IRB Study Number 25-307
Status Recruiting
Phase Phase 3
Locations Fairview Hospital, Hillcrest Hospital, Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objective
To evaluate the efficacy of inavolisib plus a CDK4/6i and letrozole compared with placebo plus a CDK4/6i and letrozole
Secondary Objectives
To evaluate the efficacy of inavolisib plus a CDK4/6i and letrozole compared with placebo plus a CDK4/6i and letrozole
To evaluate patient-reported pain severity, functioning, and HRQoL among participants treated with inavolisib plus a CDK4/6i and letrozole compared with placebo plus a CDK4/6i and letrozole
To evaluate the safety of inavolisib plus a CDK4/6i and letrozole compared with placebo plus a CDK4/6i and letrozole
To evaluate the tolerability of inavolisib plus a CDK4/6i and letrozole compared with placebo plus a CDK4/6i and letrozole from the participant's perspective
Inclusion Criteria
Signed Informed Consent Form
Age 18 years at the time of signing Informed Consent Form
Women or men with histologically or cytologically confirmed carcinoma of the breast that is locally advanced or metastatic and is not amenable to surgical or radiation therapy with curative intent
Documented ER–positive and/or progesterone receptor-positive 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 (Allison et al. 2020)
Documented HER2-negative tumor according to ASCO/CAP guidelines, defined as a HER2 immunohistochemistry (IHC) score of 0 or 1 , or an 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 if HER2 status was not retested on the most recent tumor biopsy) and assessed locally (Wolff et al. 2023)
De-novo HR , HER2 ABC, or, alternatively, relapsed HR , HER2 ABC after at least 2 years of standard neoadjuvant/adjuvant endocrine therapy (i.e., tamoxifen, anastrozole, letrozole, exemestane, and/or oral selective estrogen receptor degrader) without disease progression during that treatment and disease-free interval of at least 1 year since the completion of that treatment.
– If a CDK4/6i was included as part of that treatment, progression must not have occurred during or within 1 year of receipt of the CDK4/6i.
Participants who have bilateral breast cancers which are both HR-positive and HER2-negative can be included in the study because the metastases are suitably targeted by the study treatments.
Confirmation of biomarker eligibility: valid results from either central testing of blood or pre-existing local testing of blood or tumor tissue documenting the presence of a study-eligible PIK3CA-mutation.
Eligible PIK3CA mutations are defined as follows:
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
N1044H/I/K/S/T/Y
T1025A/I/S
– The central test for identification of eligible PIK3CA mutations is the 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.
– Unless previously collected as part of the biomarker prescreening process, all participants are required to submit a freshly collected pre-treatment blood sample during screening, regardless of whether participants are enrolled by local or central test results.
– Local tests must have been previously ordered and obtained by the healthcare provider for the participant as part of routine clinical and regional standard-of care for participants with HR , HER2 breast cancer.
– Local tests must have been an appropriately validated PCR- or NGS-based assay performed at a Clinical Laboratory Improvement Amendments (CLIA)- or equivalently-certified laboratory.
– Local test results reported from blood should be from a blood specimen representative of participant’s metastatic disease state, collected after conclusion of the participant’s most recent anti-cancer therapy.
– Local test results reported from tumor tissue should be from the participant’s metastatic disease state whenever possible.
Consent to provide and confirmed availability of a newly-collected fresh (preferred) or previously obtained 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. See Section 8.6 and the laboratory manual for tumor tissue specimen requirements. Refer to Section 8.6 for additional information on collection and analysis of screening samples.
Measurable disease per RECIST v1.1
– Participants with evaluable bone-only disease are not eligible; disease that is limited to bone but has lytic or mixed lytic/blastic lesions and at least one measurable soft-tissue component per RECIST v1.1 1 are eligible.
For women: postmenopausal or premenopausal/perimenopausal status, defined as follows:
– Postmenopausal, as defined by at least one of the following criteria:
o 12 months of amenorrhea without an alternate medical cause plus follicle-stimulating hormone (FSH) and plasma estradiol levels within postmenopausal range by local laboratory assessment, in the absence of oral contraceptive pills, hormone replacement therapy, or gonadotropinreleasing hormone agonist or antagonist. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient (Clinical Trials Facilitation Group [CTFG] Recommendations, 2014). The CFTG Recommendations can be found at the following website:
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Version_1.1_updated.pdf
o Documented bilateral oophorectomy ( 14 days prior to first treatment on Day 1 of Cycle 1 and recovery from surgery to baseline)
– Premenopausal or perimenopausal, defined as not meeting the criteria for postmenopausal, and willing to undergo and maintain treatment with approved LHRH-agonist therapy for the duration of study treatment
– If desired, patients should consider egg banking prior to enrolling in the clinical trial to preserve the potential for future fertility.
For men: willingness to undergo and maintain treatment with LHRH agonist therapy for the duration of study treatment
– If desired, male patients can consider sperm banking prior to enrolling in trial to preserve the potential for future fertility.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
ANC 1.5 109/L (1500/L), with one exception
– Participants with benign ethnic neutropenia (BEN) are eligible if:
ANC 1.3 109/L (1300/L).
BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations (Atallah-Yunes et al. 2019). BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups.
Adequate hematologic and organ function within 14 days prior to initiation of study treatment, defined by the following:
– Absolute neutrophil count meeting the threshold above
– Hemoglobin 9 g/dL
– Platelet count 100,000/L
– Adequate renal function (see exclusion criterion on glomerular filtration rate [GFR])
– Fasting glucose 126 mg/dL ( 7.0 mmol/L) and HbA1c 6.5% ( 48 mmol/mol)
– Total bilirubin 1.5 upper limit of normal (ULN) ( 3 ULN if Gilbert’s disease)
– Serum albumin 2.5 g/dL (25 g/L)
– AST and ALT 2.5 ULN with the following exception:
o Participants with documented liver metastases: AST and ALT 5.0 ULN
– ALP 2.5 ULN with the following exception:
o Participants with documented liver or bone metastases: ALP 5.0 ULN
– INR 1.5 ULN and aPTT 1.5 ULN
o For participants requiring anticoagulation therapy with warfarin or similar agents (such as 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.
Agreement to adhere to the contraception requirements described in Section 5.4
Ability, in the investigator’s judgment, and willingness to comply with all study-related procedures, including completion of patient-reported endpoints
For participants enrolled in the extended China enrollment phase at China's sites: must be current residents of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry
Exclusion Criteria
Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities, unless allowed by local regulations
Patients who are not capable of giving informed consent
Pregnant or breastfeeding, or intention of becoming pregnant during the study or within the time frame in which contraception is required (see Section 5.4.2).
– Participants of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
Metaplastic breast cancer
Treatment with investigational therapy within 28 days prior to initiation of study treatment
Radiotherapy within 2 weeks before randomization
Any prior systemic therapy for locally advanced unresectable or metastatic breast cancer
Appropriate for treatment with cytotoxic chemotherapy at time of entry into the study, as per national or local treatment guidelines (e.g., patients with visceral crisis)
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
Any history of leptomeningeal disease or carcinomatous meningitis
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:
– Measurable disease outside the CNS
– 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
– 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
– Screening CNS radiographic assessments 4 weeks since completion of radiotherapy
– No history of intracranial hemorrhage or spinal cord hemorrhage
Pleural effusion, pericardial effusion, or ascites requiring drainage procedures every 14 days or more frequently
Indwelling pleural or abdominal catheters may be allowed, provided the patient has adequately recovered from the procedure, is hemodynamically stable and symptomatically improved.
Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy
Bisphosphonate and denosumab therapy for bone metastases or osteopenia/osteoporosis is allowed.
Infection requiring intravenous (IV) antimicrobials, or serious infection requiring any antimicrobials, within 7 days prior to Day 1 of Cycle 1
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
Requirement for daily supplemental oxygen
Symptomatic active lung disease that is not specifically due to underlying breast cancer, including pneumonitis
Active tuberculosis
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 thus ineligible.
Any active bowel inflammation (including diverticulitis)
Any serious medical condition or abnormality in clinical laboratory tests that precludes an individual's safe participation in and completion of the study
Prior hematopoietic stem cell or bone marrow transplantation
Unresolved toxicity Grade 1 from prior cancer therapy, except for:
– hot flashes and alopecia (may be any grade)
– peripheral neuropathy (may be up to Grade 2)
Treatment with strong cytochrome P450 (CYP) 3A4 inhibitors or strong CYP3A4 inducers within 4 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study treatment.
Planned surgery during the study (minor procedures such as indwelling catheter placement, if needed, are encouraged to be done prior to the start of study treatment)
Known HIV infection if:
– the CD4 count is less than 350 cells/L or
– there has been an opportunistic infection within the 12 months prior to the start of study treatment or
– there is a potential drug-drug interaction with any of the study treatments (see Section 6.11.1)
Sites should include an HIV test during screening, if clinically indicated, and as allowed per local regulations.
Known clinically significant and active liver disease, including severe liver impairment (Child-Pugh Class B/C), active viral or other hepatitis, current alcohol abuse, or cirrhosis
– Sites should include hepatitis testing during screening, if clinically indicated, and as appropriate per local standards.
Blood transfusion or hematologic growth factors within the 28 days prior to the start of study treatment
GFR 50 mL/min/1.73 m2 as calculated through use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (2021)
GFR should be assessed by calculation through use of the CKD-EPI equation:
CKD‑EPI 142 (serum creatinine/A)B 0.9938Age (1.012 if female), where A and B are the following:
o Female serum creatinine 0.7 mg/dL: A 0.7 and B 0.241
o Female serum creatinine 0.7 mg/dL: A 0.7 and B 1.2
o Male serum creatinine 0.9 mg/dL: A 0.9 and B 0.302
o Male serum creatinine 0.9 mg/dL: A 0.9 and B 1.2
Body-surface area (BSA) adjusted GFR values should be used (multiply the standardized GFR by the individual’s BSA, calculated using an appropriate formula, and divide by 1.73.
History of malignancy within 5 years prior to consent, with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate 90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
History or presence of an abnormal ECG that is deemed clinically significant, (e.g., complete left bundle branch block, second- or third-degree atrioventricular heart block) or evidence of prior myocardial infarction
History of or active clinically significant cardiovascular dysfunction, including the following:
– History of stroke or transient ischemic attack within 6 months prior to first dose of study treatment
– History of myocardial infarction within 6 months prior to first dose of study treatment
– New York Heart Association Class III or IV cardiac disease or congestive heart failure requiring medication
– Uncontrolled arrhythmias, history of or active ventricular arrhythmia requiring medication
– Coronary heart disease that is symptomatic or unstable angina
– QT interval corrected through use of Fridericia’s formula (QTcF) 470 ms based on mean value of triplicate ECGs, history of long or short QT syndrome, Brugada syndrome or known history of corrected QT interval prolongation, or torsades de pointes.
Known allergy or hypersensitivity to any of the study drugs or any of their excipients
For premenopausal/perimenopausal or male-at-birth patients: known hypersensitivity to LHRH agonists
