Vindesine in head and neck cancer

Summary Vindesine was tested in 23 fully evaluable patients with advanced carcinomas of the head and neck. All had received previous chemotherapy. No complete or partial responses resulted after one or more courses of 1.5 mg/m² i.v. bolus daily × 2 days. Leukopenia was noted in 46% and peripheral neuropathy was reported in 29%. This dose-schedule of vindesine is inactive in previously treated patients with squamous carcinomas of the head and neck. Address for reprints: Southwest Oncology Group (SWOG-8062), Operations Office, 4450 Medical Drive, San Antonio, TX 78229, U.S.A.     

Pixantrone: a novel aza-anthracenedione in the treatment of non-Hodgkin's lymphomas

Pixantrone (BBR-2778) is a novel mitoxantrone-like drug, which lacks the 5,8-dihyroxy substitution groups thought to be responsible for the cardiac toxicity associated with mitoxantrone. In Phase I/II single-agent pixantrone clinical trials, neutropenia was the dose-limiting toxicity and the maximum tolerated dose was 150 mg/m²/week for 3 weeks every 4 weeks. In relapsed aggressive non-Hodgkin's lymphomas, weekly single-agent pixantrone 85 mg/m² for 3 weeks every 4 weeks was associated with a 27% overall response and a 15% complete response. When intensively pretreated patients with relapsed aggressive non-Hodgkin's lymphoma were treated with a cyclophosphamide, pixantrone, vincristine and prednisolone regimen (pixantrone substituted for doxorubicin in standard regimen [cyclophosphamide, doxorubicin, vincristine and prednisolone regimen (CHOP)]), the overall response was 74% and complete response 57%. In the BBR-2778, methylprednisolone, cisplatin and cytosine arabinoside (BSHAP) regimen, 58% overall response and 37% complete response were achieved. A number of randomised studies of pixantrone (BBR-2778) in patients with relapsed indolent or aggressive lymphomas are ongoing.     

Combination high-dose etoposide and vincristine infusion

Following the identification of a synergistic antitumor effect in a murine model, the combination of etoposide and vincristine has been explored in the clinic. Etoposide was given at 4 dose levels (250, 500, 750 or 1,000 mg/m²) with each dose given in 3 equal fractions daily for 3 days. The dose of vincristine was fixed (two 0.75 mg infusions over 22 hours each between doses of etoposide). A total of 26 patients were entered into study and 7, 11, 10 and 5 patients were treated at the 250, 500, 750, and 1,000 mg/m² dose levels, respectively. Myelosuppressioh was the principle side effect and Grade 4 WBC toxicity (<>³) developed in 14%, 27%, 40% and 40%, respectively, of the patients treated at each of these respective dose levels. Life-threatening infections occurred in 0%, 9%, 30% and 60% of the patients at these levels, respectively. Reversal of marrow toxicity was rapid with repeat courses given at 3-week intervals. Non-hematologic toxicity, including neurotoxicity, nausea, vomiting, and mucositis was generally mild when present. Objective responses were observed in 1 patient each with refractory Hodgkin's disease and immunoblastic lymphoma. Prolonged periods of stable disease occurred in 2 patients with adenocarcinoma of the lung and one patient with Hodgkin's disease. The starting dose of etoposide recommended for further trials of this agent in combination with infusion of vincristine is 500 mg/m² given in fractionated doses; dose escalation should be possible in many patients.     

Transient neutropenia after intravenous injection of vindesine in patients with lung cancer

We have found transient circulating neutropenia and pulmonary sequestration of neutrophils after the intravenous injection of vindesine, a microtubule disruptor.Experiment 1 Ten patients with lung cancer were given a bolus intravenous injection of 3 mg·m^-2 vindesine (Fildesine(r)). In all patients, total leukocyte and neutrophil counts in the venous blood fell to 65 % and 47 % of baseline values respectively within 30 min, and returned to baseline values within 6 h. In contrast, the lymphocyte count was stable.Experiment 2 Male Wistar rats were given saline or 0.08 mg·kg^-1 vindesine intravenously and were sacrificed after 30 min. Vindesine produced a 58 % reduction in the neutrophil count in the systemic circulation and a threefold increase in the neutrophil/erythrocyte ratio in the pulmonary microvasculature.Experiment 3 We studied the effects of vindesine in vitro on neutrophils and lymphocytes isolated from the venous blood of healthy volunteers. Vindesine (10^-5–10^-8 mol·1^-1) reduced neutrophil deformability (filterability) and induced neutrophil polarization, with reversibility of both effects after washout. These effects of vindesine were completely inhibited by cytochalasin B, an actin filament disrupter. Vindesine did not stimulate the neutrophil functions of adherence to polystyrene tubes, chemotaxis, or superoxide anion generation. The filterability and morphology of lymphocytes were not altered by vindesine.Thus, we conclude that a bolus injection of vindesine produces pulmonary sequestration of neutrophils, which produces circulatory neutropenia, and that it is primarily mediated by a decrease in neutrophil deformability that occurs without activation of the cells.     

Vindesine in advanced breast cancer,lymphoma and melanoma

Summary Fifty-six patients with advanced metastatic carcinoma of the breast, melanoma and lymphoma were treated with the new vinca alkaloid vindesine in a prospective Phase II study. The dose was 3 mg/M² by I.V. bolus once a week for a minimum of two doses. Patients who failed to respond to four I.V. doses were treated with 48-h intravenous infusions at a dose of 1.5 mg/M² per 24 h.Of the 26 evaluable patients with breast cancer, there were only two incomplete responses and four patients who experienced stabilization of disease. Of the 12 evaluable patients with melanoma, no responses were seen with four patients experiencing stabilization of disease. Of the 11 patients with non-Hodgkin's lymphomas, there was one complete remission which persisted for 26 months and two partial remissions. No additional responses were seen when the mode of administration was changed to 48-h infusion in three patients with breast cancer, five patients with melanoma and one patient with lymphoma. Significant toxicities included neutropenia in 24 patients and nausea and vomiting in two patients. There were no drug related deaths.Previously reported experience with vindesine in these tumors is reviewed as well.The views of the authors do not purport to reflect the positions of the Department of the Army or the Department of Defense.     

Toxicology of vindesine (desacetyl vinblastine amide) in mice, rats, and dogs.

Comparative acute intravenous toxicity studies of vinblastine sulfate (VLB), vincristine sulfate (VCR), and vindesine in mice and rats indicated that vindesine was more toxic than VLB and less toxic than VCR. Rats were able to tolerate larger repeated doses of vindesine than dogs. Rats given intravenous doses totaling 0.15 mg/kg-wk vindesine for 3 months developed no remarkable signs of toxicity. Doses of 0.3 mg/kg-wk or greater produced anorexia, depressed blood cell counts, atrophic intestinal mucosa, inhibition of spermatogenesis, extramedullary hematopoiesis, and infections. Dogs were given total weekly intravenous doses of 0.04, 0.08, 0.1, or 0.16 mg/kg vindesine for 3 months. The only observed effect in the two lower dose groups was inhibition of spermatogenesis. Groups receiving 0.1 or 0.16 mg/kg developed leukopenia, slight erythropenia, inhibition of spermatogenesis, focal skeletal muscle degeneration, elevated lactic dehydrogenase, and an increase in bone marrow myeloid: erythroid ratio. No evidence of functional or structural changes in neural tissues was found. The above effects are common to animals given VCR at lower doses and for a shorter test period. It is therefore concluded that vindesine is less toxic in animals than VCR.     

Evaluation of bleomycin,chlorozotocin, MGBG,and bruceantin in patients with advanced soft tissue sarcoma,bone sarcoma,or mesothelioma

Summary Patients with objectively measurable soft tissue sarcoma, bone sarcoma, or mesothelioma who had failed at least one prior chemotherapy regimen received either bleomycin (20 U/M2² i.v. day 1 each week), chlorozotocin (150 mg/M² i.v. q6 weeks), MGBG (500 mg/M² i.v. each week, escalated in 50 mg/M² weekly increments to a maximum dose of 700 mg/M²), or bruceantin (5.5 mg/M² days 1, 8, 15, and 22, with cycles repeated every 6 weeks). One hundred eighty patients were evaluable: 53 on bleomycin, 51 on chlorozotocin, 38 on MGBG, and 38 on bruceantin. Two partial responses resulted from bleomycin, and one each from chlorozotocin and MGBG. Both responders on bleomycin had mesothelioma. Seventy-four percent of the patients were of ECOG performance status 0 or 1, and over half on each arm had moderate or worse toxicity. At these doses and schedules, none of the four drugs tested was active against previously treated sarcomas. Bleomycin, however, should be considered for further evaluation in mesothelioma patients.     

Multicenter phase II study of brequinar sodium in patients with advanced gastrointestinal cancer

Summary Eighty-six patients with advanced colorectal, gastric or pancreatic carcinoma and no prior exposure to chemotherapy were treated with brequinar sodium. Brequinar was administered at a median weekly dose of 1200 mg/m² intravenously. The toxicity was moderate, with thirty patients (35%) experiencing grade 3 or 4 toxicity. Objective responses were observed in 1/32 evaluable colorectal and 2/29 evaluable gastric carcinoma patients. There were no objective responses in 17 evaluable pancreatic cancer patients. We conclude that, at this dose and schedule, brequinar does not have sufficient activity in these gastrointestinal malignancies to warrant further evaluation.     

A phase II study of weekly oral methotrexate and zidovudine (AZT) in advanced adenocarcinoma of the pancreas and hepatocellular carcinoma

Summary From January 1992 through May 1993, 31 patients with adenocarcinoma of the pancreas or hepatocellular carcinoma were treated with weekly oral methotrexate (7.5 mg/M² every 6 hours for 6 doses) and continuous oral AZT (200 mg four times daily). Patients were treated for a total of 6 months or until disease progression. The median age was 66 (range 44–79) and the median KPS was 80. No patient had received prior chemotherapy. Hematologic toxicity was severe with 50% of patients developing hemoglobins less than 8 gm/dl and 70% with granulocyte counts less than 1000 per mm³. One patient achieved a radiographic complete remission and 2 had stable disease. Two-thirds of patients progressed within 2 months of beginning therapy. The combination of methotrexate and AZT is an inactive regimen in pancreatic and hepatocellular carcinoma and is associated with considerable toxicity.     

Phase I study of vincristine and escalating doses of etoposide

Summary A phase I trial of vincristine and etoposide was designed following the identification of a potentially synergistic antitumor effect in a murine model. The dose of vincristine was fixed (0.5 mg daily for 3 days). Etoposide was given at 1 of 3 total dose levels (250, 500, or 750 mg/m₂) per treatment. Each dose was given in 3 equal fractions and each fraction was given daily for 3 days, i.e., 83.3 mg/m₂/d × 3d, 166.7 mg/m₂/d × 3d, or 250 mg/m₂/d × 3d. A total of 31 patients were entered into study including 10, 18, and 3 patients treated at the 250, 500, and 750 mg/m₂ dose levels, respectively. Dose-limiting toxicity occurred at the 750 mg/m₂ level, in which Grade 4 myelosuppression developed in all of the patients. Life-threatening gram negative sepsis occurred in two of these patients and both required platelet transfusions. Grade 3–4 WBC toxicity was observed in 9 of 16 (56%) evaluable patients treated at the 500 mg/m₂ level, but reversal of toxicity was generally rapid with repeat courses given at 3 week intervals in most patients. Non-hematologic toxicity was negligible. Objective responses were observed in 2 of 4 patients with Hodgkin's disease. The starting dose of etoposide recommended for phase II trials of this agent in combination with vincristine is 500 mg/m₂; dose escalation may be possible in some patients.     

Early evaluation of liposomal daunorubicin (DaunoXome®, Nexstar) in the treatment of relapsed and refractory lymphoma

We have treated 19 patients with relapsed or refractory lymphoma with liposomally encapsulated daunorubicin (DaunoXome) at two dose schedules; 40 mg/m² repeated every 14 days and 120 mg/m² repeated every 21 days. Non-haematological toxicity was mild, in particular, no patient treated with the higher dose schedule showed clinical deterioration in cardiac function. At the lower dose (10 patients) no objective responses were seen but at the higher dose (9 patients) one complete response and two partial responses were achieved. Liposomal daunorubicin at 120 mg/m² appears to have some activity against refractory lymphoma and we suggest that further studies with this agent are required.     

Phase II trial of spirogermanium in advanced non-small cell lung cancer

Summary A phase II trial of spirogermanium was conducted in advanced previously untreated non-small cell lung cancer patients. The drug was given by intravenous infusion 3 times per week for 2 weeks, twice per week for the next 2 weeks, and then weekly. Starting dose was 125 mg/m², and dose escalation of 25 mg/m² per week was required in the absence of toxicity to a maximum dose of 200 mg/m² per infusion. Fifteen eligible patients were treated, and no objective responses were seen. Primary toxicity was neurologic and reversible after withdrawal of the drug. We conclude that spirogermanium is not active against non-small cell lung cancer in the dosage used in this study.     

Mitoxantrone in malignant lymphoma

Summary Two phase II trials of mitoxantrone (Novantrone®; dihydroxyanthracenedione) in refractory malignant lymphoma have been conducted. In the first of these, mitoxantrone, 5 mg/m², was given weekly for six weeks and in the second, 14 mg/m² was administered every three weeks. The first trial was conducted by the Southeastern Cancer Study Group (SECSG) and the second was a multicenter trial sponsored by Lederle Laboratories. Of the 51 patients entered in the SECSG trial, 28 could be evaluated for response and 43 for toxicity. WBC nadirs below 4.0 × 10⁹/litre were recorded in 25 patients. Three partial responses and no complete responses were obtained. These results contrast with those of the single dose every three weeks study in which 96 patients were entered and 69 of these were evaluated for response. Responses were obtained in 30 patients (4 complete, 26 partial). Side-effects on this three-weekly dose regimen were minimal. WBC nadirs below 4.0 × 10⁹/litre occurred in 85 patients. Twenty-three patients experienced at least mild nausea and vomiting and 15 had at least mild alopecia. These preliminary data indicate that mitoxantrone has significant activity in malignant lymphoma. All of the responding patients had received extensive prior therapy, many of them with anthracyclines in combination or as single agents. The higher response rate to mitoxantrone given at 14 mg/m² every three weeks suggests that careful consideration should be given to dose schedule when this drug is examined further in phase III trials.     

Phase I evaluation of spirogermanium and 5-fluorouracil in colorectal carcinoma

We have conducted a phase I study to evaluate the toxicity and tolerance of a 5 day continuous infusion of spirogermanium and 5-fluorouracil, (5-FU). The 5-FU was administered via a peripheral vein at 1000 mg/M²/day for 5 days by continuous infusion. Simultaneously, spirogermanium was administered via an indwelling central venous catheter by continuous infusion for 5 days starting at 50 mg/M²/day and escalating to 250 mg/M²/day. Sixteen patients received a total of 54.5 courses of therapy. The most common and severe toxicity was neurotoxicity. Mild to moderate gastrointestinal toxicity also occurred. No significant hematologic toxicity occurred. Two partial responses occurred lasting 11 and 20.5 months, both at the 100 mg/M²/day level of spirogermanium. The recommended phase II dosages are 5-FU 1000 mg/M²/day and spirogermanium 200 mg/M²/day by 5 day continuous infusion with escalation of the spirogermanium in selected individuals. Patients on long term therapy should have close neurologic evaluation and follow up. Consideration should also be given to evaluating a group of patients at the 100 mg/M²/day level of spirogermanium due to the responses seen at this level.Presented in part at the 79th annual meeting of the American Association for Cancer Research, May 1988, New Orleans, LA, USA.     

Phase I trial of weekly cisplatin,irinotecan and paclitaxel in patients with advanced gastrointestinal cancer

Summary   Objectives: To determine the maximum tolerated dose (MTD), toxicities, and suitable dose for weekly 1-h paclitaxel combined with weekly cisplatin and irinotecan to treat advanced gastrointestinal malignancies. Methods: Thirty patients with metastatic or locally advanced (unresectable or recurrent) gastrointestinal solid tumors were enrolled on this single-center, phase I study. Patients were treated with paclitaxel given over 1h at 1 of 4 dose levels (40, 50, 65, or 80 mg/m²). Paclitaxel was followed by fixed doses of cisplatin (30 mg/m²) and irinotecan (50 mg/m²). All treatment was administered sequentially, once a week, in 6-week cycles (4 weeks on, 2 weeks off). Dose-limiting toxicity (DLT) was defined as a 2-week delay in treatment for grade 3 or 4 non-hematologic toxicity, neutropenic fever, a 1-week delay for grade 4 hematologic toxicity, or a 2-week delay for grade 3 hematologic toxicity. Results: Thirty patients were recruited; 28 patients were assessable for safety. Most of the patients (70%) had no prior chemotherapy. The primary first-cycle DLTs were neutropenia, diarrhea, and nausea. Paclitaxel at 65 mg/m² was defined as the MTD. The most common grade 3–4 toxicities observed during all cycles were neutropenia (57%), febrile neutropenia (11%), diarrhea (29%), fatigue (29%), and nausea (18%). No patients had G-CSF (Neupogen, Amgen Inc., Thousand Oaks, CA) support. Responses were observed in gastric, esophageal, and pancreatic cancers. Conclusion: Paclitaxel at 65 mg/m², cisplatin (30 mg/m²), and irinotecan (50 mg/m²) given weekly can be safely administered to patients with solid tumor malignancies. To improve cumulative toxicities, a schedule modification was required (3-week cycle; 2-on, 1-off) Neutropenia was the most common DLT. This combination showed substantial activity, particularly in patients with gastric and esophageal adenocarcinoma, and phase II evaluation could be considered.     

Phase I study to determine the MTD of paclitaxel given three times per week during concurrent radiation therapy for stage III non-small cell lung cancer*

ABSTRACT

Objective: To evaluate the toxicity and the maximum tolerated dose (MTD) of paclitaxel concurrently with three-dimensional (3D) conformal radiotherapy for patients with locally advanced non-small cell lung cancer (LANSCLC) after 2–3 cycles of induction chemotherapy.

Research design and methods: Patients with histologically proven stage III non-small cell lung cancer (NSCLC) were eligible. Induction chemotherapy regimen included cisplatin (40?mg/m²) on days 1 and 2, and vinorelbine (25?mg/m²) on days 1 and 8 every 3 weeks for 2 or 3 cycles, followed a month later by continual three-dimensional (3D) conformal radiotherapy (60?Gy in 30 fractions for 6 weeks) delivered concurrently with paclitaxel dose escalating from the lowest level, 15?mg/m², twice weekly, 6 weeks in all, to the highest level, 15?mg/m², three times a week, 6 weeks in all.

Main outcome measures: The MTD was defined as the highest safely tolerated dose at which no more than one patient out of six experiences dose-limiting toxicity, with the next higher dose having at least two out of six patients experience dose-limiting toxicity (DLT).

Results: Twenty-three patients were enrolled in this study. The maximum tolerated dose of paclitaxel during 3D-conformal radiotherapy was not reached at 15?mg/m², three times a week, 6 weeks in all, a level which has been recommended for Caucasian patients with LANSCLC without induction chemotherapy. The overall response rate of induction chemotherapy alone was 47.8% (0% complete remission, 47.8% partial remission, 39.1% stable disease, 13% progressive disease) and that of induction chemotherapy plus concurrent treatment was 78.3% (18/23), including 8.7% (2/23) complete remissions. None of the patients died as a result of toxicity. The median survival time was 23.0 months.

Conclusions: 15?mg/m² of paclitaxel, three times a week, concurrently with 3D-conformal radiotherapy for patients with locally advanced NSCLC after 2 or 3 cycles of induction chemotherapy is a safe and effective dose, according to our preliminary study.     

Pixantrone: a novel aza-anthracenedione in the treatment of non-Hodgkin's lymphomas

Pixantrone (BBR-2778) is a novel mitoxantrone-like drug, which lacks the 5,8-dihyroxy substitution groups thought to be responsible for the cardiac toxicity associated with mitoxantrone. In Phase I/II single-agent pixantrone clinical trials, neutropenia was the dose-limiting toxicity and the maximum tolerated dose was 150 mg/m(2)/week for 3 weeks every 4 weeks. In relapsed aggressive non-Hodgkin's lymphomas, weekly single-agent pixantrone 85 mg/m(2) for 3 weeks every 4 weeks was associated with a 27% overall response and a 15% complete response. When intensively pretreated patients with relapsed aggressive non-Hodgkin's lymphoma were treated with a cyclophosphamide, pixantrone, vincristine and prednisolone regimen (pixantrone substituted for doxorubicin in standard regimen [cyclophosphamide, doxorubicin, vincristine and prednisolone regimen (CHOP)]), the overall response was 74% and complete response 57%. In the BBR-2778, methylprednisolone, cisplatin and cytosine arabinoside (BSHAP) regimen, 58% overall response and 37% complete response were achieved. A number of randomised studies of pixantrone (BBR-2778) in patients with relapsed indolent or aggressive lymphomas are ongoing.     

Phase I clinical trial of weekly docetaxel and exisulind, a novel inducer of apoptosis

Summary Background: The objective of this phase I study was to determine the maximal tolerated dose (MTD) of the combination of weekly docetaxel and exisulind in patients with advanced solid tumors. Patients and methods: Patients with advanced or refractory solid tumors were treated with intravenous weekly docetaxel with daily oral exisulind. The following dose levels (docetaxel/exisulind) were explored: 30-mg/m²/200 mg po bid, 35/200, 35/250 and 40/250. Docetaxel was administered weekly for 6 weeks followed by 2 weeks off, and exisulind was taken twice daily. Each cycle was 8 weeks. Results: Eighteen patients were enrolled in the study. All of them had received prior systemic therapy. Most patients had either melanoma or carcinomas of the upper gastrointestinal tract. A total of 31 cycles of therapy were administered. DLTs were grade 3 diarrhea, anorexia and fatigue and grade 3 cutaneous toxicity at dose level 4 (40/250). Myelosuppression was mild. Fatigue and gastrointestinal toxicity (anorexia, dyspepsia, nausea, abdominal pain and diarrhea) represented the most common toxicities. However, grade 3 and grade 4 toxicities were uncommon. There were no treatment related deaths. No objective responses were observed and five patients achieved stable disease. Conclusions: The recommended dose for phase II studies is weekly docetaxel 35 mg/m² for 6 weeks followed by 2 weeks off in combination with oral exisulind 250 mg po bid. This combination is feasible and well-tolerated at these doses.     

A phase I clinical and pharmacological profile of dacarbazine with autologous bone marrow transplantation in patients with solid tumors

Summary Dacarbazine (DTIC) is a chemotherapy drug which has antitumor activity at standard doses, exhibits a steep dose-response effect in vitro, and is associated with relatively few non-hematologic toxicities. These characteristics suggest a potential role for this drug in bone marrow transplant preparative regimens. To pursue this hypothesis, 16 patients with refractory solid tumors were enrolled in a phase I study of single agent DTIC to determine the dose of DTIC requiring bone marrow reinfusion and to define the dose-limiting toxicity and maximum tolerated dose when given with autologous bone marrow rescue. Pharmacokinetics were evaluated at the 4394 mg/m² dose level. The marrow requiring dose was 2000 mg/m² when given as a single intravenous (IV) infusion. The extramyeloid dose-limiting toxicity of DTIC was hypotension, with the maximum tolerated dose of DTIC being 3380 mg/m² when given with bone marrow transplantation (BMT). Other toxicities were transient and tolerable. At 4394 mg/m² of DTIC, plasma concentrations declined biexponentially with a terminal half-life of 3 hours. The mean clearance was 10.6 L/hr/m² with a volume of distribution at steady state of 37.5 L/m² and a mean maximum plasma concentration of 150 mcg/ml. One patient with melanoma developed a partial response of short duration after receiving 2600 mg/m² of DTIC. Dacarbazine can be significantly dose escalated with an acceptable toxicity profile, when given with BMT. Future trials should focus on the addition of this drug to current BMT preparative regimens used for the treatment of patients with lymphoma.     

Aziridinylbenzoquinone (AZQ) in the treatment of recurrent pediatric brain and other malignant solid tumors

Summary To assess the response rates and toxicity of AZQ in children with recurrent brain and other malignant solid tumors, a phase II study was implemented by the Pediatric Oncology Group. Eligible patients received AZQ 18 mg/M²/week i.v. for 4 doses followed by a 2 week rest period. Each dose was given over four hours (1/3 over the initial 20 minutes). After the first year, the dosage was reduced to 13 mg/M² due to myelotoxicity resulting in treatment delays. No objective responses were observed in 73 evaluable children with various noncentral nervous system tumors. Of the 91 patients with brain tumors, there were 4 CR's and 2 PR's in patients with astrocytoma, ependymoma, glioblastoma multiforme, oligodendroglioma, brain stem glioma and intracranial yolk sac tumor (median duration, 10 months; range, 2–20+ months). Three of 4 CR's were achieved with a dosage of 18 mg/M²/week. An additional 13 children with brain tumors experienced stable or improved disease (duration, 2–36 + months; median 7.5 months). The principal toxicity was myelosuppression which was cumulative but there were also 3 allergic reactions to AZQ. We conclude that for selected brain tumors, the rates of objective response and stable disease plus the duration of responses support further assessment of AZQ in combination with other agents. Furthermore, the 18 mg/M² dosage may provide better responses. Address for offprints: Pediatric Oncology Group, Operations Office, 4949 West Pine Boulevard, St. Louis, MO 63108, USA