Clinical trial NCT00960960: A Study of PI3-Kinase Inhibitor GDC-0941 in Combination With Paclitaxel, With and Without Bevacizumab or Trastuzumab, and With Letrozole, in Participants With Locally Recurrent or Metastatic Breast Cancer
Official title: A Phase Ib, Open-Label, Dose-Escalation Study of the Safety and Pharmacology of PI3-Kinase Inhibitor GDC-0941 (Pictilisib) in Combination With Paclitaxel, With and Without Bevacizumab or Trastuzumab, and With Letrozole in Patients With Locally Recurrent Or Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Breast Cancer
Keywords: MBC
PI3K
Avastin
Herceptin
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2009-08-18
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an open-label, multicenter, Phase Ib dose-escalation study to assess the safety, tolerability, and pharmacokinetics of oral (PO) pictilisib administered with letrozole or intravenous (IV) paclitaxel with and without IV bevacizumab or IV trastuzumab in participants with locally recurrent or metastatic breast cancer. The study consists of three parts. Part 1 (pictilisib will be administered in 21+7 schedule along with paclitaxel and/or bevacizumab), Part 2 (pictilisib will be administered in 5+2 schedule along with paclitaxel and/or bevacizumab or trastuzumab) and Part 3 (pictilisib will be administered in combination with letrozole). Part 1 and Part 2 consists of two stages; a dose escalation stage and a cohort-expansion stage.


Eligibility criteria: Inclusion Criteria:

* Confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease
* Adequate organ and bone marrow function as assessed by laboratory tests
* Evaluable disease or disease measurable per RECIST
* Agreement to use an effective form of contraception for the duration of the study

Exclusion Criteria:

* History of malabsorption syndrome or other condition that would interfere with enteral absorption
* Any condition requiring full-dose anticoagulants, such as warfarin, heparin, or thrombolytic agents
* Prior anti-cancer therapy (e.g., chemotherapy, biologic therapy, radiotherapy, or hormonal therapy) within 4 weeks or 5 half-lives (whichever is shorter) of the first dose of study treatment
* Uncontrolled current illness
* Active small or large intestine inflammation (such as Crohn's disease or ulcerative colitis)
* Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or current known active infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus
* Known HIV infection
* New York Heart Association (NYHA) Class II or greater congestive heart failure
* Active ventricular arrhythmia requiring medication
* Pregnancy, lactation, or breastfeeding
* Known significant hypersensitivity to study drugs or excipients
* History of arterial thromboembolic disease within 6 months of first study treatment
* No more than two prior chemotherapy regimens for metastatic disease

Primary outcomes:
measure: Percentage of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: First treatment cycle (Day 1 up to Day 29)
measure: Maximum Tolerated Dose (MTD) of Pictilisib
timeFrame: First treatment cycle (Day 1 up to Day 29)
measure: Recommended Phase II Dose (RP2D) of Pictilisib
timeFrame: Baseline up to 54.2 months
measure: Number of Cycles of Each Component of the Treatment Regimen
timeFrame: Baseline up to 54.2 months
measure: Dose Intensity of Each Component of the Treatment Regimen
timeFrame: Baseline up to 54.2 months
Secondary outcomes:
measure: Minimum Observed Plasma Concentration (Cmin) of Pictilisib
timeFrame: Parts 1 and 2 (dose escalation): predose (0 hours [h]) on Day (D) 1,3,16, and 17 of Cycle (C) 1. Part 2 (dose expansion): predose (0h) on D3,16,17 of C1; Part 3: Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)
measure: Cmin of Paclitaxel
timeFrame: Parts 1 and 2 (dose escalation): pre-paclitaxel infusion (0 h) on D2 and D16 of C1. Part 2 (dose expansion): pre-paclitaxel infusion (0 h) on D1 and D16 of C1 (cycle length=28 days)
measure: Cmin of Letrozole
timeFrame: Part 3: Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)
measure: Area Under the Curve From Time Zero to Last Measurable Concentrations (AUClast) of Pictilisib
timeFrame: Parts 1 and 2: D1,D3,D16,D17 of C1; study completion. Part 2: D3,D16, D17 of C1; study completion. Part 3: D15 of C1; D1 of C1 to C6, C≥7 (cycle length=28 days; up to 54.5 months) [detailed timeframe is provided in endpoint description]
measure: AUClast of Paclitaxel
timeFrame: Parts 1 and 2 (dose escalation): D2 and D16 of C1; study completion. Part 2 (dose expansion): D1 and D16 of C1; study completion (cycle length=28 days; up to 55.5 months) [detailed timeframe is provided in endpoint description]
measure: AUClast of Letrozole
timeFrame: Part 3: 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)
measure: Maximum Observed Plasma Concentration (Cmax) of Pictilisib
timeFrame: Parts 1 and 2: D1,D3,D16,D17 of C1; study completion. Part 2: D3,D16, D17 of C1; study completion. Part 3: D15 of C1; D1 of C1 to C6, C≥7 (cycle length=28 days; up to 54.5 months) [detailed timeframe is provided in endpoint description]
measure: Cmax of Paclitaxel
timeFrame: Parts 1 and 2 (dose escalation): D2 and D16 of C1; study completion. Part 2 (dose expansion): D1 and D16 of C1; study completion (cycle length=28 days; up to 55.5 months) [detailed timeframe is provided in endpoint description]
measure: Cmax of Letrozole
timeFrame: Part 3: 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)
measure: Percentage of Participants With Objective Response According to Modified Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months])
measure: Duration of Response According to Modified RECIST
timeFrame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months])
measure: Percentage of Participants With Death or Disease Progression According to Modified RECIST
timeFrame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months])
measure: Progression-free Survival According to Modified RECIST
timeFrame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months])
Other outcomes:
Locations:
city: Peoria
country: United States
state: Illinois
city: Boston
country: United States
state: Massachusetts
city: Nashville
country: United States
state: Tennessee
city: Leuven
country: Belgium
city: Milano
country: Italy
state: Lombardia
Study officials:
affiliation: Genentech, Inc.
name: Stina Singel, M.D., Ph.D.
role: STUDY_DIRECTOR
References:
citation: Schoffski P, Cresta S, Mayer IA, Wildiers H, Damian S, Gendreau S, Rooney I, Morrissey KM, Spoerke JM, Ng VW, Singel SM, Winer E. A phase Ib study of pictilisib (GDC-0941) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer. Breast Cancer Res. 2018 Sep 5;20(1):109. doi: 10.1186/s13058-018-1015-x.