Phase 3, Open-label Study of ARV-471 (PF-07850327) vs Fulvestrant in Participants With ER(+)/ HER2(-) Advanced Breast Cancer (VERITAC-2)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Jun 2023 → ongoing

Decision date (initial)

2023-05-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Pfizer Inc.

External identifiers

EU CT number

2022-500544-38-00

ClinicalTrials.gov

NCT05654623

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To demonstrate that ARV-471 is superior to fulvestrant in prolonging PFS by BICR assessment in participants with ER(+)/HER2(-) aBC (all participants and participants with ESR1 mutation-positive BC) who have received prior endocrine-based treatment for their advanced disease

Secondary objectives 7

1. To demonstrate that ARV-471 is superior to fulvestrant in prolonging overall survival (all participants and participants with ESR1 mutation-positive BC)
2. To compare measures of tumor control between treatment arms and to evaluate the DOR by BICR assessment within each treatment arm
3. To evaluate safety and tolerability between the treatment arms
4. To characterize the effects of ARV-471 on QTc
5. To evaluate patient reported outcomes between two treatment arms
6. To determine plasma concentrations of ARV-471 and ARV-473 after repeated dosing of ARV-471
7. To assess changes from baseline levels in plasma ctDNA

Conditions and MedDRA coding

Advanced Breast Cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003358-PIP01-22

Plan to share IPD

Yes

IPD plan description

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

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. IOCBP 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 and participants in whom the collection of a biopsy is clinically contraindicated 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 on the most recent tumor biopsy and as per above in inclusion criterion a. (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. unless the participants has bone only disease or in whom the collection of a biopsy is clinicallt contraindicated. In these cases, an 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: Note: Progression during or within 12 months from the end of adjuvant therapy is counted as a line of therapy in advanced/metastatic setting a. One line of CDK4/6 inhibitor therapy in combination with ET. Only one line of CDK4/6 inhibitor is allowed in any setting. 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. This may be the endocrine treatment component of the CDK4/6 inhibitor line of therapy. d. Radiological progression during or after the last line of therapy
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

Exclusion criteria 15

1. History of any other solid tumor 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. 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 of the protocol).
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: • 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. • 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. • QTcF interval >470 msec on screening ECG. • 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 of the protocol 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, elacestrant, mTOR, PI3K, AKT pathway inhibitors, PARP inhibitor, other investigational agents (including novel endocrine therapy any SERDs, SERCAs, CERANs) for any setting b. 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: • Total bilirubin >1.5 x ULN unless the participant has documented Gilbert’s syndrome (in this case total bilirubin ≥3 x ULN); • AST and ALT >3 x ULN; >5.0 x ULN if liver metastases present; • Alkaline phosphatase >2.5 x ULN; >5 x ULN in case of bone metastasis. • 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: • ANC <1500/mm3 or <1.5 x 109/L; • Platelets <100,000/mm3 or < 100 x109/L; • Hemoglobin <9 g/dL. One transfusion allowed ≤2 weeks before randomization.
13. Renal impairment defined as an eGFR <45 ml/min/1.73m2 as calculated using the 2021 CKD-EPI equations as outlined in Appendix 7 of the protocol.
14. Known active infection including SARS-CoV-2 infection, HBV, HCV, and HIV 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS, defined as the time from the date of randomization to the date of first documented disease progression, as determined by BICR assessment per RECIST v1.1, or death due to any cause, whichever occurs first.

Secondary endpoints 7

1. OS, defined as the time from the date of randomization to the date of death due to any cause.
2. OR: confirmed CR or PR by BICR assessment • CBR defined as confirmed CR or PR at any time or SD or non-CR/non-PD ≥24 weeks by BICR assessment • DOR by BICR assessment
3. Type, incidence, severity (as graded by NCI CTCAE v5.0), seriousness and relationship to study medications of AEs and any laboratory and ECG abnormalities.
4. QTc
5. EORTC QLQ-C30 • EORTC QLQ-BR23 • EuroQol; EQ-5D-5L • BPI-SF.
6. Plasma concentrations of ARV-471 and its epimer ARV-473.
7. ctDNA plasma quantitative changes from baseline to evaluate their associations with clinical outcomes.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Third parties 11

Locations

15 EU/EEA countries · 104 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 3 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 493 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

28 submissions — initial application plus substantial / non-substantial modifications