INAVO121 WO43913

1) Signed Informed Consent Form.

2) Women or men 18 years or over of age at time of signing Informed Consent Form.

3) If female, patients must meet at least one of the following definitions:
|— a) Postmenopausal, as defined by at least one of the following criteria:
|— — ~) Age ≥ 60 years.
|— — ~) Age < 60 years and ≥ 12 months of amenorrhea plus follicle-stimulating hormone and plasma or serum estradiol levels within postmenopausal range by local laboratory assessment in the absence of oral contraceptive pills, hormone replacement therapy, or gonadotropin-releasing hormone analogue.
|— — ~) Documented bilateral oophorectomy (≥ 14 days prior to first treatment on Day 1 of Cycle 1 and recovery to baseline).
|— b) Premenopausal or perimenopausal (i.e., not meeting the criteria for postmenopausal) and meeting the following criterion:
|— — ~) Treatment with luteinizing hormone-releasing hormone (LHRH) agonist therapy (e.g., goserelin or leuprolide) beginning at least 2 weeks prior to Day 1 of Cycle 1 and continuing for the duration of study treatment.

4) If male, recommendation of treatment with LHRH agonist therapy (e.g., goserelin or leuprolide) beginning at least 2 weeks prior to Day 1 of Cycle 1 and continuing for the duration of study treatment.

5) 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.

6) Documented HR+ tumor, according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, defined as ≥ 1% of tumor cells stained positive based on the most recent tumor biopsy and assessed locally (Wolff et al. 2007).

7) Documented HER2- tumor according to ASCO/CAP guidelines, defined as: a HER2 immunohistochemistry (IHC) score of 0 or 1+, or HER2 IHC score of 2+ accompanied by a negative fluorescence, chromogenic, or silver in situ hybridization test indicating the absence of ERBB2 gene amplification, or a HER2/CEP17 ratio of < 2.0 based on the most recent tumor biopsy (or archived tumor sample).

8) Confirmation of biomarker eligibility: valid results from either central testing of blood or prior local testing of blood or tumor tissue documenting PIK3CA-mutated tumor status:
|— a) Eligible PIK3CA mutations are defined as follows:
|— — ~) H1047D/I/L/N/P/Q/R/T/Y
|— — ~) E545A/D/G/K/L/Q/R/V
|— — ~) E542A/D/G/K/Q/R/V
|— — ~) Q546E/H/K/L/P/R
|— — ~) N345D/H/I/K/S/T/Y
|— — ~) C420R
|— — ~) M1043I/T/V
|— — ~) G1049A/C/D/R/S
|— — ~) E453A/D/G/K/Q/V
|— — ~) K111N/R/E
|— — ~) G106A/D/R/S/V
|— — ~) G118D
|— — ~) R88Q
|— b) The central test for identification of eligible PIK3CA mutations is the FoundationOne(R) Liquid CDx (F1LCDx) assay performed at Foundation Medicine, Inc. (FMI). In localities where F1LCDx is not available, samples will be submitted to an alternative, Sponsor-designated central testing laboratory. All patients are required to submit a freshly collected pre-treatment blood sample, regardless of whether patients are enrolled by local or central test results, unless previously collected as part of the prescreening process. Local tests must have been ordered by the health care provider (HCP) for the patient as part of clinical and regional standard-of-care for patients with HR+ /HER2- breast cancer.
|— c) Local tests must be an appropriately validated PCR- or NGS-based assay performed at a CLIA- or equivalently-certified laboratory. In the European Union, local tests must comply with the In Vitro Diagnostic Regulation (IVDR) requirements applicable to the region.
|— d) The full laboratory report documenting the study-eligible PIK3CA mutation result must be available and submitted for confirmation upon enrollment. Local test results reported from blood should be from a blood specimen representative of the patient’s locally advanced or metastatic disease state, collected after conclusion of the patient’s most recent anti-cancer therapy. Local test results reported from tumor tissue should be from the patient’s locally advanced or metastatic disease state whenever possible.

9) Consent to provide a 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. If neither of these options is available, the Medical Monitor is available to advise as needed. Please refer to the laboratory manual for specimen requirements.

10) Disease progression after or during treatment with a combination of CDK4/6i and ET:
|— a) Patients must have received no more than two prior lines of systemic therapy in the locally advanced (recurrent or progressed) or metastatic setting.
|— b) The CDK4/6i therapy does not need to be the latest treatment regimen received prior to study entry.
|— c) Each “line” (i.e., unique regimen) is defined as a single or combination of agents given for a new relapse/progression. Maintenance therapies, where applicable, must be regarded as part of the main line of therapy.
|— d) One of the prior lines of systemic therapy in the LA/mBC setting may have included chemotherapy.

11) Measurable disease per RECIST v1.1.
|— a) Moreover, patients with no measurable disease may be eligible provided they have at least one predominantly lytic bone lesion confirmed by computed tomography (CT) or magnetic resonance imaging (MRI).
|— — ~) Any tumor lesions previously irradiated or subjected to other locoregional therapy will be deemed measurable only if disease progression at the treated site after completion of therapy is clearly documented.

12) Patients for whom endocrine-based therapy is recommended and treatment with cytotoxic chemotherapy is not indicated (e.g., patients with visceral crisis) at time of entry into the study, as per national or local treatment guidelines.

13) For women participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined below:
|— a) Women must remain abstinent or use non-hormonal contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 60 days after the final dose of inavolisib. Based on local prescribing information for fulvestrant, patients may be advised to use an effective means of contraception for up to 2 years after the final dose of fulvestrant and 1 week after the last dose of alpelisib. Women must refrain from donating eggs during this same period.
|— b) 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). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.
|— c) Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices.
|— d) The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, locally recognized acceptable methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

14) For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:
|— a) With a female partner of childbearing potential who is not pregnant, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 98 days after final dose of inavolisib. Based on local prescribing information for fulvestrant, patients may be advised to use an effective means of contraception for up to 2 years after the final dose of fulvestrant and 1 week after the last dose for alpelisib. Men must refrain from donating sperm during this same period.
|— b) With a pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 98 days after final dose of inavolisib to avoid exposing the embryo. Based on local prescribing information for fulvestrant, patients may be advised to use an effective means of contraception for up to 2 years after the final dose of fulvestrant and 1 week after the last dose for alpelisib. Men must refrain from donating sperm during this same period.
|— c) The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.

15) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.

16) Life expectancy of > 6 months.

17) Adequate hematologic and organ function prior to initiation of study treatment, defined by the following:
|— a) Absolute neutrophil count ≥ 1200 microliters.
|— b) Hemoglobin ≥ 9 g/dL.
|— c) Platelet count ≥ 100,000 microliters.
|— d) Fasting glucose < 126 mg/dL [ < 7.0 mmol/L] and HbA1c < 6.4% [< 46 mmol/mol].
|— — ~) For patients with fasting glucose ≥ 100 mg/dL [≥ 5.5 mmol/L] (i.e., threshold for pre-diabetes) at baseline, recommend lifestyle changes according to American Diabetes Association guidelines; that is, dietary advice (e.g., small frequent meals, low carbohydrate content, high fiber, balanced carbohydrate intake over the course of the day, three small meals and two small snacks rather than one large meal) and exercise. Consultation with an endocrinologist or diabetologist is highly recommended.
|— e) Total bilirubin ≤ 1.5 * upper limit of normal (ULN) (≤ 3 * ULN if Gilbert’s disease).
|— f) Serum albumin ≥ 2.5 g/dL [25 g/L].
|— g) AST and ALT ≤ 2.5 * ULN with the following exception:
|— — ~) Patients with documented liver metastases may have AST and/or ALT ≤ 5.0 * ULN.
|— h) ALP ≤ 2.5 * ULN with the following exception:
|—- —- ~) Patients with documented liver or bone metastases may have ALP ≤ 5.0 * ULN.
|— i) Serum creatinine ≤ 1.5 * ULN or creatinine clearance ≥ 50 mL/min using Cockcroft Gault formula.
|— j) INR < 1.5 * ULN.
|— — ~) For patients requiring anticoagulation therapy with warfarin or similar agents (e.g., Vitamin K antagonists), a stable INR between 2 and 3 is required.
|— — ~) If anticoagulation is required for a prosthetic heart valve, then stable INR between 2.5 and 3.5 is permitted. Consult the local prescribing information for fulvestrant.

18) Negative hepatitis B surface antigen (HBsAg) test at screening.

19) Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening

20) Negative hepatitis C virus (HCV) antibody test at screening, or a positive HCV antibody test followed by a negative HCV RNA test at screening:
|— a) The HCV RNA test must be performed for individuals who have a positive HCV antibody test.

21) Ability, in the investigator’s judgment, and willingness to comply with all study -related procedures, including completion of patient-reported outcomes.

22) For participants enrolled in a potential extended China enrollment phase at China’s sites: must be current residents of mainland China and of Chinese ancestry.

1) Metaplastic breast cancer.

2) 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.

3) Participant who relapsed with documented evidence of progression > 12 months from completion of adjuvant CDK4/6i based therapy with no treatment for metastatic disease.

4) Pregnant, lactating, or breastfeeding, or intending to become pregnant during the study or within 60 days after the final dose of study treatment (based on local prescribing information for fulvestrant, patients may be advised to use an effective means of contraception for up to 2 years after the last dose of fulvestrant and 1 week after the last dose of alpelisib.
|— a) 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.

5) Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes.

6) Inability or unwillingness to swallow pills.

7) Malabsorption syndrome or other condition that would interfere with enteral absorption.

8) Any history of leptomeningeal disease or carcinomatous meningitis.

9) Known and untreated, or active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria:
|— a) Measurable disease outside the CNS.
|— b) No ongoing requirement for corticosteroids as therapy for CNS metastases, with corticosteroids discontinued for ≥ 2 weeks prior to enrollment and no ongoing symptoms attributed to CNS metastases.
|— c) Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic assessments.
|— d) Screening CNS radiographic assessments ≥ 4 weeks since completion of radiotherapy.
|— e) No history of intracranial hemorrhage or spinal cord hemorrhage.

10) Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures every 2 weeks or more frequently.

11) Indwelling pleural or abdominal catheters may be allowed, provided the patient has adequately recovered from the procedure, is hemodynamically stable and symptomatically improved prior to enrollment.

12) Known active, systemic bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major
episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 7 days prior to Day 1 of Cycle 1.

13) Any concurrent ocular or intraocular condition (e.g., cataract or 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.

14) 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 autoimmune-associated uveitis in either eye.

15) Requirement for daily supplemental oxygen.

16) Symptomatic active lung disease, including pneumonitis.

17) 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., sulfasalazines) are considered to have active disease and are therefore ineligible.

18) Any active bowel inflammation (including diverticulitis).

19 Clinically significant and active liver disease, including severe liver impairment (Child-Pugh Class B/C), viral or other hepatitis (e.g., hepatitis B or hepatitis C),
current alcohol abuse, or cirrhosis.

20) Patients with known HIV infection (screening HIV test should be performed as allowed by local regulations), who have:
|— a) CD4+ T-cell (CD4+) counts < 350 cells microliters AND/OR…
|— b) A history of AIDS-defining opportunistic infection within the past 12 months.

21) 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.

22) Chemotherapy, radiotherapy, or any other anti-cancer therapy within 2 weeks before randomization.

23) Investigational drug(s) within 4 weeks before randomization or within 5 half-lives of the investigational drug(s), whichever is longer.

24) Prior radiotherapy to > 25% of bone marrow, or hematopoietic stem cell or bone marrow transplantation.

25) Unresolved toxicity from prior therapy, except for hot flashes, alopecia, and Grade ≤ 2 peripheral neuropathy.

26) History of other malignancy within 5 years prior to screening, except for cancers with very low risk of recurrence including, but not limited to, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer.

27) History of or active clinically significant cardiovascular dysfunction, including the following:
|— a) History of stroke or transient ischemic attack within 6 months prior to first dose of study treatment.
|— b) History of angina pectoris or myocardial infarction within 6 months prior to first dose of study treatment.
|— c) History of documented congestive heart failure (New York Heart Association Class II-IV) or cardiomyopathy.
|— d) Uncontrolled arrhythmias, history of or active ventricular arrhythmia requiring medication.
|— e) Coronary heart disease that is symptomatic or unstable angina.
|— f) 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.

28) Chronic therapy of ≥ 10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic disease.

29) Allergy or hypersensitivity to components or excipients of the inavolisib, fulvestrant, or alpelisib formulations.

30) Treatment with strong CYP3A4 inducers or strong CYP3A4 inhibitors within 1 week or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study
treatment.

31) History of severe cutaneous reactions like Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinphilia and Systemic Symptoms (DRESS).

32) Active ongoing osteonecrosis of the jaw.

33) Major surgical procedure, or significant traumatic injury, within 28 days prior to Day 1 of Cycle 1 or anticipation of the need for major surgery during the course of study treatment.

34) Patients must have sufficiently recovered from surgery, including adequate wound healing.

35) Minor surgical procedures < 7 days prior to first dose of study treatment Patients must have sufficiently recovered from surgery, including adequate wound healing.

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