Capecitabine and Temozolomide for Neuroendocrine Cancers
Condition: Neuroendocrine Tumors
MeSH terms: Neuroendocrine Tumors; Carcinoma, Neuroendocrine
Study type: Interventional
Phase: Phase 2

Summary: 
      This phase II study is designed to assess whether treatment with capecitabine/temozolomide
      (CAP/TEM) is safe and effective in treating subjects with progressive, differentiated,
      metastatic neuroendocrine tumors (NET). The primary objective of the study is to determine
      the radiologic response rate to this regimen in progressive, metastatic, differentiated
      neuroendocrine cancers.
    

Detailed description: 
      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 the lab, the investigators have found that capecitabine (5-DFUR), an oral pro-drug for
      5-fluorouracil (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 it was
      found to be important for the synergism that temozolomide be exposed to the NET cell lines
      during the end of the capecitabine exposure. The team believes 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
      temozolomide-alkylated 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.
      The investigators found that cells with prior 5-FU exposure were more sensitive to the
      induction of apoptosis by temozolomide.

      Another fundamental rationale and hypothesis which the investigators 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. The investigators believe that the hypothesis is correct
      and well grounded in pharmacologic and cell cycle principles.

      The investigators 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, the study seeks to evaluate the role of these two drugs in this disease.
    

Intervention name(s): Capecitabine; Temozolomide
Intervention type(s): Drug; Drug
Intervention description(s): Capecitabine 1500 mg/m2/day (PO divided BID) with a maximum daily dose of 2500mg Two week treatment regimen followed by two weeks off treatment, repeated for 12 cycles
After patients have completed 12 cycles with no signs of progression of disease, radiologic evaluation (CT or MRI) will be done after three cycles. This will result in two 28 day cycles and one 35 day cycle.; Temozolomide 150-200 mg/m2/day (PO divided BID).
Two week treatment regimen followed by two weeks off treatment, repeated for 12 cycles
After patients have completed 12 cycles with no signs of progression of disease, radiologic evaluation (CT or MRI) will be done after three cycles. This will result in two 28 day cycles and one 35 day cycle.
Other intervention name(s): Xeloda; Temodar
Intervention MeSH terms: Capecitabine; Temozolomide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Pancreatic cancer; Neuroendocrine tumors; Carcinoid tumors; Pheochromocytomas; Gastrinomas; Zollinger-Ellison syndrome; MEN Type I/II; Somatostatinomas; VIPomas; Merkel cell tumors; medullary thyroid carcinoma