Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or Metastatic HR+/HER2- Breast Cancer (VIKTORIA-1)

Sponsor

Celcuity, Inc. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05501886

Collaborator

(none)

701

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This is a Phase 3, open-label, randomized, clinical trial evaluating the efficacy and safety of gedatolisib plus fulvestrant with or without palbociclib for the treatment of patients with locally advanced or metastatic HR+/HER2- breast cancer following progression on or after CDK4/6 and aromatase inhibitor therapy.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Gedatolisib Drug: Palbociclib Drug: Fulvestrant Drug: Alpelisib	Phase 3

Detailed Description

This is a Phase 3, open-label, randomized clinical trial evaluating the efficacy and safety of gedatolisib plus fulvestrant with or without palbociclib for the treatment of patients with advanced (inoperable) or metastatic Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) breast cancer following progression on or after CDK4/6 and aromatase inhibitor therapy. Gedatolisib is an intravenously administered pan-PI3K/mTOR inhibitor. Palbociclib is a CDK4/6 inhibitor. Fulvestrant is a selective estrogen receptor degrader (SERD). Subjects will be assessed for PIK3CA status and then randomized to treatment arms according to their confirmed PIK3CA mutation status.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

701 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 3, Open-Label, Randomized, Study Comparing Gedatolisib Combined With Fulvestrant & With or Without Palbociclib to Standard-of-Care Therapies in Patients With HR-Positive, HER2-Negative Advanced Breast Cancer Previously Treated With a CDK4/6 Inhibitor in Combination w/Non-Steroidal Aromatase Inhibitor Therapy

Anticipated Study Start Date :

Sep 30, 2022

Anticipated Primary Completion Date :

Sep 30, 2024

Anticipated Study Completion Date :

Sep 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A - Patients Lacking PIK3CA Mutations (WT) Gedatolisib + Palbociclib + Fulvestrant	Drug: Gedatolisib Gedatolisib 180 mg IV given weekly for 3 weeks (Days 1, 8, 15) followed by 1 week off Other Names: PF-05212384 PKI-587 Drug: Palbociclib Palbociclib 125 mg PO given daily for 3 weeks (21 days), followed by 1 week off Other Names: IBRANCE PD-0332991 Drug: Fulvestrant Fulvestrant 500 mg IM (2 × 5 mL injections) given every 2 weeks during Cycle 1 (Days 1 and 15), then every 4 weeks beginning with Cycle 2 Day 1 Other Names: Faslodex
Experimental: Arm B - Patients Lacking PIK3CA Mutations (WT) Gedatolisib + Fulvestrant	Drug: Gedatolisib Gedatolisib 180 mg IV given weekly for 3 weeks (Days 1, 8, 15) followed by 1 week off Other Names: PF-05212384 PKI-587 Drug: Fulvestrant Fulvestrant 500 mg IM (2 × 5 mL injections) given every 2 weeks during Cycle 1 (Days 1 and 15), then every 4 weeks beginning with Cycle 2 Day 1 Other Names: Faslodex
Active Comparator: Arm C - Patients Lacking PIK3CA Mutations (WT) Fulvestrant	Drug: Fulvestrant Fulvestrant 500 mg IM (2 × 5 mL injections) given every 2 weeks during Cycle 1 (Days 1 and 15), then every 4 weeks beginning with Cycle 2 Day 1 Other Names: Faslodex
Experimental: Arm D - Patients with PIK3CA Mutation (MT) Gedatolisib + Palbociclib + Fulvestrant	Drug: Gedatolisib Gedatolisib 180 mg IV given weekly for 3 weeks (Days 1, 8, 15) followed by 1 week off Other Names: PF-05212384 PKI-587 Drug: Palbociclib Palbociclib 125 mg PO given daily for 3 weeks (21 days), followed by 1 week off Other Names: IBRANCE PD-0332991 Drug: Fulvestrant Fulvestrant 500 mg IM (2 × 5 mL injections) given every 2 weeks during Cycle 1 (Days 1 and 15), then every 4 weeks beginning with Cycle 2 Day 1 Other Names: Faslodex
Active Comparator: Arm E - Patients with PIK3CA Mutation (MT) Alpelisib + Fulvestrant	Drug: Fulvestrant Fulvestrant 500 mg IM (2 × 5 mL injections) given every 2 weeks during Cycle 1 (Days 1 and 15), then every 4 weeks beginning with Cycle 2 Day 1 Other Names: Faslodex Drug: Alpelisib Alpelisib 300 mg PO (2 × 150 mg tablets) given daily for 4 weeks (28 days) Other Names: Piqray Vijoice BYL719
Experimental: Arm F - Patients with PIK3CA Mutation (MT) Gedatolisib + Fulvestrant	Drug: Gedatolisib Gedatolisib 180 mg IV given weekly for 3 weeks (Days 1, 8, 15) followed by 1 week off Other Names: PF-05212384 PKI-587 Drug: Fulvestrant Fulvestrant 500 mg IM (2 × 5 mL injections) given every 2 weeks during Cycle 1 (Days 1 and 15), then every 4 weeks beginning with Cycle 2 Day 1 Other Names: Faslodex

Outcome Measures

Primary Outcome Measures

Progression Free Survival (PFS) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer [Approximately 48 months]
PFS is defined as the time from randomization to death or the first documented progression, whichever occurs first, confirmed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria, as determined based on blinded independent central review (BICR)

Secondary Outcome Measures

Overall Survival (OS) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer [From date of randomization to the date of death due to any cause, up to approximately 48 months]
OS is defined as the length of time from randomization until the date of death from any cause method, where PFS is defined as the time from randomization to death or the first documented progression, whichever occurs first, confirmed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria, as determined based on blinded independent central review (BICR)
Overall Response Rate (ORR) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer [Up to approximately 48 months]
Percentage of subjects who achieved an objective response according to RECIST v1.1 criteria (complete response [CR] or partial response [PR]) as assessed by BICR)
Duration of Response (DOR) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer [Up to approximately 48 months]
Time from the assessment of initial response (PR or better) to death or first documented disease progression as assessed by BICR, whichever occurs first
Time to Response (TTR) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer [Up to approximately 48 months]
Time form randomization to the first assessment of PR or better as assessed by BICR, whichever comes first
Clinical Benefit Rate (CBR) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer [Up to approximately 48 months]
Percentage of subjects with CR, PR, or stable disease (SD) >24 weeks as assessed by BICR
Quality of Life (QOL)Functional Assessment of Cancer Therapy - Breast Trial Outcome Index (FACT-B TOI) Questions in Patients with PIK3CA WT and PIK3CA MT Breast Cancer [From baseline to 30 Day Safety Follow-up]
The FACT-B TOI is an abbreviated (24-item) version of the full FACT-B which focuses only on the patient's Physical Well-being (PWB), Functional Well-being (FWB), and Breast Cancer Subscale (BCS) components using a 5-level scale, (Not at all, A little bit, Some-what, Quite a bit, Very much).
Quality of Life (QOL) NCCN-FACT Breast Symptom Index -16 (NFBSI-16) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer [From baseline to 30 Day Safety Follow-up]
NCCN-FACT is derived from the FACT-B and only 4 additional items will be administered to enable optional scoring of the NFBSI subscales and total score using a 5-level scale (Not at all, A little bit, Some-what, Quite a bit, Very much).
Patient-Reported Outcomes in Patients with PIK3CA WT and PIK3CA MT Breast Cancer [From baseline to 30 Day Safety Follow-up]
Patient-Reported Outcomes Measurement Information System (PROMIS®) Short Form v2.0 - Physical Function 8c using a 5-level scale (Without any difficulty, With a little difficulty, With some difficulty, With much difficulty, Unable to do)
EuroQol 5 in Patients with PIK3CA WT and PIK3CA MT Breast Cancer [From baseline to 30 Day Safety Follow-up]
EuroQol 5 Dimension 5 Level (EQ-5D-5L) - This is a 5 question, self-administered visual analog scale (VAS) where patients use 0 (worst health) to 100 (best health) to indicate how they view their health.
Adverse Events [Up to approximately 48 months]
Safety and tolerability will be evaluated by review of type, incidence, severity (as graded by the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v5.0), seriousness, and relationship to study medications of adverse events (AEs) and any laboratory abnormalities

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed diagnosis of metastatic or locally advanced breast cancer Adult females, pre- and/or post-menopausal, and adult males. Pre-menopausal (and peri-menopausal) women can be enrolled if amenable to treatment with an LHRH agonist. Patients are to have commenced concomitant treatment with LHRH agonist prior to or on Cycle 1, Day 1 and must be willing to continue on it for the duration of the study.
Negative pregnancy test for women who are not surgically sterile. Female subjects who are not surgically sterile must use a medically-effective contraceptive method from screening until 1 year after the last dose of study treatment
Confirmed diagnosis of estrogen receptor positive and/or progesterone receptor positive, as per American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines (2020), based on most recent tumor biopsy utilizing an assay consistent with local standards
Documented HER2 immunohistochemistry (IHC) negative as per ASCO-CAP 2018 guidance
Adequate archival or fresh tumor tissue for the analysis of PIK3CA mutational status
Subject has radiologically evaluable disease (measurable and/or non-measurable) according to RECIST v1.1, per local assessment. Mixed lytic/blastic or lytic lesions with measurable soft tissue component are allowed.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
Life expectancy of at least 3 months
Progressed during or after CDK4/6 inhibitor combination treatment with non-steroidal aromatase inhibitor (AI)
Adequate bone marrow, hepatic, renal and coagulation function

Exclusion Criteria:

History of malignancies other than adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥3 years
Prior treatment with a phosphoinositide 3-kinase (PI3K) inhibitor, a protein kinase B (Akt) inhibitor, or a mechanistic target of rapamycin (mTOR) inhibitor
More than one prior treatment with chemotherapy for advanced disease (prior adjuvant or neoadjuvant chemotherapy is permitted)
More than 2 lines of prior endocrine therapy treatment
Bone only disease that is only blastic with no soft tissue component
Subjects with type 1 diabetes or uncontrolled type 2 diabetes
Known and untreated, or active, brain or leptomeningeal metastases

Subjects with previously treated central nervous system (CNS) metastases may be enrolled in the study if they meet the following criteria: do not require supportive therapy with steroids; do not have seizures and do not exhibit uncontrolled neurological symptoms; stable disease confirmed by radiographic assessment within at least 4 weeks prior to enrollment

Patients with advanced, symptomatic, visceral spread that are at risk of life-threatening complication in the short-term
History of clinically significant cardiovascular abnormalities such as: Congestive heart failure (New York Heart Association (NYHA) classification ≥ II within 6 months of study entry
Myocardial infarction within 12 months of study entry
History of any cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block), supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months
Uncontrolled hypertension defined by systolic blood pressure (SBP) ≥160 mmHg and/or diastolic blood pressure (DBP) ≥100 mmHg, with or without antihypertensive medication (initiation or adjustment of antihypertensive medication[s] is allowed prior to screening)
Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:

1. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
1. Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication
1. Bradycardia (heart rate <50 beats per minute at rest) by electrocardiogram (ECG) or pulse
1. On screening, inability to determine the corrected QT interval using Fridericia's formula (QTcF) on the ECG (i.e., unreadable or not interpretable) or QTcF >450 msec for males and >460 msec for females (determined by mean of triplicate ECGs at screening)

Known hypersensitivity to the study drugs or their components
Pregnant or breast-feeding women
Concurrent participation in another clinical trial
Subjects must agree not to participate in another clinical trial at any time during participation in VIKTORIA-1.