primary • To determinne the safety and tolerability of sorafenib when administered in combination with gemcitabine and carboplatin.• To determine the maximal tolerated dose (MTD), dose limiting toxicity (DLT) and optimal treatment schedule of…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability endpoints will consist of the evaluation of adverse
events (AE*s), serious adverse events (SAE*s) and all clinically significant
changes in clinical laboratory values.
A dose regimen resulting in no more than 1 out of 6 patients with DLT will be
estimated and defined as the optimally tolerated regimen.
Secondary outcome
Pharmacokinetic endpoints will consist of parameters such as AUC, Css, Cmax,
tmax and t1/2 of i.v. carboplatin and Gemcitabine and oral Sorafenib in
combination.
Assessment (according to RECIST criteria) of antitumor activity will be
obtained every 2 cycles (6 weeks) and will be recorded as complete response,
partial response, stable disease or progressive disease
Background summary
Intravenously administered gemcitabine is the drug of choice for pancreatic
cancer as single-agent therapy and for non-small cell lung cancer (NSCLC) and
bladder cancer as combination therapy with cisplatin. It has also demonstrated
activity, either as a single-agent or in combination, in several other tumor
types, such as bladder cancer, breast cancer, testicular cancer, sarcoma and
ovarian cancer. As carboplatin has a more favourable nonhematologic toxicity
profile than cisplatin, combinations of carboplatin or cisplatin with
gemcitabine have been compared in randomized phase II and III studies in NSCLC,
bladder cancer and pancreatic cancer. Carboplatin and gemcitabine combination
chemotherapy has been shown to be very active in relapsed ovarian cancer
patients in a phase III study comparing single agent carboplatin with the
combination of carboplatin and gemcitabine.
A recently presented phase I study of the combination of gemcitabine plus
sorafenib in patients with advanced solid tumors identified gemcitabine 1000
mg/m2 weekly x 7 followed by 1 rest week plus sorafenib 400 mg BID as the
optimal treatment schedule. In this phase I study antitumor activity was
observed in patients with pancreatic and ovarian cancer.
In the light of known synergy between other targeted treatments and diverse
chemotherapeutic agents the combination of Gemcitabine, carboplatin and
sorafenib might be an efficacious treatment modality for many solid tumors like
lung cancer, bladder cancer, pancreatic cancer and ovarian cancer.
Developing a Gemcitabine, carboplatin and sorafenib combination gives us the
possibility to administer three active agents with possible synergistic
activity and favourable toxicity profile, to patients with advanced solid
tumors, in an attractive treatment schedule.
Study objective
primary
• To determinne the safety and tolerability of sorafenib when administered in
combination with gemcitabine and carboplatin.
• To determine the maximal tolerated dose (MTD), dose limiting toxicity (DLT)
and optimal treatment schedule of Gemcitabine and carboplatin plus Sorafenib in
patients with advanced solid tumors.
secundary
• To explore the pharmacokinetic and pharmacodynamic profile of systemic
exposure of Gemcitabine, carboplatin and Sorafenib in combination.
• To assess the clinical activity of gemcitabine and carboplatin in combination
with sorafenib in patients with advanced solid tumors.
Study design
This is a phase I, single centre, open-label, non-randomized study to define
the safety profile, pharmacokinetics and maximum tolerated dose (MTD) of
sorafenib in a continuous dosing schedule in combination with gemcitabine and
carboplatin in patients with advanced solid tumors. Other objectives include
determination of optimal treatment schedule, pharmacokinetic profile and
efficacy of the combination. The number of subjects to be included is expected
to be up to 28 evaluable patients in several cohorts of 3 - 6 patients per
cohort. The cohort with the safest and most feasible combination of
gemcitabine, carboplatin and sorafenib will be expanded with 6-12 patients.
Intra-patient dose escalation will be permitted across only one dose level of
all study drugs.
Intervention
Gemcitabine, carboplatin and sorafenib in a cycle of 3 weeks.
Gemcitabine infusion every 1st and 8th day
Carboplatin infusion every 1st day
Sorafenib intake twice daily continuous.
Study burden and risks
Anticipated risks are related to the experimental study medication and are
listen in the patient information sheet.
Plesmanlaan 121
1066CX Amsterdam
NL
Plesmanlaan 121
1066CX Amsterdam
NL
Listed location countries
Age
Inclusion criteria
Patients with progressive advanced solid tumor who are considered for palliative gemcitabine plus carboplatinb combination chemotherapy.
Furthermore:
• > 18 years.
• Performance: WHO 0 - 2.
• Life expectancy > 3 months.
• Histological or cytological proof of malignancy.
• Measurable disease according to RECIST criteria.
• Minimal acceptable safety laboratory values.
o ANC of >= 1.5 × 109/L
o Platelet count of >= 100 × 109/L
o Haemoglobin level of >= 10 g/dL (>= 6.2 mmol/L)
(prior transfusion is permitted)
o Hepatic function as defined by serum bilirubin <= 1.25 times the upper limit of normal (ULN), ALT and AST <= 2.5 times the ULN, except if liver metastases then ALAT and ASAT < 5 times the ULN.
o Renal function as defined by serum creatinine <= 1.25 times ULN or creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula).
• Able to swallow and retain oral medication.
• Written informed consent.
• Willingness to use a medically approved method of contraception
• Caution is recommended when administering sorafenib with inhibitors of the CYP3A4 family (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, warfarine).
Exclusion criteria
• Previous investigational cytotoxic or biological treatment for malignant disease within 30 days before the start of the study.
• Any treatment with non-oncological investigational drugs within 30 days before the start of the study.
• Radiotherapy within 2 weeks prior to study entry.
• Major surgery within 4 weeks prior to study treatment.
• Patients using medications or substances known to affect, or with the potential to affect the activity or pharmacokinetics of sorafenib.
• 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). All patients must use adequate contraceptive protection.
• History of alcoholism, drug addiction, or any psychiatric or psychological condition, which in the opinion of the investigator would impair study compliance.
• 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
• Legal incapacity
• Uncontrolled or poorly controlled hypertension (Systolic blood pressure >= 150 mmHg, diastolic blood pressure >= 90 mmHg). Initiation or adjustment of blood pressure medications is permitted prior to study treatment provided that 3 consecutive BP readings are less than 150/90 mmHg, each separated by at least 24 hours
• History of malabsorption syndrome or other disease that could significantly affect absorption of drugs
• Systemic steroids within 2 weeks prior to study treatment
• Myocardial infarction or cerebrovascular accident (CVA) within 6 months prior to study treatment
• Congestive heart failure requiring medication.
• Symptomatic brain metastases.
• Hepatic dysfunction
• Uncontrolled infections.
• Known human immunodeficiency virus (HIV) infection
• Known chronic or acute viral hepatitis
• Patients who have known hypersensitivity to the study medication
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 | EUCTR2007-004129-75-NL |
| CCMO | NL19076.031.07 |