History of Changes for Study: NCT05501886

Version	Submitted Date	Changes
1	August 12, 2022	None (earliest Version on record)
2	November 9, 2022	Recruitment Status, Study Status and Contacts/Locations
3	December 22, 2022	Contacts/Locations, Eligibility and Study Status
4	June 2, 2023	Contacts/Locations and Study Status
5	July 30, 2023	Contacts/Locations and Study Status

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.

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.

Arms

Assigned Interventions

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

Primary Outcome Measures:

Progression Free Survival (PFS) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer
[ Time Frame: 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
[ Time Frame: 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
[ Time Frame: 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
[ Time Frame: 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
[ Time Frame: 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
[ Time Frame: 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
[ Time Frame: 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
[ Time Frame: 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
[ Time Frame: 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
[ Time Frame: 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.

10.

Adverse Events
[ Time Frame: 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


Minimum Age:	18 Years
Maximum Age:
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	No
Criteria:	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 a. 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: i. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia ii. 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 iii. Bradycardia (heart rate <50 beats per minute at rest) by electrocardiogram (ECG) or pulse iv. 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.