Phase II trial of 13-cis-retinoic acid plus interferon-α in recurrent head and neck cancer

13-cis-retinoic acid (isotretinoin) and interferon- have limited activity as single agents in advanced cancer. Preclinical data indicate that these agents have different mechanisms of action and, in combination have greater activity (that is, the ability to modulate growth and differentiation) in a number of malignant cell types than either agent alone. In clinical trials, the new biological regimen of 13-cis-retinoic acid and interferon- was shown to have major activity in advanced squamous cell carcinoma of the skin and cervix. We conducted a phase II trial of this regimen in recurrent squamous cell carcinoma of the head and neck. Of the 21 evaluable patients, none had a complete response, and only one had a partial response (5%). Two patients had minor responses, four had stable disease, and 14 experienced disease progression. Five patients developed grade 3 toxic effects, including skin toxicity, fatigue, headache, and anorexia/weight loss. The median survival duration was 25.5 weeks (range, 4–95). The combination of 13-cis- retinoic acid and interferon- at this dose and schedule is ineffective for the treatment of recurrent squamous cell carcinoma of the head and neck.     

Phase II trial of 4′-epi-doxorubicin in metastatic colorectal carcinoma

Summary Twenty-three patients with metastatic colorectal carcinoma were treated with 4-epi-doxorubicin (Epirubicin, 4-epi-DX) 90 mg/m² i.v. every 4 weeks. Out of 18 patients evaluable for response, 11 were previously untreated. One complete response of 21 + months was observed in a patient with rectosigmoid carcinoma. Furthermore there was one minor response in pretreated rectosigmoid series, and 6 patients had stabilization of disease. Median survival for all patients, including early deaths, was 4 months. For patients who were not pretreated and who received at least 2 cycles of therapy, median survival was 15 months. Further studies in patients with rectosigmoid carcinoma are warranted.     

Phase II trial of 4′ deoxydoxorubicin (DXDX) for unresectable non-small cell bronchogenic carcinoma

Summary A phase II trial of 4 Deoxydoxorubicin (DXDX) was conducted in unresectable previously untreated non-small cell lung cancer patients. DXDX was administered every 3 weeks by short intravenous infusion at a starting dose of 30 mg/m², with dose escalation to 40 mg/m² toxicity permitting. Four responses, all partial, were observed in 35 evaluable patients, for a response rate of 11% (95% confidence limits 3.2% and 26.7%). Myelosuppression was the dose-limiting toxicity. Cardiotoxicity was not seen. DXDX has minimal activity against non-small cell lung cancer as a single agent at the dosage used in this study.Supported in part by Public Health Service Grant CA-21742 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services     

Phase I/II study of cisplatin, 5-fluorouracil and α-interferon for recurrent carcinoma of the head and neck

Summary Current chemotherapy regimens have failed to demonstrate a significant impact on the overall survival of patients with recurrent head and neck cancer; therefore, new agents or combinations of agents are necessary to improve outcome. Alpha-interferon potentiates the activity in vitro of both agents of one of the most active regimens currently available, cisplatin and 5-fluorouracil. The purpose of the current study was to evaluate the feasibility and efficacy in patients with recurrent head and neck cancer of adding -interferon to cisplatin 14 mg/m² daily and 5-fluorouracil 700 mg/m² daily for 5 days. No significant toxicity occurred with -interferon at dose level 0,1 × 10⁶ units/m² daily for five days. Of four patients treated at dose level +1, -interferon 3 × 10⁶ units/m², two developed prolonged grade III neutropenic following the fourth course. One of three patients developed grade IV thrombocytopenia and 6 of 13 courses at this dose level resulted in grade III neutropenia. A phase II study was performed in 19 patients with cisplatin 17 mg/m²/ day, 5-fluoruracil 700 mg/m²/day and a-interferon 3 × 10⁶ units/m²/day. During the phase II study grade III neutropenia occurred in 6 patients and grade IV neutropenia in another patient during at least one course. Grade III and IV thrombocytopenia occurred in one patient each during the phase II study. Overall, major responses occurred in 7 or 23 patients (30%): 5 in phase I and 2 in phase II.In conclusion, the addition of -interferon to cisplatin and 5-fluorouracil is feasible, but does not appear to increase response rates in recurrent head and neck cancer.     

Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza™, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer

Summary This phase II trial was initiated to assess the efficacy and safety of oral vorinostat (Zolinza™, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Eligible patients must have recurrent and/or metastatic head and neck cancer unresponsive to or intolerant of conventional chemotherapy. Patients must have measurable disease, adequate hematologic, hepatic, and renal function, and be able to swallow capsules. Four or more weeks must have elapsed since prior chemotherapy, radiation therapy, major surgery or investigational anticancer therapy, and patients must have recovered from prior toxicities. Study endpoints included response rate, duration of stable disease and progression-free survival. Thirteen patients were enrolled (9 males); 1 withdrew consent prior to starting therapy. Twelve patients received oral vorinostat 400 mg once daily and were evaluable for response. The median age was 54 years (range 40–82). All patients had received prior chemotherapy (including 10 with platinum- or taxane-based combination therapy), and 9 had prior radiation therapy. No confirmed partial or complete responses were observed. One unconfirmed partial response was seen. Three patients had stable disease ranging from 9 to 26 weeks. Nine patients discontinued due to progressive disease, two withdrew consent, and one discontinued therapy for grade 3 anorexia. Grades 3–4 drug-related toxicities included thrombocytopenia (n = 3), anorexia (n = 2), and dehydration (n = 2). Oral vorinostat 400 mg qd was generally well tolerated but did not demonstrate efficacy as defined by tumor response in this small group of heavily pre-treated patients. Presented in part as a poster at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5–8, 2004. This research has not been published elsewhere and has not been submitted simultaneously for publication elsewhere.     

Phase II trial of imatinib (Gleevec®) in patients with metastatic renal cell carcinoma

Summary Fourteen patients with metastatic renal cell carcinoma (RCC) were treated on a Phase II trial with imatinib. Eligible patients had histologically confirmed RCC, metastatic and measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), Karnofsky performance status (KPS) of at least 70%, life expectancy of more than 3 months, and adequate hematological, renal, and liver function. Imatinib was given orally at a dose of 400 mg bid. The most common toxicities were Grade II/III nausea (28%) and Grade II renal insufficiency (14%). All patients had tumor tested by immunohistochemistry (IHC) for KIT protein (CD117, DAKO). One tumor (7%) demonstrated strong, diffuse expression and the rest were negative. No complete or partial responses were observed in 12 evaluable patients treated with imatinib.     

Phase II trial of 4′-deoxydoxorubicin (esorubicin) in hormone resistant prostate cancer

Summary Fifteen patients with hormone resistant advanced prostate cancer were treated with anthracycline analog 4-deoxydoxorubicin (Esorubicin). No patient had objective evidence of tumor regression. Six patients (40%) were classified using the National Prostatic Cancer Project criteria as having stable disease after two courses of therapy. Treatment was associated with significant hematologic toxicity with 50% of patients experiencing grade III or IV neutropenia. Clinical cardiac toxicity was not observed. Further trials of 4 -deoxydoxorubicin do not appear to be warranted in advanced prostate cancer.     

Phase II trial of esorubicin (4′deoxydoxorubicin,DxDx) in patients with small cell lung cancer

Summary Esorubicin (4-deoxydoxorubicin or DxDx) is an analog of doxorubicin with preclinical antitumor activity and no significant cardiotoxicity in model systems. Eleven patients with small cell lung cancer who had previously received chemotherapy were given esorubicin (25 mg/m² intravenously) every 3 weeks. No major objective responses were observed (95% confidence limits: 0–25%). Nine of the 11 patients had grade 2 or greater toxicity, with 55% of the patients experiencing grade 3 or greater toxicity [myelosuppression (4/11), anemia (2/11) or elevated liver enzymes (3/11)]. Nausea, vomiting, alopecia and intravenous site phlebitis were also seen. Three of the 11 patients received 3 or more course of esorubicin without evidence of significant cardiotoxicity. At this dose and shedule, no significant antitumor response were seen in this population of patients. Esorubicin, with this low response rate and significant toxicity, appears to be of limited utility in this disease.     

Phase II study of 2′-deoxycoformycin in patients with renal cell carcinoma

Summary The National Cancer Institute of Canada Clinical Trials Group undertook a phase II study of 2-deoxycoformycin in patients with metastatic renal cell carcinoma. When 2-deoxycoformycin 4 mg/m² was administered intravenously weekly for three weeks then every two weeks no significant antitumor activity was noted in 19 evaluable patients. Toxic effects experienced were as expected, consisting primarily of nausea/vomiting, anorexia, and lethargy. It is concluded that 2-deoxycoformycin at this dose and schedule has no clinical activity in the treatment of metastatic renal cell carcinoma.     

Phase II trial of ZD1839 (IRESSA™) in patients with advanced renal cell carcinoma

Eighteen patients with advanced renal cell carcinoma (RCC) were treated on a phase II trial with ZD1839 (IRESSA). Treatment efficacy was determined using the endpoint of improvement in time to progression (TTP) compared to TTP in patients who received interferon- therapy. The Memorial Sloan Kettering Cancer Center database of renal cell patients shows that patients receiving therapy with interferon- had a median TTP of 4.7 months, with 40% of patients having disease progression at 4 months. To show efficacy in this trial, 60% of evaluable patients would have to remain progression free at 4 months. Treatment with ZD1839 did not result in any complete or partial responses, and 13 patients (81%) had progression of disease within 4 months of start of therapy. At the dose and schedule used in this trial, the lack of antitumor activity associated with ZD1839 does not support further study in patients with metastatic RCC.     

Phase II trial of gemcitabine (2,2′-difiuorodeoxycytidine) in patients with adenocarcinoma of the pancreas

Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical acitivity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m² was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2–20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 × 10³/l (range 1.6–9.3) and the median absolute neutrophil (ANC) nadir was 2.0 × 10³/l (range 0.4–7.2). Thrombocytopenia - 100.0 × 10³/l was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0–245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemcitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.     

Phase II study of esorubicin (4′-deoxydoxorubicin) in advanced or metastatic squamous carcinoma of the uterine cervix: A Gynecologic Oncology Group study

Summary Twenty-eight patients with advanced, measurable squamous carcinoma of the uterine cervix were treated with 62 courses of esorubicin at doses ranging from 20–35 mg/m² every three weeks. All patients were evaluable for response and toxicity. All patients had received prior therapy including radiation therapy in 28, chemotherapy in 23, and surgery in 11. All patients were Gynecologic Oncology Group (GOG) performance status 0, 1 or 2. There were no responses seen. Severe (grade 3 or 4) leukopenia, thrombocytopenia, and anemia were seen in 13, 3, and 9 patients, respectively. Gastrointestinal toxicity as well as alopecia were the other adverse effects. Mucositis and phlebitis were not seen. Neither clinical congestive cardiomyopathy nor decrement in left ventricular ejection fraction was observed. Lack of response in association with moderate toxicity using this dose and schedule of esorubicin in squamous carcinoma of the cervix previously treated with chemotherapy makes further study as a salvage agent unwarranted. Address for offprints: GOG Headquarters, Suite 1945, 1234 Market Street, Philadelphia, PA 19107, USA.     

Epidermal growth factor receptor – targeted molecular therapeutics for head and neck squamous cell carcinoma

Several molecular-targeted therapeutics have been tested in clinical trials for the treatment of head and neck squamous cell carcinoma (HNSCC). Of these, therapeutics targeting the epidermal growth factor receptor (EGFR) have been studied most extensively and some agents have demonstrated measurable clinical effectiveness. However, molecular studies designed to define HNSCC patient subcohorts of likely responders to EGFR-targeted therapy have not identified molecular signatures that correlate with clinical response. Here, the authors summarise the relevant clinical findings and highlight reported molecular correlative studies for EGFR-targeted therapeutics for HNSCC. The authors focus especially on molecular markers evaluated for association with clinical response and include data from EGFR-targeted clinical studies in other cancer sites that they anticipate will be of interest to the head and neck cancer research and treatment communities.     

Phase II trial of esorubicin (4′ deoxydoxorubicin) in cancers of the breast,colon, kidney,lung and melanoma

A phase II trial of esorubicin (4 deoxydoxorubicin) was performed in patients with cancers of the breast, colon, kidney, lung and melanoma. Two partial responses were observed out of 16 patients with breast cancer treated with esorubicin. No objective responses (complete or partial) were seen in patients with colon cancer (18 patients), lung cancer (12 patients), renal cell cancer (12 patients) and melanoma (18 patients). Myelosuppression was the most significant toxicity encountered with granulocytopenia (neutrophils < 1,000) observed in 38% of patients. As discussed, we feel that further investigation of esorubicin in anthracyclinesensitive tumors is warranted.     

Phase II trial of oral β-all trans-retinoic acid in hepatocellular carcinoma (SWOG 9157)

Twenty-nine chemotherapy-naive patients with primary hepatocellular carcinoma were treated with oral -all trans-retinoic acid (retinoic acid, TRA 50 mg/m2 tid) on a 3-week on/one week off schedule until progression or grade 3 or 4 toxicity. Eligibility requirements allowed abnormal liver function tests as long as the creatinine and bilirubin levels were normal. No responses were seen and the median survival was four months. Grade 3 side effects occurred in 11 patients and grade 4 in four and included a wide range of toxicities. The results indicate that oral TRA is ineffective against primary hepatocellular carcinoma and suggest that dose-modification of this retinoid may be required in patients with significant malignant hepatic involvement.     

Phase II study of esorubicin (4′-deozydoxorubicin) in advanced epithelial carcinoma of the ovary: A Gynecologic Oncology Group study

Summary Twenty-six patients with advanced, measurable epithelial carcinoma of the ovary were treated with 76 courses of esorubicin at doses ranging from 20–30 mg/m² every 3 weeks. All patients are evaluable for toxicity and response. All patients had received prior therapy including radiation therapy in 9, non-anthracycline chemotherapy in 25, and surgery in 25. All patients were GOG performance status 0, 1 or 2. Two partial responses were seen. Severe (grade 3 or 4) leukopenia, thrombocytopenia, and anemia were seen in 13, 1 and 4 patients, respectively. Moderate gastrointestinal toxicity was also noted. Alopecia and mucositis were rare. Phlebitis was not seen. Neither clinical congestive cardiomyopathy nor decrement in left ventricular ejection fraction was observed. We conclude that using this dose and schedule of esorubicin as second-line chemotherapy in ovarian epithelial neoplasms lacks significant activity and is associated with moderate toxicity.     

Phase II study of 4 ′ -deoxydoxorubicin (esorubicin) in advanced or metastatic adenocarcinoma of the stomach

Summary 4 -deoxydoxorubicin (DxDx) was administered to 17 patients with locally advanced or metastatic gastric adenocarcinoma. Treatment cycles were repeated every 21 days. 15 eligible patients with a Karnofsky performance status of 50% or better (median: 70%) received at least one course of treatment; a median of 2 courses of DxDx was delivered (range 1 to 13). The median dose per treatment course was 26 mg/m² (range 8.5 mg/m² to 53 mg/m²). 69% of patients required dose reduction following the first course of therapy due to grade 3 or 4 myelosuppression, primarily neutropenia. The principal side effects included anemia, mild gastrointestinal toxicities, and alopecia; one patient experienced a 10% decrease in cardiac ejection fraction without clinical cardiac toxicity. Of the 15 patients assessable for response and toxicities, 1 patient had a partial response lasting 2.5 months. The median survival from the time of the first treatment was 3.3 months. We conclude that DxDx has only limited activity in the treatment of advanced gastric adenocarcinoma.     

A phase II trial of oral 4′ demethoxydaunorubicin (DMDR) in inoperable non small cell lung cancer

Summary 4 Demethoxydaunorubicin, an orally active daunorubicin analogue, was administered to 22 patients with inoperable non small cell lung cancer (NSCLC). Patients were stratified into good and poor risk categories and received doses of 45 mg/m² and 40 mg/m² respectively at 28 day intervals. All 22 patients were evaluable for response: No tumour responses occurred. Therapy was well tolerated. Mild gastrointestinal toxicity occurred in 41% of patients. Leucopenia with a wcc < 3 × 10⁹/L occurred in 33% of patients and thrombocytopenia < 100 × 10⁹/L in 9%. Severe marrow toxicity was rare and there appeared to be no difference in terms of toxicity between the different dose levels. DMDR appears to have no useful clinical activity in NSCLC.     

Phase I trial of 4′-deoxydoxorubicin given weekly

Summary Twenty-six patients with various solid tumors entered a Phase I trial with 4 -Deoxydoxorubicin (Esorubicin, IMI-58), a new doxorubicin analogue. The drug was administered weekly i.v. for 3–4 weeks. Leukopenia proved to be dose limiting. The maximum tolerated dose (MTD) was reached at 20 mg/m² weekly for 3 weeks. For Phase II trials, a weekly dose of 15 and 17.5 mg/m² can be proposed for poor and good risk patients respectively. Non-hematologic toxicity was minimal. Phase II trials with this new anthracycline are warranted.