VERITAC-2 C48910001

1) Participants aged 18 years or older (or the minimum age of consent in accordance with local regulations) at screening.
|— a) Female participants under 60 years of age, with cessation of regular menses for 12 consecutive months and with no other alternative medical cause, must have a FSH level within the post-menopausal level, as per local laboratory reference range.
|— b) Pre/ peri-menopausal female and male participants must agree to initiate or continue to use an LHRH agonist as per Table 2 and Section 6.9.1.
|— c) WOCBP female and male participants must agree to use contraception. Refer to Appendix 4 for further details.

2) Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.

3) Histological or cytological confirmation of breast cancer with evidence of locoregional recurrent or metastatic disease which is not amenable to surgical resection or radiation therapy with curative intent.
|— a) Documented ER(+) tumor, defined as ER(+) ≥10% stained cells by an assay consistent with local standards, on the most recent tumor biopsy, ie, at diagnosis of recurrence or metastatic disease (Allison et al, 2020). The sole exception is those participants with bone only disease for whom ER(+) using archival tissue at initial diagnosis is acceptable.
|— b) Documented HER2(-) tumor by either IHC or in-situ hybridization per ASCO/CAP guidelines (Wolff et al, 2018).
|— c) Participants who have bilateral breast cancers which are both ER(+)/HER2(-) are eligible.
|— d) Participants must provide a blood sample AND a tumor sample collected at the time of diagnosis of locoregional recurrent or metastatic disease. If not available, a de novo biopsy is required. Participants with bone lesions only: archival tumor tissue at initial diagnosis is acceptable. Refer to Section 8.7.1 for details.

4) Prior therapies for locoregional recurrent or metastatic disease must fulfill all the following criteria:
|— a) One line of CDK4/6 inhibitor therapy in combination with ET.
|— b) ≤1 endocrine therapy in addition to CDK4/6 inhibitor with ET.
|— c) Most recent endocrine treatment duration must have been given for ≥6 months prior to disease progression.
|— d) Radiological progression during or after the last line of therapy.
NOTE: A neoadjuvant/adjuvant treatment is counted as a line for locoregional recurrent or metastatic disease if relapse occurs on or within 12 months after last dose.

5) At least one measurable lesion as defined by RECIST version 1.1. Bone only disease: participants with only non-measurable disease are eligible. Refer to Section 8.2.1.

6) ECOG PS ≤1.

1) History of any other solid tumor malignancies within the past three years, except for the following:
|— a) Adequately treated basal or squamous cell carcinoma of the skin.
|— b) Curatively treated in situ carcinoma of the cervix. For all other solid tumors, must have been curatively treated and with no evidence of disease for >3 years. Participants with inflammatory breast cancer are excluded.

2) Participants with newly diagnosed brain metastasis or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Participants with a history of CNS metastases or cord compression are eligible if they have been definitively treated (e.g., radiotherapy, stereotactic surgery) and clinically stable (including participants with residual CNS symptoms/deficits) off enzyme-inducing anticonvulsants and steroids for at least 14 days prior to randomization.

3) Major surgery or radiotherapy or prior endocrine therapy, CDK4/6 inhibitor, or other anticancer treatments within 14 days of randomization (28 days or 5 half-lives, whichever is shorter, for anticancer therapy containing an antibody- based agent, approved or investigational). Participants who received prior radiotherapy to ≥ 25% of bone marrow are not eligible independent of when it was received (Appendix 12).

4) Participants in visceral crisis at risk of immediately life-threatening complications in the short term, including participants with massive uncontrolled effusions (pleural, pericardial, and peritoneal), pulmonary lymphangitis, or liver involvement > 50%.

5) Impaired cardiovascular function or clinically significant cardiovascular diseases, defined as:
|— a) Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Class III or IV), cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism or other clinically significant episode of thromboembolic disease, congenital long QT syndrome, Torsade de Pointes, clinically important arrhythmias, left anterior hemiblock (bifascicular block), ongoing cardiac dysrhythmias of NCI-CTCAE Grade ≥2, atrial fibrillation of any grade.
|— b) Participants with cardiac rhythm device/ pacemaker (QTc Sub-study). For all the other participants with cardiac rhythm device/pacemaker eligibility must be discussed in detail with the sponsor medical monitor.
|— c) QTcF interval >470 msec on screening ECG.
|— d) Symptomatic cardiac valve disease. Participants with mitral valve prolapse which is asymptomatic or not associated with clinically significant sequelae (eg, mitral regurgitation) are eligible.

6) Refractory nausea and vomiting, chronic GI disease, GI ulcer, GI bleeding, inability to swallow the formulated product, or previous significant gastric (total or partial) or bowel resection that would preclude adequate absorption of study drug.

7) Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.

8) Concurrent administration of medications, food or herb supplements that are strong inhibitors and inducers of CYP3A and drugs known to predispose to Torsade de Pointes or QT interval prolongation (see Section 6.9 and Appendix 10 for the list of prohibited medications). Prior use of strong CYP3A inhibitors must be stopped 7 days and strong inducers of CYP3A must be stopped 14 days before randomization.

9) Prior treatment with:
|— a) ARV-471, fulvestrant, mTOR, PI3K, AKT pathway inhibitors, PARP inhibitor, other investigational novel endocrine therapy (ie, SERD, SERCA, CERAN) for any setting
|— b) Prior CDK4/6 inhibitor treatment in the neoadjuvant/adjuvant setting
|— c) Prior chemotherapy for advanced/metastatic disease. Participation in other studies involving investigational drug(s) within 28 days prior to randomization. If in the FU Phase, the participant is eligible provided at least 5 half-lives have elapsed from the last dose.

10) Any unresolved toxicities from prior surgeries or therapies Grade >1 (Grade > 2 for peripheral neuropathy) by NCI-CTCAE Version 5.0 at the time of randomization except for alopecia.

11) Hepatic dysfunction defined as:
|— a) Total bilirubin >1.5 x ULN unless the participant has documented Gilbert’s syndrome (in this case total bilirubin ≥3 x ULN).
|— b) AST and ALT >3 x ULN; >5.0 x ULN if liver metastases present.
|— c) Alkaline phosphatase >2.5 x ULN; >5 x ULN in case of bone metastasis.
|— d) aPTT >1.25 x ULN and INR >1.25 unless the participant is receiving anticoagulation, then aPTT and INR should be within the therapeutic range of the intended use.

12) Hematologic abnormalities defined as:
|— a) ANC <1,500/mm^3 or <1.5 x 10^9/L.
|— b) Platelets <100,000/mm^3 or < 100 x10^9/L.
|— c) Hemoglobin <9 g/dL. One transfusion allowed ≤2 weeks before randomization.

13) Renal impairment defined as an eGFR <45 mL/min/1.73m^2 as calculated using the 2021 CKD-EPI Equations as outlined in Appendix 7.

14) Known active infection including SARS-CoV-2 infection, HBV, HCV, andHIV or AIDS-related illness (screening for chronic conditions is not required).

15) Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.

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