MK-0646 and Gemcitabine +/- Erlotinib for Patients With Advanced Pancreatic Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT00769483
First received: October 8, 2008
Last updated: January 27, 2014
Last verified: January 2014
  Purpose

Objectives:

Primary Objectives:

  • Phase I: Determine the maximal tolerated dose (MTD) of MK-0646 in combination with gemcitabine or gemcitabine plus erlotinib and recommended phase II dose.
  • Phase II:
  • Assess progression-free survival (PFS) with a) gemcitabine plus MK-0646 b) gemcitabine plus erlotinib plus MK-0646 and c) gemcitabine plus erlotinib.
  • Explore IGF1 tissue level as a predictive biomarker for MK-0646 therapy in phase II expansion cohort.

Secondary Objectives:

  • Assess overall response rate (ORR), treatment toxicity, and overall survival (OS) with the addition of MK-0646 to gemcitabine or gemcitabine plus erlotinib.
  • Correlate PFS and OS with IGF-1, IGFBP-3 levels and the expression of p-IRS, IGF-1R, EMT biomarkers, Akt, Erk, mTOR, and PI13k in tumor cells.
  • To assess the incidence of single nucleotide polymorphisms of the IgF1R pathway related genes (IGF1, IGF1R, IRS1 and IRS2). These genotypes will be correlated with the clinical endpoints of this study, including OS, ORR and PFS.

Condition Intervention Phase
Pancreatic Cancer
Pancreatic Adenocarcinoma
Drug: MK-0646
Drug: Gemcitabine
Drug: Erlotinib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/ Randomized Phase II Study of Gemcitabine Plus Erlotinib Plus MK-0646; Gemcitabine Plus MK-0646 and Gemcitabine Plus Erlotinib for Patients With Advanced Pancreatic Cancer (IISP#33337)

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Phase I: Maximal Tolerated Dose (MTD) [ Time Frame: Weekly during 28 day cycle ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Phase II: Progression-Free Survival (PFS) with a) Gemcitabine plus MK-0646 b) Gemcitabine plus Erlotinib plus MK-0646 and c) Gemcitabine plus Erlotinib [ Time Frame: 4 Years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 100
Study Start Date: November 2008
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase I, Arm A
MK-0646 + Gemcitabine
Drug: MK-0646
Starting Dose Level: 5 mg/kg given intravenously over 60 minutes Days 1, 8, 15, 22 of 28 Day Cycle.
Drug: Gemcitabine
1000 mg/m^2 given intravenously over 1-1/2 hours Days 1, 8, and 15 of each 28 Day Cycle.
Other Names:
  • Gemzar
  • Gemcitabine Hydrochloride
Experimental: Phase I, Arm B
MK-0646 + Gemcitabine + Erlotinib
Drug: MK-0646
Starting Dose Level: 5 mg/kg given intravenously over 60 minutes Days 1, 8, 15, 22 of 28 Day Cycle.
Drug: Gemcitabine
1000 mg/m^2 given intravenously over 1-1/2 hours Days 1, 8, and 15 of each 28 Day Cycle.
Other Names:
  • Gemzar
  • Gemcitabine Hydrochloride
Drug: Erlotinib
100 mg by mouth daily.
Other Names:
  • OSI-774
  • Tarceva
  • Erlotinib Hydrochloride
Experimental: Phase II, Arm A
Gemcitabine + Erlotinib
Drug: MK-0646
Starting Dose Level: 5 mg/kg given intravenously over 60 minutes Days 1, 8, 15, 22 of 28 Day Cycle.
Drug: Gemcitabine
1000 mg/m^2 given intravenously over 1-1/2 hours Days 1, 8, and 15 of each 28 Day Cycle.
Other Names:
  • Gemzar
  • Gemcitabine Hydrochloride
Experimental: Phase II, Arm B
MK-0646 + Gemcitabine + Erlotinib
Drug: MK-0646
Starting Dose Level: 5 mg/kg given intravenously over 60 minutes Days 1, 8, 15, 22 of 28 Day Cycle.
Drug: Gemcitabine
1000 mg/m^2 given intravenously over 1-1/2 hours Days 1, 8, and 15 of each 28 Day Cycle.
Other Names:
  • Gemzar
  • Gemcitabine Hydrochloride
Drug: Erlotinib
100 mg by mouth daily.
Other Names:
  • OSI-774
  • Tarceva
  • Erlotinib Hydrochloride
Experimental: Phase II, Arm C
Gemcitabine + Erlotinib
Drug: Gemcitabine
1000 mg/m^2 given intravenously over 1-1/2 hours Days 1, 8, and 15 of each 28 Day Cycle.
Other Names:
  • Gemzar
  • Gemcitabine Hydrochloride
Drug: Erlotinib
100 mg by mouth daily.
Other Names:
  • OSI-774
  • Tarceva
  • Erlotinib Hydrochloride

  Hide Detailed Description

Detailed Description:

Phase I

The Study Drugs:

MK-0646 is designed to block proteins that are thought to cause cancer cells to grow and spread. This drug may help slow the growth of tumors.

Gemcitabine is designed to disrupt the growth of cancer cells, which may cause cancer cells to die.

Erlotinib hydrochloride is designed to block the activity of a protein found on the surface of many tumor cells that may control the growth and survival of cancer cells. This may stop cancer cells from growing.

Study Drug Dose Level and Groups If you are found to be eligible to take part in this study, you will be assigned to a group (Arm A or Arm B) based on when you joined the study, how many participants have been enrolled before you, and on the safety data that is available at that time.

  • If you are in Arm A, you will receive MK-0646 and gemcitabine.
  • If you are in Arm B, you will receive MK-0646, gemcitabine, and erlotinib hydrochloride.

There are 2 dose levels of MK-0646 in each arm. There will be 3-6 participants enrolled in each dose level in each arm. Enrollment will begin in Arm A. Arm B will use the same 2 dose levels as Arm A. If the first dose level of Arm A is found to be tolerable, at least 3 patients will be enrolled in Arm B, Level 1, and then at least 3 patients will be enrolled in Arm A, Level 2. If Arm B, Level 1 and Arm A, Level 2 can be safely given, the last group of 3-6 patients will be enrolled in Arm B, Level 2. The first group of participants in each arm will receive the lower dose level. The next group in each arm will receive a higher dose than the first group, if no intolerable side effects were seen.

The dose of gemcitabine and/or erlotinib hydrochloride will be the same for every group.

Study Drug Administration:

  • If you are in Arm A, on Days 1, 8, and 15 of each 28-day study cycle, you will receive gemcitabine through a needle into your vein over about 1 1/2 hours. On Days 1, 8, 15, and 22 of each cycle, you will receive MK-0646 by vein over 1 hour.
  • If you are in Arm B, you will take erlotinib hydrochloride by mouth once a day (in the morning) every day. You should take it with about 1 cup (8 oz.) of water 1 hour before or 2 hours after eating. On Days 1, 8, and 15 of each cycle, you will receive gemcitabine by vein over about 1 1/2 hours. On Days 1, 8, 15, and 22 of each cycle, you will receive MK-0646 by vein over 1 hour.

Depending upon how well you tolerate gemcitabine, your doctor may decide that you should receive gemcitabine on Days 1 and 15 instead of Days 1, 8, and 15.

Phase II

Study Groups If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of the dice) into 1 of 3 groups.

  • If you are in Arm A, you will receive gemcitabine and MK-0646.
  • If you are in Arm B, you will receive erlotinib hydrochloride, gemcitabine, and MK-0646.
  • If you are in Arm C, you will receive erlotinib hydrochloride and gemcitabine.

Study Drug Administration

  • If you are in Arm A, on Days 1, 8, and 15 of each 28-day study cycle, you will receive gemcitabine through a needle into your vein over about 1 1/2 hours as an infusion once a week for 3 weeks. On Days 1, 8, 15, and 22 of each cycle, you will receive MK-0646 by vein over 1 hour.
  • If you are in Arm B, you will take erlotinib hydrochloride by mouth once (in the morning) every day. On Days 1, 8, and 15 of each cycle, you will receive gemcitabine by vein over about 1 1/2 hours. On Days 1, 8, 15, and 22 of each cycle, you will receive MK-0646 by vein over 1 hour.
  • If you are in Arm C, you will take erlotinib hydrochloride by mouth once (in the morning) every day. On Days 1, 8, and 15 of each cycle, you will receive gemcitabine by vein over about 1 1/2 hours.
  • If you are taking erlotinib hydrochloride, you should take it with about 1 cup (8 oz.) of water 1 hour before or 2 hours after eating.

Depending upon how well you tolerate gemcitabine, your doctor may decide that you should receive gemcitabine on Days 1 and 15 instead of Days 1, 8, and 15.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Pathologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma, American Joint Committee on Cancer (AJCC) stage IV
  2. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as =/>20 mm with conventional techniques or as =/>10 mm with spiral computed Tomography (CT) scan. Measurable disease must be present outside a previous radiation field or if inside, it must be a new lesion.
  3. At least 6 months must have elapsed after completion of adjuvant therapy (if applicable).
  4. Age =/>18 years.
  5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 (Karnofsky =/>60%).
  6. Patients must have adequate organ and marrow function as defined below: 1) leukocytes =/>3,000 cells/mm^3; 2) absolute neutrophil count =/>1,500 cells/mm^3; 4) platelets =/>100,000 cells/mm^3; 5) total bilirubin <1.5mg/dl; 6) aspartate aminotransferase (AST or SGOT) /alanine aminotransferase (ALT or SGPT) =/<2.5 times institutional upper limit of normal for patients without liver metastasis, =/< 5 times institutional upper limit of normal for patients with liver metastasis; 7) creatinine - within normal institutional limits OR creatinine clearance =/>60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  7. Fasting blood glucose =/<160 mg/dl, prior to study enrollment. (For higher values, blood glucose may be controlled by dietary intervention, oral hypoglycemics and/ or insulin prior to enrollment).
  8. Women of child-bearing potential (defined as not post-menopausal for 12 months or no previous surgical sterilization) and fertile men must agree to use adequate contraception for the duration of study participation. Acceptable contraception is defined as double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Acceptable contraception must be used for 90 days after last dose of study drugs.
  9. (Continuation of inclusion criteria # 8) Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  10. Ability to understand and the willingness to sign a written informed consent document. Signed informed consent form must be obtained prior to initiation of study evaluations and/or activities.
  11. international normalized ratio (INR) <1.5 (or =/<3 if on anticoagulation therapy)
  12. Both men and women and members of all races and ethnic groups are eligible for this trial.
  13. In phase II expansion cohort, which is primarily for predictive biomarker correlation, patients enrolled will be those with pre-existing core biopsies of primary tumor or metastatic site or must be willing to undergo a biopsy for correlative studies.

Exclusion Criteria:

  1. Prior systemic chemotherapy or biological therapy for metastatic disease
  2. Prior exposure to IGF-1R inhibitors.
  3. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used in the study.
  5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  6. Pregnant or nursing women are excluded from this study because there is an unknown but potential risk for adverse events in infants secondary to treatment of the mother the study agents. If a pregnancy test (serum or urine) is positive, patient will be excluded.
  7. Patients who are known to be HIV-positive are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
  8. No other prior malignancy is allowed except for the following: adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or any other cancer from which the patient has been disease-free for two years.
  9. Patients must not be currently enrolled in a therapeutic study for pancreatic cancer.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00769483

Locations
United States, Texas
UT MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Milind Javle, MD UT MD Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT00769483     History of Changes
Other Study ID Numbers: 2007-0910
Study First Received: October 8, 2008
Last Updated: January 27, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by M.D. Anderson Cancer Center:
Pancreas
Pancreatic Cancer
Advanced cancer of the pancreas
Pancreatic Adenocarcinoma
MK-0646
Gemcitabine
Gemzar
Erlotinib hydrochloride
Erlotinib
OSI-774
Tarceva

Additional relevant MeSH terms:
Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Erlotinib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on July 28, 2014