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Pertuzumab and Cetuximab in Treating Patients With Previously Treated Locally Advanced or Metastatic Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT00551421
Recruitment Status : Completed
First Posted : October 31, 2007
Results First Posted : February 23, 2015
Last Update Posted : March 31, 2015
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Adenocarcinoma of the Colon
Adenocarcinoma of the Rectum
Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage III Colon Cancer
Stage III Rectal Cancer
Stage IV Colon Cancer
Stage IV Rectal Cancer
Interventions Biological: pertuzumab
Biological: cetuximab
Drug: irinotecan hydrochloride
Other: immunohistochemistry staining method
Other: fluorescence in situ hybridization
Other: gene expression analysis
Other: mutation analysis
Other: polymerase chain reaction
Other: laboratory biomarker analysis
Enrollment 17
Recruitment Details 3 patients were enrolled into the original protocol between 11/07 and 05/08. 1 subject developed Grade 3 diarrhea, all 3 subjects experienced significant skin toxicity. The protocol was therefore amended to recruit cetuximab-refractory mCRC patients only. 14 patients were enrolled in this part of the study between 03/09 and 07/10 at 6 US centers.
Pre-assignment Details One patient enrolled into the amended part of the protocol withdrew consent prior to receiving any study drug.
Arm/Group Title Pertuzumab and Cetuximab
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Original Protocol, Phase I: Patients receive pertuzumab IV over 30-60 minutes on day 1 of each cycle (loading dose cycle 1 only). Patients also receive cetuximab IV over 60-120 minutes on days 2 (loading dose only), 8, and 15 of cycle 1 and on days 1, 8, and 15 in all subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Amended Protocol, Phase I: Same as Original Protocol (see above) without a loading dose of Cetuximab (maintenance dose given on cycle 1, day 2 instead).

Phase II: Patients receive treatment as in phase I. Pertuzumab is administered at the recommended phase II dose (determined in phase I).

Given IV: irinotecan hydrochloride, pertuzumab, cetuximab

Correlative Studies: laboratory biomarker analysis, gene expression analysis, fluorescence in situ hybridization, mutation analysis, polymerase chain reaction, immunohistochemistry staining method

Period Title: Original Protocol, Dose Level 1
Started 3
Completed 3 [1]
Not Completed 0
[1]
1 subject developed Grade 3 diarrhea, all 3 subjects experienced significant skin toxicity.
Period Title: Amended Protocol (Cetuximab-refr. mCRC)
Started 14
Completed 13
Not Completed 1
Reason Not Completed
Withdrawal by Subject             1
Arm/Group Title Pertuzumab and Cetuximab
Hide Arm/Group Description Phase I: Patients receive pertuzumab IV over 30-60 minutes on day 1. Patients also receive cetuximab IV over 60-120 minutes on days 2, 8, and 15 of course 1 and on days 1, 8, and 15 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Baseline Participants 17
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 17 participants
60
(46 to 73)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants
Female
9
  52.9%
Male
8
  47.1%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 17 participants
17
1.Primary Outcome
Title Recommended Phase II Dose of Pertuzumab When Administered in Combination With Cetuximab (Phase I)
Hide Description The regimen was deemed intolerable so there was no recommended phase II dose.
Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Pertuzumab and Cetuximab
Hide Arm/Group Description:

Original Protocol, Phase I: Patients receive pertuzumab IV over 30-60 minutes on day 1 of each cycle (loading dose cycle 1 only). Patients also receive cetuximab IV over 60-120 minutes on days 2 (loading dose only), 8, and 15 of cycle 1 and on days 1, 8, and 15 in all subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Amended Protocol, Phase I: Same as Original Protocol (see above) without a loading dose of Cetuximab (maintenance dose given on cycle 1, day 2 instead).

Phase II: Patients receive treatment as in phase I. Pertuzumab is administered at the recommended phase II dose (determined in phase I).

Given IV: irinotecan hydrochloride, pertuzumab, cetuximab

Correlative Studies: laboratory biomarker analysis, gene expression analysis, fluorescence in situ hybridization, mutation analysis, polymerase chain reaction, immunohistochemistry staining method

Overall Number of Participants Analyzed 14
Measure Type: Number
NA [1] 
[1]
The regimen was deemed intolerable so there was no recommended phase II dose.
2.Primary Outcome
Title Objective Tumor Response Rate Defined as the Proportion of Patients With a Best Overall Response of CR or PR, Per RECIST Criteria (Phase II)
Hide Description Objective tumor response rate defined as the proportion of patients with a best overall response of CR or PR, per RECIST criteria (Phase II).
Time Frame Best tumor response from time period of start of study treatment to study discontinuation.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm I
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Phase I: Patients receive pertuzumab IV over 30-60 minutes on day 1. Patients also receive cetuximab IV over 60-120 minutes on days 2, 8, and 15 of course 1 and on days 1, 8, and 15 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Phase II: Patients receive treatment as in phase I. Pertuzumab is administered at the recommended phase II dose (determined in phase I).

pertuzumab: Given IV

cetuximab: Given IV

irinotecan hydrochloride: Given IV

immunohistochemistry staining method: Correlative study

fluorescence in situ hybridization: Correlative study

gene expression analysis: Correlative study

mutation analysis: Correlative study

polymerase chain reaction: Correlative study

laboratory biomarker analysis: Correlative study

Overall Number of Participants Analyzed 7
Measure Type: Number
Unit of Measure: percentage of patients
Confirmed Partial Response 14
Best Response of Stable Disease 29
Best Response of Progressive Disease 57
3.Secondary Outcome
Title Progression-free Survival
Hide Description The duration of time from start of study treatment to time of objective disease progression or death.
Time Frame The duration of time from start of study treatment to time of objective disease progression or death.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm I
Hide Arm/Group Description:

Phase I: Patients receive pertuzumab IV over 30-60 minutes on day 1. Patients also receive cetuximab IV over 60-120 minutes on days 2, 8, and 15 of course 1 and on days 1, 8, and 15 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Phase II: Patients receive treatment as in phase I. Pertuzumab is administered at the recommended phase II dose (determined in phase I).

pertuzumab: Given IV

cetuximab: Given IV

irinotecan hydrochloride: Given IV

immunohistochemistry staining method: Correlative study

fluorescence in situ hybridization: Correlative study

gene expression analysis: Correlative study

mutation analysis: Correlative study

polymerase chain reaction: Correlative study

laboratory biomarker analysis: Correlative study

Overall Number of Participants Analyzed 7
Median (95% Confidence Interval)
Unit of Measure: months
2.1
(1.5 to 4.9)
4.Secondary Outcome
Title Overall Survival
Hide Description The duration of time from start of study treatment to death from any cause.
Time Frame The duration of time from start of study treatment to death from any cause.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm I
Hide Arm/Group Description:

Phase I: Patients receive pertuzumab IV over 30-60 minutes on day 1. Patients also receive cetuximab IV over 60-120 minutes on days 2, 8, and 15 of course 1 and on days 1, 8, and 15 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Phase II: Patients receive treatment as in phase I. Pertuzumab is administered at the recommended phase II dose (determined in phase I).

pertuzumab: Given IV

cetuximab: Given IV

irinotecan hydrochloride: Given IV

immunohistochemistry staining method: Correlative study

fluorescence in situ hybridization: Correlative study

gene expression analysis: Correlative study

mutation analysis: Correlative study

polymerase chain reaction: Correlative study

laboratory biomarker analysis: Correlative study

Overall Number of Participants Analyzed 7
Median (95% Confidence Interval)
Unit of Measure: months
3.7
(1.6 to 7.9)
Time Frame Adverse event information was collected between November 2007 and October 2010.
Adverse Event Reporting Description 3 patients were enrolled to Dose Level 1. 1 subject developed gr. 3 diarrhea (hospitalized), and skin toxicity was seen among the 3 subjects. The study was amended and the loading dose of cetuximab was eliminated. We report the adverse event results of the subjects enrolled on the original and the amended protocol.
 
Arm/Group Title Pertuzumab and Cetuximab
Hide Arm/Group Description

Original Protocol: Patients received pertuzumab IV over 30-60 minutes on day 1 of each cycle (loading dose on cycle 1, day 1 only). Patients also receive cetuximab IV over 60-120 minutes on days 2 (loading dose), 8, and 15 of cycle 1 and on days 1, 8, and 15 in all subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Amended Protocol, Phase I: Same as the Original Protocol (see above) except the Cetuximab loading dose was no longer given on cycle 1, day 2 (maintainance dose given).

Phase II: Patients receive treatment as in phase I. Pertuzumab is administered at the recommended phase II dose (determined in phase I).

Given IV: pertuzumab, cetuximab, irinotecan hydrochloride

Corrlateive studies: immunohistochemistry staining method, fluorescence in situ hybridization, gene expression analysis, mutation analysis, polymerase chain reaction, laboratory biomarker analysis

All-Cause Mortality
Pertuzumab and Cetuximab
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Pertuzumab and Cetuximab
Affected / at Risk (%)
Total   13/16 (81.25%) 
Cardiac disorders   
cardiac ischemia  1  1/16 (6.25%) 
troponin elevation  1  1/16 (6.25%) 
Gastrointestinal disorders   
small bowel obstruction  1  1/16 (6.25%) 
diarrhea  1  4/16 (25.00%) 
mucositis or stomatitis  1  5/16 (31.25%) 
dehydration  1  1/16 (6.25%) 
General disorders   
insomnia  1  1/16 (6.25%) 
Metabolism and nutrition disorders   
AST elevation  1  1/16 (6.25%) 
hyperbilirubinemia  1  1/16 (6.25%) 
hyperglycemia  1  1/16 (6.25%) 
hypoalbuminemia  1  1/16 (6.25%) 
hypokalemia  1  1/16 (6.25%) 
hypophosphatemia  1  1/16 (6.25%) 
Respiratory, thoracic and mediastinal disorders   
dyspnea  1  1/16 (6.25%) 
Skin and subcutaneous tissue disorders   
acneiform rash  1  1/16 (6.25%) 
dry skin  1  1/16 (6.25%) 
rash/desquamation  1  8/16 (50.00%) 
skin pain  1  3/16 (18.75%) 
hand-foot reaction  1  1/16 (6.25%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (3.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Pertuzumab and Cetuximab
Affected / at Risk (%)
Total   16/16 (100.00%) 
Blood and lymphatic system disorders   
anemia  1  9/16 (56.25%) 
leukopenia  1  2/16 (12.50%) 
lymphopenia  1  1/16 (6.25%) 
thrombocytopenia  1  1/16 (6.25%) 
hemoglobin  1  2/16 (12.50%) 
neutropenia  1  1/16 (6.25%) 
Eye disorders   
eyelid dysfunction  1  1/16 (6.25%) 
blurry vision  1  1/16 (6.25%) 
ocular (other)  1  2/16 (12.50%) 
Gastrointestinal disorders   
abdominal pain  1  6/16 (37.50%) 
anorexia  1  7/16 (43.75%) 
constipation  1  1/16 (6.25%) 
dehydration  1  2/16 (12.50%) 
diarrhea  1  6/16 (37.50%) 
distension/bloating  1  1/16 (6.25%) 
dyspepsia  1  1/16 (6.25%) 
esophagitis  1  1/16 (6.25%) 
mucositis or stomatitis  1  5/16 (31.25%) 
nausea  1  8/16 (50.00%) 
vomiting  1  4/16 (25.00%) 
gastrointestinal (other)  1  1/16 (6.25%) 
General disorders   
fatigue  1  13/16 (81.25%) 
fever without neutropenia  1  2/16 (12.50%) 
insomnia  1  2/16 (12.50%) 
rigors/chills  1  3/16 (18.75%) 
weight loss  1  2/16 (12.50%) 
weakness (non-neuropathic)  1  1/16 (6.25%) 
epistaxis  1  3/16 (18.75%) 
voice changes/dysarthria  1  1/16 (6.25%) 
Infections and infestations   
urinary tract  1  1/16 (6.25%) 
colitis - infectious  1  1/16 (6.25%) 
infection (other)  1  1/16 (6.25%) 
Metabolism and nutrition disorders   
ALT elevation  1  2/16 (12.50%) 
AST elevation  1  5/16 (31.25%) 
alkaline phosphatase elevation  1  6/16 (37.50%) 
hepatic (other)  1  1/16 (6.25%) 
hyperbilirubinemia  1  1/16 (6.25%) 
hyperglycemia  1  6/16 (37.50%) 
hyperkalemia  1  1/16 (6.25%) 
hypoalbuminemia  1  7/16 (43.75%) 
hypocalcemia  1  4/16 (25.00%) 
hypokalemia  1  4/16 (25.00%) 
hypomagnesemia  1  7/16 (43.75%) 
hyponatremia  1  4/16 (25.00%) 
hypophosphatemia  1  4/16 (25.00%) 
INR elevation  1  1/16 (6.25%) 
PTT prolongation  1  1/16 (6.25%) 
metabolic/lab (other)  1  1/16 (6.25%) 
Musculoskeletal and connective tissue disorders   
back pain  1  1/16 (6.25%) 
Nervous system disorders   
neuropathy (sensory)  1  3/16 (18.75%) 
neurologic (other)  1  1/16 (6.25%) 
Psychiatric disorders   
depression  1  1/16 (6.25%) 
Renal and urinary disorders   
incontinence - urinary  1  1/16 (6.25%) 
proteinuria  1  1/16 (6.25%) 
Reproductive system and breast disorders   
vaginal discharge  1  1/16 (6.25%) 
Respiratory, thoracic and mediastinal disorders   
dyspnea  1  1/16 (6.25%) 
Skin and subcutaneous tissue disorders   
acneiform rash  1  4/16 (25.00%) 
dry skin  1  2/16 (12.50%) 
edema of head and neck  1  2/16 (12.50%) 
edema of limb  1  3/16 (18.75%) 
edema trunk/genital  1  1/16 (6.25%) 
erythema multiforme  1  3/16 (18.75%) 
lymphedema  1  1/16 (6.25%) 
nail changes  1  4/16 (25.00%) 
other  1  1/16 (6.25%) 
pruritis  1  7/16 (43.75%) 
rash/desquamation  1  5/16 (31.25%) 
skin (other)  1  1/16 (6.25%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (3.0)
Combination intolerable due to overlapping toxicities of diarrhea, rash and mucositis; a unique rash with desquamation seen in most patients across all dose levels. Correlative study inconclusive with too few patients and timepoints with results.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
Results Point of Contact
Name/Title: Dr. Kimmie Ng
Organization: Dana-Farber Cancer Institute
Phone: 617-632-4150
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00551421     History of Changes
Other Study ID Numbers: NCI-2009-00241
07-070
U01CA062490 ( U.S. NIH Grant/Contract )
First Submitted: October 30, 2007
First Posted: October 31, 2007
Results First Submitted: December 17, 2014
Results First Posted: February 23, 2015
Last Update Posted: March 31, 2015