Gary Dukart

Randomized Phase II Study of Multiple Dose Levels of CCI-779, a Novel Mammalian Target of Rapamycin Kinase Inhibitor, in Patients With Advanced Refractory Renal Cell Carcinoma

PURPOSE To evaluate the efficacy, safety, and pharmacokinetics of multiple doses of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma (RCC). PATIENTS AND METHODS Patients (n = 111) were randomly assigned to receive 25, 75, or 250 mg CCI-779 weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, survival, and adverse events. Blood samples were collected to determine CCI-779 pharmacokinetics. RESULTS CCI-779 produced an objective response rate of 7% (one complete response and seven partial responses) and minor responses in 26% of these advanced RCC patients. Median time to tumor progression was 5.8 months and median survival was 15.0 months. The most frequently occurring CCI-779-related adverse events of all grades were maculopapular rash (76%), mucositis (70%), asthenia (50%), and nausea (43%). The most frequently occurring grade 3 or 4 adverse events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Neither toxicity nor efficacy was significantly influenced by CCI-779 dose level. Patients were retrospectively classified into good-, intermediate-, or poor-risk groups on the basis of criteria used by Motzer et al for a first-line metastatic RCC population treated with interferon alfa. Within each risk group, the median survivals of patients at each dose level were similar. CONCLUSION In patients with advanced RCC, CCI-779 showed antitumor activity and encouraging survival and was generally well tolerated over the three dose levels tested.

Randomized clinical trial comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer.

Three hundred twenty-five women with metastatic adenocarcinoma of the breast who had failed one prior chemotherapeutic regimen for advanced disease were randomized to receive 14 mg/m2 of mitoxantrone or 75 mg/m2 of doxorubicin intravenously (IV) every 3 weeks. Enrollment was closed on October 31, 1984, after 165 patients were randomized to mitoxantrone and 160 patients to doxorubicin. Patients randomized to the two treatment groups were compared for response rate, duration of response, time to progression or death, time to treatment failure (TTF), and survival. The response rate to mitoxantrone was 20.6%, to doxorubicin 29.3% (P = .07). The median response duration was 151 days for the mitoxantrone group and 126 days for the doxorubicin group (P = .16). The median TTF was 70 days in the mitoxantrone group and 104 days in the doxorubicin group (P = .36). The median survival of patients initially randomized to receive mitoxantrone was 273 days; for doxorubicin 268 days (P = .40). There were three responses among 77 patients crossed over to mitoxantrone after initial treatment with doxorubicin. The major dose-limiting toxicity for both drugs was leukopenia. There was significantly less severe and less frequent toxicity with mitoxantrone administration. Severe nausea and vomiting occurred in 9.5% of mitoxantrone patients and 25.3% of doxorubicin patients (P less than .001). The incidence of severe stomatitis and mucositis was 0.6% in the mitoxantrone group and 8.4% in the doxorubicin group (P = .001). Severe alopecia occurred in 5.1% of mitoxantrone patients and 61.0% of doxorubicin patients (P less than .001). A life-table comparison of the cumulative dose to the development of a cardiac event showed that mitoxantrone had significantly less cardiotoxicity than doxorubicin (P = .0005). This study demonstrates that mitoxantrone is active as a single agent in the treatment of metastatic breast cancer. Compared with doxorubicin it appears to be marginally less active and significantly less toxic. We conclude that mitoxantrone can be used alone or with other standard drugs to palliate the symptoms of metastatic breast cancer, especially in settings where drug toxicity is an important consideration.

A Phase I and Pharmacokinetic Study of Temsirolimus (CCI-779) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients with Advanced Cancer

Purpose: Patients with advanced cancer received temsirolimus (Torisel, CCI-779), a novel inhibitor of mammalian target of rapamycin, i.v. once daily for 5 days every 2 weeks to determine the maximum tolerated dose, toxicity profile, pharmacokinetics, and preliminary antitumor efficacy. Experimental Design: Doses were escalated in successive cohorts of patients using a conventional phase I clinical trial design. Samples of whole blood and plasma were collected to determine the pharmacokinetics of temsirolimus and sirolimus, its principal metabolite. Results: Sixty-three patients were treated with temsirolimus (0.75-24 mg/m2/d). The most common drug-related toxicities were asthenia, mucositis, nausea, and cutaneous toxicity. The maximum tolerated dose was 15 mg/m2/d for patients with extensive prior treatment because, in the 19 mg/m2/d cohort, two patients had dose-limiting toxicities (one with grade 3 vomiting, diarrhea, and asthenia and one with elevated transaminases) and three patients required dose reductions. For minimally pretreated patients, in the 24 mg/m2/d cohort, one patient developed a dose-limiting toxicity of grade 3 stomatitis and two patients required dose reductions, establishing 19 mg/m2/d as the maximum acceptable dose. Immunologic studies did not show any consistent trend toward immunosuppression. Temsirolimus exposure increased with dose in a less than proportional manner. Terminal half-life was 13 to 25 hours. Sirolimus-to-temsirolimus exposure ratios were 0.6 to 1.8. A patient with non–small cell lung cancer achieved a confirmed partial response, which lasted for 12.7 months. Three patients had unconfirmed partial responses; two patients had stable disease for ≥24 weeks. Conclusion: Temsirolimus was generally well tolerated on this intermittent schedule. Encouraging preliminary antitumor activity was observed.

Mitoxantrone: an overview of safety and toxicity

SummaryMitoxantrone (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.

A sensitive human bone assay for quantitation of tigecycline using LC/MS/MS

Tigecycline (Tygacil,Wyeth) is a first-in-class, broad spectrum antibiotic with activity against multiple-resistant organisms. In order to address the unexpectedly low tigecycline concentrations in human bone samples analyzed using a LC/MS/MS method developed elsewhere, we have developed and validated a new and sensitive human bone assay for the quantitation of tigecycline using LC/MS/MS. The new method utilizes the addition of a stabilizing agent to the human bone sample, homogenization of human bone in a strong acidic-methanol extraction solvent, centrifugation of the bone suspension, separation by liquid chromatography, and detection of tigecycline by mass spectrometry. Linearity was demonstrated over the concentration range from 50 to 20,000 ng/g using a 0.1g human bone sample. The intra- and inter-day accuracy of the assay was within 100+/-15%, and the corresponding precision (CV) was <15%. The stability of tigecycline was evaluated and shown to be acceptable under the assay conditions. The extraction recovery of tigecycline with the current method was 79% when using radio-labeled rat bone samples as a substitute for human bone samples. Twenty-four human bone samples collected previously from volunteers without infections who had elective orthopedic surgery after receiving a single dose of tigecycline were re-analyzed using the current validated method. Tigecycline concentrations in these samples ranged from 238 to 794 ng/g with a mean value 9 times higher than the mean concentration previously reported. The data demonstrated that the current method has significantly higher extraction efficiency than the previously reported method.

A randomized trial comparing mitoxantrone with doxorubicin in patients with stage IV breast cancer

SummaryMitoxantrone (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.In summary, mitoxantrone appears to be as active as doxorubicin in patients with stage IV breast cancer previously treated with chemotherapy; however, mitoxantrone causes significantly less nausea, vomiting, stomatitis and alopecia at doses which induce equal or greater myelosuppression than doxorubicin, and appears to be less cardiotoxic.

A randomized multicenter trial of cyclophosphamide, Novantrone and 5-fluorouracil (CNF) versus cyclophosphamide, Adriamycin and 5-fluorouracil (CAF) in patients with metastatic breast cancer

SummaryAs 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.

Comment on Mitoxantrone

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Dose Proportionality of Bisoprolol Enantiomers in Humans After Oral Administration of the Racemate

Dose proportionality of racemic bisoprolol and the stereoselectivity of its enantiomers were studied after single oral dosing of 5 to 40 mg of bisoprolol hemifumarate in eight healthy male volunteers in an open‐label, randomized, four‐way cross‐over trial. There were dose‐proportional increases in mean peak plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) values for the racemate and the individual enantiomers. No statistically significant differences were detected between the mean half life (t1/2), Cmax, and time to reach Cmax (tmax) of the R‐ and S‐isomers at each of the four dose levels studied. These findings support dose proportionality and absence of stereoselective pharmacokinetics for bisoprolol in the dose range studied.

Mitoxantrone in refractory acute leukemia in children: A phase I study

SummaryNine children with acute non-lymphocytic leukemia (ANLL), ages 16 months to 16 years (median 7 years), and 15 children with acute lymphocytic leukemia (ALL), ages 10 months to 18 years (median 5 years), were treated with 5-day courses of mitoxantrone (Novantrone®; dihydroxyanthracenedione) as induction therapy. All the children had leukemia which was resistant to conventional therapy and all but one patient had received anthracycline therapy prior to the initiation of this trial. Three patients (two with ANLL, one with ALL) received the drug at a dose of 6 mg/m2/day i.v. for 5 days. Both patients with ANLL achieved partial remissions (PR) (105 and 87 days duration). The child with ALL failed to respond to two courses of the drug, and died of progressive disease 45 days after the institution of therapy. Twenty-one patients (14 with ALL, seven with ANLL) were treated with 8 mg/m2/day i.v. mitoxantrone for 5 days. There were three early deaths (all ALL) which were not felt to be secondary to drug toxicity. Four of the 18 children achieved complete remission (CR) (one ANLL — 35 days; three ALL — 39, 31 and 13 days). One child with ANLL achieved a PR (13 days) and one child with ALL showed improvement in his bone marrow status. Twelve children failed to respond to this therapy.Dose-limiting toxicity was not seen among the patients who received 6 mg/m2/day for 5 days. There were five patients who had mucositis and one patient who had nausea and vomiting among those patients who received 8 mg/m2/day for 5 days. Four of these children had significant decreases in the myocardial shortening fraction as measured by echocardiography. None of these patients had clinical signs of cardiotoxicity.The CR plus PR rate for both dose levels is 33%. Mitoxantrone appears to be an effective agent for remission induction in children with late stage ALL and ANLL. Toxicity was not a significant problem at the doses used in this trial.