Phase I–II trial of mitoxantrone in acute leukemia: an interim report

Summary We evaluated the effect of mitoxantrone (Novantrone®; dihydroxyanthracenedione) in the treatment of refractory acute leukemia and acute leukemia in relapse. In this study, 70 patients are currently evaluable. Of the 25 patients who received mitoxantrone 10 mg/m² × 5, two of 10 with ANLL in relapse, one of five with ALL in relapse achieved complete remission, and one of seven with blastic phase CML responded. At a dose of 12 mg/m² × 5, nine of 22 patients with ANLL in relapse, one of five patients with blastic phase CML and none of the nine patients with ALL responded. At this dose all remissions occurred after one course of treatment. None of the patients with ANLL or ALL refractory to primary therapy achieved a remission. Toxicities encountered with both dose levels were comparable. However, second courses at 12 mg/m² × 5 led to severe stomatitis and prolonged cytopenia. We conclude that mitoxantrone is effective therapy for ANLL in relapse and that 12 mg/m² per day × 5 is the optimal dose schedule. A randomized trial comparing daunorubicin with mitoxantrone in combination with cytarabine in untreated patients with ANLL should answer whether mitoxantrone is less toxic and whether it should replace daunorubicin in standard induction therapy in ANLL.See Table 1     

Phase II trial of mitoxantrone in acute lymphocytic leukemia of childhood

Summary Thirty children with refractory acute lymphocytic leukemia (ALL) were treated with mitoxantrone, 8 mg/m²/day, for 5 days. Three children received a second course of the drug 3 to 4 weeks later. All but two patients had received prior anthracycline therapy. There were 2 complete responses, 4 early deaths, and 24 patients with persistent leukemia. Of the 21 patients with circulating blasts at the start of mitoxantrone who did not achieve remission, 16 (76%) had complete clearance of their peripheral blood blasts. Although all patients developed profound neutropenia (< 100 per mm³), mucosal and hepatic toxicities were uncommon and mild. Mitoxantrone has moderate activity in childhood ALL and should be considered for further trials in less heavily pretreated patients.     

FLAG联合米托蒽醌治疗复发急性白血病

目的探讨FLAG＋MIT方案治疗难治复发急性白血病的疗效和不良反应。方法 12例患者,年龄16～78岁,中位年龄46岁,难治病例4例,复发病例8例,福达拉宾（Flu）30mg/m230min静脉滴注第1～5天,阿糖胞苷（Ara-C）0.5-1.0g/m24h静脉滴注第1～5天（福达拉宾开始输注4h后）,粒细胞集落刺激因子G-CSF300μg/d（WBC〈1.0×10^9/L开始直到中性粒细胞绝对值〉0.5×10^9/L）,米托蒽醌（MIT）6-10mg第1～3天。结果第一疗程完全缓解（CR）9例,部分缓解（PR）1例,未缓解（NR）2例。CR中8例为急性粒细胞白血病,1例为急性淋巴细胞白血病,PR1例为AML-M4,NR2例为急性淋巴细胞白血病。主要的不良反应是骨髓抑制,发热和感染是最常见。胃肠道反应较低,各例均可耐受,按WHO分级属1-2级;2例发生静脉炎;心脏损害1例,通过支持治疗可控制,无早期死亡。结论 FLAG＋MIT对难治复发急性髓系白血病疗效较好,对部分急性淋巴细胞白血病有效,毒副作用可以耐受。     

A phase II trial of oral etoposide with mitoxantrone and ifosfamide/mesna consolidated with intravenous etoposide,methylprednisolone, high-dose arabinoside,and cisplatin as salvage therapy for relapsing and/or refractory lymphomas

SummaryPurpose To evaluate the response to oral Etoposide when combined with mesna, ifosfamide, and mitoxantrone in patients with relapsed and/or refractory lymphoma. To evaluate response and its duration after administration of intravenous Etoposide, methylprednisolone, high-dose cytosine arabinoside, and cisplatin (ESHAP) as consolidation therapy after complete or partial responses (CR or PR, respectively) or after crossover therapy for progressive disease.Methods Patients received MINE(o) consisting of mesna, 1.33 g/m² infused over 1 hour daily × 3 followed 4 hours later by oral mesna at 500 mg; ifosfamide, 1.33 g/m² infused over 1 hour daily × 3; mitoxantrone, 8 mg/m² intravenously on day 1, and oral VP-16, 30 mg/m² daily × 13. The ESHAP regimen consisted of intravenous VP-16, 40 mg/m² infused over 2 hours daily × 4; methylprednisolone, 500 mg intravenously daily × 4; cytosine arabinoside, 1.5 g/m² infused over 3 hours on day 4; and cisplatin, 25 mg/m² given as a continuous 24-hour infusion daily × 4. Statistical analysis was performed using the 2-stage design described by Simon. For the oral VP-16 regimen to be of interest, at least 36% patients had to achieve a complete remission.Results The overall response rate achieved with MINE(o) was 40% (15% CR, 25% PR). Seven patients with prior exposure to cytosine arabinoside and cisplatin (AP) received MINE(o) alone of whom only one achieved a response (CR). Thirteen patients without prior exposure to AP received consolidation (2 patients) or crossover (11 patients) therapy with ESHAP. Crossover therapy with ESHAP further improved the response in only two of five patients with partial response to MINE(o) and none of six patients who failed MINE(o). Median response duration for the patients who received MINE(o)/ESHAP was 12 weeks (range, 4–55 weeks).Conclusions Oral VP-16 combined with ifosfamide/mesna and mitoxantrone at the doses and schedules indicated has little activity against relapsed and/or refractory lymphomas. Crossover therapy with ESHAP did not further improve the response rate. The duration of response after MINE(o)/ESHAP was short.     

Phase I clinical and pharmacokinetic study of menogaril (7-con-O-methylnogarol) in previously treated patients with acute leukemia

Summary Fifteen patients with relapsed or refractory acute leukemia were treated in this phase I study of menogaril (7-con-O-methylnogarol), a nogalamycin anthracycline derivative. Doses ranged from 50 mg/m²/day to 130 mg/m²/day, administered daily for 5 days. Pharmacokinetic studies were performed at each dose level and confirmed the findings of pharmacokinetic data derived from previous studies in patients with solid tumors. All patients experienced grade 4 hematologic toxicity and the dose limiting toxicity was mucositis. Two patients, one with acute myeloid leukemia and one with acute lymphoid leukemia, achieved complete responses. The AML complete response lasted 10 months and the ALL patient died in CR at 2 + months. Both patients were treated at a dose of 100 mg/m²/day for five days. At this dose, a second induction or consolidation course could be given without severe mucositis, and this is the dose recommended for further phase II studies in leukemia using this schedule.     

A phase II study of mitoxantrone in acute leukemia

Summary A phase II study of mitoxantrone (Novantrone®; dihydroxyanthracenedione) was conducted in 35 patients (22 male: 13 female) with acute leukemia. There were 35 evaluable cases with a mean age of 34 (range 8–61). Twenty-eight patients had acute non-lymphocytic leukemia (ANLL) and seven had acute lymphocytic leukemia (ALL). Mitoxantrone was administered intravenously 2–4 mg/m² daily for five days and after the nadir a further 2–3 doses were added if necessary. All previously treated cases (22 patients) had been treated with anthracyclines; 13 had no previous treatment. Out of the 13 untreated cases there were six complete remissions (CRs) (46.2%) and five partial remissions (PRs) (38.5%), while out of 22 pretreated cases, four CRs (18.2%) and five PRs (22.7%) were obtained. In seven of the untreated cases the decrease of leukemic cells and neutrophil leukocytes were analysed. Mitoxantrone showed a longer duration of decrease and higher log decrease of leukemic cells in the bone marrow than daunorubicin or cytosine arabinoside. Seventy-three percent of patients showed gastrointestinal disturbances such as nausea or loss of appetite. In 38.1% SGPT elevation and in 8.8% abnormal ECG findings were observed. All side-effects were mild and reversible. From this data mitoxantrone seems a very promising agent in the treatment of acute leukemia and a phase III study is now being carried out.     

Mitoxantrone in the treatment of acute leukemia

Summary Forty-six patients with acute leukemia were treated with mitoxantrone as a single agent. Twenty-nine patients had relapsed and/or refractory acute leukemia. Seventeen patients with acute non-lymphatic leukemia had received no prior treatment. Twelve mg/m² of mitoxantrone was given intravenous on five consecutive days. Treatment related side effects included bone marrow suppression, mucositis, alopecia, nausea, vomiting and infection. Cardiotoxicity was documented in 7 patients. This study reconfirms that mitoxantrone is an active agent in acute leukemia with complete response documented in 10 of 29 patients with relapsed and/or refractory acute leukemia (34% response rate, 95% confidence limits 18–53%) and complete response documented in 11 of 17 patients (65% response rate, 95% confidence limits 38–87%) with previously untreated acute non-lymphatic leukemia.     

Phase I Study of Irofulven (MGI 114), an Acylfulvene Illudin Analog, in Patients with Acute Leukemia

Irofulven (MGI 114, 6-hydroxymethylacylfulvene, HMAF)is a semisynthetic illudin analog with broad in vitroanti-neoplastic activity. In this leukemia phase I study, weinvestigated the toxicity profile and activity of Irofulven inpatients with primary refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), ormyelodysplastic syndromes (MDS). Irofulven was given as anintravenous infusion over five minutes daily for five days.The starting dose was 10 mg/m²/day (50mg/m²/course). Courses were scheduled to be givenevery 3-4 weeks according to toxicity and antileukemicefficacy. Twenty patients {AML: 17 patients; MDS: onepatient; ALL: one patient; mixed lineage acute leukemia: onepatient} were treated. Nausea, vomiting, hepatic dysfunction,weakness, renal dysfunction, and pulmonary edema were doselimiting toxicities, occurring in two of five patientstreated at 20 mg/m²/day and two of three patientstreated at 12.5 mg/m²/day. The MTD was defined as10 mg/m²/day for five days. One patient withprimary resistant AML achieved complete remission. Proposedphase II studies will further define the activity of Irofulvenin patients with better prognosis AML and in otherhematological malignancies, both as a single agent and incombination regimens, particularly with topoisomerase 1inhibitors.     

Gemcitabine and mitoxantrone in metastatic breast cancer: A phase-I-study

Background: Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen. Patients and methods: Patients with metastatic breast cancer were treated with gemcitabine (1000–1400 mg/m²) on days 1, 8 and 15 and mitoxantrone (10–14 mg/m²) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme. Results: Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m² gemcitabine and 14 mg/m² mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m² based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively. Conclusion: In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m².     

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.     

Sequential studies on the role of mitoxantrone in the treatment of acute leukaemia

Summary Mitoxantrone (Novantrone®; 1, 4-dihydroxy-5, 8-bis [[2-[(2-hydroxyethyl) amino]ethyl]amino-] 9, 10 anthracenedione dihydrochloride (NSC 301739)) is a synthetic anthracenedione with intercalating properties. Activity has been shown in preclinical studies in mice bearing intraperitoneal P388 and L1210 leukaemias, ADJ-Pc6 plasmacytoma and a variety of solid tumours.In a phase I/II collaborative study (1) fourteen consecutive patients with relapsed or primarily refractory acute leukaemia received a single infusion of mitoxantrone (20–32 mg/m²) at fourteen-day intervals. Antileukaemic activity was seen but there were no complete remissions and toxicity was minimal. Mitoxantrone was subsequently given in a five-day schedule at a dose of 10mg/m² daily to twenty-one patients with relapsed or refractory acute leukaemia or chronic myeloid leukaemia in blast crisis (CML-BC). Four of five patients in first relapse of acute non-lymphoblastic leukaemia (ANLL) achieved a complete remission (CR). The overall response rate (CR + partial remission (PR)) was 48% (2). In an ongoing phase III study the same (5-day) mitoxantrone treatment has been given in conjunction with a 7-day continuous infusion of cytosine arabinoside (Ara-C) in a kinetically designed schedule based upon the preclinical studies of the Mount Sinai group (3).     

Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies

SummaryPurpose To determine the maximally tolerated dose (MTD) and pharmacokinetics of high-dose mitoxantrone and document the toxicities and side effects of mitoxantrone when administered with GM-CSF.Patients and methods Twenty-three patients with advanced solid tumors were entered into a phase I and pharmacokinetic study. Mitoxantrone was administered at doses of 12, 21, 28, 32, 37, and 48 mg/m² on day 1; GM-CSF (5 g/kg once or twice daily) was administered on days 2 to 14. Therapy was repeated every 3 weeks. Dose escalation continued in sets of three patients until the dose limiting toxicity (DLT) was observed. The DLT was based on hematologic, non-hematologic, and cardiac toxicity, and delay of therapy by more than 1 week due to toxicity. Plasma samples were assayed for mitoxantrone concentrations using high performance liquid chromatography (HPLC).Results Twelve patients required either mitoxantrone dose reductions or delays. DLT of neutropenia was observed at a mitoxantrone dose of 48 mg/m²/day. Therefore, we conclude the MTD was 37 mg/m²/day. Myelosuppression appeared to be cumulative. Two patients were withdrawn from the study due to a drop in left ventricular ejection fraction (LVEF). Two of 23 patients experienced a partial response. The mean area under the curve (AUC) and peak mitoxantrone levels increased linearly with dose; triexponential elimination of mitoxantrone was observed. No statistically significant correlation was observed between either peak mitoxantrone level or AUC and duration of absolute neutrophil count (ANC) < 500/mm³.Conclusion The use of GM-CSF allows administration of mitoxantrone at a dose greater than three times that given in standard therapy; treatment is well tolerated. Further studies are needed to determine whether mitoxantrone has cumulative cardiac or hematologic toxicity.     

A phase I trial of vinorelbine in combination with mitoxantrone in patients with refractory solid tumors

Vinorelbine (Navelbine®) is a unique semi-synthetic vinca-alkaloid with a favorable safety profile that has demonstrated significant antitumor activity in patients with non-small cell lung cancer, advanced breast cancer, advanced ovarian cancer and Hodgkin's disease. The most common dose-limiting toxicity is neutropenia, while other reported toxicities are minimal. Mitoxantrone (Novantrone®) is an anthracene derivative that has demonstrated antitumor activity in patients with breast cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone also has a very favorable toxicity profile with significantly less nausea and vomiting, alopecia, and stomatitis as compared with anthracyclines. The dose-limiting toxicity for mitoxantrone is leukopenia. The study was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantrone for the treatment of patients with refractory solid tumors. Vinorelbine was administered on days 1 and 8 of the treatment regimen as a short IV infusion. The starting dose was 15 mg/m². Mitoxantrone was administered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/m². Seventeen patients with solid malignancies were entered in the study. For personal reasons, one patient decided to discontinue the treatment after day 1 of cycle 1. Therefore, 16 patients were evaluable for toxicity. The main toxicity was myelosuppression which was dose-limiting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m² on days 1 and 8 and mitoxantrone 10 mg/m² on day 1 without growth factor support. These doses can be recommended for phase II study of the regimen as salvage treatment.     

A phase I trial of vinorelbine in combination with mitoxantrone in patients with refractory solid tumors

Vinorelbine (Navelbine®) is a unique semi-synthetic vinca-alkaloid with a favorable safety profile that has demonstrated significant antitumor activity in patients with non-small cell lung cancer, advanced breast cancer, advanced ovarian cancer and Hodgkin's disease. The most common dose-limiting toxicity is neutropenia, while other reported toxicities are minimal. Mitoxantrone (Novantrone®) is an anthracene derivative that has demonstrated antitumor activity in patients with breast cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone also has a very favorable toxicity profile with significantly less nausea and vomiting, alopecia, and stomatitis as compared with anthracyclines. The dose-limiting toxicity for mitoxantrone is leukopenia. The study was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantrone for the treatment of patients with refractory solid tumors. Vinorelbine was administered on days 1 and 8 of the treatment regimen as a short IV infusion. The starting dose was 15 mg/m². Mitoxantrone was administered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/m². Seventeen patients with solid malignancies were entered in the study. For personal reasons, one patient decided to discontinue the treatment after day 1 of cycle 1. Therefore, 16 patients were evaluable for toxicity. The main toxicity was myelosuppression which was dose-limiting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m² on days 1 and 8 and mitoxantrone 10 mg/m² on day 1 without growth factor support. These doses can be recommended for phase II study of the regimen as salvage treatment.     

Mitoxantrone in the treatment of relapsed and refractory acute leukemia

Summary Twenty-four patients with acute leukemia or blast crisis (BC) of chronic myelocytic leukemia (CML) in relapse or refractory to standard chemotherapy, were eligible for treatment with mitoxantrone. Mitoxantrone (Novantrone®; dihydroxyanthracenedione) was administered in a dose of 8–13 mg/m² on five consecutive days. Five of 20 evaluable patients were induced into complete remission, one patient achieved a partial remission. Side-effects included moderate to severe bone marrow suppression, moderate mucositis and hair loss. No cardiotoxicity was observed. We believe that mitoxantrone is an active agent in the treatment of acute leukemia and suggest further studies in combination chemotherapy.     

Toxicity trials of amsacrine (AMSA) and etoposide +/− azacitidine (AZ) in childhood acute non-lymphocytic leukemia (ANLL): a pilot study

Recurrent or induction therapy-resistant ANLL carries a grave prognosis. The combination of AMSA at 100 mg/M² daily for 5 days and etoposide at 200 mg/M² daily for the first 3 days of therapy was given to 40 patients with refractory ANLL. An additional 17 patients received those two agents plus azacitidine at a dosage of 250 mg/M² on days 4 and 5. All three drugs were given as one-hour infusions. All patients had normal electrolyte determinations daily and were on cardiac monitors during the period of drug administration. No arrhythmias were detected in 522 doses of AMSA. Toxicities observed were primarily related to myelosuppression. Forty-nine of the 57 patients required hospitalization for suspected or proven infection. Nausea/vomiting and mucositis were the next most commonly occurring toxicities. Responses were seen in 22 patients.     

Phase I study of liposomal daunorubicin in patients with acute leukemia

The dose of anthracyclines used during induction has been identified as a significant prognostic factor in acute leukemias. Liposomal encapsulation of anthracyclines has been proposed as a way of decreasing toxicity and probably increasing efficacy of these agents, therefore allowing the exploration of high-dose anthracycline therapy in acute leukemias. We conducted a phase I study of liposomal daunorubicin (Daunoxome® DNX) in patients with refractory or relapsed acute leukemias. Patients received three daily doses of DNX at 75, 100, 150 or 200 mg/m² on each cycle, to a total dose of 225, 300, 450, and 600 mg/m², respectively. At least three patients were included at each dose level before escalating to the next level, and patients could receive more than one course at the next dose level. Twenty-four patients were included and 23 are evaluable. Fifteen patients received one course, seven received two courses, and one received three courses of DNX. Seventeen patients had previously received anthracyclines. The dose-limiting toxicity was mucositis which occurred (grade 3–4) in 3 of 5 patients treated at 200 mg/m², 2 of 9 treated at 150 mg/m² and 1 of 6 at 100 mg/m². Other non-hematologic toxicity was mild and infrequent. There was no change in post-LVEF among 9 patients with available data and no significant cardiac events were documented. Two patients had a complete response: one patient with chronic myeloid leukemia in refractory blast phase went back to chronic phase, and one patient with second relapse acute promyelocytic leukemia achieved a third complete remission. We conclude that the maximally tolerated dose of DNX in this schedule is 150 mg/m² and has significant anti-leukemia activity.     

Phase I study of JM-216 (an oral platinum analogue) in combination with paclitaxel in patients with advanced malignancies

This phase I study wasconducted to determine the dose limitingtoxicity, maximum tolerated doses, andrecommended phase II doses of thecombination of JM-216 and paclitaxel. Patients received paclitaxel intravenouslyover one hour on day 1 of each cycle. OralJM-216 was administered on days 1–5starting after the paclitaxel infusion. Cycles were repeated every 21 days. Patients were accrued at nine differentdosing combinations. JM-216 doses rangedfrom 10–80 mg/m²/day and werecombined with paclitaxel doses of 150, 175,or 200 mg/m². Forty-three patientswere treated with 146 cycles of therapy. Dose-limiting toxicity, consisting offebrile neutropenia and grade 3thrombocytopenia, was encountered in 2patients at the seventh dose level (JM-21680 mg/m²/day + paclitaxel175 mg/m²). Two intermediate doselevels were explored. The first level(JM-216 70 mg/m²/day + paclitaxel175 mg/m²) produced dose-limitingthrombocytopenia in 1 of 6 patients. However, two additional patients alsodemonstrated delayed recovery fromthrombocytopenia following treatment. As aresult, a second intermediate dose level(JM-216 60 mg/m²/day + paclitaxel200 mg/m²) was filled with sixpatients. No dose-limiting toxicities werereported in any patients at this doselevel. The combination of oral JM-216 andpaclitaxel is well-tolerated with minimalnon-hematologic and reversible hematologictoxicity. The recommended dose for phaseII study is JM-216 60 mg/m²/day for 5days and paclitaxel 200 mg/m² on day 1repeated every 21 days. Higher doses ofJM-216 are associated with more severethrombocytopenia and delayed hematologicrecovery resulting in subsequent dosingdelays.     

A phase II study of mitoxantrone in advanced gastric cancer

Summary Sixteen patients with advanced adenocarcinoma of the stomach were entered into a phase II study of mitoxantrone at a dosage of either 12 mg/m² or 14 mg/m² given at 3 weekly intervals. Nine patients had received prior chemotherapy including doxorubicin. No patients achieved either a complete or partial response, five patients had stable disease and the remainder disease progression. Moderate to severe leukopenia occurred in 10 patients with one septic death. Median survival for all patients was eight weeks (range 1–49 weeks). It is concluded that mitoxantrone has no worthwhile activity in gastric cancer at the described doses.     

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.