Primary objective: To evaluate the safety of Gemcitabine and Lapatinib in combination for the treatment of advanced breast cancer.Secondary objectives: Assessment of the effect of Gemcitabine and Lapatinib on the pharmacokinetics of each other and…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety Outcome Measures: Toxicity will be evaluated according to the NCI Common
Terminology Criteria for Adverse Events (CTCAE) v3.0 (van 10 june 2003). Safety
assessments will be based on medical review of adverse events reports and the
results of vital sign measurements, physical examinations, and clinical
laboratory tests throughout the conduct of the study.
Secondary outcome
Pharmacokinetic Measures: Pharmacokinetic parameters (Cmax, Tmax, AUC(inf) en
T1/2) will be derived froma plasma concentration versus time data.
Tumor Response Outcome Measures: Tumor response will be obtained from all
patients with measurable lesions, using the RECIST criteria. The assessments
will be made every two cycles (after cycle 2, 4, 6 etc.) or more frequently if
indicated. Furthermore, a response is considered confirmed if it is noted on
two examinations at least four weeks apart.
Background summary
Gemcitabine has a broad range of activity and favourable toxicity profile. In
phase I and II trials gemcitabine mono-therapy, or in combination, has been
shown to be active and well tolerated in both chemotherapy naïve and
pre-treated breast cancer patients. As mono-therapy gemcitabine gives response
rate ranging from 14 - 37% and 12 - 30% in fist and second line treatment,
respectively. Studies have shown that gemcitabine can safely be combined with
paclitaxel, docetaxel, vinorelbine, cisplatin, carboplatin and capecitabine in
breast cancer patients. Furthermore, phase III trials have confirmed the
activity of gemcitabine in combination with capecitabine.
In preclinical studies gemcitabine and trastuzumab has been shown to act
synergistically in Her2/neu overexpressing breast cancer cell lines.
Gemcitabine plus trastuzumab has been evaluated in a small phase II study in
Her2/neu positive breast cancer patients showing that this combination is both
effective and tolerable in previously treated breast cancer patients.
Lapatinib has been shown to be active as monotherapy and in combination with
various chemotherapeutic agents in patients with advanced Her2/neu
overexpressing breast cancer previously treated with both chemotherapy and
trastuzumab. Developing a lapatinib and gemcitabine combination gives us the
possibility to administer two active agents with possible synergistic activity
and favourable toxicity profile, to women with advanced breast cancer, in an
attractive treatment schedule.
Study objective
Primary objective: To evaluate the safety of Gemcitabine and Lapatinib in
combination for the treatment of advanced breast cancer.
Secondary objectives: Assessment of the effect of Gemcitabine and Lapatinib on
the pharmacokinetics of each other and assessment of the efficacy of
Gemcitabine and Lapatinib in patients with advanced breast cancer.
Study design
This is a phase I, open label study of Gemcitabine in combination with
Lapatinib in patients with advanced breast cancer.
The recommended dose of Lapatinib and Gemcitabine in combination will be
determined by dose adjustment. Patients will be treated in cohorts of three per
dose level. Each cycle consists of 4 weeks of therapy. The starting doses will
be 750 mg of Lapatinib, given as tablets once daily on day 1 - 28, and
Gemcitabine, 750 mg/m2, given as a 30 min. intravenous infusion on day 1, 8 and
15, repeated 4 weekly. Further dose escalation (see table below) will be
performed according to the toxicity and pharmacokinetic profile observed at
prior dose levels.
Previously, Gemcitabine 1000 mg/m2 on day 1, 8 and 15 (q 4 weeks) plus
Lapatinib 1500 mg/day continue has been shown to be safe in patients with
advanced pancreatic cancer.
Should one patient of the first three experience dose-limiting toxicity (DLT),
the number of patients treated at this dose level will be expanded to maximally
six. Provided none of the additional three patients experience DLT, further
dose escalation will continue.
Dose escalation will continue until a dose is reached at which more than one of
the expanded cohort of six patients experience DLT during their first cycle of
the combination (maximum tolerated dose, MTD).
In case of MTD and determination of optimal treatment regimen 6 - 12 additional
patients will be entered at this dose level for PK analysis.
Intra-patient dose escalation will be permitted across only one dose level of
both Gemcitabine and Lapatinib.
Dose escalation table:
Cohort 1: Gemcitabine 750 mg/m2 + Lapatinib 750 mg OD continue
Cohort 2: Gemcitabine 1000 mg/m2 + Lapatinib 750 mg OD continue
Cohort 3: Gemcitabine 1000 mg/m2 + Lapatinib 1000 mg OD continue
Cohort 4: Gemcitabine 1000 mg/m2 + Lapatinib 1250 mg OD continue
Cohort 5: Gemcitabine 1000 mg/m2 + Lapatinib 1500 mg OD continue
Cohort 6: Gemcitabine 1250 mg/m2 + Lapatinib 1500 mg OD continue
Blood samples for pharmacokinetics of Gemcitabine and Lapatinib will be
collected over 24 hours on day 1 and 2 of the first cycle (hospital admission)
and over 1 hour on day 8, 15 and 29 (outpatient care).
Intervention
Chemotherapy with Gemcitabine and Lapatinib combination according to the
following schedule:
Gemcitabine infusion on day 1, 8 and 15 in a cycle of 28 days.
Lapatinib tablets once daily continue day 1 - 28 in a cycle of 28 days.
Study burden and risks
Patients will undergo pharmacokinetic analyses during 12 hours on day 1 of the
first cycle. Furthermore, one additional blood sample will be collected on day
2, 8 and 15 of the first cycle and on day 1 of cycle 2. Thereafter visits are
scheduled once weekly before each Gemcitabine administration on day 1, 8 and 15
of a 4 week schedule. Anticipated risks are related to the experimental study
medication and listed in the patient information sheet.
Plesmanlaan 121
1066CX Amsterdam
NL
Plesmanlaan 121
1066CX Amsterdam
NL
Listed location countries
Age
Inclusion criteria
All patients who are considered for palliative Gemcitabine chemotherapy for advanced breast cancer.
Furthermore:
1. > 18 years
2. Performance status: WHO 0 - 2
3. Life expectancy > 3 months
4. Histological or cytological proof of breast cancer
5. Evaluable or measurable disease according to RECIST criteria
6. Previous chemotherapy with an anthracycline and a taxane.
7. Previous Trastuzumab (Herceptin®) in case of Her2/neu overexpression (IHC) or gene amplification (FISH/CISH)
8. No radiotherapy for at least 2 weeks prior to study entry
9. Minimal acceptable safety laboratory values
a. ANC of >= 1.5 × 109/l
b. Platelet count of >= 100 × 109/l
c. Haemoglobin level of >= 10 g/dl (>= 6.2 mmol/l)
(prior transfusion is permitted)
d. Hepatic function as defined by serum bilirubin <= 1.5 times the upper limit of normal, ALT and AST <= 2.5 times the upper limit of normal.
e. Renal function as defined by serum creatinine <= 1.5 times upper limit of normal or creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula).
10. Cardiac ejection fraction (LVEF) within the institutional range of normal as measured by echocardiogram or MUGA scan (i.e. > 50%). Baseline and on treatment scans should be performed using the same modality.
11. Able to swallow and retain oral medication
12. Written informed consent
Exclusion criteria
1. More than three previous courses of chemotherapy including adjuvant chemotherapy
2. Patients who have received a cumulative dose of adriamycine more than 360 mg/m2 or a cumulative dose of epirubicine more than 600 mg/m2.
3. Symptomatic CNS metastases.
4. Previous investigational cytotoxic or biological treatment for malignant disease within 30 days before the start of the study.
5. Any treatment with non-oncological investigational drugs within 30 days before the start of the study
6. Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors.
7. Patients using medications or substances known to affect, or with the potential to affect the activity or pharmacokinetics of Lapatinib.
8. Treatment within one week before the start of the study with any of the following: terfenadine, cisapride, cyclosporin, tacrolimus, theophylline, diazepam, sulphonylurea hypoglycaemics, phenytoin, or carbamazepine.
9. Uncontrolled infections.
10. All herbal (alternative) medicines are excluded, but multivitamins are allowed.
11. Pregnancy or breast feeding (all women of childbearing potential must have a pregnancy test before inclusion in the study; post-menopausal women must have amenorrhoea for at least 12 months). Female patients must use adequate contraceptive protection.
12. HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with Lapatinib.
13. Clinically significant cardiac impairment or unstable ischaemic heart disease including a myocardial infarction (< 3 months of study entry)
14. History of alcoholism, drug addiction, or any psychiatric or psychological condition which in the opinion of the investigator would impair study compliance
15. Malabsorption syndrome or other condition which may affect absorption of Lapatinib.
16. Concurrent or previous malignancy of a different tumour type within five years of starting the study except for adequately treated non-melanoma skin cancer or cervical intraepithelial neoplasia
17. Patients who have had previous treatment with Lapatinib.
18. Legal incapacity
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 | EUCTR2006-003778-82-NL |
| CCMO | NL14053.031.07 |