To increase the major pathological response rate (< 10% vital tumor cells) to neoadjuvant treatment by integrating both trastuzumab and pertuzumab into perioperative chemotherapy for HER-2 positive, resectable gastric cancer.
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is major pathological response rate (< 10% vital residual
tumor cells).
Secondary outcome
Secondary endpoints are:
* R0 resection rate
* Pathological complete response
* Locoregional failure
* Distant failure
* Progression-free survival according to RECIST v1.1
* Recurrence-free-survival (from surgery)
* Overall survival
* Adverse event assessment according to CTCAE v 4.0
Background summary
With an estimated almost one million cases in 2012, gastric cancer is currently
the 5th most common malignancy and the third leading cause of cancer-related
mortality worldwide (Ref. 1). Approximately 25% of all patients with gastric
cancer have resectable disease at presentation. Even for patients with
localized gastric or gastroesophageal junction adenocarcinoma, the prognosis is
poor in *Western* countries with 5-year survival rates of approximately 35 %
after standard perioperative chemotherapy followed by curative surgery (Ref. 2,
Ref. 9). Between 10 and 20% of patients in clinical trials for gastric and
gastroesophageal cancer are HER-2 positive (Ref. 3; Ref. 4). However, several
epidemiological studies observed lower rates of HER-2 positive disease (Ref.
5). In advanced gastric and gastroesophageal cancer, the addition of
trastuzumab to standard chemotherapy has significantly improved
progression-free survival, overall survival, and response rates (Ref. 3). In
HER-2 positive breast cancer, the addition of trastuzumab to standard
neoadjuvant chemotherapy significantly improves both, pathological complete
response rates and overall survival (Ref. 6). A further significant improvement
of histopathological complete response rates after neoadjuvant treatment of
HER-2 positive breast cancer has been observed recently; when the dimerization
inhibitor pertuzumab was added to trastuzumab and chemotherapy (pathological
complete response rates 29% versus 45%) (Ref. 7). In advanced breast cancer,
the addition of pertuzumab to trastuzumab and docetaxel increased
progression-free survival from 12.4 to 18.5 months (HR 0.62; 95% CI 0.51-0.75;
p<0.001) (Ref. 8). With respect to targeted, perioperative treatment of HER-2
positive gastric and gastroesophageal junction cancer there is neither clinical
trial data available, nor a randomized clinical trial ongoing.
In view of the significant benefit of the addition of trastuzumab and
pertuzumab to the neoadjuvant treatment of breast cancer, this study has been
developed to address to potential added value of a perioperative treatment
regimen which integrates HER-2 targeting drugs for gastric and gastroesophageal
junction cancer.
Study objective
To increase the major pathological response rate (< 10% vital tumor cells) to
neoadjuvant treatment by integrating both trastuzumab and pertuzumab into
perioperative chemotherapy for HER-2 positive, resectable gastric cancer.
Study design
This is a randomized phase II trial with a 1:2:2 randomization (control:
experimental arm 1: experimental arm 2). Potentially eligible patients will be
screened centrally for HER-2 status. After confirmation of HER-2 positive
disease, eligible patients will be centrally randomized through the EORTC
randomization system. A minimization technique will be used for random
treatment allocation between the three treatment arms. Stratification will be
done by Asia versus Europe; GEJ versus GC (non-GEJ); HER-2 IHC 3+ versus
IHC2+/FISH+; intestinal versus non-intestinal; and chemotherapy regimen
(Cisplatin+Capecitabine/5-FU /CapOx/mFOLFOX6/FLOT).
Standard arm: chemotherapy alone
-- FLOT is administered in cycles of 2 weeks for 4 cycles (= 8 weeks) on day
1, 15, 29 and 43 pre- and postoperatively.
- CapOx is given for 3 cycles of 3 weeks (= 9 weeks) on day 1, 22 and 43 pre-
and postoperatively.
- mFOLFOX6 is given for 4 cycles of 2 weeks (=8 weeks) on day 1, 15, 29 and
43 pre- and postoperatively
Experimental arms (neoadjuvant and adjuvant treatment)
Experimental arm 1: chemotherapy as in the control group, plus trastuzumab (8
mg/kg loading dose, followed by 6 mg/kg every 3 weeks) at day 1, independent of
the chemotherapy regimen chosen for 3 cycles of 3 weeks before and after
surgery.
Experimental arm 2: chemotherapy plus trastuzumab as in experimental arm 1,
plus pertuzumab (840 mg every 3 weeks) at day 1, independent of the
chemotherapy regimen chosen. In the absence of contraindications after
completion of adjuvant treatment, maintenance treatment with trastuzumab
/trastuzumab and pertuzumab will continue.
Intervention
Standard arm: chemotherapy alone
-- FLOT is administered in cycles of 2 weeks for 4 cycles (= 8 weeks) on day
1, 15, 29 and 43 pre- and postoperatively.
- CapOx is given for 3 cycles of 3 weeks (= 9 weeks) on day 1, 22 and 43 pre-
and postoperatively.
- mFOLFOX6 is given for 4 cycles of 2 weeks (=8 weeks) on day 1, 15, 29 and
43 pre- and postoperatively
Experimental arms (neoadjuvant and adjuvant treatment)
Experimental arm 1: chemotherapy as in the control group, plus trastuzumab (8
mg/kg loading dose, followed by 6 mg/kg every 3 weeks) at day 1, independent of
the chemotherapy regimen chosen for 3 cycles of 3 weeks before and after
surgery.
Experimental arm 2: chemotherapy plus trastuzumab as in experimental arm 1,
plus pertuzumab (840 mg every 3 weeks) at day 1, independent of the
chemotherapy regimen chosen. In the absence of contraindications after
completion of adjuvant treatment, maintenance treatment with trastuzumab
/trastuzumab and pertuzumab will continue
Study burden and risks
Trastuzumab and pertuzumab are no standard treatments in adjuvant therapy. Both
treatment could cause a benefit for the patient an increase the pathological
response rate and could affect progression-free survival and overall survival
positively.Due to pertuzumab is an small risk for an increase in ejection
fraction.
Avenue E. Mounier 83/11
Brussel 1200
BE
Avenue E. Mounier 83/11
Brussel 1200
BE
Listed location countries
Age
Inclusion criteria
* All patients (HER-2 positive and negative) should be registered in the
trial as soon as possible after written informed consent for screening
according to ICH/GCP, and national/local regulations.
* Histologically proven, gastric or GE-junction adenocarcinoma (Siewert I-III)
* Absence of distant metastases on CT scan of thorax and abdomen
* Patient medically fit for gastrectomy/oesophagectomy as decided by the
investigator
* Age >= 18 years
* WHO performance status 0 - 1,
Randomization:
- HER-2 overexpression, as determined by central testing using
immunohistochemistry (IHC 3+) or the combination of IHC 2+ and HER-2 FISH
positive.
* Amenable to gastrectomy/oesophagectomy with curative intent as confirmed by a
multidisciplinary team discussion
* UICC (7th edition) tumor stage Ib to III, as defined by CT scan and/or MRI.
Endosonography (EUS) is recommended, but not mandatory. EUS should especially
be considered to distinguish T1 and T2 tumors and to evaluate local
resectability. (In case of conflicting results of CT scan and/or MRI and
endoscopic ultrasound, the final decision on which finding the staging is based
should be taken by the multidisciplinary team).
- The cardiac ejection fraction (LVEF), as determined by echocardiography,
MUGA or cardiac MRI should be at least 55%.
* Adequate organ function:
* White blood cell count (WBC) > 3 x 109/L
* Absolute neutrophil count (ANC) > 1.5 x 109/L
* Platelets >= 100 x 109/L
* Hemoglobin >= 9 g/dL (transfusions are permitted to reach this value)
* Estimated glomerular filtration rate (eGFR) according to MDRD should be > 50
ml/min for patients treated with oxaliplatin-based regimens upfront
Note: for patients that will receive CISPLATIN upfront, a GFR > 60 ml/min is
required
* Total bilirubin within normal limits (if the patient has documented Gilbert*s
disease <= 1.5 × ULN or direct bilirubin <= ULN)
* Aspartate transaminase (AST) and alanine transaminase (ALT) <= 2.5 × ULN
- Absence of preexisting neuropathy > grade I
- Investigator and patient have to agree to replace any oral anticoagulations
by subcutaneous administration of low-molecular weight heparin
- Absence of any psychological, familial, sociological or geographical
condition potentially hampering compliance with study protocol & follow-up
schedule;
- For women who are not postmenopausal (> 12 months of nontherapy induced
amenorrhea)or surgically sterile(absence of ovaries and/or uterus):
- agreement to remain abstinent or use single or combined contraceptive methods
that result in a failure rate of < 1% per year during treatment period &for at
least 7 months after last
treatment dose
- Negative serum pregnancy test
- For men: agreement to remain abstinent or use a condom plus additional
contraceptive method that together result in a failure rate of < 1% per year
during the treatment period &for at least 7
months after last dose of study treatment.
Exclusion criteria
* No prior chemo- or antibody therapy
* No history of significant cardiac disease defined as:
* Symptomatic CHF (NYHA classes II-IV, see Appendix D)
* High-risk uncontrolled arrhythmias, i.e. atrial tachycardia with a
heart rate > 100/min at rest, significant ventricular arrhythmia
(ventricular tachycardia) or higher-grade AV-block (second degree AV-block Type
2 [Mobitz 2] or third degree AV-block)
* History of myocardial infarction within 6 months prior to randomization
* Clinically significant valvular heart disease
* No central nervous system metastasis or leptomeningeal tumor spread. For
patients without any neurological symptoms, a brain MRI is recommended, but not
obligatory. For patients with any clinical symptoms which may be attributed to
brain metastases, a brain MRI is compulsory to rule out cerebral metastases.
* No known hypersensitivity to the components of trastuzumab, pertuzumab,
cisplatin, oxaliplatin, docetaxel, 5-FU or capecitabine
- no patients with interstitial lung disease
* Absence of preexisting neuropathy > grade I
* No known dihydropyrimidine dehydrogenase (DPD) deficiency (testing not
required). In case of specific recommendations due to institutional and/or
national guidelines please proceed accordingly.
* No ongoing or concomitant use of the antiviral drug sorivudine or its
chemically related analogs, such as brivudine
* No chronic treatment with high-dose intravenous corticosteroids (> 10 mg/day
prednisone equivalents)
* No previous malignancy within the last 5 years, with the exception of
adequately treated cervical carcinoma in situ, localized non-melanoma skin
cancer, or other curatively treated cancer without impact on the patient*s
overall prognosis according to the judgment of the investigator.
* Female patients should not be breast feeding.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000722-38-NL |
| ClinicalTrials.gov | NCT02205047 |
| CCMO | NL51319.031.15 |