Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma. Patients had ECOG performance status 0–2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m−2 of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations. Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m−2, and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response. The recommended phase II dose is dasatinib70 mg b.i.d with dacarbazine 800 mg m−2. PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.

BACKGROUND Docosahexaenoic acid-paclitaxel (DHA-paclitaxel, Taxoprexin(®)) is made by covalently conjugating the essential fatty acid DHA to the paclitaxel molecule. Preclinical studies of DHA-paclitaxel have demonstrated increased activity relative to paclitaxel and the potential for an improved therapeutic ratio. In the present study, the efficacy and toxicity profiles of DHA-paclitaxel were compared with those of dacarbazine. METHODS In this study, 393 chemonaive patients with metastatic melanoma were randomly assigned to receive either DHA-paclitaxel at a starting dose of 900 mg/m(2) IV on day 1 every 3 weeks or dacarbazine at a starting dose of 1000 mg/m(2) IV on day 1 every 3 weeks. The primary end point of the study was the comparison of overall survival (OS). RESULTS No significant difference in OS was noted between patients in the DHA-paclitaxel and dacarbazine arms. Similarly, there were no significant differences in response rate, duration of response, time to progression, and time to treatment failure between the two drugs. Safety results of the two drugs were as predicted from prior studies. Myelosuppression was more common with DHA-paclitaxel. CONCLUSIONS DHA-paclitaxel was not superior to dacarbazine. We conclude that further studies with the drug on an every 3-week schedule in melanoma are not warranted.

Sagopilone is a novel fully synthetic epothilone with promising preclinical activity and a favourable toxicity profile in phase I testing. A phase II pharmacokinetic and efficacy trial was conducted in patients with metastatic melanoma. Patients had measurable disease, Eastern Cooperative Oncology Group performance status 0–2, adequate haematological, and organ function, with up to 2 previous chemotherapy and any previous immunotherapy regimens. Sagopilone, 16 mg m−2, was administered intravenously over 3 h every 21 days until progression or unacceptable toxicity. Thirty-five patients were treated. Sagopilone showed multi-exponential kinetics with a mean terminal half-life of 64 h and a volume of distribution of 4361 l m−2 indicating extensive tissue/tubulin binding. Only grade 2 or lower toxicity was observed: these included sensory neuropathy (66%), leukopenia (46%), fatigue (34%), and neutropenia (31%). The objective response rate was 11.4% (one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response). Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%). Sagopilone was well tolerated with mild haematological toxicity and sensory neuropathy. Unlike other epothilones, it shows activity against melanoma even in pretreated patients. Further clinical testing is warranted.

High-dose pegylated interferon α-2b (peginterferon α-2b) significantly decreased disease recurrence in patients with resected stage III melanoma in a clinical study. We investigated the pharmacokinetics (PK) and safety of high-dose peginterferon α-2b in patients with high-risk melanoma.

9031 Background: Sagopilone (ZK-Epothilone) is a novel, fully synthetic epothilone with promising preclinical activity in several cancer models. This phase II study aims to define the efficacy and safety of sagopilone in patients with metastatic melanoma, as well as perform pharmacokinetic evaluation of this dose and schedule. Methods: Patients with unresectable stage III or IV malignant melanoma, with up to 2 prior chemotherapy and any prior immunotherapy regimens with measurable disease were eligible. Sagopilone was administered at 16 mg/m2 as a 3-hour IV infusion every 21 days. The primary end point of the trial was response rate, and secondary endpoints included time to progression, overall survival, and tolerability. Pharmacokinetic analysis was done on the first 10 patients. A total of 37 patients were to be accrued to have 33 evaluable patients. The trial had a 0.90 power and assumed α of 0.03. Results: Thirty four patients have been enrolled to date. Sagopilone appears to be well tolerated: The most common side effects seen have been sensory neuropathy, (55%, 19/34, 5 Grade 2, 14Grade 1) motor neuropathy (23%, 8/34, All Grade 1); anemia (26 %, 9/34) neutropenia (14%, 5/34 1 Grade 2, 4 Grade 1) thrombocytopenia (14%, 5/34) and fatigue (38%, 13/34). Two patients have shown grade 3 events (syncope and mental status changes, respectively, possibly related to therapy), both of which resolved and an additional patient had a pulmonary embolism which was considered unlikely to be related to therapy. Responses have been seen in 4 patients (3 RECIST confirmed PR, 1 unconfirmed PR). Stable disease was seen for at least 12 weeks in an additional 10 patients for a clinical benefit rate (CR+PR+SD) of 44%. No grade 4 events have been reported. Conclusions: Unlike the epothilone analogs patupilone or ixabepilone, sagopilone appears to be an active drug in advanced melanoma. The side effect profile seen to date at 16 mg/m2 given over 3 hours repeated every 3 weeks appears to be notably free of myelosuppression indicating that it could be combined with other drugs active in melanoma. Pharmacokinetic studies show a prolonged terminal half life, probably due to release from deep tissue compartments. [Table: see text]

6051 Background: Salvage re-irradiation (ReRT) is a treatment option for squamous cell carcinoma of the head and neck (SCHN) that recurs in a previously irradiated area. ReRT, though toxic, can produce long-term survival, even when tumor is unresectable or poor prognostic feature is present after salvage surgery. The degree to which patient co-morbidities serve as a predictor of survival following re-RT has not been studied to date. Methods: Patients (pts) with SCHN who underwent ReRT with an overlapping target to previous RT during 1998–2007 at our institution were eligible. Co-morbidity burden was assessed by Charlson Index (CI), measuring frequency of co- morbid diseases as score 2–27, and Adult Comorbidity Evaluation-27 (ACE-27), measuring frequency & severity of co-morbid diseases as score 0–3. Results: 69 total pts, including 25 who had salvage surgery, had a median age of 62 yrs. Most common site was oropharynx (48%). Median time since previous RT was 35 mos. Of 41 pts with measurable disease, median tumor bulk was 3 cms. ReRT was delivered at a median of 60 Gy. IMRT/3-D RT was used in 51%; Concurrent chemotherapy, in 78%. Median survival (MS) was 18.3 mos (95% CI 14–30); PFS 13.4 mos. Comorbidity burden by CI showed that 58% of pts had a score >2 (i.e. had ≥1 comorbid disease other than the current cancer). By ACE-27, 20% of pts had a score of 2 or 3 (mod or severe decompensation). Higher co-morbidity scores predicted worse survival. By CI, MS was 30 mos if score ≤2 vs. 14 mos if score >2 (p=0.003). By ACE-27, MS was 19 mos if score 0–1 vs. 12 mos if score 2 or 3 (p=0.004). Using Cox model, this remained significant after adjusting for ReRT dose and tumor bulk, which were also survival predictors (p=0.007, 0.001). Time from previous RT, new primary, IMRT/3-D RT, or salvage surgery were not significant predictors. Grade ≥3 toxicities were 36% at baseline & 68% at follow-ups (dysphagia most common). Late toxicities including trismus, fistula, and soft tissue necrosis occurred in 7, 2, and 4 pts. Conclusions: Co-morbidity burden is a strong, independent predictor of survival among selected pts undergoing salvage ReRT. This information, along with other prognostic factors, may help refine patient selection and improve future treatment outcome. No significant financial relationships to disclose.

9046 Background: Sagopilone is a novel, fully synthetic epothilone that has shown promising preclinical activity in many tumor models, including those with taxane resistance, and in melanoma xenografts. This Phase II study aims to define the efficacy and safety of sagopilone in patients with metastatic melanoma, as well as perform pharmacokinetic evaluation of this dose and schedule. Methods: Patients with histologically confirmed unresectable Stage III or IV malignant melanoma, with ≤2 prior cytotoxic chemotherapy regimens with measurable disease were eligible. Sagopilone was administered at 16 mg/m2 as a 3-hour IV infusion every 21 days. The primary end point of the trial was response rate, and secondary endpoints included time to progression, overall survival, and tolerability. Pharmacokinetic analysis was done on the first 10 patients. Results: Twenty patients (14 male and 6 female) have been enrolled from May to December 2007, and efficacy and safety data are currently available for 14 patients. Accrual continues to a goal of 33 patients. Major Grade 1 and 2 toxicities to date have been anemia (n=6), fatigue (n=8), neutropenia (n=4), thrombocytopenia (n=3), and neuropathy (n=11). Of the patients experiencing neuropathy, 10 were grade 1 and 1 was grade 2. Only 2 patients have shown grade 3 events (hypotension and pneumonia, respectively), both of which resolved. There were no grade 4 events. Objective responses by RECIST criteria have been seen in 2 patients (confirmed partial response) and 4 patients currently show stable disease as their best response. Both responders had previously failed cytotoxic chemotherapy, one having received DTIC and the other having received Temozolomide. Ten patients withdrew from the study (9 due to disease progression, and 1 due to reasons unrelated to the study). Conclusion: Sagopilone is well tolerated, and is active even in patients who have failed prior chemotherapy. Responses have been seen in sites such as the liver, which are not typically seen with other cytotoxic chemotherapy. Detailed pharmacokinetic data was also obtained for this dose and schedule. Even though accrual continues, we have already seen confirmed responses (2/14) and stable disease (4/14) in patients who have progressed on prior cytotoxics. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Bayer

Purpose To determine the response rate, survival and toxicity of infusional cisplatin plus fluorouracil (CF) versus cisplatin plus paclitaxel (CP) in patients with incurable squamous cell cancer of the head and neck, with the hypothesis that CP is superior. Patients and Methods Two hundred eighteen patients with locally advanced, recurrent, or metastatic disease were randomly assigned to CF (cisplatin 100 mg/m2 day 1 and fluorouracil 1,000 mg/m2/24 hours by continuous intravenous infusion day 1 through 4) or CP (cisplatin 75 mg/m2 day 1 and paclitaxel 175 mg/m2 over 3 hours on day 1). Cycles were repeated every 3 weeks until progression or a minimum of 6 cycles with complete response or stable disease. The primary outcome was overall survival. Secondary outcomes included response rate and toxicity. Results No significant difference in overall survival or response rate was seen. Estimated median survival was 8.7 months in the CF group and 8.1 month in the CP group. Objective response rate (complete response plus partial response) was 27% in the CF group and 26% in the CP group. Toxicity was similar between groups, with the most frequent including myelosuppression, thrombocytopenia, anemia, nausea, vomiting, and stomatitis. A total of 12 deaths occurred (CF, seven; CP, five) during treatment; eight from infection, two from hemorrhage, one from cardiac causes and one from unknown causes. Gastrointestinal and hematologic toxicities were more common in the CF group, whereas neurotoxicity was equivalent between groups. Conclusion This phase III, randomized, multicenter trial showed no difference in survival between patients treated with CF or CP.

Purpose: A phase II trial of the novel camptothecin karenitecin (BNP1350) was conducted to determine its efficacy and tolerability in patients with metastatic melanoma. Patients were biopsied to determine topoisomerase expression at baseline and response to therapy. Patients and Methods: Eligible patients had metastatic melanoma with up to three prior chemotherapy and/or any number of immunotherapy regimens. Treatment consisted of an i.v. infusion of 1 mg/m2 karenitecin daily for 5 days with cycles repeated every 3 weeks. Fine-needle aspiration biopsies were done before treatment and on day 3 to determine topoisomerase expression from patients' tumors. Results: Forty-three patients were evaluable for response and toxicity. Most patients (72%) had stage M1C disease and were previously exposed to chemotherapy (56%). The investigational agent was well tolerated with limited gastrointestinal side effects or fatigue. The major toxicity seen was reversible noncumulative myelosuppression. One patient had a complete response after 11 months of therapy. No partial responses were seen, but 33% of the patients had disease stabilization lasting ≥3 months. Topoisomerase I, IIα, and IIβ expression and localization were determined in a subset of patients. Topoisomerase I expression was highest, followed by topoisomerase IIβ and topoisomerase IIα. Conclusion: Karenitecin was a well-tolerated investigational agent in this phase II study; side effects were generally mild and mostly hematologic. Karenitecin has significant activity in metastatic melanoma. Melanoma metastases express high levels of topoisomerase I. We did not observe any compensatory increase in topoisomerase II upon treatment with karenitecin.

7514 Introduction: While the mechanism of action of Interferon α-2b (IFNα) in melanoma is not clear, IFNα receptors are known to signal through the \(\underline{\mathrm{Ja}}\)nus \(\underline{\mathrm{K}}\)inase (JAK) - \(\underline{\mathrm{S}}\)ignal \(\underline{\mathrm{T}}\)ransducers and \(\underline{\mathrm{A}}\)ctivators of \(\underline{\mathrm{T}}\)ransduction (STAT) pathway in melanoma cell lines. STAT 3 has been implicated as a tumor promoter and STAT 1 as a growth suppressor in some preclinical studies. We examined the expression of STAT proteins and IFN receptors in human melanocytic neoplasms by immunohistochemistry Methods: Compound Nevi (6), dysplastic nevi (4), congenital nevi (2), primary melanoma (14) and melanoma metastatic to the (40) sentinel lymph node (SLN) were examined. All patients with SLN mets were treated with standard IFN. All specimens were evaluated for activated or phospho-Stat 1 (p-STAT-1), phospho-Stat 3 (p-STAT-3), and IFN receptor by immunohistochemistry. Staining was scored from 1–3 based on % of tumor cells staining and intensity of stained cells. The recurrence history of patients with SLN metastasis was determined using the Moffitt melanoma database. Results: Only 1/6 compound nevi, 0/4 dysplastic nevi and 0/2 congenital nevi expressed p-STAT-3 while 6/14 primary melanomas had p-STAT-3. A total of 28/40 SLN metastases had evaluable and stainable tumor. Of these 15/28 had high-level expression of p-STAT 3 but only 4/28 had activated p-STAT-1 expression. Most tumors (18/22) expressed IFN receptors. 12/28 patients have recurred to date. Patients who recurred were more likely to express high levels of activated STAT 3 (70% expressed 3+ p-STAT-3) than those who did not recur (30% expressed 3+ p-STAT-3). Conclusion: p-STAT-3 expression was infrequent in normal melanocytes or benign (8%) lesions but more frequent in cutaneous melanoma (42%) and SLN mets (53%) .IFN receptor was expressed in 81% of SLN melanoma mets. Increased p-Stat-3 and decreased p-STAT-1 were positively correlated with recurrence. IFN receptor expression was not correlated to recurrence in this small sample but all components of the IFN-JAK-STAT pathway are present in human melanoma No significant financial relationships to disclose.

PURPOSE:To determine dose-response effects and the activity of paclitaxel combined with cisplatin in patients with incurable squamous cell carcinoma of the head and neck.PATIENTS AND METHODS:Two hundred ten patients with locally advanced, recurrent, or metastatic disease were randomly placed in either Arm A, paclitaxel 200 mg/m(2) (24-hour infusion) + cisplatin 75mg/m(2) + granulocyte colony-stimulating factor, or Arm B, paclitaxel 135 mg/m(2) (24-hour infusion) + cisplatin 75 mg/m(2). Cycles were repeated every 3 weeks until progression or a total of 12 cycles for complete responses. Primary outcomes were event-free and overall survival.RESULTS:No significant differences in outcomes were observed between the high- and low-dose paclitaxel regimens. The estimated median survival was 7.3 months (95% confidence interval, 6.0 to 8.6). The 1-year survival rate was 29%, and event-free survival was 4.0 months. The objective response rate (complete response plus partial response) was 35% for the high-dose patients and 36% for the low-dose patients. Myelosuppression was the most frequent toxicity: grade 3 or 4 granulocytopenia, 70% of patients in Arm A and 78% in Arm B; febrile neutropenia, 27% of patients in Arm A and 39% in Arm B. Grade 5 toxicities occurred in 22 patients (10.5%). Treatment was terminated early in 31% because of excessive toxicity or patient refusal.CONCLUSION:This phase III multicenter trial showed (1) no advantage for high-dose paclitaxel and (2) excessive hematologic toxicity associated with both regimens. Therefore, neither of the paclitaxel regimens evaluated in this trial can be recommended.

BACKGROUND. Electrochemotherapy (ECT) is performed by locally administering a chemotherapeutic agent in combination with electric pulses. Previous clinical studies have demonstrated the effectiveness of ECT. In these initial trials, the drug was administered intravenously, followed by administration of electric pulses directly to the tumor. This study was initiated to determine whether an intralesional injection of the drug in combination with electric pulses could provide an improved result. A group of 34 patients was studied.METHODS. The dose of intralesional bleomycin was based on tumor volume. This was followed 10 minutes later by 6 or 8 99-mu sec pulses of electricity at an amplitude of 1.3 kV/cm. Both the bleomycin and the electric pulses were administered after 1% lidocaine with ephinephrine solution was injected around the treatment site.RESULTS. Ail patients responded to the treatment. Responses were observed in 142 (99%) of 143 metastatic nodules or primary tumors within 12 weeks, with complete responses observed in 130 (91%) of the nodules, No complete responses were observed in nodules treated with bleomycin only or electric pulses only. Random biopsies confirmed the clinical findings. All patients tolerated the procedure well, and no significant side effects were noted. Muscle contraction was evident during administration of each electric pulse but promptly subsided after the pulse.CONCLUSIONS. ECT was shown to be an effective local treatment for cutaneous malignancies. The results suggest that ECT may have a tissue-sparing effect and result in minimal scarring. ECT may be a suitable alternative therapy for the treatment of basal cell carcinoma, local or regional recurrent melanoma, and other skin cancers. (C) 1998 American Cancer Society.

A number of single agents have been tested in patients with carcinoma of the head and neck receiving palliative treatment. In general, 15‐30% of patients achieve a partial response lasting 3‐4 months. Treatment has not been shown to alter survival rates. It is clear that new drugs with potentially greater activity need to be identified. For this purpose, the Eastern Cooperative Oncology Group conducted a Phase II evaluation of paclitaxel.

We conducted a multiinstitutional phase II clinical trial to determine the toxicity, response, and survival rate of concurrent 72-h continuous infusion of etoposide and cisplatin in patients with metastatic breast cancer. A total of 26 women were enrolled, 4 of whom received no prior chemotherapy for metastatic disease. All patients were evaluated for toxicity, response, and survival employing the National Cancer Institute (NCI) Common Toxicity Criteria and the Eastern Cooperative Oncology Group (ECOG) response criteria. A total of 84 cycles of therapy were administered, median 3 (range 1 to 6). Severe grade 3 and grade 4 neutropenia occurred in 22 cycles (26%), and there were only 11 episodes (11%) of similar grade thrombocytopenia. Nausea and vomiting were seen in one third of cycles. A single patient (4%) had a complete remission, and seven patients (27%) had partial remissions for an overall objective response rate of 31% (95% confidence interval, 13 to 49%). Three of four patients (75%) without prior therapy for metastatic disease had objective responses. Median survival was 7 months. This combination regimen is active in extensively treated patients with metastatic breast cancer. It is responsible to further investigate the role of etoposide-cisplatin combination chemotherapy as firstline therapy for patients with metastatic breast cancer.

Electroporation is a process that causes a transient increase in the permeability of cell membranes. It can be used to increase the intracellular concentration of chemotherapeutic agents in tumor cells (electrochemotherapy; ECT). A clinical study was initiated to determine if this mode of treatment would be effective against certain primary and metastatic cutaneous malignancies. A group of six patients, three with malignant melanoma, two with basal cell carcinoma, and one with metastatic adenocarcinoma, were enrolled in the study. The treatment was administered in a two‐step process.

In a randomized multi-center study, 83 patients with small cell lung cancer were randomly assigned to treatment with cisplatin 100 mg/m2 intravenously (IV) day 1 and etoposide 120 mg/m2 IV days 1, 2, and 3 or cisplatin 100 mg/m2 IV day 1 and etoposide 120 mg/m2 IV day 1 and 240 mg/m2 orally days 2 and 3. Both regimens were repeated every 4 weeks. Prior to randomization, patients were stratified by extent of disease, performance status, and gender. A total of 41 patients were randomly assigned to the parenteral treatment only regimen, and 42 patients received cisplatin and IV/oral etoposide therapy. Both treatment arms were comparable regarding patient characteristics. Limited disease (LD) patients constituted 52% and 49% of the patient population for the oral and IV etoposide regimens, respectively. The overall complete response (CR) and partial response (PR) rate was 50% (95% confidence interval [CI] 35% to 65%) for the oral etoposide regimen and 59% (95% CI 44% to 74%) for the IV etoposide regimen (P = 0.438). For both regimens, 55% of the LD patients achieved either CR or PR. Time to progression and survival were comparable for both treatment arms. Hematologic toxicity was comparable in both treatment arms, with 80% of patients experiencing grade 3 or 4 neutropenia or thrombocytopenia. Moderate to severe anemia and weight loss were more predominant with the IV than with the oral regimen.

Thirty-seven of 54 human squamous head and neck carcinomas were successfully grown as first transplant generation xenografts under the kidney capsule of conventional mice immunosuppressed by daily treatment with 60 mg/kg of cyclosporine. Of the 18 different tumors evaluated for chemosensitivity, 39% responded to cis-platinum, 19% to 5-fluorouracil, 33% to methotrexate, and 40% to Cis-Pt/5Fu. In comparing the assay results in nine patients who received the same chemotherapeutic drugs, two of three patients responded to their drug with xenograft shrinkage noted, whereas four of six patients who did not respond had tumor growth in the mouse. It is hoped that this model will become useful for new drug testing and, in certain cases, for selection of chemotherapy for patients with refractory tumors.