Inavolisib for PIK3CA Mutated Advanced Endometrial Cancer: MITO END-4

The PTEN-PI3K-AKT pathway is frequently altered in gynecological tumors, notably in endometrial cancer (EC). Inavolisib is a highly potent and selective PI3K inhibitor that also facilitates the degradation of mutated PI3Kα isoform. The aim of the current trial is to test if inavolisib in PIK3CA mutated endometrial cancer is active enough to merit further future investigations. Patients whose tumors harbor a pathogenic PIK3CA mutation will receive single agent therapy with Inavolisib. Inavolisib will be given orally at a dosage of 9 mg once daily for each day of a 28-day cycle until disease progression or unacceptable toxicity. Approximately 48 patients with PIK3CA mutation will be overall enrolled in the study. Primary Endpoint is the Objective response rate (ORR) defined as a complete response (CR) or partial response (PR) by the Investigator using RECIST 1.1 criteria on the whole treatment period. Secondary objectives are: -description of 6 months progression-free survival (PFS), Description of disease-control rate (DCR), Description of duration of response (DoR), Description of response rate in patients with different PIK3CA mutations, Description of response rate in patients with PIK3CA mutations and PTEN intact, Description of 1 year overall survival (OS), Description of response rate to inavolisib with respect to the PTEN molecular status including LOF in order to assess its potential predictive role of response, to evaluate the safety of inavolisib in the overall study population. Explorative objectives: To evaluate the response to inavolisib in correlation with molecular characteristics of the tumour evaluated on the tissue samples and to follow the identified mutations in the blood during therapy.

Inclusion criteria

• Signed informed consent prior to any study specific procedures.
• Female, age ≥ 18 years at time of signing informed consent.
• Patients with histologically or cytologically confirmed diagnosis of advanced, recurrent or metastatic endometrial carcinoma (endometrioid, serous, clear cell, carcinosarcoma or mixed histology).
• Biomarker eligibility: valid results from testing of tumor tissue documenting PIK3CA mutations listed below (a-m); however, activating PIK3CA mutations not listed may also be included, capped at 20% of the study population.

H1047D/I/L/N/P/Q/R/T/Y G1049A/C/D/R/S E545A/D/G/K/L/Q/R/V E453A/D/G/K/Q/V E542A/D/G/K/Q/R/V K111N/R/E Q546E/H/K/L/P/R G106A/D/R/S/V N345D/H/I/K/S/T/Y G118D C420R R88Q M1043I/T/V

• Data from the reports indicating the pertinent PIK3CA mutation as well as the status of PTEN gene, and relative variant of allelic frequency (VAF) for each altered gene must be available upon enrollment. Local test results reported from tumor tissue should be from the patient's locally advanced or metastatic disease state whenever possible. Specifically, the detection of PIK3CAm combined with knowledge of PTEN molecular status is mandatory for the screening.
• All patients are required to submit a paraffin embedded block from the primary surgery/biopsy (chemotherapy - naive patients) and a freshly collected pre-treatment blood samples. A quality control analysis of samples will be performed by the Sponsor, before patient's enrollment. Only patients with adequate tumor sample will be enrolled.
• Patients must have progressed after or during a platinum based-chemotherapy with or without immunotherapy in any setting. Specifically, patients receiving previous platinum-based chemotherapy in the neoadjuvant or adjuvant setting must have progressed within 6 months of last platinum therapy.
• Patients must have received no more than 4 previous systemic therapy for endometrial cancer. Specifically, endocrine therapies, maintenance with PARP inhibitor or selinexor are not counted as a systemic line of therapy.
• At least 1 measurable target lesion according to RECIST 1.1
• Patients must have a life expectancy ≥ 16 weeks.
• ECOG performance status of 0 to 1 within 28 days of enrollment.
• Documented markers such as mismatch repair (MMR) status, hormone receptors (estrogen and progesterone receptors) and p53 status according to molecular or immunohistochemical classification of EC.
• Patient must be able to take oral medications.
• Patients must have normal organ and bone marrow function measured as defined below:

Haemoglobin ≥ 9.0 g/dL with no blood transfusion in the past 28 days Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN Total bilirubin < 1.5 x upper limit of normal (ULN) (< 3 x ULN if Gilbert's disease).

• Patients must have creatinine clearance (CrCL) estimated of ≥30 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test: Estimated creatinine clearance = (140-age [years]) x weight (kg) / a serum creatinine (mg/dL) x 72 (x F) (where F=0.85 for females).

The recommended starting dosage of inavolisib for patients with moderate renal impairment (CrCL 30 to <60 mL/min) is 6 mg orally once daily.

INR or PT aPTT/PTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (INR between 2.5 and 3.5 x ULN is permitted).

Fasting blood glucose ≤140 mg/dL and HbA1c <6.5%. Specifically, patients with Type 2 diabetes are eligible to enroll provided they meet the above criteria for fasting blood glucose and HbA1C and are on a stable dose of no more than one oral antidiabetic agent for ≥2 weeks prior to initiation of study treatment. The administration of insulin should not be counted as a 2nd agent.

• Patients are eligible to participate only if they are not not pregnant or breastfeeding, and at least one of the following conditions applies.

• Is not a Women of Childbearing Potential (WOCBP) A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis).
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for at least 1 weeks after the final dose of inavolisib. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) within 24 hours before the first dose of study intervention.

Note If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion criteria

• Endometrial tumors with the following histologies: squamous carcinomas, sarcomas.
• Prior treatment in locally advanced or metastatic setting with any PI3K, AKT, or mTOR inhibitor or any agent whose mechanism of action is to inhibit the PI3K/AKT/mTOR pathway.
• Any history of Type 1 diabetes and Type 2 diabetics patients with fasting blood glucose >140 and HbA1C ≥6.5%, and/or those that require 2 or more anti-diabetic agents should be excluded.
• Subjects known to be positive for Human Immunodeficiency Virus (HIV).
• Patients with known active hepatitis (i.e. Hepatitis B or C)

• Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Patients unable to swallow orally administered medication and patients with gastrointestinal malabsorption or any other condition that may interfere with absorption of Inavolisib.
• Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment.
• Major surgery within 28 days weeks of starting study treatment and patients must have recovered from any effects of major surgery. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
• Minor surgical procedures < 7 days prior to first dose of study treatment.
• Patients must have sufficiently recovered from surgery, including adequate wound healing.
• Known untreated CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (i.e. without evidence of progression) for at least 4 weeks by repeat imaging (Note: The repeat imaging should be performed during study Screening.), clinically stable, and without requirement of steroid treatment for at least 14 days before the first dose of study intervention.
• Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS).
• Participation in another clinical study with an investigational drug product within 4 weeks before randomization.
• Subjects who have not recovered adequately from any toxicity from other anti-cancer treatment regimens except for hot flashes, alopecia, and Grade 2 peripheral neuropathy.
• Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, coronary heart disease, myocardial infarction, cerebrovascular accident/stroke within 12 months of the first dose of study drug, or cardiac arrhythmia associated with hemodynamic instability. Medically controlled arrhythmia would be permitted.
• Congenital long QT syndrome or QT interval corrected through use of Fridericia's formula > 470 ms demonstrated by at least two ECGs >30 minutes apart, or family history of sudden unexplained death or long QT syndrome.
• Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia).
• Chronic corticosteroid therapy of ≥10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic disease.
• Allergy or hypersensitivity to formulation components of inavolisib or any other drug under study.
• Serious infection requiring IV antibiotics within 7 days prior to Day 1 of Cycle 1
• Symptomatic active lung disease, including pneumonitis.
• History of or active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis).
• Patients currently receiving immunosuppressants for inflammatory bowel disease (e.g., sulfasalazine) are considered to have active disease and are therefore ineligible.
• Any active bowel inflammation (including diverticulitis).
• Any concurrent ocular or intraocular condition (e.g., diabetic retinopathy) that, in the opinion of the investigator, 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., eratitis, scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye.
• Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, metabolic, or infectious disease) or 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 that renders the patient at high risk from treatment complications.