None listed
Conditions
Brief summary
This is a multi-center, open-label, non-comparative, two-step phase I / II trial. Patients who meet the selection criteria having histologically demonstrable advanced pancreatic cancer will consecutively enter the phase I, dose-finding study. In the Phase I, 2-30 patients will be accrued. Patients will receive treatment consisting of temsirolimus [up to 25mg weekly in a 30 minute intravenous (iv) infusion, 30 minutes after premedication with 4mg of iv dimethindene - bolus 30 min before the start of each temsirolimus infusion) followed by infusion of gemcitabine. Once the Maximum Tolerated Dose (MTD) for the combination is achieved, the proposed dose will be defined. The proposed dose will be the dose of the previous level in which the MTD will be reached. In the Phase II, all patients will start therapy with the determined proposed dose (previous dose level of the MTD) of temsirolimus and gemcitabine. Treatment will be administered for 7 cycles.
Interventions
Phase I: In the phase I, 2-30 patients will be accrued. A minimum of 2 patients will be treated at the first dose levels. As per protocol design there is no -1 level and therefore, if two DLTs occur at the first two patients, trial has to be closed prematurely. Each dose level will include at least 3 subjects.
Patients will receive treatment consisting of temsirolimus [up to 25 milligrams (mg) weekly] followed by infusion of gemcitabine. The starting doses of temsirolimus and gemcitabine will b
Phase I: In the phase I, 2-30 patients will be accrued. A minimum of 2 patients will be treated at the first dose levels. As per protocol design there is no -1 level and therefore, if two DLTs occur at the first two patients, trial has to be closed prematurely. Each dose level will include at least 3 subjects. Patients will receive treatment consisting of temsirolimus [up to 25 milligrams (mg) weekly] followed by infusion of gemcitabine. The starting doses of temsirolimus and gemcitabine will be 15mg [30 min intravenous (iv) infusion] and 800 mg/m2 [30 min intravenous (iv) infusion] respectively. Three subjects will be included in each dose level. If no subject experiences Dose Limiting Toxicity (DLT), the study moves to the higher dose level. Level 1 Gemcitabine: 800mg/m2 Days 1, 15 four week cycle, Temsirolimus 15 mg Weekly Level 2 Gemcitabine: 800mg/m2 Days 1, 15 four week cycle, Temsirolimus: 20mg Weekly Level 3 Gemcitabine: 800mg/m2 Days 1, 15 four week cycle, Temsirolimus 25mg Weekly Level 4 Gemcitabine: 1000mg/ m2 Days 1, 15 four week cycle, Temsirolimus: 20mg Weekly Level 5 Gemcitabine: 1000mg/ m2 Days 1, 15 four week cycle, Temsirolimus: 25mg Weekly If only 1 of the 3 subjects experiences DLT or other unacceptable toxicity, the number of subjects in the cohort will be increased to 6. If 2 or more of the 6 subjects experience DLT, no further dose escalation (level increase) will take place. This will be considered the Maximum Tolerated Dose (MTD) of the combination. Once the MTD is achieved and is/or exceeds the 20mg/800mg/m2 dose level, the 3 (or 6) subjects enrolled at this dose level can continue on the clinical study Phase II: All patients will start therapy with the determined proposed dose (previous dose level of the MTD) of temsirolimus and gemcitabine. Both drugs are administered on Days 1 and 15 of each 4 week cycle. Temsirolimus is also administered alone on day 8 and day 22. Treatment will be administered for 7 cycles.
Sponsors
Hellenic Cooperative Oncology Group
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of written informed consent 2. Age 18 years or older 3. Histologic proof of pancreatic cancer 4. Performance status between 50% and 100% on the Karnofsky scale 5. Life expectancy of greater than 12 weeks 6. Prior radiotherapy is allowed except for evaluable sites 7. Measurable or evaluable disease as according to Response Evaluation Criteria in Solid Tumors (RECIST) 8. All females of childbearing potential must have a negative serum or urine pregnancy test obtained within 2 days prior to initiation of treatment 9. White Blood Count >4000/microliter (mcl), platelets > 100,000/mcl and a hemoglobin level > 9.5 grams per deciliter (g/dl). Adequate baseline hepatic function, defined as a total bilirubin level < 2 miligrams per deciliter (mg/dl), serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) < 3 times the upper limits of normal, unless the liver is involved, in which case the transaminase levels could be up to five times the upper limits of normal. Creatinine < 1.5 mg/dl or creatinine clearance > 60 milliliter per minute (ml/min). 10 Provision of adequate paraffin-embedded tumor tissue for translational studies and 10 milliliter (ml) peripheral blood for Deoxyribonucleic acid (DNA) study.
Exclusion criteria
1. Patients with ampullary, periampullary, bile duct cancers or endocrine tumors of the pancreas 2. History of atrial or ventricular arrhythmias and/or history of congestive heart failure, even if medically controlled. History of clinical and electrocardiographically documented myocardial infarction within the last 6 months from study entry 3. Any evidence of clinically active interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) 4. Pre-existing motor or sensory neurotoxicity grade 2 according to the World Health Organization (WHO) criteria (intolerable paresthesia and/or marked motor loss or worse) 5. History of previous chemotherapy 6. Symptomatic brain metastases 7. Known, severe hypersensitivity to temsirolimus or any of the excipients of this product 8. Other coexisting malignancies or malignancies diagnosed within the last 5 years with the exception of basal cell carcinoma or cervical cancer in situ 9. Any unresolved chronic toxicity greater than Common Terminology Criteria (CTC) grade 2 from previous anticancer therapy 10. As judged by the investigator, any evidence of severe or uncontrolled systemic disease (eg unstable or uncompensated respiratory, cardiac, hepatic or renal disease) 11. Alanine amino transferase (ALT) or aspartate amino transferase (AST) greater or equal than 3 times the Upper Limit of the Reference Range (ULRR) if no demonstrable liver metastases or greater than 5 times the ULRR in the presence of liver metastases 12. Active infection or evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the trial/ receive protocol treatment 13. Pregnancy or breast feeding 14. Concomitant use of Cytochrome P450, family 3, subfamily A (Cyp3 A) inducers (phenytoin, carbamazepine, rifampicin, barbiturates or St John’s Wort) should be avoided and as should treatment wih strong CyP 3A inhibitors 15. Treatment with a non-approved or investigational drug within 30 days before Day 1 of trial treatment 16. Hypersensitivity to gemcitabine
Outcome results
None listed