Clinical trial NCT04650581: Fulvestrant and Ipatasertib for Advanced HER-2 Negative and Estrogen Receptor Positive (ER+) Breast Cancer Following Progression on First Line CDK 4/6 Inhibitor and Aromatase Inhibitor
Official title: Double-Blind Placebo-Controlled Randomized Phase III Trial of Fulvestrant and Ipatasertib as Treatment for Advanced HER-2 Negative and Estrogen Receptor Positive (ER+) Breast Cancer Following Progression on First Line CDK 4/6 Inhibitor and Aromatase Inhibitor
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: Hoffmann-La Roche
First posted: 2020-12-02
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to find out whether a new drug, Ipatasertib, can slow the growth of advanced breast cancer when added to standard therapy (Fulvestrant).

Detailed description: Patients enrolled in this study will receive either Ipatasertib plus Fulvestrant or placebo (a substance that looks like the study drug but does not have any active or medicinal ingredient) plus Fulvestant. The study will provide information about the ability of Ipatasertib plus Fulvestrant to control the cancer, the side effects and safety of the treatment, how patients feel while taking the treatment and associated costs.

Eligibility criteria: Inclusion Criteria:

* Histologically and/or cytologically confirmed ER positive, HER-2 negative breast cancer
* Female patients must be post-menopausal; female patients who are pre-menopausal must have ovarian suppression using LHRH agonist while on study
* Clinical and/or radiographic progression during treatment with or within 28 days after discontinuation of first line of treatment with a CDK 4/6 inhibitor and an aromatase inhibitor (AI) for advanced/metastatic disease
* Evidence of clinically and/or radiologically documented disease
* ≥ 18 years of age
* ECOG performance status of 0 or 1
* No concurrent anti-cancer therapy and must satisfy the following criteria for previous therapy

  * Must not have received more than one prior line of treatment with a CDK 4/6 inhibitor and an AI in the advanced disease setting.
  * Treatment with CDK 4/6 inhibitor and AI must have been the most recent treatment prior to registration for this study
* Adequate hematology and organ function, in the absence of growth factors

  * Absolute neutrophils \> 1.5 x 10\^9/L
  * Platelets ≥ 100 x 10\^9/L
  * Hemoglobin \> 90 g/L
  * Total Bilirubin ≤ 1.5 x ULN (upper limit of normal) or ≤ 3 x ULN if confirmed Gilbert's Syndrome
  * ALT and AST ≤ 2.5 x ULN (or ≤ 5.0 x ULN if liver or bone metastasis)
  * Alkaline phosphatase ≤ 2.0 x ULN (or ≤ 5.0 x ULN if liver metastases, ≤ 7.0 x ULN if bone metastasis)
  * Fasting glucose ≤ 8.3 mmol/L
  * HbA1c ≤ 7.5%
  * Serum albumin ≥ 30 g/L
  * INR ≤ 1.2
  * Serum Creatinine or Creatinine clearance ≤ 1.5 x ULN or ≥ 50 mL/min; measured directly by 24-hour urine sampling or as calculated by Crockcroft and Gault equation

Exclusion Criteria:

* Untreated or symptomatic CNS metastases, radiation treatment for CNS metastases within 28 days
* Active inflammatory bowel disease, bowel inflammation, inability to swallow oral medication or GI condition that alters oral absorption
* Prior treatment with fulvestrant, selective estrogen receptor degraders (SERDs) or known inhibitors of the PI3K pathway including PI3K inhibitors, AKT inhibitors, or mTOR inhibitors
* Mean QT interval corrected for heart rate (QTc) ≥ 480 msec by ECG or history of familial long QT syndrome
* Active or uncontrolled infections or serious illnesses or medical conditions
* Clinically significant liver diseases
* History of lung disease or history of opportunistic infections
* Type 1 or Type 2 diabetes mellitus requiring insulin
* Grade ≥ 2 uncontrolled hypercholesterolemia or hypertriglyceridemia
* Known abnormalities in coagulation
* History of hypersensitivity to the study drugs or components
* Pregnant or lactating women

Primary outcomes:
measure: Progression-free survival (PFS) using RECIST 1.1
timeFrame: 5 years
Secondary outcomes:
measure: To compare the two treatment arms with respect to investigator assessed PFS (per RECIST 1.1) in the PIK3CA/AKT1/PTEN altered cohort
timeFrame: 5 years
measure: Investigator assessed PFS (per RECIST 1.1) in the PIK3CA/AKT1/PTEN non-altered cohort
timeFrame: 5 years
measure: PFS as assessed by blinded central radiology review in all enrolled patients, PIK3CA/AKT1/PTEN altered and non-altered cohorts
timeFrame: 5 years
measure: Response rate (RR) (per RECIST 1.1)
timeFrame: 5 years
measure: Duration of Response (DoR)
timeFrame: 5 years
measure: Clinical Benefit Rate (CBR);
timeFrame: 5 years
measure: Overall survival (OS)
timeFrame: 5 years
measure: Time to commencement of subsequent line of systemic therapy or death (TSST)
timeFrame: 5 years
measure: Number of participants with treatment-related adverse events as assessed by CTCAE version 5.0
timeFrame: 5 years
measure: Quality of Life (QOL) as measured using EORTC QLQ-C30 questionnaire
timeFrame: 5 years
measure: Adverse events as measured using NCI PRO-CTCAE questionnaire
timeFrame: 5 years
measure: Economic Evaluation of healthcare utilization using average cost per study subject by treatment arm to estimate an overall mean cost per study arm.
timeFrame: 5 years
measure: Economic Evaluation of health utilities measured using EQ-5D-5L
timeFrame: 5 years
Other outcomes:
Locations:
city: Bowral
country: Australia
facility: Southern Highlands Cancer Centre
state: New South Wales
city: Gateshead
country: Australia
facility: Lake Macquarie Private Hospital
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Macquarie University
country: Australia
facility: Macquarie University Hospital
state: New South Wales
city: Nowra
country: Australia
facility: Shoalhaven Cancer Care Centre
state: New South Wales
city: Birtinya
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Toowoomba
country: Australia
facility: Toowoomba Hospital
state: Queensland
city: East Melbourne
country: Australia
facility: Victorian Breast and Oncology Care
state: Victoria
city: Epping
country: Australia
facility: The Northern Hospital
state: Victoria
city: Frankston
country: Australia
facility: Frankston Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: St. Albans
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Bunbury
country: Australia
facility: St John of God Bunbury
state: Western Australia
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Garran
country: Australia
facility: Canberra Hospital
city: Herston
country: Australia
facility: Royal Brisbane and Womens Hospital
city: Kelowna
country: Canada
facility: BCCA - Cancer Centre for the Southern Interior
state: British Columbia
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Saint John
country: Canada
facility: Regional Health Authority B, Zone 2
state: New Brunswick
city: Halifax
country: Canada
facility: QEII Health Sciences Centre
state: Nova Scotia
city: Barrie
country: Canada
facility: Royal Victoria Regional Health Centre
state: Ontario
city: Brampton
country: Canada
facility: William Osler Health System
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Newmarket
country: Canada
facility: Stronach Regional Health Centre at Southlake
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Algoma District Cancer Program
state: Ontario
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Sciences Centre/
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Cancer Centre
state: Ontario
city: Greenfield Park
country: Canada
facility: Centre Integre de Sante et de Services Sociaux
state: Quebec
city: Montreal
country: Canada
facility: CHUM-Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Quebec City
country: Canada
facility: CHA-Hopital Du St-Sacrement
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Wellington
country: New Zealand
facility: Wellington Cancer Centre, Wellington Hospital
Study officials:
affiliation: BCCA - Vancouver Cancer Centre, BC Canada
name: Stephen Chia
role: STUDY_CHAIR
References: