Download The BRIGHTER trial: A phase III randomized

The BRIGHTER trial: A phase III randomized, double-blind, placebo-controlled clinical trial of
first-in-class cancer stemness inhibitor BBI608 plus weekly paclitaxel versus placebo plus
weekly paclitaxel in adult patients with advanced, previously treated gastric and gastroesophageal junction adenocarcinoma.
Shah MA1,8, Muro K2,8, Shitra K3,4,8, Tebbutt NC5,8, Bang YJ6,8, Lordick F7,8, other BRIGHTER Investigators8, Borodyansky L9, Li CJ9
1New
York-Presbyterian Hospital Weill Cornell Medical School, New York, NY; 2Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; 3Departiment of Gastroenterology GI Oncology Division, National Cancer Center Hospital East, Chiba, Japan; 4Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan;
5Austin Health, Heidelberg, Victoria, Australia; 6Department of Medical Oncology, Seoul National University, Seoul, Republic of Korea; 7University Cancer Center, University Hospital Leipzig, Germany; 8Authorship was determined by the order of regional activation and patient enrollment; 9Boston Biomedical Inc.
Background
Treatment
Methods
Cancer Stem Cells (CSC)
•Highly tumorigenic, responsible for malignant growth
•Initiators (seeds) of metastasis
•Resistant to chemotherapy and current targeted therapies
• This randomized, double-blind, placebo (PBO)-controlled study will assess
the efficacy and safety of BBI608+Paclitaxel versus placebo+Paclitaxel in pts
with pre-treated, advanced gastric and GEJ adenocarcinoma.
Study Schema
N=680 Advanced Gastric and GEJ Adenocarcinoma Progressed
on 1-st Line Metastatic Therapy
•“Bulk” or non-CSCs induced toward stemness by chemotherapy exposure, priming
chemotherapy refractory cancer for treatment with a CSC inhibitor.
•Characteristic CSC cell surface markers including Lgr5, CD133, CD44, CD24, CD29,
CD166, and Musashi-1.
STAT-3 and b-catenin in gastric cancer
•Elevated expression by IHC of p-STAT-3 and nuclear b-catenin associated with
advanced disease and decreased survival1,2,3,4,5,6
•Both STAT-3 and b-catenin are important regulators of self-renewal and survival of
CSCs in gastric and GEJ adenocarcinoma.
WNT
SRC
STAT3
STAT3
STAT3
JAK
TCF/LEF
CSC genes:
WNT5A, Myc, Nanog
CSC genes:
Myc, STAT3
Maintenance of cancer stemness
BBI608
•Orally-administered first-in-class cancer stemness inhibitor
•Blocks cancer stem cell (CSC) self-renewal and induces cell death in CSCs as
well as non-stem cancer cells
Pre-clinical
•Mechanism of action is by inhibition of the Stat3 and Wnt/β-catenin pathways.
•Blockade of CD44high sphere formation with BBI608 surpasses blockade by
chemotherapeutics and biologics tested.7
•p-Stat3 and β-catenin protein expression inhibited in human colon cancer
(SW480) xenograft nude mouse model after treatment with BBI608.7
Phase Ib/II Study8
•Multicentre, open-label, dose escalation study of BBI608 administered in
combination with weekly paclitaxel at 80 mg/m2 in patients with advanced solid
tumors.
•BBI608 administered with continuous BID oral administration with multiple 4
week cycles.
•Paclitaxel administered IV weekly on days 3, 10 and 17 of each 4 week cycle.
•5 patients with gastric/GEJ adenocarcinoma enrolled and all 5 responded to
treatment
– 3 patients had tumor regression (45%, 48%, 24%)
– 2 patients who failed prior taxane had prolonged stable disease (>5 m)
•Ongoing gastric/GEJ cohort with 39 gastric or GEJ adenocarcinoma patients
enrolled with encouraging signs of anti-cancer activity being positively
confirmed.
•AE profile similar to that of both agents in monotherapy, with no new or
additive effects observed. Most common adverse events (AEs):
– Gr 1-2 diarrhea, nausea, anorexia and fatigue
– Gr 3 events: reversible diarrhea (18%), abdominal pain (4%), nausea
(1%), vomiting (3%), fatigue (6%) and dehydration (2%)
•RP2D of BBI608 determined as full monotherapy dose
•Pharmacokinetics
– No evidence of pharmacokinetic interaction.
Japanese Phase I Study9
•An open-label, study of BBI608 administered in combination with weekly
paclitaxel at 80 mg/m2 in 6 patients with gastric and GEJ adenocarcinoma with
response rate of 33.3% (2 out 6 pts), with 1 pt maintaining response > 7.5
months.
BBI608 480 mg PO BID +
Paclitaxel 80 mg/m2 IV
weekly (3 out of every 4
weeks)
1:1
Placebo PO BID +
Paclitaxel 80 mg/m2 IV
weekly (3 out of every 4
weeks)
RECIST Disease Progression or unacceptable toxicity
Overall Survival
Endpoints
Primary
•Overall survival (OS) in general study
population
Secondary
•Overall survival in predefined
biomarker-positive sub-population¥
•Progression-Free Survival (PFS) in
general study population
•PFS in predefined biomarker-positive
sub-population¥
• Objective response rate (OR) in
general study population
• Disease Control Rate (DCR)
• Safety profile
¥Patients with nuclear β-catenin positivity on IHC staining of archival tissue.
Eligibility (abbreviated)
Inclusion:
•Histologically or cytologically confirmed advanced unresectable gastric or GEJ
adenocarcinoma
•Appropriate for Paclitaxel therapy
•Failed treatment with prior 1st line regimen containing at least a
platinum/fluoropyrimide doublet in the unresectable or metastatic disease
setting with progression of disease during treatment or < 4 months after last
dose of treatment
– Concomitant treatment with anthracycline or anti-HER2 therapy allowed
– Taxane therapy in neo/adjuvant setting included as long as progression
occurred > 6 months following completion of treatment.
•ECOG PS 0 or 1.
•Age ≥ 18 years
•Contraception; negative pregnancy testing (WOCBP)
•Hgb ≥ 90 g/L, Neutrophils ≥ 1.5 x 109/L, Platelet ≥ 100 x 109/L
•Total bilirubin ≤ 1.5 × ULN [≤ 2.0 x ULN if liver metastases], ALT ≤ 3 × ULN [≤
5 × ULN if liver metastases]
•Cr ≤ 1.5 × ULN or CrCl > 50 ml/min
•Consent to tumour + blood sample banking
•Able and willing to complete QOL questionnaires
Exclusion Criteria:
•Anti-cancer therapy within the lesser of the usual cycle length of the prior
regimen (a minimum of 10 days must be observed for oral fluoropyrimidines)
•Radiotherapy, immunotherapy, or investigational agents within 4 wks (14 days
for single palliative dose of RT≤ 8 Gy)
• Patients who received taxane therapy in 1st line metastatic setting are
excluded.
•Major surgery within 4 weeks
•Symptomatic brain metastases requiring steroids.
•Women who are pregnant or breastfeeding.
•GI disorder which would significantly impede absorption of an oral agent
•Unable or unwilling to swallow BBI608/placebo capsules.
•Uncontrolled intercurrent illness, situation or geography that would limit
compliance with study requirements.
•History of other malignancies (except treated non-melanoma skin cancer, Cis
cervix, or solid tumour DFS ≥ 5 years)
•Prior treatment with BBI608
• Randomized in a 1:1 ratio to receive BBI608 480 mg or matching placebo twice
daily continuously.
• Treatment will continue until disease progression, death, intolerable toxicity, or
patient/investigator decision to stop.
• Disease assessment q8w (RECIST 1.1).
Statistical Design
• Analysis will be according to randomized group, stratified by:
• Geographical region (Asia vs North America, Europe, and Australia vs South
America)
• Time to progression on 1st line therapy (<6 months vs. >6 months from start of
1st line therapy)
• Disease measurability by RECIST 1.1 (measurable disease present vs .not
present)
• Prior taxane therapy (yes vs. no)
Sample Size Calculation
• Power of 90% and a two-sided alpha of 5% to detect a 24% reduction in the
continuous risk of death (HR 0.76, corresponding to an increase of median survival
from 7.36 to 9.67 months
• 566 events required to detect this reduction
• Randomizing 680 pts over 24 months, follow additional 12 months.
Interim Analysis
• Performed on OS (stratified log rank), when > 2/3rds (380) events observed:
H0: survival on BBI608 + paclitaxel < survival on placebo + paclitaxel
versus
H1: survival on BBI608+paclitaxel > survival on placebo + paclitaxel
• H0 rejected, BBI608 superiority declared early if p < 0.005.
• H1 rejected, BBI608 superiority not declared, if p > 0.005 and accrual continued to
final analysis for overall survival.
Correlative Studies
•
•
•
•
Analysis of archival tissue for predictive biomarkers
Analysis of blood and plasma for predictive and pharmacodynamic biomarkers
Population pharmacokinetics
QOL questionnaire
Study Status
• As of May 21, 2015 there were 107 pts randomized.
• Trial accrual is on target and study is actively accruing patients.
Registration and Support
• ClinicalTrials.gov Identifier: NCT02178956
• Supported by Boston Biomedical Inc.
References
1. Kim DY, et al (2009). STAT3 expression in gastric cancer indicates a poor
prognosis. J Gastroenterol Hepatol 24:646-51.
2. Yakata Y, et al (2007). Expression of p-STAT3 in human gastric carcinoma:
significant correlation in tomour invasion and prognosis. Int J Oncol 30:437-42.
3. Liu W-F, et al (2012). CD146 expression correlates with epithelial-mesenchymal
transition markers and a poor prognosis in gastric cancer. Int J Mol Sci 13:6399406.
4. Jawhari A, et al (1997). Abnormal immunoreactivity of the E-cadherin-catenin
complex in gastric carcinoma: relationship with patient survival.
Gastroenterology 112:46-54.
5. Radulescu S, et al (2013). Acute WNT signaling activation perturbs
differentiation within the adult stomach and rapidly leads to tumour formation.
Oncogene 32:2048-2057.
6. Barker N, et al (2010). Lgr5(+ve) stem cells drive self-renewal in the stomach
and buld long-lived gastric units in vitro. Cell Stem Cell 6:25-36.
7. Langleben A, et al (2013). A dose-escalation phase I study of a first-in-class
cancer stemness inhibitor in patients with advanced malignancies. J Clin Oncol
31, 2013 (suppl; abstr 2542).
8. Stephenson J, et al (2014). A phase Ib study of the cancer stem cell inhibitor
BBI608 administered with paclitaxel in patients with advanced malignancies.
ASCO abstr.
9. Shitara K, et al (2015). A phase I study of BBI608, a cancer stemness inhibitor,
administered with paclitaxel (PTX) as combination therapy (Rx) for pretreated
unresectable or recurrent gastric cancer. J Clin Oncol 33, 2015 (suppl; abstr
e15089)