MK0752 and Gemcitabine Hydrochloride in Treating Patients With Stage III and IV Pancreatic Cancer That Cannot Be Removed by Surgery
Primary Purpose
Pancreatic Cancer
Status
Completed
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Notch signaling pathway inhibitor MK0752
gemcitabine hydrochloride
imaging biomarker analysis
laboratory biomarker analysis
pharmacological study
Sponsored by
About this trial
This is an interventional treatment trial for Pancreatic Cancer focused on measuring stage III pancreatic cancer, stage IV pancreatic cancer, duct cell adenocarcinoma of the pancreas
Eligibility Criteria
DISEASE CHARACTERISTICS:
Histologically or cytologically confirmed ductal adenocarcinoma of the pancreas
- Stage III and IV, unresectable disease
- Assessable disease by endoscopic ultrasound or CT guidance
- Tissue that is assessed by the Investigator as being accessible to biopsy - for patients recruited to dose escalation phase where three previous patients have not already provided biopsies
No known brain metastases
- Patients with stable symptoms within the past 4 weeks, on a stable dose of steroids, and able to give informed consent are eligible
PATIENT CHARACTERISTICS:
- WHO performance status 0-1
- Life expectancy ≥ 12 weeks
- Hemoglobin ≥ 9.0 g/dL
- Absolute neutrophil count ≥ 1.5 x 10^9/L
- Platelet count ≥ 100 x 10^9/L
- Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
- ALT ≤ 2.5 times ULN (≤ 5 times ULN if due to liver metastases)
- PT ≤ 1.5 times ULN
- Creatinine clearance ≥ 50 mL/min (uncorrected)
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use two forms of highly effective contraception (females) 4 weeks prior to, during, and for 6 months after completion of study therapy or 1 form of highly effective contraception (males) during and for 6 months after completion of study therapy
- Written (signed and dated) informed consent and capable of cooperating with treatment and follow-up
- No nonmalignant systemic disease, including active uncontrolled infection, that confers a high medical risk to the patient
- No known serologically positive HIV or hepatitis B or C infection
- No other concurrent malignancies except adequately treated cone-biopsied carcinoma in situ of the uterine cervix, basal or squamous cell carcinoma of the skin, or cancer survivors who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease ≥ 5 years, and are deemed at negligible risk for recurrence
- No concurrent congestive heart failure
- No prior history of cardiac disease (New York Heart Association class III-IV disease), cardiac ischemia, or cardiac arrhythmia
- No other condition that, in the investigator's opinion, would not make the patient a good recommendation for the clinical trial
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- Recovered from prior treatments
- Previous chemotherapy for advanced disease is permitted. If gemcitabine treatment was given previously, the patient must have tolerated a dose of at least 800mg/m2. Previous chemotherapy for malignant disease must be complete at least 3 weeks before treatment on this trial (six weeks for mitomycin C)
- No major thoracic or abdominal surgery from which the patient has not yet recovered
No concurrent participation or planned participation in another interventional clinical study
- Concurrent participation in an observational study allowed
No concurrent warfarin
- Low molecular weight heparin allowed
- No concurrent radiotherapy (except palliative for bone pain), endocrine therapy, or immunotherapy
- No other concurrent anticancer therapy or investigational drugs
Sites / Locations
- Addenbrooke's Hospital
- Leicester Royal Infirmary
- Barts and the London School of Medicine
- Beatson West of Scotland Cancer Centre
- St James' Hospital
Outcomes
Primary Outcome Measures
Maximum-tolerated dose of MK0752 in combination with gemcitabine hydrochloride OR the single agent recommended Phase II dose in combination with either 800 mg/m² or 1000 mg/m² as agreed by DDO and clinicians
Adverse event and severity according to NCI CTCAE Version 4.02
Secondary Outcome Measures
Complete response, partial response, or stable disease as defined by RECIST criteria
Progression-free survival
Survival at 1 year
Percentage change in CA19-9 levels
Plasma concentrations of MK0752
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01098344
Brief Title
MK0752 and Gemcitabine Hydrochloride in Treating Patients With Stage III and IV Pancreatic Cancer That Cannot Be Removed by Surgery
Official Title
A Cancer Research UK Phase I Trial of an Oral Notch Inhibitor (MK-0752) in Combination With Gemcitabine in Patients With Stage III and IV Pancreatic Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
October 2015
Overall Recruitment Status
Completed
Study Start Date
April 2010 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
October 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Cancer Research UK
4. Oversight
5. Study Description
Brief Summary
RATIONALE: MK0752 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving MK0752 together with gemcitabine hydrochloride may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of giving MK0752 together with gemcitabine hydrochloride and to see how well it works in treating patients with stage III or IV pancreatic cancer that cannot be removed by surgery.
Detailed Description
OBJECTIVES:
Primary
To determine the recommended phase II dose of MK0752 in combination with gemcitabine hydrochloride in patients with unresectable stage III and IV pancreatic cancer. (Phase I)
Secondary
To evaluate tumor response in patients treated with this regimen.
To determine the time to disease progression and 6 months and 1-year survival.
To determine the percentage of change in CA19-9 levels.
Tertiary
To assess target inhibition of MK0752 in plasma.
To explore the feasibility of measuring MK0752 levels in tumor tissue.
To establish relationships between measures of tumor expression of molecular target and objective tumor response.
To determine the pharmacokinetic profile of MK0752 in plasma when administered with and without gemcitabine hydrochloride.
OUTLINE: This is a multicenter, phase I, dose-escalation study of MK0752 and gemcitabine hydrochloride.
Patients receive gemcitabine hydrochloride IV on days 1, 8, and 15. Patients receive oral MK0752 on days -14, -7, 1, 8, 15, and 22 in course 1 only and on days 1, 8, 15, and 22 beginning in course 2 and for all subsequent courses. Treatment with MK0752 and gemcitabine hydrochloride repeats every 28 days* for 6 courses in the absence of disease progression or unacceptable toxicity.
NOTE: *The first course is 42 days.
Patients undergo biopsy of tumor at baseline and on day -7. Tumor samples are analyzed to determine Notch pathway inhibition via IHC and qualitative RT-PCR analysis and for MK0752 concentrations. Hair follicle (from the head) samples are collected at baseline and on day -7 to determine Notch pathway inhibition via RT-PCR. Blood samples are collected periodically to determine changes in CA 19-9 levels and MK0752 concentrations.
After completion of study treatment, patients are followed for 28 days and then every 2 months for 1 year. Patients will then be followed up as part of their normal clinic visits for up to one year after the last patient was treated on the study.
Peer Reviewed and Funded or Endorsed by Cancer Research UK
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pancreatic Cancer
Keywords
stage III pancreatic cancer, stage IV pancreatic cancer, duct cell adenocarcinoma of the pancreas
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
44 (Actual)
8. Arms, Groups, and Interventions
Intervention Type
Drug
Intervention Name(s)
Notch signaling pathway inhibitor MK0752
Intervention Type
Drug
Intervention Name(s)
gemcitabine hydrochloride
Intervention Type
Other
Intervention Name(s)
imaging biomarker analysis
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Type
Other
Intervention Name(s)
pharmacological study
Primary Outcome Measure Information:
Title
Maximum-tolerated dose of MK0752 in combination with gemcitabine hydrochloride OR the single agent recommended Phase II dose in combination with either 800 mg/m² or 1000 mg/m² as agreed by DDO and clinicians
Title
Adverse event and severity according to NCI CTCAE Version 4.02
Secondary Outcome Measure Information:
Title
Complete response, partial response, or stable disease as defined by RECIST criteria
Title
Progression-free survival
Title
Survival at 1 year
Title
Percentage change in CA19-9 levels
Title
Plasma concentrations of MK0752
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS:
Histologically or cytologically confirmed ductal adenocarcinoma of the pancreas
Stage III and IV, unresectable disease
Assessable disease by endoscopic ultrasound or CT guidance
Tissue that is assessed by the Investigator as being accessible to biopsy - for patients recruited to dose escalation phase where three previous patients have not already provided biopsies
No known brain metastases
Patients with stable symptoms within the past 4 weeks, on a stable dose of steroids, and able to give informed consent are eligible
PATIENT CHARACTERISTICS:
WHO performance status 0-1
Life expectancy ≥ 12 weeks
Hemoglobin ≥ 9.0 g/dL
Absolute neutrophil count ≥ 1.5 x 10^9/L
Platelet count ≥ 100 x 10^9/L
Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
ALT ≤ 2.5 times ULN (≤ 5 times ULN if due to liver metastases)
PT ≤ 1.5 times ULN
Creatinine clearance ≥ 50 mL/min (uncorrected)
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use two forms of highly effective contraception (females) 4 weeks prior to, during, and for 6 months after completion of study therapy or 1 form of highly effective contraception (males) during and for 6 months after completion of study therapy
Written (signed and dated) informed consent and capable of cooperating with treatment and follow-up
No nonmalignant systemic disease, including active uncontrolled infection, that confers a high medical risk to the patient
No known serologically positive HIV or hepatitis B or C infection
No other concurrent malignancies except adequately treated cone-biopsied carcinoma in situ of the uterine cervix, basal or squamous cell carcinoma of the skin, or cancer survivors who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease ≥ 5 years, and are deemed at negligible risk for recurrence
No concurrent congestive heart failure
No prior history of cardiac disease (New York Heart Association class III-IV disease), cardiac ischemia, or cardiac arrhythmia
No other condition that, in the investigator's opinion, would not make the patient a good recommendation for the clinical trial
PRIOR CONCURRENT THERAPY:
See Disease Characteristics
Recovered from prior treatments
Previous chemotherapy for advanced disease is permitted. If gemcitabine treatment was given previously, the patient must have tolerated a dose of at least 800mg/m2. Previous chemotherapy for malignant disease must be complete at least 3 weeks before treatment on this trial (six weeks for mitomycin C)
No major thoracic or abdominal surgery from which the patient has not yet recovered
No concurrent participation or planned participation in another interventional clinical study
Concurrent participation in an observational study allowed
No concurrent warfarin
Low molecular weight heparin allowed
No concurrent radiotherapy (except palliative for bone pain), endocrine therapy, or immunotherapy
No other concurrent anticancer therapy or investigational drugs
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Duncan Jodrell, MD
Organizational Affiliation
Cambridge University Hospitals NHS Foundation Trust
Official's Role
Principal Investigator
Facility Information:
Facility Name
Addenbrooke's Hospital
City
Cambridge
State/Province
England
ZIP/Postal Code
CB2 2QQ
Country
United Kingdom
Facility Name
Leicester Royal Infirmary
City
Leicester
State/Province
England
ZIP/Postal Code
LE1 5WW
Country
United Kingdom
Facility Name
Barts and the London School of Medicine
City
London
State/Province
England
ZIP/Postal Code
EC1M 6BQ
Country
United Kingdom
Facility Name
Beatson West of Scotland Cancer Centre
City
Glasgow
State/Province
Scotland
ZIP/Postal Code
G12 0YN
Country
United Kingdom
Facility Name
St James' Hospital
City
Leeds
ZIP/Postal Code
L59 7TF
Country
United Kingdom
12. IPD Sharing Statement
Learn more about this trial
MK0752 and Gemcitabine Hydrochloride in Treating Patients With Stage III and IV Pancreatic Cancer That Cannot Be Removed by Surgery
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