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

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ClinicalTrials.gov Identifier: NCT00769483
Recruitment Status : Active, not recruiting
First Posted : October 9, 2008
Results First Posted : March 20, 2019
Last Update Posted : April 30, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

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 or disease Intervention/treatment Phase
Pancreatic Cancer Pancreatic Adenocarcinoma Drug: MK-0646 Drug: Gemcitabine Drug: Erlotinib Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 81 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (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)
Actual Study Start Date : November 2008
Actual Primary Completion Date : December 5, 2014
Estimated Study Completion Date : June 30, 2019


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. MK-0646 Maximum Tolerable Dose [ Time Frame: up to 12 cycles ]
    MK-0646 10 mg/kg was declared to be the MTD in combination with gemcitabine and 5 mg/kg the MTD in combination with Gemcitabine and erlotinib

  2. Progression Free Survival [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months ]
    Time interval (in months) from date of randomization until the date of first documented progression or date of death from any cause, whichever came first


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: From date of randomization until the date of death from any cause, assessed up to 100 months ]
    Time interval (in months) from date of randomization until the date of death from any cause

  2. Overall Response Rate [ Time Frame: From start of the treatment until disease progression/recurrence; or through study completion (average of 1 year) ]
    Complete response + Partial response using RECIST (Response Evaluation Criteria in Solid Tumors)

  3. Treatment Toxicity [ Time Frame: Through the treatment cycles ]
    Number of patients who developed toxicity from treatment according to the National Cancer Institute's Common Terminology Criteria


Other Outcome Measures:
  1. Correlation Between Tissue IGF-I Expression in Patients Treated With MK-0646 and OS [ Time Frame: After completing treatment ]
    IGF1 expression in tissue was measured and correlated with 1 year patients survival. Inadequate biopsy data for outcome measure.

  2. Correlation Between Plasma IGF-I Expression in Patients Treated With MK-0646 and OS [ Time Frame: After completing treatment ]

    IGF1 expression in plasma was measured in patients and correlated with 1 year patients survival.

    Inadequate biopsy data for outcome measure.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Pathologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma, 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 CT scan. See Section 11 for the evaluation of measurable disease. 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. 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) AST(SGOT)/ALT(SGPT) =/<2.5 X institutional upper limit of normal for patients without liver metastasis, =/< 5X 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. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00769483


Locations
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United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Milind Javle, MD M.D. Anderson Cancer Center
  Study Documents (Full-Text)

Documents provided by M.D. Anderson Cancer Center:

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT00769483     History of Changes
Other Study ID Numbers: 2007-0910
NCI-2010-01049 ( Registry Identifier: NCI CTRP )
First Posted: October 9, 2008    Key Record Dates
Results First Posted: March 20, 2019
Last Update Posted: April 30, 2019
Last Verified: April 2019
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:
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Pancreatic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Pancreatic Diseases
Adenocarcinoma
Carcinoma
Digestive System Diseases
Endocrine System Diseases
Gemcitabine
Erlotinib Hydrochloride
Antibodies, Monoclonal
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors