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Amino Acids

Gemcitabine

Pancrelipase

Erlotinib Hydrochloride

Pancreatin

Antimetabolites

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Starting Dose Level: 5 mg/kg given intravenously over 60 minutes Days 1, 8, 15, 22 of 28 Day Cycle.

MK-0646

1000 mg/m\^2 given intravenously over 1-1/2 hours Days 1, 8, and 15 of each 28 Day Cycle.

Erlotinib

Milind Javle, MD

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.

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

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)

IGF1 expression in tissue was measured and correlated with 1 year patients survival. Inadequate biopsy data for outcome measure.

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

Inadequate biopsy data for outcome measure.

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

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

Time interval (in months) from date of randomization until the date of death from any cause

Complete response + Partial response using RECIST (Response Evaluation Criteria in Solid Tumors)

Number of patients who developed toxicity from treatment according to the National Cancer Institute's Common Terminology Criteria

Merck Sharp & Dohme LLC

M.D. Anderson Cancer Center

Arm A: MK-0646 (MK) + gemcitabine (G) G dose: 1000 mg/m2 over 100 min on D1,8,15 of a 28-day cycle MK dose: intravenously at two dose levels: 5 mg/kg (level I) or 10 mg/kg (level II) on D1,8,15,22.

Arm A / Phase I

Arm B: MK-0646 (MK) + gemcitabine (G) + Erolotinib (E) G dose: 1000 mg/m2 over 100 min on D1,8,15 of a 28-day cycle E dose: 100 mg orally daily MK dose: intravenously at two dose levels: 5 mg/kg (level I) or 10 mg/kg (level II) on D1,8,15,22.

Arm B / Phase I

Arm A: MK-0646 (MK) + gemcitabine (G) G dose: 1000 mg/m2 over 100 min on D1,8,15 of a 28-day cycle MK dose: 10 mg/kg

Arm A / Phase II Randomization

Arm B: MK-0646 (MK) + gemcitabine (G) + Erolotinib (E) G dose: 1000 mg/m2 over 100 min on D1,8,15 of a 28-day cycle E dose: 100 mg orally daily MK dose: 5 mg/kg

Arm B / Phase II Randomization

Arm C: gemcitabine (G) + Erolotinib (E) G dose: 1000 mg/m2 over 100 min on D1,8,15 of a 28-day cycle E dose: 100 mg orally daily

Arm C / Phase II Randomization

MK-0646 (MK) + gemcitabine (G) G dose: 1000 mg/m2 over 100 min on D1,8,15 of a 28-day cycle MK dose: 10 mg/kg

Phase II Expansion

Arm A: MK-0646 (MK) + gemcitabine(G) G dose: 1000 mg/m2 over 100 min on D1,8,15 of a 28-day cycle MK dose: intravenously at two dose levels: 5 mg/kg (level I) or 10 mg/kg (level II) on D1,8,15,22. .

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Milind Javle, MD/Professor, GI Medical Oncology

MK 5mg +G: #DLT

MK 10mg +G: # DLT

The primary endpoint is MTD which was analyzed based on phase I participants only. Phase II (Arms A and B) or phase II expansion participants were not included in the analysis per design.

MK-0646 Maximum Tolerable Dose

Arm B: MK-0646 (MK) + gemcitabine (G) + Erolotinib (E)G dose: 1000 mg/m2 over 100 min on D1,8,15 of a 28-day cycle E dose: 100 mg orally daily MK dose: 5 mg/kg

For any group that was not analyzed for Progression Free Survival (PFS) outcome the number of participants has been set to be zero.

Progression Free Survival

For any group that was not analyzed for Overall Survival (OS) outcome the number of participants has been set to be zero.

Overall Survival

Arm B: MK-0646 (MK) + gemcitabine (G) + Erolotinib (E)G dose: 1000 mg/m2 over 100 min on D1,8,15 of a 28-day cycle E dose: 100 mg orally daily MK dose: intravenously at two dose levels: 5 mg/kg (level I) or 10 mg/kg (level II) on D1,8,15,22.

For any group that was not analyzed for Overall Response Rate outcome the number of participants has been set to be zero.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
MK-0646 and Gemcitabine +/- Erlotinib for Patients With Advanced Pancreatic Cancer	NCT00769483	Pancreatic Canc... Pancreatic Aden...	MK-0646 Gemcitabine Erlotinib	18 Years -	M.D. Anderson Cancer Center
MK-0646 and Gemcitabine +/- Erlotinib for Patients With Advanced Pancreatic Cancer	NCT00769483	Pancreatic Canc... Pancreatic Aden...	MK-0646 Gemcitabine Erlotinib	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for advanced cancer of the pancreas