Multicenter phase II trial of docetaxel and carboplatin in patients with stage IIIB and IV non-small-cell lung cancer.

PURPOSE: To evaluate the safety and efficacy of docetaxel and carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this multicenter, phase II trial, 33 patients with previously untreated stage IIIB (n = 8) or IV (n = 25) NSCLC received intravenous infusions of docetaxel 80 mg/m2 followed immediately by carboplatin dosed to AUC of 6 mg/ml/min (Calvert's formula) every three weeks. Patients also received dexamethasone 8 mg orally twice daily for three days beginning one day before each docetaxel treatment. Filgrastim was not allowed during the first cycle and was added only if a patient experienced febrile neutropenia or grade 4 neutropenia lasting > or = 7 days. RESULTS: There were 1 complete and 11 partial responses for an objective response rate of 43% (95% CI: 24%-63%) in 28 evaluable patients and 36% (95% CI: 20%-55%) in the intent-to-treat population. The median duration of response was 5.5 months (range 3.0-12.5 months). The median survival was 13.9 months (range 1-35+ months); one-year survival was 52%. The most common toxicity was hematologic, which included grade 4 neutropenia (79% of patients and 7% percent of cycles) and febrile neutropenia (15% of patients); there were no episodes of grade 3 or 4 infection. The most common severe nonhematologic toxicities were asthenia (24%) and myalgia (12%); there were no grade 3 or 4 neurologic effects. CONCLUSIONS: The combination of docetaxel and carboplatin has an acceptable toxicity profile and is active in the treatment of previously untreated patients with advanced NSCLC. This combination is being evaluated in a randomized phase III trial involving patients with advanced and metastatic NSCLC.

Docetaxel (Taxotere): preclinical and general clinical information.

Docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) is the second member of the taxane class of cytotoxic agents to reach clinical use. The development of docetaxel was remarkably rapid, from the initial hemisynthesis in 1986 to worldwide filing for commercial use in 1994. Docetaxel is now approved in over 90 countries. As the use of docetaxel expands as a result of continuing preclinical and clinical investigation, better strategies for treatment of patients with cancer are emerging. This report reviews certain important new developments regarding docetaxel involving both its pharmacology and use in practice.

A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer.

PURPOSE: To evaluate the efficacy and safety of docetaxel in patients with paclitaxel-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: Docetaxel (100 mg/m2) was administered every 3 weeks to 46 patients registered at four centers. Patients had previously received < or = two chemotherapy regimens for MBC. All patients had progressive disease while receiving paclitaxel therapy. Treatment was repeated until there was evidence of disease progression or for a maximum of three cycles after best response. RESULTS: Objective responses were seen in eight of 44 assessable patients (18.1%; 95% confidence interval [CI], 6.7% to 29.5%). Seven patients had partial responses and one patient responded completely. Response rates were not significantly different by previously received paclitaxel dose or resistance. No responses were seen in 12 patients who had previously received paclitaxel by 24-hour infusion, but the response rate in 32 patients who had received paclitaxel by 1- to 3-hour infusion was 25%. The median response duration was 29 weeks and the median time to disease progression was 10 weeks. Median survival was 10.5 months. Clinically significant (severe) adverse events included neutropenic fever (24% of patients), asthenia (22%), infection (13%), stomatitis (9%), neurosensory changes (7%), myalgia (7%), and diarrhea (7%). CONCLUSION: Docetaxel is active in patients with paclitaxel-resistant breast cancer, particularly in those who failed to respond to brief infusions of paclitaxel. Response rates were comparable to or better than those seen with other therapies for patients with paclitaxel-resistant MBC. This confirms preclinical studies, which indicated only partial cross-resistance between paclitaxel and docetaxel.

Phase I study with the DNA sequence-specific agent adozelesin.

Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v. infusion, (ii) characterize the toxic effects of the drug using this schedule and (iii) document any antitumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10 microg/m2, corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies were entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180 microg/m2. The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined as 180 microg/m2. A minor response with a 4 month duration was reported in one previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150 microg/m2, repeated every 4 weeks.

Phase I trial of Adozelesin using the treatment schedule of daily x5 every 3 weeks.

CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a potent synthetic analog that was chosen for clinical development because it had a similar preclinical antitumor spectrum, but did not produce deaths similar to CC-1065 at therapeutic doses. Phase I evaluations using a variety of Adozelesin treatment schedules have been conducted. This report describes our experience using a multiple dose treatment schedule. Endpoints including antitumor response, maximum tolerated dose, dose limiting toxicity as well as other toxicities and the recommended Phase II starting dose were determined. Adozelesin was given as a 10 minute IV infusion for 5 consecutive days every 21 days or upon recovery from toxicity. The dose range evaluated was 6-30 mcg/m2/day. All patients had refractory solid tumors and had received prior cytotoxic treatment. Thirty-three patients (22 men: 11 women) were entered onto the study and 87 courses were initiated. Dose limiting toxicity was cumulative myelosuppression (leucopenia, thrombocytopenia). The maximum tolerated dose was 30 mcg/m2/day. The only other significant toxicity was an anaphylactoid syndrome that occurred in 2 patients. A partial response was observed in a patient with refractory soft tissue sarcoma. The recommended Phase II starting dose of Adozelesin using a 10 minute IV infusion for 5 consecutive days is 25 mcg/m2/day to be repeated every 4-6 weeks to allow recovery from myelotoxicity, based on our experience. Additional Phase I and II studies with Adozelesin are recommended.

Evidence for paracrine regulation of experimental metastasis in 13762NF rat mammary adenocarcinoma cell clones.

The ability of tumor cell lines to form experimental pulmonary metastases is determined in part by characteristics which are stable over many cell generations; in part by characteristics that are acquired by adaptation or phenotypic instability; but also in part by characteristics which may change over less than one cell generation. This study was designed to examine the hypothesis that tumor cells secrete and respond to paracrine factors which can reversibly modulate metastasis. The number of experimental lung metastases increased for 13762NF rat mammary adenocarcinoma cell clones MTF7 and MTLn3 as they approach 100% confluence. This observation corresponded to increased attachment to bovine brain capillary and bovine corneal endothelial monolayers and to ability of tumor cells to invade reconstituted basement membrane barriers in the Membrane Invasion Culture System (MICS), but did not correspond to cell cycle distribution, susceptibility to NK or PMN cell killing or average cell size/Coulter volume. While changing confluence did not qualitatively alter metastatic potential, modification of metastasis in a quantitative manner suggested that some properties pertinent to metastasis are transient and manipulatable. Tumor cell-conditioned medium (CM) collected from donor cells grown to defined levels of confluence when placed onto recipient cells reversibly raised or lowered metastatic potential depending upon the medium source and confluence of the recipient cells. CM from 20% confluent donor cultures reduced recipient cell metastatic potential. In contrast CM from 100% confluent cultures increased metastatic potential of subconfluent cells. Replacement with fresh unconditioned medium or leaving the medium unchanged did not alter experimental metastasis. These data suggest that metastasis involves steps which may be influenced by paracrine factors elaborated by tumor cells.

Phase I study of adozelesin administered by 24-hour continuous intravenous infusion.

BACKGROUND: Adozelesin, a synthetic analogue of the antitumor antibiotic CC-1065, is the first of a class of potent sequence-specific alkylating agents to be brought to clinical trial. In preclinical in vitro testing, it has demonstrated antitumor activity at picomolar concentrations. PURPOSE: We conducted a phase I study of adozelesin to (a) determine a recommended dose for phase II testing using a 24-hour intravenous infusion, (b) characterize the toxic effects of the drug using this schedule, and (c) document any antitumor activity observed. METHODS: Adozelesin was given as a 24-hour continuous intravenous infusion. Treatments were initially scheduled every 3 weeks, but the prolonged myelosuppression observed necessitated a final dosing interval of every 6 weeks. The starting dose of 30 micrograms/m2 was escalated using a modified Fibonacci scheme until dose-limiting toxicity was encountered. RESULTS: Twenty-nine patients were entered in the study. Successive dose levels used were 30, 60, 100, 150, 120, and 100 micrograms/m2. Prolonged thrombocytopenia and granulocytopenia were dose limiting. No antitumor responses were observed. CONCLUSION: We recommend that the phase II dose of adozelesin given as a continuous 24-hour intravenous infusion be 100 micrograms/m2, repeated every 6 weeks. Other potentially less myelosuppressive schedules could be pursued.

Phase I study of adozelesin (U-73,975) in patients with solid tumors.

During a phase I clinical and pharmacologic trial, 26 patients with refractory solid tumors were treated with increasing doses of adozelesin by brief intravenous infusion every 3 weeks. Overall, adozelesin was well tolerated. The dose-limiting toxicity was myelosuppression, mainly thrombocytopenia and leukopenia. Nonhematologic toxicity was generally mild, with fatigue (36%), local reaction at the infusion site (24%), nausea or vomiting (20%) and hypersensitivity reaction (16%) being the most common adverse effects. There were no objective clinical responses. The maximally tolerated dose on this schedule was 188 micrograms/m2 with the recommended phase II starting dose being 150 micrograms/m2 on an every 3 week schedule. Adozelesin merits broad investigation at the phase II level.

A phase I clinical and pharmacokinetic study of the oral and the oral/intravenous administration of menogaril.

Thirty-five patients with advanced refractory cancer were enrolled on this phase I study of menogaril administered orally every 4 weeks at dosages ranging from 85 mg/m2 to 625 mg/m2. An additional 12 patients received alternating oral and IV doses of menogaril (250 mg/m2 IV; 250-500 mg/m2 oral) with accompanying blood and urine sampling for pharmacokinetics analysis. Nausea and vomiting were the dose-limiting toxicities at the 625 mg/m2 dosage level; vomiting was inadequately relieved by prophylactic antiemetics at this dosage level. Other toxicities included sporadic leukopenia at all dosage levels; at dosages of 500 mg/m2 and 625 mg/m2, leukopenia < 3000/microliters occurred in 7 of 24 patients. Anemia and thrombocytopenia were much less frequent toxicities. Among the patients receiving IV menogaril, peripheral vein phlebitis, leukopenia and anemia were the predominant toxicities. No antitumor responses were observed, yet one patient with non-small cell lung cancer experienced a 30% reduction in metastatic tumor nodules. For the patients receiving alternating oral and IV menogaril, comparative pharmacokinetic analyses were performed by HPLC. After oral administration, maximum plasma concentrations were achieved in an average of 6 hours; maximum plasma concentrations were less than one-quarter of those achieved after intravenous administration. The harmonic mean (+/- SD) terminal disposition half-life after oral dosing was 29.3 +/- 9.2 hours; mean systemic bioavailability was 33.6 +/- 10.5% after oral dosing. Forty-eight hours after an oral dose, mean cumulative urinary excretions of menogaril and the primary metabolite, N-demethylmenogaril, were 4.00 +/- 0.96% and 0.44 +/- 0.16%, respectively. Because of the poor tolerance of oral menogaril and minimal evidence of biological activity, this schedule of drug administration is not recommended for phase II evaluation. Based on this and other published studies of oral menogaril, frequent chronic low-intermediate dosages of the drug may be given orally with potentially better tolerance and antitumor activity.

Human autopsy-tissue distribution of menogaril and its metabolites.

Autopsy-tissues were obtained from eight patients who had last received menogaril (total cumulative dose, 175-1080 mg/m2) intravenously (one patient) or orally (seven patients) from 1 to 285 days prior to death. Tissue samples were assayed for menogaril and its metabolities by high-pressure liquid chromatography. Unchanged menogaril was found only in a single lung-tissue sample from a patient who had died < 24 h after receiving his last treatment. N-Demethylmenogaril was found in two lung-tissue samples and in single samples of the thyroid, lymph node, pancreas, cerebellum, and tumor. The major menogaril metabolite found in human autopsy-tissues was 7-deoxynogarol. The highest 7-deoxynogarol concentrations were found in the large bowel (median, 201 ng/g), liver (median, 183 ng/g), and lung (median, 177 ng/g). The heart ranked as the 9th of 18 organs in median 7-deoxynogarol concentration, after the large bowel, liver, lung, tumor, thyroid, skeletal muscle, adrenal gland, and kidney. The lowest concentrations were detected in brain tissue. Our results suggest that the low degree of cardiac toxicity and the possible pulmonary toxicity of menogaril may be related to relative tissue concentrations of menogaril metabolites. Tumor 7-deoxynogarol concentrations were comparable with those in normal tissues, except that concentrations in intracerebral tumors were higher than those in the normal brain. Tissue 7-deoxynogarol concentrations appeared to be directly related to the cumulative dose and inversely related to the time from the last treatment to death; the value obtained by dividing dose by time correlated (P < 0.05) with tissue 7-deoxynogarol concentrations.

Phase II study of weekly intravenous menogaril in the treatment of recurrent astrocytomas in adults.

Twenty patients with astrocytomas recurrent after surgery +/- radiation were treated on a phase II protocol of the new anthracycline derivative menogaril 115 mg/m2 administered intravenously once per week. Sixteen patients were evaluable for treatment efficacy. No patient achieved a major therapeutic response. Three patients (19%) had stable disease for greater than 8 weeks, including one who showed minor evidence of tumor regression, but less than 50%. Thirteen patients failed. Treatment was well tolerated. One patient developed granulocytopenia, while none developed thrombocytopenia. Four patients required an interruption in their treatment for one to two weeks because of development of granulocytopenia (one patient) or other reasons. Other toxic effects included arm vein phlebitis and skin irritation, skin discoloration of the infused arm, mild to moderate nausea and vomiting, diarrhea, stomatitis, and a fatal central venous catheter infection. Despite the fact that menogaril appeared to have therapeutic activity against recurrent astrocytomas in our phase I studies, we could not document any activity in this phase II study.

Phase I study of oral menogaril administered daily for 14 consecutive days.

Twenty-eight patients were treated with oral menogaril daily x 14 every 4 weeks. Granulocytopenia was dose-limiting at 50-60 mg/m2 per day. Neutropenic fever occurred in one patient. Thrombocytopenia occurred in 3 of 6 patients treated with menogaril 60 mg/m2/day. Nausea and vomiting and other toxic effects were generally mild. No cardiac toxicity was seen. One partial remission and three minor responses were noted among 11 previously treated patients with carcinoma of the bladder. One minor response was noted among 3 patients with colorectal cancer. The dose recommended for phase II studies is 50 mg/m2 per day for 14 days. Phase II studies are recommended in carcinoma of the bladder. Gastrointestinal toxicity is substantially less on this schedule than with oral menogaril administered on a weekly or q4wk schedule, but thrombocytopenia may be more common.

Phase 1 trial of oral bropirimine in superficial bladder cancer.

A total of 34 patients with measurable superficial transitional cell cancer of the bladder entered into a phase 1, nonrandomized, noncomparative trial to assess the toxicity of the oral interferon inducer bropirimine. Of the patients 26 were also evaluable for response. The toxicity of bropirimine was minimal. At the 3-month evaluation 6 patients had experienced complete regression of tumor and had negative cytology studies, and 2 had partial responses. The majority of complete responses were in patients with carcinoma in situ only, with most responses seen at higher dose levels. One patient with papillary tumor and carcinoma in situ had a complete response. Some early responses appear to be durable. Most importantly, a high rate of complete response was noted at higher dose levels among patients who had failed prior therapy with bacillus Calmette-Guerin. Further clinical trials of bropirimine in bladder cancer appear warranted.

Prevention of central nervous system toxicity of the antitumor antibiotic acivicin by concomitant infusion of an amino acid mixture.

Acivicin is an investigational amino acid antitumor antibiotic currently being evaluated in Phase II clinical trials. In humans acivicin causes reversible, dose-limiting central nervous system (CNS) effects including somnolence, ataxia, personality changes, and hallucinations. We have observed and reported previously that acivicin-treated cats exhibit symptoms (ataxia, sedation, somnolence) resembling CNS toxicity reported in humans. We hypothesized that if acivicin uptake into brain were mediated by a saturable transport system common to endogenous amino acids, drug uptake and CNS toxicity might be blocked by elevation of normal amino acid concentrations in circulating plasma. To test this hypothesis, cats received constant-rate i.v. infusions of either saline or Aminosyn, 10% (a commercially available mixture of 16 amino acids not containing glutamine, glutamate, aspartate, or cysteine) for 4 h prior to and 18 h subsequent to administration of acivicin at a dose producing marked behavioral changes in control cats. Presence or absence of ataxia and sedation were noted at intervals after acivicin treatment. Results showed that Aminosyn infusion prevented CNS symptoms in six of eight cats. Subsequent experiments showed that acivicin levels in brain tissue of Aminosyn-treated cats were 13% of the drug levels in saline-infused cats. Acivicin levels in most peripheral tissues were also decreased significantly by Aminosyn infusion but not to the extent observed in brain. Decreased brain uptake was shown to be due to a combination of amino acid blockade of drug transport into that organ and of increased total body clearance of drug. Concomitant Aminosyn treatment did not alter the efficacy of acivicin in mice bearing L1210 leukemia or MX-1 human mammary carcinoma. Further studies demonstrated that a solution containing only four large neutral amino acids (leucine, isoleucine, phenylalanine, and valine) could also protect cats from acivicin-induced CNS toxicity, apparently without increasing acivicin total body clearance. However, a mixture of several other amino acids contained in Aminosyn (alanine, arginine, tyrosine, histidine, proline, serine, and glycine) failed to prevent CNS toxicity. We conclude that cotreatment with Aminosyn or a mixture of large neutral amino acids could protect cancer patients from acivicin-induced CNS toxicity without ablating antitumor efficacy.

A phase II study of menogaril (NSC-269148) in colorectal carcinoma. A Southwest Oncology Group study.

In this phase II trial, menogaril was administered to patients with metastatic colon cancer at a dose of 200 mg/m2 IV over one hour with cycles repeated every 28 days provided the absolute granulocyte count was greater than or equal to 2000 cells/microliters. Dose adjustments up or down were made depending upon nadir counts. Twenty-four patients were entered on this study with 21 eligible and evaluable for response. There was 1 CR lasting four and one-half months and 1 PR lasting three months for an overall CR + PR rate of 10% with a 95% confidence interval of 1% to 30%. Six patients (29%) had stable disease and 13 (62%) progressed. Median survival is 13.1 months. Toxicity was primarily hematologic with two cases of life-threatening leukopenia (less than 1000 cells/microliters) and one case of life-threatening granulocytopenia (less than 250 cells/microliters) among the 21 eligible patients, and one case of life-threatening leukopenia and granulocytopenia in one ineligible patient. There were no deaths due to treatment.

Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas.

Ninety-eight patients with previously-treated advanced soft tissue sarcoma, bone sarcoma, or mesothelioma were randomly assigned to one of two intravenous single-agent treatment regimens, either 6-diazo-5-oxo-l-norleucine (DON; brief infusions of 50 mg/m2/day for 5 consecutive days every 4 weeks) or aclacinomycin-A (ACM-A, as 30-min infusions of 100 mg/m2 or 85 mg/m2, administered every 3 weeks). Of 43 patients who were evaluable for response, survival and toxicity, there were two responses (5%) produced by ACM-A; one in a male with mesothelioma, and one in a female with malignant fibrous histiocytoma. None of the 36 evaluable patients treated with DON developed an objective tumor response. Median survival was 4.8 months in the DON treatment arm, and 6.8 months in the ACM-A treatment arm. No patients on the DON arm experienced lethal or life-threatening toxicities, and severe toxicities resulting from this treatment included nausea and emesis (10%), stomatitis (2%), gastrointestinal toxicity (2%), and anemia (2%). Moderate toxicities included vomiting (24%), hematologic toxicity (24%), neurologic toxicity (7%), diarrhea (7%), mucositis (5%), fever (5%), palpitations (2%), hepatotoxicity (2%), bleeding (2%) and edema (2%). Fifteen percent experienced at least one severe reaction, and 63% experienced at least one moderate or greater toxicity. ACM-A was associated with four cases of life-threatening myelosuppression (7%); severe toxicities included myelosuppression (11%), neurologic toxicity (4%), diarrhea (2%), respiratory toxicity (2%), pain and muscle spasms (2%), edema (2%), and ulceration following extravasation (2%).(ABSTRACT TRUNCATED AT 250 WORDS)

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

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

Phase I study of weekly intravenous administration of menogaril to adults with solid tumors.

Thirty-nine adults with solid tumors were treated on a Phase I study of menogaril administered i.v. once each week. Granulocytopenia was dose-limiting at a menogaril dose of 115 mg/m2/wk. Ten patients required delays in treatment of 1-4 weeks (median, 1 week) at some point during their treatment until they recovered from granulocytopenia. The average dose intensity possible on this schedule was at least 80% higher than that possible using a single-day or a five-times-daily schedule every 4 weeks. One patient developed infection while neutropenic, and only one patient developed thrombocytopenia. Dexamethasone appeared to reduce the degree of myelosuppression. Gastrointestinal toxicity was quite mild, and alopecia was uncommon. Arm vein phlebitis frequently followed menogaril administration, requiring the use of Hickman catheters (or equivalents). Two patients had myocardial infarcts while on treatment. It was unclear if the menogaril was in any way responsible. Reversible dyspnea and cough (with no evidence of congestive heart failure) were seen in some patients. Responses were seen in patients with gliomas, renal-cell carcinoma, and bladder carcinoma, and marked subjective improvement occurred in a single patient with prostate cancer. We plan to conduct a Phase II study in astrocytoma patients using a menogaril dose of 115 mg/m2/wk i.v.

Phase II trial of continuous drug infusions in advanced ovarian carcinoma: acivicin versus vinblastine.

Sixty-six women with advanced ovarian carcinoma of coelomic epithelial origin were randomly assigned to one of two intravenous single-agent infusion treatment regimens, either acivicin (60 mg/m2/course, administered as a 72-hr infusion) or vinblastine (7.5 mg/m2/course, administered as a 120-hr infusion) every three weeks. All had progressive disease after one to three prior chemotherapeutic regimens. Of 62 patients who were evaluable for response, survival and toxicity, there was one partial response (2%) produced by vinblastine. Median survival was 13 weeks on either treatment arm. Three patients (10%) on the acivicin arm experienced life-threatening myelosuppression. Severe toxicities resulting from this treatment included myelosuppression (26%), neurotoxicity (16%), mucositis (3%) and vomiting (6%). Vinblastine was associated with one lethal pneumonia and five cases of life-threatening myelosuppression (16%); severe toxicities included myelosuppression (58%), genitourinary toxicity (6%), infection (3%), and edema (3%). Neither regimen produces useful clinical results in patients who have relapsed after prior chemotherapy for ovarian carcinoma.

Phase I clinical trial of a combination of dipyridamole and acivicin based upon inhibition of nucleoside salvage.

A Phase I clinical trial of simultaneous 72-h infusions of dipyridamole and acivicin was carried out in patients with advanced malignancies. The objective of this trial was to determine the maximum tolerated dose of dipyridamole when administered as a 72-h infusion in combination with acivicin. The development of this combination is of interest because of in vitro observations which demonstrate that dipyridamole potentiates the cytotoxic action of acivicin by blocking nucleoside salvage. Patients were treated with concomitant i.v. infusions of dipyridamole and acivicin for 72 h. The acivicin dose infused remained constant during the trial at 60 mg/m2/72 h. The maximum tolerated dose (MTD) of dipyridamole was 23.1 mg/kg/72 h. Limiting toxicities at the MTD of dipyridamole with acivicin were severe gastrointestinal and constitutional symptoms which appeared to be caused by the high doses of dipyridamole administered. Escalation of dipyridamole did not potentiate the mild myelosuppression or the neurotoxicity which occurs with acivicin alone. At a dose of dipyridamole which was well below the MTD, one patient experienced symptomatic orthostatic hypotension, and another patient with coronary artery disease developed dizziness and transient electrocardiogram abnormalities. However, no other hypotensive or cardiovascular events occurred as dipyridamole was escalated to the MTD. Phlebitis occurred at the site of infusion when the dose of dipyridamole exceeded 13.5 mg/kg/72 h. Because of this local toxicity, it was necessary to administer dipyridamole through a central venous catheter to achieve maximum plasma levels. At the MTD of dipyridamole, steady-state total and free plasma levels of 11.9 microM and 27.8 nM, respectively, were attained by 24 h. These are free dipyridamole levels which in vitro were sufficient to block cytidine salvage and to potentiate the biochemical and cytotoxic effects of acivicin against human colon cancer cells (P.H. Fischer et al., Cancer Res., 44:3355-3359, 1984).