Clinical trial NCT00769483
Conditions: Pancreatic Cancer Pancreatic Adenocarcinoma
Keywords: Pancreas Pancreatic Cancer Advanced cancer of the pancreas Pancreatic Adenocarcinoma MK-0646 Gemcitabine Gemzar Erlotinib hydrochloride Erlotinib OSI-774 Tarceva
Sponsor: M.D. Anderson Cancer Center
Start date: 2008-11-13; Completion date: 2020-09-01
Enrollment: 81 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

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.

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.

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.

Arms: arm 1: MK-0646 + Gemcitabine arm 2: MK-0646 + Gemcitabine + Erlotinib arm 3: Gemcitabine + Erlotinib arm 4: MK-0646 + Gemcitabine + Erlotinib arm 5: Gemcitabine + Erlotinib
Interventions: intervention 1: MK-0646 intervention 2: Gemcitabine intervention 3: Erlotinib
Intervention descriptions: intervention 1: Starting Dose Level: 5 mg/kg given intravenously over 60 minutes Days 1, 8, 15, 22 of 28 Day Cycle. intervention 2: 1000 mg/m\^2 given intravenously over 1-1/2 hours Days 1, 8, and 15 of each 28 Day Cycle. intervention 3: 100 mg by mouth daily.

Protocol documents:
Prot_SAP_000.pdf: 
2007-0910 
 October 6, 2014 
 
 
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 
 
 
 
Study Center: 
 
 
The University of Texas M. D. Anderson Cancer Center  
Department of Gastrointestinal Medical Oncology, Unit 0426 
1515 Holcombe Boulevard 
Houston, TX  77030 
 
Principal Investigator: 
Milind Javle, MD 
 
Co-Investigators: 
 
Naifa Busaidy, MD 
David Fogelman, MD 
Linus Ho, MD, PhD 
Ahmed Kaseb, MD 
Michael Overman, MD 
Gauri Varadhachary, MD 
Robert A. Wolff, MD 
Rachna Shroff, MD 
Statistician: 
 
 
 
Xuemei Wang, MS 
 
       
 
 
 
 
 
 
 
 
 
 
 
 


2007-0910 
 October 6, 2014 
 
 
TABLE OF CONTENTS 
Page 
 
1. OBJECTIVES ..........................................................................................................................1 
1.1 
Primary Objectives ........................................................................................................1 
1.2 
Secondary Objectives ....................................................................................................1 
 
2. BACKGROUND ......................................................................................................................1 
2.1 
Pancreatic Cancer  ..........................................................................................................1 
2.2 
IgF-1R and Pancreatic Cancer  ......................................................................................2 
2.3 
IgF1R and EGFR Inhibition ...........................................................................................2 
2.4 
MK-0646  .......................................................................................................................3 
2.5 
Erlotinib  ........................................................................................................................8 
2.6 
Gemcitabine  ..................................................................................................................8 
2.7 
Study Rationale  .............................................................................................................9 
2.8 
Correlative Studies Background ..................................................................................10 
 
3. PATIENT SELECTION .......................................................................................................10 
3.1 
Inclusion Criteria  .........................................................................................................10 
3.2 
Exclusion Criteria ........................................................................................................11 
3.3 
Inclusion of Women and Minorities ............................................................................12 
 
4. REGISTRATION PROCEDURES ......................................................................................12 
 
5. TREATMENT PLAN ............................................................................................................13 
5.1  
Agent Administration ...................................................................................................13 
5.2  
Phase I  .........................................................................................................................13 
5.3  
Phase II  ........................................................................................................................17 
5.4  
General Concomitant Medication and Supportive Care Guidelines ............................18 
5.5       Duration of Therapy/Criteria for Removal from Study ...............................................21 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................21 
 
6.1       Dose Modification of Erlotinib ....................................................................................22 
 
6.2       Dose Modification of Gemcitabine  .............................................................................23 
 
 
6.3       Dose Modification of MK-0646  .................................................................................24 
 
6.4       New Cycle of Therapy  ................................................................................................26 
 
6.5       Adverse Event Follow-up  ...........................................................................................26 
 
 
 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................26 
7.1  
Adverse Effects of MK-0646  ......................................................................................27 
7.2  
Adverse Effects of Erlotinib  .......................................................................................28 
7.3  
Adverse Effects of Gemcitabine  .................................................................................28 
7.4  
Adverse Event Attribution  ..........................................................................................29 
7.5  
Serious Adverse Events  ..............................................................................................30 


2007-0910 
 October 6, 2014 
 
 
7.6  
Instructions for Rapid Notification of Serious Adverse Events ..................................30 
7.7  
Investigator Communications with Study Supporter  ..................................................31 
7.8  
Pregnancies  .................................................................................................................31 
 
8. PHARMACEUTICAL INFORMATION ............................................................................31 
8.1  
MK-0646  .....................................................................................................................32 
8.2  
Gemcitabine  ................................................................................................................32 
8.3  
Erlotinib  ......................................................................................................................33 
 
9. CORRELATIVE/SPECIAL STUDIES ...............................................................................33 
9.1 
IGF-1 and IGFBP-3 Circulating Levels  ......................................................................33 
9.2 
IGF-1R Signaling Pathway Proteins Tissue Levels  ....................................................34 
9.3 
Single nucleotide polymorphisms of IgF1R and related genes……………………....34 
 
10. STUDY CALENDAR ............................................................................................................35 
10.1 
Pre-treatment Evaluations  ...........................................................................................37 
10.2 
During Treatment Evaluations  ....................................................................................37 
10.3 
End of Treatment Evaluations  ....................................................................................39 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors ................................................................................39 
 
12. DATA COLLECTION ..........................................................................................................44 
 
13. STATISTICAL CONSIDERATIONS .................................................................................44 
 
REFERENCES .............................................................................................................................49 
 
Appendix 1: Statistical Output………………………………………………………………...52 
 


2007-0910 
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Page 1 
 
1. OBJECTIVES 
 
1.1 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.  
 
1.2  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. 
 
2. BACKGROUND 
 
2.1 Pancreatic Cancer 
 
The five-year survival rate of patients with pancreatic cancer has not improved over time and 
remains below 5%. Gemcitabine, the most widely used chemotherapeutic agent in pancreatic 
cancer has a palliative role and provides a survival advantage as compared with 5-
fluorouracil for advanced, unresectable disease.1 No significant improvement in survival was 
observed in phase III trials when doublets of gemcitabine plus a cytotoxic drug were 
compared with single-agent gemcitabine. These doublets have included cytotoxic agents, 
such as cisplatin, 5-fluorouracil, capecitabine, exatecan, oxaliplatin and irinotecan.2-5 The 
addition of targeted agents, including cetuximab, bevacizumab, farnesyl transferase inhibitors 
and matrix metalloproteinase inhibitors to gemcitabine have also led to disappointing 
results.6-8  Gemcitabine plus erlotinib may result in a modest survival improvement when 
compared with single-agent gemcitabine.9 However, whether this modest survival advantage 
is accompanied by an improved quality of life is unknown at the current time. 
Pharmacological studies have shown that fixed-dose rate gemcitabine, administered at 10 
mg/m2/minute, results in a pharmacodynamic and clinical advantage due to saturable kinetics 
noted after the rapid, 30-minute infusional schedule.10 However, the course of this 
chemotherapy-refractory disease is unlikely to be altered by cytotoxic drugs alone and the 
addition of molecularly-targeted agents, based on the knowledge of pancreatic 
carcinogenesis, is likely to lead to therapeutic gains. 
     
 


2007-0910 
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Page 2 
 
      2.2  IgF-1R and Pancreatic Cancer 
 
IGF-1R initiates signals that activate the phosphoinositide 3-kinase (PI3-kinase)/Akt and 
MEK/ Erk pathways and is thought to play a crucial role in the pathology underlying 
pancreatic and other cancers.  
 
The signaling cascades that are activated by the IGF-1R and IGF-2R transmembrane receptor 
tyrosine kinases are regulated by the IGF family of ligands (IGF-1 and -2), their binding 
proteins (IGFBP 1-10), specific proteases and IGFBP-interacting molecules. IGF-1R 
signaling inhibition enhances gemcitabine and cisplatin-induced apoptosis in pancreatic 
cancer xenografts and ovarian cancer cell lines, respectively.11, 12 IGFBPs transport IGFs to 
the peripheral circulation and are the major determinants of IGF bioavailability. IGFBP-3, 
one of the most important members of the IGFBP family, binds to 75% of the circulating 
IGF. Decreased IGFBP-3 levels are associated with an increased risk of endometrial, head 
and neck and hepatocellular cancer progression13-15, while inconsistent findings were 
reported with pancreatic cancer.16, 17 Upon ligand binding, IGF-1R is activated and results in 
autophosphorylation of tyrosine 950 in the juxtamembrane which can serve as the docking 
site for the insulin receptor substrates (IRS)1-4 and shc. In parallel to the PI-3 kinase 
signaling pathway, recruitment of Grb2/SOS by p-IRS-1 and shc leads to recruitment of Ras 
and activation of the Raf/ MEK/Erk pathway, eventually leading to cellular proliferation. We 
recently showed that IRS-specific small interfering RNA potently inhibited activation of PI3-
kinase and Akt in transfected pancreatic cancer cells.18 Activated IRS and IGF-1R expression 
in the tumor may be important predictors for response to IGF-1R-directed therapy, while 
changes in activated Erk and Akt expression resulting from IGF-1R inhibition may be 
important for the assessment of a pharmacodynamic effect. 
 
We postulate that the IgF1R inhibitor plus gemcitabine combination is worthy of 
investigation in pancreatic cancer. In summary, IGF-1R is an attractive target in pancreatic 
cancer, due to the important role of the Erk and PI3-kinase/ Akt signaling in this disease. 
IGF-1R inhibition enhances the anti-tumor effect of gemcitabine in preclinical studies. 
 
2.3  IgF1R and EGFR inhibition 
 
EGFR expression is common in pancreatic cancer and represents an important target in this 
disease. EGFR overexpression, mutation, and gene amplification are associated with 
increased sensitivity and improved outcome with the EGFR tyrosine kinase inhibitor 
erlotinib.19 As discussed above, the EGFR tyrosine-kinase inhibitor erlotinib is FDA-
approved for the treatment of pancreatic cancer, based on the superior survival of the 
gemcitabine plus erlotinib combination vs. gemcitabine monotherapy.  Response to erlotinib 
is influenced by mutations in EGFR and K-ras gene. Patients with mutant EGFR but no K-ras 
mutations are most responsive to erlotinib treatment. Those who respond to EGFR inhibition 
will ultimately develop resistance which can be attributed to multiple mechanisms including 
development of secondary EGFR mutations, c-met amplification, and potentially cross talk 
between EGFR and IGF-1R pathways.  


2007-0910 
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Page 3 
 
Cross talk between the EGFR and IGF1R pathways has been shown to contribute to 
transformation, growth, and tumor responsiveness to EGFR inhibitors. Combination therapy 
with EGFR monoclonal antibody C225 and recombinant humanized anti-IGF-1R antibody 
h7C10 in A549 NSCLC xenografts models of wild-type EGFR and activated ras mutation led 
to 95% growth inhibition as opposed to 72% with C225 alone.20 Ueda et al, demonstrated 
that the expression of IgF1R and EGFR was commoner in metastatic disease sites than in the 
primary, surgically-resected pancreatic cancer.21  Suppression of IGF1R signaling not only 
augmented erlotinib activity in wild-type EGFR NSCLC tumor cells, but also abolished 
resistance to erlotinib and induced apoptosis in erlotinib-resistant NSCLC cells.22   Dual 
inhibition of EGFR and IGF1R pathways therefore may improve responsiveness in patients 
with wild-type (WT) EGFR and/or activating K-ras mutation tumors who are otherwise less 
responsive to erlotinib single agent treatment; may delay the development of acquired 
resistance to erlotinib, or overcome acquired resistance to erlotinib after initial response; and 
may further improve response to erlotinib in patients with mutant EGFR.  
 
 
2.4   MK-0646 
 
MK-0646 is a humanized IgG1 monoclonal antibody that binds to the insulin-like growth 
factor receptor type 1 (IGF-1R) and is being developed for the treatment of cancer based on 
the hypothesis that monoclonal antibodies to growth factor receptor tyrosine kinases are 
effective cancer treatments. IGF-1R is a receptor tyrosine kinase and activation and 
overexpression of IGF-1R induces mitosis, is required to establish and maintain a 
transformed phenotype, and protects cells against apoptosis. Multiple cancer types are 
potential indications for treatment with an IGF-1R antibody.  
2.4.1  Pharmacology of MK-0646 
MK-0646 is a humanized antibody against the human insulin-like growth factor receptor I 
(IGF-1R). It binds to IGF-1R from non-human primates (cynomolgus and rhesus macaques), 
but does not recognize mouse, rat, or dog receptor. MK-0646 binds human IGF-1R with a Kd 
of 0.9 nM and specifically recognizes IGF-1R over the closely related insulin receptor 
(InsR). MK-0646 is of IgG1 isotype and has the potential to elicit antibody-dependent 
cellular cytotoxicity (ADCC).  
MK-0646 inhibits IGF-1 and IGF-2 -dependent proliferation of MCF7 breast cancer cells in 
vitro with similar potency. Binding of MK-0646 results in receptor down-regulation and 
pathway inhibition, with reduced levels of phospho-IGF-1R and of the downstream effectors 
phospho-Akt and phospho-MapK (range >50% to >90%). Receptor down-regulation on 
various human tumor cell lines ranged from 8 to 80% and correlated significantly with 
receptor density and with the ratio of IGF-1R to InsR. Receptor internalization from 75% to 
100% was also demonstrated by flow cytometry on human CD8- T cells and granulocytes 
exposed to MK-0646 ex vivo. Receptor internalization in vivo was demonstrated in 
granulocytes and CD8-CD3+ T cells isolated from cynomolgus macaques treated with a 
single dose of MK-0646. IGF-1R was completely internalized starting approximately 4 hours 


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following infusion and remained internalized through Day 6 and Day 10 after a 0.5 mg/kg 
and 2 mg/kg dose, respectively.  
MK-0646 shows anti-tumor activity in mouse xenograft models with multiple human tumor 
cell lines derived from lung, breast, colon and pancreatic carcinomas. When administered 
weekly for five weeks to mice bearing A549 NSCLC xenografts, MK-0646 resulted in dose-
dependent tumor growth inhibition, reaching a maximum of ~60% inhibition at 50 μg 
antibody per dose, and concomitant downregulation of IGF-1R and phospho-IGF-1R levels 
by > 80%. 
The therapeutic efficacy of MK-0646 was also evaluated using [18F]FDG PET/CT imaging in 
geriatric rhesus macaques with naturally-occurring ileocecocolic adenocarcinomas that 
overexpress IGF-1R. In two animals in which the once-weekly 10 mg/kg IV dosing regimen 
achieved the targeted trough serum levels of 3 μg/mL, MK-0646 monotherapy caused 
regression of the adenocarcinomas. By Day 9 post-first dose a decrease in the [18F] FDG 
PET-defined volume of hypermetabolic activity was apparent in both animals (57% and 85% 
reduction, respectively), corresponding with a 33% and 34% decrease in CT-defined tumor 
volume. Following 6 weeks of treatment, the final imaging studies demonstrated CT-defined 
tumor regression of 58% and 19%, respectively. In a third geriatric rhesus similarly dosed 
with MK-646 there was no response but MK-0646 was non-detectable at all time points. 
Serum analysis suggested that this was due to development of a robust anti-human antibody 
response. 
Studies have been conducted in propofol anesthetized rhesus and cynomolgus macaque 
monkeys to discover a radiotracer for IGF1R that could be used to identify tumors and 
patients for therapy that have the highest likelihood of response. A total of 46 scans have 
been conducted using either 64Cu labeled Fab2 MK-0646, 64Cu MK-0646 or 123I-MK-0646 in 
the absence and presence of MK-0646. An adverse reaction to MK-0646 infusion was 
observed in one anesthetized cynomolgus monkey that had been previously exposed to 123I 
MK-0646 one week earlier. In plasma from this animal 123I MK-0646 was unstable and 
converted rapidly to high and low molecular weight products suggesting an immune 
response. The adverse event observed was consistent with an apparent anaphylactic reaction. 
Two other cynomolgus monkeys similarly exposed had no reaction. 
2.4.2  Pharmacokinetics and Metabolism of MK-0646 
The pharmacokinetics of MK-0646 were evaluated following intravenous (iv) administration 
of MK-0646 at 10 mg/kg to CD-1 mice, Sprague-Dawley rats, and Cynomolgus monkeys, 
and at 3 mg/kg to Beagle dogs. In all species studied, MK-0646 exhibited a very low 
clearance (ranging from 0.005 mL/min/kg in dogs and monkeys to 0.02 mL/min/kg in rats), 
low volume of distribution (0.05 - 0.27 L/kg) and long half-life (ranging from 5 days in 
monkeys to 14 days in mice). In rats and monkeys, the pharmacokinetics of MK-0646 was 
linear over an iv dose range of 10 to 100 mg/kg. However, apparent non-linearity in the 
pharmacokinetics was noted over a low dose range in monkeys; after 0.5 and 2 mg/kg doses, 
values for clearance and half-life were 0.02 and 0.01 mL/min/kg, and approximately 1 and 2 
days, respectively. This apparent non-linearity is not unexpected and consistent with a 


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specific receptor-mediated elimination mechanism commonly observed with other 
monoclonal antibodies. Based on an allometric scaling method, it is anticipated that in 
humans MK-0646 would also exhibit a very low clearance and low volume of distribution, 
with a relatively long half-life. However, as was the case in monkeys, there is also a 
possibility for non-linear pharmacokinetics (increased clearance and shorter half-life than 
predicted values) following administration of a low dose range (≤10 mg/kg) of MK-0646 in 
humans. 
2.4.3  Toxicity of MK-0646 
MK-0646, a humanized monoclonal antibody (IgG1) against the insulin-like growth factor 
receptor type 1 (IGF-1R) was tested in a series of preclinical toxicity studies in order to 
support the initiation of studies in humans. The preclinical toxicity studies included in vitro 
hemolytic assays, an ex vivo tissue cross-reactivity study with human and cynomolgus 
monkey tissues, and a 4-week repeated-dose toxicity study followed by a 6-week recovery 
period in cynomolgus monkeys and a 12-week repeated-dose toxicity study in cynomolgus 
monkeys. A 39-week repeated-dose toxicity study followed by an  
8-week treatment-free period  in cynomolgus monkeys is currently on-going.  
There was no hemolysis with up to 18.18 mg/mL of MK-0646 (MK-0646 20 mg/mL) in 
cynomolgus or human washed red blood cells or with the vehicle.  
The cross-reactivity of MK-0646 with cryosections of human and cynomolgus monkeys’ 
tissues was studied by immunohistochemistry using biotin-conjugated MK-0646 (biotin-MK-
0646). The tissue distribution of staining with biotin-MK-0646 was similar in cynomolgus 
monkey tissues and in human tissues, with the exception of the staining of the spinal cord, 
observed in human tissues only, although inconsistently. This difference is not likely of 
significance, since MK-0646 is unlikely to penetrate the blood/central nervous system 
barrier. 
In a 4-week intravenous repeated-dose toxicity study followed by a 6-week recovery period 
in cynomolgus monkeys, MK-0646 was administered via 1-hour intravenous infusion once 
weekly at dose levels of 3, 10, and 40 mg/kg/week. The mean systemic exposures (expressed 
as area under the curve, AUC0-168 hr, sexes combined) to MK-0646 after 4 weekly infusions at 
dose levels of 3, 10, and 40 mg/kg/week were 2.98 ± 1.12, 17.8 ± 1.41 and 70.4 ± 6.70 
mg/hr/mL, respectively. For some animals in the 3 mg/kg/week dose group, substantial 
reductions in serum MK-0646 concentrations and/or individual toxicokinetic parameters 
were observed after 4 weekly infusions, when compared with values following the first 
administration and were likely due to the presence of anti-MK-0646 antibodies.  There were 
no observable differences in serum MK-0646 concentrations or toxicokinetic parameters in 
the 10 mg/kg/week and 40 mg/kg/week dose groups.  MK-0646 was generally well tolerated. 
There was no treatment-related mortality. There were no treatment-related effects on physical 
signs, food consumption, ophthalmic examinations, neurological examinations, blood 
pressure or heart rate measurements, electrocardiographic assessments, and urinalyses. There 
was a treatment-related decrease in body weight occurring by the end of the 4-week 
treatment period in some animals in the 3-, 10- and 40 mg/kg/week dose groups. The effect 


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was slight to moderate (generally less than 10% decrease compared to individual prestudy 
values), and partially reversible. There was a reversible treatment-related decrease in serum 
alkaline phosphatase levels in all treated-groups that did not correlate with any other 
alterations and that was not considered of any toxicologic significance. There were no 
treatment-related changes in any of the other hematological, (including the distribution of 
peripheral blood T and B lymphocyte subsets), coagulation and serum biochemical 
parameters examined. There was a treatment-related histomorphological thymic atrophy in 
both sexes, at all dose levels, at the end of the 4-week treatment period. This effect was fully 
reversible after the recovery period, in females at all dose-levels and in males in the 3 
mg/kg/week and 10 mg/kg/week dose groups. The thymic effects were partially reversible in 
males in the 40 mg/kg/week dose group.  MK-0646 did not cause a treatment-related increase 
in local irritation at the injection site. Anti-MK-0646 antibodies were detected in the recovery 
animals across all MK-0646-treated groups, at a higher incidence and mean titer in the 3 
mg/kg/week and 10 mg/kg/week dose groups (compared to the 40 mg/kg/week dose group). 
In all cases, anti- MK-0646 antibodies were able to neutralize MK-0646 in a cell-based 
receptor internalization assay. 
Based on histomorphological thymic atrophy, consistent with a pharmacologically-mediated 
effect, body weight loss, and a decrease in serum alkaline phosphatase levels (considered of 
no toxicological significance), the no-effect level of MK-0646 for this study was <3 
mg/kg/week. The no-adverse effect level of MK-0646 for this study was >40 mg/kg/week. 
Mean trough (168-hour) concentrations were 8.69 ± 1.04, 45.2 ± 6.33 and 129 ± 15.2 μg/mL 
in the 3-, 10-, and 40-mg/kg/week dose groups, respectively, on Drug Day 7; and 5.02 ± 
3.55, 53.4 ± 15.0 and 234 ± 43.5 μg/mL in the respective dose groups on Drug Day 28.  
In a 12-week intravenous repeated-dose toxicity study in cynomolgus monkeys, MK-0646 
was administered via 1-hour intravenous infusion once weekly at a dose level of 40 
mg/kg/week. The mean systemic exposure (expressed as area under the curve, AUC0-168 hr, 
sexes combined) to MK-0646 at 40 mg/kg/week was 62.3 ± 3.03 mg/hr/mL on Drug Day 1 
and was 97.1 ± 10.7 mg/hr/mL on Drug Day 71. MK-0646 was generally well tolerated. 
There was no treatment-related mortality. There were no treatment-related effects on physical 
signs, food consumption, ophthalmic examinations, blood pressure or heart rate 
measurements, electrocardiographic assessments, and urinalyses. 
There was a treatment-related decrease in body weight in treated males (incidence: 2/3). This 
effect was slight (less than 9% decrease compared to individual prestudy values, by the end 
of the dosing period) and was not considered adverse. There were treatment-related decreases 
in serum alkaline phosphatase and gamma glutamyltransferase levels in both sexes, that were 
not associated with any other alterations and that were not considered of any toxicologic 
significance. There were no treatment-related changes in any of the other hematological 
(including the distribution of peripheral blood T and B lymphocyte subsets), coagulation and 
serum biochemical parameters examined. There was a treatment-related decrease in thymus 
weights in all treated females and males, that corresponded histomorphologically to thymic 


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atrophy. There was no evidence of treatment-related local irritation at the injection site, 
associated with the intravenous infusion of MK-0646. 
Based on histomorphological thymic atrophy, consistent with a pharmacologically-mediated 
effect, body weight loss (considered not adverse), and decreases in serum alkaline 
phosphatase and gamma glutamyltransferase levels (considered of no toxicological 
significance), the no-effect level of MK-0646 for this study was <40 mg/kg/week. The no 
adverse effect level of MK-0646 for this study was >40 mg/kg/week 
In an on-going 39-week repeated-dose toxicity study followed by an  
8-week treatment-free period, cynomolgus monkeys are administered MK-0646 (MK-0646 
20 mg/mL) via 1-hour intravenous infusion once weekly at dose levels of 3, 10, or 40 
mg/kg/week.  Preliminary data collected and analyzed up to week 25 show that the 
administration of MK-0646 was well tolerated and not associated with any treatment-related 
clinical signs, ophthalmological findings, food consumption changes, changes in 
cardiovascular or urinary parameters. One female administered 40 mg/kg/week was 
sacrificed early on day 62, due to a moribund state caused by acute inflammatory and 
necrotic changes in the gastrointestinal tract. Any relationship to treatment is currently 
considered unlikely, pending histopathological assessment of all animals at study 
termination. There was a transient reduction in mean body weight during the first 7 weeks in 
the mid- and high-dose groups, a slight decrease in red blood cell parameters in the high-dose 
groups and in the mid-dose females, a slight decrease in alkaline phosphatase in the high-
dose and mid-dose groups and in the low-dose females and a slight transient increase in total 
bilirubin in the mid- and high-dose females. 
2.4.4  Clinical Studies of MK-0646 
The activity of MK-0646 in vitro as well as in vivo cancer models, along with the toxicity 
profile for this compound, position the drug for first-in-human studies to be conducted in 
cancer patients.   
MK 0646 is currently being tested in two Phase I studies:  1) An Open-Label, Dose 
Escalation Phase I Trial of MK-0646 Given as a Once Weekly Infusion in Patients With 
Advanced Solid Tumors and Multiple Myeloma (PN001) and 2) An Open-Label, Dose 
Escalation Phase I Trial of MK-0646 Given as a One to Two Hour Every Other Week 
Infusion in Patients With Relapsed or Refractory Locally Advanced or Metastatic Cancers 
(PN002). The preliminary analysis of safety parameters in the ongoing Phase I studies 
demonstrates that MK-0646 has been generally well-tolerated in advanced cancer patients.  
There have been a total of 44 patients treated with MK-0646.  These patients have been 
treated with doses as high as 15 mg/kg weekly (PN001) or 20 mg/kg loading followed by 5 
mg/kg maintenance (PN002).   No maximum tolerated dose has been identified. 
Preliminary pharmacokinetic analysis from PN001 suggests that mean MK-0646 serum 
concentrations after the first IV dose appear to decline at least biexponentially after peak 
through 168 hrs.  The mean terminal half-life for the 15 mg/kg cohort averaged 95 hours, 
with a trend toward increasing values with dose.  In general, the clearance and volume of 


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distribution were in very good agreement with the values obtained in cynomolgus monkeys.  
The mean serum clearance for the 15.0 mg/kg cohort averaged 0.007 mL/min/kg, which was 
relatively unchanged from the values for 5.0 and 10 mg/kg. Mean trough concentrations 
exceeded the target of 25 mg/mL for doses greater than 5.0 mg/kg. Efficacy is not a primary 
objective of Phase I studies, and no objective responses have been observed to date.  
2.5  Erlotinib 
 
2.5.1  Clinical Pharmacology of Erlotinib 
Bioavailability of erlotinib following a 150-mg oral dose is about 60% and peak plasma 
levels occur 4 hours after dosing. Food increases bioavailability substantially, to almost 
100%. 23 The pharmacokinetics of erlotinib is dose dependent, and repetitive daily treatment 
does not result in drug accumulation when administered at an average dose of 150 mg/day. 
The maximum concentration of drug was achieved 3 hours after a single dose. 24 A 
pharmacokinetic analysis in patients receiving single-agent erlotinib, showed a median half-
life of 36.2 hours. Time to reach steady-state plasma concentration would therefore be 7 to 8 
days.  
2.5.2  Drug Interactions of Erlotinib 
In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized 
primarily by CYP3A4 and to a lesser extent by CYP1A2 and the extrahepatic isoform 
CYP1A1. In vitro and in vivo studies suggest that erlotinib is cleared primarily by the liver; 
caution should be used when giving erlotinib to patients with hepatic impairment.  
2.6  Gemcitabine  
 
2.6.1  Clinical Pharmacology of Gemcitabine  
 
Gemcitabine is a pyrimidine antimetabolite that inhibits DNA synthesis by inhibition of 
DNA polymerase and ribonucleotide reductase, specific for the S-phase of the cycle. 
Gemcitabine is phosphorylated intracellularly by deoxycytidine kinase to gemcitabine 
monophosphate, which is further phosphorylated to active metabolites gemcitabine 
diphosphate and gemcitabine triphosphate. Gemcitabine diphosphate inhibits DNA synthesis 
by inhibiting ribonucleotide reductase; gemcitabine triphosphate incorporates into DNA and 
inhibits DNA polymerase. 
 
Pharmacodynamics/Kinetics of gemcitabine are as follows: Distribution: Vd: Male: 15.6 mL 
mL/m2; Female: 11.3 L/m2. The protein binding of gemcitabine is low. Metabolism: Hepatic, 
metabolites: di- and triphosphates (active); uridine derivative (inactive). Half-life 
elimination: Infusion time: ≤1 hour: 32-94 minutes; Infusion time: 3-4 hours: 4-10.5 hours. 
Time to peak: 30 minutes. Excretion: Urine (99%, 92% to 98% as intact drug or inactive 
uridine metabolite); feces (<1%). 
 


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2.6.2  Drug Interactions of Gemcitabine 
Bleomycin: Concurrent use with gemcitabine may lead to severe pulmonary toxicity. 
Fluorouracil: Gemcitabine may increase the levels/effects of fluorouracil; Ethanol use with 
gemcitabine therapy may lead to GI irritation. 
 
2.7  Study Rationale 
 
 
The MEK/ Erk and the PI3-kinase/ Akt signaling pathways play an important role in cellular 
proliferation, survival (anti-apoptosis) and drug resistance in pancreatic cancer. Our recent study 
demonstrated the prognostic importance of activated (p-)Erk and Akt in surgically resected 
specimens of pancreatic cancer.25 There was a significant association between p-Erk expression 
and epithelial-mesenchymal transition (EMT) in these cases.26 We also demonstrated that the 
PI3-kinase/ Akt pathway was constitutively activated in pancreatic cancer, which in turn 
activated two important transcription factors, NF-kappaB and c-myc.27  Antagonists of PI3-
kinase and MEK were also shown in this study to inhibit pancreatic cancer cell proliferation.  
Therefore, the inhibition of signals that trigger p-Erk and Akt activation in pancreatic cancer is 
likely to have a therapeutic impact.  The insulin-like growth factor receptor-1 (IGF-1R) initiates 
signals that activate the PI3-kinase/Akt and MEK/ Erk pathways and is thought to play a crucial 
role in the pathology underlying pancreatic and other cancers.  
 
MK-0646, a humanized antibody against IGF-1R, blocks the interaction of the IGF-I and II 
ligands with the IGF-1R and induces the internalization and degradation of this receptor. IGF-1R 
signaling inhibition enhances gemcitabine and cisplatin-induced apoptosis in pancreatic cancer 
xenografts and ovarian cancer cell lines, respectively.28, 29 It is believed that there is crosstalk or 
pathway switching between the EGFR and the IGF-1R, which can ultimately influence the 
effectiveness of anti-EGFR agents, such as the small molecule inhibitors gefitinib or erlotinib. 
IGF-1R activation may be associated with acquired resistance to gefitinib and other EGFR-
targeted therapies.30, 31 It was demonstrated that cytoplasmic expression of EGFR and membrane 
expression of  IGF1R were more frequent in higher-grade pancreatic cancers and correlated with 
poor prognosis.32 Therefore simultaneous targeting of EGFR plus IgF1R has a sound scientific 
basis. The hypotheses to be tested are: a. MK-0646 can be combined safely with gemcitabine or 
with gemcitabine plus erlotinib in the phase I or II setting, b. Gemcitabine plus erlotinib plus 
MK-0646 and gemcitabine plus MK-0646 result in an improved PFS as compared with 
gemcitabine plus erlotinib, c. Improved RR, OS and QOL will result in the MK-0646 containing 
arms as compared with gemcitabine plus erlotinib, and d.IGF1/ IGFBP-3 ratio, pretreatment 
tissue levels of p-Erk, Akt, IRS-p, IGF-1R, mTOR, and PI3K correlate with response and e. 
SNPs related to IgF1R pathway may correlate with clinical response to MK-0646. 
 
Phase I portion of this study has been completed. The next, randomized phase II portion has been 
completed with 45 patients enrolled in the 3 arms (15 in arm A, B and C). 
 
Updated analysis of the present study on 8/7/2012 indicates that the median overall survival in arm A 


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(Gemcitabine + MK-0646), arm B (Gemcitabine + MK-0646 + Erlotinib) and arm C (Gemcitabine + 
Erlotinib) was 45 weeks, 29 weeks and 25 weeks, respectively (p=0.09). There was no significant 
progression-free survival difference between the three arms, however (Fig.1). Based on these data, we 
hypothesize that a subset of patients treated with MK-0646 experience therapeutic benefit and our goal is 
to explore hypothesis-based predictive biomarkers in a phase II expansion cohort of patients treated as per 
Arm A. 
 
 
Fig.1 Updated survival of patients treated on current study (Aug 2012) 
 
2.8  Correlative Studies Background 
 
 
2.8.1  IGF-1 and IGFBP-3 circulating levels 
 
More than 80% of circulating IGF-1 is bound to IGFBP-3, in a protein complex that is 
confined to the vascular compartment. Tissue IGF bioactivity is thought to be determined by 
free IGF, the component of IGF not bound to IGF binding proteins, which binds to the IGF-
1R on the target cell surface.33 High plasma levels of IGF-1 and low levels of IGFBP-3 are 
associated with the development of prostate, colorectal, and premenopausal breast cancer. In 
a nested case-control study within four large, prospective cohorts, no association was 
observed between prediagnostic plasma levels of IGF-I, or IGFBP-3 and incident diagnosis 
of pancreatic cancer.34 However, these levels have not been correlated with response to IGF-
1R directed therapy. We hypothesize that elevated levels of IGF-1 and/or depressed levels of 
IGFBP-3 would predict responsiveness to MK-0646 IGF-1R inhibition. 
 
2.8.2  IGF-1R Signaling Pathway Proteins Tissue Levels 
 
IGF-1R is composed of two covalently linked polypeptide chains, each with an extracellular -
subunit and a transmembrane ß-subunit, which possesses tyrosine kinase activity. Ligand 
binding of IGF-1 to IGF-1R results in a conformational change leading to 
transphosphorylation of one ß-subunit by the other. Activated IGF-1R recruits and 


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phosphorylates adaptor proteins belonging to the IRS family. The phosphorylated adaptor 
proteins then serve as docking sites for other signaling molecules, resulting in the activation 
of the downstream pathways such as PI3K/AKT and ERK1/2. We hypothesize that elevated 
phosphorylated/ total IGF-1R, IRS, AKT, mTOR, PI3K, and ERK 1/2 ratios would predict 
responsiveness to MK-0646 IGF-1R inhibition. Based on recent data, tissue IGF1 mRNA 
expression may be a promising predictive biomarker for MK-0646 therapy. In the current 
study, 21 core biopsy samples were analyzed for IGF1 expression using RT-PCR. In 8 
patients, where in the expression was above the median value, overall survival was >11 
months in 4 cases. While these data are very limited, they are supported by study PN004 
results. In the recent colorectal cancer trial of MK-0646 (PN004), patients with advanced 
colorectal cancer received irinotecan + cetuximab (control arm) or irinotecan + cetuximab + 
MK-0646 (at 7.5 mg/kg or 10 mg/kg dose levels). IGF1 expression was an adverse 
prognostic factor in the control arm. However, in the treatment arms, an improved PFS was 
noted with MK-0646 in those with high IGF-1 expression (Fig.2). 
 
 
 
                                     Days 
 
3.  PATIENT SELECTION 
 
3.1  Inclusion Criteria 
 
3.1.1    Pathologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma, 
AJCC stage IV (See Appendix H). 
 
3.1.2 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. 
 
 
3.1.3 At least 6 months must have elapsed after completion of adjuvant therapy (if 
applicable).  
Figure 2. Kaplan-Meier 
estimates for PFS by 
treatment arm in patients 
with high tissue IGF-1 in 
colorectal study PN004 
 


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3.1.4 Age >18 years.   
 
3.1.5 ECOG Performance Status 0-1 (Karnofsky >60%; see Appendix I). 
 
3.1.6 Patients must have adequate organ and marrow function as defined below: 
 
- 
leukocytes  
 
 
 
 
>3,000 cells/mm3  
- 
absolute neutrophil count  
>1,500 cells/mm3  
- 
platelets 
 
 
 
 
 
>100,000 cells/mm3 
- 
total bilirubin  
 
 
 
<1.5mg/dl 
- 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
without liver metastasis 
 
 
 
 
 
 
 
<5 X institutional upper limit of normal for 
patients with liver metastasis 
- 
creatinine  
 
 
 
 
within normal institutional limits 
OR 
- 
creatinine clearance  
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
 
3.1.7 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). 
 
3.1.8 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.   Should a 
woman become pregnant or suspect she is pregnant while participating in this study, 
she should inform her treating physician immediately. 
 
3.1.9 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.  
 
3.1.10  INR <1.5 (or ≤3 if on anticoagulation therapy). 
 
3.1.11 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. 
 
 
 


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3.2  
Exclusion Criteria 
 
3.2.1 Prior systemic chemotherapy or biological therapy for metastatic disease.  
 
3.2.2 Prior exposure to IGF-1R inhibitors.  
 
3.2.3 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. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to the agents used in the study. 
 
3.2.5  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. 
 
3.2.6 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. 
 
3.2.7 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. 
 
3.2.8 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.  
 
3.2.9 Patients must not be currently enrolled in a therapeutic study for pancreatic cancer. 
 
 
3.3 Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
4.0 REGISTRATION PROCEDURES 
 
All patients must be registered on the M. D. Anderson Cancer Center Clinical Oncology 
Research (CORe) system prior to initiation of treatment. 
 
Once the Phase II portion of the study begins, participants will be assigned to treatment arms 
by adaptive randomization performed through the Department of Biostatistics at M.D. 


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Anderson Cancer Institute.  No randomization is planned in the phase II expansion cohort. 
Please refer to Section 13 for additional details.   
  
 
 
 
5. TREATMENT PLAN 
 
This is an open label single center two-part study in which the combination of 
gemcitabine, erlotinib and MK-0646 will be evaluated for the first time in a 
clinical setting to patients with advanced, untreated pancreatic cancer.  
 
Clinical endpoints to be evaluated are evaluation of MTD, progression-free 
survival, response rate, adverse experiences, and overall survival.  
 
5.1  Study Agents 
 
Reported adverse events and potential risks for MK-0646, gemcitabine and erlotinib are 
described in Section 7.  Appropriate dose modifications for these agents are described in 
Section 6.  No other investigational or commercial agents or therapies may be administered 
concurrently with the intent to treat the patient's malignancy. 
 
Treatment will be administered on an outpatient basis. A cycle is defined as 4 weeks in 
duration.  MK-0646 and gemcitabine must be administered at M. D. Anderson Cancer 
Center.  
 
Treatment schedules shall have a standing window of allowance of +/- 1 day.  In 
addition, any treatment day that falls on a weekend or holiday may be scheduled 
on the next business day.  
 
5.2 Phase I 
The Phase I portion of the study will be an open label safety assessment of:  
a. Gemcitabine (G)  + MK-0646 (MK) 
b. Gemcitabine (G)  + MK-0646 (MK) + erlotinib (E) 
Two dose levels of MK-0646 (5 mg/kg and 10 mg/kg) will be evaluated in each arm, using a 
standard “3+ 3” phase I design 
 
Arm A 
Arm B 
Level 1 
G 1000 mg/m2 Days 1, 8, 15 
MK 5 mg/kg Days 1, 8, 15, 22 
G 1000 mg/m2 Days 1, 8, 15 
MK  5 mg/kg Days 1, 8, 15, 22 
E 100 mg Days 1-28 
 
Level 2 
G 1000 mg/m2  Days 1, 8, 15,  
MK 10 mg/kg Days 1, 8, 15, 22 
G 1000 mg/m2 Days 1, 8, 15  
MK  10 mg/kg Days 1, 8, 15, 22 


2007-0910 
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E 100 mg Days 1-28   
 
 
Sequential Enrollment of Patients 
Arm A, 
Level 1 
G 1000 mg/m2  
MK 5 mg/kg 
Enroll 3-6 patients (as per “3 + 3” method) and evaluate  for 
DLT.  Once all patients have completed cycle 1, if criteria are 
met to continue escalation, accrual may proceed in  Arm B, 
Level 1.   
 
Arm B, 
Level 1 
G 1000 mg/m2  
Erlotinib 100 mg   
MK  5 mg/kg 
 
Enroll 3 patients.* Once 3 patients are enrolled, accrual may 
begin in Arm A, Level 2.   
 
Arm A, 
Level 2 
G 1000 mg/m2  
MK 10mg/kg 
Enroll 3 patients.*    
 
Arm B, 
Level 2 
G 1000 mg/m2  
 Erlotinib 100 mg  
 MK  10 mg/kg 
Do not enroll any patients in Arm B, Level 2 until all patients 
enrolled in Arm A, Level 2 and Arm B, Level 1 have completed 
1 cycle of therapy and are evaluable for DLT.     
If criteria for dose escalation are met in both levels, enroll 3-6 
patients in Arm B, Level 2.   
 
 
* If cohort requires expansion, up to 3 additional patients will be enrolled. If criteria for cohort 
expansion are met both in Arm B, Level 1 and Arm A, Level 2, expansion of the cohort will be 
completed first in the Arm/Level where DLT first occurred.  
 
• Patients will not be randomized to a treatment arm in the Phase I portion of the study.  
Enrollment will begin on arm (a).  Arm (b) will begin enrollment at a particular dose 
level only when enrollment at that dose level is complete in Arm (a).  Thus, enrollment at 
dose level 1 in Arm (b) will begin only after dosing at level 1 is completed safely in Arm 
(a). 
• A minimum of 3 patients will be treated at each dose level.  Once 3 patients are enrolled 
in Arm A, Level 1, additional accrual will be held until all 3 patients have completed 
their first cycle.  If there is one DLT, up to 3 additional patients will be entered at the 
same dose level and evaluated for DLT.  If the criteria for dose escalation are met, 3 new 
patients will be enrolled in Arm B, Level 1. Once 3 patients have been enrolled in Arm B, 
Level 1, 3 patients may be accrued to Arm A, Level 2.  Patients in both of these 
Arms/Levels will be evaluated for DLT during cycle 1.  If DLT is observed, up to 3 


2007-0910 
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additional patients will be enrolled in the Arm/Level that DLT occurred, as described 
above.  Once accrual and cycle 1 evaluation have been completed in Arm B, Level 1 and 
Arm A, Level 2, if the criteria for dose escalation are met in both arms, accrual may 
proceed in Arm B, Level 2.  
• If at any time 2 patients develop DLTs at a level, this level will be considered above the 
MTD. In each arm, six patients will be treated at the dose identified as the MTD.  The 
MTD is defined as the highest dose level that can be administered with  ≤ 1 DLT 
observed in 6 patients.   
 
Definition of Dose-Limiting Toxicity 
All toxic effects will be graded according to the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE) v3.0. 
 
An adverse event must be considered by the Investigator to be at least possibly related 
to study treatment to qualify as a DLT. Infusion reactions are to be treated as indicated 
in section 5.4.1 and will not  be regarded as DLTs, unless they recur and are serious 
and life-threatening, despite these measures. 
 
All enrolled patients who complete one cycle of therapy or fail to complete one cycle of 
therapy due to toxicity will be included in the determination of the MTD. If a patient fails to 
complete one cycle of therapy at any dose level, for reasons other than toxicity, that patient is 
deemed not evaluable for determining the MTD and is to be replaced. 
 
The evaluation for DLT will be during cycle 1 (first 4 weeks of treatment). DLT will 
be defined as: 
• Hematologic: grade 4 thrombocytopenia; grade 4 neutropenia of ≥7 days duration 
or ≥grade 3 neutropenia of any duration with fever ≥ 38.5° C.  
• Nonhematologic: grade 3 or 4 events, excluding hyperglycemia, rash, nausea, 
vomiting, and/or diarrhea, unless these occur despite maximal prophylaxis and/or 
treatment. 
• Delayed dosing for >14 days due to toxic effects.  
 
In Arm A, the order of drug administration is gemcitabine followed by MK-0646.  
In Arm B, the order of drug administration is erlotinib followed by gemcitabine 
followed by MK-0646.    
 
 


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 Table 1. Arm A (Phase I) 
 
Level 
 
Agent 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
 
1 
Gemcitabine 
followed by 
 
MK-0646 
1000 mg/m2 in  
500 cc NS 
 
5 mg/kg 
 
IV over 100 
minutes 
 
IV over 60 
minutes 
Days 
1,8,15  
 
Days 
1,8,15,22 
4 weeks 
(28 
days) 
 
 
2 
Gemcitabine 
followed by 
 
MK-0646 
1000 mg/m2 in  
500 cc NS 
 
10 mg/kg 
 
IV over 100 
minutes 
 
IV over 60 
minutes 
Days 
1,8,15  
 
Days 
1,8,15,22 
 
 
Table 2  Arm B (Phase I) 
  
MK-0646 will be administered intravenously at 5 mg/kg once a week for 4 weeks 
and then dose escalated in a new cohort to 10 mg/kg weekly. Gemcitabine will be 
administered at 1000 mg/m2 over 100 min as a fixed-dose rate infusion once a 
week for 3 weeks.  Since there is no evidence suggesting overlapping toxicities of 
erlotinib and MK-0646, in Arm B erlotinib will be administrated orally at 100 mg 
daily. 
 
 
Level 
 
Agent 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
 
 
 
1 
Erlotinib 
followed by 
 
Gemcitabine 
followed by 
 
 
MK-0646 
100 mg 
 
 
1000 mg/m2 in  
500 cc NS 
 
 
5 mg/kg 
 
Oral 
 
 
IV over 100 
minutes 
 
 
IV over 60 
minutes 
Days 1-28 
 
 
Days 
1,8,15  
 
 
Days 
1,8,15,22 
 
4 weeks 
(28 
days) 
 
 
2 
 
Erlotinib 
 
Gemcitabine 
followed by 
 
MK-0646 
 
100 mg 
 
1000 mg/m2 in  
500 cc NS 
 
10 mg/kg 
 
 
Oral 
 
IV over 100 
minutes 
 
IV over 60 
minutes 
 
Days 1-28 
 
Days 
1,8,15  
 
Days 
1,8,15,22 


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5.3 
 Phase II  
 
Assuming safety and tolerability of the combination, the MTD determined in Part 
I will be used in the Phase II portion of the trial.  Patients participating in Phase II 
will be randomly assigned to one of the three treatment arms:  
 
a. Gemcitabine + MK-0646 
b. Gemcitabine + erlotinib + MK-0646  
c. Gemcitabine + erlotinib 
 
Participants will be assigned to treatment arms by adaptive randomization 
performed through the Department of Biostatistics at M.D. Anderson Cancer 
Center.  Please refer to Section 13 for additional details.  In the phase II 
expansion cohort, arm A (Gemcitabine + MK-0646) will be expanded by adding 
30 subjects, who have a prior core biopsy of tumor or are agreeable for a trial-
specific biopsy for correlative studies. 
 
As previously indicated, one of the hypotheses of this study is that the 
combination of erlotinib and MK-0646 may delay the development of acquired 
resistance to erlotinib, or overcome acquired resistance to erlotinib after initial 
response. Therefore, upon disease progression, patients in the gemcitabine + 
erlotinib will be permitted to cross over to the combination treatment arm of 
gemcitabine + erlotinib + MK-0646. The dose of MK-0646 will be the 
recommended phase II dose. Note: in the phase II expansion cohort, all patients 
will receive MK-0646, therefore no cross-over is planned. 
 
In Arm A, the order of drug administration is gemcitabine followed by MK-0646. 
In Arm B, the order of drug administration is erlotinib followed by gemcitabine 
followed by MK-0646.   In Arm C, the order of drug administration is erlotinib 
followed by gemcitabine 
 
Table 3 – Phase II – Arm A (Gemcitabine + MK-0646) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agent 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Gemcitabine 
followed by 
 
MK-0646 
1000 mg/m2 in  
500 cc NS 
 
Ph I MTD 
mg/kg 
 
IV over 100 
minutes 
 
IV over 60 
minutes 
Days 
1,8,15  
 
Days 
1,8,15,22 
4 weeks 
(28 
days) 
 


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Table 4 -  Phase II – Arm B (Gemcitabine + erlotinib + MK-0646) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 5 – Phase II – Arm C (Gemcitabine + erlotinib) 
  
 
 
 
 
 
 
 
 
 
 
5.4  General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1  Premedications 
 
No specific premedications are recommended for MK-0646.  
Although serious allergic reactions have not been described with this antibody, which is fully 
humanized, routine medications and procedures for allergic reactions will be available in the 
treatment center. These reactions will be treated with IV fluids, antihistamines, NSAIDS, 
acetaminophen, narcotics, oxygen, pressors, and corticosteroids.  
Patients will be monitored for infusion reactions and hypersensitivity (during infusion and at 
least two hours afterward until such toxicities (if any) resolve.  
Ondansetron 8 mg IV + dexamethasone 10 mg IV is recommended prior to gemcitabine 
administration. Other 5HT3 antagonists may be used if clinically indicated.   
 
Agent 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Erlotinib 
followed by 
 
Gemcitabine 
followed by 
 
 
MK-0646 
100 mg 
 
 
1000 mg/m2 in  
500 cc NS 
 
 
Ph I MTD 
mg/kg 
 
Oral 
 
 
IV over 100 
minutes 
 
 
IV over 60 
minutes 
Days 1-28 
 
 
Days 
1,8,15  
 
 
Days 
1,8,15,22 
 
4 weeks 
(28 
days) 
 
 
Agent 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Erlotinib 
followed by 
 
Gemcitabine 
 
100 mg 
 
 
1000 mg/m2 in  
500 cc NS 
 
 
Oral 
 
 
IV over 100 
minutes 
 
 
Days 1-28 
 
 
Days 
1,8,15  
 
 
4 weeks 
(28 
days) 
 


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No additional premedications are generally recommended with erlotinib. Oral antiemetics 
may be used if clinically indicated. 
 
5.4.2  Management of Stomatitis/Oral Mucositis/Mouth Ulcers:  
Stomatitis/oral mucositis/mouth ulcers should be treated using local supportive 
care. Please note that investigators in earlier trials have described the oral 
toxicities associated with erlotinib as mouth ulcers, rather than mucositis or 
stomatitis. If the examination reveals mouth ulcers rather than a more general 
inflammation of the mouth, the event should be classified as such. Follow the 
paradigm below for treatment of stomatitis/oral mucositis/mouth ulcers: 
 
A.  For mild toxicity (grade 1), use conservative measures such as non-alcoholic 
mouthwash or salt water (0.9%) mouthwash several times a day until 
resolution.  
 
B.  For more severe toxicity (grade 2 in which case patients have pain but are 
able to maintain adequate oral alimentation, or grade 3 in which case patients 
cannot maintain adequate oral alimentation), the suggested treatments are 
topical analgesic mouth treatments (i.e., local anesthetics such as, 
benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or 
phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®). Agents containing hydrogen peroxide, 
iodine, and thyme derivatives may tend to worsen mouth ulcers. It is 
preferable to avoid these agents. Antifungal agents must be avoided unless a 
fungal infection is diagnosed. Topical antifungal agents are preferred if an 
infection is diagnosed to avoid possibility of drug interactions. Similarly, 
antiviral agents such as acyclovir should be avoided unless a viral infection 
is diagnosed. 
5.4.3  Management of Hyperglycemia  
Hyperglycemia may be observed in patients receiving anti IGF-1R therapy.  
Optimal glucose control should be achieved before starting a patient on this 
therapy and should be monitored closely. Endocrinology consult is encouraged. 
5.4.4 Management of Skin Rash 
Patients should be informed that skin toxicity is to be expected during treatment 
with erlotinib.  Skin toxicity may take the form of dry skin, rash, acneiform 
eruption, or hair or nail changes.  Prophylactic treatment of the skin may prevent 
or reduce skin toxicity.  The patient should be encouraged to use an alcohol-free, 
emollient cream applied twice a day to the entire body as soon as the patient 
starts therapy with erlotinib.  Creams and ointments are recommended because 
they have a greater ability to retain moisture than lotions.  Examples of suitable 


2007-0910 
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emollient creams include:  Neutrogena® Norwegian formula, SARNA® Ultra, 
Vanicream™, Aveeno® (fragrance-free formulation), and Eucerin® cream.  
Other over-the-counter aqueous creams or emulsifying ointments may also 
provide symptomatic benefit.  Lotions should be avoided because they often 
contain alcohol, which will dry the skin.  Patients should also be encouraged to 
use a titanium dioxide or zinc oxide-based sunscreen product applied to sun-
exposed areas twice per day. 
 
Patients who develop skin toxicity and are symptomatic should be treated with 
topical therapy such as clindamycin lotion or gel.  If needed, oral minocycline or 
oral doxycycline may be combined with the topical therapy.  For more severe 
rash, oral corticosteroids may be beneficial.  Patients who fail to respond to 
these measures may have the dose of erlotinib interrupted or reduced.  
Minocycline is known to interfere with anticoagulants and oral contraceptives.  
Patients treated with minocycline who are taking anticoagulants and/or oral 
contraceptives should be monitored accordingly.   
 
5.4.5 Management of Non-Infectious Diarrhea  
 
Antidiarrheal medications may be introduced if clinically indicated. Previous 
Phase I and II studies of erlotinib have demonstrated the frequency and severity 
of diarrhea can be managed with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2 to 4 hours until 
diarrhea resolves for 12 hours. Alternatives include diphenoxylate and 
sandostatin. In the event of severe or persistent diarrhea, nausea, anorexia, or 
vomiting associated with dehydration, erlotinib therapy should be interrupted 
and appropriate measures should be taken to intensively treat the dehydration.  
Since there have been rare reports of hypokalemia and/or acute renal failure 
(including fatalities), secondary to severe dehydration, renal function and serum 
electrolytes (including potassium) should be monitored in this setting. All 
interruptions or changes to study drug administration must be recorded. 
5.4.6  Management of Non-infectious Pneumonitis 
Both asymptomatic radiological changes (grade 1) and symptomatic non-
infectious pneumonitis (grade 2 = not interfering with activities of daily living or 
grade 3 = interfering with activities of daily living and oxygen indicated) have 
been noted in patients receiving erlotinib therapy.  Non-infectious pneumonitis 
has been associated with EGFR inhibitors. In order to monitor for asymptomatic 
(grade 1) pulmonary infiltrates, a chest X-ray is required if a CT scan of chest is 
not used for bi-monthly disease evaluations. Additional chest X-rays/CT scans 
may be done, when clinically necessary. If non-infectious pneumonitis develops, 
consultation with a pulmonologist should be considered. For any pneumonitis 
suspected to be secondary to erlotinib, this medication will be discontinued 
permanently. 
 


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5.5 Duration of Therapy/Criteria for Removal from Study 
 
Treatment may continue until one of the following criteria applies: 
 
• Disease progression or symptomatic deterioration 
 
• Intercurrent illness that prevents further administration of treatment 
 
• Any clinical adverse event or laboratory abnormality which in the opinion of the treating 
investigator indicates that continued treatment is not in the best interest of the patient  
 
• Treatment delay > 21 days for any reason 
 
• Patient decides to withdraw from the study, or 
 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
This study will utilize the CTCAE Version 3.0 for toxicity and adverse event reporting.   
 
Doses of gemcitabine and MK-0646 will be calculated based on the patient’s current 
weight recorded at the beginning of each cycle.  If there is a dose adjustment during a 
cycle of therapy the patient’s current weight will be used. Once a study drug dose is 
reduced, it may not be re-escalated.   The only exception to this is for patients 
currently being treated at a dose of gemcitabine below 250 mg/m2 (see section 6.2 for 
clarification).  
If in the opinion of the treating investigator, a toxicity requiring a dose reduction or 
omission is clearly related to one of the study drugs but not the others, the other drugs 
are not required to be omitted and/or reduced. 
 
If any single drug must be discontinued permanently, study treatment may be continued if in 
the opinion of the treating investigator the patient is deriving benefit from the other drug(s).  
 
 
 
6.1 Dose Modification of Erlotinib 
Dosage adjustments are based on grade of toxicity experienced by the patient.  
Reduction of erlotinib is in a 50 mg decrement. The lowest dose on the study allowed 
is 50 mg.  


2007-0910 
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Table 6 - Erlotinib Dose Levels 
Starting Level 
100 mg 
-1 
50 mg 
 
Criteria for dose-modification in case of suspected Erlotinib toxicity and re-initiation 
of Erlotinib treatment.  
Table 7 - Dose Modification Criteria for Erlotinib-related Toxicities 
Toxicity 
(NCI CTCAE 
v3.0) 
Dose Modification 
Diarrhea 
Grade 1 or 2 
None.  Initiate therapy with loperamide. 
Grade 3 or 4 
Interrupt Erlotinib until resolution to < grade 2 and then restart 1 dose level 
lower. 
Rash 
Grade 1 
None 
Grade 2 
None.  Initiate treatment as in section 5.4.4 if rash persists and is intolerable to 
patient or worsens over 10 – 14 days. 
Grade 3 
Reduce by 1 dose level.  If rash persists or worsens over 10 - 14 days, then 
interrupt Erlotinib until resolution to < grade 2 and then restart 1 dose level 
lower. 
Grade 4 
Permanently discontinue Erlotinib 
Interstitial Lung Disease 
Any Grade 
If ILD is suspected, Erlotinib should be interrupted immediately  
pending diagnostic evaluation.  If ILD is diagnosed, Erlotinib should be 
discontinued permanently and appropriate treatment instituted as necessary. 
Other Toxicities 
Grade 1 or 2 
None 
Grade 3 
Interrupt Erlotinib until resolution to < grade 2 and then restart 1 dose level 
lower. 
Grade 4 
Permanently discontinue Erlotinib 
 
 
 
 
6.2  Dose Modification of Gemcitabine 
Dosage adjustments are based on grade of toxicity experienced by the patient. 
 
Hematologic:  Patients receiving gemcitabine should be monitored prior to each dose 
with a complete blood count (CBC), including differential and platelet count. If 


2007-0910 
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marrow suppression is detected, therapy should be modified or suspended according to 
the guidelines below in Table 8.  
 
Table 8: Dose Modification Criteria for Gemcitabine-Related Hematologic 
Toxicities (Also see 6.2.2) 
Absolute granulocyte 
count  (AGC) (cells/mm3) 
 
Platelet count 
(cells/mm3)  
% of current  dose 
≥1000  
And 
≥75,000 
100 
500-999 
Or 
50,000-74,999 
75 
<500 
Or 
<50,000 
Hold until resolution to ≥ 
1,000 cells/mm3 AGC and ≥ 
75,000 cells/mm3 platelets, 
then give at 75% of current 
dose.   
Febrile neutropenia 
 
 
Hold until resolution to ≥ 
1,000 cells/mm3 AGC, then 
give at 75% of current dose.   
 
Laboratory evaluation of renal and hepatic function, including transaminases and serum 
creatinine, should be performed prior to initiation of therapy as outlined in the study 
calendar. Gemcitabine should be administered with caution in patients with evidence of 
significant renal or hepatic impairment as there is insufficient information from clinical 
studies to allow clear dose recommendation for these patient populations.   
 
Table 9 - Dose Modification Criteria for Gemcitabine-Related Non-Hematologic 
Toxicities (Also see 6.2.2) 
 
 
6.2.2  Additional Gemcitabine Dose Modification Information 
 If a patient is at a dose of 330 mg/m2 or less of gemcitabine and requires a 25% dose 
reduction, the minimum dose will be initially capped at 250 mg/m2. 
 
If further dose reduction is required for toxicity, the first step would be to administer 
gemcitabine at a dose of 250 mg/m2 on Days 1 and 15 (skipping Day 8) instead of 
every week (Days 1, 8, 15).  Further dose reductions below 250 mg/m2 will be 
permitted as per Tables 8 and 9, if deemed to be in the patient’s best interest by the 
Investigator.    
 
 
Toxicity 
Dose Modification 
Grade 
% of Current Dose 
0-1 
100 
2 
75 
3 
Hold until resolution to ≤Grade 1 or baseline, then give at 
75% of current dose.  
4 
Hold until resolution to ≤Grade 1 or baseline, then give at 
50% of current dose. 


2007-0910 
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Any patient who is currently receiving weekly (Days 1, 8, 15) gemcitabine at a dose 
below 250 mg/m2 may have this dose increased to 250 mg/m2 every 2 weeks, at the 
discretion of the Investigator.   Future dose reductions will be made as indicated in 
the paragraph above. 
 
Growth factors, including Neupogen and Neulasta, can be used at the Investigators 
discretion as per the American Society of Clinical Oncology (ASCO) guidelines.  
 
 
6.3 
Dose Modification for MK-0646 
 
Guidelines for MK-0646 
 
The following toxicities, if thought to be due to MK-0646, would cause modifications in MK-
0646 dosing: 
 
• Grade 3 or Grade 4 non-hematologic toxicity, except alopecia and inadequately 
controlled diarrhea, nausea and vomiting, and hyperglycemia 
 
• Anemia will not be considered dose limiting; patients are allowed erythropoietin and 
blood transfusions are needed 
 
• Infusion reactions and hypersensitivity reactions will not require dose reduction 
 
Dosage adjustments are based on grade of toxicity experienced by the patient.  Up to 
2 dose reductions are allowed for MK-0646. 
  
 


2007-0910 
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Toxicity (NCI 
CTCAE 
Grade) † * 
MK-0646 
 
1 
Dose 
Occurrence 
Dose Reduction 
5 mg/kg 
1 
No change 
2 
No change 
10 mg/kg 
1 
No change 
2 
No change 
 
2 
5 mg/kg 
1 
No change 
2 
No change 
10 mg/kg 
1 
No change 
2 
No change 
 
3 
5 mg/kg 
1 
Discontinue MK-0646 
 
 
 
10 mg/kg 
1 
Omit dose until resolved to 
less than or equal to Grade 
2 and then continue at 7.5 
mg/kg every 2 weeks 
2 
Omit dose until resolved to 
less than or equal to Grade 
2 and then continue at 6.0 
mg/kg every 2 weeks 
3 
Discontinue MK-0646 
 
4 
5 mg/kg 
1 
Discontinue  MK-0646 
 
 
10 mg/kg 
1 
Omit dose until resolved to 
less than or equal to Grade 
2 and then continue dosing 
at 6.0 mg/kg every 2 weeks 
if toxicity is not considered 
life-threatening 
2 
Discontinue  MK-0646 
† For non-hematologic toxicities exclude alopecia, anorexia, asthenia, 
inadequately treated hyperglycemia. 
* See table below for auditory toxicity. 


2007-0910 
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Page 27 
 
 
 
Auditory Toxicity  
(New Onset or Change in Baseline Grade) 
Grade 
MK-0646 
Action 
1 or 2 
No Change. 
3 
Permanently discontinue MK-0646 
4 
Permanently discontinue MK-0646 
 
6.4  New Cycle of Therapy  
A new cycle of therapy will be delayed until: 
• Absolute neutrophil count ≥1000 cells/mm3 and platelet count ≥100,000 cells/mm3 
• Recovery from any treatment-related non-hematological toxicity to baseline or ≤  grade 1. 
In case of ongoing grade 2 hearing loss, MK-0646 may continue if in the opinion of the 
Investigator, continued treatment is beneficial to the patient.  
6.5  Adverse Event Follow-Up 
Patients whose treatment is interrupted or permanently discontinued due to an adverse 
event or abnormal laboratory value suspected to be related to the study agent(s) must 
be followed at least weekly until the adverse event or abnormal laboratory resolves or 
returns to grade 1. If a patient requires a dose delay of > 21 days from the intended 
day of the next scheduled dose, then the patient must be discontinued from the study. 
 
 
7. ADVERSE EVENTS LIST AND REPORTING REQUIREMENTS  
 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug(s) even if the event is not 
considered to be related to study drug(s). Medical conditions/diseases present before starting 
study drug(s) are only considered adverse events if they worsen after starting study drug(s). 
Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms, are considered clinically significant, or require therapy. 
The Recommended Adverse Event Recording Guidelines in Section 7.4 will be used. 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit during the study. Adverse events also may be detected when they are 
volunteered by the patient during or between visits or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine: 


2007-0910 
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• 
the severity grade (Grade 1 to Grade 5) 
• 
its relationship to the study drug(s) (unrelated, unlikely, possible, probable, or definite) 
• 
its duration (start and end dates or if continuing at final exam) 
• 
action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
• 
whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, 
or any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the study 
drug, the interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the [Investigators’ Brochure] or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
 
7.1 Adverse Effects of MK-0646 
 
MK-0646 has been administered at high doses, up to 20 mg/kg, without any dose-limiting 
toxicities. Some of the expected toxicities, based on clinical and preclinical studies are listed 
below. 
 
Hepatic: transient hyperbilirubinemia, altered alkaline phosphatase, liver enzymes changes 
(decrease in alkaline phosphatase and GGT was noted in animal studies). 
 
Although there were a total of 58 unique preferred clinical adverse experience terms 
reported to have occurred in ≥2% of the patient population, only 18 of these unique terms 
were observed in >5% of the patient population. Greater than 10% of the patient 
population experienced abdominal pain, nausea, asthenia, fatigue, hyperglycemia, 
vomiting, anemia, back pain, constipation, cough, diarrhea, anorexia, dyspnea, and 
weight decreased (note: listed in order of decreasing frequency). Between 5% and 10% 
of the patient population experienced peripheral edema, urinary tract infection, 
hypotension, and pyrexia (note: listed in order of decreasing frequency). 
 
Other adverse effects noted are: thrombocytopenia, skin rash, headaches, dizziness, tumor 
pain, chills, and vasculitis. 
 
The Food and Drug Administration recently provided new safety information regarding 
monoclonal antibodies to IGF-1R.     Adverse reactions of middle to high range sensorineural 
hearing loss were reported in both healthy volunteer subjects and patients with malignancies 


2007-0910 
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Page 29 
 
who received as little as one dose of antibody.  The FDA deemed this information applicable 
to all antibodies targeting the IGF-1 receptor. 
 
7.2  Adverse Effects of Erlotinib 
Common: - diarrhea (54%), nausea (33%), vomiting (23%), anorexia (52%), dyspnea (41%), 
cough (33%), fatigue (52%), rash (75%), visual changes, keratitis, and conjunctivitis (12%). 
Serious: - bleeding (including GI when administered with anticoagulants) and elevated liver 
enzymes. 
 
7.3 Adverse Effects of Gemcitabine 
Occurring in >10%:  
Cardiovascular: Peripheral edema (20%), edema (13%) 
Central nervous system: Pain (10% to 48%), fever (30% to 41%), somnolence (5% to 11%) 
Dermatologic: Rash (24% to 30%), alopecia (15% to 18%), pruritus (13%) 
Gastrointestinal: Nausea/vomiting (64% to 71%; grades 3/4: 1% to 13%), constipation (10% 
to 31%), diarrhea (19% to 30%), stomatitis (10% to 14%)  
Hematologic: Anemia (65% to 73%; grade 4: 1% to 3%), leukopenia (62% to 71%; grade 4: 
≤1%), neutropenia (61% to 63%; grade 4: 6% to 7%), thrombocytopenia (24% to 47%; grade 
4: ≤1%), hemorrhage (4% to 17%; grades 3/4: <1% to 2%); myelosuppression is the dose-
limiting toxicity 
Hepatic: Transaminases increased (67% to 78%; grades 3/4: 1% to 12%), alkaline 
phosphatase increased (55% to 77%; grades 3/4: 2% to 16%), bilirubin increased (13% to 
26%; grades 3/4: <1% to 6%) 
Renal: Proteinuria (10% to 45%; grades 3/4: <1%), hematuria (13% to 35%; grades 3/4: 
<1%), BUN increased (8% to 16%; grades 3/4: 0%)  
Respiratory: Dyspnea (6% to 23%) 
Miscellaneous: Flu-like syndrome (19%), infection (8% to 16%; grades 3/4: <1% to 2%)  
Occurring in 1% to 10%:  
Local: Injection site reactions (4%)  


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Neuromuscular & skeletal: Paresthesia (2% to 10%)  
Renal: Creatinine increased (2% to 8%)  
Respiratory: Bronchospasm (<2%)  
 
7.4  Adverse Event Attribution 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Recommended Adverse Event Recording Guidelines  
 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
 
  
  
  
  
Unrelated 
Phase I 
  Phase I 
  Phase I       
Phase II   
  
Phase I       
Phase II  
Phase III 
  
Phase I        
Phase II  
Phase III 
Unlikely 
Phase I 
  Phase I 
  Phase I       
Phase II   
  
Phase I       
Phase II  
Phase III 
  
Phase I        
Phase II  
Phase III 
Possible 
Phase I      
Phase II 
  
Phase I       
Phase II  
Phase III 
  
Phase I       
Phase II  
Phase III 
  
Phase I       
Phase II  
Phase III 
  
Phase I        
Phase II  
Phase III 
Probable 
Phase I      
Phase II 
  
Phase I       
Phase II  
Phase III 
  
Phase I       
Phase II  
Phase III 
  
Phase I       
Phase II  
Phase III 
  
Phase I        
Phase II  
Phase III 
Definitive 
Phase I      
Phase II 
  
Phase I       
Phase II  
Phase III 
  
Phase I       
Phase II  
Phase III 
  
Phase I       
Phase II  
Phase III 
  
Phase I        
Phase II  
Phase III 
 
 
 


2007-0910 
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7.5 Serious Adverse Events 
 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred 
in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A congenital anomaly/birth defect. 
 
7.6  Serious Adverse Events Reporting  
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse (21 
CFR 312.32). 
 Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”. Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
 All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge 
of the event to the Safety Project Manager in the IND Office.  
 Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  


2007-0910 
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 Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
 Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
Reporting to FDA: 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
7.7  Investigator Communications with Study Supporter  
A SAE must be reported by the Principal Investigator to Merck & Co., Inc. Attention:  
Worldwide Product Safety, by FAX (215-993-1220) within two working days of learning of 
its occurrence. This includes serious, related, labeled (expected) and serious, related, 
unlabeled (unexpected) adverse experiences. All deaths during treatment or within 30 days 
following completion of active protocol therapy must be reported within 2 working days.  
      7.8  Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also be reported to Merck & Co., Inc. Attention:  Worldwide 
Product Safety, by FAX (215-993-1220) within 2 working days of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of birth, and the presence or absence of any birth defects, 
congenital abnormalities or maternal and newborn complications. Patients who become 
pregnant will be taken off the study agents. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational and  
commercial agents administered in this study can be found in Section 7. 
 
 


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8.1 MK-0646: Physical, Chemical, and Pharmaceutical Properties and Formulation 
 
General Information 
 
MK-0646 is a humanized IgG1 monoclonal antibody (mAb) against IGF-1R (insulin-like 
growth factor receptor type 1).  This IGF-1R mAb blocks IGF-1- and IGF-2−mediated 
proliferation of cells and auto-phosphorylation of the receptor without acting as an agonist.  
In addition to its effect on signaling pathways, MK-0646 may also have the potential for 
antibody-directed cellular cytotoxicity.  Drug Product 
 
The final drug product is formulated at Merck & Co., Inc. (Merck, West Point, PA, U.S.) as a 
sterile, clear liquid at a target concentration of 20 mg/mL The drug product contains the 
excipients listed in the Investigators Brochure.  These components are controlled and tested 
to the standards appropriate for their intended use and function.   
Stability :  Drug product stability studies are ongoing.  
Storage:  Vials are stored at 2−8 °C.    
Supplier:  MK-0646 will be provided free of charge by Merck, Inc. for this study.     
 
 
 
8.2  
Gemcitabine 
 
Product description:  Gemcitabine is manufactured by Eli Lilly, Incorporated. Two vials are 
available: 200 mg lyophilized powder in 10 ml size, sterile single use vial and 1000 mg  
lyophilized powder in 50 ml size, sterile single use vial. 
Solution preparation: The recommended diluent for reconstitution of gemcitabine is 0.9% 
Sodium Chloride Injection without preservatives. Due to solubility considerations, the 
maximum concentration for gemcitabine upon reconstitution is 40 mg/mL. Reconstitution at 
concentrations greater than 40 mg/mL may result in incomplete dissolution, and should be 
avoided. To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200 mg vial or 
25 mL of 0.9% Sodium Chloride Injection to the 1 g vial. Shake to dissolve. These dilutions 
each yield a gemcitabine concentration of 38 mg/mL, which includes accounting for the 
displacement volume of the lyophilized powder (0.26 mL for the 200 mg vial or 1.3 mL for 
the 1 g vial). The total volume upon reconstitution will be 5.26 mL or 26.3 mL, respectively. 
Complete withdrawal of the vial contents will provide 200 mg or 1 g of gemcitabine, 
respectively. The appropriate amount of drug may be administered as prepared or further 
diluted with 0.9% Sodium Chloride Injection to concentrations as low as 0.1 mg/mL.  
Reconstituted gemcitabine is a clear, colorless to light straw-colored solution. After 
reconstitution with 0.9% Sodium Chloride Injection, the pH of the resulting solution lies in 
the range of 2.7 to 3.3. The solution should be inspected visually for particulate matter and 


2007-0910 
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discoloration, prior to administration, whenever solution or container permit. If particulate 
matter or discoloration is found, do not administer.  
Storage and Stability:  When prepared as directed, gemcitabine solutions are stable for 24 
hours at controlled room temperature 20° to 25°C (68° to 77°F). Discard unused portion. 
Solutions of reconstituted Gemcitabine should not be refrigerated, as crystallization may 
occur.  
Route of administration:  Gemcitabine will be administered intravenously at a rate of 10 
mg/m2/minute. Thus 1000 mg/m2 will be administered over 100 minutes. 
 
Supplier:  Commercial product will be used.  
 
8.3  
Erlotinib  
 
Product description:  The 25 mg, 100 mg and 150 mg strengths are supplied as white film-
coated tablets for daily oral administration. 
 
Storage:  Store at 25°C (77°F); excursions permitted to 15° — 30°C (59° — 86°F).  
 
Route of administration:  Erlotinib is administered orally.  Tablets should be taken once 
daily preferably in the morning with up to 200 mL of water at least one hour before or two 
hours after the ingestion of food.  
 
Supplier:  Commercial product will be used.  
 
 
9. CORRELATIVE/SPECIAL STUDIES 
 
9.1 A. IGF-1 and IGFBP-3 Circulating Levels 
 
Serum IGF-1and IGFBP-3 will be measured at screening and cycle 1, day 22, 1 hour post 
dose (+/-30 min) using Enzyme-Linked Immunosorbent Assay (ELISA). These tests will be 
performed in the biochemistry laboratory at M. D. Anderson Cancer Center. 
 
9.1 B. Free IGF1 levels.  
 
Blood samples (archival) obtained from subjects in the trial will also be analyzed for free IGF1 
level. One sample per patient (obtained per patient) will be sent. One frozen vial of minimum 
400 ul is required.  If the volume is larger than needed, residual sample will be shipped back by 
vendor after testing is completed. De-identified samples will be sent on dry ice to the following 
vendor:  
 


2007-0910 
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Attention: Deanna Stevens 
Aushon BioSystems, Inc. 
43 Manning Road, 1st floor 
Billerica, MA 01821-3925 
Ph: 978-436-6424 
Fax: 978-667-3970 
Each sample will be labelled with: protocol #, patient trial ID #. 
 
 
9.2 IGF-1R Signaling Pathway Proteins Tissue Levels 
For the Phase II expansion cohort, core biopsies from metastatic site or from primary tumor  
will be utilized for the following  tests. Archival core biopsies, or study-specific biopsies that 
are formalin-fixed and paraffin-embedded will be used.  
 
a.   Pretreatment core biopsies (archived or study-specific) will be analyzed for expression of 
p- IRS, IGF-1R, Akt, Erk, mTOR, and PI3k by immunohistochemistry .  In addition we 
will also examine IGF-1 mRNA expression using RT-PCR.  The sample requirements for 
this test are as follows: 
o Unstained slides for molecular marker analysis (4 μm of formalin-fixed, paraffin-
embedded tissue sections;  minimum 5 slides, maximum: 20 ). Alternatively, 
paraffin-embedded tissue blocks can also be shipped. 
 
• 
Tissue  sample shipping instructions are as follows:  
o Shipments should be sent Monday through Thursday by priority overnight 
delivery.   
o Do not ship on Fridays or on days prior to holidays.  
 
Label the sample with the following information 
o Protocol Number  
o Patient Trial ID #  and initials 
o Date of tumor tissue collection 
o Specimen – Origin of Tumor Tissue   
 
• 
Samples will be sent in batched shipments to the following address: 
 
Almac Diagnostics, 19 Seagoe Industrial Estate, Craigavon, BT63 5QD. United Kingdom; Tel: 
+44(0)28 3833 7575.  
 
 
 
 
9.3 Single nucleotide polymorphisms of IgF1R and related genes 


2007-0910 
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Page 36 
 
 
     The following analysis will not be performed in the Phase II expansion cohort. 
If the patient agrees, a 5 ml blood sample will be collected on day 1 prior to treatment in a 
green top tube (Heparinized tube).  Samples will be delivered to Dr. Donghui Li’s laboratory 
at 2SCRB2.3207 and processed for isolation of peripheral lymphocytes.  DNA will be 
extracted from the cells using a Promega Maxiwell automated system. Single nucleotide 
polymorphisms of the IGF1, IGF1R, IRS1, and IRS2 genes will be analyzed using the Sequenom 
method.   (See Appendix E). 


2007-0910 
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10. STUDY CALENDAR (Table 11) 
 
Procedure 
Screening 
Phase 
(within 14 days 
of treatment start 
except  MRI/CT 
scans and 
audiometry 
testing may be 
obtained within 
28 days) 
Treatment Phase 
 
Cycle 1 
Cycle 2  onwardI 
End of 
Treat 
mentJ 
Day 
1A  
Day 
8B 
Day 
15 B 
Day 
22 B 
Day 
1A 
Day 8 
B 
Day 
15 B 
Day 
22 B 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
HematologyC 
X 
X 
X 
X 
XP 
X 
X 
X 
 
X 
Serum chemistryD 
X 
X 
X 
X 
XP 
X 
X 
X 
 
X 
PT/INRE 
X 
 
 
 
 
 
 
 
 
 
CA19-9 estimation 
X 
 
 
 
 
X 
 
 
 
X 
Complete urinalysis with 
microscopic examination 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
Physical examination (PE) 
X 
X 
 
X 
 
X 
 
 
 
X 
Height  
X 
 
 
 
 
 
 
 
 
 
Vital signsF,  weight 
X 
X 
X 
X 
XP 
X 
X 
X 
XP 
X 
ECOG performance status 
X 
X 
 
X 
 
X 
 
 
 
X 
Review concomitant medications G 
X 
X 
 
X 
 
X 
 
 
 
X 
Archival Tumor Tissue (Core 
biopsy) if available or trial-specific 
tumor biopsy in the phase II 
expansion cohort 
X 
 
 
 
 
 
 
 
 
 
CT Scans or MRI of  chest, 
abdomen, pelvis 
X 
 
 
 
 
 
 
 
XN 
 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
Serum or urine pregnancy test (if 
applicable) 
X 
 
 
 
 
 
 
 
 
 
Comprehensive audiometry  testingR 
X 
 
 
 
 
 
 
 
 
 
Adverse event evaluationH 
X 
X 
X0 
X 
X0 
X 
X0 
X0 
X0 
X 
IGF-1 and IGFBP-3 correlative 
(diagnostic center) 
XS 
 
 
 
XS 
 
 
 
 
 
Tissue expression and EMT 
biomarkers in the phase II expansion 
cohort 
 
X 
 
 
 
 
 
 
 
 
 
 
IgF1R correlative (optional) (Dr. 
Donghui Li’s Lab).  NOTE: This 
will NOT be performed in the Phase 
II expansion cohort. 
 
X M 
 
 
 
 
 
 
 
 
Collect Serum for HAHA-shipped to 
Merck’s designated lab, PPD L, P, Q,  
NOTE: This will NOT be performed 
in the Phase II expansion cohort. 
 
X L,  
 
 
XL 
 
 
 
XL 
XL 
Survival Status 
 
 
 
 
 
 
 
 
 
XK 


2007-0910 
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A.   For Cycle 1, any evaluations performed for screening assessments that were performed within 3 days prior to 
Day 1 do not need to be repeated on Day 1.  Except as previously noted, Day 1 evaluations of each cycle may 
be performed up to 2 days prior to Day 1.   
B.   Days 8, 15, and 22 evaluations may be performed up to 1 day prior.  
C.   Hematology includes hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and differential.  
D.   Serum chemistry includes sodium, potassium, chloride, CO2, calcium, phosphorus, fasting glucose, creatinine, 
blood urea nitrogen, albumin, total protein, SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase 
and uric acid.  
E.    PT (INR) evaluation will be included for baseline evaluations. If warfarin anticoagulation is required, patients 
should have their PT/INR monitored at least weekly until stabilized and then on a periodic basis. 
F.    Pulse, blood pressure, respiration rate, and temperature 
G.   Patients will be instructed to notify study personnel if there are any changes to their concomitant medications.  
H.   In addition to scheduled adverse event evaluations, research nurse will review adverse events weekly with 
patients as clinically indicated. Patients will also be instructed to inform the study research nurse any time they 
experience new adverse events or previously reported events increase in severity.  
I     For subsequent cycles, assessments will continue as previously described for Cycle 2. Imaging studies will be 
performed after every 2 cycles (within 7 days of the end of Cycle 2, Cycle 4, Cycle 6, etc.). Treatment may 
continue until one of the criteria for treatment discontinuation outlined in Section 5.5 applies.   
J.    Evaluations will be performed within 30 days (+ 7 days allowed) of last dose of study drug(s). CA19-9 and 
imaging studies are not required if disease progression was previously documented.  In patients who 
discontinue study treatment for reasons other than progression, imaging studies will continue to be performed 
every 8 weeks until disease progression is documented.     Any adverse event assessed to be related to study 
therapy that has not returned to Grade 1 or baseline will continue to be followed after this evaluation until 
recovery or the treating investigator determines the event is irreversible.    
K.  Each patient who discontinues study treatment will be followed for survival  every 3 months (+ 1 week). Follow-up may 
be done either by phone contact or a clinic visit. 
L.   HAHA will NOT be performed in the Phase II expansion cohort. Serum HAHA should be measured at baseline 
(Screening Phase or pretreatment C1D1), at Week 4 (Cycle 1 – Day 22), at Week 8 (Cycle 2 – Day 22), and every eight 
weeks thereafter; and at Week 4 and Week 8 and Week 12 Post-study (End of Treatment).  (See Appendix F). After 
baseline assessment +/- 7 day window is allowed. 
M.  This will NOT be performed in the Phase II expansion cohort. This test will be drawn pre-treatment on cycle 1 day 1 
after it is determined that patient qualifies for the study. 
N.   CT/MRI evaluations will be performed at the end of every 2 cycles (weeks 8, 16, etc.). 
O.   The research nurse may call the patients weekly as clinically indicated if they are not scheduled for treatment.  This call 
would be to determine if the patient is having a major toxicity that would require holding treatment. If the call occurs, 
this information will be documented in a telephone note, formal AE reporting will be done at the end of each cycle. 
P.   Not required for patients on Phase II part of the study who are randomized to Gemcitabine and Erlotinib. 
Q.   Not required for patients who are crossed-over to Gemcitabine + Erlotinib + MK-0646. (As described in Section 5.3). 
R.   Comprehensive audiometry testing will be performed at baseline on all patients enrolled in the phase II portion of the 
study.  Audiometry testing will be repeated in any patient treated with MK-0646 who has suspected change in hearing.  
Follow-up testing will be performed as clinically indicated.  
 S.   IGF1 and IGFBP3 level will be drawn at screening and on Cycle 1, Day 22; one hour (+/-30 min) post dose # 4 of MK-
0646 
 
Please refer to table 11 and accompanying footnotes for any time allowances (windows) for performing study 
evaluations.   


2007-0910 
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10.1  Pre-treatment Evaluations 
 
Except for MRI/CT scans and audiometry testing which may be performed within 28 days, 
the following baseline evaluations shall be performed within 14 days to treatment initiation: 
• Hematology: must include hemoglobin, hematocrit, platelets, total white blood cell 
count (WBC) and differential. PT (INR) evaluation will be included for baseline 
evaluations. If warfarin anticoagulation is required, patients should have their PT/INR 
monitored at least weekly until stabilized and then on a periodic basis. 
• Serum chemistry: must include sodium, potassium, chloride, CO2, calcium, phosphorus, 
fasting glucose, creatinine, blood urea nitrogen, albumin, total protein, SGOT (AST), 
SGPT (ALT), total bilirubin, alkaline phosphatase and uric acid.  
• CA 19-9 estimation 
• Complete urinalysis with microscopic examination 
• Medical History and Physical Exam 
• ECOG Performance Status 
• Vital signs: height (first visit), pulse, blood pressure, respiration rate, temperature and 
weight. 
• Assessment of concurrent medications 
• Assessment of baseline AEs. 
• 12-Lead ECG 
• Serum or urine pregnancy test for women of childbearing potential 
• Comprehensive audiometry testing  
• Radiological evaluation: Chest, abdomen and pelvis by either CT scan or MRI. Same 
imaging technique should be used on a patient throughout the study. 
• Determination if archival tumor tissue (Core biopsy) is available for correlative 
studies. If inadequate, patient will undergo core biopsy of tumor with informed consent 
in the expansion cohort. 
 
10.2 During Treatment Evaluations 
 
 
Prior to Treatment on Day 1 of Cycle 1 
• When it has been determined the patient qualifies for the study, blood samples for 
determination of circulating levels of IGF-1, IGFBP-3 (section 9.1) will be collected.  
HAHA samples must be collected in all patients except those assigned to treatment 
with Gemcitabine + Erlotinib.  HAHA will NOT be performed in the Phase II 
expansion cohort. 
 
During cycle 1: 
 
• Hematology and serum chemistry: obtained on Days 1, 8, 15, and 22.* 
• Physical Exam: obtained on Days 1 and 15  
• ECOG Performance Status: obtained on Days 1 and 15 
• Vital signs and weight: obtained on Days 1, 8, 15, and 22* 
• Determination of erlotinib dose compliance (if applicable)  
• Blood sample for circulating level of IGF-1 and IGFBP-3 will be collected on Cycle 


2007-0910 
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Page 40 
 
1, Day 22, 1 hour post dose of MK-0646. 
• Assessment of concurrent medications: obtained on Days 1, and 15 Patients also will 
be instructed to notify study personnel at any time there are changes to their concomitant 
medications.  
• Adverse event evaluation: obtained on Days 1 and 15.  In addition to scheduled adverse 
event evaluations, research nurse will review adverse events weekly with patient as 
clinically indicated. Patients will also be instructed to inform the study research nurse 
any time they experience new adverse events or previously reported events increase in 
severity.  
• Collect Serum for HAHA: collected on Day 22 of Cycle 1. (Not required for patients 
assigned to Gemcitabine + Erlotinib). This will NOT be performed in the Phase II 
expansion cohort. 
* Day 22 assessment not required for patients assigned to treatment with Gemcitabine + 
Erlotinib. 
 
During cycles 2 and beyond: 
 
• Hematology and serum chemistry: obtained on Days 1, 8, 15 of every cycle  
• CA 19-9 estimation: Day 1 of every cycle. 
• Physical Exam: Day 1 of each cycle 
• ECOG Performance Status: Day 1 of each cycle 
• Vital signs and weight: obtained on Days 1, 8, 15, and 22* 
• Determination of erlotinib dose compliance (if applicable)  
• Assessment of concurrent medications: Day 1 of each cycle.  Patients also will be 
instructed to notify study personnel at any time there are changes to their concomitant 
medications.  
• Adverse event evaluation: obtained Day 1 of each new cycle.  In addition to scheduled 
adverse event evaluations, research nurse will review adverse events weekly with patient 
as clinically indicated. Patients will also be instructed to inform the study research nurse 
any time they experience new adverse events or previously reported events increase in 
severity.  
• Radiological evaluation (CT scan or MRI): evaluation shall be performed at the end of 
every 2 cycles (weeks 8, 16, etc.).  
• Collect Serum for HAHA: collected on Day 22 of Cycle 2 and every 8 weeks 
thereafter. (Not required for patients assigned to treatment with Gemcitabine + 
Erlotinib). This will NOT be performed in the Phase II expansion cohort. 
*   Day 22 assessment not required for patients assigned to treatment with Gemcitabine + 
Erlotinib. 
 
Follow-up audiometry testing will be performed for any MK-0646 treated patient who has suspected 
change in hearing from baseline evaluation.  Frequency of any subsequent testing will be as clinically 
indicated.  
 
 
10.3 End of Treatment Evaluations 


2007-0910 
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When a patient discontinues study treatment, the following evaluations will be completed 30 
days (+ 7 days) from last dose of study drug  
• Physical exam 
• ECOG Performance Status 
• Vital Signs and weight 
• Hematology and serum chemistry  
• Assessment of concurrent medications 
• Determination of erlotinib dose compliance (if applicable)  
• Adverse event evaluation: Any adverse event assessed to be related to study therapy 
that has not returned to Grade 1 or baseline will continue to be followed after this 
evaluation until recovery or the treating investigator determines the event is irreversible.   
• Collect Serum for HAHA: collect at Week 4, Week 8 and Week 12 Poststudy (End of 
Treatment) (+/- 7 day window allowed. Not required for patients assigned to treatment 
with Gemcitabine + Erlotinib).  This will NOT be performed in the Phase II expansion 
cohort. 
• CA 19-9 
• Imaging studies are not required if disease progression was previously documented or if 
performed within the last 5 weeks.  In patients who discontinue study treatment for 
reasons other than progression, imaging studies will continue to be performed every 8 
weeks until disease progression is documented.  
 
Survival Status  
 
Each patient who discontinues study treatment will be followed for survival at least  every 3 months. 
This may be done either by phone contact or a clinic visit. 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1  Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be reevaluated for response every eight weeks.   
 
Response and progression will be evaluated in this study using the international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 92(3):205-216, 
2000].  Changes in only the largest diameter (one-dimensional measurement) of the tumor lesions 
are used in the RECIST criteria. 
 
11.1.1  Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with the study agents. 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 


2007-0910 
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baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response.  These patients will have their response classified according to 
the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to the 
end of cycle 1 will also be considered evaluable.) 
 
11.1.2  Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, 
MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or 
MRI), and cystic lesions are all non-measurable. 
 
Target lesions.  All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be calculated 
and reported as the baseline sum LD.  The baseline sum LD will be used as reference by which to 
characterize the objective tumor response. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over and 
above the 10 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence or absence of each should 
be noted throughout follow-up.  
 
11.1.3  Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
The Research Nurse will complete a Tumor Measurement worksheet for each patient, which will be 
signed by the doctor and sent to medical records to be scanned into the Research Folder. 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  


2007-0910 
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Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  These techniques should be performed with cuts of 10 mm or less in 
slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and neck 
tumors and those of extremities usually require specific protocols. 
 
Ultrasound (US)  When the primary endpoint of the study is objective response evaluation, US 
should not be used to measure tumor lesions.  It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  US 
might also be useful to confirm the complete disappearance of superficial lesions usually assessed by 
clinical examination. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation has not 
yet been fully and widely validated.  Their uses in this specific context require sophisticated 
equipment and a high level of expertise that may only be available in some centers.  Therefore, the 
utilization of such techniques for objective tumor response should be restricted to validation 
purposes in reference centers. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained. 
 
Tumor markers  Tumor marker such as CA 19-9 level cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response. 
 
Cytology, Histology  These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
 
 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):Disappearance of all target lesions 
 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD 
 


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Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment started 
or the appearance of one or more new lesions. 
 
Stable Disease (SD):  
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
 
 
Incomplete Response/ 
Stable Disease (SD):     
Persistence of one or more non-target lesion(s) and/or maintenance  of 
tumor marker level above the normal limits 
 
Progressive Disease (PD): 
      Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the Principal Investigator. 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
 
Table 12  Evaluation of Best Overall Response 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once >4 
wks. from baseline 


2007-0910 
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PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration”.  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that recurrent disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started.  
 
11.1.6  Progression-Free Survival 
 
PFS is defined as the time from date of first dose of study drug until date of disease progression 
(clinical or radiological) or death, if progression not previously documented. .  
 
 
11.1.7  Overall Survival 
 
Overall survival is defined as the time from the date of the first dose of study drug to the  date of 
death. In the absence of death confirmation, survival time will be censored at the date of the last 
study follow-up.  
 
 
12.   DATA COLLECTION   
Designated research personnel must enter the information required by the protocol onto electronic 
Case Report Forms (CRFs). The University of Texas M. D. Anderson Cancer Center’s Protocol Data 
Management System(PDMS) CRF system will be used for this study.  PDMS is a clinical research 
information management system. The PDMS CRF is an electronic document designed to record all 
the protocol-required information to be reported on each trial subject. 
 
PDMS provides data entry templates as defined in the protocol. Laboratory results are automatically 
transferred from M. D. Anderson Cancer Center Laboratory Medicine’s server to PDMS each 
morning. Users must have clearance through the M. D. Anderson Cancer Center Information 


2007-0910 
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Services Security Department in order to access PDMS. PDMS login is password protected.  
 
 
13. STATISTICAL CONSIDERATIONS 
 
Overview of Statistical Considerations 
Part One:  
Phase I study of (a) gemcitabine + MK-0646 and (b) gemcitabine + erlotinib + MK-0646.  We are 
only considering two dose levels, so we will carry out a 3+ 3 phase I design. 
• Enrollment will begin on arm (a).  Arm (b) will begin enrollment at a particular dose level only 
when enrollment at that dose level is complete in Arm (a).  Thus, enrollment at dose level 1 in 
arm (b) will begin only after dosing at level 1 is completed safely in arm (a). 
•    A minimum of 3 patients will be treated at each dose level.  Once 3 patients are enrolled in Arm 
A, Level 1, additional accrual will be held until all 3 patients have completed their first cycle.  If 
there is one DLT, up to 3 additional patients will be entered at the same dose level and evaluated 
for DLT.  If the criteria for dose escalation are met, 3 new patients will be enrolled in Arm B, 
Level 1. Once 3 patients have been enrolled in Arm B, Level 1, 3 patients may be accrued to 
Arm A, Level 2.  Patients in both of these Arms/Levels will be evaluated for DLT during cycle 
1.  If DLT is observed, up to 3 additional patients will be enrolled in the Arm/Level that DLT 
occurred, as described above.  Once accrual and cycle 1 evaluation have been completed in Arm 
B, Level 1 and Arm A, Level 2, if the criteria for dose escalation are met in both arms, accrual 
may proceed in Arm B, Level 2. 
•    If at any time 2 patients develop DLTs at a level, this level will be considered above the MTD. In 
each arm, six patients will be treated at the dose identified as the MTD.  The MTD is defined as 
the highest dose level that can be administered with  ≤ 1 DLT observed in 6 patients.   
 
 
 
Part two: 
 
The phase II part of the study will utilize an adaptive randomization design with 3 arms: Arm A: 
gemcitabine + MK-0646 (G+I), Arm B: gemcitabine + erlotinib + MK-0646 (G+E+I), and Arm C: 
gemcitabine +erlotinib (G+E). The primary endpoint is progression-free survival (PFS). Technical 
details of the adaptive randomization algorithm are given in the Appendix.  Briefly, the first 45 patients 
will be equally randomized among the three arms.  Thereafter, as the trial progresses and data accrue, 
the randomization will become unbalanced and in favor of the treatment arm that, on average, has better 
results in terms of PFS.  A minimum of 45 and a maximum of 78 patients will be accrued in the phase II 
part of this study.  Based on an anticipated accrual rate of 4 patients per month, it will take about 20 
months to enroll all 78 patients. 
 
Additionally, a safety monitoring rule will be in place, allowing us to stop accruing patients to 


2007-0910 
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treatments that appear to be unsafe.  Each arm will be monitored separately using the following stopping 
rule: Pr(Toxicity rate >.30|data) > 0.95 and starting from the 5th patient. A beta(0.6, 1.4) prior is assumed 
for the toxicity rate and the corresponding stopping boundaries are to stop the trial if, at any given time, 
(number of patients with toxicities/number of evaluable patients) >/= 4/5, 5/6, 6/9, 7/11, 8/13, 9/16, 
10/19, 11/21, 12/24, 13/26, 14/29, 15/32, 16/35, 17/37, 18/40, 19/43, 20/46.   
 
 
Part Three (expansion phase): 
 
We will expand Arm A: gemcitabine + MK-0646 (G+I) by adding an additional 30 patients. The 
estimated accrual rate is 2-3 patients per month. The primary objective for this expansion cohort is to 
further explore IGF1 tissue level as a predictive biomarker for MK-0646 therapy. To meet this goal, we 
will combine the data already collected up- to-date from 21 patients treated in arm A (6 from phase I 
MTD cohort and 15 from phase II) with these 30 patients’ data in order to further assess the potential 
differential effect of MK-0646 treatment on PFS among patients with high vs. low IGF-1 groups. Our 
hypothesis is that patients with relatively higher IGF1 level may benefit more from the therapeutic effect 
of MK-0646. Our preliminary data showed that the median PFS was 8.0 months (95% CI: 1.8 – Not 
estimable) and 2.0 months (95% CI: 1.2 – not estimable), respectively, among patients with high versus 
low IGF1 level (using median as the cutoff).  
 
In this expansion phase of the trial, we will continue to monitor those patients treated with G+M for 
futility (based on PFS) and safety.  
 
Futility Monitoring 
 
The Bayes factor single-arm time-to-event model (Johnson & Cook, 2009) will be used to monitor the 
PFS. Based on the preliminary data on 15 patients treated with gemcitabine+erlotinib (G+E, control 
arm) in the randomized portion of this study (part 2), the median PFS for this control arm was 2.1 month 
(mean PFS= 3.0 months), and we expect that the treatment of G+M would prolong the median PFS to be 
3.6 months (mean PFS = 5.2 months).  Therefore, under this Bayesian hypothesis testing based design 
framework, the null hypothesis is a median PFS of 2.1 months, while the alternative hypothesis is a 
median PFS of 3.6 months.  We assume that the sample distribution of PFS follows an exponential 
distribution, and use an inverse moment prior for the mean PFS under the alternative hypothesis. We 
will stop the trial for futility if the posterior probability of the alternative hypothesis is less than 0.10, i.e. 
Pr(H1|Data) < 0.10.   
 
 The operating characteristics of the design were produced using a design software, BayesFactorTTE, 
version 1.0.0, developed by the Department of Biostatistics at M. D. Anderson Cancer Center.  
   
 
 
Scenario 
True median 
(mean) PFS 
Pr(Stopping for the 
null) 
Average # patients 
treated  
(10%, 25%, 50%, 75%, 
90%)  


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1 
2.1 ( 3.03 ) 
0.919 
23.27 (10, 14, 20, 30, 47 ) 
2 
3 ( 4.33 ) 
0.373 
40.87 (15, 29, 51, 51, 51 ) 
3 
3.6 ( 5.19 ) 
0.116 
47.51 (34, 51, 51, 51, 51 ) 
4 
4.6 ( 6.64 ) 
0.016 
50.43 (51, 51, 51, 51, 51 ) 
 
 
Stopping Boundaries 
 
The entire design output from running the BayesFactorTTE is attached as an Appendix, which includes 
the input parameters, simulation results, as well as the stopping boundaries for declaring futility.  
 
Trial Conduct 
 
Patient enrollment and futility stopping rule assessment will be conducted through a website developed 
and maintained by the Department of Biostatistics 
(https://biostatistics.mdanderson.org/ClinicalTrialConduct/ ). The Clinical Trial Conduct (CTC) website 
resides on a secure server, and access is gained through usernames and passwords provided to personnel 
responsible for enrolling patients and updating patient data.  The website is accessed through a browser 
using secure socket layer technology. Personnel responsible for enrolling patients on trials will be 
trained in the use of the trial website, with emphasis on the importance of timely updating of follow-up 
times and recording of events. The futility monitoring rules described above will be automatically 
evaluated each time patient data are updated on the trial website. If the stopping rule is met, the study 
statistician, research nurse, and principal investigator will each receive an automatic email notification. 
 
Toxicity Monitoring 
 
In addition, we will expand the toxicity monitoring for the G+M arm to account for a maximum of 51 
patients (i.e., 21 already enrolled plus 30 more in the expansion).   Again, the Bayesian design of Thall, 
Simon, Estey (1995) will be applied in all patients treated with G+M.  Specifically, the trial will be 
stopped if Prob(πT>0.30 | data)>0.95. That is, if at any given time, there is more than 95% probability 
that the toxicity rate of the G+M is greater than 30%, the trial will be stopped. We will apply this 
toxicity stopping rule starting from the 5th patient. A beta(0.6, 1.4) prior is assumed for the toxicity rate 
and the corresponding stopping boundaries are to stop the trial if, at any given time, (number of patients 
with toxicities/number of evaluable patients) >/= 4/5, 5/6, 6/9, 7/11, 8/13, 9/16, 10/19, 11/21, 12/24, 
13/26, 14/29, 15/32, 16/35, 17/37, 18/40, 19/43, 20/46, 21/49.  The operating characteristics for the 
toxicity monitoring rule are shown below.  
 
True Toxicity Rate 
Pr (Stop the trial early) 
Median # patients (25th, 75th 
percentile) 
0.2 
0.025 
51 (51,51) 
0.25 
0.065 
51 (51,51) 
0.3 
0.174 
51 (51,51) 


2007-0910 
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0.35 
0.376 
51 (25,51) 
0.4 
0.627 
34 (12, 51) 
 
Analysis Plan: 
 
The probability of PFS and OS will be estimated using the method of Kaplan and Meier. For PFS, we 
will also compute the posterior probability of the null and alternative hypothesis being true. To explore 
the association between patients’ tissue IGF-1 level and their PFS outcome, we will first dichotomize the 
IGF-1 level as “high” vs. “low”, using the sample median as cutoff. The median PFS and the 
corresponding 95% confidence interval will be estimated for each subgroup separately.  Log-rank test 
will also be performed to assess whether there is any significant difference in PFS between these two 
groups of patients. Patients’ AE data will be summarized by AE term, grade and relationship to the 
study drug using descriptive statistics.  
 
Reference: 
 
 
1. Johnson VE and Cook JD. Bayesian design of single-arm phase II clinical trials with continuous 
monitoring. Clinical Trials. 2009 Jun; 6(3): 217-26.  
2. Thall, PF, Simon, R, Estey, EH: Bayesian sequential monitoring designs for single-arm clinical 
trials with multiple outcomes. Statistics in Medicine 14:357-379, 1995.  
 
 
 
 
 
 
 
 
 
 


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Appendix 1: Statistical Output 
 
Simulation output from the Bayes factor one-arm time-to-event design.  
 
Output Report 
 
BayesFactorTTE (version 1.0.0) 
 
Bayes Factor One-arm Time-to-event Outcome  
 
8/22/2012 9:51:27 AM 
 
Random seed for simulation: 12345 
 
Input file name: InputFile_BayesFactorTTE.txt 
 
Output file name: output.html 
Design input parameters: 
Parameter 
Value 
Maximum number of patients  
51 
Null hypothesis of median (mean) TTE in month 
2.1 ( 3.03 ) 
Alternative hypothesis of median (mean) TTE in month  3.6 ( 5.19 ) 
Cutoff to stop for inferiority if Pr(H1|Data)     <  
0.1 
Cutoff to stop for superiority if Pr(H1|Data)   >  
1 
Accrual rate per month  
3 
Number of repetitions for the simulation  
1000 
Do you need to print out the stopping boundaries  
Yes  
 
Note: H1 = alternative hypothesis 
  
Simulation Results 
Scenario 
True median (mean) 
TTE 
Pr(Stopping for 
H0) 
Average # patients treated (10%, 25%, 50%, 
75%, 90%)  
1 
2.1 ( 3.03 ) 
0.919 
23.27 (10, 14, 20, 30, 47 ) 
2 
3 ( 4.33 ) 
0.373 
40.87 (15, 29, 51, 51, 51 ) 
3 
3.6 ( 5.19 ) 
0.116 
47.51 (34, 51, 51, 51, 51 ) 
4 
4.6 ( 6.64 ) 
0.016 
50.43 (51, 51, 51, 51, 51 ) 
 
Note:H0 = null hypothesis;  


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Stopping Boundaries 
Number Events 
Max total time-on-test in days (months) to claim inferiority 
0 
0 ( 0 )  
1 
0 ( 0 )  
2 
0 ( 0 )  
3 
0 ( 0 )  
4 
94 ( 3.1 )  
5 
218 ( 7.2 )  
6 
341 ( 11.2 )  
7 
463 ( 15.2 )  
8 
585 ( 19.2 )  
9 
706 ( 23.2 )  
10 
827 ( 27.2 )  
11 
948 ( 31.1 )  
12 
1068 ( 35.1 )  
13 
1188 ( 39 )  
14 
1308 ( 43 )  
15 
1427 ( 46.9 )  
16 
1546 ( 50.8 )  
17 
1665 ( 54.7 )  
18 
1783 ( 58.6 )  
19 
1902 ( 62.5 )  
20 
2020 ( 66.4 )  
21 
2138 ( 70.2 )  
22 
2256 ( 74.1 )  
23 
2373 ( 78 )  
24 
2490 ( 81.8 )  
25 
2608 ( 85.7 )  
26 
2725 ( 89.5 )  
27 
2841 ( 93.3 )  


2007-0910 
 October 6, 2014 
Page 55 
 
28 
2958 ( 97.2 )  
29 
3075 ( 101 )  
30 
3191 ( 104.8 )  
31 
3307 ( 108.6 )  
32 
3423 ( 112.5 )  
33 
3539 ( 116.3 )  
34 
3655 ( 120.1 )  
35 
3771 ( 123.9 )  
36 
3887 ( 127.7 )  
37 
4002 ( 131.5 )  
38 
4117 ( 135.3 )  
39 
4233 ( 139.1 )  
40 
4348 ( 142.9 )  
41 
4463 ( 146.6 )  
42 
4578 ( 150.4 )  
43 
4693 ( 154.2 )  
44 
4808 ( 158 )  
45 
4922 ( 161.7 )  
46 
5037 ( 165.5 )  
47 
5151 ( 169.2 )  
48 
5266 ( 173 )  
49 
5380 ( 176.8 )  
50 
5494 ( 180.5 )