Phase II study of interferon-alpha and doxycycline for advanced renal cell carcinoma

Summary Objective: To assess the efficacy and toxicity of the combination of interferon-alpha and doxycycline in patients with metastatic renal cell carcinoma and to assess the effect of this treatment on serum vascular endothelial growth factor (VEGF) levels. Patients and Methods: Seventeen patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and life expectancy greater than 4 months with radiologically evident advanced renal cell carcinoma were enrolled. Eight patients had prior nephrectomy and 10 patients were treated within 4 months of their diagnosis. Treatment consisted of interferon-alpha up to 9 million units subcutaneously three times per week and doxycycline 300 mg orally twice per day for weeks one and three of each four-week cycle. Toxicity was evaluated on a biweekly basis and response on a bimonthly basis. VEGF plasma levels were assessed monthly as a measure of potential antiangiogenic effect. Results: No objective responses were seen. The mean duration of study was 2.6 cycles (range: 0.8–6.0 cycles). Three patients (17%) tolerated therapy and displayed stable disease for greater than four months. Five patients withdrew from study before the first response evaluation. Ten patients experienced grade 2 gastrointestinal toxicity requiring dose reduction of doxycycline. Eight patients experienced grade 2 fatigue requiring dose reduction of interferon. VEGF plasma levels were initially suppressed in patients who demonstrated progressive disease but not in patients with stable disease. Conclusion: This regimen of doxycycline and interferon-alpha was not efficacious as treatment for renal cell carcinoma. Plasma VEGF levels were significantly decreased during the first two cycles of treatment, but this does not correlate with clinical outcome.     

Phase II trial of interferon and thalidomide in metastatic renal cell carcinoma

Summary Objectives: To evaluate the toxicity and efficacy of interferon and thalidomide combination in a phase II clinical trial. Patients and methods: Eligibility included metastatic renal cancer with a maximum of two prior regimens, performance status of 0‐2 and adequate renal, hepatic and bone marrow function. Results: Twenty patients were enrolled on this phase II trial. Median age was 60.5 years (Range: 39–75 years). 17 patients had visceral metastases (lung/liver/both) and 3 patients had lymph node only metastases. A total of 26 cycles of 4 weeks each were administered; median of 1 cycle and range from 0‐9 cycles. The therapy was poorly tolerated with grade 3 adverse events noted in 12 (60%) of the 20 patients. No objective responses were noted. Of the 14 response evaluable patients, one had an unconfirmed response (38% decrease in size) and one had prolonged disease stabilization for 10 months. The median time to progression was 1.0 month and median survival was 2.8 months. Pre and post therapy PET scans were performed nine weeks apart on one patient. The mean standardized uptake values (SUV) declined from 1.45 (SUV min-max 0.89–1.76) to 1.12 (SUV min-max 0.55–1.47), denoting anti vascular effect. The patient did not have an objective response but had a disease stabilization sustained for 10 months. Conclusion: The combination of interferon and thalidomide has minimal efficacy and considerable toxicity which makes this combination unworthy of future investigation in metastatic renal cancer.     

Phase II trial of irofulven (6-hydroxymethylacylfulvene) for patients with advanced renal cell carcinoma

The aim of this study was to determine the antitumor activityof irofulven (6-hydroxymethylacylfulvene) in patients withadvanced renal cell carcinoma (RCC). Eligible patients hadadvanced renal cell carcinoma with bidimensionally measurabledisease, a Karnofsky performance status of at least 70, lifeexpectancy of greater than three months, no prior treatmentwith chemotherapy, and no evidence of brain metastases.Irofulven was administered at a dose of 11 mg/m² by 5-minintravenous infusion, on 5 consecutive days. Cycles wererepeated every 28 days. Thirteen patients were enrolled inthis study and 12 were evaluable for response. Of the twelveevaluable patients, no major responses were achieved. Eightpatients had stable disease as best response. Toxicityincluded myelosuppression and gastrointestinal side effects.At the dose and schedule used in this trial, irofulven did notproduce clinical response in RCC.     

Phase II trial of topotecan in patients with advanced renal cell carcinoma

Summary Fifteen patients with advanced renal cell carcinoma were treated on a phase II trial with topotecan. None of the fourteen evaluable patients achieved a complete or partial response. Myelosuppression was the most common toxicity. Eighty percent (12 of 15) of patients experienced grade III or IV neutropenia and/or anemia. Topotecan is not efficacious in the treatment of advanced renal cell carcinoma.     

Phase II trial of LY 186641 in advanced renal cancer

Summary LY 186641 is a diarylsulfonylurea with a broad spectrum antitumor activity against both murine and human solid tumors. We report here the results of a phase II trial of LY 186641 in advanced renal cell adenocarcinoma.The drug was administered orally, once daily for 2 weeks, every 21 days at a 700 mg/m²/d dose. Sixteen patients were enrolled in this phase II trial; 12 males, 4 females, with a median age of 58 years. All patients had progressive measurable metastatic disease. The primary tumor was surgically removed in all but one patient. Three patients were previously treated by biologic response modifiers (BRMs). A total of 72 courses were administered. The most common side effects were methemoglobulinemia (MetHgb) and anemia which occurred in 13 and 10 patients respectively. The MetHgb did not exceed 15%, and only 3 patients required blood transfusion for grade 3 (2 patients) and grade 4 (1 patient) anemia. Reversible hepatotoxicity was observed in 3 patients.There were one pathological complete response, seven stable disease and 8 progressive disease.     

Phase II trial of fludarabine phosphate in advanced renal cell carcinoma: An Illinois Cancer Council study

Summary Fludarabine Phosphate (FP), the 2-fluoro, 5 phosphate derivative of adenosine arabinoside (ara-A), was studied in 18 patients with advanced renal cell carcinoma. These patients had measurable disease and had not received chemotherapy. FP was administered at a loading dose of 20 mg/m² followed by a 48-hour infusion at 30 mg/m²/day given every 21 days. There were no complete or partial responses seen. Toxicity was mainly hematologic, with leukopenia most commonly observed. FP given in this manner had no activity in advanced renal cell carcinoma.     

Phase II trial of Didemnin B in patients with advanced renal cell carcinoma

Summary Twenty-three patients with advanced renal cell cancer were treated with Didemnin B. One partial response was achieved (5%) in 21 evaluable patients. An allergic reaction was noted in four patients including one patient with anaphylaxis. Didemnin B is not recommended in the treatment of renal cell carcinoma.     

Phase II trial of arsenic trioxide in patients with metastatic renal cell carcinoma

Fourteen patients with metastatic renal cell carcinoma (RCC)were treated on a Phase II trial with arsenic trioxide(As₂O₃). Eligible patients had metastatic renal cellcarcinoma with bidimensionally measurable disease, a Karnofskyperformance status of at least 70%, life expectancy ofgreater than three months, and no evidence of brainmetastases. Arsenic trioxide was given intravenously at a doseof 0.3 mg/kg/day for five consecutive days every four weeks.The most common toxicity observed was grade II elevation inliver function tests (36%), anemia (21%), renalinsufficiency (14%), rash (7%), and diarrhea (7%). Bestresponse was stable disease in 3 patients with one patientremaining on study at 8+ months At the dose and schedule usedin this trial, arsenic trioxide did not achieve a complete orpartial response in metastatic renal cell carcinoma.     

Phase II trial of echinomycin for the treatment of advanced renal cell carcinoma

Summary Forty-nine patients with metastatic or recurrent renal cell carcinoma were treated on a phase II trial of Echinomycin. Treatment consisted of Echinomycin 1.25 mg/m² intravenously every 28 days. Among the 47 evaluable patients there were no complete responses and only one partial response for an overall response rate of 2% (95% confidence interval, 0–11%). Eighteen patients (38%) experienced toxicity of grade 3 or worse. The most common toxicities were nausea and vomiting. The results of this study indicate that Echinomycin is not sufficiently active to warrant further trials for the treatment of renal cell carcinoma.     

Phase II trial of liposomal encapsulated doxorubicin in patients with advanced renal cell carcinoma

Summary Fourteen patients with advanced renal cell carcinoma were treated on a phase II trial with liposomal encapsulated doxorubicin (Lipodox, LED). None of the fourteen evaluable patients achieved a complete or partial response. Myelosuppression was the most common toxicity and no cardiac toxicity was evident. Seventynine percent (11 of 14) of patients experienced grade III or IV neutropenia. In summary, LED did not show antitumor activity in the treatment of advanced renal cell carcinoma.     

Phase II trial of menogaril in advanced colorectal cancer

Summary Menogaril, a new semisynthetic anthracycline antibiotic, was administered to 35 patients with advanced colorectal cancer. The drug was infused over 2 hr at a dose of 160 mg/sqm or 200 mg/sqm repeated every 4 weeks. Twenty-seven patients were evaluable for response and no objective responses were achieved. Myelosuppression, only leukopenia, was usually of mild-moderate degree and occurred in 63% of the patients. Twenty-seven percent of the patients experienced severe leukopenia. Local erythema and phlebitis were frequently observed and were severe in 13% of the patients. Nausea/vomiting (66%) and alopecia (50%) were of mild-moderate degree.This study suggests that menogaril at these doses and schedule had no activity in advanced colorectal cancer.for the EORTC Early Clinical Trials Group (EORTC/ECTG)     

N-(4-羟基苯基)维生素甲酰胺诱导肿瘤细胞凋亡的机制

N-(4-羟基苯基)维生素甲酰胺(4-HPR)是一种维甲酸类化合物，通过诱导肿瘤细胞凋亡抑制肿瘤生长，其诱导凋亡的机制包括升高活性氧、神经酰胺的水平和增加Caspase活性等不依赖受体的机制和依赖维甲酸受体的机制，以及在其中发挥作用的其他因素。     

Phase II trial of N-methylformamide in advanced head and neck cancer

Summary Eighteen patients with advanced epidermoid carcinoma of the head and neck were entered into a phase II trial of N-Methylformamide (NMF), 800 mg/M² IV daily for 5 days every 4 weeks. Seventeen patients had received prior radiation therapy and 11 were previously treated with chemotherapy. No complete or partial responses were observed. The major toxicity was gastrointestinal. Fifty percent of patients experienced nausea and vomiting or reversible hepatotoxicity with greater than a 3-fold elevation of liver enzymes. Mild reversible myelosuppression occurred in 2 patients. NMF in this dose and schedule was not a useful agent to treat recurrent epidermoid carcinoma of the head and neck.     

Phase II trial of pirarubicin in the treatment of advanced bladder cancer

Summary Doxorubicin is one of the standard drugs in the chemotherapy of advanced urothelial tumors. Pirarubicin, a new anthracycline, turned out to be equally active and less toxic than its parent compound in preclinical studies. Twenty one patients with either metastatic or inoperable locally advanced bladder carcinoma were treated with intravenous infusion of pirarubicin: 25 mg/m²/day for 3 days every 4 weeks in the first 15 patients and 20 mg/m²/day for 3 days every 3 weeks in the others. Fifteen patients were not pretreated and 6 received prior chemotherapy (5 patients with doxorubicin containing regimen). Twenty patients were evaluable for response; there were 2 partial response, 8 stable disease and 10 progressive disease. All pretreated patients progressed. Hematological toxicity was moderate, however there was one toxic death with grade 4 neutropenia which occured in a heavily pretreated patient receiving a dose of 25 mg/m²/day for 3 days. There was no clinical cardiac toxicity. Single agent Pirarubicin displays an objective response rate of 10% (95% of CI 0 to 23%) which reaches 14% (95% CI 0 to 29%) when non pretreated patients are analyzed separately. This rate is in the range of doxorubicin activity.     

Phase II trial of antiepidermal growth factor receptor antibody C225 in patients with advanced renal cell carcinoma

Fifty-five patients with metastatic renal cell carcinoma (RCC) were treated on a multicenter, single-arm Phase II trial. Patients received single-agent Cetuximab (C225) administered by intravenous infusion at a loading dose of 400 or 500mg/m² followed by weekly maintenance doses at 250mg/m². None of the patients treated with C225 achieved either a complete or partial response. The median time to progression was 57 days. The most frequently reported grade 3 or 4 toxicity treatment-related adverse events were acne (17%) and rash or dry skin (4%). The lack of clinical response or suggestion of prolonging time to progression compared to historical data with interferon-alfa supports no further study of single-agent C225 in patients with metastatic RCC.     

Phase II study of the efficacy and safety of oral GD0039 in patients with locally advanced or metastatic renal cell carcinoma

Seventeen patients with locally advanced or metastatic renal cell carcinoma (RCC) were enrolled in this phase II trial. The purpose of the trial was to assess the efficacy of the administration of oral GD0039, and to further assess the pharmacokinetics and pharmacodynamics of this drug. Patients were given an initial dose of 37.5 μ g/kg b.i.d for 3 weeks followed by one week off in each cycle, with the treatment continuing until disease progression or adverse effects. All 17 patients discontinued treatment due to disease progression or toxicity. Adverse events such as fatigue, nausea and diarrhea were common but generally mild. No evidence of anti-tumor activity of GD0039 was seen in this study.     

Phase II trial of pegylated-liposomal doxorubicin (Doxil) in renal cell cancer

Twelve patients with refractory renal cell cancer weretreated on a phase II study of pegylated-liposomaldoxorubicin (Doxil). The initial dose per course was55 mg/m² every four weeks with dose modification based onmucositis and hand-foot syndrome (the main limitingtoxicities). Toxicities were mild and similar to previousreports but dose reduction per the study protocol, which wasdesigned to control the skin and mucosal toxicities, wascommon. No definite cardiac toxicity was observed. Noobjective responses were observed in 11 evaluable patients. This study did not demonstrate activity ofpegylated-liposomal doxorubicin in renal cell cancer,although it can be given with mild toxicity.     

Phase II evaluation of menogaril in patients with advanced cervical carcinoma

Fourteen patients with advanced/recurrent squamous cell carcinoma of the uterine cervix received menogaril, 200 mg/m² by one hour intravenous infusion at four-week intervals. No objective regressions were observed. Median time to progression was less than two months and median survival was seven months. All patients experienced neutropenia. Platelet toxicity was negligible. Venous irritation and phlebitis occurred at the infusion site in 43% of patients. Menogaril as administered in this protocol is ineffective in treating previously irradiated advanced/recurrent squamous cell carcinoma of the uterine cervix and warrants no further investigation in this disease at the dosage and administration schedule used in this protocol. Address for offprints: H.J. Long, Mayo Clinic, 200 First Street S.W., Rochester, MN, 55905, USA     

Phase II study of Fenretinide (N-[4-Hydroxyphenyl]retinamide) in advanced breast cancer and melanoma

Summary Retinoids, the natural and synthetic analogs of vitamin A, are growth-inhibiting and differentiation-inducing agents and show clinical promise as chemopreventive and antineoplastic agents. Fenretinide, a new synthetic retinoid, has antitumor activity in certain in vitro and in vivo model systems and was relatively nontoxic in phase I trials. Based on these data, we designed a phase II study of Fenretinide involving 31 patients with advanced breast cancer [15] and melanoma [16], two cancers shown to be responsive to this agent in preclinical models. Fenretinide was inactive in patients with advanced disease. Toxicity was mild, and reversible. Mucocutaneous side effects occurred in 16 (52%) patients. Nyctalopia developed in three patients one of whom developed decreased B-wave amplitude of the scotopic electroretinogram. The minimal toxicity and significant activity in preclinical studies make this an attractive agent for future breast cancer chemoprevention studies.