carubicin and Nausea

KRN8602 (MX2) is a newly developed morpholino anthracycline that crosses the blood-brain barrier where it becomes distributed in brain tissue after intravenous administration. This morpholino anthracycline has been found to be effective against human glioma cells and the intracerebrally transplanted tumors in vivo, We performed a phase II trial using KRN8602 as a single agent in malignant glioma patients who had not received prior adjuvant therapy. The 13 patients (5 glioblastomas, 7 anaplastic astrocytomas and 1 malignant oligodendroglioma) enrolled received at least 1 cycle of KRN8602 at 35 mg/m2/day in 3-4 week intervals by intravenous bolus. Ten of these patients could be evaluated for response, and 13 for toxicity. Three patients (1 glioblastoma and 2 anaplastic astrocytomas) demonstrated a complete response (3/10, 30%). Concerning side effects, myelosuppression was moderately severe, with 30.7% of patients developing grade 3 leukopenia. Severe nausea/vomiting was observed in 69% of the patients, however, cardiotoxicity was not observed. The results indicate that KRN8602 demonstrated modest activity against malignant glioma with relatively severe, but manageable toxicity. Further assessment of the efficacy and toxicity of KRN8602 against malignant glioma may be worthwhile.

Topics: Adult; Antibiotics, Antineoplastic; Astrocytoma; Brain Neoplasms; Cardiomyopathies; Carubicin; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Glioblastoma; Humans; Leukopenia; Male; Middle Aged; Nausea; Oligodendroglioma; Treatment Outcome; Vomiting

In order to determine the clinically optimal dose of KRN8602, a new anthracycline derivative, in combination therapy for acute leukemia, we performed a pilot late phase II study in combination with cytarabine (Ara-C) for acute myelogenous leukemia (AML), and with vincristine (VCR) and prednisolone (PSL) for acute lymphocytic leukemia (ALL). KRN8602 was given at a dose of 12 or 15 mg/m2 for 5 consecutive days, Ara-C at a dose of 100 mg/m2 for 7 consecutive days, VCR 1.4 mg/m2 (max. 2.0 mg/body) weekly for 4 weeks, and PSL 40 mg/m2 for principally 28 consecutive days. Of 14 patients with relapsed or refractory leukemia entered in the study, thirteen patients were evaluable for safety and 12 were evaluable for response. In AML, there was 1 partial response (PR) in 4 patients at a dose of 12 mg/m2. Against 1 complete response (CR) and 3 PRs in 4 patients at a dose of 15 mg/m2. In ALL, there was 1 PR in 1 case at a dose of 12 mg/m2, and 1 CR and 2 PR in 3 at a dose of 15 mg/m2. Major toxicities were nausea/vomiting and anorexia, but incidences and grades of toxicities were not dose-dependent, and all toxicities were tolerable and manageable. From these results it is concluded that the optimal dose of KRN8602 is 15 mg/m2 for 5 consecutive days in combination with Ara-C for AML, and with VCR and PSL for ALL.

Topics: Adult; Aged; Anorexia; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carubicin; Cytarabine; Female; Humans; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Middle Aged; Nausea; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Vincristine; Vomiting, Anticipatory

We performed a clinical phase II study of KRN8602, a new anthracycline derivative, for relapsed or recurrent malignant lymphoma. KRN8602 was given at doses of 12-15 mg/m2 for 3 consecutive days, repeating every 3-4 weeks. Among 44 patients entered into the study, 36 were evaluable for safety, and 35 were evaluable for efficacy. The response rate was 18.2% (6PR/33) for non-Hodgkin's lymphoma and 0% (0/2) for Hodgkin's disease. Major toxicities were bone marrow suppression and gastrointestinal toxicity. Leukopenia was observed in 77.8%, thrombocytopenia in 44.4%, hemoglobin decrease in 44.4%, nausea and vomiting in 94.4% and anorexia in 80.6%. However, all toxicities were clinically manageable.

Topics: Anorexia; Antibiotics, Antineoplastic; Carubicin; Drug Administration Schedule; Hodgkin Disease; Humans; Leukopenia; Lymphoma, Non-Hodgkin; Nausea; Thrombocytopenia; Vomiting

We performed an early phase II study of KRN8602, a new anthracycline derivative for refractory or relapsed acute leukemias. KRN8602 was given at a dose of 15 mg/m2 for 3 to 5 consecutive days, repeating every 3-4 weeks. Among 53 patients entered in the study, 51 were evaluable for safety, and 46 were evaluable for efficacy. The response rate at schedules of 3 and 4 consecutive days was 9.1% (1 PR/11), while that at a schedule of 5 consecutive days was 22.9% (3 CR + 5 PR/35). With the 5 consecutive day schedule, the response rates were 21.4% (1 CR + 2 PR/14) for acute myelogenous leukemia and 29.4% (2 CR + 3 PR/17) for acute lymphocytic leukemia, but no response was observed in 4 patients with blastic crisis of chronic myelogenous leukemia. Major toxicities were nausea/vomiting and anorexia, however, all these toxicities were clinically manageable. From these results it is concluded that KRN8602 is effective against acute leukemias, and the optimal dose is 15 mg/m2 for 5 consecutive days.

Topics: Adult; Aged; Anorexia; Antibiotics, Antineoplastic; Carubicin; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Nausea; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vomiting

Sixty-three evaluable patients with advanced breast cancer were randomly allocated to receive three-week intravenous courses of carminomycin (18 mg/m2) or 4'-epidoxorubicin (90 mg/m2). The former yielded one (3%) partial response for nine weeks among 29 patients whereas, in the other arm, nine (27%) of 34 patients achieved partial response for a median of 28 weeks (range, nine to 36 weeks; p less than 0.02). The major toxic effect of these anthracyclines was leukopenia with median white blood cell nadirs of 1,600/microL (range, 300-4,000/microL) versus 1,800/microL (range, 500-4,300/microL), respectively. Acute nonhematologic toxic effects were qualitatively similar but carminomycin produced significantly less gastrointestinal intolerance and alopecia. Patients whose disease failed to respond to first-line anthracycline received doxorubicin (60 mg/m2) every three weeks. Four partial responses were obtained among 19 patients previously treated with carminomycin. Following 4'-epidoxorubicin therapy, one of 12 evaluable patients also attained partial response. Survival curves were not affected by the initial treatment option. Carminomycin has marginal activity against breast cancer whereas 4'-epidoxorubicin deserves further evaluation of its therapeutic index relative to doxorubicin. The design used in this trial appears attractive for prompt phase II evaluation of anthracycline analogs.

Topics: Adult; Aged; Alopecia; Breast Neoplasms; Carubicin; Daunorubicin; Doxorubicin; Drug Evaluation; Epirubicin; Female; Follow-Up Studies; Heart Diseases; Humans; Leukopenia; Middle Aged; Nausea; Neoplasm Metastasis; Random Allocation; Vomiting

Topics: Adult; Aged; Bleomycin; Carcinoma, Squamous Cell; Carubicin; Clinical Trials as Topic; Daunorubicin; Humans; Leukopenia; Lung Neoplasms; Male; Methotrexate; Middle Aged; Nausea; Vomiting

KRN 8602 is a new antineoplastic drug with the chemical structure, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride. This drug was developed in an attempt to improve the clinical efficacy of currently used anthracyclines. In preclinical studies, KRN 8602 has been shown to produce less cardiotoxicity and alopecia, yet has comparable antitumor effects to adriamycin. In addition, KRN 8602 has shown antitumor effects on adriamycin-resistant tumors. A phase I clinical study was undertaken to determine the toxicity of KRN 8602 given as a single i.v. dose. Toxicity evaluation included CBC with differentials, platelet counts, SMA chemistry profile, EKG, urinalysis, plain chest X-ray and physical examination. Myelosuppression was the major side effect noted with leukopenia, and especially neutropenia, being dose-limiting. The degree of WBC suppression was dose-related and MTD appears to be 30 mg/m2. Nausea and vomiting were observed in cases who had received more than 10 mg/m2. No patient had alopecia. No obvious cardiotoxicity in this study. Maximum total cumulative dose of KRN 8602 was 450 mg/m2. Further observation is necessary to confirm this point. In this study of 10 cases, one breast carcinoma with bilateral lung metastasis revealed definite regression of metastasis for more than 18 months with this agent alone. This patient had previous chemo- and hormone therapy, containing adriamycin. The above preliminary phase I clinical study suggests strongly the usefulness of KRN 8602, and further investigations are indicated.

Topics: Adult; Antibiotics, Antineoplastic; Breast Neoplasms; Carubicin; Daunorubicin; Drug Evaluation; Female; Humans; Injections, Intravenous; Leukopenia; Male; Middle Aged; Nausea; Stomach Neoplasms; Vomiting