A Phase II Trial of Topotecan in Esophageal Carcinoma: A Southwest Oncology Group Study (SWOG 9339)

Background. Chemotherapeutic treatments containingtopoisomerase I inhibitors have shown antitumor activity against anumber of solid tumors. Responses have been seen in Phase I trialsusing topotecan in ovarian, lung, and esophageal cancer. A phase II trial using continuous infusion topotecan was completed toassess activity in esophagus cancer. Methods. Forty-fiveeligible patients with locally-advanced or metastatic squarnouscell carcinoma or adenocarcinoma of the esophagus received a regimen consisting of 24-hour continuous infusion topotecan at 1.5mg/m²/day on Days 1, 8, 15, 22 (of 42-day cycle). Patientscontinued on treatment until evidence of disease progression orunacceptable toxicity. Results. Partial response was demonstrated in 1 patient (2% confirmed response rate). Thirty-sixpatients progressed during the first cycle of treatment. The mediansurvival was 3 months, and the median progression-free survival was1 month. Toxicity was mild with only one Grade 4 toxicity reported.Conclusions. This phase II trial indicates nosignificant anti-neoplastic activity for topotecan administered inthe dose and schedule to patients with squamous cell oradenocarcinoma of the esophagus.     

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 trial of topotecan by continuous infusion in patients with advanced soft tissue sarcomas,a SWOG study. Southwest Oncology Group

Purpose: Based upon the hypothesisthat prolonged exposure to the S-Phasespecific agent topotecan would be moreefficacious in the treatment of soft tissuesarcomas than a conventional 5-day scheduleof the drug, the Southwest Oncology Groupperformed a Phase II trial of topotecanadministered as a continuous infusion inadult patients with advanced soft tissuesarcomas. Methods: Patients who had receivedno prior chemotherapy for advanced diseasewere treated with topotecan at a dose of0.50 mg/m²/day on days 1–21 ofrepeated 28 day cycles. Results: Twenty-two patients wereenrolled on the study, of whom 21 wereeligible. No objective responses wereobserved (95% confidence interval of 0–16%). The mediansurvival was 12 months(95% confidence interval of 5–16months). Conclusions: We conclude thattopotecan, given either according to a5-day or a 21-day schedule, has minimalactivity in the treatment of adult softtissue sarcomas.     

Phase II trial to topotecan in hepatocellular carcinoma: A Southwest Oncology Group study

Hepatocellular carcinoma remains a highly chemoresistant neoplasm. In this study of the topoisomerase I inhibitor topotecan a response rate of 13.9% (95% confidence interval 4.7%–29.5%) was obtained utilizing a five consecutive day bolus infusion schedule. There were no complete responses and the median survival was only eight months. Furthermore, treatment with topotecan produced significant toxicity with two-thirds of patients experiencing life-threatening (grade 4) neutropenia. When used in this dose and schedule, topotecan does not appear to be effective for patients with advanced hepatocellular 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.     

Phase II trial of R115777 (NSC #70818) in patients with advanced colorectal cancer: A Southwest Oncology Group study

Summary Purpose: The purpose of this Phase II multi-institutional trial was to determine the efficacy and toxicity of R115777 in previously untreated patients with metastatic colorectal carcinoma. Patients and methods: Patients were required to have histologically confirmed colorectal cancer with distant metastatic disease that was not surgically curable. They could not have received prior chemotherapy for metastatic disease. R115777 was given at a dose of 300 mg p.o. twice a day for 21days every 28 days until tumor progression or toxicity or other reason for discontinuation occurred. The primary endpoint was to determine the confirmed response probability with this treatment. Results: There were 55 eligible patients accrued to the study. There were no complete responses, but one confirmed partial response for a confirmed response probability of 2% (95%CI 0–10%). Three additional patients had an unconfirmed partial response for an overall response probability of 7%. The time to treatment failure was 1.7 months and the estimated median survival was 8.1 months. One patient died of treatment related infection and there were 7 other patients with grade 4 toxicities consisting of neutropenia, leukopenia, febrile neutropenia and thrombocytopenia, depression, increased bilirubin, anemia, and pneumonitis/infiltrates. Conclusion: R115777 given as a single agent by this dose and schedule is ineffective in patients with metastatic colorectal cancer.     

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)     

Phase II trial of topotecan in advanced or metastatic adenocarcinoma of the pancreas

SummaryPurpose A phase II trial of topotecan, an inhibitor of topoisomerase I, was conducted in patients with advanced or metastatic adenocarcinoma of the pancreas to determine the activity and toxicity of topotecan.Patients and Materials 35 patients, previously untreated with chemotherapy, received topotecan 1.5 mg/ m²/d for five days intravenously and repeated every 21 days. Patients were assessed for response after 3 cycles. Those with either clinical response or stable disease received additional cycles of the drug until toxicity developed or disease progression occurred.Results Among 30 patients evaluable for response there were no complete responses and 3 partial responses (10%) for a total response rate of 10% (95% confidence interval = 0–20.6%). Stable disease for at least eight weeks was seen in 11 patients (36%). Median survival was 19 weeks (95% confidence interval 11 to 26 weeks). Therapy was generally well tolerated, with reversible granulocytopenia being the most common toxicity.Conclusion Topotecan given on a 5 day, short infusion schedule, demonstrated limited activity in pancreatic carcinoma with minimal toxicity. Further exploration of topotecan in pancreatic carcinoma using different dosing schedules is warranted.     

Phase II trial of topotecan in patients with cisplatin-refractory germ cell tumors

Summary Fifteen patients with advanced, cisplatin-refractory germ cell tumors (GCT) were treated on a phase II trial with topotecan. None of the 14 evaluable patients achieved a complete or partial response. Myelosuppression was the major toxicity. The median nadir leukocyte count was 1.75 cells/mm³, neutrophil count was 1.55 cells/mm³, hemoglobin was 8.75 gm/dl, and platelet count was 20,500 cells/mm³. Topotecan is not efficacious in the treatment of cisplatin-refractory GCT.     

Biochemical modulation of 5-fluorouacil through dihydropyrimidine dehydrogenase inhibition: a Southwest Oncology Group phase II trial of eniluracil and 5-fluorouracil in advanced resistant colorectal cancer

Purpose. To investigate thehypothesis that a systemic agent designedto inhibit dihydropyrimidine dehydrogenase(DPD), the first enzyme in thefluoropyrimidine degradative pathway, couldimprove the effective amount of5-fluorouracil (5-FU) delivered to a tumorresulting in enhanced response. Patients and methods. Eligibility includedcytologically or pathologically verifieddiagnosis of colorectal cancer thatrecurred during or within 12 months ofcompletion of adjuvant therapy,representing patients generally consideredresistant to fluorinated pyrimidinetherapy. Stratification was into twocohorts: recurrence while receivingadjuvant therapy, and relapse within 12months of completing adjuvant therapy.Treatment consisted of 28 days of oraltherapy every five weeks with eniluraciland 5-FU administered in a 10:1 ratio. Thedaily dose of eniluracil was 10 mg/m²with 5-FU 1 mg/m², divided into twodoses. Results. Twenty-five patientsare evaluable for response: 9 relapsedduring therapy and 16 relapsed within oneyear of adjuvant therapy. In the firstgroup, there was one partial response (9%;95% CI 0–41%); in the second cohort therewas one confirmed complete response (5%;95% CI 0–23%) and one unconfirmed partialresponse, for an overall response rate of10%. Conclusions. This regimen lackssignificant activity in this targetpopulation. Pre-treatment intratumoral DPDexpression was not assessed, therefore themechanism of fluorinated pyrimidineresistance cannot be specificallyattributed to elevated DPD levels.Attempting restoration of chemotherapysensitivity through blockade of enzymes orsignal transduction molecules responsiblefor resistance is rational, provided thattumor target expression is the basis fortrial entry.     

A Phase II trial of epothilone B analogue BMS-247550 (NSC #710428) ixabepilone, in patients with advanced pancreas cancer: A Southwest Oncology Group study

Summary Purpose: The purpose of this Phase II multi-institutional study was to define the efficacy and toxicity of ixabepilone in patients with advance pancreatic adenocarcinoma. Patients and methods: Patients were required to have pancreatic adenocarcinoma and metastatic or recurrent disease that was not amenable to curative resection. Performance status was 0-1, and patients could not have had prior chemotherapy, or chemoradiation therapy for their advanced disease although prior local palliative radiation was allowed. Ixabepilone was administered iv as a 3 hour infusion every 21 days. Initially, the dose was 50 mg/m² but this was lowered to 40 mg/m² shortly after the trial opened because of concerns about neurotoxicity. Results: Sixty-two patients were registered however 2 were ineligible because they did not have recurrent or metastatic disease. For the 60 eligible patients, 22 had performance status of 0 and 38 performance status of 1. The estimated 6-month survival was 60% (95% CI 48%–72%) with a median survival of 7.2 months and an estimated time to treatment failure of 2.3 months. Out of 56 patients with measurable disease there were 5 confirmed partial responses for a confirmed response probability of 9% (95% CI 3%–20%) and 7 unconfirmed partial responses for an overall response probability of 21% (95% CI 12%–34%). Common toxicities were neutropenia/granulocytopenia, nausea and vomiting and neuropathy. There was one death, cause not determined but judged “possibly” related to treatment. Conclusion: Ixabepilone shows encouraging activity in patients with advanced pancreatic cancer and should be investigated further in this disease. This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA38926, CA32102, CA20319, CA35090, CA52654, CA12644, CA45560, CA35431, CA45807, CA16385, CA76447, CA46441, CA35178, CA11083, CA46282, CA58686, CA76429, CA46368, CA04919, CA45377, CA67663, CA35176, CA63848, CA27575, CA35281, CA35119.     

VM-26 in colorectal carcinoma: A Southwest Oncology Group study

Summary In this multi-institutional phase II study, VM-26 or Teniposide was administered to forty-two patients with advanced colorectal cancer. Patients were initially treated at 60 mg/M² daily for 5 days with dose adjustments depending on toxicity. One complete response and one partial response were observed lasting six and four months respectively. Leukopenia was severe in 40% of patients. No drug related deaths were seen. In this Southwest Oncology Group (SWOG) study, VM-26 appeared to have minimal benefit in advanced colorectal cancer. Address for offprints: Southwest Oncology Group (SWOG 8426), Operations Office, 5430 Fredericksburg Road, Suite #618, San Antonio, TX 78229, USA     

Phase II study of didemnin B in advanced colorectal cancer

Summary Didemnin B is a depsipeptide derived from a Caribbean tunicate (sea squirt) that has demonstrated antineoplastic activity against a variety of murine tumor models, including the L1210 and P388 leukemia, the B16 melanoma, and M5076 sarcoma cell lines. Based on these data, we designed a phase II trial in which 15 patients with measureable, unresectable colorectal cancer were treated with Didemnin B at an initial dosage of 3.47 mg/m² over 30 minutes administered by intravenous infusion every 28 days; the dosage was altered in accordance with the toxicity observed, with only one patient requiring a dosage reduction for pronounced nausea and vomiting. No hematologie or nonhematologic toxicity developed. No complete or partial responses were observed. These results do not compare favorably with results of treatments using other single agents or combinations that are currently available for the treatment of advanced colorectal cancers. However, because of the tolerable levels of toxicity experienced by in our patients, it is possible that an insufficient dose of the medication was delivered. We concluded that Didemnin B is not active against of colorectal cancers at the dosage and schedule at which it was administered in this study.     

Phase II trial of edatrexate in relapsed or refractory germ cell tumors: A Southwest Oncology Group study (SWOG 9124)

Up to 30% of patients with advanced germ cell tumors will fail induction chemotherapy or will relapse. New agents with activity in this still potentially curable subgroup of patients are needed. Edatrexate (10-ethyl, 10-deaza-aminopterin) is a methotrexate analogue that has preclinical and clinical activity in breast, lung, and head and neck cancers, as well as in non-Hodgkin's lymphomas. A phase II trial of edatrexate in relapsed or refractory malignant germ cell tumors was conducted by the Southwest Oncology Group (SWOG). Twenty-five patients were enrolled in the trial. Edatrexate was administered intravenously at a dose of 80 mg/m² weekly for four weeks followed by a one-week rest period. The treatment course was repeated every five weeks. Among the 23 patients evaluable for response, there were no objective responses with all patients developing progressive disease. Thirteen patients (56%) developed Grade 3–4 toxicities, predominantly stomatitis and malaise/fatigue/lethargy. One patient developed Grade 4 anemia while another developed grade 4 anemia and thrombocytopenia. No patients discontinued treatment due to toxicity nor were there any toxic deaths. Edatrexate administered in this dose and schedule has no antitumor activity and has substantial toxicity in patients with relapsed or refractory germ cell tumors.     

Phase II trial of edatrexate in relapsed or refractory germ cell tumors: A Southwest Oncology Group study (SWOG 9124)

Up to 30% of patients with advanced germ cell tumors will fail induction chemotherapy or will relapse. New agents with activity in this still potentially curable subgroup of patients are needed. Edatrexate (10-ethyl, 10-deaza-aminopterin) is a methotrexate analogue that has preclinical and clinical activity in breast, lung, and head and neck cancers, as well as in non-Hodgkin's lymphomas. A phase II trial of edatrexate in relapsed or refractory malignant germ cell tumors was conducted by the Southwest Oncology Group (SWOG). Twenty-five patients were enrolled in the trial. Edatrexate was administered intravenously at a dose of 80 mg/m2 weekly for four weeks followed by a one-week rest period. The treatment course was repeated every five weeks. Among the 23 patients evaluable for response, there were no objective responses with all patients developing progressive disease. Thirteen patients (56%) developed Grade 3-4 toxicities, predominantly stomatitis and malaise/fatigue/lethargy. One patient developed Grade 4 anemia while another developed grade 4 anemia and thrombocytopenia. No patients discontinued treatment due to toxicity nor were there any toxic deaths. Edatrexate administered in this dose and schedule has no antitumor activity and has substantial toxicity in patients with relapsed or refractory germ cell tumors.     

Phase II trial and pharmacokinetic study of thalidomide in patients with metastatic colorectal cancer

Introduction. This study was designed to estimate the percentage of objective tumor responses, toxicity profile, and obtain additional information about the plasma pharmacokinetics of thalidomide in patients with refractory and progressing metastatic colorectal cancer. Study design. This phase II clinical trial was conducted according to the two-stage Simon method with the inclusion of consecutive patients. The study protocol was approved by the Institutional Review Board (IRB) of the Academic Hospital (HCPA) of the Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. Patients and methods. Seventeen patients with previously treated, refractory progressive metastatic colorectal cancer were eligible. Six patients had prior radiotherapy. The patients had a median of one previous chemotherapy regimen. Patients were initially treated with 200mg/day of thalidomide with an increase in dose by 200mg/day every 2 weeks until a final daily dose of 800mg/day was achieved. Patients were evaluated every 8 weeks for response by radiographic criteria. Plasma pharmacokinetics studies were performed in four patients at 200mg level and in one patient at 600mg during the first 24h. Main outcome measures and results. A total of 17 patients were accrued, all of them being evaluable for toxicity and 14 for response. Thalidomide was well tolerated, with constipation, somnolence, dizziness, and dry mouth being the major toxicities. There were no objective response or stable disease. The median survival was 3.6 months. Single-agent thalidomide is a generally well-tolerated drug that showed no antitumor activity in patients with advanced pretreated metastatic colorectal cancer. Although thalidomide did not show antitumor activity in this patient population, future studies of this agent in patients at initial stages of the disease (when its antiangiogenic properties may be more relevant to disease progression) could be considered.     

Phase I trial of recombinant platelet factor 4 (rPF4) in patients with advanced colorectal carcinoma

Summary Background: Recombinant platelet factor 4 (rPF4) is a naturally occurring protein found in platelet alpha granules that can inhibit angiogenesis. Methods: In this Phase I trial, 9 patients with metastatic colorectal cancer who had failed 5-FU treatment received rPF4 at doses ranging from 0.3 to 3.0 mg/kg via 30-minute infusion. Three additional patients were treated with the 3 mg/kg dose over a 6-hour period of infusion. Results: The only toxicity encountered was mild leg twitching in 2/3 patients treated with the 6-hour infusion. One patient with a history of phlebitis developed a lower extremity deep venous thrombosis after the first dose of rPF4. A mild rise in fibrinogen level was noted in several patients. Of the 11 evaluable patients, there were no clinical responses to treatment. Conclusions: rPF4 is well tolerated at the doses and schedules tested. No clinical responses were observed. Prolonged infusion schedules should be investigated.     

Phase II trial of 150-minute weekly infusion of gemcitabine in advanced colorectal cancer: minimal activity in colorectal cancer

Metastatic colorectal cancer is very common in the Western hemisphere and current treatment modalities are not effective. In this study a prolonged (150-minute) infusion of gemcitabine at a constant dose rate of 10 mg/m2/min administered weekly for 3 consecutive weeks repeated every 4 weeks revealed a response rate of 4% (90% CI < 1%–18%). There were no complete responses. Treatment with gemcitabine produced moderate to severe toxicity as grade 3–4 neutropenia requiring dose modification was seen in 40% of patients treated. When used in this dose and schedule, gemcitabine does not appear to be effective for patients with metastatic colorectal cancer.