To establish the MaximumTolerated Dose, Dose Limiting Toxicities, and the safety profile of BMS-833923 administered in combination with cisplatin and capecitabine as first-line therapy. To describe preliminary evidence of tumor response as measured…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Toxicity will be evaluated according to the NCI Common Terminology Criteria for
Adverse Events (CTCAE) v3.0. Safety assessments will be based on medical review
of adverse event reports and the results of vital sign measurements, ECGs,
multiple gated acquisition scan (MUGA) or
echocardiograms, physical examinations, and clinical laboratory tests.
Pharmacokinetic parameters including Cmax, Tmax and AUC (TAU) will be derived
from plasma concentration versus time data for BMS-833923 alone on days 11-14
for any subjects undergoing tumor biopsy in the dose escalation cohort, and all
subjects in the dose expansion cohort, and in combination with cisplatin and
capecitabine on cycle 2 day 1 for subjects in the dose expansion cohort.
Secondary outcome
Trough samples for the assessment of 5-FU, the active moiety of capecitabine,
will be collected on cycle 1, day 35 and cycle 2, day 14 in all subjects during
dose escalation, on cycle 1, day 35, cycle 2, day 2, and cycle 2, day 14 in at
least 12 subjects during dose expansion. Tumor response will be determined for
all subjects by radiological responses as defined by RECIST criteria.
Radiological and/or clinical tumor assessments to evaluate response and
progression will be done after even cycles of therapy or more frequently if
indicated.
Pretreatment biopsies will serve as baseline samples for comparison with
subsequent on-treatment biopsies to assess PD changes. The tumor biopsies will
be used to evaluate effects of study drug treatment on mRNA and/or protein
levels of Hedgehog pathway components and a marker of apoptosis.
Background summary
There is no proven curative therapy for patients receiving standard of care for
inoperable, metastatic gastric, gastroesophageal and esophageal
adenocarcinoma. At diagnosis the prognosis is poor with time to protression
5.6 month and median overall survival about 9 months. In this study, all
subjects will have access to treatment regimens that have proven therapeutic
value (cisplatin plus capecitabine). Therefore there is clearly an unmet
medical need. The purpose of this study is to determine the maximum tolerated
dose (MTD), dose limiting toxicities (DLT(s)),
and safety profile of BMS-833923 administered in combination with cisplatin and
capecitabine as first-line therapy in subjects with inoperable metastatic
gastric, gastroesophageal or esophageal adenocarcinomas.
Eligibility criteria for this study have been carefully considered to ensure
the safety of the study subjects and to ensure that the results of the study
can be used. .
Study objective
To establish the MaximumTolerated Dose, Dose Limiting Toxicities, and the
safety profile of BMS-833923 administered in combination with cisplatin and
capecitabine as first-line therapy. To describe preliminary evidence of tumor
response as measured by RECIST and to evaluate the Pharmacodynamic effects of
BMS-833923 in tumor biopsy samples taken prior to and during single-agent and
combination treatment by evaluation of protein or mRNA. of biomarkers of
Hedgehog pathway activation such as GLI-l and on markers of apoptosis such as
caspase-3.
In addition to evaluate trough concentrations of the active moiety of
capecitabine when BMS-833923 is co-administered with cisplatin and
capecitabine. To evaluate biomarkers that are potentially predictive of
anti-tumor activity after BMS-833923 treatment.
Study design
This is a multiple ascending dose study of BMS-833923 administered in
combination with fixed doses of cisplatin and capecitabine as first-line
therapy. The study will be conducted in two phases, with a dose escalation
phase to identify a potential MTD, followed by a dose expansion phase to
confirm the MTD.
During dose escalation, safety and tolerability will be assessed in cohorts of
up to 6 evaluable subjects using a *Rolling Six* design, a modification of the
standard 3 + 3 design. Dose-limiting toxicity (DLT) is defined as toxicity
related to BMS-833923 occurring during the first 35 days of treatment.
All subjects must consent to a pre-treatment biopsy to be eligible. Subjects in
the dose expansion phase must consent to three tumor biopsies (one
pre-treatment, and two on-treatment biopsies) to be eligible. Subjects in the
dose escalation phase are required to undergo pre-treatment biopsy, and are
encouraged to provide on-treatment biopsies on the same schedule as those
subjects in the dose expansion phase. However, all on-treatment biopsies are
optional for subjects in the dose escalation phase. The first cycle for each
dose cohort is longer than subsequent cycles, cycle 1 is 35 days long (14 days
single-agent plus 21 days combination therapy), while cycle 2 and subsequent
cycles will be 21 days long (combination therapy only). The 14-day window
period will only occur at the beginning of the first cycle for every subject.
For each dose cohort, BMS-833923 will be administered once daily on a
continuous basis. Cisplatin will be administered on day 1 (day 15 of cycle 1)
and capecitabine will be administered on days 1-14 (days 15-28 of cycle 1) of
each 21 day cycle until end of treatment.
Samples to assess the pharmacokinetic properties of BMS-833923 in combination
with cisplatin and capecitabine will be collected in all subjects in the dose
escalation portion and in at least 12 subjects from the dose expansion portion
of the study. PK samples for the assessment of 5-FU (the active moiety of
capecitabine) will be collected during dose escalation and in at least 12
subjects from the dose expansion portion of the study.
Intervention
BMS-833923 administered with cisplatin and capecitabine as a combined therapy.
Study burden and risks
Patients will be subject to invasive medical procedures (blood sampling, ECGs,
CT/MRIs, FDG-PET scans, chest X-Rays, pregnancy test, Echo or MUGA, Pulmonary
function test, Biopsy) but these medical procedures will be performed by
trained medical staff so any risks or pain associated with these procedures
should be minimised. Patients will be followed closely for toxicities and
appropriate medical care given.
Vijzelmolenlaan 9
3400 AM Woerden
NL
Vijzelmolenlaan 9
3400 AM Woerden
NL
Listed location countries
Age
Inclusion criteria
1) Signed Written Informed Consent
2) Subjects with histologically or cytologically confirmed metastatic esophageal,gastric, or gastroesophageal adenocarcinoma.
3) Eastern Cooperative Oncology Group (ECOG) performance status 0-2
4) Estimated life expectancy of at least 3 months
5) Biopsies - Subjects in the dose escalation portion of the study will have one pre-treatment biopsy. Subjects in the dose expansion portion of the study will have one pre-treatment biopsy and two on-treatment for biomarker and predictive marker analyses.
6) No prior chemotherapy for the target disease is permitted.
7) Men and women, ages 18 and above.
8) WOCBP must have a negative serum or urine pregnancy test
Exclusion criteria
1) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 3 months after the last dose of investigational product.
2) Sexually active fertile men not using effective birth control while on study and for at least 3 months following treatment with BMS-833923.
3) Subjects with known symptomatic brain metastasis.
4) Any serious, uncontrolled medical disorder or acute infection which would impair the ability of the subject to receive protocol therapy.
5) Any gastrointestinal surgery, unresolved bowel obstruction or malabsorption syndrome that could impact the absorption of study drug.
6) Uncontrolled or significant cardiovascular disease.
7) Active or chronic infection with HIV, HepB, or HepC.
8) Positive Pregnancy Test
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 | EUCTR2010-018743-33-NL |
| CCMO | NL33938.018.10 |