A Study of Ipatasertib Plus Palbociclib and Fulvestrant Versus Placebo Plus Palbociclib and Fulvestrant in Hormone Receptor Positive and HER2 Negative Locally Advanced Unresectable or Metastatic Breast Cancer
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT04060862
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
The open-label Phase Ib portion of this study will evaluate the safety and pharmacokinetics of ipatasertib in combination with palbociclib and fulvestrant to identify a dose of ipatasertib that can be combined with palbociclib and fulvestrant in the Phase III portion. The randomized Phase III portion of this study will evaluate the efficacy, safety, and patient-reported outcome (PRO) objectives of ipatasertib + palbociclib + fulvestrant compared with placebo + palbociclib + fulvestrant in patients with HR+ HER2-, locally advanced unresectable or metastatic breast cancer who had relapsed during adjuvant endocrine therapy or progressed during the initial 12 months of first-line endocrine therapy in locally advanced unresectable or metastatic breast cancer.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 20
- HR+ HER2- adenocarcinoma of the breast that is locally advanced unresectable or metastatic
- For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs
- For men: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating sperm
- Radiologic/objective relapse during adjuvant endocrine therapy or disease progression during the initial 12 months of 1L endocrine therapy in locally advanced unresectable or metastatic breast cancer
- At least one measurable lesion via Response Evaluation Criteria in Solid Tumors, Version 1.1
- Phase III only: Tumor specimen from the most recently collected, available tumor tissue
- Pregnant or breastfeeding, or intending to become pregnant
- Prior treatment with fulvestrant or other selective estrogen receptor down-regulator
- Prior treatment with PI3K inhibitor, mTOR inhibitor or AKT inhibitor
- Phase III only: Prior treatment with CDK4/6 inhibitor for locally advanced unresectable or metastatic breast cancer
- Prior treatment with a cytotoxic chemotherapy regimen for metastatic breast cancer
- History of Type I or Type II diabetes mellitus requiring insulin
- History of or active inflammatory bowel disease or active bowel inflammation
- Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 3: Placebo + Palbociclib + Fulvestrant Placebo - Phase 1b and Phase 3: Ipatasertib + Palbociclib +Fulvestrant Palbociclib - Phase 1b and Phase 3: Ipatasertib + Palbociclib +Fulvestrant Fulvestrant - Phase 3: Placebo + Palbociclib + Fulvestrant Palbociclib - Phase 3: Placebo + Palbociclib + Fulvestrant Fulvestrant - Phase 1b and Phase 3: Ipatasertib + Palbociclib +Fulvestrant Ipatasertib -
- Primary Outcome Measures
Name Time Method Phase III: Progression-Free Survival (PFS), as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) From randomization in Phase III until the first occurrence of disease progression or death from any cause, whichever occurs first, up to approximately 36 months PFS was defined as the time from randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurred first. Progressive disease (PD) is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of ≥ 5 millimeters (mm).
- Secondary Outcome Measures
Name Time Method Phase Ib: Number of Participants With Adverse Events and Adverse Events With Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) Up to 36 Months AE=any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. Severity of AEs were rated per NCI CTCAE v5 where, Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental Activities of Daily Living (ADL); Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; Grade 4 Life-threatening consequences; urgent intervention indicated; Grade 5 Death related to AE.
Phase Ib: Plasma Concentration of Ipatasertib and Its Metabolite G-037720 Cycle 1, Day 1 and 15: 0.25 hours pre-dose, 0.5, 1, 2, 3, 4 and 6 hours post- dose ; Cycle 2, Day 15: 0.25 hours pre-dose; Cycle 3, Day 15: 0.15 hours pre-dose, 2 hours post-dose (each cycle = 28 days) Plasma concentrations of Ipatasertib and its metabolite G-037720 are reported.
Phase Ib: Maximum Concentration (Cmax) of Ipatasertib and Its Metabolite G-037720 in Plasma Cycle 1: Day 1 and Day 15 Cmax of ipatasertib and its metabolite G-037720 in plasma is reported.
Phase Ib: Area Under the Plasma Concentration Time-curve From Zero to 24 Hours (AUC0-24) of Ipatasertib and Its Metabolite G-037720 Cycle 1: Day 1 and Day 15 AUC0-24 of Ipatasertib and its metabolite G-037720 is reported
Phase Ib: Time to Maximum Concentration (Tmax) of Ipatasertib and Its Metabolite G-037720 Cycle 1: Day 1 and Day 15 Tmax of ipatasertib and its metabolite G-037720 isreported.
Phase III: Objective Response Rate (ORR) as Determined by the Investigator According to RECIST v1.1 From randomization in Phase III up to approximately 36 months ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to RECIST v1.1. CR is defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in the short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.
Phase III: Duration of Objective Response (DOR) as Determined by the Investigator According to RECIST v1.1 From randomization in Phase III until the first occurrence of disease progression or death from any cause, whichever occurs first, up to approximately 36 months DOR was defined as time from first occurrence of a documented objective response to the first occurrence of disease progression as determined by investigator per RECIST v1.1, or death from any cause, whichever occurs first. Objective response was defined using RECIST v1.1 criteria as: CR = disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR = at least a 30% decrease in sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in absence of CR. PD = at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to relative increase of 20%, sum of diameters must also demonstrate an absolute increase of ≥ 5 mm. Stable disease (SD): Neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD.
Phase III: Clinical Benefit Rate (CBR) as Determined by the Investigator According to RECIST v1.1 From randomization in Phase III until the first occurrence of disease progression or death from any cause, whichever occurs first, up to approximately 36 months CBR was defined as the percentage of participants who had a CR or PR, or SD for at least 24 weeks, as determined by the investigator according to RECIST v1.1. CR is defined as disappearance of all target lesions. Any pathological lymph nodes must have a reduction in the short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. SD is defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of ≥ 5 mm.
Phase III: Overall Survival (OS) as Determined by the Investigator According to RECIST v1.1 From randomization in Phase III until the first occurrence of disease progression or death from any cause, whichever occurs first, up to approximately 36 months OS was defined as the time from randomization to death from any cause.
Phase III: Time to Deterioration (TTD) in Severity of Pain, According to the Brief Pain Inventory-Short Form (BPI-SF) From randomization in Phase III to the first documentation of a ≥2-point increase in pain scale (up to approximately 36 months) TTD in severity of pain is defined as the time from randomization to the first documentation of a 2-point or more increase from baseline on the "worst pain" item from the BPI-SF. A 2-point change is defined as clinically meaningful. The BPI-SF is a widely used patient-reported outcome (PRO) for assessing pain, and the "worst pain" item, frequently used for evaluating increases in the severity of pain. The BPI-SF asks participants to rate their pain at its worst in the last week on a scale from 0 (No pain) to 10 (pain as bad as one can imagine). Higher score indicates more pain.
Phase III: TTD in Presence and Interference of Pain According to the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) Pain Scale From randomization in Phase III to the first documentation of a ≥10-point increase (up to approximately 36 months) TTD in presence \& interference of pain is defined as time from randomization to the first documentation of ≥10-point increase from baseline in EORTC QLQ-C30 pain scale (items 9 \& 19). EORTC QLQ-C30 is a validated 30-item self-report measure assessing 5 aspects of participant functioning (physical, emotional, role, cognitive, \& social), eight symptom scales (fatigue, nausea \& vomiting, pain, dyspnea, insomnia, appetite loss, constipation, \& diarrhea), financial difficulties, \& global health status/quality of life (GHS/QoL) with a recall period of the previous week. Functioning \& symptoms items are scored on a 4-point scale (1=Not at All to 4=Very Much). Pain scale is scored on a 4-point scale (1=Not at All to 4=Very Much) including Item 9: have you had pain? and Item 19: did pain interfere with your daily activity? both range from 1=Not at All to 4=Very Much. All sub-scores are linearly transformed to a total score range of 0-100. Higher scores indicate worse pain symptoms.
Phase III: TTD in Physical Functioning (PF), Role Functioning (RF), GHS/QoL According to EORTC QLQ-C30 From randomization in Phase III to the first documentation of a ≥10-point decrease in the PF, RF and GHS/QoL of EORTC QLQ-C30 (up to approximately 36 months) TTD in PF, RF and GHS/QoL is defined as the time to first documented ≥10-point decrease from baseline in following scales of the EORTC QLQ-C30: PF, RF and GHS/QoL. EORTC QLQ-C30 is a validated 30-item self-report measure assessing 5 aspects of participant functioning (physical, emotional, role, cognitive, \& social), eight symptom scales (fatigue, nausea \& vomiting, pain, dyspnea, insomnia, appetite loss, constipation, \& diarrhea), financial difficulties, \& GHS/QoL with a recall period of the previous week. The PF scale has 5 questions about participants' physical functioning and is scored on a 4-point scale (1=Not at All to 4=Very Much). The RF scale is scored on a 4-point scale (1=Not at All to 4=Very Much). The GHS/QoL scale has 7 possible scores of responses (1=Very Poor to 7=Excellent). All sub-scores are linearly transformed to a total score range of 0-100. Higher scores indicate a higher response level (better functioning/QoL).
Phase III: Number of Participants With Adverse Events Up to approximately 36 months An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product; any new disease or exacerbation of an existing disease; recurrence of an intermittent medical condition; any deterioration in a laboratory value or other clinical test; AEs that are related to a protocol-mandated intervention, including those that occur prior to assignment of study treatment.
Trial Locations
- Locations (20)
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
Hopital du Saint Sacrement
🇨🇦Quebec City, Quebec, Canada
Dana-Farber Cancer Institute; GYN Oncology
🇺🇸Boston, Massachusetts, United States
Christie Hospital NHS Trust
🇬🇧Manchester, United Kingdom
Piedmont Cancer Institute, PC
🇺🇸Atlanta, Georgia, United States
Juravinski Cancer Clinic; Clinical Trials Department
🇨🇦Hamilton, Ontario, Canada
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Hospital Clínico Universitario de Valencia; Servicio de Oncología
🇪🇸Valencia, Spain
Tom Baker Cancer Centre-Calgary
🇨🇦Calgary, Alberta, Canada
Royal Marsden Hosp NHS Fnd; Medicine - Breast Unit
🇬🇧Sutton, United Kingdom
Hospital Sao Lucas - PUCRS
🇧🇷Porto Alegre, RS, Brazil
Hospital das Clinicas - UFRGS
🇧🇷Porto Alegre, RS, Brazil
The Royal Marsden Hospital; Dept of Medicine
🇬🇧London, United Kingdom
Vall d?Hebron Institute of Oncology (VHIO), Barcelona
🇪🇸Barcelona, Spain
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Sunshine Hospital
🇦🇺St Albans, Victoria, Australia
National Hospital Organization Kyushu Cancer Center
🇯🇵Fukuoka, Japan
Kanagawa Cancer Center
🇯🇵Kanagawa, Japan
Summit Medical Group; MD Anderson Cancer Center
🇺🇸Florham Park, New Jersey, United States
Cabrini Medical Centre; Oncology
🇦🇺Malvern, Victoria, Australia