Phase II trial of N-methylformamide in patients with metastatic melanoma

Summary Sixteen patients with metastatic melanoma were treated with N-methylformamide (NMF), a polar-planar compound with in vitro cytotoxic and differentiating properties. Sixteen patients were evaluable for toxicity and 14 for response. The initial four patients received an intravenous bolus of NMF 800 mg/m² daily for 5 consecutive days every 28 days. Because of excessive gastrointestinal toxicity, the dose was reduced to 700 mg/m²/day for the subsequent 12 patients. Two patients had immediate adverse effects from NMF; one had a grand mal seizure and the other developed severe abdominal pain. Nausea, vomiting and abdominal pain were dose-limiting. Transient elevation of liver function tests occurred in all patients. Myelosuppression was not observed. There were no objective responses among 14 evaluable patients (95% confidence limits 0–20%). One patient with pulmonary metastases had a minor response lasting 13 months. Median time to progression of disease was one month. NMF in these doses and schedule lacks clinical efficacy in the treatment of metastatic melanoma.     

Phase II trial of trimetrexate in advanced esophageal cancer: A southwest oncology group study

Trimetrexate (TMQ) is a synthetic folate antagonist that has demonstrated non-cross resistance with methotrexate in preclinical screens. A phase II trial was performed with TMQ given to patients with advanced squamous cell carcinoma of the esophagus. TMQ was administered as an i.v. bolus on a daily × 5 schedule, every 3 weeks; a starting dose of 12 mg/m² was used for patients with no prior irradiation, and of 8 mg/m² for patients with prior irradiation. Twenty-four patients were entered onto study, with 23 patients eligible, and a median of 2 courses of TMQ administered per patient. Twenty-three patients were evaluable for toxicity. Toxicities of SWOG grade 3 included granulocytopenia (9 patients), leukopenia (7 patients), thrombocytopenia (4 patients), anemia (3 patients), mucositis (3 patients), nausea and vomiting (2 patients), dermatitis (1 patient), diarrhea (1 patient), and fever (1 patient). Fifteen patients had some hematologic toxicity, and eleven patients had hematologic toxicity of grade 3. Two treatment related deaths occurred in association with myelosuppression. One patient achieved a complete response and one patient achieved a partial response, with response durations of 8.5 months and 6 months, respectively. The overall response rate was 8% [95% confidence interval of 1 to 28%], with a median survival for the 23 eligible patients of 5.1 months.     

A phase II trial of piroxantrone in disseminated malignant melanoma

Summary Piroxantrone is one of the anthrapyrazoles developed in an effort to combine the broad antitumor activity of the anthracyclines with decreased myocardial toxicity. It has shown activity in metastatic melanoma during phase I trials. The Southwest Oncology Group (SWOG) conducted a phase II trial in disseminated malignant melanoma with piroxantrone administered at 150 mg/m² intravenously over 1 h every 21 days, based upon the phase I experience. Forty-six eligible patients were registered to the trial and 44 were evaluable for response. Two partial responses, Wayne of 6 and 9 months duration were observed for an overall response rate of 5% (95% confidence interval 1%–15%). Thirty-six of 46 eligible patients have died with an estimated median survival of 5 months (95% confidence interval 3–8 months). Toxicities were tolerable with granulocytopenia being the predominant toxicity. Based upon the observed response rate, it is concluded that piroxantrone administered at this dose and schedule has detectable but minimal activity, and does not warrant further investigation in this disease.     

Phase II trial of cisplatin and etoposide in patients with metastatic melanoma

Summary Fourteen patients with metastatic melanoma were treated with cisplatin and etoposide by bolus intravenous infusion daily for 5 consecutive days each month. All patients were evaluable for toxicity and twelve for response. Eight patients were treated with cisplatin 20 mg/m² and etoposide 100 mg/m² daily. Because of excessive myelosuppression, the daily dose of etoposide was reduced to 75 mg/m² in the remaining six patients. There were no major responses among 12 evaluable patients (major response rate 24% with 95% confidence). The median time to progression was one month. One patient with a liver metastasis had a minor response lasting 6 + months. The combination of cisplatin and etoposide in these doses and schedule lacked sufficient clinical efficacy in the treatment of metastatic melanoma.     

Phase II trial of vinblastine in advanced ovarian carcinoma

Summary A phase II trial of vinblastine in patients with refractory epithelial ovarian adenocarcinoma of the ovary was conducted by the Gynecologic Oncology Group (GOG) between March 9, 1988 and July 7, 1988. Vinblastine was administered in a dose of 9 mg/m² intravenously every three weeks until disease progression or toxicity supervened. Twenty patients were entered initially. One was ineligible due to a previous primary cancer. Thus, 19 patients are evaluable for toxicity and response. All patients had cisplatin-combination chemotherapy and four had prior radiotherapy. Median age was 63 years (range 40–75 years). Thirteen patients had disease in the pelvis and six had extrapelvic metastases. Ten patients had grade 3 lesions and seven had grade 2. A median of two courses (range: 1–6) were administered. Toxicity was moderate. Seven patients (36.8%) experienced GOG grade 3 or 4 leukocytopenia and six had grade 3 or 4 granulocytopenia. Median nadir WBC was 2,000 cells/1 (range 600–3,500) and platelet nadirs for the three patients with thrombocytopenia were 60,000, 116,000, and 147,000. Other toxicity included grade 3 gastrointestinal and renal toxicity in one patient each. Seven patients (36.8%) had stable disease on therapy and 12 had increasing disease. No responses were observed. Vinblastine in this dose and schedule is inactive in patients with resistant epithelial ovarian adenocarcinoma progressing on first-line chemotherapy. Responsible author: Dr. Gregory P. Sutton, Indiana University Medical Center, Section of Gyn. Oncology, Dept. of Obstetrics & Gynecology, 926 West Michigan Street, Indianapolis, IN 46223, USA.     

Phase II trial of topotecan in advanced gastric cancer: A Southwest Oncology Group study

Topotecan (NSC 609099) is a camptothecin analogue that demonstrated activity against a variety of human tumors in preclinical studies. A phase II trial was performed with topotecan given to patients with locally advanced or metastatic adenocarcinoma of the stomach. Topotecan was administered IV Bolus over 30 minutes on a daily × 5 schedule, every three weeks, with a starting dose of 1.5 mg/m². Twenty patients were entered onto the study, all of whom were eligible. All patients were evaluable for toxicities. Half of these patients experienced at least one Grade 4 hematologic toxicity, comprised of either granulocytopenia or leukopenia (4 patients with both, 3 patients with grade 4 granulocytopenia, and 2 patients with only grade 4 leukopenia). Other non-life threatening (Grade 3) toxicities included nausea (2 patients), weakness (2 patients), weight loss (1 patient), blurred vision (1 patient), diarrhea (1 patient) and malaise/fatigue/lethargy (1 patient). Two patients achieved a partial response, for an overall response rate of 10% (95% confidence interval of 1.2 to 31.7%). The median survival for the 20 patients was five months.     

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.     

Phase II evaluation of topotecan in patients with advanced colorectal cancer. A Southwest Oncology Group trial (SWOG 9241)

The topoisomerase-1 inhibitor, topotecan, was tested in 48 eligible patients with advanced colorectal cancer. The patients had no prior chemotherapy and a Southwest Oncology Group performance status of 0–2. Topotecan was administered intravenously at 1.5 mg/m²/day for five days and repeated every 21 days. The major toxicity was hematologic with 19 out of 48 (40%) patients having grade IV granulocytopenia and 4 out of 48 (8%) patients demonstrating grade IV thrombocytopenia. Two patients (4%) demonstrated partial response. Thirty patients have died and the Kaplan-Meier estimate of median survival is 9 months (95% confidence interval; 7–16 months). Topotecan in this dose and schedule does not appear active in patients with advanced colorectal cancer.     

Amonafide treatment of refractory esophageal cancer

Summary Amonafide, a synthetic benzisoquinolinedione, was evaluated for treatment of squamous esophageal cancer. Eleven men and 5 women were eligible with a median performance status of 1 and median age of 63 years. Six had no prior treatment. All patients had measurable disease. Therapy consisted of amonafide 300 mg/m²d days 1–5 every 21 days. Thirty-five courses of therapy were delivered. The median number of courses received was two. Sixteen patients are evaluable for toxicity. Thirteen are evaluable for response. Toxicity was severe. Seven patients were hospitalized for toxicity. Six patients had grade IV granulocytopenia; two, grade IV thrombocytopenia. Angioedema developed in one patient; severe exfoliative dermatitis in another. A single partial response, with the decrease in size a supraclavicular node, was noted in a previously untreated patient. Amonafide, in this dose and schedule, is associated with occasionally severe toxicity precluding its likely use in squamous cell esophageal carcinoma.     

Vinorelbine in pre-treated advanced head & neck squamous cell carcinoma

Summary Background: There are few moderately active single-agents for the treatment of recurrent or metastatic head & neck cancer. Thus, the identification of novel active agents is warranted. We performed the present phase II trial to evaluate activity and toxicity of vinorelbine (VNB) in previously treated patients with advanced head & neck cancer.Patients and methods: 16 patients entered the study, 15 of whom were évaluable. The main characteristics were: M/F=14/1; median age of 58 yrs (18–67); median PS (Karnofsky score) of 70 (60–100); primitive tumor sites were: oropharynx in 5; larynx in 4, hypopharynx in 3, rhynopharynx in 2, and oral cavity in 1 patient; initial clinical stage was IV in 9, III in 4 and II in 2 patients. Previous treatments were: cisplatinum with concurrent radiotherapy in 6 and cisplatinum + fluorouracil (for at least 2 cycles) in 9 patients. VNB was given at the dose of 20 mg/m² i.v. infusion for 1 hr, weekly, for a minimum of 8 doses. Response and toxicity were evaluated after at least 8 doses of VNB.Results: Overall, 139 courses of VNB were given (median 9, range 8–19). Objective responses were: partial response in 1 patient (6%); stable disease, lasting at least 2 months, in 4 patients (27%) and progression in the other 10 patients (67%). Three patients had a one week delay in subsequent courses due to severe hematological toxicity.Toxicities observed were: leucopenia of grade IV (W.H.O.) in 2 patients and of grade I-II in 12 patients; granulocytopenia of grade III in 1 patient and of grade IV in 2 patients; grade I-II anemia in 4 patients; grade II phlebitis in 3 patients; grade II constipation in 2 patients, grade I-II peripheral neuropathy in 3 patients, grade I-II nausea and vomiting in 4 patients, and grade II stomatitis in 2 patients. Conclusions: VNB, in this series of heavily pre-treated patients with head & neck cancer, did not reveal an antitumor activity of interest.     

A phase II study of menogaril (NSC-269148) in colorectal carcinoma

Summary In this phase II trial, menogaril was administered to patients with metastatic colon cancer at a dose of 200 mg/m² IV over one hour with cycles repeated every 28 days provided the absolute granulocyte count was 2000 cells/l. Dose adjustments up or down were made depending upon nadir counts. Twenty-four patients were entered on this study with 21 eligible and evaluable for response. There was 1 CR lasting four and one-half months and 1 PR lasting three months for an overall CR \s&#x002B; PR rate of 10% with a 95% confidence interval of 1% to 30%. Six patients (29%) had stable disease and 13 (62%) progressed. Median survival is 13.1 months. Toxicity was primarily hematologic with two cases of life-threatening leukopenia (< 1000 cells/l) and one case of life-threatening granulocytopenia (< 250 cells/l) among the 21 eligible patients, and one case of life-threatening leukopenia and granulocytopenia in one ineligible patient. There were no deaths due to treatment.     

Phase II trial of trimetrexate in untreated advanced gastric carcinoma

Summary Twenty-three evaluable patients with advanced gastric adenocarcinoma were treated with trimetrexate at doses of 8–12 mg/m² intravenously daily for five days, with cycles repeated every 21 days. One complete response was seen for an overall response rate of 4% (95% confidence interval 0–22%). Hematologie toxicities of grade 3 were seen in 10/23 patients, and overall any grade 3 or greater toxicity was seen in 14/ 23 patients. Trimetrexate has minimal activity against gastric adenocarcinoma in this study, and no further investigation of this agent at this dose and schedule is recommended in this disease.     

Phase II trial of merbarone in soft tissue sarcoma

Thirty-seven patients with advanced soft tissue sarcoma were treated with merbarone utilizing a daily intravenous schedule for five days. Only one partial response was observed in the thirty-three evaluable patients. The major toxicities were renal, with elevation of creatinine and/or proteinuria, and gastrointestinal, with mild to moderate nausea and vomiting. Merbarone in this dose and schedule has minimal activity in soft tissue sarcoma.     

Mitomycin C continuous infusion as salvage chemotherapy in pretreated patients with advanced gastric cancer

Our purpose was to evaluate the safety and therapeutic activity of continuously infused mitomycin C in patients with recurring or progressive metastatic gastric cancer following first-line chemotherapy. Patients were treated with mitomycin C 20 mg/m2 i.v. over a time period of 120 h followed by a 3-week rest period. All patients received prednisone 50 mg p.o. prophylactically for 5 days to prevent hemolytic uremic syndrome and pulmonary side effects. Twenty-two consecutively enrolled patients were assessable for toxicity and 20 for response evaluation completing at least one full course of chemotherapy (two patients evaluable but not measurable). Patient characteristics: median age: 63 years (39-76); Sex (M/ F): 13/9; median Karnofsky status: 70% (50-100%); resection of primary tumor n = 12 (55%); sites of metastases: liver n = 17 (77%), locally advanced n = 10 (45%), peritoneum n = 13 (59%), lungs n=5 (23%), bone n=3 (14%) and lymph nodes n=14 (64%). Previous chemotherapy regimens: bolus 5-FU/folinic acid n=6 (27%), ELF n=4 (18%), EAP n=3 (14%) and continuous 5-FU/folinic acid/cisplatin/paclitaxel n=9 (41%). In 20 evaluable patients one complete and five partial remissions were observed; overall response rate 30.0% [95% confidence interval (CI): 9.1-50.9%] with a median response duration of 2.1 months (range: 2-6). The median survival was 3.6 months (95% CI: 2.1-6.0) resulting in a 6-month survival rate of 30% since start of mitomycin C. WHO grade III/IV mucositis, diarrhea and fever/infection occurred in 9% of patients each. Cumulative thrombo- and leukocytopenia (WHO grade II/IV) were observed in four and two patients, respectively. Treatment had to be stopped early in two patients. No severe renal dysfunction, pulmonary toxicity or evidence of hemolytic uremic syndrome was observed. Fatigue during the 120 h infusion of mitomycin C was common (11 of 22 patients). We conclude that continuous infusion of mitomycin C is feasible on an outpatient basis, revealing an acceptable toxicity. Mitomycin C demonstrates single-agent activity in pretreated gastric cancer, but has only limited efficacy following cisplatin/paclitaxel-based first-line chemotherapy.     

A phase II trial of pemetrexed in patients with metastatic renal cancer

Background. Metastatic renal cell carcinoma (RCC) is rising in incidence but remains difficult to treat. This clinical trial evaluated the effects of pemetrexed (multitargeted antifolate, ALIMTA®) for the treatment of metastatic RCC. Patients and methods. Patients were required to have histological diagnosis of metastatic RCC with measurable disease and no prior chemotherapy. In addition, patients were required to have a World Health Organization (WHO) performance status of 0–2 and adequate bone marrow reserve. Patients received pemetrexed at a dose of 600mg/m² as a 10min infusion every 3 weeks. Patients did not receive folic acid or vitamin B₁₂ supplementation. Results. Thirty-nine patients were enrolled and thirty two were evaluable for response. Three patients had a partial response for a response rate of 9% (95% CI 2–25%). The median time to progressive disease was 10.5 months. Of the nonresponders, twenty two had stable disease (median duration was 5.8 months; range 1.5–27.7) and seven had progressive disease (median time to progression was 5.4 months). Median time to progression for all qualified patients was 5.7 months. Common toxicities experienced were diarrhea and infection. Fatigue, stomatitis, and rash were also reported. The most common hematologic toxicity was grade 3/4 lymphopenia in 76% of patients. Leukopenia, granulocytopenia, and thrombocytopenia were also frequently reported. Conclusion. Single-agent pemetrexed has moderate activity in the treatment of metastatic RCC and should be investigated in combination with other potential active agents, as first-line treatment.     

Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma

PURPOSE: To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system. PATIENTS AND METHODS: Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m(2) IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles. RESULTS: 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8-9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received >/=90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity. CONCLUSIONS: Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.     

A phase II study of topotecan in patients with anaplastic oligodendroglioma or anaplastic mixed oligoastrocytoma

To determine the efficacy and toxicity of a novel chemotherapeutic approach with topotecan, a camptothecin analog, for progressive or recurring anaplastic oligodendroglioma or mixed oligoastrocytoma.Patients from seven centers with recurrent or progressive disease were treated with topotecan, 1.5mg/m² intravenously (i.v.), 30min daily×5 days every 3 weeks. Efficacy and toxicity were assessed clinically and radiologically. The study was planned to accrue up to 30 evaluable patients if there was at least one response among the first 15 patients treated.Sixteen eligible patients entered the study. No response was documented in 14 evaluable patients. Eleven patients had stable disease of a median of 3.8 months and three had progressive disease. Sixteen patients were evaluable for toxicity. The most significant toxic effect was myelosuppression. Grade 3 or 4 granulocytopenia was experienced by 15 of 16 patients and led to dose reduction in nearly half of the cycles delivered. Other adverse effects were fatigue, nausea, stomatitis, alopecia, and vomiting.Topotecan, delivered in the daily×5 regimen, is relatively well tolerated. We could not demonstrate significant activity among the population studied to justify completing accrual to 30 patients. Topotecan did not demonstrate, with this small sample size, efficacy as a salvage chemotherapy monotherapy after exposure to procarbazine, CCNU and vincristine. Further trials with different agents in this indication are certainly warranted.     

Hepatoma/merbarone

Summary Sixteen eligible patients with hepatocellular carcinoma, previously untreated, received merbarone 1000 mg/ m²/d for five consecutive days every 21 days. No complete or partial response to treatment was obtained. Seven patients had grade 4 granulocytopenia. One patient died with renal failure. Merbarone in this dose and schedule was ineffective in the treatment of hepatocellular carcinoma.     

A phase II study of taxol in patients with malignant melanoma

Based on results of a phase I study demonstrating antitumor activity of taxol in patients with melanoma, 34 patients with documented metastatic melanoma received taxol, 250 mg/m², as a 24-hours infusion, repeated every 21 days, in this phase II study. All patients received premedication with dexamethasone, diphenhydramine and cimetidine. Four patients experienced anaphylactic reactions and stopped treatment. Other significant toxicity of this drug included short-lived but severe neutropenia (< 1,0007mm²) and peripheral neurotoxicity. Four of 28 evaluable patients demonstrated objective response (14%) (confidence interval, 4%–33%) including 3 complete responses and 1 partial response. Two complete responders are continuing at 25 + and 38 + months after achieving CR. Minor evidence of anti-tumor activity was noted in five additional patients. Taxol has significant activity in melanoma and should be further studied in combination with other agents in this disease.     

Phase II study of paclitaxel (BMS-181339) intravenously infused over 3 hours for advanced or metastatic breast cancer in Japan

A Phase II study of paclitaxel in patients with primary advanced or metastatic breast cancer was conducted by a cooperative study group consisting of 16 institutions in Japan. Paclitaxel at a dose of 210 mg/m2 was intravenously infused over 3 hours, along with premedication to prevent hypersensitivity reactions. The course was repeated at 21-day intervals. Of 62 eligible patients, 60 were evaluable for toxicity and 59 were evaluable for efficacy. Forty-five patients were previously treated with anthracyclines. Twenty-one of 59 patients (35.6%) had a major objective response including 2 CRs and 19 PRs (95% confidence interval, 23.6–49.1%). A response rate of 35.5% (CR1, PR10) was observed in 31 patients refractory to the anthracyclines containing prior metastatic chemotherapy. Median (range) time was 41 (6–100) days to onset of and median duration of response was 125 (36–305) days. Toxicities included leukopenia (grade 3, 4: 67%), anemia (grade 1–3: 80%), thrombocytopenia (grade 1: 8%), alopecia (grade 3: 43%), peripheral neuropathy (grade 1–3: 93%), arthralgia (59%), myalgia (46%), nausea and vomiting (40%), fever (33%), allergic reaction (grade 3: 2%) and hypotension (grade 3: 5%). All toxicities were tolerable and manageable. Paclitaxel intravenously infused over 3 hours demonstrated a significant antitumor activity for metastatic breast cancer. Furthermore, paclitaxel exhibited non-cross resistance to anthracycline. Paclitaxel administered as a convenient 3-hour infusion is effective for patients with metastatic breast cancer and has an acceptable toxicity profile.