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

 Study Visits:

 On Day 1 of Cycle 1, the following tests and procedures will be performed:

 -  Your medical history will be recorded.

 -  You will have a performance status evaluation.

 -  You will be asked to list any drugs you may be taking and if you have experienced any
 side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 -  Blood (about 1 teaspoon) will be drawn to make sure your body has not created cells to
 fight against MK-0646. These cells are called human anti-human antibodies (also known as
 HAHA).

 On Day 8 of Cycle 1, the following tests and procedures will be performed:

 -  Your vital signs and weight will be measured.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 -  You will be asked if you have experienced any side effects.

 On Day 15 of Cycle 1, the following tests and procedures will be performed:

 -  You will have a performance status evaluation.

 -  You will be asked to list any drugs you may be taking and if you have experienced any
 side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 On Day 22 of Cycle 1, the following tests and procedures will be performed:

 -  Your vital signs and weight will be measured.

 -  Blood (about 1 teaspoon) will be drawn to test for HAHA.

 -  You will be asked if you have experienced any side effects.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 On Day 1 of Cycles 2 and beyond, the following tests and procedures will be performed:

 -  You will have a performance status evaluation.

 -  You will be asked to list any drugs you may be taking and if you have experienced any
 side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 -  Blood (about 1 teaspoon) will be drawn for testing of CA 19-9.

 On Days 8 and 15 of Cycles 2 and beyond, the following tests and procedures will be
 performed:

 -  Your vital signs and weight will be measured.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 -  You will be asked if you have experienced any side effects.

 On Day 22 of Cycles 2 and beyond, your vital signs and weight will be measured and you will
 be asked if you have experienced any side effects.

 On Day 22 of Cycle 2 and every even cycle (Cycles 4, 6, 8, and so on), you will have a CT
 scan or MRI scan to check the status of the disease. Blood (about 1 teaspoon) will also be
 drawn to test HAHA.

 Length of Study:

 You may remain on study for as long as you are benefiting. You will be taken off study if the
 disease gets worse or you experience intolerable side effects.

 End-of-Study Visit:

 After you go off study, you will have an end-of-study visit. At this visit, the following
 tests and procedures will be performed:

 -  You will have a performance status evaluation.

 -  You will be asked to list any drugs you may be taking and if you have experienced any
 side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight.

 -  You will have a CT scan or MRI scan to check the status of the disease.

 -  Blood (about 2 teaspoons) will be collected for routine tests.

 -  Blood (about 1 teaspoon) will be drawn to test HAHA.

 -  Blood (about 1 teaspoon) will be drawn to test CA 19-9.

 At Weeks 4, 8, and 12 after the end of study visit, blood (about 1 teaspoon) will be drawn to
 test HAHA.

 Long-Term Follow Up:

 Once you are off study, every 3 months from then on, the study staff will ask you how you are
 doing, either in the clinic or by telephone. If you are called, the phone call will take
 about 10-15 minutes.

 This is an investigational study. MK-0646 is not FDA approved or commercially available. At
 this time, MK-0646 is only being used in research. Gemcitabine is FDA approved and
 commercially available for the treatment of pancreatic cancer. Erlotinib hydrochloride is FDA
 approved and commercially available for the treatment of pancreatic cancer in combination
 with gemcitabine.

 Up to 100 patients will take part in this study. All will be enrolled at MD Anderson.

 Phase II:

 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 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.

 Study Visits:

 On Day 1 of Cycle 1, the following tests and procedures will be performed:

 -  Your medical history will be recorded.

 -  You will have a performance status evaluation.

 -  You will be asked to list any drugs you may be taking and if you have experienced any
 side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 -  If you are assigned to receive MK-0646, blood (about 1 teaspoon) will be drawn to make
 sure your body has not created cells to fight against MK-0646. These cells are called
 human anti-human antibodies (also known as HAHA).

 On Day 8 of Cycle 1, the following tests and procedures will be performed:

 -  Your vital signs and weight will be measured.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 -  You will be asked if you have experienced any side effects.

 On Day 15 of Cycle 1, the following tests and procedures will be performed:

 -  You will have a performance status evaluation.

 -  You will be asked to list any drugs you may be taking and if you have experienced any
 side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 On Day 22 of Cycle 1, the following tests and procedures will be performed if you are
 receiving MK-0646:

 -  Your vital signs and weight will be measured

 -  Blood (about 1 teaspoon) will be drawn to test for HAHA.

 -  You will be asked if you have experienced any side effects.

 On Day 1 of Cycles 2 and beyond, the following tests and procedures will be performed:

 -  You will have a performance status evaluation.

 -  You will be asked about any other drugs you may be taking and if you have experienced
 any side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 -  Blood (about 1 teaspoon) will be drawn for testing of CA 19-9.

 On Days 8 and 15 of Cycles 2 and beyond, the following tests and procedures will be
 performed:

 -  Your vital signs and weight will be measured.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 -  You will be asked if you have experienced any side effects.

 On Day 22 of Cycles 2 and beyond, your vital signs and weight will be measured, (if you are
 receiving MK-0646). and you will be asked if you have experienced any side effects.

 On Day 22 of Cycle 2 and every even cycle (Cycles 4, 6, 8, and so on), you will have a CT
 scan or MRI scan to check the status of the disease. Blood (about 1 teaspoon) will be also be
 drawn to test HAHA if you are receiving MK-0646.

 Length of Study:

 You may remain on study for as long as you are benefiting. You will be taken off study if the
 disease gets worse or you experience intolerable side effects.

 If you are in Arm C (erlotinib and gemcitabine) and the disease gets worse, you may be
 allowed to join Arm B (gemcitabine, erlotinib, and MK-0646).

 End-of-Study Visit:

 After you go off study, you will have an end-of-study visit. At this visit the following
 tests and procedures will be performed:

 -  You will have a performance status evaluation.

 -  You will be asked to list any drugs you may be taking and if you have experienced any
 side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight.

 -  You will have a CT scan or MRI scan to check the status of the disease.

 -  Blood (about 2 teaspoons) will be collected for routine tests.

 -  Blood (about 1 teaspoon) will be drawn for testing of CA 19-9.

 -  Blood (about 1 teaspoon) will be drawn for testing to test HAHA if you are receiving
 MK-0646.

 At Weeks 4, 8, and 12 after the end of study visit, blood (about 1 teaspoon) will be drawn to
 test HAHA if you were receiving MK-0646.

 Long-Term Follow Up:

 Once you are off study, every 3 months from then on, the study staff will ask you how you are
 doing, either in the clinic or by telephone. If you are called, this phone call will take
 about 10-15 minutes.

 This is an investigational study. MK-0646 is not FDA approved or commercially available. At
 this time, MK-0646 is only being used in research. Gemcitabine is FDA approved and
 commercially available for the treatment of pancreatic cancer. Erlotinib hydrochloride is FDA
 approved and commercially available for the treatment of pancreatic cancer in combination
 with gemcitabine.

 Up to 100 patients will take part in this study. All will be enrolled at MD Anderson.

 Phase II Expansion Cohort:

 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.

 Study Treatments:

 If you are found to be eligible to take part in this study, you will receive gemcitabine and
 MK-0646.

 Study Drug Administration:

 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.

 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.

 Study Visits:

 On Day 1 of Cycle 1, the following tests and procedures will be performed:

 -  Your medical history will be recorded.

 -  You will have a performance status evaluation.

 -  You will be asked to list any drugs you may be taking and if you have experienced any
 side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 On Day 8 of Cycle 1, the following tests and procedures will be performed:

 -  Your vital signs and weight will be measured.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 -  You will be asked if you have experienced any side effects.

 On Day 15 of Cycle 1, the following tests and procedures will be performed:

 -  You will have a performance status evaluation.

 -  You will be asked to list any drugs you may be taking and if you have experienced any
 side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 On Day 22 of Cycle 1, the following tests and procedures will be performed if you are
 receiving MK-0646:

 -  Your vital signs and weight will be measured

 -  You will be asked if you have experienced any side effects

 -  Blood (about 1 tablespoon) will be drawn for biomarker testing.

 On Day 1 of Cycles 2 and beyond, the following tests and procedures will be performed:

 -  You will have a performance status evaluation.

 -  You will be asked about any other drugs you may be taking and if you have experienced
 any side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 -  Blood (about 1 teaspoon) will be drawn for testing of CA 19-9.

 On Days 8 and 15 of Cycles 2 and beyond, the following tests and procedures will be
 performed:

 -  Your vital signs and weight will be measured.

 -  Blood (about 2 teaspoons) will be drawn for routine tests.

 -  You will be asked if you have experienced any side effects.

 On Day 22 of Cycles 2 and beyond, your vital signs and weight will be measured and you will
 be asked if you have experienced any side effects.

 On Day 22 of Cycle 2 and every even cycle (Cycles 4, 6, 8, and so on), you will have a CT
 scan or MRI scan to check the status of the disease.

 Length of Study:

 You may remain on study for as long as you are benefiting. You will be taken off study if the
 disease gets worse or you experience intolerable side effects.

 End-of-Study Visit:

 After you go off study, you will have an end-of-study visit. At this visit the following
 tests and procedures will be performed:

 -  You will have a performance status evaluation.

 -  You will be asked to list any drugs you may be taking and if you have experienced any
 side effects.

 -  You will have a physical exam, including measurement of your vital signs and weight.

 -  You will have a CT scan or MRI scan to check the status of the disease.

 -  Blood (about 2 teaspoons) will be collected for routine tests.

 -  Blood (about 1 teaspoon) will be drawn for testing of CA 19-9.

 Long-Term Follow Up:

 Once you are off study, every 3 months from then on, the study staff will ask you how you are
 doing, either in the clinic or by telephone. If you are called, this phone call will take
 about 10-15 minutes.

 This is an investigational study. MK-0646 is not FDA approved or commercially available. At
 this time, MK-0646 is only being used in research. Gemcitabine is FDA approved and
 commercially available for the treatment of pancreatic cancer.

 Up to 100 patients total will take part in this study. All will be enrolled at MD Anderson.
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.