Obatoclax mesylate, a pan-bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer.

INTRODUCTION: The proapoptotic small-molecule pan-Bcl-2 inhibitor obatoclax mesylate (GX15-070) may enhance the cytotoxicity of chemotherapy in relapsed/refractory non-small-cell lung cancer (NSCLC). METHODS: Obatoclax was administered with docetaxel in patients with relapsed or refractory NSCLC- docetaxel as a 1-hour infusion on day 1 and obatoclax as a 24-hour infusion on days 1 and 2-every 3 weeks for up to eight cycles. Four dose levels were evaluated in phase 1 (level 1: docetaxel 55 mg/m × 1 and obatoclax 30 mg × 2; levels 2-4: docetaxel 75 mg/m and obatoclax 30 mg, 45 mg, or 60 mg × 2) to identify dose-limiting toxicity and a phase 2 dose. In phase 2, response and tolerability were evaluated. RESULTS: Eighteen patients were included in phase 1. Two dose-limiting toxicities occurred during cycle 1: one febrile neutropenia each at dose levels 3 and 4. Maximum tolerated dose was not reached; 32 patients (including 3 from phase 1) were treated in phase 2 with docetaxel 75 mg/m and obatoclax 60 mg (median 2 cycles). Three patients (11%) had partial responses in phase 2; two demonstrated stable disease lasting 12 weeks or more. Median duration of response was 4.8 months. Overall, median progression-free survival was 1.4 months. Neutropenia (31%), febrile neutropenia (16%), and dyspnea (19%) were the most common grade 3/4 adverse events observed. CONCLUSIONS: Combined obatoclax mesylate plus docetaxel is tolerable in patients with NSCLC, but response was minimal and neutropenia was a common adverse event.

The significance of circulating epithelial cells in Breast Cancer patients by a novel negative selection method.

PURPOSE: A negative selection method for the enumeration and characterization of circulating epithelial/cancer cells (CCC) in Breast Cancer (BC) patients is described. This manual procedure yields reproducible results of high sensitivity and selectivity suitable for research laboratories. PATIENTS AND METHODS: We conducted a prospective blood sampling study in 105 women with stage 1-4 BC attending clinics at the University of Maryland Greenebaum Cancer Center to define the prevalence of CCC utilizing our sensitive double gradient centrifugation and magnetic cell sorting CCC detection and enumeration method. CCC were isolated and enumerated from 15 to 20 ml of venous blood drawn before the start of systemic therapy and periodically thereafter for up to 24 months. One or more CCC/sample was considered a positive result. RESULTS: We analyzed 487 samples for the presence of CCC; the median number of samples/patient was 4 (range 1-8). CCC were detected in 56% of patients, 19%-stage 1; 43%-stage 2; 46%-stage 3; 83%-stage 4. The probability of being positive for the presence of CCC is significantly associated with the stage of cancer (P < 0.0001). The frequency of CCC positive patients and samples increased with the advancing stage of disease. Presence of more than 10 CCC/sample was associated with the decreased survival and increased probability of having metastatic disease P = 0.001. CONCLUSIONS: Increasing number of CCC/sample correlates with the adverse outcome and poorer survival (P < 0.0001). Our CCC test based on the negative selection procedure may provide valuable prognostic information.

Combination nonviral interleukin 2 gene therapy and external-beam radiation therapy for head and neck cancer.

OBJECTIVES: To demonstrate that the combination of nonviral murine interleukin 2 (mIL-2) gene therapy and external-beam radiation therapy (XRT) have an enhanced therapeutic effect for the treatment of head and neck squamous cell carcinoma (HNSCC) in an orthotopic murine model and to elucidate the mechanism of action. METHODS: Randomized, controlled studies in the murine orthotopic model of HNSCC. Squamous cell carcinoma VII cells were injected into the floor of the mouth to establish tumors in immunocompetent mice. The intervention groups were treated with mIL-2, radiation therapy, empty plasmid, no treatment, combination mIL-2/XRT, and combination empty plasmid/XRT. Nonviral mIL-2 gene transfer was performed on days 5 and 9. The XRT was administered to the assigned groups 24 hours after first mIL-2 delivery. The mice were killed on day 13. Tumors and local lymph nodes were harvested and evaluated. Primary and secondary cytokine expression, cytotoxic T-lymphocyte activity, and apoptosis were assayed. RESULTS: The combination mIL-2/XRT demonstrated a significant increase in antitumor effects compared with single therapy or controls. Increased expression levels of primary and secondary cytokines were found in the group treated with mIL-2, and this effect was preserved when mIL-2 treatment was combined with XRT. Combination therapy significantly increased apoptosis compared with monotherapy. CONCLUSIONS: The present study demonstrates that combination mIL-2/XRT generates potent antitumor immune responses and significantly increases apoptosis in an orthotopic murine model of HNSCC. Further optimization of this strategy is warranted as well as consideration for human clinical trials.

Phase II study of docetaxel and topotecan combination chemotherapy in patients with advanced head and neck cancer.

PURPOSE: To evaluate the activity of combination chemotherapy with docetaxel and topotecan in patients with advanced head and neck cancer. METHODS: Docetaxel was given at 60 mg/m2 as a 60-min intravenous infusion on day 1. Topotecan at 0.75 mg/m2 per day was infused over 30 min on days 1, 2 and 3. Cycles were repeated every 21 days. RESULTS: There were no responses (CR+PR) seen in the ten patients. Only one patient had stable disease and was able to receive six cycles of chemotherapy. Median survival was 81 days (range 67-161 days). CONCLUSIONS: The combination of docetaxel and topotecan at these doses and in this schedule is not recommended for patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck. Other investigational approaches are needed.

Physical aspects of yttrium-90 microsphere therapy for nonresectable hepatic tumors.

Administration of yttrium-90 microspheres via the hepatic artery is an attractive approach to selectively deliver therapeutic doses of radiation to liver malignancies. This procedure allows delivering radiation absorbed doses in excess of 100 Gy to the tumors without significant liver toxicity. The microsphere therapy involves different specialties including medical oncology, radiation oncology, nuclear medicine, interventional radiology, medical physics, and radiation safety. We have treated 80 patients with nonresectable hepatic tumors with yttrium-90 microspheres during the past two years on an institutional study protocol. The nominal radiation absorbed dose to the tumor in this study was 150 Gy. Required activity was calculated based on the nominal radiation absorbed dose and patient's liver volume obtained from the CT scan, assuming a uniform distribution of the microspheres within the liver. Microspheres were administered via a catheter placed into the hepatic artery. The actual radiation absorbed doses to tumors and normal liver tissue were calculated retrospectively based on the patient's 99mTc-MAA study and CT scans. As expected, the activity uptake within the liver was found to be highly nonuniform and multifold tumor to nontumor uptake was observed. A partition model was used to calculate the radiation absorbed dose within each region. For a typical patient the calculated radiation absorbed doses to the tumor and liver were 402 and 118 Gy, respectively. The radiation safety procedure involves confinement of the source and proper disposal of the contaminated materials. The average exposure rates at 1 m from the patients and on contact just anterior to the liver were 6 and 135 uSv/h, respectively. The special physics and dosimetry protocol developed for this procedure is presented.

Interleukin 2 gene transfer prevents NKG2D suppression and enhances antitumor efficacy in combination with cisplatin for head and neck squamous cell cancer.

Cisplatin has been the most promising single chemotherapeutic agent usedagainst head and neck squamous cell cancer to date. However, dose-related toxicity has been one of the major limiting factors in cisplatin-based therapies, because high doses are required for obtaining a significant antitumor effect. To face the challenge of this limiting factor, a novel interleukin 2 (IL-2)-based combination strategy has been developed. Here we show that the strategy of combination of cisplatin with nonviral IL-2 gene therapy resulted in significant antitumor effects while avoiding dose-limiting toxicity in a head and neck squamous cell cancer murine model. Cisplatin systemic therapy alone suppressed NKG2D expression in lymphocytes. The use of local regional IL-2 gene transfer prevented NKG2D suppression. The combination strategy demonstrated a clear synergistic interaction between cisplatin and IL-2, and NKG2D-based cytotoxicity manifested by increased tumor specific lysis from CTLs and natural killer cells. Moreover, the combination of cisplatin and IL-2 gene therapy greatly enhanced apoptosis and growth inhibition in the treated tumors. This novel combination strategy holds promise for the treatment of head and neck cancer, and the mechanism of NKG2D in activating natural killer and CTL receptors provides a foundation for additional investigation, and development of immune modulation and chemotherapy regimens.