CTRI/2023/05/052598 [Registered on: 12/05/2023] Trial Registered Prospectively
Last Modified On:
29/02/2024
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group, Multiple Arm Trial
Public Title of Study
A Study to Learn About a New Medicine Called ARV-471 (PF-07850327) in People Who Have Advanced Metastatic Breast Cancer. (VERITAC-2)
Scientific Title of Study
A Phase 3, Randomized, Open-Label, Multicenter Trial of ARV-471 (PF-07850327) vs Fulvestrant in Participants with Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer Whose Disease Progressed After Prior Endocrine Based Treatment for Advanced Disease (VERITAC-2)
C4891001 Final Protocol, Amendment 1, 25 October 2022
Protocol Number
NCT05654623
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Designation
Affiliation
Address
Phone
Fax
Email
Details of Contact Person Scientific Query
Name
Dr Seema Pai
Designation
Director-Clinical Site Operations
Affiliation
Pfizer Limited
Address
Global Site and Study Operations, Clinical Development and Operations, Global Product Development, Pfizer Limited, The Capital, 1802/1901, Plot No. C70, G Block, Bandra Kurla Complex, Bandra(E)
Mumbai MAHARASHTRA 400051 India
Phone
8826422322
Fax
Email
seema.pai@pfizer.com
Details of Contact Person Public Query
Name
Dr Seema Pai
Designation
Director-Clinical Site Operations
Affiliation
Pfizer Limited
Address
Global Site and Study Operations, Clinical Development and Operations, Global Product Development, Pfizer Limited, The Capital, 1802/1901, Plot No. C70, G Block, Bandra Kurla Complex, Bandra(E)
Mumbai MAHARASHTRA 400051 India
Phone
8826422322
Fax
Email
seema.pai@pfizer.com
Source of Monetary or Material Support
Pfizer Inc., 235 East 42nd Street, New York, NY 10017, USA
Primary Sponsor
Name
Pfizer Inc
Address
235 East 42nd Street, New York, NY 10017
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
Argentina Australia Austria Belgium Brazil Bulgaria Canada China Czech Republic Finland France Germany Greece Hungary India Israel Italy Japan Mexico Norway Poland Republic of Korea Slovenia South Africa Spain Sweden Switzerland Taiwan Turkey United Kingdom United States of America
Institute of Post Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital
Dept of Radiotherapy, Ground floor, 244 A.J.C Bose Road, 700020 Kolkata WEST BENGAL
919874357580
drkoushik.chatterjee@gmail.com
Dr Devavrat Arya
Max Super Speciality Hospital
Department of Medical Oncology, Saket (East
Block) - A Unit of Devki Devi Foundation, 2, Press Enclave Road, Saket New Delhi DELHI
9711400908
devavrat200@gmail.com
Dr Dinesh Doval
Rajiv Gandhi Cancer Institute and Research Centre
Department of Medical Oncology, Sir Chotu Ram Marg, Sector- 5, Rohini,
New Delhi – 110085 North West DELHI
911127051011
dcdoval@gmail.com
Dr Shona Nag
Sahyadri Super Speciality Hospital
Hadapsar, S N 163, Bhosale Nagar,
Hadapsar, 411028 Pune MAHARASHTRA
919371072441
shonanag3@gmail.com
Dr Satheesh Thungappa
Spandana Oncology Centre Pvt Ltd
Medical Oncology Department, #919 and New No 68, 28th main Road, 9th Block Jayanagar, 560069 Bangalore KARNATAKA
919242698750
drsatheeshct@gmail.com
Dr Sudeep Gupta
Tata Memorial Hospital
Medical Oncology, Division of breast Cancer, Room No. 1109, 11th Floor, Tata Memorial Hospital, Tata Memorial Hospital, Parel 400012l Mumbai MAHARASHTRA
Artemis Health sciences IEC, Artemis Hospital, Sector 51, Gurugram, Haryana, 122001, India
Approved
Bhaktivedanta Hospital Ethics Committee Bhaktivedanta HEC office, 6th floor, Bhaktivedanta Hospital & Research Institute, Srishti Complex, Bhaktivedanta Swami Marg,Opp lSKON Temple, Mira Road ( E), Thane- 401107,Maharashtra India
Approved
IEC Venkateshwar Hospital, 110075 Dwarka, New Delhi Sector 18 A,
Approved
Institutional Ethics committee - HCG Curie City, 44-1-1/3, Machavaram Down, Gunadala, Vijayawada, Andhra Pradesh, India, 520004
Approved
Institutional Ethics Committee III, TMC ACTREC Tata Memorial Centre ACTREC Sector 22, Near Owe camp Kharghar Navi Mumbai Raigad Maharashtra - 410210 India
Approved
Institutional Ethics Committee, BGS-GIMS, #67, BGS Health & Education City, Uttarahalli Road Kengeri, Bangalore -560060
Submittted/Under Review
Institutional Ethics Committee, Devki Devi Foundation, Service Floor, Office of Ethics Committee East Block, Next to Conference Room Max Super Specialty Hospital, Saket (A unit of Devki Devi Foundation), 2, Press Enclave Road, Saket, New Delhi, 110017
Approved
Institutional Ethics Committee, Old OT block, room no 102, All India Institute of Medical Sciences hospital, Ansari Nagar, New Delhi - 110029, Delhi
Approved
Institutional Ethics CommitteeClinicalStudiesIndraprastha Apollo Hospitals DelhiMathuraRoadSaritaViharNewDelhiDelhi110076
Approved
Institutional Review Board, Rajiv Gandhi Cancer Institute and Research Centre. Sir Chotu Ram Marg, Sector- 5, Rohini, New Delhi - 110085
Approved
IPGMEandR Research Oversight Committee IPGMEandR 244 Acharya J. C. Bose Road - Kolkata Kolkata West Bengal - 700020 India
Approved
Manavata Clinical Research Institute Ethics Committee HCG Manavata Cancer Centre Behind Shivang Auto Mumbai Naka Nashik Nashik Maharashtra - 422002 India
Approved
Sahyadri Hospitals Ltd. Ethics committee Sahyadri Clinical Research & Development Center (A Unit of Sahyadri Hospitals Ltd.), 33/34B, Makarand Bhave Path, Karve Road, Pune- 411004, Maharashtra, India
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: C509||Malignant neoplasm of breast of unspecified site,
Intervention / Comparator Agent
Type
Name
Details
Intervention
ARV-471
Participants will receive ARV-471 200 mg orally, once daily on a 28-day continuous dosing schedule
Comparator Agent
fulvestrant
Participants will receive fulvestrant 500 mg, intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle starting from C2D1 (28-day cycle).
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
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.
c. WOCBP female and male participants must agree to use contraception.
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
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
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
6. ECOG PS ≤1
ExclusionCriteria
Details
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
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. 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:
• 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
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.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
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 by PFS which 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
≤18 weeks
Secondary Outcome
Outcome
TimePoints
1) To demonstrate that ARV-471 is superior to fulvestrant in prolonging OS
2) Overall response rate (ORR) in participants
3) Duration of response (DOR) in participants
4) Clinical benefit rate (CBR) in participants
5) To evaluate safety and tolerability between the treatment arms by Type, incidence, severity, seriousness and relationship to study medications of AEs and any laboratory and ECG abnormalities
6)To characterize the effects of ARV-471 on QTc
7)To evaluate patient reported outcomes between two treatment arms by EORTC QLQ-C30, EORTC QLQ-BR23, EuroQol; EQ-5D-5L and BPI-SF
8) To determine Plasma concentrations of ARV-471 and its epimer ARV-473
9) ctDNA plasma quantitative changes from baseline to evaluate their associations with clinical outcomes
1)At predefined intervals throughout the treatment period
2)Up to approximately 1 year
3)Up to approximately 1 year
4)≥24 weeks
5)At predefined intervals throughout the treatment period
6)At predefined intervals throughout the treatment period
7)At predefined intervals throughout the treatment period
8)At predefined intervals throughout the treatment period
9) At predefined intervals throughout the treatment period
Target Sample Size
Total Sample Size="560" Sample Size from India="30" Final Enrollment numbers achieved (Total)= "0" Final Enrollment numbers achieved (India)="0"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
In nonclinical studies, ARV-471 has demonstrated robust ER degradation, superior activity against clinically relevant ER mutated forms (eg,Y537S and D538G), and improved TGI as single agent compared to fulvestrant in ER wild type and ESR1 mutant patient-derived xenograft models as administered as single agent. In the FIH study, ARV-471 administered orally QD as a single agent appears to be safe and well tolerated across total daily doses of 30 mg to 700 mg with preliminary evidence of efficacy in participants pretreated with CDK4/6 inhibitor plus endocrine therapy. These results support the hypothesis that ARV-471 may represent an important therapeutic approach in patients with ER(+)/HER2(-) advanced breast disease.
This is an international Phase 3 multicenter, randomized, open-label, parallel-group study aimed to demonstrate that ARV-471 is superior to fulvestrant in prolonging the PFS (by BICR assessment) in participants with ER(+)/HER2(-) aBC who have progressed after prior endocrine treatment-based regimen(s)for advanced disease. Approximately 560 participants (of which approximately 280 are participants with ESR1 mutation) will be randomly assigned to Arm A (ARV-471, PF-07850327) or Arm B (fulvestrant).
Participants will be randomly assigned on a 1:1 basis to: • Arm A: (Investigational Arm; n ≈ 280). Participants will receive ARV-471 200 mg orally, once daily on a 28-day continuous dosing schedule. • Arm B: (Comparator Arm; n ≈ 280). Participants will receive fulvestrant 500 mg, intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle starting from C2D1 (28-day cycle).
Participants will be stratified by ESR1 mutational status (Mutant, Yes/No) and visceral disease (Yes/No). Visceral refers to lung, liver, brain, pleural, and peritoneal involvement.
Pre- and peri-menopausal female and male participants must receive therapy with an LHRH agonist starting on Cycle 1 Day 1 (if not already on treatment) and continued during the study.
The study includes a QTc sub-study in approximately 80 participants in Arm A enrolled at selected sites which will evaluate the effect of ARV-471 on QTc interval via triplicate ECGs (central reading) time-matched with PK draws.
An E-DMC will be established to review aggregate safety data to monitor safety and tolerability by treatment arm.
A Global Steering Committee will be established at the program level for ARV-471. It will be responsible for providing scientific advice and medical input on the ongoing and future clinical development plans for ARV-471 in ER(+) breast cancer, including for this study.
Participants will undergo efficacy assessments. Efficacy analyses will be performed using BICR tumor assessments as the primary data source. All radiographic images as well as other information will be collected and objectively verified by BICR as described in the Study Imaging Manual.
It is anticipated that the final PFS analysis will occur at approximately 310 PFS events in all participants population and 165 PFS events in the ESR1 mutant subgroup population. The final OS analysis will occur at approximately 396 OS events in all participants population and 194 OS events in ESR1 mutant subgroup population.