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.     

Echinomycin (NSC 526417) in recurrent and metastatic squamous cell carcinoma of the cervix

Nineteen evaluable patients with recurrent or metastatic squamous cell carcinoma of the uterine cervix were treated with 1,500 micrograms/m2 of echinomycin every 4 weeks. No patient had received prior chemotherapy. There was one partial response (5% response, 95% confidence interval for response of 0% to 26%). The major toxicity was nausea and vomiting which was moderate to severe in six patients. Myelosuppression was not observed. Echinomycin, in this dose and schedule displays no major activity in chemotherapy-naive patients with advanced squamous-cell carcinoma of the cervix.     

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.     

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 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.     

A phase II study of interleukin-2 with and without beta-interferon in the treatment of advanced renal cell carcinoma

Background Biologic response modifiers have activity in renal cell carcinoma. The combination of interleukin-2 (IL-2) and beta-interferon (B-IFN) is synergisticin vitro. This trial was initiated to determine the efficacy of IL-2 alone and with B-IFN in advanced RCC.Methods Ambulatory patients with advanced RCC were randomly allocated to either IL-2 6×10⁶ units/ M² intravenously (IV) three days a week for four weeks or IL-2 5×106 units/M² IV plus B-IFN 6×10⁶ units/ M² IV three days a week for 4 weeks. This induction phase was followed by a maintenance phase of the same drugs and doses administered for two weeks out of every four.Results 84 patients were entered onto this phase II trial with 75 considered eligible for response and survival. Toxicity is reported for the 81 patients on whom data was received, irrespective of eligibility. The overall response rate (RR) was 9.3% (7/75). Of the 3 responses in the IL-2 arm (RR=8.3%), one was a complete response. 4 patients in the IL-2 + B-IFN arm (RR=10.3%) achieved a partial response. Median survival was estimated to be 8.4 months for patients given IL-2 and 8.0 months for patients given the IL-2 and B-IFN combination. Multivariate analysis of survival data identified initial performance status, metastases of >1 site, and weight loss as being important prognostic factors for survival. There were 2 lethal and 3 life threatening toxicities with the IL-2 treatment. While there were no lethal toxicities on the combination arm, there were 4 life threatening toxicities.Conclusions The results of this study indicate that further investigation of IL-2 with or without B-IFN at this dose and schedule as treatments for renal cell carcinoma is probably not warranted.Deceased; formerly at Lanenkau Hospital Cancer Treatment Center, Wynnewood, PA.     

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.     

Altretamine for the treatment of metastatic renal cell carcinoma. A Hoosier Oncology Group trial

Summary Thirty patients with advanced renal cell carcinoma weretreated on a phase 11 trial with altretamine. Altretamine wasadministered orally at a dosage of 260 mg/m² days 1 through14 with cycles repeated every 28 days. Nausea and vomitingwere the most common toxicities. Ten percent (3 of 30)experienced Grade 3 gait abnormalities. None of the thirtyevaluable patients achieved a complete or partial response. Insummary, altretamine did not show antitumor activity in thetreatment of advanced renal cell carcinoma.     

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 study of vinflunine in patients with metastatic renal cell carcinoma

Summary Purpose: An open-label, multicentre, non-comparative phase II trial to determine the response rate of intravenous vinflunine as first line chemotherapy in patients with metastatic renal cell carcinoma (RCC). Patients and methods: Patients with metastatic RCC were treated with vinflunine 350 mg/m² (n = 11) or 320 mg/m² (n = 22) administered intravenously every 21 days. Results: Out of 33 patients included in this study, one partial response was observed in the group treated at 350 mg/m² and none in the group receiving 320 mg/m² resulting in a response rate in this population of 9.1% (95% CI: 0.2–41.3). Median progression free survival was 5.6 months (95% CI: 2.8–14.4) for patients treated at 350 mg/m², and 3.3 months (95% CI: 1.6–6.4) for those treated at 320 mg/m².The median survival time was 10.4 months (95% CI: 6.8–12.4) for the whole study population. The principal toxicities were grade 3/4 neutropaenia —90.9% at 350 mg/m² and 68.1% at 320 mg/m², febrile neutropaenia was recorded in 3 patients (27.3%) at 350 mg/m² and in 5 patients (22.7%) at 320 mg/m². One episode of thromboembolic event was reported in 1 patient at each dose level. Conclusion: Vinflunine given intravenously once every 3 weeks has not shown any clinically relevant activity in the management of patients with metastatic renal cell carcinoma; tolerance of the treatment was better at a dose of 320 mg/m² than at 350 mg/m². Supported by Institute de Recherche Pierre Fabre Oncologie, Boulogne-Billancourt, France.     

Phase II study of echinomycin in patients with advanced breast cancer: A report of cancer and leukemia group B protocol 8641

Summary Twenty-five women with advanced histologically documented stage IV recurrent or inoperable breast cancer were enrolled on a phase II study of echinomycin administered at a dose of 1.2 mg/m² intravenously over 30 minutes weekly for 4 weeks followed by a two week rest period. Seventy-six percent of patients had visceral dominant disease at study entry and all patients had previously received chemotherapy. One of 21 eligible patients had a partial response lasting 147 days. The median survival for this group of patients was 5.9 months and the median time to treatment failure was 1.7 months. Nausea and vomiting was the primary toxic effect and was severe or life-threatening in 43% of patients. Transient elevation of liver enzymes occurred in 30% of patients. Bone marrow suppression was not significant. Echinomycin as employed in this study did not demonstrate significant antitumor activity in previously treated patients with advanced breast cancer.     

Polyethylene glycol conjugated interleukin-2: Clinical and immunologic effects in patients with advanced renal cell carcinoma

Summary Recombinant interleukin-2 (rIL-2) modified with monomethoxypolyethylene glycol (PEG IL-2) was utilized in patients with metastatic renal cell carcinoma in two separate multi-institutional trials. PEG IL-2 was administered as an I.V. bolus days 1, 8, 15, and 22 with cycles repeated every six weeks. The two trials employed different dose levels: A) 20x10⁶ I.U./m² day 1 followed by 12x10⁶ I.U./m² days 8, 15, 22; and B) 12x10⁶ I.U./m² days 1, 8, 15, 22. Thirty-five patients were entered and 31 were evaluable for response (A–15/18, B–16/17). Two of 31 patients had partial responses. Median therapy duration was four weeks (range 1–15), and dose reduction for grade III or IV toxicity was required in 14/35 patients (A-6/18, B-8/17). Toxicity ( grade III) seen included: hypotension 51%, dyspnea 17%, seizures 6%, and mental status changes 11%. No differences in response or toxicity between the two schedules were noted. Hematologic changes included lymphocytosis and eosinophilia in the majority of patients. PEG IL-2 given once weekly has significant toxicity, and may produce tumor regression in patients with renal cell carinoma.     

Phase II study of ifosfamide and mesna in patients with previously-treated carcinoma of the cervix

Summary Thirty patients with advanced squamous carcinoma of the uterine cervix recurrent after radiotherapy or surgery and refractory to first-line chemotherapeutic agents were treated with ifosfamide in a dose of 1.2 grams/m² IV daily for five days every four weeks and Mesna 300 mg/m² IV every four hours for three doses daily for five days. One patient had an inadequate trial and two were inevaluable for response, leaving 27 patients evaluable for response. All but two patients had received prior radiotherapy and all but one prior cisplatin-based or cisplatin analog chemotherapy. Seventeen patients had prior surgery. All patients were Gynecologic Oncology Group performance status 0, 1, or 2. Partial responses were observed in three patients (11.1%), two with pelvic and one with extrapelvic disease. A 90% confidence interval for the true response rate is 4.5%–24.8%. Severe (grade 3 or 4) leukopenia and anemia were seen in nine and seven patients, respectively. Severe thrombocytopenia was not observed. Three patients had grade 3 or 4 neurotoxicity, and one had grade 3 renal impairment. Reversible alopecia was universal. This dose and schedule of ifosfamide and Mesna is active in patients with squamous carcinoma of the cervix failing platinum-based therapy. Phase II testing in untreated patients is currently underway.     

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.     

A phase II study of tandutinib (MLN518), a selective inhibitor of type III tyrosine receptor kinases, in patients with metastatic renal cell carcinoma

Therapies which target VEGF and mTOR are now available for patients with metastatic renal cell carcinoma, but there is a continued need to develop agents for patients who become refractory to these initial agents. Tandutinib is a relatively selective inhibitor of type III tyrosine kinase receptor kinases with promising activity in some tumors. In this trial, 10 patients with metastatic renal cell carcinoma refractory to previous therapy with sunitinib or sorafenib (median age 61 years, 80% performance status 0, 60% intermediate MSKCC risk classification) received tandutinib 500 mg bid daily with RECIST-defined response as the primary endpoint and progression-free survival (PFS) and overall survival (OS) as secondary endpoints. No patient had more than 2 cycles of therapy and 50% of patients only received 1 cycle with 70% of patients discontinuing for progressive disease and 30% for toxicity. Tandutinib was not well tolerated with dose reduction in 60% of patients due to adverse events. The most common grade 3 toxicity was fatigue (30%). Tandutinib had no clinical activity and due to the excessive toxicity should not be developed further in patients with sunitinib or sorafenib-refractory metastatic renal cell carcinoma.     

Phase II evaluation of menogaril in patients with advanced hypernephroma

Summary Fifteen patients with advanced renal cell carcinoma were treated with Menogaril, 200 mg/m² by one-hour, intravenous infusion at four-week intervals. No objective regressions were observed. Median time to progression was two months, and median survival was seven months. All patients experienced neutropenia. Platelet toxicity was negligible. Venous irritation and phlebitis at the infusion site was seen in 47% of patients. Menogaril as administered in this protocol is ineffective in advanced renal cell carcinoma.     

Capecitabine monotherapy and in combination with immunotherapy in the treatment of metastatic renal cell carcinoma

This prospective trial aimed to evaluate the therapeutic effects and systemic toxicities of capecitabine monotherapy and capecitabine treatment combined with biological response modifiers in patients with metastatic renal cell carcinoma. Fifty-four patients suffering from metastatic renal cell carcinoma progressing under first-, second- or third-line treatment entered the trial. Capecitabine was given orally at a dose of 2500 mg/m2 daily divided into two doses for 14 days, followed by a 7-day rest in the monotherapy as well as in the combination treatment. This schedule was repeated in 3-week cycles. The combination therapy consisted of capecitabine and an immunotherapy treatment, which consisted either of interferon (IFN)-gamma1b (100 mg/day) administered consecutively 5 times weekly during weeks 1 and 2, and recombinant interleukin (IL)-2 (4.5 MU/day) administered on 4 consecutive days during weeks 3 and 4, every 6 weeks, or IFN-alpha (6 MioIE/day) administered 3 times a week. Fifty-two patients are now evaluable for response and 54 patients for toxicity. We observed a partial response to treatment in five patients (9.6%), minor response in five patients (9.6%), stable disease in 32 patients (61.6%) and only 10 patients (19.2%) showed continued disease progression despite treatment. Outpatient capecitabine was well tolerated. We did not observe any WHO grade IV toxicities. We conclude that capecitabine monotherapy and capecitabine treatment in combination with biological response modifiers appear to be effective regimens with favorable toxicity profiles in patients with advanced renal cell carcinoma. Capecitabine monotherapy seems to be superior than the combination treatment because of its easier application form.     

Phase II trial of piroxantrone in patients with recurrent and metastatic squamous cell carcinoma of the head and neck

Summary Twenty-two patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with piroxantrone 150 mg/m² intravenously every 21 days. There were no objective responses. The 95% upper confidence bound for response is 15%. Primary toxicity was hematologic.     

A Phase II Pilot Study of KW-2189 in Patients with Advanced Renal Cell Carcinoma

Background: KW-2189 is a semi-synthetic, water-soluble analog of duocarmycin B₂, a new class of potent antitumor antibiotics produced by streptomyces, with improved in vitro antitumor potency. Patients and methods: Forty patients with pathologically confirmed metastatic renal cell carcinoma were treated in this multicenter, open-label phase II trial. All patients received 0.4mg/m² KW-2189 as an IV infusion for Cycle 1. Cycles were repeated every 5 to 6 weeks with escalations to 0.5 mg/m² in the absence of significant toxicity or disease progression. Results:No patient had an objective response. The most common drug-related toxicity was hematological-delayed neutropenia and thrombocytopenia, with recovery by week 6. Non-hematologic toxicity consisted of mild to moderate fatigue, nausea and vomiting, and anorexia that was generally manageable. Conclusions: KW-2189 in this dose and schedule has a predictable safety profile of reversible myelosuppression. No activity in metastatic renal cell carcinoma was demonstrated.