Dual Epidermal Growth Factor Receptor Inhibition With Erlotinib and Panitumumab With or Without Chemotherapy for Advanced Colorectal Cancer

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00940316
• Collaborator: Genentech, Inc. (Industry), OSI Pharmaceuticals (Industry), Amgen (Industry)
• Enrollment: 28
• Locations: 10
• Arms: 3
• Actual Duration (Months): 59.4
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Panitumumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether erlotinib hydrochloride given together with panitumumab is more effective with or without irinotecan in treating patients with metastatic colorectal cancer.

PURPOSE: This randomized phase II trial is studying giving erlotinib hydrochloride together with panitumumab to see how well it works with or without irinotecan hydrochloride as second-line therapy in treating patients with metastatic colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Biological: panitumumab; Drug: erlotinib hydrochloride; Drug: irinotecan hydrochloride	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the response rate in patients with metastatic colorectal cancer treated with erlotinib hydrochloride and panitumumab with versus without irinotecan hydrochloride as second-line therapy .

Secondary

• Determine time to disease progression and time to treatment failure in patients treated with these regimens.

• Determine the safety of these regimens in these patients.

• Determine the effect of these regimens on downstream targets of EGFR in skin rash associated with pharmacologic EGFR inhibition (exploratory).

• Determine the association between KRAS mutations and response to EGFR inhibition (exploratory).

OUTLINE: This is a multicenter study. Patients are stratified according to wild-type Kras tumors ( 6/6 UGT1A1 vs 6/7 UGT1A1), and are randomized to 1 of 2 treatment arms. Patients with wild-type Kras tumor 7/7 UGT1A1 receive treatment in arm III.

• Arm I: Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.

• Arm II: Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm I.

• Arm III: Patients receive erlotinib hydrochloride and panitumumab as in arm II. Skin biopsies and blood samples may be collected for further analysis.

After completion of study therapy, patients are followed every 6 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study of Dual Epidermal Growth Factor Receptor Inhibition With Erlotinib and Panitumumab With or Without Irinotecan as Second Line Therapy in Patients With Metastatic Colorectal Cancer
• Actual Study Start Date: Jan 18, 2010
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: Erlotinib + Panitumumab + Irinotecan Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.	Biological: panitumumab; Given intravenously 6mg/kg every 2 weeks; Other Names: Vectibix ; Drug: erlotinib hydrochloride; Given orally 150mg daily; Other Names: Tarceva ; Drug: irinotecan hydrochloride; Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype; Other Names: Camptosar CPT-11
Experimental: Arm B: Erlotinib + Panitumumab Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A.	Biological: panitumumab; Given intravenously 6mg/kg every 2 weeks; Other Names: Vectibix ; Drug: erlotinib hydrochloride; Given orally 150mg daily; Other Names: Tarceva ; Drug: irinotecan hydrochloride; Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype; Other Names: Camptosar CPT-11
Experimental: Arm C: Erlotinib + Panitumumab Patients receive erlotinib hydrochloride and panitumumab as in arm B.	Biological: panitumumab; Given intravenously 6mg/kg every 2 weeks; Other Names: Vectibix ; Drug: erlotinib hydrochloride; Given orally 150mg daily; Other Names: Tarceva

Outcome Measures

Primary Outcome Measures

1. Tumor Response Rate Based on Complete Response (CR)+ Partial Response (PR) + Stable Disease (SD) [At baseline and every 8 weeks during treatment until progressive disease for maximum of 51 cycles where 1 cycle = 2 weeks.]

   Tumor response rate will be measured by CT scan of the chest and CT scan or MRI scan of abdomen and pelvis every 8 weeks until disease progression response rate will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions evaluated using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for 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. 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

Secondary Outcome Measures

1. Time to Disease Progression [At baseline and every 8 weeks during treatment until disease progression and for a maximum of 51 cycles where 1 cycle = 2 weeks]

   Time to disease progression will be measured by CT scan of the chest and CT scan or MRI scan of abdomen and pelvis every 8 weeks until disease progression . Time to disease progression will be defined as the time elapsed from the day of 1st study drug administration to the day disease progression is documented or death occurs and will . Progressive Disease will be defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) : At least a 20% increase in the sum of the longest diameter (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.

2. Time to Treatment Failure [From first day of study drug treatment until the date of stopping all study drugs for any reason for a maximum of 51 cycles where 1 cycle=2weeks]

   Time to treatment failure will be measured as the time elapsed from the day of first study drug administration to the date a subject stops all study drugs for any reason.

3. Toxicity of the Combination of Study Drugs [Day 1 of every 2 week treatment cycle while on study treatment and 30 days after the last treatment for a maximum of 51 cycles.]

   Data on the toxicity of the combination of study drugs is assessed by laboratory blood draws done on day 1 of every treatment cycle and by patient report while on study treatment and up to 30 days after the last treatment. Grade 3 and grade 4 adverse events (AE) where the relationship between the AE and at least one of the study drugs were considered to be definite, probable or possible, were collected using National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). AEs are graded as: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

4. Effect on Downstream Targets of Epidermal Growth Factor Receptor (EGFR) in Skin Rash Associated With Pharmacologic EGFR Inhibition [At baseline and at a time-point reflecting maximum rash intensity during treatment, at a maximum of 51 cycles.]

   Effect on downstream targets of EGFR in skin rash associated with pharmacologic EGFR inhibition. Skin biopsies will be performed at baseline (before the first days of treatment) and and at a time-point reflecting maximum rash intensity determined by a dermatologist.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal cancer

• Metastatic disease

• Biopsy of either the primary cancer or metastatic site required

• Tumor expressing wild-type Kras mutations

• Progressive disease within 3 months after treatment with first-line fluorouracil (5-FU) and oxaliplatin-based chemotherapy OR evidence of metastatic disease within 6 months of completing adjuvant therapy with 5-FU and oxaliplatin

• Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques OR as ≥ 10 mm with spiral CT scan

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• Life expectancy > 6 months

• ANC > 1,500/mm^3

• Platelet count > 100,000/mm^3

• Hemoglobin ≥ 9 g/dL

• Creatinine < 1.5 times upper limit of normal (ULN)

• Bilirubin < 1.5 times ULN (or < 2 mg/dL)

• AST and/or ALT < 3 times ULN (< 5 times ULN with liver metastases)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No concurrent malignancy requiring therapy except minor surgery for non-melanoma skin cancer removal

• No interstitial lung disease with symptoms (e.g., dyspnea or cough) including any of the following significant conditions:

• Parenchymal lung disease

• Metastatic disease

• Pulmonary infections

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior EGFR inhibitors, irinotecan hydrochloride, or other second-line chemotherapy regimens

• More than 4 weeks since prior radiotherapy

• No other concurrent investigational agents

• No other concurrent anticancer treatment modalities (e.g., radiotherapy)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cancer Care & Hematology Specialists of Chicagoland	Arlington Heights	Illinois	United States	60005
2	Northwestern University, Northwestern Medical Faculty Foundation	Chicago	Illinois	United States	60611-3013
3	Hematology/Oncology Associates	Chicago	Illinois	United States	60611
4	Joliet Oncology-Hematology Associates, Ltd.	Joliet	Illinois	United States	60435
5	Hope Cancer Center	Terre Haute	Indiana	United States	47802
6	Cancer Center of Kansas	Wichita	Kansas	United States	67214
7	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
8	Virtua Memorial (Regional Cancer Care Associates of Mount Holly)	Mount Holly	New Jersey	United States	08060
9	Mercy Clinic Oncology and Hematology	Oklahoma City	Oklahoma	United States	73120-9309
10	The Jones Clinic	Germantown	Tennessee	United States	38138

Sponsors and Collaborators

• Northwestern University
• Genentech, Inc.
• OSI Pharmaceuticals
• Amgen

Investigators

• Principal Investigator: Al Benson, MD, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Al Benson, Al Benson, MD, Northwestern University
• ClinicalTrials.gov Identifier: NCT00940316
• Other Study ID Numbers: NU 07I4; STU00004101; OSI 4263s
• First Posted: Jul 16, 2009
• Last Update Posted: May 7, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by Al Benson, Al Benson, MD, Northwestern University: recurrent colon cancer; stage IV colon cancer; recurrent rectal cancer; stage IV rectal cancer
• Additional relevant MeSH terms: Colorectal Neoplasms; Irinotecan; Erlotinib Hydrochloride; Panitumumab

Study Results

Participant Flow

Recruitment Details	The study opened for accrual on July 9, 2009 with an accrual goal of up to 96 patients. The study was designed to enroll 13 patients on each arm and do an interim efficacy assessment. Accrual was suspended on March 31 2015 fand closed permanently on April 13, 2015 with 28 patients enrolled on the study.
Pre-assignment Detail	Subjects with either 6/6 UGT1A1 genotype or 6/7 UGT1A1 genotype will be randomized into either Arm A and Arm B. Subjects with 7/7 UGT1A1 genotype enrolled in Arm C.

Arm/Group Title	Arm A: Erlotinib + Panitumumab + Irinotecan	Arm B: Erlotinib + Panitumumab	Arm C: Erlotinib + Panitumumab
Arm/Group Description	Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily irinotecan hydrochloride: Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype	Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily irinotecan hydrochloride: Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype	Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily
Period Title: Reached First Response at 8 Weeks
STARTED	13	13	2
COMPLETED	10	9	2
NOT COMPLETED	3	4	0
Period Title: Reached First Response at 8 Weeks
STARTED	10	9	2
COMPLETED	8	9	2
NOT COMPLETED	2	0	0
Period Title: Reached First Response at 8 Weeks
STARTED	8	9	2
COMPLETED	8	8	1
NOT COMPLETED	0	1	1
Period Title: Reached First Response at 8 Weeks
STARTED	0	3	0
Treated for Cycle One	0	3	0
COMPLETED	0	3	0
NOT COMPLETED	0	0	0
Period Title: Reached First Response at 8 Weeks
STARTED	13	13	2
COMPLETED	13	13	2
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Arm A: Erlotinib + Panitumumab + Irinotecan	Arm B: Erlotinib + Panitumumab	Arm C: Erlotinib + Panitumumab	Total
Arm/Group Description	Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily irinotecan hydrochloride: Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype	Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily irinotecan hydrochloride: Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype	Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily	Total of all reporting groups
Overall Participants	13	13	2	28
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	8 61.5%	9 69.2%	2 100%	19 67.9%
>=65 years	5 38.5%	4 30.8%	0 0%	9 32.1%
Sex: Female, Male (Count of Participants)
Female	6 46.2%	5 38.5%	0 0%	11 39.3%
Male	7 53.8%	8 61.5%	2 100%	17 60.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 23.1%	2 15.4%	0 0%	5 17.9%
Not Hispanic or Latino	10 76.9%	11 84.6%	2 100%	23 82.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 7.7%	1 7.7%	1 50%	3 10.7%
White	12 92.3%	12 92.3%	1 50%	25 89.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	13 100%	13 100%	2 100%	28 100%
UGT1A1 genotyping 6/6 (Count of Participants)
Count of Participants [Participants]	9 69.2%	7 53.8%	0 0%	16 57.1%
UGT1A1 genotyping 6/7 (Count of Participants)
Count of Participants [Participants]	4 30.8%	6 46.2%	0 0%	10 35.7%
UGT1A1 genotyping 7/7 (Count of Participants)
Count of Participants [Participants]	0 0%	0 0%	2 100%	2 7.1%

Outcome Measures

1. Primary Outcome

Title	Tumor Response Rate Based on Complete Response (CR)+ Partial Response (PR) + Stable Disease (SD)
Description	Tumor response rate will be measured by CT scan of the chest and CT scan or MRI scan of abdomen and pelvis every 8 weeks until disease progression response rate will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions evaluated using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for 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. 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
Time Frame	At baseline and every 8 weeks during treatment until progressive disease for maximum of 51 cycles where 1 cycle = 2 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: Erlotinib + Panitumumab + Irinotecan	Arm B: Erlotinib + Panitumumab	Arm C: Erlotinib + Panitumumab
Arm/Group Description	Arm A - Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily Irinotecan hydrochloride: Given intravenously 120mg/m2 every 2 weeks	Arm B - Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily	Arm C - Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily
Measure Participants	13	13	2
Complete Response	0 0%	1 7.7%	0 0%
Partial Response	4 30.8%	3 23.1%	0 0%
Stable disease	6 46.2%	3 23.1%	2 100%

2. Secondary Outcome

Title	Time to Disease Progression
Description	Time to disease progression will be measured by CT scan of the chest and CT scan or MRI scan of abdomen and pelvis every 8 weeks until disease progression . Time to disease progression will be defined as the time elapsed from the day of 1st study drug administration to the day disease progression is documented or death occurs and will . Progressive Disease will be defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) : At least a 20% increase in the sum of the longest diameter (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.
Time Frame	At baseline and every 8 weeks during treatment until disease progression and for a maximum of 51 cycles where 1 cycle = 2 weeks

Outcome Measure Data

Analysis Population Description

All patient data analyzed reported together regardless of arm allocation. Data not collected and analyzed for this outcome measure.

Arm/Group Title	Arm A + Arm B + Arm C
Arm/Group Description	Arm A - Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Arm B - Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. Arm C - Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily Irinotecan hydrochloride: Given intravenously 120mg/m2 every 2 weeks
Measure Participants	0

3. Secondary Outcome

Title	Time to Treatment Failure
Description	Time to treatment failure will be measured as the time elapsed from the day of first study drug administration to the date a subject stops all study drugs for any reason.
Time Frame	From first day of study drug treatment until the date of stopping all study drugs for any reason for a maximum of 51 cycles where 1 cycle=2weeks

Outcome Measure Data

Analysis Population Description

Data was not collected and analyzed for this outcome measure

Arm/Group Title	Arm A + Arm B + Arm C
Arm/Group Description	Arm A - Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Arm B - Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. Arm C - Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily Irinotecan hydrochloride: Given intravenously 120mg/m2 every 2 weeks
Measure Participants	0

4. Secondary Outcome

Title	Toxicity of the Combination of Study Drugs
Description	Data on the toxicity of the combination of study drugs is assessed by laboratory blood draws done on day 1 of every treatment cycle and by patient report while on study treatment and up to 30 days after the last treatment. Grade 3 and grade 4 adverse events (AE) where the relationship between the AE and at least one of the study drugs were considered to be definite, probable or possible, were collected using National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). AEs are graded as: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE
Time Frame	Day 1 of every 2 week treatment cycle while on study treatment and 30 days after the last treatment for a maximum of 51 cycles.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: Erlotinib + Panitumumab + Irinotecan	Arm B: Erlotinib + Panitumumab	Arm C: Erlotinib + Panitumumab	Arm B Cross Over - Erlotinib + Panitumumab + Irinotecan
Arm/Group Description	Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily irinotecan hydrochloride: Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype	Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily irinotecan hydrochloride: Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype	Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily	Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily irinotecan hydrochloride: Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype After progression patients cross over to Arm A and Irinotecan is added. irinotecan hydrochloride IV over 90 minutes on day 1 or a 14 day cycle.
Measure Participants	13	10	2	3
Hemoglobin decrease	3 23.1%	1 7.7%	0 0%	0 0%
Leukocyte decrease	7 53.8%	0 0%	1 50%	0 0%
Lymphopenia	1 7.7%	0 0%	0 0%	0 0%
Neutrophil decrease	7 53.8%	0 0%	1 50%	0 0%
Fatigue	1 7.7%	1 7.7%	1 50%	0 0%
Dry skin	1 7.7%	0 0%	0 0%	0 0%
Rash/desquamation	0 0%	0 0%	1 50%	0 0%
Rash: Hand-foot skin reaction	4 30.8%	7 53.8%	2 100%	0 0%
Anorexia	1 7.7%	0 0%	0 0%	0 0%
Diarrhea	6 46.2%	0 0%	1 50%	0 0%
Nausea	1 7.7%	0 0%	1 50%	0 0%
Infection	1 7.7%	0 0%	0 0%	0 0%
Alkaline phosphatase decrease	0 0%	2 15.4%	0 0%	0 0%
Magnesium decrease	5 38.5%	4 30.8%	1 50%	0 0%
Phosphate decrease	2 15.4%	1 7.7%	3 150%	0 0%
Sodium decrease	1 7.7%	0 0%	0 0%	0 0%
Syncope/fainting	1 7.7%	0 0%	0 0%	0 0%
Pruritus/itching	0 0%	1 7.7%	0 0%	0 0%

5. Secondary Outcome

Title	Effect on Downstream Targets of Epidermal Growth Factor Receptor (EGFR) in Skin Rash Associated With Pharmacologic EGFR Inhibition
Description	Effect on downstream targets of EGFR in skin rash associated with pharmacologic EGFR inhibition. Skin biopsies will be performed at baseline (before the first days of treatment) and and at a time-point reflecting maximum rash intensity determined by a dermatologist.
Time Frame	At baseline and at a time-point reflecting maximum rash intensity during treatment, at a maximum of 51 cycles.

Outcome Measure Data

Analysis Population Description

All patient data analyzed reported together regardless of arm allocation.This outcome measure was based on optional biopsies that patients were required to consent to. Data was not collected or analyzed for this outcome measure.

Arm/Group Title	Arm A + Arm B + Arm C
Arm/Group Description	Arm A - Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Arm B - Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. Arm C - Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily Irinotecan hydrochloride: Given intravenously 120mg/m2 every 2 weeks
Measure Participants	0

6. Post-Hoc Outcome

Title	Median Overall Survival
Description	Median Overall Survival (OS) is measured from treatment initiation until death due to any cause.
Time Frame	From the time of first treatment to death

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: Erlotinib + Panitumumab + Irinotecan	Arm B: Erlotinib + Panitumumab	Arm C: Erlotinib + Panitumumab
Arm/Group Description	Arm A - Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Arm B - Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. Arm C - Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily Irinotecan hydrochloride: Given intravenously 120mg/m2 every 2 weeks	Arm B - Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily	Arm C - Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily
Measure Participants	13	13	2
Median (95% Confidence Interval) [Months]	12.6	8.6	2.4

7. Post-Hoc Outcome

Title	Progression Free Survival (PFS)
Description	Progression free survival will be measured every 8 weeks during treatment by CT or MRI scans. Progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST). Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter (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.
Time Frame	At baseline and every 8 weeks during treatment until disease progression and for a maximum of 51 cycles where 1 cycle = 2 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: Erlotinib + Panitumumab + Irinotecan	Arm B: Erlotinib + Panitumumab	Arm C: Erlotinib + Panitumumab
Arm/Group Description	Arm A - Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily Irinotecan hydrochloride: Given intravenously 120mg/m2 every 2 weeks	Arm B - Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. Arm C - Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily	Arm C - Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily
Measure Participants	12	13	2
Median (95% Confidence Interval) [Months]	4.6	3.8	2.4

Adverse Events

Time Frame	Adverse events (AE) for the study were collected over a 5 year period. AEs were collected for each patient whilst on treatment and for 30 days post last treatment for a maximum of up to 51 cycles (longest number of cycles any one patient received treatment)
Arm/Group Title	Arm A: Erlotinib + Panitumumab + Irinotecan		Arm B: Erlotinib + Panitumumab		Arm C: Erlotinib + Panitumumab		Arm B Cross Over - Erlotinib + Panitumumab + Irinotecan
Arm/Group Description	Patients receive oral erlotinib hydrochloride once daily on days 1-14, panitumumab IV over 30-90 minutes on day 1, and irinotecan hydrochloride IV over 90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily irinotecan hydrochloride: Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype		Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily irinotecan hydrochloride: Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype		Patients receive erlotinib hydrochloride and panitumumab as in arm B. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily		Patients receive oral erlotinib hydrochloride once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients receive irinotecan hydrochloride as in arm A. panitumumab: Given intravenously 6mg/kg every 2 weeks erlotinib hydrochloride: Given orally 150mg daily irinotecan hydrochloride: Given intravenously 120mg/m2 for 6/6 genotype and 60mg/m2 for 6/7 genotype After progression patients cross over to Arm A and Irinotecan is added. irinotecan hydrochloride IV over 90 minutes on day 1 or a 14 day cycle.
All Cause Mortality
	Arm A: Erlotinib + Panitumumab + Irinotecan		Arm B: Erlotinib + Panitumumab		Arm C: Erlotinib + Panitumumab		Arm B Cross Over - Erlotinib + Panitumumab + Irinotecan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/13 (84.6%)		10/10 (100%)		1/2 (50%)		3/3 (100%)
Serious Adverse Events
	Arm A: Erlotinib + Panitumumab + Irinotecan		Arm B: Erlotinib + Panitumumab		Arm C: Erlotinib + Panitumumab		Arm B Cross Over - Erlotinib + Panitumumab + Irinotecan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/13 (23.1%)		4/10 (40%)		1/2 (50%)		1/3 (33.3%)
Blood and lymphatic system disorders
Neutropenic fever	1/13 (7.7%)	1	0/10 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Gastrointestinal disorders
Diarrhea	0/13 (0%)	0	0/10 (0%)	0	0/2 (0%)	0	1/3 (33.3%)	1
Small bowel obstruction	1/13 (7.7%)	1	0/10 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Gastritis	0/13 (0%)	0	1/10 (10%)	1	0/2 (0%)	0	0/3 (0%)	0
Partial Small Bowel Obstruction	0/13 (0%)	0	1/10 (10%)	1	0/2 (0%)	0	0/3 (0%)	0
Infections and infestations
Pneumonia	0/13 (0%)	0	1/10 (10%)	1	0/2 (0%)	0	0/3 (0%)	0
Bronchitis	0/13 (0%)	0	1/10 (10%)	1	0/2 (0%)	0	0/3 (0%)	0
Investigations
Hypoglycemia	0/13 (0%)	0	1/10 (10%)	1	0/2 (0%)	0	0/3 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/13 (0%)	0	0/10 (0%)	0	1/2 (50%)	1	0/3 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Death NOS- progressive disease	1/13 (7.7%)	1	0/10 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Nervous system disorders
Altered mental status	0/13 (0%)	0	1/10 (10%)	1	0/2 (0%)	0	0/3 (0%)	0
Renal and urinary disorders
Urinary Track infection	0/13 (0%)	0	0/10 (0%)	0	1/2 (50%)	1	0/3 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A: Erlotinib + Panitumumab + Irinotecan		Arm B: Erlotinib + Panitumumab		Arm C: Erlotinib + Panitumumab		Arm B Cross Over - Erlotinib + Panitumumab + Irinotecan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		10/10 (100%)		2/2 (100%)		3/3 (100%)
Blood and lymphatic system disorders
Hemoglobin (Anemia)	9/13 (69.2%)		8/10 (80%)		1/2 (50%)		2/3 (66.7%)
Neutrophils (neutropenia)	6/13 (46.2%)		1/10 (10%)		0/2 (0%)		1/3 (33.3%)
Leukocytes (total white blood cells)	9/13 (69.2%)		1/10 (10%)		0/2 (0%)		1/3 (33.3%)
lymphopenia	6/13 (46.2%)		2/10 (20%)		0/2 (0%)		0/3 (0%)
Platelets (thrombocytopenia)	2/13 (15.4%)		1/10 (10%)		0/2 (0%)		1/3 (33.3%)
Elevated BUN	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Edema - limb	0/13 (0%)		2/10 (20%)		0/2 (0%)		0/3 (0%)
Cardiac disorders
Hypertension	4/13 (30.8%)		2/10 (20%)		0/2 (0%)		0/3 (0%)
Hypotension	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		1/3 (33.3%)
Ear and labyrinth disorders
Hearing: patients without baseline audiogram and not enrolled in a monitoring	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Otitis, external ear (non-infectious)	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Endocrine disorders
Glucose intolerance	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Eye disorders
Dry eye	2/13 (15.4%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Blurred vision	0/13 (0%)		0/10 (0%)		0/2 (0%)		1/3 (33.3%)
Eye lesion	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Eye irritation	0/13 (0%)		0/10 (0%)		1/2 (50%)		0/3 (0%)
Meibomian gland dysfunction	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Blepharitis	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Cloudy vision	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Eythema/conjunctive	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Conjunctivitis	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Gastrointestinal disorders
Anorexia	4/13 (30.8%)		1/10 (10%)		0/2 (0%)		1/3 (33.3%)
Constipation	5/13 (38.5%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Diarrhea	9/13 (69.2%)		5/10 (50%)		0/2 (0%)		3/3 (100%)
Distension/bloating of abdomen	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		1/3 (33.3%)
Mucositis/stomatitis	4/13 (30.8%)		0/10 (0%)		0/2 (0%)		1/3 (33.3%)
Heartburn (dyspepsia)	0/13 (0%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Nausea	7/13 (53.8%)		3/10 (30%)		0/2 (0%)		2/3 (66.7%)
Taste alteration (dysgeusia)	2/13 (15.4%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Vomiting	3/13 (23.1%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Retal burning	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Colon cancer with liver metastasis and likely bone metastasis	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Hemorrhoids	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
General disorders
Fatigue	8/13 (61.5%)		4/10 (40%)		0/2 (0%)		1/3 (33.3%)
Fever	3/13 (23.1%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Insomnia	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Rigors	2/13 (15.4%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Weight loss	2/13 (15.4%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Nosebleed	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Rectum pain	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Flank pain	0/13 (0%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Pain NOS	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Oral dysesthesia	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Infections and infestations
Infection in pelvis (with normal ANC or grade 1 or 2 neutrophils)	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Infection in upper airway (with normal ANC or Grade 1 or 2 neutrophils)	0/13 (0%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Infection in abdomen (with normal ANC or Grade 1 or 2 neutrophils)	0/13 (0%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Infection in urinary tract (unknown ANC)	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Paronychia (infection with grade 3 or 4 neutrophils)	0/13 (0%)		0/10 (0%)		0/2 (0%)		1/3 (33.3%)
Skin infection (Cellulitis)	0/13 (0%)		1/10 (10%)		0/2 (0%)		1/3 (33.3%)
Ear infection	2/13 (15.4%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Pseudomonas Bactermia	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Escherichia coli	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Investigations
International Normalized Ratio of prothrombin time (INR)	0/13 (0%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	8/13 (61.5%)		3/10 (30%)		0/2 (0%)		2/3 (66.7%)
Alkaline phosphatase increase	5/13 (38.5%)		6/10 (60%)		2/2 (100%)		2/3 (66.7%)
ALT increase (serum glutamic pyruvic transaminase)	5/13 (38.5%)		2/10 (20%)		1/2 (50%)		2/3 (66.7%)
AST increase (serum glutamic oxaloacetic transaminase)	8/13 (61.5%)		6/10 (60%)		2/2 (100%)		3/3 (100%)
Bilirubin increase (hyperbilirubinemia)	6/13 (46.2%)		4/10 (40%)		1/2 (50%)		2/3 (66.7%)
Creatinine increase	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Creatine phosphokinase (CPK)	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Calcium, serum high (hypercalcemia)	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Calcium, serum low (hypocalcemia)	7/13 (53.8%)		2/10 (20%)		0/2 (0%)		2/3 (66.7%)
Glucose, serum high (hyperglycemia)	7/13 (53.8%)		4/10 (40%)		0/2 (0%)		0/3 (0%)
Magnesium, serum low (hypomagnesemia)	10/13 (76.9%)		10/10 (100%)		2/2 (100%)		3/3 (100%)
Phosphate, serum low (hypophosphatemia)	6/13 (46.2%)		3/10 (30%)		0/2 (0%)		3/3 (100%)
Potassium, serum high (hyperkalemia)	1/13 (7.7%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Potassium, serum low (hypokalemia)	10/13 (76.9%)		6/10 (60%)		1/2 (50%)		3/3 (100%)
Sodium, se high (hypernatremia)	3/13 (23.1%)		3/10 (30%)		0/2 (0%)		1/3 (33.3%)
Sodium, serum low (hyponatremia)	4/13 (30.8%)		3/10 (30%)		2/2 (100%)		1/3 (33.3%)
Depression	0/13 (0%)		0/10 (0%)		0/2 (0%)		1/3 (33.3%)
Neck stiffness	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Musculoskeletal and connective tissue disorders
Muscle weakness generalized	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Muscle cramps	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Muscle spasms	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Abdomen pain	4/13 (30.8%)		4/10 (40%)		0/2 (0%)		1/3 (33.3%)
Back pain	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Extremity/limb pain	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Nervous system disorders
Sensory Neuropathy	0/13 (0%)		1/10 (10%)		1/2 (50%)		0/3 (0%)
Confusion	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Dizziness	3/13 (23.1%)		1/10 (10%)		1/2 (50%)		1/3 (33.3%)
Fainting (syncope episode)	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Renal and urinary disorders
Urine color change	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Decreased GFR	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Reproductive system and breast disorders
Erectile dysfunction	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Vaginal dryness	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Respiratory, thoracic and mediastinal disorders
Pain in throat	0/13 (0%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Cough	1/13 (7.7%)		2/10 (20%)		0/2 (0%)		1/3 (33.3%)
Dyspnea (shortness of breath)	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Hiccoughs	2/13 (15.4%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Voice changes/dysarthria	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Congestion	0/13 (0%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Wheezing	0/13 (0%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Skin and subcutaneous tissue disorders
Cheilitis	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Hair loss (alopecia)	3/13 (23.1%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Hyperpigmentation	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Nail changes	2/13 (15.4%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Pruritis	2/13 (15.4%)		2/10 (20%)		0/2 (0%)		0/3 (0%)
Acne/acneiform	9/13 (69.2%)		10/10 (100%)		1/2 (50%)		2/3 (66.7%)
Rash/desquamation	2/13 (15.4%)		1/10 (10%)		0/2 (0%)		0/3 (0%)
Rash: Hand-foot skin reaction	2/13 (15.4%)		2/10 (20%)		0/2 (0%)		0/3 (0%)
Dry skin	4/13 (30.8%)		0/10 (0%)		1/2 (50%)		0/3 (0%)
Palmar-plantar erythrodysesthesia syndrome	2/13 (15.4%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Paronychia	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Fungal infection beneath left breast	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Pseudomonas	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Extensive growth of eyelashes	1/13 (7.7%)		0/10 (0%)		0/2 (0%)		0/3 (0%)
Scalp rash	0/13 (0%)		0/10 (0%)		1/2 (50%)		0/3 (0%)
Face rash	0/13 (0%)		0/10 (0%)		1/2 (50%)		0/3 (0%)

Limitations/Caveats

Sponsor did not renew contract and only 28 patients of the anticipated 96 were enrolled and treated on the study.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.