Lapatinib (Tykerb, GlaxoSmithKline) is a dual inhibitor of tyrosine kinase, which activates HER-2 and the epidermal growth factor receptor (EGF-R). A prospective study in patients with newly diagnosed inflammatory, the most aggressive form of invasive breast cancer, was conducted to evaluate the efficacy and safety of lapatinib combined with paclitaxel (Taxol, Bristol-Myers Squibb) as neoadjuvant therapy.

The multicenter, international clinical trial included patients who had not received prior exposure to chemotherapy. Two cohorts were treated; Cohort A patients exhibited over-expression (level 2 to 3+) or amplification of HER-2, and patients in Cohort B had overexpression of EGF-R alone.

Treatment consisted of oral lapatinib monotherapy (1,500 mg/daily for 14 days), followed by lapatinib plus weekly paclitaxel 80 mg/m2 for 12 doses. Clinical responses were assessed by combined digital photography and imaging.
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At the completion of neoadjuvant treatment, patients underwent mastectomy. A pathological complete response was defined as the disappearance of invasive breast disease and of the local marker in the axillary nodes.

Data for 35 patients are available. The median age was 53 years (range, 31 to 75 years), and 26% had metastatic disease at the initial diagnosis. Negative hormone-receptor status was demonstrated in 77% of cases. Thirty patients demonstrated HER-2 overexpression and achieved a clinical objective response in 77% of cases. Eighteen patients underwent surgery, and pathological complete responses were observed for three of these patients (17%). It is interesting that in 10 patients (30%), a clinical response was already demonstrated after lapat-inib monotherapy.

Among the five patients with EGF-R overexpression, four achieved objective remission, but none had a pathological complete response. Toxicity was manageable and consisted mainly of diarrhea and other gastrointestinal symptoms, fatigue, and rash. In almost all cases, the investigators also observed overexpression of the protein p53 (a tumor suppressor); E-cadherin (a protein found in epithelial tissue); and Rho-C (ras homolog gene family member C), which regulates cell movement. cialis canadian pharmacy

In summary, lapatinib showed promising clinical activity alone and in combination with paclitaxel when used as neo-adjuvant therapy for patients with inflammatory breast cancer and HER-2 overexpression. Future studies are planned with la-patinib in combination with anthracyclines.

Chemotherapy and Sorafenib (Nexavar) For Melanoma Patients With and without Brain Metastases

Despite decades of clinical trials, the median survival of melanoma patients without brain metastases remains at eight months; for patients with brain metastases, median survival is three months. No standard of care has been established for the treatment of these patients.

Results of recently completed and ongoing clinical trials have been reviewed. The trials were designed to test the effects of combining chemotherapy and sorafenib (Nexavar, Bayer/ Onyx), an oral Raf kinase/VEGF-R2 inhibitor. (On November 19, sorafenib was also approved for the treatment of unresectable hepatic cancer.)

A phase 2 four-arm trial was conducted to evaluate sorafenib plus the oral alkylating agent temozolomide (Temodar, Scher-ing) in patients with metastatic melanoma. The primary objective was to measure the rate of six-month progression-free survival. Secondary objectives were to determine response rates, toxicity rates, and optimal dosing for temozolomide.

Correlative studies included B-Raf genotyping. The study accrued its target of 167 patients in one stage. All patients received oral sorafenib 400 mg twice daily.

After one week of sorafenib therapy alone, patients without brain metastases or without a prior temozolomide regimen were randomly assigned to receive either extended dosing with temozolomide 75 mg/m2 once daily for six or eight weeks (Arm A) or standard dosing with temozolomide 150 mg/m2 once daily for days one to five for 28 weeks (Arm B).

Patients who had been treated with temozolomide earlier received extended dosing with temozolomide (Arm C).

Patients with brain metastases who had not received temo-zolomide earlier received standard dosing (Arm D).

An analysis of 152 patients indicated that the six-month progression-free survival rates were 50% for patients in Arm A, 40% in Arm B, 11% in Arm C, and 26% in Arm D.

For patients in Arm A and Arm B, sorafenib/temozolomide resulted in a 19% overall response rate (95% CI, 11, 30). In this group, four of 78 patients (5%) developed metastases of the central nervous system during the study.

The overall response rate for patients in Arm C was 0%.

The overall response rate for those in Arm D was 17% (95% CI, 7, 34).

Common grade 3 toxicities were hand-foot syndrome, rash, nausea, and diarrhea. Grade 3 lymphopenia was more common in Arm A (in 43%) than in Arm B (16%) (P = 0.01). No significant difference in progression-free survival was observed between patients with the wild-type and those with the mutant B-Raf genotype (n = 33).

Thus, sorafenib/temozolomide was a tolerable regimen in patients with metastatic melanoma with and without brain metastases. This combination deserves further study in a randomized controlled trial.
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IRX-2: A Novel Immunotherapy for Head and Neck Cancer

Head and neck squamous cell cancer represents a complex, heterogeneous group of neoplasms associated with profound immune suppression. Most patients present with advanced disease, for which survival rates are poor. There have been few improvements in treatment over the last 25 years. Treatment is traditionally based on stage of disease and tumor location, and it involves a combination of surgery, radiotherapy, and chemotherapy. In recent years, neoadjuvant lym-phokine immunotherapy approaches have shown promise and may represent an effective fourth treatment modality.

IRX-2 (IRX Therapeutics) is a biologic product containing naturally derived human cytokines that act on multiple cell types. It is a potent stimulant of the TH1 (T-helper cell) specific cellular immune response and of the dendritic cells. When delivered to regional lymph nodes at very low doses before surgery, IRX-2 produces low toxicity and impressive T-cell infiltration to produce tumor regression and histological tumor fragmentation in patients with advanced cancers.

IRX-2 is part of a treatment regimen that includes contra-suppression (blocking the tumor’s ability to suppress the immune system) by using low-dose cyclophosphamide with in-domethacin (e.g., Indocin) and zinc. Low-dose cyclophosphamide inhibits the immunosuppressive activity of T-regulatory cells. Indomethacin suppresses the production of prostaglandin E2 activity, which inhibits cytotoxic T-cells and is thought to contribute to the immunosuppressive tumor environment. Zinc is used as an immunorestorative agent, because low concentrations of this element have been documented in patients with head and neck cancer. Zinc is also crucial for cellular immunity.

In phase 1 and 2 trials at Mexico’s National Cancer Institute (INCAN), IRX-2 demonstrated an excellent safety profile and displayed significant activity in stimulating T-cell-associated tumor rejection. IRX-2 demonstrated an improved survival compared with concurrent nonrandomized INCAN control patients matched according to site and stage. Using Kaplan-Meier survival estimates, the researchers found that IRX-2 patients experienced statistically significant four-year overall survival (61%), compared with a rate of 32% for controls. suhagra

A multicenter phase 2 study is ongoing in the U.S., and similar histological responses are being observed. A randomized phase 2 trial of 450 patients is being planned at more than 75 sites worldwide for 2008.