(3S)-3-[6-[4-[[1-[4-[(1R,2S)-6-HYDROXY-2-PHENYL-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL]PHENYL]PIPERIDIN-4-YL]METHYL]PIPERAZIN-1-YL]-3-OXO-1H-ISOINDOL-2-YL]PIPERIDINE-2,6-DIONE for Advanced breast cancer | Metastatic breast cancer

Inclusion criteria

• {"criterion_text":"-Participants aged 18 years or older (or the minimum age of consent in accordance with local regulations) at screening."}
• {"criterion_text":"-Histological or cytological diagnosis of breast cancer. At time of enrollment this must not be amenable to surgical resection with curative intent (≥1% ER+ stained cells as per local practice on the most recent tumor biopsy HER2- tumor by immunohistochemistry (IHC) or in-situ hybridization per ASCO/CAP). -Participants who have bilateral breast cancers that are both ER+/HER2- are eligible. -Tumor block collected at the time of diagnosis with local recurrent or metastatic disease or archival tumor tissue is required for inclusion (Phase 1b and Phase 2)."}
• {"criterion_text":"-Prior anticancer therapies, Phase 1b: Participants should have received at least 1 line of standard of care (SOC) for A/MBC. ; Prior fulvestrant allowed. ; ≤1 prior chemotherapy line (no antibody-drug conjugates permitted) for A/MBC setting allowed."}
• {"criterion_text":"-Prior anticancer therapies; Phase 2: At least one and maximum 2 lines of endocrine therapy (ET) in A/MBC setting and most recent ET-based regimen for >6 months.; 1, and only 1, prior CDK4/6 inhibitor, inhibitor-based regimen required (independent of the setting eg, adjuvant or advanced/metastatic). ; Up to 1 prior regimen of cytotoxic chemotherapy (no antibody-drug conjugates permitted) in the A/MBC setting. ; Prior fulvestrant allowed."}
• {"criterion_text":"-Lesions at study entry; Phase 1b:Participant with only non-measurable lesion (including skin or bone lesion only) are eligible."}
• {"criterion_text":"-Lesions at study entry; Phase 2: Participants must have at least 1 measurable lesion as defined by RECIST v1.1. Participants with bone lesions only can be included if at least one bone lesion has a measurable component as for RECIST v1.1."}
• {"criterion_text":"-Eastern Cooperative Oncology Group (ECOG) performance status (PS) at study entry: Phase 1b: -ECOG PS 0 or 1. Phase 2: -ECOG PS ≤2."}

Exclusion criteria

• {"criterion_text":"-Participants in visceral crisis at risk of life-threatening complications in the short term, including participants with massive uncontrolled effusions (pleural, pericardial, and/or peritoneal), pulmonary lymphangitis, and liver involvement >50%."}
• {"criterion_text":"-Concurrent administration of medications, food, or herb supplements that are strong inhibitors /inducers of cytochrome P (CYP)3A or UGT2B7, moderate inducers of CYP3A (Phase 1b only), and drugs known to predispose to Torsade de Pointes or QT interval prolongation. Prior use of strong inhibitors of CYP3A or UGT2B7 must be stopped 7 days, strong inducers of CYP3A or UGT2B7, and moderate inducers of CYP3A (Phase 1b only) must be stopped 14 days before enrollment in the study."}
• {"criterion_text":"-Renal impairment defined by an estimated Glomerular Filtration Rate (eGFR) <50 mL/min/. In equivocal cases, a 24-hour urine collection test can be used to estimate the creatinine clearance more accurately."}
• {"criterion_text":"-Hepatic dysfunction defined as: -Total bilirubin >1.5 × upper limit of normal (ULN) unless the participant has documented Gilbert’s syndrome (in this case total bilirubin ≥3 × ULN); -Aspartate aminotransferase (AST) >3 × ULN (>5 × ULN if attributed to liver metastases); -Alanine aminotransferase (ALT) >3 × ULN (>5 × ULN if attributed to liver metastases); -Alkaline phosphatase >2.5 × ULN or >5 x ULN if liver or bone metastases present.; -aPTT >1.25 × ULN and international normalized ratio (INR) >1.25 unless the participant is receiving anticoagulation, then activated partial thromboplastin time (aPTT) and INR should be within the therapeutic range of the intended use."}
• {"criterion_text":"-Hematologic abnormalities defined as: -Absolute neutrophil count (ANC) < 1,500/mm3 or 1.5 × 109/L; -Platelets <100,000/mm3 or 100 × 109/L; -Hemoglobin <9 g/dL. Receipt of a blood transfusion (blood or blood products) within 14 days before the first dose is allowed."}
• {"criterion_text":"-Known active infection including hepatitis B virus, hepatitis C virus, and human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)- related illness (screening for chronic conditions is not required). A participant who has a positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is known to have asymptomatic infection, or is suspected of having SARS-CoV-2, is not eligible for the study, except in case SARS-CoV-2 infection occurring during the screening period is resolved at least 14 days prior to enrollment. Note: active viral hepatitis infection is defined as untreated/uncontrolled hepatitis (eg, hepatitis B patients who are treated and whose liver function tests (LFTs) meet eligibility are not considered to have active hepatitis B). For HIV infection, the study participant is eligible if the disease is controlled with treatment, and the therapy does not exclude the participant as per Exclusion criterion."}
• {"criterion_text":"-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."}
• {"criterion_text":"-Participants with newly diagnosed brain metastases, or symptomatic central nervous system (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 (eg, radiotherapy, stereotactic surgery) and clinically stable (including participants with residual CNS symptoms/deficits) and discontinued anti-seizure medications and corticosteroids for at least 28 days prior to first dose of IMP."}
• {"criterion_text":"-Refractory nausea and vomiting, chronic gastrointestinal (GI) disease, GI ulcer, GI bleeding, active inflammatory bowel disease, inability to swallow the formulated product, or previous, significant gastric-bowel resection that would preclude adequate absorption of study interventions."}
• {"criterion_text":"-History of any other malignancies within the past three years, except for the following: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated in situ carcinoma of the cervix. All other malignancies must have been curatively treated with no evidence of disease for >3 years. Participants with inflammatory breast cancer are excluded."}
• {"criterion_text":"-Impaired cardiovascular function or clinically significant cardiovascular diseases, as defined as: -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. -Symptomatic cardiac valve disease. Participants with mitral valve prolapse that is asymptomatic or not associated with clinically significant sequalae (eg, mitral regurgitation) are eligible. -Corrected QT-Fridericia method (QTcF) >470 msec at screening or any of the following in the previous 6 months: congenital long QT syndrome, Torsade de Pointes, clinically important arrhythmias, left anterior hemiblock (bifascicular block), ongoing cardiac dysrhythmias of Grade ≥2, atrial fibrillation of any grade."}
• {"criterion_text":"-The following prior procedures and treatment are not permitted: •Anticancer systemic therapies: Phase 1b and Phase 2: -Prior therapy with selective estrogen receptor degraders (SERDs) (fulvestrant is allowed), selective estrogen receptor modulators (SERMs) (tamoxifen is allowed), selective estrogen receptor covalent antagonists (SERCAs), complete estrogen receptor antagonists (CERANs), and Proteolysis Targeting Chimeras (PROTACs) (approved or experimental), or elacestrant. -Major surgery, radiotherapy, prior endocrine therapy, CDK4/6 inhibitors, or other anticancer treatments within ≤14 days prior to first dose of investigational medicinal product (IMP) (for anticancer therapy containing an antibody-based agents, approved or investigational, 28 days or 5 half-lives, whichever is shorter). -Participants who received: prior radiotherapy to ≥25% of bone marrow, or prior hematopoietic stem cell, or bone marrow transplantation are not eligible independent of when it was received."}
• {"criterion_text":"-Any unresolved toxicities from prior surgeries or therapies Grade >1 at the time of study enrollment except for Grade 2 alopecia, peripheral neuropathy, arthralgia, or other toxicities not considered a safety risk for the participant per the investigator’s judgment."}
• {"criterion_text":"-Any 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, or any social situations that would limit study compliance."}
• {"criterion_text":"-Previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). Participation in studies of other investigational products (drug or vaccine) at any time during their participation in this study."}

Primary endpoints

• {"endpoint_text":"-Phase 1b: DLTs during DLT observation period (Cycle 1).","definition_or_measurement_approach":"DLTs during DLT observation period (Cycle 1)."}
• {"endpoint_text":"-Phase 2: Confirmed OR (CR or PR) determined by investigator assessment.","definition_or_measurement_approach":"Confirmed objective response (CR or PR) as determined by investigator assessment."}

Secondary endpoints

• {"endpoint_text":"-Phase 1b: -AEs as characterized by type, frequency, intensity (as graded by NCI CTCAE version 5.0), seriousness, and relationship to vepdegestrant in combination with PF-07220060; -Incidence of laboratory abnormalities. -Incidence of ECG abnormalities.","definition_or_measurement_approach":"Adverse events graded by NCI CTCAE v5.0; incidence of laboratory and ECG abnormalities."}
• {"endpoint_text":"-Phase 1b: -Confirmed OR (CR or PR) by investigator assessment. -DoR by investigator assessment. -CBR (confirmed CR or PR at any time, or SD ≥24 weeks) by investigator assessment.-PFS by investigator assessment.","definition_or_measurement_approach":"Investigator-assessed confirmed objective response, duration of response (DoR), clinical benefit rate (CBR), and progression-free survival (PFS)."}
• {"endpoint_text":"-Phase 1b: -Plasma concentrations of vepdegestrant, ARV-473, and PF- 07220060. -Steady-state Cmax, Tmax, and AUClast of vepdegestrant, ARV-473, and PF-07220060. -If data permit CL/F, Vz/F, and t½ of vepdegestrant, ARV-473, and PF- 07220060.","definition_or_measurement_approach":"Pharmacokinetic measurements: plasma concentrations, Cmax, Tmax, AUClast, and if possible CL/F, Vz/F, t½."}
• {"endpoint_text":"-Phase 2: -DoR by investigator assessment. -CBR (confirmed CR or PR at any time or SD ≥24 weeks) by investigator assessment. -PFS by investigator assessment. -OS.","definition_or_measurement_approach":"Investigator-assessed DoR, CBR, PFS and overall survival (OS)."}
• {"endpoint_text":"-Phase 2: -AEs as characterized by type, frequency, intensity (as graded by NCI CTCAE version 5.0), seriousness, and relationship to vepdegestrant in combination with PF-07220060. -Incidence of laboratory abnormalities. -Incidence of ECG abnormalities","definition_or_measurement_approach":"Adverse events graded by NCI CTCAE v5.0; incidence of laboratory and ECG abnormalities."}
• {"endpoint_text":"-Phase 2: -Plasma concentrations of vepdegestrant, ARV-473, and PF-07220060.","definition_or_measurement_approach":"Pharmacokinetic plasma concentration measurements of vepdegestrant, ARV-473 and PF-07220060."}
• {"endpoint_text":"-Phase 2: ctDNA plasma quantitative changes from pre-treatment to evaluate potential predictability of their associations with clinical outcomes.","definition_or_measurement_approach":"Quantitative changes in plasma circulating tumour DNA (ctDNA) from pre-treatment to assess associations with clinical outcomes."}

Spain

Earliest CTIS Part Ii Submission Date

15-03-2024

Latest Decision Or Authorization Date

28-01-2026

Processing Time Days

684

Number Of Sites

4

Number Of Participants

7

Belgium

Earliest CTIS Part Ii Submission Date

31-01-2024

Latest Decision Or Authorization Date

21-01-2026

Processing Time Days

721

Number Of Sites

5

Number Of Participants

7

France

Earliest CTIS Part Ii Submission Date

05-04-2024

Latest Decision Or Authorization Date

23-01-2026

Processing Time Days

658

Number Of Sites

4

Number Of Participants

12

Primary sponsor

Full Name

Pfizer Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States