Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12611000643976
Ethics application status
Approved
Date submitted
10/05/2011
Date registered
23/06/2011
Date last updated
20/05/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
Investigation of gemcitabine combined with temsirolimus, in patients with inoperable or metastatic pancreatic cancer.
A phase I-II study by the Hellenic Cooperative Oncology Group with biomarker evaluation (HE3/07)
Scientific title
Patients with inoperable or metastatic pancreatic cancer treated with gemcitabine and temsirolimus combination to determine safety and efficacy of the combination.
Secondary ID [1] 260032 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Patients with inoperable or metastatic pancreatic cancer 265688 0
Condition category
Condition code
Cancer 265827 265827 0 0
Pancreatic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 264563 0
Treatment: Drugs
Comparator / control treatment
N/A
Control group
Uncontrolled

Outcomes
Primary outcome [1] 266726 0
Phase I
Determine the feasibility and Maximum Tolerated Dose (MTD) for a combination of temsirolimus and gemcitabine. The proposed dose will be the dose of the previous level in which the MTD will be reached.
Timepoint [1] 266726 0
In the phase I of the study, 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.
Once the MTD is reached and the proposed dose is defined, the study will move on to the phase II .
Primary outcome [2] 266727 0
Phase II
6-month Progression Free Survival (PFS)
Timepoint [2] 266727 0
Response will be evaluated according to RECIST criteria. Tumor assessments will be performed by Computed Tomography (CT) in cylces 2, 4 and 7.
Secondary outcome [1] 276265 0
Phase II
To explore for potential correlation of tumor molecular profile with clinical outcome in patients treated at the recommended doses
Timepoint [1] 276265 0
Blood/Paraffin embedded tumor samples will be collected prior to first infusion. This procedure is for translational research purposes only and will not have an impact on patients' management.
Secondary outcome [2] 276266 0
To estimate the Quality of Life (QoL) benefits measured by the EuroQoL 5D scale.
Timepoint [2] 276266 0
Quality of Life Questionnaires (EuroQoL 5D) will be completed at screening-baseline, on cycles 4, 7 and 6 months after completion of treatment
Secondary outcome [3] 276267 0
To estimate the overall survival (OS) of the combination at trial closure
Timepoint [3] 276267 0
OS will be calculated from the date of treatment initiation to the date of death or last contact. Patients will be followed for a minimum of 5-years post treatment completion
Secondary outcome [4] 276268 0
To evaluate the nature, incidence and severity of adverse events (AEs) and serious adverse events (SAEs) of the combination of temsirolimus and gemcitabine
Timepoint [4] 276268 0
Adverse Events (AEs) (e.g. hematological and non-hematological toxicities) of all participants will be recorded and assessed upon signature of the informed consent form until 30 days after the last administration of study treatmentToxicity is assessed by laboratory evaluation of hematology and biochemistry, physical examination etc.

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
9/05/2009
Actual
19/05/2009
Date of last participant enrolment
Anticipated
Actual
12/03/2013
Date of last data collection
Anticipated
Actual
Sample size
Target
85
Accrual to date
Final
Recruitment outside Australia
Country [1] 3414 0
Greece
State/province [1] 3414 0

Funding & Sponsors
Funding source category [1] 265014 0
Other Collaborative groups
Name [1] 265014 0
Hellenic Cooperative Oncology Group
Country [1] 265014 0
Greece
Primary sponsor type
Other Collaborative groups
Name
Hellenic Cooperative Oncology Group
Address
Hatzikostandi 18, 11524, Athens
Country
Greece
Secondary sponsor category [1] 266346 0
None
Name [1] 266346 0
Address [1] 266346 0
Country [1] 266346 0

Ethics approval
Ethics application status
Approved

Summary
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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32514 0
Prof George Fountzilas
Address 32514 0
"Papageorgiou" Hospital, Nea Efkarpia, 564 29, Thessaloniki
Country 32514 0
Greece
Phone 32514 0
+302313323959
Fax 32514 0
Email 32514 0
[email protected]
Contact person for public queries
Name 15761 0
Ms Eleni Papakostaki
Address 15761 0
Hatzikostandi 18, 11524, Athens
Country 15761 0
Greece
Phone 15761 0
+30 2106912520
Fax 15761 0
Email 15761 0
[email protected]
Contact person for scientific queries
Name 6689 0
Prof Prof. George Fountzilas
Address 6689 0
"Papageorgiou" Hospital, Nea Efkarpia, 564 29, Thessaloniki
Country 6689 0
Greece
Phone 6689 0
+30 2313323959
Fax 6689 0
Email 6689 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseGemcitabine Combined with the mTOR Inhibitor Temsirolimus in Patients with Locally Advanced or Metastatic Pancreatic Cancer. A Hellenic Cooperative Oncology Group Phase I/II Study.2018https://dx.doi.org/10.1007/s11523-018-0605-y
N.B. These documents automatically identified may not have been verified by the study sponsor.