Inability to comply with study and follow-up procedures
• History of other malignancy within 5 years prior to screening, with the exception of patients with a negligible risk of metastasis or death and/or treated with expected curative outcome (such as appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer)
• History of or active ventricular dysrhythmias or congestive heart failure requiring medication or coronary heart disease that is symptomatic
• Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia)
• Congenital long QT syndrome or QT interval corrected with Fridericia’s formula (QTcF) 470 ms demonstrated by at least two ECGs 30 minutes apart, or family history of sudden unexplained death or long QT syndrome
• Current treatment with medications that are well known to prolong the QT interval
• Allergy or hypersensitivity to components of the inavolisib formulation and paclitaxel
• Pregnancy, lactation, or intention to become pregnant or fathering a child during the study
• Women of childbearing potential (including those who have had a tubal ligation) must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

Exclusion Criteria Specific to Patients Enrolling Part 1, Arm A:

• History of prior significant toxicity related to a PI3K, AKT, or mTOR inhibitor requiring discontinuation of treatment. Patients may have received prior treatment with a PI3K, AKT, or mTOR inhibitor
• History of prior significant toxicity related to paclitaxel treatment requiring discontinuation of treatment. Patients may have received prior treatment with paclitaxel
• Treatment with chemotherapy, immunotherapy, or biologic therapy as anti-cancer therapy within 21 days prior to initiation of study treatment, except for the following: Kinase inhibitors, approved by regulatory authorities, may be used up to 2 weeks prior to initiation of study treatment, provided any drug-related toxicity has resolved up to Grade 1 and prior approval is obtained from the Medical Monitor. Treatment with an investigational agent within 3 weeks or five half-lives prior to initiation of study treatment, whichever is shorter. A shorter washout period may be allowed if the patient has adequately recovered from any clinically relevant toxicity and with prior approval from the Medical Monitor.
• Prior anti-cancer therapy that fulfills the following criteria: High dose chemotherapy requiring stem-cell support; Irradiation to 25% of bone marrow-bearing areas

Exclusion Criteria Specific to Patients Enrolling Part 2, Arm A:

• History of prior significant toxicity related to a PI3K, AKT, or mTOR inhibitor requiring discontinuation of treatment.
• Prior treatment with any PI3K-specific inhibitor
• History of prior significant toxicity related to paclitaxel treatment requiring discontinuation of treatment. Patients may have received prior treatment with paclitaxel
• Treatment with chemotherapy, immunotherapy, or biologic therapy as anti-cancer therapy within 21 days prior to initiation of study treatment, except for the following: Kinase inhibitors, approved by regulatory authorities, may be used up to 2 weeks prior to initiation of study treatment, provided any drug-related toxicity has resolved up to Grade 1 and prior approval is obtained from the Medical Monitor Treatment with an investigational agent within 3 weeks or five half-lives prior to initiation of study treatment, whichever is shorter
• Prior anti-cancer therapy that fulfills the following criteria: high dose chemotherapy requiring stem-cell support Irradiation to 25% of bone marrow-bearing areas