MK0752 and Gemcitabine Hydrochloride in Treating Patients With Stage III and IV Pancreatic Cancer That Cannot Be Removed by Surgery

Pancreatic Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01098344
• Other study ID #: CDR0000669535
• Secondary ID: CRUK-CR0720-11CR
• Status: Completed
• Phase: Phase 1
• First received: April 1, 2010
• Last updated: October 13, 2015
• Start date: April 2010
• Est. completion date: October 2014

Study information

• Verified date: October 2015
• Source: Cancer Research UK
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: Research Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: October 2014
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Pancreatic Cancer
• Pancreatic Neoplasms

Intervention

Drug:
• Notch signaling pathway inhibitor MK0752

• gemcitabine hydrochloride

Other:
• imaging biomarker analysis

• laboratory biomarker analysis

• pharmacological study

Locations

Country	Name	City	State
United Kingdom	Addenbrooke's Hospital	Cambridge	England
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow	Scotland
United Kingdom	St James' Hospital	Leeds
United Kingdom	Leicester Royal Infirmary	Leicester	England
United Kingdom	Barts and the London School of Medicine	London	England

Sponsors (1)

Lead Sponsor	Collaborator
Cancer Research UK

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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			No
Primary	Adverse event and severity according to NCI CTCAE Version 4.02			Yes
Secondary	Complete response, partial response, or stable disease as defined by RECIST criteria			No
Secondary	Progression-free survival			No
Secondary	Survival at 1 year			No
Secondary	Percentage change in CA19-9 levels			No
Secondary	Plasma concentrations of MK0752			No