Trial Information

Phase II Study of Capecitabine and Temozolomide for Progressive, Differentiated, Metastatic Neuroendocrine Cancers

Neuroendocrine tumor (NET) is a classification that has evolved over time to include a group
of related tumors which all originate from neuroendocrine cells. This group includes
carcinoid tumors, pancreatic endocrine tumors (PETs), catecholamine-secreting tumors (e.g.
pheochromocytomas), medullary carcinoma of the thyroid and small cell lung cancer. Carcinoid
tumors are mostly derived from serotonin-producing enterochromaffin cells, occuring most
frequently in the gastrointestinal tract (67.5%) and the bronchopulmonary system (25.3%).
Pancreatic endocrine tumors (PETs) arise from the several types of pancreatic islet cells,
which manifest as insulinomas, somatostatinomas or glucagonomas. NETs are broadly classified
as functional or nonfunctional, as determined by whether plasma hormone elevation and
endocrine symptoms occur. NETs are classified into two groups: 1) rapidly growing anaplastic
small cell cancers such as small cell lung cancer and small cell carcinomas of the GI tract
and 2) slow growing, more differentiated NETs such as carcinoid and PET.

In total, an estimated 12,000 - 15,000 cases of NETs (not counting small cell carcinomas)
are diagnosed in the United States annually. The incidence of carcinoid tumors alone is
estimated to be 2 per 100,000 in the United States (5,400 cases/yr/U.S.). PETs are less
common, with about 1,000 new cases per year in the United States. Carcinoids and PETs are
potentially curable by surgical resection; the 5-year survival rates in patients with
localized carcinoid is 78.2%. However, these tumors are frequently indolent in their growth
and patients often present with unresectable or metastatic disease (80% of all cases). The
hormonal symptoms that may accompany their disease, as exemplified by carcinoid syndrome,
complicate the management of these patients. Hormonal therapy, namely octreotide, is used to
relieve symptoms and has been reported to have a response rate of 1-5% by itself. Metastatic
disease is associated with significantly worse prognosis; carcinoid patients with visceral
metastases have a 5-year survival rate of 38.5%. Based on the efficacy of the combination of
cisplatin and etoposide in treating small cell lung cancer, these agents have been explored
in the treatment of pancreatic islet cell tumors and carcinoids. In general,
etoposide-cisplatin regimens have poor response rates for the slow growing, differentiated
NET group with an average response rate of 7-10%. Furthermore, these cisplatin-etoposide
regimens have been associated with significant toxicities, including frequent severe
neutropenia, ototoxicity, neurotoxicity and nephrotoxicity.

An Eastern Cooperative Oncology Group (ECOG) trial of patients with metastatic or
unresectable progressive pancreatic islet cell tumors, including poorly and
well-differentiated PETs, showed that a regimen of streptozocin and doxorubicin had a
significantly superior objective response rate compared to a combination of streptozocin and
fluorouracil (69 versus 45%, p=0.05). The study used a definition for objective response
that included regression of the tumor mass, regression of malignant tumor causing
hepatomegaly or a reduction in excessive hormone production. Streptozocin-doxorubicin was
also significantly superior to streptozocin-fluorouracil in terms of median time to tumor
progression and of median overall survival (2.2 versus 1.4 years, p=0.004). However,
significant toxicity was associated with either streptozocin-based regimen with roughly 80%
in either arm experiencing vomiting that lasted throughout the 5-day course of streptozocin
per cycle. Additionally, Grade 3/4 leukopenia occurred in 25% of patients who received
streptozocin-fluorouracil, with one treatment-related death secondary to leukopenia
complicated by sepsis. Notably, streptozocin has significant renal toxicity causing
significant proteinuria. Thus, the doubtful efficacy of streptozocin-based combinations and
the significant associated toxicity has limited the role of cytotoxic chemotherapy in the
treatment of differentiated NETs.

In our lab, we have found that capecitabine (5-DFUR), an oral pro-drug for 5-FU, and
temozolomide were synergistic for induction of apoptosis in 2 human NET cell lines. The
mechanism and pathways involved are under investigation, but we found it was important for
the synergism that temozolomide be exposed to the NET cell lines during the end of the
capecitabine exposure. We believe that the combination of temozolomide and capecitabine will
prove to be an effective regimen. Our hypothesis is that the DNA damage induced by
capecitabine by incorporation of 5-FdUTP into DNA and reducing thymidine pools by inhibition
of thymidylate synthase via 5-FdUMP will synergistically potentiate the effect of
temozolomide as an alkylator by reducing the repair activity of
O6-alkylguanyl-alkyl-transferase (O6-AGAT). O6-AGAT is a DNA repair enzyme which removes
temozolomidealkylated groups from guanine. A 5-day regimen of temozolomide is vital to
decreasing O6-AGAT levels by direct binding which leads to a suicide inactivation of
O6-AGAT-mediated DNA repair. This saturates O6-AGAT after 23 days of temozolomide, thus
allowing the last 23 days of dosing to induce alkylation of DNA and thereby induce
apoptosis. We found that cells with prior 5-FU exposure were more sensitive to the induction
of apoptosis by temozolomide.

Another fundamental rationale and hypothesis which we have developed into the synthesis of a
novel regimen for NET is based upon cytokinetics and p53. NET are characteristically very
slow growing, yet fatal, cancers with the great majority of them having wild type p53.
Therefore, their drug resistance is probably not based upon mutational p53 causes because of
the wild type p53 status but rather upon their slow cytokinetics. The best way to kill slow
growing tumors with a long interval in G0 phase is with lipophilic alkylators (i.e. Temodar)
and utilizing continuous exposure to antimetabolites such as Xeloda or continuous infusion
5-FU. Xeloda's half-life is 11 hrs so q 12 hr dosing is roughly equivalent to continuous
infusion. We believe our hypothesis is correct and well grounded in pharmacologic and cell
cycle principles.

We have to date pilot experience of ten patients who received capecitabine, total of 1500
mg/m2/day/PO, for fourteen days, with temozolomide 150-200 mg/m2 given on the last five days
of their course of capecitabine. All of our initial 10 patients with progressive,
differentiated NET have had dramatic symptomatic pain relief and at least 75% reduction in
their tumor markers. Five patients had metastatic carcinoid and 5 had metastatic pancreatic
NET. All patients had progressive liver metastases, all 10 patients had failed octreotide
therapy with long acting somatostatin, and 7/10 had failed prior chemotherapy regimens. One
carcinoid patient had a complete response (CR) proven by surgery and is now without any
tumor recurrence 22 months out from surgery and chemotherapy. Three patients had a partial
response (PR) and one patient had a minor response (MR) in their liver metastases. Two other
patients experienced stable disease (SD) for 6 and 8 months while on therapy. The overall
response rate proven by CT or MRI scans (CR, PR and MR) is 50% to date. Overall, clinical
benefit of this lab based regimen occurred in 7/10 patients (CR, PR, MR and SD). Toxicities
have all been minor with none over grade 2 myelosuppression. There were no hospitalizations
or complications or side effects except grade 12 nausea during temozolomide therapy.
Therefore, we wish to begin a formal protocol evaluating the role of these two drugs in this
disease.