1. Case study-erbitux
Name:eman abd elraouf ahmed
Immunology department
Medical research institute

2. 1-Cetuximab Rechallenge Study
Purpose:To determine the objective overall response of
re-treatment with cetuximab-based chemotherapy in
patients upon disease progression while under
observation, who had previously responded to first-line
or second-line treatment with cetuximab-based
chemotherapy for metastatic colorectal cancer (mCRC),
but had stopped treatment for reasons other than
disease progression.

3. Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Case-control Study of Second or Third
Line Treatment With Cetuximab-containing Chemotherapy in
Patients With Metastatic Colorectal Cancer Who Were
Previously Treated With Cetuximab-based Chemotherapy

4. Primary Outcome Measures:overall response of re-treatment with cetuximab-•
based chemotherapy [ Time Frame: 2 years ] [ Designated as safety issue: No ]in
patients experiencing disease progression while under observation, who had
previously responded to first-line or second-line treatment with cetuximab-based
chemotherapy for metastatic colorectal cancer (mCRC), but had stopped treatment
for reasons other than disease progression.
Secondary Outcome Measures:Adverst event and toxicity during treatment period
[ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
disease control rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
progression-free survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]

5. Experimental: cetuximab-containing chemotherapyCetuximab may be given
at either one of the following schedules at the investigator's discretion:
2-weekly: Cetuximab is started on day 1 of each cycle of chemotherapy, at
500mg/m2 every 2 weeks over 120/90/60minutes.
Weekly: Cetuximab may be given at a loading dose of 400mg/m2 on day
1over 120 minutes, followed by weekly dosing at 250mg/m2 on day 1, over
60 minutes of each cycle of chemotherapy.

6. Chemotherapy: Only one of the following regimens may be
combined with cetuximab at the investigator's discretion
according to institutional standard. Some recommended
regimens used in Hong Kong.
Regimens to be combined with biweekly cetuximab:
Irinotecan at 2-weekly schedule.
FOLFIRI (as inpatient or via ambulatory pump).
FOLFOX (as inpatient or via ambulatory pump).

7. Eligibility
18 Years and older Ages Eligible for Study:
Both Genders Eligible for Study:
No Accepts Healthy Volunteers

8. Criteria
Inclusion Criteria:
Age 18 years or older.
Able to give written informed consent.
Histologically confirmed colorectal adenocarcinoma: must be either metastatic disease
or unresectable recurrent disease.
KRAS mutation status of the primary or metastastic CRC tumor must be wild-type.
ECOG performance status of 0-1 at study entry.
Must have measurable disease by RECIST (ver 1.1) criteria.
Have progressive disease based on all of the following criteria (from a-d):
(a) Previously received cetuximab-based chemotherapy as first- or second-line
treatment for metastatic or recurrent disease with, any one of the following drug
combinations: (i) Cetuximab, fluoropyrimidines and oxaliplatin; or, (ii) Cetuximab,
fluoropyrimidines and irinotecan; or (iii) Cetuximab and irinotecan. (b) Must have
achieved at least stable disease, partial or complete response to treatment stated in
'(a)' above.

9. (c) Experienced disease progression after more than 60 days
from the last date of administration of the treatment stated in
'(a)' above.
(d) 'Disease progression' can be defined as radiological or clinical
progression.
Adequate hematologic, renal, hepatic function as defined by:
absolute neutrophil count >= 1.5 x 109/L, hemoglobin >= 9 g/L,
platelets >= 100 x 109/L, calculated creatinine clearance >=55
ml/min, total bilirubin <= 2 x the upper limit of normal (ULN),
alanine aminotransferase (ALT) <2.5 upper limit of normal or <=
5 x ULN in the presence of liver metastases.
Must have recovered to grade 0-1 in severity, any toxicity related
to previous cetuximab.

10. Exclusion Criteria:
Disease progression during first-line or second-line treatment with cetuximab and chemotherapy
in combination.
Patients who had prior cetuximab in BOTH first and second-line setting.
Previous use of bevacizumab.
Prior grade 3 to 4 hypersensitivity reaction to cetuximab.
Clinically significant and poorly controlled medical illnesses within the last 6 months which may
be exacerbated by study treatment.
Estimated life expectancy of less than 3 months.
Radiotherapy, surgery (excluding prior diagnostic biopsy) or any investigational drug in the 30
days before enrollment. Radiotherapy for pain relief is allowed as long as not targeted at an index
or non-index lesion, e.g., bone metastases.
Known brain and/or leptomeningeal metastases.
Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable
angina pectoris, history of myocardial infarction within the last twelve months, significant
arrhythmias
Pregnancy or lactation
Previous malignancy other than colorectal cancer in the last 5 years except basal cell cancer of
the skin or preinvasive cancer of the cervix. The non-CRC malignancy must be in known complete
remission for at least 5 years prior to enrollment.
The presence of KRAS mutation in any of the CRC tumor tissue(s) - for example, patients with
synchronous primary CRCs with different KRAS mutation status.
Participants with reproductive potential who are unwilling to perform effective contraception.

11. Cetuximab in the treatment of metastatic mucoepidermoid carcinoma
of the salivary glands: A case report and review of literature
Introduction
Salivary gland carcinomas (SGC) are rare neoplasms that account for less than 1% of all
human cancers. Among SGCs, the mucoepidermoid carcinoma (MEC) is the most
common primary neoplasm, representing approximately 30% of salivary malignancies.
MEC is histologically characterized by a heterogeneous cellular composition, including
squamoid (epidermoid), mucus producing and intermediate cells. The tumor grade is
defined according to five histological features (the cystic component, neural invasion,
necrosis, number of mitoses and anaplasia) and is important in classifying low,
intermediate and high grade neoplasms.

12. High-grade MEC is an aggressive disease with a 5-year survival rate of 25 to
30%. Although the disease is often localized at presentation and rarely
presents with metastases, MEC tends to recur locally and to metastasize. The
initial treatment of MEC, regardless of grade, is essentially based on surgical
resection and eventually on adjuvant radiotherapy. Due to the rarity of the
disease, current literature is scarce and often reflects data from small and
heterogeneous series. Thus, no guidelines are available to support the
clinician's decision and the management of metastatic MEC remains
challenging. Local recurrences not amenable to further loco-regional
treatments and metastatic disease are treated with systemic chemotherapy.
Single-agent or combination chemotherapy with cisplatin, fluorouracil and/or
paclitaxel has demonstrated activity in published series but overall response
rates are unsatisfactory and of short duration

13. Overexpression of the human epidermal growth factor receptor (HER) family
of oncoproteins, HER1/epidermal growth factor receptor (EGFR) and HER2,
has been described in approximately 70% of salivary gland carcinomas
including MEC and adenoid cystic carcinoma but few studies have evaluated
the therapeutic relevance of an anti-EGFR/HER2 strategy in these neoplasms.
Here we report the case of a metastatic MEC of the major salivary glands that
was refractory to platinum-containing regimens and was treated with the
anti-EGFR monoclonal antibody cetuximab in combination with
chemotherapy.

14. Case presentation
In January 2006, a 40-year-old Caucasian man underwent a non
radical resection of a high-grade MEC of the right submandibular
salivary gland at another institution. Post-operative radiotherapy
was not advised, and three months later, the disease progressed
locally and in the cervical lymph nodes. At our institution, he was
then treated with three cycles of the paclitaxel, cisplatin,
fluorouracil (TPF) regimen; however, the disease progressed
systemically with diffuse subcutaneous neoplastic infiltrates. He
therefore received a second line chemotherapy with carboplatin
and vinorelbine, but further progression occurred after two
cycles. The total body [18F]fluorodeoxyglucose (FDG) positron
emission tomography (PET) with fusion of CT-scan imaging (CT-PET)
documented the onset of mediastinal adenopathies, pleural
effusion and multiple bone lesions

15. Total body computed tomography-positron emission tomography with
[18F]fluorodeoxyglucose before (left panel) and after (right panel)
treatment. Metabolically active neoplastic disease is located by high
standardized uptake value of tracer: maximum standardized uptake value
values are reported for each lesion before and after treatment.
Grisanti et al. Journal of Medical Case Reports 2008 2:320 doi:10.1186/1752-
1947-2-320

16. Immunohistochemical analysis of the primary tumor specimen showed an
intense and diffuse staining for EGFR. Cytogenetic fluorescence in situ
hybridization (FISH) analysis for the EGFR gene was negative for gene
amplification but demonstrated polysomy of the chromosome 7p12 (CEP7)
with an average of five copies (range 3–7) of chromosome 7 per cell. Analysis
of EGFR activating mutations was not performed. The patient was then
treated with cetuximab (Erbitux®, Merck KGaA, Darmstadt, Germany),
administered iv at a loading dose of 400 mg/m2 over 2 hours and then at 250
mg/m2 weekly in combination with cisplatin (100 mg/m2) every 21 days as
described by Herbst et al. After the second cycle, a minor response was
documented clinically and by CT-PET, along with the onset of a WHO grade 2
classic anti-EGFR-dependent acneiform rash; the patient continued treatment
with four complete cycles of cisplatin and 11 doses of cetuximab. He also
experienced WHO grade 1 paresthesias of the extremities and mild renal
function impairment. Both these side effects were attributed to cisplatin.

17. In September 2006, during the treatment, the patient
experienced recurrent convulsive seizures that required
hospitalization. Neurologic examination was normal. An EEG
showed a diffuse slowing of background activity. Rare and brief
sequences of slow waves were recorded on the central regions,
bilaterally. A brain CT-scan demonstrated the presence of at least
five bilobar, parenchymal, metastatic lesions (Figure 2). Total-body
CT-PET documented a partial response (PR > 50%) of all the
evaluable extracranial metastatic lesions (Figure 1). Response
was assessed according to the RECIST criteria for radiological CT
imaging and to the 1999 EORTC recommendations for the use of
[18F]fluorodeoxyglucose PET.

18. Contrast enhancement (white arrows) in brain computed tomography
scan showing synchronous multiple metastases during cetuximab
treatment.
Grisanti et al. Journal of Medical Case
Reports 2008 2:320 doi:10.1186/1752-1947-2-320
The patient received palliative whole brain irradiation up to 30 Gy with a
daily 3 Gy fractionation and was then returned to supportive care.

19. Discussion
The epidermal growth factor receptor (EGFR) signalling pathway is
involved in the physiological cell differentiation of secretory acinus
and related ducts, the functional unit of salivary glands.
Immunohistochemical studies demonstrated different degrees of
EGFR expression in several salivary gland carcinomas, including
MECs and adenoid cystic carcinomas (ACCs). In MECs, the
percentage of membrane staining of EGFR is approximately 77%
which is higher than in normal tissue.

20. EGFR overexpression is related to a poorer prognosis and a more aggressive
behaviour of the disease but its overall prognostic value has not been
completely established
Thus, the development of anti-HER2 or anti-EGFR strategies in salivary gland
carcinomas could represent a reasonable approach based on a biological
rationale. In head and neck squamous cell carcinoma (HNSCC), the anti-EGFR
monoclonal antibody cetuximab has been proven to prolong overall survival
and to enhance response rates in recurrent/metastatic disease in
combination with cisplatin or fluorouracil in combination with radiotherapy
Whether cetuximab can overcome platinum resistance in cisplatin-pretreated
patients remains controversial Among predictive factors of
response to anti-EGFR strategies in HNSCC, EGFR gene amplification status is
predictive of sensitivity to the EGFR-tyrosine kinase inhibitor, gefitinib
On the other hand, no activating mutations in the EGFR gene are associated
with response to anti-EGFR strategies.

21. To date, only a few, small clinical trials have investigated the antitumor
activity of anti-EGFR targeted agents in the salivary gland neoplasms. In a
phase II study of cetuximab monotherapy in 22 patients with
recurrent/metastatic salivary gland carcinomas, including two MECs, 11
patients had stable disease, seven of which remained progression-free for
over 6 months. None of these patients displayed EGFR amplification or
chromosome 7 polysomy .In a recent phase II study of lapatinib, a dual
inhibitor of EGFR and HER2, in recurrent/metastatic salivary gland
carcinomas, including two MECs, Agulnik et al. demonstrated disease
stabilization that lasted for more than 6 months in 36% of the patients; no
objective responses were observed. None of the patients in the cohort with
disease stabilization, however, were patients with MEC

22. In our report, the patient was pretreated with two lines of platinum-containing
chemotherapy with no evidence of response; a response was only
observed upon treatment with cisplatin along with cetuximab. We do not
know whether the response was due to cetuximab alone or due to a
synergistic effect with the restoration of cisplatin sensitivity. The chromosome
7 polysomy, documented in the patient, may account for increased protein
expression at the membrane level and clinical response. However, a clear
genotype/phenotype correlation cannot be established on the basis of only
this data. Finally, a mixed pattern of central nervous system (CNS) progression
and systemic response was concomitantly observed in our patient. Such an
effect is often seen in metastatic breast cancer patients treated with
trastuzumab who develop CNS metastases while responding at different
metastatic sites. The creation of a CNS sanctuary for cancer cells results from
the inability of trastuzumab to cross the blood-brain barrier due to its
relatively high molecular weight; this mechanism presumably also applies to
cetuximab in different neoplastic conditions, as our case demonstrates.

23. Conclusion
In conclusion, this case report indicates cetuximab function in a
recurrent and metastatic MEC of the salivary glands. EGFR expression
is a prerequisite for cetuximab use but EGFR gene amplification, or at
least chromosome 7 polysomy, seems to be necessary for elicitation of
biological activity. Our findings also emphasize the importance of CT-PET
in monitoring neoplastic diseases during molecular targeted
therapies. The inability of cetuximab to cross the blood-brain barrier
and the consequent development of CNS metastases during treatment
is a subject of concern that requires further study.

24. ERBITUX® Phase III Study Meets Primary Endpoint In First-Line Treatment of
Metastatic Colorectal Cancer
ImClone Systems Incorporated (NASDAQ: IMCL) and Bristol-Myers Squibb Company
(NYSE: BMY) today announced that a Phase III study of ERBITUX® (cetuximab) plus
FOLFIRI (an irinotecan- based chemotherapy) met the primary endpoint of increasing
median duration of progression-free survival over FOLFIRI alone in patients with
previously untreated metastatic colorectal cancer (mCRC). More than 1,000 patients
were recruited from around the world to participate in the study, known as the CRYSTAL1
study.
"Despite advancements, metastatic disease remains difficult to treat. This study
demonstrates the potential benefit of adding ERBITUX to first-line treatment of
metastatic colorectal cancer," said Eric Rowinsky, M.D., Chief Medical Officer and Senior
Vice President of ImClone Systems.
"These results provide important new information for patients with metastatic colorectal
cancer, and are part of a comprehensive clinical development program designed to fully
understand the potential uses of ERBITUX for cancer patients," said Martin Birkhofer,
M.D., Vice President, Oncology Global Medical Affairs, Bristol-Myers Squibb.
The study was conducted by Merck KGaA, Darmstadt, Germany, ImClone Systems'
ERBITUX partner outside of North America. Results have been submitted for presentation
at the 2007 American Society of Clinical Oncology Annual Meeting in Chicago in June.

25. About ERBITUX® (Cetuximab)
ERBITUX is a monoclonal antibody (IgG1 Mab) designed to inhibit the function of a molecular
structure expressed on the surface of normal and tumor cells called the epidermal growth factor
receptor (EGFR, HER1, c-ErbB-1). In vitro assays and in vivo animal studies have shown that
binding of ERBITUX to the EGFR blocks phosphorylation and activation of receptor-associated
kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix
metalloproteinase and vascular endothelial growth factor production. In vitro, ERBITUX can
mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types.
While the mechanism of ERBITUX' anti-tumor effect(s) in vivo is unknown, all of these processes
may contribute to the overall therapeutic effect of ERBITUX. EGFR is part of a signaling pathway
that is linked to the growth and development of many human cancers, including those of the
head and neck, colon and rectum.
ERBITUX (Cetuximab), in combination with radiation therapy, is indicated for the treatment of
locally or regionally advanced squamous cell carcinoma of the head and neck. ERBITUX as a single
agent is indicated for the treatment of patients with recurrent or metastatic squamous cell
carcinoma of the head and neck for whom prior platinum-based therapy has failed.
ERBITUX is indicated for the treatment of EGFR-expressing, metastatic colorectal carcinoma
(mCRC) in combination with irinotecan for patients who are refractory to irinotecan-based
chemotherapy, and as a single agent for patients who are intolerant to irinotecan-based therapy.
The effectiveness of ERBITUX for the treatment of EGFR-expressing mCRC cancer is based on
objective response rates. Currently, no data are available that demonstrate an improvement in
disease-related symptoms or increased survival with ERBITUX for the treatment of EGFR-expressing
mCRC.

26. Grade 3/4 infusion reactions, rarely with fatal outcome (<1 in 1000), occurred in
approximately 3% (46/1485) of patients receiving ERBITUX (Cetuximab) therapy. These
reactions are characterized by rapid onset of airway obstruction (bronchospasm,
stridor, hoarseness), urticaria, hypotension, and/or cardiac arrest. Severe infusion
reactions require immediate and permanent discontinuation of ERBITUX therapy.
Most reactions (90%) were associated with the first infusion of ERBITUX despite the
use of prophylactic antihistamines. Caution must be exercised with every ERBITUX
infusion as there were patients who experienced their first severe infusion reaction
during later infusions. A 1-hour observation period is recommended following the
ERBITUX infusion. Longer observation periods may be required in patients who
experience infusion reactions.
Cardiopulmonary arrest and/or sudden death occurred in 2% (4/208) of patients with
squamous cell carcinoma of the head and neck treated with radiation therapy and
ERBITUX as compared to none of 212 patients treated with radiation therapy alone.
Fatal events occurred within 1 to 43 days after the last ERBITUX treatment. ERBITUX in
combination with radiation therapy should be used with caution in patients with
known coronary artery disease, congestive heart failure and arrhythmias. Close
monitoring of serum electrolytes, including serum magnesium, potassium, and
calcium during and after ERBITUX therapy is recommended.

27. Severe cases of interstitial lung disease (ILD), which was fatal in one case, occurred in
less than 0.5% of 774 patients with advanced colorectal cancer (mCRC) receiving
ERBITUX. There was one case of ILD reported in 796 patients with head and neck
cancer receiving ERBITUX in clinical studies.
In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin
drying and fissuring, and inflammatory and infectious sequelae (eg, blepharitis,
cheilitis, cellulitis, cyst) were reported. In 208 patients receiving ERBITUX + RT,
acneform rash was reported in 87% (17% severe) as compared to 10% in 212 patients
treated with radiation therapy alone (1% severe). In patients receiving ERBITUX alone,
76% (N=103) experienced acneform rash (1% severe). In patients with mCRC,
acneform rash was reported in 89% (686/774) of all treated patients, and was severe
in 11% (84/774). Subsequent to the development of severe dermatologic toxicities,
complications including S. aureus sepsis and abscesses requiring incision and drainage
were reported. Sun exposure may exacerbate these effects. A related nail disorder,
occurring in 12% (0.4% Grade 3) of patients, was characterized as a paronychial
inflammation.

28. The safety of ERBITUX in combination with radiation therapy and cisplatin has not
been established. Death and serious cardiotoxicity were observed in a single-am trial
with ERBITUX, delayed, accelerated (concomitant boost) fractionation radiation
therapy, and cisplatin (100 mg/m2) conducted in patients with locally advanced
squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a
result of pneumonia and one of an unknown cause. Four patients discontinued
treatment due to adverse events. Two of these discontinuations were due to cardiac
events (myocardial infarction in one patient and arrhythmia, diminished cardiac
output, and hypotension in the other patient).
The incidence of hypomagnesemia (both overall and severe [NCI CTC Grades 3 & 4])
was increased in patients receiving ERBITUX alone or in combination with
chemotherapy as compared to those receiving best supportive care or chemotherapy
alone based on ongoing, controlled clinical trials in 244 patients. Approximately one-half
of these patients receiving ERBITUX experienced hypomagnesemia and 10-15%
experienced severe hypomagnesemia. Electrolyte repletion was necessary in some
patients and in severe cases, intravenous replacement was required. Patients receiving
ERBITUX therapy should be periodically monitored for hypomagnesemia, and
accompanying hypocalcemia and hypokalemia during, and up to 8 weeks following the
completion of, ERBITUX therapy.

29. The most serious adverse reactions associated with ERBITUX in combination with
radiation therapy in 208 patients with head and neck cancer were infusion reaction
(3%), cardiopulmonary arrest (2%), dermatologic toxicity (2.5%), mucositis (6%),
radiation dermatitis (3%), confusion (2%), and diarrhea (2%).
The most serious adverse reactions associated with ERBITUX in mCRC clinical trials
(N=774) were infusion reaction (3%), dermatologic toxicity (1%), interstitial lung
disease (0.4%), fever (5%), sepsis (3%), kidney failure (2%), pulmonary embolus (1%),
dehydration (5% in patients receiving ERBITUX with irinotecan, 2% in patients
receiving ERBITUX as a single agent) and diarrhea (6% in patients receiving ERBITUX
with irinotecan, 0.2% in patients receiving ERBITUX as a single agent).
The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX
in combination with radiation therapy compared with radiation therapy alone. The
following sites were affected: salivary glands (65%/56%), larynx (52%/36%),
subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus
(44%/35%), skin (42%/33%), brain (11%/9%), lung (11%/8%), spinal cord (4%/3%), and
bone (4%/5%) in the ERBITUX and radiation versus radiation alone arms, respectively.
The incidence of Grade 3 or 4 late radiation toxicities were generally similar between
the radiation therapy alone and the ERBITUX plus radiation therapy arms.

30. The most common adverse events seen in patients with carcinomas of the head and
neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation
alone (n=212) were mucositis-stomatitis (93%/94%), acneform rash (87%/10%),
radiation dermatitis (86%/90%), weight loss (84%/72%), xerostomia (72%/71%),
dysphagia (65%/63%), asthenia (56%/49%), nausea (49%/37%), constipation
(35%/30%) and vomiting (29%/23%). The most common adverse events seen in
patients with carcinomas of the head and neck receiving ERBITUX as a single agent
(N=103) were acneform rash (76%), asthenia (45%), pain (28%), fever (27%) and
weight loss (27%).
The most common adverse events seen in patients with mCRC receiving ERBITUX with
irinotecan (n=354) or ERBITUX as a single agent (n=420) were acneform rash
(88%/90%), asthenia/malaise (73%/48%), diarrhea (72%/25%), nausea (55%/29%),
abdominal pain (45%/26%), vomiting (41%/25%), fever (34%/27%), constipation
(30%/26%), and headache (14%/26%).

31. References:
http://www.jmedicalcasereports.com/content/2/1/320