Robert H. Earhart

Phase I clinical trial and pharmacokinetics of carboplatin (NSC 241240) by single monthly 30-minute infusion

Carboplatin (diammine[1,1‐cyclobutanedicarboxylate(2‐)‐O,ó]platinum) is a second generation platinum coordination complex. It has a spectrum of activity that is similar to that of cisplatin and is less nephrotoxic and emetogenic in experimental animals. Fifty‐two 30‐minute infusions of carboplatin were given to 20 evaluable patients with a variety of solid tumors. Maximum tolerated dose was 440 mg/m2. Thrombocytopenia (<100,000/mm3) occurred in six of seven patients; two patients experienced a leukocyte count less than 2000/mm3. Platelet and leukocyte count nadirs occurred on day 21. No nephrotoxicity was seen. Blood urea nitrogen, serum creatine levels, and creatinine clearances remained normal, and no consistent elevation of urinary β2‐microglobulin, leucine aminopeptidase, or N‐acetyl‐β‐glucosaminidase occurred. Nausea and vomiting were mild to moderate. A single patient developed mild peripheral neuropathy. No auditory toxicity was noted. The recommended dose for Phase II studies is 400 mg/m2 every 28 days for good risk patients; heavily pretreated patients should receive 320 mg/m2.

Acivicin in 1985

This review, as its title indicates, views acivicin at a particular point in the ongoing process of its development. There is a large body of biochemical information which permits the formulation of a number of hypotheses regarding the drugs optimal regimen, mechanism of CNS toxicity, and potential role in combination chemotherapy. We have attempted to survey those data and to project some avenues of future research which may circumvent the drugs limitations. Current deficits exist in our information, particularly in the area of the clinical activity spectrum of acivicin. Yet the final definition of the set of human tumors in which acivicin may find clinical utility will probably not occur until we have defined the optimal regimen for the drug, both as a single agent and in combination, and have identified and addressed the toxic effects which limit its use. A coordinated effort between the preclinical pharmacologists and clinicians will be necessary in the next few years, if acivicin is to play an important role in the treatment of human malignancies.

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

SummaryNinety-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 aclacinomycinA (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%). Moderate toxicities included diarrhea (9%), mucositis (7%), hepatotoxicity (7%), infection (5%), fever (7%), gastrointestinal toxicity (4%), respiratory (2%), dehydration (2%), cardiac (2%), alopecia (2%), ulceration following extravasation (7%), and edema (2%). Thirty-eight percent of patients on the ACM-A arm developed one or more severe or worse toxicity, and 76% had at least one moderate or worse toxicity. Neither regimen produces useful clinical results in patients with advanced sarcomas or mesotheliomas.

Phase II study of PALA and AMSA in advanced renal cell carcinoma

Ninety-two evaluable patients with measurable renal cell carcinoma participated in a phase II trial of PALA (1500 mg/m2/day for 5 days every 3 weeks) versus AMSA (120 mg/m2 every 4 weeks). No complete responses occurred; objective partial response rates were 5% for PALA and 3% for AMSA. Treatment did not influence survival, but ambulatory patients survived longer than did nonambulatory patients. Mucocutaneous and acute gastrointestinal toxicity occurred with PALA, while hematologic toxicity predominated in AMSA treatments. At these schedules neither drug has significant single-agent activity in renal cell carcinoma.

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

SummaryForty-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 doseintensity that is approximately double that attainable with other oral schedules that have been studied.

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.

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

SummaryThirty-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/μl 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 nonsmall 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 trial of continuous drug infusions in advanced ovarian carcinoma: Acivicin versus vinblastine

SummarySixty-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 vin-blastine. 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 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. Gran-ulocytopenia 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.