Phase I trial of diaziquone (AZQ) plus GM-CSF

Summary Diaziquone (AZQ) is a lipid soluble alkylating agent which was designed for increased CNS penetration. Its principle toxicity is myelosuppression. We conducted a phase I trial using AZQ in combination with GM-CSF to determine if the maximal tolerated dose (MTD) of AZQ could be escalated. Using GM-CSF on a standard schedule, we were unable to escalate the previously determined MTD of diaziquone with the use of this colony stimulating factor.     

A phase II clinical trial of diaziquone (AZQ) in the treatment of patients with recurrent leiomyosarcoma of the uterus

Summary Based upon the activity observed in this trial, there does not appear to be a significant role for AZQ as a salvage agent for leiomyosarcoma of the uterus at the dose and schedule tested. Address for offprints: GOG Headquarters, Suite 1945, 1234 Market Street, Philadelphia, PA 19107, USA     

A phase II trial of diaziquone (AZQ) in mixed mesodermal sarcomas of the uterus

Summary AZQ was given intravenously to 23 patients with mixed mesodermal sarcoma of the uterus refractory to conventional treatment at a dose of 22.5–30 mg/m² q three weeks. There was one partial reponse lasting seven weeks and one drug-related death. Based upon the activity observed in this trial, there does not appear to be a significant role for AZQ as a salvage agent for mixed mesodermal sarcomas of the uterus at the dose and schedule tested. Address for offprints: GOG Administrative Office, Suite 1945, 1234 Market Street, Philadelphia, PA 19107, USA     

A phase II clinical trial of diaziquone (AZQ) in the treatment of patients with recurrent adenocarcinoma and adenosquamous carcinoma of the cervix

Summary Twenty-six patients with recurrent adenocarcinoma and adenosquamous carcinoma of the uterine cervix were treated with diaziquone (AZQ) 22.5 mg/m² diluted in 150 ml normal saline every three weeks. In the absence of adverse effects the second dose and all subsequent doses were escalated to 30 mg/m². All patients had measurable disease and only 11 had received prior chemotherapy. Two partial responses were noted among 15 patients with no prior chemotherapy, while no responses were observed among 11 previously treated patients. The major toxicity was leukopenia and thrombocytopenia. Median progression-free interval was 1.5 months and median survival was 4 months. AZQ displays minimal activity against recurrent nonsquamous carcinoma of the cervix at the dose and schedule used.     

Novantrone for childhood malignant solid tumors

Summary One hundred one patients with advanced pediatric malignant solid tumors, refractory to conventional chemotherapy, were given Novantrone in a Phase II study. A dosage of 18 mg/m² was administered as a short intravenous infusion every 3 weeks. One complete and 2 partial responses were observed among 26 patients treated for rhabdomyosarcoma; one of 22 patients with neuroblastoma developed a partial response. Nausea and vomiting were uncommon. Leukopenia and/or granulocytopenia developed in 90 of 98 evaluable entries. Two patients developed fatal congestive heart failure, which may have been related to the fact that these patients previously had received doxorubicin; 3 other patients developed evidence of changes in cardiac function, without congestive heart failure. Evidence of activity of this agent in patients who had previously received doxorubicin suggests that Novantrone should be evaluated in pediatric subjects with malignant solid tumors who have had no prior exposure to anthracyclines.     

Phase I–II study of high-dose etoposide in patients with refractory breast cancer

Address for offprints: G. Fraschini, The University of Texas M.D. Anderson Cancer Center, Box 56, 1515 Holcombe Boulevard, Houston, TX, 77030, USA     

Phase I trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer

Summary Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. Batimastat inhibits at least 50% of MMP activity at concentrations less than or equal to 10 ng/ml in vitro. Batimastat retarded ascites accumulation and increased survival in mice with human ovarian tumor xenografts. Acute and long-term toxicological studies revealed no major toxicity in animals. Batimastat is poorly soluble and was administered intraperitoneally (i.p.) as a suspension. Previous studies in patients with malignant ascites have shown no major toxicities at doses as high as 1350 mg/m².     

Phase I and pharmacologic evaluation of nafazatrom in patients with cancer

Summary Nafazatrom was evaluated in escalating daily oral doses ranging from 0.25 to 8.0 g/m² without producing significant toxicities. Malabsorption proved dose limiting at 8.0 g/m² as a single daily dose, but splitting the same total dose into two or four doses circumvented this problem. Doses of 2.0 g/m² at 6-h intervals or 4.0 g/m² every 12 h are reasonable for Phase II and adjuvant trials. Pharmacologic evaluation of nafazatrom confirmed malabsorption at the highest single daily dose level tested and suggests that absorption was impaired in patients with extensive liver metastases.     

Phase I/II study of gemcitabine plus vinorelbine in non-small cell lung cancer

Background: Because gemcitabine andvinorelbine have demonstrated single-agentactivity in non-small cell lung cancer(NSCLC), we conducted this phase I/II studyto determine the maximum tolerated dose(MTD) and activity of these drugs combined. Patients and methods: Patients withinoperable or advanced NSCLC and no priorchemotherapy were treated with gemcitabineplus vinorelbine on days 1 and 8 every 21days. The initial doses of gemcitabine1,000 mg/m² and vinorelbine25 mg/m² were escalated by250 mg/m² and 5 mg/m²,respectively, in separate patient cohortsuntil the MTD was established. Results: In phase I, 32 patientsreceived a total of 115 cycles. Dose-limiting toxicities were neutropeniaand hepatotoxicity, occurring at the doselevel of 1,500 mg/m² and30 mg/m². Thus, the MTD used forphase II was 1,250 mg/m² and30 mg/m². Of 41 patients in phase II,16 (39%) achieved objective responses(95% confidence interval [CI] 24% to54%), with a median time to progression of4.2 months. Overall survival was 9 months(95% CI 5.7 to 12.7 months) and the 1-yearsurvival rate was 31%. World HealthOrganization (WHO) grade 3neutropenia and reversible thrombocytosisoccurred in 15% and 65% of patients,respectively. Non-hematologic toxicity wasmild at all dose levels. Grades 3 and 4hepatotoxicity were reported in one patienteach. Conclusion: The combination of1,250 mg/m² gemcitabine and30 mg/m² vinorelbine on days 1 and 8every 21 days is well tolerated and activein patients with NSCLC. These resultsshould be confirmed in comparativestudies.     

Phase II evaluation of the AMAP, 773U82 mesylate,in pancreatic cancer

Summary Pancreatic cancer is the fifth leading cause in cancer related death among adults in the United States. Thirtythousand new cases of pancreatic cancer are diagnosed each year, most are metastatic at diagnosis and no effective systemic therapy is available. 773U82 mesylate is one of a series of compounds (arylmethylaminopropanediols-AMAPS) which was synthesized at the Wellcome Research Laboratories. AMAPS bind to DNA, show evidence of topoisomerase 2 inhibition and are active in a variety of murine and human preclinical screens. Based on these data a phase II trial of 773U82 mesylate administered at 800 mg/ m² daily × 3 at a 4 h infusion repeated every three weeks was carried out. Patients eligible for these trials had histologic proof of adenocarcinoma, good performance status, and normal organ function. This was a multi-institutional trial. Nineteen patients were entered; 15 patients were fully eligible and 4 were ineligible, but were evaluated. Thirteen patients were fully evaluable for response and no response was seen. Median time to progressive disease among eligible patients was 56 days. Toxicity of 773U82 mesylate was myelosuppression which was not prohibitive. 773U82 mesylate is not active in pancreatic cancer.     

5-Fluorouracil and Folinic Acid: a Phase I–II trial in gastrointestinal malignancy

Summary Fifty-one patients with metastatic adenocarcinoma received Folinic Acid (FA) combined with 5-Fluorouracil (5FU) in a Phase I–II clinical trial. Two different schedules were used: (a) bolus infusion — 5FU 7 –12 mg/kg/d I.V. d1–5, FA 1.6 mg/kg/d I.V. d1–5; (b) continuous infusion — 5FU 600–1200 mg/m²/d I.V. d1–4, FA 60 mg/m²/d I.V. d1–4. Mucositis and myelosuppression were dose-limiting, with recommended dose levels of 5FU for further trials being 10 mg/kg/d I.V. d1–5 and 1000 mg/m²/d I.V. d1–4 on the bolus and continuous infusion schedules, respectively. Forty-one evaluable patients with measurable disease were treated. Thirty-six had metastatic colorectal carcinoma, and 14/36 patients responded (CR-1, PR-13), including responses in three patients who had previously failed 5FU treatment alone. In the two patients with unknown primary sites and three with gastric cancer, no response were seen. 5FU and FA have activity equivalent to 5FU alone, and the responses in patients receiving prior 5FU suggest it may be superior. The possibility that toxicity may be enhanced does exist. Further trials of these two agents are warranted.     

Phase I/II trial of gemcitabine plus docetaxel in advanced non small cell lung cancer (NSCLC)

INTRODUCTION: The poor prognosis of non small cell lung cancer (NSCLC), as well as the significant toxicity from many conventional cytotoxic regimens warrants the investigation of combinations of new active agents for treatment. This is a phase I-II (dose-finding, efficacy, and toxicity) study of docetaxel + gemcitabine in patients with stage IIIB-IV NSCLC without prior systemic therapy. Patients were treated in cohorts of 3 with alternating increasing doses of docetaxel and gemcitabine at each level. Patients: Fifty patients were entered, of which 49 were eligible including 28 males and 21 females; 15 stage IIIB and 34 stage IV; median age 57 yrs (35-74). RESULTS: The Maximum Tolerated Dose (MTD) was docetaxel 60 mg/m(2) day 1 and gemcitabine 750 mg/m(2) d1 & 8, every 21 days. The overall response rate is 20%. Eight patients are not formally assessable for response due to early discontinuation or loss to follow-up and are considered to have progressive disease. The median time to progression (TTP) is 3.5 months (1-25), with 11 pts with at least 7 months TTP. There were 10 pts (20%) with a partial response (PR); 18 (37%) maintained stable disease; 21 (43%) had progressive disease (PD) or were not assessable. Toxicity: Forty-nine patients are evaluable for assessment for toxicity: Grade (Gr) 3/4 toxicity was documented thus: 14 with neutropenia, 1 with anemia, 1 with nausea, 2 liver function, 2 dyspnea, 2 fatigue, 1 allergy, 1 neurologic. CONCLUSION: This regimen is well tolerated and results in phase I-II testing in this patient population warrant further consideration of the study of docetaxel + gemcitabine for advanced NSCLC.     

Phase I and pharmacokinetic study of intraperitoneal topotecan

Objective. To determine the maximum tolerated dose and pharmacokinetics of topotecan when administered by the intraperitoneal route. Methods. A dose-escalating Phase I trial was conducted in which fifteen % of the total dose was given as an intraperitoneal bolus in two litres of D5W and the remainder was given as a continuous intraperitoneal infusion over 24 hours. Treatments were given every 21 days. Pharmacokinetic analyses were performed at the recommended phase II dose. Results. Seventeen patients received a total of 43 cycles at 21-day intervals. The maximum tolerated dose was 4 mg/m2 and acute dose-limiting toxicity was neutropenia. Other toxicities included leukopenia, anemia, emesis, fever, and abdominal pain. Although no objective responses were achieved, five of ten patients with ascites had a decrease in fluid accumulation with administration of intraperitoneal topotecan. The recommended phase II dose is 3 mg/m2. Pharmacokinetic analysis performed at a dose of 3 mg/m2 demonstrated that elimination from the peritoneal cavity followed second-order kinetics with k1 = 1.6 hr-1, k2 = 0.3 hr-1 and first and second-phase half-lives of 0.49 and 2.7 hours, respectively. Plasma pharmacokinetic behavior was best described by first-order kinetics with k = 0.5 hr-1 and a half-life of 3.9 hours. The pharmacologic advantage, expressed as the peritoneal to plasma AUC ratio was 31.2. Conclusions. Intraperitoneal administration of topotecan at 3 mg/m2 results in a substantial increase in drug exposure for the peritoneal cavity without compromising systemic exposure; this may be beneficial for the treatment of patients with ovarian cancer or intraperitoneal carcinomatosis.     

Phase I study of oral menogaril administered on a once weekly schedule

Summary Forty-seven patients with solid tumors were treated on a phase I study of menogaril administered by mouth once per week. Nausea and vomiting were excessive at weekly doses of 350 and 450 mg/m²/week but were tolerable and controlled reasonably well by antiemetics at lower doses. There appeared to be a relatively shallow dose-vs-granulocytopenia curve above a menogaril dose of 180 mg/m²/week. No patient receiving chronic dexamethasone for cerebral edema developed granulocytopenia, even at menogaril doses of 350–450 mg/m²/week. Two patients developed neutropenic infection. No patient developed thrombocytopenia. Mild arrhythmias were seen in 3 patients. Two patients suffered possible myocardial infarcts that may not have been related to treatment. Asymptomatic blood pressure fluctuations were common and were probably not related to treatment. Diarrhea was dose-related but was generally not severe. Alopecia and stomatitis occurred occasionally. Minor responses were seen in two patients with gliomas, and three of five evaluable prostate cancer patients experienced marked pain relief. The dose recommended for phase II studies is 250–300 mg/m²/week with antiemetic pretreatment. This schedule appears to allow an oral menogaril doseintensity that is approximately double that attainable with other oral schedules that have been studied.Presented at the 24th Annual Meeting of the American Society of Clinical Oncology, New Orleans, Louisiana, May 22–24, 1988 [1].     

Phase I/II study of amrubicin,a novel 9-aminoanthracycline,in patients with advanced non-small-cell lung cancer

Purpose: Amrubicin is a novel, totally synthetic 9-aminoanthracycline. The present phase I/II study was performed to define its maximum-tolerated dose (MTD), efficacy and toxicity in the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Chemonaive patients were required to have cytologically or histologically proven measurable NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and adequate organ functions. Amrubicin was administered by daily intravenous injection for 3 consecutive days every 3 weeks. Results: In a phase I study, four patients were enrolled at dose level 1 (40 mg/m²/day) and four at dose level 2 (45 mg/m²/day). No dose limiting toxicity (DLT), which was defined as toxicity consisting of grade 4 neutropenia and leukopenia lasting four days or more, and grade 3 or 4 toxicity other than neutropenia, leukopenia, anorexia, nausea/vomiting, and alopecia, was observed at these dose levels. Subsequently, at dose level 3 (50 mg/m²/day), 3 of 5 patients experienced DLTs (leukopenia, neutropenia, thrombocytopenia, or gastrointestinal complications). The MTD and recommended dose (RD) were determined to be 50 mg/m²/day and 45 mg/m²/day, respectively. Three partial responses (PRs) were achieved in 13 patients (response rate, 23.1%) in a phase I study. In a phase II study, 15 patients were assessable for efficacy and toxicity at the RD, and four PRs were obtained (response rate, 26.7%). The major toxicities were leukopenia and neutropenia, while non-hematologic toxicities were mild. The overall response rate in the combined patient population of the phase I/II study was 25.0% (7 PRs in 28 patients), with a 95% confidence interval of 10.7% to 44.9%. Conclusion: Amrubicin exerted promising antitumor activity on NSCLC with acceptable toxicity.     

Phase II trial with oral idarubicin in advanced breast cancer

Summary Idarubicin, a new analogue of daunorubicin, was administered to 27 patients with advanced breast cancer in a phase II trial. The drug was given orally at a dose of 30–35 mg/m² every 3 weeks. Twenty-two patients were evaluable for response. All evaluable patients were previously treated with one or more chemotherapeutic regimens, including an anthracycline in more than 50% of the cases. Partial remissions were obtained in 5 patients, for a response rate of 23%. The median duration of response was 191 days. Mild nausea and vomiting were common. Diarrhea, which occurred in less than 50% of the patients, was usually short-lived. Alopecia was generally minimal. Myelosuppression was the dose-limiting toxic effect. Leukopenia was frequently seen, with full recovery by day 28 in 81 % of the courses. Thrombocytopenia was less common than leukopenia. Four cases of grade 1 acute cardiac toxicity were recorded. This study suggests that idarubicin can induce regressions in advanced carcinoma of the breast, and justifies further studies in combination with other agents.     

Phase I/II trial of dipyridamole, 5-fluorouracil,leukovorin, and mitoxantrone in metastatic breast cancer

Summary Based upon the hypothesis that dipyridamole would potentiate the cytotoxicity of mitoxantrone and the combination of 5-fluorouracil (5-FU) and leukovorin, we performed a phase I/II trial of the combination of dipyridamole, 5-FU, leukovorin, and mitoxantrone in patients with metastatic breast cancer. The dose of dipyridamole was fixed at 175 mg/m² by mouth every 6 h (700 mg/m²/day), based upon a previous phase I trial of oral dipyridamole with 5-FU and leukovorin. Dipyridamole therapy began 24 h prior to the first dose of chemotherapy and continued until 24 h after the last dose of chemotherapy for each course of treatment. At the initial dose level, leukovorin 200 mg/m² was given intravenously immediately prior to 5-FU 375 mg/ m² intravenously on days 1–5. Mitoxantrone 6 mg/m² was given as a single dose on day 3. Unacceptable toxicity was observed at this dose level, leading to successive dose decrements rather than dose increments. The maximum tolerated dose was leukovorin 200 mg/m² days 1–2, 5-FU 375 mg/m² days 1–2, mitoxantrone 6 mg/m² on day 2, and dipyridamole 175 mg/m² every 6 h on days 0–3. Two responses were produced in 15 patients. This regimen is not recommended for further investigation in the treatment of breast cancer.     

Phase I study of paclitaxel administered by ten-day continuous infusion

Purpose: Pre-clinical data have suggested that prolonged exposure to paclitaxel enhances its cytotoxicity, but various clinical trials utilizing long-term infusions of paclitaxel have been limited by unacceptable hematologic toxicity, most notably significant neutropenia. A phase I study of paclitaxel administered over 10 days, was performed to evaluate the hematologic and non-hematologic toxicities as well as to determine the maximum-tolerated dose for the 10-day infusion duration.Patients and methods: Twenty-nine solid tumor patients (predominantly non-small cell lung cancer and head and neck cancer) were treated with paclitaxel at doses ranging from 5 mg/m2/day to 25 mg/m2/day administered as a 10-day continuous infusion via a pump every 21 days. Dose escalation was permitted within individual patients. Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic toxicity, ANC 500 or platelet count 25,000 for 7 days or febrile neutropenia. The maximum tolerated dose (MTD) was defined as the highest dose level at which less than two out of six patients developed DLT. All of the patients had received prior chemotherapy; approximately two-thirds had received prior radiation as well. All patients received standard pre-medications for paclitaxel, including anti-histamines and corticosteroids. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used.Results: A total of 110 courses of paclitaxel were administered to 29 patients. The incidence of hematologic and non-hematologic toxicity was quite low among the patients treated at dose levels below 17 mg/m2/day. At higher doses, non-hematologic toxicities including arthralgias, myalgias, fatigue, nausea, stomatitis, and peripheral neuropathy were seen, although nearly all of the toxicities were less than grade 3 (NCI toxicity criteria). Hematologic toxicity mostly consisted of neutropenia and was more common at dose levels of 17 mg/m2/day or higher. Nevertheless, even at the highest dose levels (21 mg/m2/day and 25 mg/m2/day) grade 3 or 4 neutropenia occurred in only 50% of patients. Dose-limiting hematologic toxicity occurred in 2 of 4 patients treated at the 25 mg/m2/day dose level.Conclusion: Paclitaxel can be safely administered as a 10-day infusion. The MTD for this schedule is 210 mg/m2. Unlike the 96-hour paclitaxel infusions, dose-reduction for myelosuppression may not be necessary because the MTD of paclitaxel when administered over a 10-day infusion is similar to the MTD of paclitaxel when infused over 3 or 24 hours.     

Phase I study of combined alpha Interferon,alpha difluoromethylornithine (DFMO), and doxorubicin in advanced malignancy

Interferon (IFN) and conventional cytotoxic chemotherapeutic agents have been successfully combined in various studies. Alpha difluoromethylornithine (DFMO) is a novel antitumor agent which is an inhibitor of polyamine metabolism. A phase I study of IFN 24 × 10⁶ U/m²/day IM (days 3–7), DFMO 9 gm/m² p.o. daily (days 1–7), and a variable dose of doxorubicin starting at 20 mg/m² (day 6), of each 28 day cycle was performed. The aim of the study was to determine the maximally tolerable dose of doxorubicin in this combination. Three patients were treated with doxorubicin at 20 mg/m² and six patients at 40 mg/m². The dose limiting toxicities were neutropenia, fatigue and fever. All other toxicities were mild and there was no grade IV toxicity. A doxorubicin dose of 40 mg/m² produced tolerable toxicity and is recommended for phase II studies. No major antitumor effects were seen.     

A Phase I Study of Vitamin E, 5-Fluorouracil and Leucovorin for Advanced Malignancies

Six patients with incurable malignancies wereoriginally treated with vitamin E, 3200 IU/day for fourteendays, followed by the same dose of vitamin E daily plus LCV(20 mg/m² iv bolus daily × 5) with 5FU (425mg/m² iv bolus immediately following LCV). The sameschedule of LCV and 5FU was repeated 4 weeks later, then every5 weeks indefinitely. When 3 of the first 6 had grade 3/4toxicity, six more patients were treated on the identicaldrugs and schedule. Seven of twelve total patients had one ormore grade 3/4 toxicities. Neutropenia, abdominal pain, anddiarrhea were most common. No patient had a documentedresponse, though seven patients did have stable disease.Though the combination of vitamin E and chemotherapy wastoxic, this trial demonstrated maximal therapeutic doses ofvitamin E can be combined with standard 5FU and LCV, withoutsignificantly increasing the side effects of thechemotherapy itself.