Irinotecan Cetuximab

Parameter Week 3 (cetuximab alone) Week 4 (cetuximab+irinotecan) Week 4 as % of week 3a ... 

Upon disease progression following standard initial therapy, appropriate treatment options may include oxaliplatin plus fluorouracil and leucovorin, irinotecan plus cetuximab, cetuximab, irinotecan, continuous-infusion fluorouracil, capecitabine plus irinotecan or... 

Note that application in the particular indications is usually restricted either to patients expressing the target (e.g. trastuzumab, cetuximab, lapatinib, imatinib) and/or after failure of prior therapies (e.g. cetuximab, erlotinib, lapatinib, sutinib, dasatinib). Furthermore, for cancer treatment most tyrosine kinase inhibitors are applied in combination with conventional chemotherapeutic drugs, such as fluorouracil, taxanes, platin-based regimens, anthracylines and irinotecan or radiotherapy. 

Cetuximab plus irinotecan Continue irinotecan as previously dosed, plus cetuximab 400 mg/m2 IV loading dose, then cetuximab 250 mg/m2 Asthenia, diarrhea, nausea, acneiform rash,... 

Cetuximab, either alone or in combination with irinotecan, can be used in patients with disease progression on irinotecan. Cetuximab monotherapy can also be considered as salvage therapy in patients with oxaliplatin-refractory disease. 

Patients should be closely monitored for side effects that require aggressive intervention such as irinotecan-induced diarrhea and bevacizumab-induced GI perforation. Patients should be evaluated for other treatment-specific side effects such as oxaliplatin-induced neuropathy, cetuximab and panitumumab-induced skin rash, and bevacizumab-induced hypertension and proteinuria. 

Cetuximab is a chimeric monoclonal antibody, against epidermal growth factor receptor (EGFR). It is given by intravenous injection with weekly intervals for the treatment of metastatic colorectal cancer and head and neck cancer. It is given in combination with the chemotherapeutic agent irinotecan. The... 

Cetuximab has modest activity in relapsed colorectal cancer as a single agent but is more effective with irinotecan and possibly oxaliplatin based regimens where a doubling of the response rate has been observed. There is some evidence that cetuximab may reverse irinotecan resistance. Toxic effects of cetuximab include hypersensitivity reactions, malaise, nausea, headache and an acneiform rash. 

Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A et al. Cetuximab monotherapy or cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004 351 337-45. 

Cetuximab is used for treatment of metastatic colorectal carcinoma, which expresses EGFR, in combination with irinotecan, provided that these patients are refractory to irinotecan-based standard chemotherapeutic regimen. However, in patients who could not tolerate irinotecan-based chemotherapeutic regimen, it is used as a single treatment for EGFR-expressing metastatic colorectal cancer. The doses are similar to the doses used for squamous cell carcinoma of the head and neck. 

Bevacizumab, a humanized IgG and cetuximab, a chimeric IgGx, are currently marketed in the US for treatment of metastatic colorectal cancer [92, 93]. Bevacizumab neutralizes the biological activity of vascular endothelial growth factor (VEGF), while cetuximab binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Bevacizumab, in combination with IV 5-fluorouracil (5-FU) -based chemotherapy, is indicated for first-line treatment of metastatic colorectal cancer, whereas cetuximab is used in patients refractory to or intolerant to irinotecan-based chemotherapy. The clinical pharmacokinetics of cetuximab are discussed in detail in Chapter 14. 

Currently, cetuximab (Erbitux ) is indicated for the treatment of patients with EGFR-expressing metastatic colorectal cancer after failure of irinotecan-including cytotoxic therapy. Depending on the country, cetuximab is approved in combination with irinotecan or in addition as monotherapy. The approved dosing regimen consists of an initial dose of 400 mg/m2 body surface area (BSA), followed by weekly doses of 250 mg/m2. The (intravenous IV) infusion durations are 2 h for the initial infusion, and 1 h for the subsequent weekly infusions. 

First approval worldwide was granted for cetuximab in Switzerland in December 2003 for the combination therapy with irinotecan. Subsequently, approvals were granted in the US (mono- and combination therapy) and all 25 membership... 

The PK of cetuximab were investigated after single IV doses ranging from 5 to 500 mg/m2. PK data obtained after administration of cetuximab monotherapy were available from 82 patients in five of the dose-escalation studies, and from 214 patients in four of the studies with the approved dosing regimen. In two studies, cetuximab was administered both as a monotherapy and in combination with irinotecan single- as well as multiple-dose cetuximab concentration data were available from 300 patients in these two studies. 

In 10 studies the corresponding clinical study protocol stipulated that cetuximab was to be given in combination with a chemotherapeutic agent (irinotecan, paclitaxel, gemcitabine, cisplatin, carboplatin, or doxorubicin) or in combination with radiation therapy. 

The main PK parameters for irinotecan are summarized in Table 14.5. The PK parameters for irinotecan at week 1 were similar to those at week 4, suggesting the absence of a PK interaction with cetuximab. For the metabolite SN-38 the measured concentrations were in good agreement with those cited in the literature [27] however, the number of samples with quantifiable concentrations was not sufficient to allow a meaningful analysis. 

Table 14.5 Pharmacokinetic parameters of irinotecan before and after cetuximab co-administration.

The main PK parameters for cetuximab are summarized in Table 14.6. The PK parameters for cetuximab in week 3 were similar to those in week 4, suggesting the absence of a PK interaction with irinotecan. 

The possible impact of co-administered chemotherapies and radiation therapy on the PK of cetuximab was furthermore assessed using the population PK approach, as described in Section 14.6. The co-administered chemotherapies included cisplatin, carboplatin, paclitaxel, doxorubicin, irinotecan, and gemcitabine. The results of the analysis indicate that neither the co-administered chemotherapies nor radiation therapy had a significant impact on the PK of cetuximab. This finding suggests that the potential for PK-based drug-drug interactions with cetuximab is low. 

Table 14.6 Pharmacokinetic parameters of cetuximab before and after irinotecan co-administration.

C. Verslype, I. Chau, and E. van Cutsem. 2004. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refrac-tory metastatic colorectal cancer. N. Engl. 

A. Kovar, and E. Raymond. 2005. Pharmacokinetic profile of cetuximab (Erbitux ) alone and in combination with irinotecan in patients with advanced EGFR-positive adenocarcinoma. Eur. J. Cancer 41 1739-1745. 

Cyclophosphamide <1,500 mj nrr Daunorubicin Doxorubicin Epirubicin Idarubicin Ifosfamide Irinotecan Oxaliplalin Bortezomib Cetuximab Cytarabine <1 g/m ... 

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