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)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Gedatolisib
* Drug: Palbociclib
* Drug: Fulvestrant
* Drug: Alpelisib


Participation Criteria
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Eligibility Criteria
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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 of childbearing potential. Female subjects of childbearing potential must use an effective and/or acceptable 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 must have documentation of radiological disease progression on or after the last prior treatment and also have radiologically evaluable disease (measurable and/or non-measurable) according to RECIST v1.1, per local assessment. Subjects with bone only disease must have lytic or mixed lytic/blastic lesions that can be accurately assessed; bone only blastic lesions with no soft tissue component is not 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 Prior treatment with chemotherapy and antibody drug conjugates for advanced disease is not permitted (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 uncontrolled (or untreated) clinically significant 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, or history of clinically significant/symptomatic bradycardia ii. 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 >480 msec (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 interventional clinical trial Subjects must agree not to participate in another clinical trial (other than observational) at any time during participation in VIKTORIA-1.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - Patients Lacking PIK3CA Mutations (WT)<br>Gedatolisib + Palbociclib + Fulvestrant | Drug: Gedatolisib<br>* Gedatolisib 180 mg IV given weekly for 3 weeks (Days 1, 8, 15) followed by 1 week off<br>* Other names: PKI-587;Drug: Palbociclib<br>* Palbociclib 125 mg PO given daily for 3 weeks (21 days), followed by 1 week off<br>* Other names: PD-0332991;Drug: Fulvestrant<br>* 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<br>* Other names: Faslodex;|
| Experimental: Arm B - Patients Lacking PIK3CA Mutations (WT)<br>Gedatolisib + Fulvestrant | Drug: Gedatolisib<br>* Gedatolisib 180 mg IV given weekly for 3 weeks (Days 1, 8, 15) followed by 1 week off<br>* Other names: PKI-587;Drug: Fulvestrant<br>* 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<br>* Other names: Faslodex;|
| Active Comparator: Arm C - Patients Lacking PIK3CA Mutations (WT)<br>Fulvestrant | Drug: Fulvestrant<br>* 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<br>* Other names: Faslodex;|
| Experimental: Arm D - Patients with PIK3CA Mutation (MT)<br>Gedatolisib + Palbociclib + Fulvestrant | Drug: Gedatolisib<br>* Gedatolisib 180 mg IV given weekly for 3 weeks (Days 1, 8, 15) followed by 1 week off<br>* Other names: PKI-587;Drug: Palbociclib<br>* Palbociclib 125 mg PO given daily for 3 weeks (21 days), followed by 1 week off<br>* Other names: PD-0332991;Drug: Fulvestrant<br>* 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<br>* Other names: Faslodex;|
| Active Comparator: Arm E - Patients with PIK3CA Mutation (MT)<br>Alpelisib + Fulvestrant | Drug: Fulvestrant<br>* 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<br>* Other names: Faslodex;Drug: Alpelisib<br>* Alpelisib 300 mg PO (2 × 150 mg tablets) given daily for 4 weeks (28 days)<br>* Other names: BYL719;|
| Experimental: Arm F - Patients with PIK3CA Mutation (MT)<br>Gedatolisib + Fulvestrant | Drug: Gedatolisib<br>* Gedatolisib 180 mg IV given weekly for 3 weeks (Days 1, 8, 15) followed by 1 week off<br>* Other names: PKI-587;Drug: Fulvestrant<br>* 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<br>* Other names: Faslodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer | 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) | Approximately 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer | 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) | From date of randomization to the date of death due to any cause, up to approximately 48 months | 
| Overall Response Rate (ORR) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer | 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) | Up to approximately 48 months | 
| Duration of Response (DOR) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer | Time from the assessment of initial response (PR or better) to death or first documented disease progression as assessed by BICR, whichever occurs first | Up to approximately 48 months | 
| Time to Response (TTR) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer | Time form randomization to the first assessment of PR or better as assessed by BICR, whichever comes first | Up to approximately 48 months | 
| Clinical Benefit Rate (CBR) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer | Percentage of subjects with CR, PR, or stable disease (SD) >24 weeks as assessed by BICR | Up to approximately 48 months | 
| 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 | 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). | From baseline to 30 Day Safety Follow-up | 
| Quality of Life (QOL) NCCN-FACT Breast Symptom Index -16 (NFBSI-16) in Patients with PIK3CA WT and PIK3CA MT Breast Cancer | 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). | From baseline to 30 Day Safety Follow-up | 
| Patient-Reported Outcomes in Patients with PIK3CA WT and PIK3CA MT Breast Cancer | 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) | From baseline to 30 Day Safety Follow-up | 
| EuroQol 5 in Patients with PIK3CA WT and PIK3CA MT Breast Cancer | 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. | From baseline to 30 Day Safety Follow-up | 
| Adverse Events | 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 | Up to approximately 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Advanced or Metastatic, gedatolisib, HR Positive, ER Positive, HER2 Negative, PIK3CA MT, PI3K