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 (IPATunity150)

A Phase Ib/III 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

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.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Ipatasertib; Drug: Palbociclib; Drug: Fulvestrant; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Malvern, Victoria, Australia, 3144
      • Cabrini Medical Centre; Oncology
    • St Albans, Victoria, Australia, 3021
      • Sunshine Hospital
• Brazil
  • RS
    • Porto Alegre, RS, Brazil, 90610-000
      • Hospital Sao Lucas - PUCRS
    • Porto Alegre, RS, Brazil, 90035-903
      • Hospital das Clinicas - UFRGS
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre-Calgary
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Clinic; Clinical Trials Department
  • Quebec
    • Quebec City, Quebec, Canada, G1S 4L8
      • Hopital du Saint Sacrement
• Japan
  • Fukuoka, Japan, 811-1395
    • National Hospital Organization Kyushu Cancer Center
  • Kanagawa, Japan, 241-8515
    • Kanagawa Cancer Center
• Korea, Republic of
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
• Spain
  • Barcelona, Spain, 08035
    • Vall d?Hebron Institute of Oncology (VHIO), Barcelona
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia; Servicio de Oncología
• United Kingdom
  • London, United Kingdom, SW3 5PT
    • The Royal Marsden Hospital; Dept of Medicine
  • Manchester, United Kingdom, M20 4BX
    • Christie Hospital Nhs Trust
  • Sutton, United Kingdom, SM2 5PT
    • Royal Marsden Hosp NHS Fnd; Medicine - Breast Unit
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Piedmont Cancer Institute, PC
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University Of Chicago Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114-2621
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute; GYN Oncology
  • New Jersey
    • Florham Park, New Jersey, United States, 07932
      • Summit Medical Group; MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1b and Phase 3: Ipatasertib + Palbociclib +Fulvestrant	Drug: Ipatasertib; Phase 1b: Ipatasertib, 300 mg starting dose administered orally once daily (PO QD) during an initial 5-7 day run-in period, then continued on Days 1-21 during the first cycle. Starting with Cycle 2, Day 1 ipatasertib will be taken orally once daily on Days 1-21 of each 28-day cycle. Phase 3: Ipatasertib, administered PO QD on Days 1-21 of each 28-day cycle at the dose confirmed in the Phase Ib portion.; Other Names: RO5532961, GDC-0068; Drug: Palbociclib; Palbociclib, administered PO QD on Days 1-21 of each 28-day cycle.; Drug: Fulvestrant; Fulvestrant, 500 mg administered as two intramuscular injections of 250 mg each on Cycle 1 Days 1 and 15 and Day 1 of each subsequent 28-day cycle.
Placebo Comparator: Phase 3: Placebo + Palbociclib + Fulvestrant	Drug: Palbociclib; Palbociclib, administered PO QD on Days 1-21 of each 28-day cycle.; Drug: Fulvestrant; Fulvestrant, 500 mg administered as two intramuscular injections of 250 mg each on Cycle 1 Days 1 and 15 and Day 1 of each subsequent 28-day cycle.; Drug: Placebo; Phase 3: Matching placebo, administered PO QD on Days 1-21 of each 28-day cycle at the dose confirmed in the Phase Ib portion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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).	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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.	Up to 36 Months
Phase Ib: Plasma Concentration of Ipatasertib and Its Metabolite G-037720	Plasma concentrations of Ipatasertib and its metabolite G-037720 are reported.	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)
Phase Ib: Maximum Concentration (Cmax) of Ipatasertib and Its Metabolite G-037720 in Plasma	Cmax of ipatasertib and its metabolite G-037720 in plasma is reported.	Cycle 1: Day 1 and Day 15
Phase Ib: Area Under the Plasma Concentration Time-curve From Zero to 24 Hours (AUC0-24) of Ipatasertib and Its Metabolite G-037720	AUC0-24 of Ipatasertib and its metabolite G-037720 is reported	Cycle 1: Day 1 and Day 15
Phase Ib: Time to Maximum Concentration (Tmax) of Ipatasertib and Its Metabolite G-037720	Tmax of ipatasertib and its metabolite G-037720 isreported.	Cycle 1: Day 1 and Day 15
Phase III: Objective Response Rate (ORR) as Determined by the Investigator According to RECIST v1.1	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.	From randomization in Phase III up to approximately 36 months
Phase III: Duration of Objective Response (DOR) as Determined by the Investigator According to RECIST v1.1	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.	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
Phase III: Clinical Benefit Rate (CBR) as Determined by the Investigator According to RECIST v1.1	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.	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
Phase III: Overall Survival (OS) as Determined by the Investigator According to RECIST v1.1	OS was defined as the time from randomization to death from any cause.	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
Phase III: Time to Deterioration (TTD) in Severity of Pain, According to the Brief Pain Inventory-Short Form (BPI-SF)	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.	From randomization in Phase III to the first documentation of a ≥2-point increase in pain scale (up to approximately 36 months)
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	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.	From randomization in Phase III to the first documentation of a ≥10-point increase (up to approximately 36 months)
Phase III: TTD in Physical Functioning (PF), Role Functioning (RF), GHS/QoL According to EORTC QLQ-C30	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).	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)
Phase III: Number of Participants With Adverse Events	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.	Up to approximately 36 months

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2019
• Primary Completion (Actual): August 29, 2023
• Study Completion (Actual): August 29, 2023

Study Registration Dates

• First Submitted: August 13, 2019
• First Submitted That Met QC Criteria: August 15, 2019
• First Posted (Actual): August 19, 2019

Study Record Updates

• Last Update Posted (Actual): November 8, 2024
• Last Update Submitted That Met QC Criteria: August 23, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Protein Kinase Inhibitors; Hormone Antagonists; Estrogen Receptor Antagonists; Estrogen Antagonists; Fulvestrant; Palbociclib; Ipatasertib
• Other Study ID Numbers: CO41012; 2019-001072-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on Sharing of Clinical Study Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No