Showing papers in "Investigational New Drugs in 1985"
TL;DR: Novantrone was less cardiotoxic than Adriamycin and cardiac events were rare in patients without predisposing risk factors, which make it a promising agent for patients requiring cytotoxic chemotherapy.
Abstract: Mitoxantrone (Novantrone), is an anthracenedione which in preclinical studies demonstrated a spectrum of antitumor activity similar to the anthracyclines, but with less cardiotoxicity. Novantrone is a cytotoxic agent that produces dose-dependent myelosuppression. When administered to patients intravenously every three weeks, white blood cell (WBC) and platelet nadirs occurred between days 8 and 15 with hematologic recovery by day 22. In multiple clinical trials in over 4450 patients, including 372 patients in randomized trials against Adriamycin, Novantrone was consistently associated with a reduced incidence of moderate and severe acute side-effects. In four randomized trials the adverse experience profile associated with Novantrone was superior to that of Adriamycin with statistically significant lower incidences of mucositis/stomatitis, nausea, vomiting and alopecia. Novantrone was less cardiotoxic than Adriamycin and cardiac events were rare in patients without predisposing risk factors. The high level of activity combined with improved patient tolerance and decreased toxicity make Novantrone a promising agent for patients requiring cytotoxic chemotherapy.
103 citations
TL;DR: The pharmacokinetic parameters are adequately described by a three-compartment model with a terminal half-life of 214.8 hours, a volume of distribution (ss) of 3792 litres, and the total body clearance was 358 ml/min and the renal clearance was 26.2 ml/minute.
Abstract: An HPLC method using paired-ion chromatography on RP C-18 material was developed. After sample clean up on XAD columns, mitoxantrone (Novantrone; dihydroxyanthracenedione) in concentrations below 1 ng/ml in serum and 0.2 ng/ml in urine were measurable with a coefficient of variation less than 9.3% at a wavelength of 658 nm. Four metabolites were separated in urine. The major metabolite cochromatographed with the synthesized dicarboxylic acid of mitoxantrone. Within 48 hours 4.4% of the administered dose was excreted in urine as mitoxantrone, 0.5% as metabolite 1 and 0.3% as metabolite 2. The pharmacokinetic parameters are adequately described by a three-compartment model with a terminal half-life of 214.8 hours, and a volume of distribution (ss) of 3792 litres. The total body clearance was 358 ml/min and the renal clearance was 26.2 ml/min.
79 citations
TL;DR: Distribution and half-life data provide a pharmacological rationale for the use of mitoxantrone on an intermittent dosing schedule and preliminary data show that abnormal liver function leads to decreased rates of total body mitoxanrone clearance, suggesting a possible need for dose reduction in patients with severe liver dysfunction.
Abstract: Although a number of investigators have established that mitoxantrone (Novantrone®; dihydroxyanthracenedione) inhibits RNA and DNA synthesis and intercalates with DNA in vitro, its exact mechanism of action is unclear. Mitoxantrone is structurally related to a series of substituted anthraquinones and has features known to be essential for DNA intercalation; however, we have determined recently that mitoxantrone binds DNA in intact L1210 leukemia cells by a non-intercalative, electrostatic interaction and induces both protein associated and non-protein associated DNA strand scissions. The difference between mitoxantrone and doxorubicin with respect to their interactions with DNA could account for their relative lack of cross-resistance in the treatment of lymphoma and acute leukemia.
75 citations
TL;DR: Preclinical studies in several animal models indicate that mitoxantrone does not have the cumulative cardiotoxic liability associated with anthracycline antibiotics such as doxorubicin and combination studies with standard anticancer agents gave evidence of therapeutic synergy in a number of cases.
Abstract: Mitoxantrone (Novantrone®; dihydroxyanthracenedione) belongs to a new structural class of antineoplastic agents, the anthracenediones. It was the outcome of a program in synthetic chemistry, at the Medical Research Division of the American Cyanamid Company, which started from a molecule with structural features predicted to favor intercalation with double stranded DNA.
63 citations
TL;DR: Nausea, vomiting, reversible liver enzyme abnormalities, and allergic reactions were the most common toxicities encountered in echinomycin clinical trials, and the major toxic effects were found in the gastrointestinal, hepatic, and lymphoreticular systems.
Abstract: Echinomycin is a quinoxaline antibiotic that was originally isolated from Streptomyces echinatus. Based on its antitumor activity against two i.p. implanted murine tumors, the B16 melanoma, and the P388 leukemia, it was brought into clinical trials by the National Cancer Institute. Recent studies on its cytotoxic action have related its antitumor activity with its ability to bifunctionally intercalate with double stranded DNA.
54 citations
TL;DR: It is concluded that mitoxantrone does show morphologic evidence of cardiac toxicity; however, the structural changes are minor and are haemodynamically insignificant.
Abstract: Sixty-six patients who underwent endomyocardial biopsy for detection of mitoxantrone (Novantrone®; dihydroxyanthracenedione) cardiac toxicity were evaluated All but one had breast cancer, 29 had received prior doxorubicin and 29 of the 37 patients who had not had prior doxorubicin received it or another anthracycline subsequently Endomyocardial biopsy was carried out initially after four courses of chemotherapy with increasing intervals thereafter Although cardiac ejection fraction was determined before each course of chemotherapy, our data are limited to cardiac ejection fractions from our own institution which were repeated approximately every four courses Endomyocardial biopsy changes consisting of dilatation of the sarcoplasmic reticulum with vacuole formation, and myofibrillar dropout are similar to the early changes of anthracycline cardiomyopathy
50 citations
TL;DR: These results are consistent with the diminished cardiotoxicity of mitoxantrone and ametantrone relative to DOX or DNR and may require a reassessment of the role of lipid peroxidation in the mechanism(s) of quinone antineoplastic agent-mediated cardiot toxicity.
Abstract: Results of comparative studies on stimulation of the rates of cofactor consumption, superoxide generation and hydrogen peroxide production by mitoxantrone (Novantrone®; dihydroxyanthracenedione; MXN), ametantrone (AM), doxorubicin (DOX) and daunorubicin (DNR) in the presence of NADPH-cytochrome P-450 reductase, NADH dehydrogenase, or rabbit hepatic microsomes have been reported. MXN and AM were substantially less effective in stimulating the rate of cofactor oxidation, superoxide formation or hydrogen peroxide production relative to the anthracyclines. In the presence of P-450 reductase, the rate of NADPH oxidation or superoxide generation produced by 100 μM MXN or AM was only 15% and 2% respectively of that produced by 100 μM anthracycline. The effects of MXN and AM on lipid peroxidation in hepatic microsomes, cardiac sarcosomes and cardiac mitochondria were determined and compared with those produced by ADM. MXN and AM at 50 μM inhibited the basal rate of NADPH-dependent rabbit liver microsomal lipid peroxidation by 50%; in contrast, DOX enhanced the rate of hepatic microsomal lipid peroxidation by 2-and 2.5-fold at 100 and 200 μM, respectively. Rabbit cardiac sarcosomal NADPH-dependent lipid peroxidation was inhibited completely at 100 μM anthracenedione. NADH-dependent lipid peroxidation in cardiac mitochondria was diminished by 50 μM MXN and AM, whereas 50 μM DOX produced a 2-fold stimulation in lipid peroxidation. The anthracenediones also effectively inhibited DOX-stimulated lipid peroxidation with 50% inhibition occurring at 4 μM (MXN) and 6 μM (AM). Moreover, both MXN and AM potently inhibited iron (100 μM)-stimulated lipid peroxidation in rabbit hepatic microsomes with 80% inhibition produced by 15 μM anthracenedione. These results are consistent with the diminished cardiotoxicity of mitoxantrone and ametantrone relative to DOX or DNR and may require a reassessment of the role of lipid peroxidation in the mechanism(s) of quinone antineoplastic agent-mediated cardiotoxicity.
43 citations
TL;DR: Mitoxantrone appears to be as active as doxorubicin in patients with stage IV breast cancer previously treated with chemotherapy; however, mitoxanrone causes significantly less nausea, vomiting, stomatitis and alopecia at doses which induce equal or greater myelosuppression than doxorbicin, and seems to be less cardiotoxic.
Abstract: Mitoxantrone (Novantrone®; dihydroxyanthracenedione) is an anthraquinone previously shown to be active in human breast cancer. It appears to have less toxicity than doxorubicin. Results of this phase II–III randomized cross-over trial to determine the relative efficacy and toxicity of mitoxantrone in comparison to doxorubicin, are presented. Patients with measurable, recurrent breast cancer with limited prior chemotherapy with or without radiotherapy for metastatic disease, and who had not been exposed to prior doxorubicin, were randomized to receive either mitoxantrone or doxorubicin every three weeks with crossover on progression. Response rates, duration of remission, time to treatment failure, and drug toxicity, including cardiac toxicity evaluated with serial radionuclide angiocardiography, were evaluated. Differences in the response rates for the two groups were not statistically significant. Neither time to treatment failure nor duration of response are significantly different (p>0.05). With respect to toxicity, mitoxantrone treated patients consistently exhibited a lower incidence and less severe drug toxicity as compared to their doxorubicin-treated counterparts. Cardiac toxicity was carefully monitored and thus four patients on doxorubicin have had drug related congestive heart failure, as compared to none on mitoxantrone.
38 citations
TL;DR: The preclinical differences in therapeutic and toxicologic manifestations of 4′-epidoxorubicin, reflecting apparent alterations in pharmacologic properties and mode of action in comparison with doxorubICin, support the broad spectrum clinical trials of this already-demonstrated clinically active drug.
Abstract: The current report presents the data of the Division of Cancer Treatment of the National Cancer Institute (NCI) on the antitumor activity of the anthracycline antibiotic 4′-epidoxorubicin in experimental tumor systems. Direct comparisons are made with doxorubicin in individual experiments, and the data are related to those of earlier studies in the form of a review of experimental activity, in order to assess the relative activity of 4′-epidoxorubicin and doxorubicin. The experimental test models utilized by the NCI for these studies included the leukemias P388 and L1210, B-16 melanoma, Lewis lung carcinoma, the colon tumors 26 and 38, and the mammary tumors CD8F1 and C3H16/C. The human tumors growing in xenograft in athymic mice included the models LX-1 lung tumor, CX-1 colon tumor, and MX-1 mammary tumor. Additional comparisons were made with the tumor models Gross leukemia, sarcoma 180, MSV-induced sarcoma, MS-2 tumor, and a variety of human tumors growing in athymic mice, as well as with in vivo toxicologic and in vitro cytotoxicity models. Although for 4′-epidoxorubicin there is only a minimal alteration of the configuration of the doxorubicin molecule, quantitative comparison of 4′-epidoxorubicin and doxorubicin revealed not only similarities but also differences in biological activity. Both drugs showed activity against a broad spectrum of experimental tumors, with 4′-epidoxorubicin more effective against some tumors and equally effective against others. 4′-Epidoxorubicin evidenced less toxicity than doxorubicin in both acute and chronic toxicity studies with retention of therapeutic effectiveness and showed reduced cardiotoxicity. With 4′ -epidoxorubicin there resulted a higher therapeutic index and therapeutic ratio, permitting the use of higher dosage and a greater margin of safety. The preclinical differences in therapeutic and toxicologic manifestations of 4′-epidoxorubicin, reflecting apparent alterations in pharmacologic properties and mode of action in comparison with doxorubicin, support the broad spectrum clinical trials of this already-demonstrated clinically active drug.
31 citations
TL;DR: The toxicity of the glutamine antagonist 6-diazo-5-oxo-L-norleucine administered as a 24 hour infusion has been evaluated and the drug does not exhibit renal, hepatic or central nervous system toxicity.
Abstract: The toxicity of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) administered as a 24 hour infusion has been evaluated. Studies of the clinical pharmacology of the drug have also been performed in 3 patients. The limiting toxicity of the drug was acute nausea, vomiting and diarrhea that was dose dependent in its severity and duration. The maximum tolerated dose was 600 mg/m2 over 24 hours. The other major toxicity was thrombocytopenia that was maximal 7–10 days after the completion of the infusion. The drug does not exhibit renal, hepatic or central nervous system toxicity. DON achieves steady state levels during these infusions and is eliminated by first order kinetics when the infusion is completed (t1/2α = 1.81 h). The principal route of excretion is renal. A starting dose of 400 mg/m2 would be acceptable for Phase II studies of this drug administered on this schedule.
29 citations
TL;DR: 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.
Abstract: 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 X 10(9)/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 X 10(9)/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.
TL;DR: Trimetrexate is active against tumors which are methotrexate-resistant on the basis of impaired transport, and has a broader range of antitumor activity in preclinical models.
Abstract: Trimetrexate, a 2,4-diaminoquinazoline derivative, is a new antifol recently introduced into clinical trials. It differs from methotrexate principally in its transport (not carrier-mediated), and its intracellular retention (not polyglutamylated). Trimetrexate is active against tumors which are methotrexate-resistant on the basis of impaired transport, and has a broader range of antitumor activity in preclinical models. Animal studies predict toxicity principally to the central nervous system, gastrointestinal tract and bone marrow.
TL;DR: Treatment of patients by 5 day continuous intravenous (rather than bolus) infusion resulted in more pronounced myelosuppression and clinically significant but tolerable hypotension and further investigations of the hypotensive and cardiac effects of homoharringtonine are indicated.
Abstract: Homoharringtonine is one of several Cephalotaxine esters which have shown experimental antineoplastic activity as well as anti-leukemia effects in patients in China. In a Phase I trial of homoharringtonine administered daily × 5 by bolus intravenous injection, the dose limiting toxicity was hypotension and the maximum tolerated dose was 3.5 mg/m2/d × 5. Evidence of drug induced cardiac irritability with resulting ventricular and atrial dysrhythmias was seen. Minimal myelosuppression was seen at this dose. Treatment of patients by 5 day continuous intravenous (rather than bolus) infusion resulted in more pronounced myelosuppression and clinically significant but tolerable hypotension. Significant reduction of white blood cell and platelet counts occurred at a dose of 3.5 mg/m2/day. Further investigations of the hypotensive and cardiac effects of homoharringtonine and Phase II trials using continuous infusion are indicated.
TL;DR: It is concluded that epirubicin at the present dose and schedule is an ineffective agent in patients with metastatic colorectal cancer.
Abstract: Epirubicin, a stereoisomer of doxorubicin with suggested lower potential for cardiotoxicity in experimental animal tumor systems, was studied in a disease-oriented phase II trial in patients with advanced colorectal cancer. The drug was given as a direct iv injection of 90 mg/m2 q 3 weeks. No objective response was observed in 52 evaluable patients with colon (n = 34) and rectal (n = 18) carcinoma. Fourteen patients (27%) had stable disease for a median of four treatment courses. Leukopenia (88%), nausea and vomiting (71%) and alopecia (54%) were the most common toxic effects. We conclude that epirubicin at the present dose and schedule is an ineffective agent in patients with metastatic colorectal cancer.
TL;DR: The data indicate that mitoxantrone is an effective agent for the treatment of advanced breast cancer with mild side-effects, especially with respect to nausea/vomiting, hair loss and cardiotoxicity.
Abstract: Forty-two women with measurable or evaluable advanced breast cancer who had received neither prior chemotherapy for advanced disease nor any anthracycline-containing regimen as adjuvant were entered in a phase II study of mitoxantrone (Novantrone; dihydroxyanthracenedione). Patients were aged from 36 to 80 years, performance status was from 0 to 2. All patients had normal hematological status and normal renal and liver function tests. Cardiac scintigraphy and sonography techniques were used to monitor cardiac function. Mitoxantrone was administered at a dose of 14 mg/m2 in 100 ml 5% dextrose solution over 30 minutes, repeated every three weeks. The number of courses per patient ranged from 2 to 12. Of 42 eligible patients 39 were fully evaluable for response and all for drug toxicity. Responses to treatment were: complete response four patients, partial response 10 patients, stable disease 18 patients and progressive disease seven patients. The overall response rate was 36% (95% confidence limits 20-52%). Three patients showed decreased left ventricular ejection fraction but no patient developed signs of overt left ventricular failure during the treatment period. Hematological and gastrointestinal toxicities were mild. Hair loss was minimal. The data indicate that mitoxantrone is an effective agent for the treatment of advanced breast cancer with mild side-effects, especially with respect to nausea/vomiting, hair loss and cardiotoxicity.
TL;DR: Mitoxantrone (Novantrone®; dihydroxyanthracenedione) was administered in a dose of 8-13 mg/m2 on five consecutive days as mentioned in this paper.
Abstract: 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.
TL;DR: Difluoromethylornithine (DFMO), a non-competitive inhibitor of ornithine decarboxylase (ODC), the rate limiting enzyme of the polyamine synthetic pathway was evaluated in a Phase I trial and no patient achieved a remission but there was stabilization or decrease in circulating blast cells in several patients.
Abstract: Difluoromethylornithine (DFMO), a non-competitive inhibitor of ornithine decarboxylase (ODC), the rate limiting enzyme of the polyamine synthetic pathway was evaluated in a Phase I trial. Intravenous DFMO was given to twenty patients with refractory leukemia by continuous infusion in doses from 5.5 to 64 g/m2. Toxicity clearly attributable to the drug was not severe and other than nausea and vomiting did not increase with dose. The previously reported ototoxicity which occurred with the oral form appeared to be less frequent. Loss of hearing which improved when the drug was stopped was seen in four patients, three of whom were simultaneously receiving aminoglycosides. Anorexia occurred in some patients at all doses. Vomiting, necessitating dosage reduction, was a significant problem at the highest dose administered. No patient achieved a remission but there was stabilization or decrease in circulating blast cells in several patients. This growth inhibition did not appear to be dosage related.
TL;DR: N-acetylcysteine was administered to AT-125 treated rats in an attempt to supply cysteine to the brain in the face of γ-GTP inhibition, suggesting that it can serve as a source of Cysteine under these conditions.
Abstract: AT-125 (Acivicin) is an inhibitor of γ-glutamyltranspeptidase (γ-GTP) which initiates glutathione catabolism to cysteine. We measured plasma and brain glutathione and cysteine in rats treated with AT-125. Six h after AT-125 treatment, plasma glutathione had increased 6-fold and plasma cysteine had fallen significantly. Brain cysteine fell after 24 h of AT-125 treatment, and brain glutathione had also decreased 18%. AT-125 pretreatment inhibited brain uptake of 35S when it was given as 35S-GSH but had no effect when it was given as 35S-cysteine. These results suggest that plasma glutathione is catabolized by γ-GTP, and cysteine derived from it is taken up by the brain. N-acetylcysteine was administered to AT-125 treated rats in an attempt to supply cysteine to the brain in the face of γ-GTP inhibition. N-acetylcysteine supported brain glutathione levels, suggesting that it can serve as a source of cysteine under these conditions.
TL;DR: It is concluded that mitoxantrone is effective therapy for ANLL in relapse and that 12 mg/m2 per day × 5 is the optimal dose schedule.
Abstract: 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.
TL;DR: The case of a woman with multiple myeloma, who developed fulminant encephalopathy following 4 days of continuous vincristine, adriamycin, and day 1–4 pulse dexamethasone (VAD) combination therapy is described.
Abstract: Neurotoxicity is a well-recognized and commonly observed side effect associated with the use of vincristine sulfate in cancer chemotherapy. The clinical manifestations of vincristine neuropathy cover a wide spectrum of peripheral neurologic dysfunctions that have been described to be reversible and cumulative in most instances (1, 2). Paresthesias, loss of tendon reflexes, and progressive weakness are the most common clinical features (3, 4). Sensory impairment, cranial nerve palsies, gastrointestinal disturbances, and autonomie dysfunctions including atonic bladder, impotence, and orthostatic hypotension may occur (5). Acute CNS complications, usually presenting as generalized seizures, are extremely rare and only a few cases have been reported which were without underlying biochemical or structural abnormalities (1, 5–9). We describe the case of a woman with multiple myeloma, who developed fulminant encephalopathy following 4 days of continuous vincristine, adriamycin, and day 1–4 pulse dexamethasone (VAD) combination therapy.
TL;DR: Mitoxantrone offers comparable efficacy and less acute toxicity than the most active single agents currently available in the treatment of advanced breast cancer.
Abstract: Mitoxantrone (Novantrone®; dihydroxyanthracenedione) is a substituted anthraquinone with a spectrum of activity similar to doxorubicin in experimental tumors.
TL;DR: In this preliminary evaluation, 117 patients are evaluable for response and 110 for toxicity, and the predominant toxicity is leukopenia with a nadir WBC count <2000 in 45% of all courses administered.
Abstract: New agents with increased activity and/or reduced toxicity are needed for the treatment of advanced breast cancer. The anthracene derivatives mitoxantrone and bisantrene had significant activity and acceptable toxicity in phase II trials. In an ongoing phase III trial we have now randomized 150 patients with advanced breast cancer to either doxorubicin (60 mg/m2), mitoxantrone (14 mg/m2) or bisantrene (260 mg/m2) i.v. q 3 weeks with re-randomization for cross-over at the time of progression to determine the relative efficacy and toxicity of these three agents. To be eligible, patients must have had only one previous chemotherapy regimen. ER positive patients must have failed endocrine therapy. Patients with CHF or severe cardiac disease were ineligible. In this preliminary evaluation, 117 patients are evaluable for response and 110 for toxicity. Median age for all patients is 58 years (range 26–78). The majority (86%) are postmenopausal. Fifty-nine percent of the patients have visceral dominant disease. Estrogen receptor is positive in 37%, negative in 39% and unknown in 24% of patients. Median performance status (SWOG) is 1, range 0–2. Objective responses have been observed on each arm (doxorubicin 9/35, mitoxantrone 6/38, bisantrene 6/44). Thirty-two patients are evaluable for cross-over response (doxorubicin 2/13, mitoxantrone 1/11, bisantrene 0/8). The predominant toxicity is leukopenia with a nadir WBC count <2000 in 45% of all courses administered. Leukopenia is similar with the three drugs. Significant nausea, vomiting and alopecia are common with doxorubicin and uncommon with the other agents. Congestive heart failure has been observed in one patient (doxorubicin). Definitive conclusions regarding the efficacy and toxicity of these agents await the completion of this trial.
University of Rochester1, Georgetown University2, Yeshiva University3, Tufts University4, University of Miami5, Tulane University6, New York University7, City of Hope National Medical Center8, University of Chicago9, Wake Forest University10, Thomas Jefferson University11, University of Alabama at Birmingham12, Louisiana State University13, American Cyanamid14
TL;DR: CNF is an effective regimen for patients with advanced breast cancer, with less toxicity than CAF, with a non-significant difference in response rate and time to treatment failure.
Abstract: As of August 1984, 115 women with advanced breast cancer have been randomized to receive a combination of either cyclophosphamide, Novantrone (mitoxantrone) and 5-fluorouracil (CNF) or cyclophosphamide, Adriamycin (doxorubicin) and 5-fluorouracil (CAF). Seventy-one percent of all patients were postmenopausal and 44% of CNF patients and 57% of CAF patients were estrogen receptor (ER) negative. Slightly over 30% of all patients had received hormonal therapy or chemotherapy in an adjuvant setting. Hematologic toxicity was similar in regard to platelet counts but slightly lower nadirs were experienced with CNF therapy than with CAF. However, there were fewer dosage decreases with CNF. Significantly less nausea and vomiting were observed with the CNF regimen compared to CAF. Moreover, alopecia was reduced appreciably in patients who received CNF. The response rate to CNF for the first 38 eligible and evaluable patients was 42%, and for 53 eligible and evaluable patients who received CAF the response rate was 45%, a non-significant difference. Median response durations were similar also, 140 days for CNF and 168 days for the CAF regimen. Time to treatment failure was similar for both regimens. CNF is an effective regimen for patients with advanced breast cancer, with less toxicity than CAF.
TL;DR: Four of five patients in first relapse of acute non-lymphoblastic leukaemia (ANLL) achieved a complete remission (CR) and the overall response rate (CR + partial remission (PR) was 48% (2).
Abstract: 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).
TL;DR: Ara-AC appeared to be more efficacious than ara-C and as active as the positive control compound, BCNU, in some instances, and excellent activity for aRA-AC was also observed against the intracerebral P388 leukemia system.
Abstract: Arabinosyl-5-azacytosine (ara-AC) is a new compound which combines the structural characteristics of arabinosyl cytosine (ara-C) and 5-azacytidine (5-AC). These three compounds, injected intraperitoneally, were evaluated in direct comparison against the intracerebral L1210 leukemia model. 5-AC was active in a non-schedule dependent manner producing increase in life span (ILS) values of 70%. The effects of both araC and ara-AC were schedule-dependent with the best activity (ILS ca. 600%; multiple long term survivors) observed using an around-the-clock treatment schedule. In all experiments, ara-AC appeared to be more efficacious than ara-C. In some instances, ara-AC was as active as the positive control compound, BCNU. Excellent activity for ara-AC was also observed against the intracerebral P388 leukemia system.
TL;DR: Tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide, TCAR) is a synthetic C-nucleoside that demonstrated significant in vivo activity against a variety of animal tumors as well as in vitro activity against human tumor-derived cell lines.
Abstract: Tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide, TCAR) is a synthetic C-nucleoside that demonstrated significant in vivo activity against a variety of animal tumors as well as in vitro activity against human tumor-derived cell lines. Thirteen patients were treated with TCAR administered as a 5-day continuous infusion in this Phase I trial. Seventeen complete cycles were administered in three dose levels ranging from 550 to 1450 mg/M2. Dose-limiting toxicities were myelosuppression and neurotoxicity including severe lethargy. Other toxicities including superficial skin peeling, myalgias, and tearing were seen at all doses. One patient had chest pain on day 4 resulting in stopping the drug, however, there was no evidence of cardiac or pericardial disease. Uric acid levels rose within one day in the absence of allopurinol treatment. There were no treatment related deaths. HPLC measurement of drug levels demonstrated steady-state plasma levels during the infusion, and a half-life following the infusion of 7.7 ± 0.6 hours. Minor abnormalities in renal function were associated with dramatic changes in pharmacokinetics and toxicity. No clinical responses were observed in this trial.
TL;DR: The stability of the potential antitumour agent 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ) has been investgated by high-performance liquid chromatography and was adversely affected by increased temperatures, increased buffer concentration and light.
Abstract: The stability of the potential antitumour agent 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ; NSC 224070) has been investgated by high-performance liquid chromatography. At 22°C in 0.05M buffer, BZQ was most stable at pH 9 with an apparent first-order rate constant (k) of about 0.014 h−11. There was reduced stability at pH values above and below 9.0. At a pH of 3 and 12 the values of k were 38 and 0.3 h−1, respectively. Stability of BZQ was adversely affected by increased temperatures (above 0°C), increased buffer concentration and light. Solutions of BZQ could not be frozen for any length of time, as the drug precipitated out in a form that would not redissolve (possibly a polymer). For parenteral administration to patients, it is suggested that BZQ would be most stable in 1.26% sodium bicarbonate solution when at room temperature, under normal laboratory lighting, 5% of the drug degraded (t0.95) in 5.5 h. Increased stability is obtainable in this medium by refrigeration and vigorous exclusion of light. Long term (24 h) infusions of BZQ could be considered in hypotonic sodium bicarbonate (30 mM) with careful exclusion of light as long as the volume of the infusion was small, e.g. 1 ml/h. Under these conditions to.95 was 42 h at 21.5°C.
TL;DR: It is probable, that the severe venous pain and the mucosal irritation are caused by the high local concentration of 4-hydroxy-cyclophosphamide or by a metabolite, and an oxazaphosphorine derivative undergoing slower hydrolysis therefore leading to lower active drug concentrations within the injected vein may be more promising.
Abstract: Mafosfamide-cyclohexylamine is a new oxazaphosphorine derivative. It was chosen for phase-I clinical testing because of an expected higher therapeutic index and lack of complete cross resistance in animal tumors compared to cyclophosphamide. The schedule consisted of a single iv dose repeated every three weeks. The compound was found to cause as it's dose limiting toxicity severe pain along the injected vein and acute irritation of mucous membranes. The maximal tolerated dose was around 1000 mg/m2 given as a slow infusion over 2–3 hours. Hematological toxicity was mild. A limited phase-I study with the lysine salt of mafosfamide showed an identical type of toxicity. Mafosfamide given iv in a high-dose intermittent schedule is of little interest for further clinical trials.
TL;DR: A more sensitive method, such as radioimmunoassay, which can be utilized in pharmacokinetic studies to measure mitoxantrone levels in biological fluids, over extended periods of time after dosing is developed.
Abstract: A sensitive and specific radioimmunoassay for mitoxantrone in serum has been developed. The procedure allows direct measurement of mitoxantrone in unextracted serum samples, by using antisera from rabbits immunized with mitoxantrone-BSA antigen. Tritiated mitoxantrone of high specific radioactivity (ca. 15 Ci/mmol) was used as a radio-tracer ligand. The assay allows the detection of as little as 50 pg/ml and the quantitation of 75 pg/ml in 0.5 ml serum samples. Standard curves were linear in the concentration range of 75–2500 pg/ml, at antiserum dilutions of 1:15,000. The assay shows good reproducibility: coefficients of variation of 3–6% were obtained by analyzing five samples/concentration at 75, 100, 250, 500, and 1000 pg/ml. There was no cross reactivity with the major metabolite in human serum, having concentrations of up to 10,000 pg/ml. Serum samples collected at various time intervals from rats dosed intravenously with mitoxantrone (0.5 mg/kg), were analyzed for unchanged mitoxantrone by RIA. The drug concentrations decreased from 32 ng/ml at 0.5 h to 0.45 ng/ml by 24 h after dosing.
TL;DR: None of the four drugs tested was active against previously treated sarcomas at these doses and schedules, but bleomycin, however, should be considered for further evaluation in mesothelioma patients.
Abstract: 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 iv day 1 each week), chlorozotocin (150 mg/M2 iv q6 weeks), MGBG (500 mg/M2 iv each week, escalated in 50 mg/M2 weekly increments to a maximum dose of 700 mg/M2), or bruceantin (55 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