Phase II trial of lenalidomide in patients with metastatic renal cell carcinoma

Summary Lenalidomide (CC-5013) is a structural derivative of thalidomide, with antiangiogenic and immunomodulatory effects. Fourteen patients with metastatic renal cell carcinoma (RCC) were enrolled on a phase 2 trial of lenalidomide administered orally at 25 mg daily for 21 days followed by a rest period of 7 days. The best response was stable disease in eight patients (57%) of the 14 evaluable patients. Toxicities included fatigue, hyperglycemia, dyspnea, and myelosuppression with decreased hemoglobin, lymphopenia, and neutropenia. Lenalidomide is tolerable, but no objective responses were observed in this clinical trial.     

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 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.     

A Phase II study of 13-cis-retinoic acid in patients with advanced renal cell carcinoma

The aim of this study was to determine the antitumor activity of 13-cis-retinoic acid as a single agent in patients with advanced renal cell carcinoma. Eligible patients had advanced renal cell carcinoma with bi-dimensionally measurable disease, a Karnofsky performance status of at least 70, life expectancy of greater than three months, no evidence of brain metastases, and treatment with no more than one chemotherapy regimen. Patients were treated with one mg/kg/day of 13-cis-retinoic acid orally. Twenty-six patients were enrolled in this study and 25 were evaluable for response and toxicity. Of the twenty-five evaluable patients, no major responses were achieved. Toxicity was mild, with no patient requiring a dose reduction. At the dose administered in this trial, 13-cis-retinoic acid is inactive as a single agent in 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 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.     

A phase II study of rebeccamycin analog (NSC-655649) in metastatic renal cell cancer

Objective: Rebeccamycin analog (NSC-655649) is an antibiotic with antitumor properties demonstrated in preclinical and phase I studies. We conducted a phase II trial to evaluate the efficacy and toxicity of this agent in patients with advanced renal cell cancer (RCC). Methods: Eligible patients had histologically or cytologically confirmed diagnosis of RCC that was either locally advanced unresectable, locally recurrent, or metastatic. Patients had to have measurable disease, no prior chemotherapy, life expectancy of greater than 12 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, adequate-organ function, and be 18 years old. Patients were treated with NSC-655649 at a dose of 165mg/m² daily i.v. over 30–60min for 5 days. Treatment was repeated every 21 days. Response was assessed every two courses. Results: Twenty-four patients were enrolled. There were sixteen males and eight females with a median age of 60.5 years (range 42–76). Nineteen were Caucasians, seventeen had prior nephrectomy, and thirteen had prior immunotherapy. The major toxicity was myelosuppression with grade 3 and 4 neutropenia in 38% of patients and anemia in 33% of patients. There were two partial responses (2/24, 8%) and 11 patients (46%) achieved stable disease (SD). The 6-month progression-free rate for patients with SD was 30%. Of the seventeen patients with progressive disease at registration, one had a PR and eight had SD. The overall median survival time for all 24 patients was 10.0 months (90% CI=5.2, 17.4 months). The 12-month survival rate was 39%, with 90% CI=(0.21, 0.58). Nine patients are still alive with survival times ranging from 3.8 to 24.2 months, at a median follow-up time of 11.9 months. Conclusion: Rebeccamycin analog (NSC-655649) is well tolerated and has modest antitumor activity in patients with advanced RCC.     

Phase I trial of thalidomide and Interleukin-2 in patients with metastatic renal cell carcinoma

Summary Background: The treatment of advanced renal cell cancer remains unsatisfactory, therefore new combination regimens such as thalidomide and IL-2 are of interest. A phase I trial of SC IL-2 and oral thalidomide was performed to identify the toxicity, maximum tolerated dose (MTD) and preliminary clinical activity of this regimen. Methods: 33 patients with advanced/metastatic RCC were enrolled. An established 8-week outpatient schedule of subcutaneously administered IL-2 in escalating doses, days 1–5, for 6 weeks with a 2 week rest was utilized with daily oral thalidomide. Cohorts of 4–6 patients were treated at 4 dose levels. Results: Toxicity was moderate to severe and related to dose level. All patients developed fever, chills and fatigue. 29/33 patients developed ≤ Grade 2 desquamation of hands and feet and/or rash. Dose limiting toxicity (DLT) included Grade 3 neutropenia and pulmonary embolus. The maximum tolerated dose (MTD) of IL-2 and thalidomide was 9.0 MIU/m² SC days 1–5, weeks 1 to 6 and 100 mg po daily, respectively. A median of 2 cycles of therapy was administered (range 1–9). 2/33 patients responded (1 CR—prior IL-2 therapy, 1 PR—no prior therapy) with an overall response of 6% (95% CI, 1–20%). One minimal response was converted to a surgical CR (remains disease free at 24 + months). Conclusion: Outpatient administration of IL-2 and thalidomide is possible with acceptable toxicity. Further evaluation of this regimen is underway.     

Phase II evaluation of merbarone in renal cell carcinoma

Summary The Southwest Oncology Group (SWOG) studied the response rate and toxicity of merbarone (1,000 mg/m² IV continuous infusion days 1–5, q 21 days) in patients with advanced metastatic renal cell carcinoma. Among 36 eligible patients, there was one partial response for a response rate of 3% (95% C.I. 0.1–15%). There were no mixed responses. There were no treatment related deaths or adverse drug reactions. Significant anemia, diarrhea, and hypercalcemia were observed. Mild to moderate degrees of malaise/fatigue/lethargy, dizziness/vertigo, hyperglycemia, creatinine increase, nausea, vomiting, weight loss, pedal edema, dyspnea, and granulocytopenia were noted. Merbarone does not have significant activity as a single agent in advanced renal cell carcinoma.     

索拉非尼治疗转移性肾细胞癌的疗效及安全性研究

目的 评价索拉非尼治疗转移性肾癌的疗效及安全性.方法 转移性肾癌40例患者,均给予甲基磺酸索拉非尼片治疗,初始剂量为800 mg/d,2次/d,连续给药21 d,停药7d,观察疗效和不良反应,以及免疫组织化学检测结果.结果 40例患者中未见完全缓解（CR）和部分缓解（PR）;疾病稳定（SD） 32例（80.0％）和疾病进展（PD）8例（20.0％）;消化系统不良反应发生28例（70.0％）;间隙连接蛋白32（ Cx32）在局限性肾癌中表达阳性率为30.5％,明显低于转移性肾癌组织的1.2％（x2=8.123,P＜0.01）,Cx32表达与临床分期呈负相关（r=-0.419,P＜0.05）;肾癌组织中血管内皮生长因子（VEGF）蛋白表达的阳性率75.5％,明显高于正常肾组织的18.5％ （x2 =8.723,P＜0.01）;VEGF在局限性肾癌阳性表达率72.0％与转移性肾癌的89.1％差异无统计学意义（x2=1.978,P＞0.05）.结论 索拉非尼对晚期肾癌病情控制有较好的效果,是治疗转移性肾癌的新选择.     

Phase II evaluation of piroxantrone in renal cell carcinoma

Summary The Southwest Oncology Group (SWOG) studied the response rate and toxicity of piroxantrone (150 mg/m² q 21 days) in patients with advanced metastatic renal cell carcinoma. Among 32 eligible patients, there were no partial nor complete responses. There were two mixed responses. Significant white cell toxicity, anemia, nausea, and vomiting were observed. Mild or moderate degrees of fever, malaise, and stomatitis occurred. No significant cardiac toxicity was noted. Piroxantrone does not have significant activity as a single agent in advanced renal cell carcinoma.     

Phase II evaluation of amonafide in renal cell carcinoma

Summary Twenty four patients with advanced renal cell carcinoma were treated in a phase II trial with amonafide 300–450 mg/m²/day on days 1–5 every 21 days. There were no responders, 6 patients had stable disease, 14 experienced progressive disease and 4 were assumed to be non-responders as no evaluation was performed. There were no fatal toxicities although 8 patients had grade 3 or 4 granulocytopenia, 1 patient had grade 4 thrombocytopenia. Other toxicities included grade 3 diarrhea in 1 patient, grade 3 myopathy in 1 patient, severe nausea and vomiting in 1 patient and a facial rash, possibly a hypersensitivity reaction, in 1 patient. The median survival is 7.5 months. At this dosage and schedule, there is no evidence that amonafide has meaningful anti-tumor activity in patients with advanced renal cell carcinoma. Address for offprints: Southwest Oncology Group (SWOG- 8716), Operations Office, 5430 Fredericksburg Road, Suite #618, San Antonio, TX 78229-6197, USA     

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.     

A phase II study of pyrazoloacridine in patients with advanced renal cell carcinoma

The aim of this study was to determine the antitumor activity of pyrazoloacridine in patients with renal cell carcinoma. Eligible patients had advanced renal cell carcinoma with bidimensionally measurable disease, a Karnofsky performance status of at least 70, life expectancy of greater than three months, no prior treatment with chemotherapy, and no evidence of brain metastases. Patients were treated intravenously with 750 mg/m² every three weeks. Twelve patients were enrolled in this study and all were evaluable for response and toxicity. Of the twelve patients, no major responses were achieved. Toxicity was mild, with three patients requiring a 20% dose reduction. At the dose and schedule used in this trial, pyrazoloacridine is inactive in renal cell carcinoma.     

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 study of echinomycin in the treatment of renal cell carcinoma ECOG study E2885

Summary Seventeen patients were treated with echinomycin for metastatic renal cell carcinoma. Echinomycin is a bifunctional DNA intercalating agent with broad preclinical antitumor activity. It was given at 1200 mg/m² by intravenous infusion over 30–60 min weekly for 4 weeks. The treatment was repeated every 6 weeks. There were no responses observed in the study. No life threatening or lethal toxicity was documented in 13 eligible patients. The median survival of these patients was 13.7 months. We conclude that echinomycin is not active against metastatic renal cell carcinoma at the dose and schedule tested.     

A phase II study of thalidomide in advanced metastatic renal cell carcinoma

Objectives: To evaluate the toxicityand activity of thalidomide in patientswith advanced metastatic renal cell cancerand to measure changes of one angiogenicfactor, vascular endothelial growth factor(VEGF)165, with therapy. Patients and methods: 29 patients were enrolled on astudy of thalidomide using an intra-patientdose escalation schedule. Patients beganthalidomide at 400 mg/d and escalated astolerated to 1200 mg/d by day 54.Fifty-nine per cent of patients had hadprevious therapy with IL-2 and 52% wereperformance status 2 or 3. Systemic plasmaVEGF165 levels were measured by dualmonoclonal ELISA in 8 patients. Results: 24 patients were evaluable forresponse with one partial response of 11months duration of a patient with hepaticand pulmonary metastases (4%), one minorresponse, and 2 patients stable for over 6months. Somnolence and constipation wereprominent toxicities and most patientscould not tolerate the 1200 mg/day doselevel. Systemic plasma VEGF165 levels didnot change with therapy. Conclusion: These results are consistent with a lowlevel of activity of thalidomide in renalcell carcinoma. Administration of dosesover 800 mg/day was difficult to achieve inthis patient population, however lowerdoses were practical. The dose-responserelationship, if any, of thalidomide forrenal cell carcinoma is unclear.     

15-氧代绣线菊内酯对转移性肾癌细胞系ACHN恶性表型的抑制作用

目的 探讨15-氧代绣线菊内酯对转移性肾癌细胞的体外抗肿瘤效应及其机制.方法 采用不同浓度15-氧代绣线菊内酯处理ACHN细胞株,MTT比色法、划痕损伤实验、膜联蛋白A5-绿色荧光素/碘化丙啶(Annexin V-HTC/H)染色以及流式细胞术分别观察ACHN细胞株增殖、迁移、细胞凋亡的变化,RT-PCR和/或Western blot检测Wnt信号通路靶基因表达.结果 15-氧代绣线菊内酯能明显抑制肾癌ACHN细胞株的增殖,其半数抑制浓度为0.987μmol/L.15-氧代绣线菊内酯呈浓度依赖性降低细胞迁移距离(P＜0.05)、诱导细胞凋亡发生(P＜0.05)、减少G0/G1期细胞、增加G2/M期细胞(P＜0.05).15-氧代绣线菊内酯能够显著抑制Axin2、LEF1、NKD1、Cyclin D1和生存素等Wnt靶基因以及Cdc25和Cdc2等细胞周期相关基因的表达.结论 15-氧代绣线菊内酯能在体外细胞水平显著抑制转移性肾癌ACHN细胞的增殖和迁移作用,诱导细胞凋亡,使细胞停滞于G2/M期;其对肾癌恶性表型的影响是通过抑制Wnt信号通路来实现的,可能是一种潜在的治疗转移性肾癌的药物.     

A phase II trial of 17-(Allylamino)-17-demethoxygeldanamycin in patients with papillary and clear cell renal cell carcinoma

Summary The aim of this study was to determine the antitumor activity of 17-(Allylamino)-17-demethoxyge-ldanamycin (17-AAG), a heat shock protein 90(hsp90) inhibitor in patients with metastatic papillary renal cell carcinoma (RCC) or metastatic clear cell RCC. Eligible patients were divided into 2 cohorts based on histological subtype: papillary or clear cell RCC. All patients had advanced RCC with measurable disease, a Karnofsky performance status of at least 70, and no evidence of brain metastases. Twelve patients with clear cell RCC and 8 patients with papillary RCC were treated with 17-AAG on this phase II trial. 17-AAG was given intravenously at 220 mg/m² twice weekly for 2 weeks followed by a week of rest. Cycle length was 21 days. No patient in either cohort achieved a complete or partial response. Toxicities included elevated liver function tests, optic neuritis, dyspnea, fatigue, and gastrointestinal side effects. Six of the 20 patients required dose reduction. At the dose and schedule used in this trial, 17-AAG did not achieve objective response in the treatment of clear cell or papillary renal cell carcinoma patients.