A phase Ib/II and pharmacokinetic study of EP0057 (formerly CRLX101) in combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

BACKGROUND: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC). METHODS: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response. RESULTS: The RP2D was established as 15 mg/m2 EP0057 Q2W plus 80 mg/m2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed >1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%). CONCLUSIONS: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words.

Final report on serial phase II trials of all-intraperitoneal chemotherapy with or without bevacizumab for women with newly diagnosed, optimally cytoreduced carcinoma of Müllerian origin.

BACKGROUND: Intraperitoneal (IP) chemotherapy can improve outcomes for women with optimally cytoreduced epithelial ovarian cancer but toxicities are a concern. We conducted 2 phase 2 trials of an IV/IP regimen using carboplatin and paclitaxel without (Trial A) and with bevacizumab (Trial B). METHODS: Both trials consisted of carboplatin AUC 6 day 1, and paclitaxel 60 mg/m2 on days 1,8, 15 of a 21-day cycle; in Trial B, patients received IV bevacizumab 15 mg/kg every cycle starting cycle 2. Chemotherapy was administered IV for cycle 1 and then IP for all subsequent cycles. Primary objectives included safety and tolerability, pathologic CR rate (Trial A), and the rate of completion of IP cycles of therapy (Trial B). Progression-free (PFS), overall survival (OS), and pharmacokinetic analysis were secondary endpoints. RESULTS: 81 patients were treated on both trials (n = 40 and 41 in trials A and B, respectively). Median age for trials A and B was 59 (range, 36-76) and 55 (range, 19-69) years, respectively. 68% and 85% of patients, respectively for A and B, completed at least 4 cycles of treatment in both trials. Treatment with bevacizumab resulted in higher rates of grade 3 fatigue (37 versus 33%) and grade 3-4 diarrhea (22 versus 8%). Median PFS was 23.5 (95%CI 16.2-35.3) and 25 (95%CI 16.4-42.7) months, respectively; median OS was 68 (95%CI 49.5-NR) and 79.7 (95%CI 59.0-79.7) months, respectively for Trial A and B. CONCLUSIONS: Weekly administered IP carboplatin and IP paclitaxel is tolerable and safe with similar activity with and without concommittant bevacizumab in these 2 trials.

Inhibitors of HIV nucleocapsid protein zinc fingers as candidates for the treatment of AIDS.

Strategies for the treatment of human immunodeficiency virus-type 1 (HIV-1) infection must contend with the obstacle of drug resistance. HIV-1 nucleocapsid protein zinc fingers are prime antiviral targets because they are mutationally intolerant and are required both for acute infection and virion assembly. Nontoxic disulfide-substituted benzamides were identified that attack the zinc fingers, inactivate cell-free virions, inhibit acute and chronic infections, and exhibit broad antiretroviral activity. The compounds were highly synergistic with other antiviral agents, and resistant mutants have not been detected. Zinc finger-reactive compounds may offer an anti-HIV strategy that restricts drug-resistance development.

Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study.

PURPOSE: To evaluate the response rate, toxicity profile, and pharmacokinetics of ecteinascidin-743 (ET-743) as first-line therapy in patients with unresectable advanced soft tissue sarcoma (STS). PATIENTS AND METHODS: Thirty-six patients with STS were enrolled onto the study between September 1999 and August 2000. Patients were treated with 1.5 mg/m2 of ET-743 given as a 24-hour continuous intravenous (IV) infusion every 21 days. Pharmacokinetic sampling was performed in 23 patients. RESULTS: One complete and five partial responses were achieved in 35 assessable patients for an overall response rate of 17.1% (95% CI, 6.6% to 33.6%). In addition, one patient had a minor response, leading to an overall clinical benefit of 20%. Neutropenia and transaminitis were the main grade 3 to 4 toxicities, which occurred in 33% and 36% of the patients. The estimated 1-year progression-free and overall survival rates were 21% (95% CI, 11% to 41%) and 72% (95% CI, 59% to 88%), respectively. Total body clearance (L/h) was not significantly correlated with body-surface area (r = -0.28; P = .21). Mild hepatic impairment or the extent of prior cytotoxic therapy does not seem to contribute significantly to the high interpatient variability (49%) in the clearance of this drug. Severity of treatment-related toxicity was not correlated with pharmacokinetic variables. CONCLUSION: ET-743 demonstrates clinical activity as first-line therapy against STS with acceptable toxicity. Additional studies to establish empirical dosing guidelines may be necessary to improve the safety of the drug in patients with varying degrees of hepatic dysfunction and definitively establish the role of ET-743 for patients with these malignancies.

Pharmacokinetics of the 9-amino and 10,11-methylenedioxy derivatives of camptothecin in mice.

Although 20(S)-camptothecin (CA) exhibited potent cytotoxicity against a broad spectrum of tumor models, clinical trials with the sodium salt of its opened lactone ring form were discontinued due to highly variable and severe toxicity. Recently, the 9-amino (AC) and 10,11-methylenedioxy (MC) derivatives of CA were selected for preclinical evaluation by the National Cancer Institute. In the present investigation, the pharmacokinetic behavior of CA, its sodium salt CA, AC, and MC in mice was characterized using specific liquid chromatographic assays which permitted determination of the intact lactone and opened ring carboxylate forms of these compounds. CA disposition was triexponential with a prolonged terminal phase that had a 24.6-h half-life (t1/2,z) that comprised only 14.6% of the area under the concentration-time profile. The relative magnitudes of the total body apparent volume of distribution (Vz) and terminal phase rate constant suggest that the high observed total plasma clearance (CL, 104 ml/min/kg) may be associated with extensive accumulation in peripheral tissue regions from which the drug is slowly released. In comparison, the terminal disposition phase of MC accounted for 49.7% of the area under the curve profile. It also had a shorter t1/2,z (15.2 h) and appreciably greater CL (526 ml/min/kg) and Vz (694 liters/kg). This suggested that the degree of binding to tissues relative to plasma proteins was enhanced by the methylenedioxy moiety. In contrast, the 9-amino substituent profoundly diminished the apparent extent of tissue distribution, as indicated by the magnitude of Vz (7.7 liters/kg), effecting an enhanced rate of elimination (t1/2,z, 1.4 h). Comparison of the CL of CA and its two derivatives provided an inaccurate indication of drug elimination due to the influence of their unusually large Vz values. For these compounds, the relative ease of elimination from the body was best represented by mean residence times, which were 0.55, 7.24, and 11.2 h for AC, CA, and MC, respectively. Intact lactone plasma levels achieved after dosing with the lactone form of CA and its 9-amino and 10,11-methylenedioxy derivatives exceeded the far less active carboxylate at all times. In summary, these studies indicate that considerable alterations in pharmacokinetic behavior result from structural modification of the A ring of CA.

Phase I evaluation and pharmacokinetic study of pyrazine-2-diazohydroxide administered as a single bolus intravenous injection in patients with advanced solid tumors.

The sodium salt of pyrazine-2-diazohydroxide (PZDH; NSC 361456) was identified as an active congener of the antitumor lead pyridine-2-diazotate with enhanced chemical stability under physiological conditions. In a phase I trial of PZDH administered as a single i.v. bolus injection, 19 patients with refractory solid tumors received 44 courses of therapy at dose levels ranging from 50 to 350 mg/m2. No objective responses to PZDH were noted. Myelosuppression characterized by prolonged, delayed onset leukopenia and thrombocytopenia was the dose limiting toxicity. A maximum tolerated dose of 350 mg/m2 was identified for this treatment schedule. Nonhematological toxicity was limited to severe nausea and vomiting, experienced by all patients treated at the lower doses, although reasonably well controlled when antiemetics were given prior to chemotherapy. The plasma pharmacokinetics of PZDH was evaluated following a single course of therapy in 16 patients. Drug levels were monitored using a specific capillary gas chromatographic assay with a 1-ng/ml lower limit of quantitation. In patients treated with doses greater than 50 mg/m2, the concentration of PZDH in plasma declined in a distinctly triexponential manner and remained above 1.5 ng/ml for at least 8 h. However, the initial decay phase, characterized by a harmonic mean half-life of 3.9 +/- 3.5 (SD) min (range, 2.2-6.3 min), was the primary determinant of drug disposition, as indicated by its 85.5-93.1% contribution to the area under the plasma concentration-time profiles from time zero to infinity. The harmonic mean terminal half-life increased with escalations in dose from 2.7 +/- 0.8 h (n = 2) at 100 mg/m2 to 8.5 +/- 3.0 h at 350 mg/m2 (n = 6). Total plasma drug clearance was very similar in patients treated with doses of 50-250 mg/m2, exhibiting a mean value of 42.5 +/- 7.8 liters/h/m2 (n = 10); however, it was significantly lower at the 350 mg/m2 dose level, 27.2 +/- 6.6 liters/h/m2 (n = 6; P < 0.002), denoting a departure from linear pharmacokinetic behavior. The rather low steady state apparent volume of distribution, which ranged from 6.0 +/- 1.5 (50 mg/m2, n = 2) to 12.7 +/- 8.0 (350 mg/m2, n = 6) liters/m2, was indicative of limited distribution of the drug into body tissue. The absence of objective antitumor effects should not discourage continued evaluation of PZDH against solid tumors selected for probable sensitivity as indicated by preclinical testing. A dose of 250 mg/m2 on a single i.v. bolus schedule is recommended for these phase II trials.

Tyrphostin AG17, [(3,5-Di-tert-butyl-4-hydroxybenzylidene)- malononitrile], inhibits cell growth by disrupting mitochondria.

[(3,5-Di-tert-butyl-4-hydroxybenzylidene)-malononitrile] (AG17), a "tyrphostin" tyrosine kinase antagonist, was found to inhibit tumor cell growth with 50% growth inhibition ranging from 0.7 to 4.0 microM in a panel of 13 human tumor cell lines, as evaluated by tetrazolium dye reduction and inhibition of precursor incorporation into macromolecules. The promyelocytic leukemia cell line HL-60(TB), was the most sensitive with irreversible total growth inhibition after 12 h of exposure to 1.5 microM drug. Antiproliferative effects of AG17 in HL-60(TB) cells were temporally related to disruption of mitochondrial function, which occurred within 1 h after drug exposure as demonstrated by a significantly decreased mass of ATP in drug-treated cells, loss of the fluorescent mitochondrial membrane potential probe rhodamine 123, and ultrastructural examination of mitochondria using fluorescence and electron microscopy. Specific decreases of total or tyrosine-phosphorylated substrate at concentrations of the drug not affecting ATP levels were not detected. These data raise the possibility that AG17 may act in part by altering mitochondrial function and/or structure, and that impairment of mitochondrial function may be exploitable as a potentially useful mechanism to modulate tumor cell proliferation. This study also emphasizes the importance of evaluating carefully the effects of potential protein kinase antagonists, since these structures have effects in intact cells in addition to what might be expected from in vitro enzyme assays.

Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy.

PURPOSE: To assess the efficacy of the marine-derived alkaloid ecteinascidin 743 (ET-743) in patients with soft tissue sarcomas that progressed despite prior conventional chemotherapy and to characterize the pharmacokinetic profiles of ET-743 in this patient population. PATIENTS AND METHODS: Thirty-six previously treated soft tissue sarcoma patients from three institutions received ET-743 as a 24-hour continuous intravenous (IV) infusion at a dose of 1,500 microg/m(2) every 3 weeks. Pharmacokinetic studies were also performed. Patients were restaged every two cycles for response by objective criteria. RESULTS: Objective responses were observed in three patients, with one complete response and two partial responses, for an overall response rate of 8% (95% CI, 2% to 23%). Responses were durable for up to 20 months. Two minor responses (43% and 47% tumor reduction) were observed, for an overall clinical benefit rate of 14%. The predominant toxicities were neutropenia and self-limited transaminitis of grade 3 to 4 severity in 34% and 26% of patients, respectively. The estimated 1-year time to progression and overall survival rates were 9% (95% CI, 3% to 27%) and 53% (95% CI, 39% to 73%), respectively. The maximum observed plasma concentration and total plasma clearance of ET-743 (mean +/- standard deviation), 1.04 +/- 0.48 ng/mL and 35.6 +/- 16.2 L/h/m(2), respectively, were consistent with previously reported values from phase I studies of the drug given as a 24-hour IV infusion. CONCLUSION: ET-743 is a promising new option for the management of several histologic subtypes of sarcoma. Durable objective responses were obtained in a subset of sarcoma patients with disease progression despite prior chemotherapy. Additionally, the relatively high survival rate noted in this series of previously treated patients further justifies development of this agent.

A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer.

PURPOSE: Flavopiridol is a potent cyclin-dependent kinase inhibitor with preclinical activity against non-small cell lung cancer (NSCLC), inhibiting tumor growth in vitro and in vivo by cytostatic and cytotoxic mechanisms. A Phase II trial was conducted to determine the activity and toxicity of flavopiridol in untreated patients with metastatic NSCLC. EXPERIMENTAL DESIGN: A total of 20 patients were treated with a 72-h continuous infusion of flavopiridol every 14 days at a dose of 50 mg/m(2)/day and a concentration of 0.1-0.2 mg/ml. Dose escalation to 60 mg/m(2)/day was permitted if no significant toxicity occurred. Response was initially assessed after every two infusions; patients treated longer than 8 weeks were then assessed after every four infusions. Plasma levels of flavopiridol were measured daily during the first two infusions to determine steady-state concentrations. RESULTS: This study was designed to evaluate a total of 45 patients in two stages. However, because no objective responses were seen in the first 20 patients, the early-stopping rule was invoked, and patient accrual was halted. In four patients who received eight infusions, progression was documented at 15, 20, 40, and 65 weeks, respectively. The most common toxicities included grade 1 or 2 diarrhea in 11 patients, asthenia in 10 patients, and venous thromboses in 7 patients. The mean +/- SD steady-state concentration of drug during the first infusion was 200 +/- 89.9 nM, sufficient for cytostatic effects in in vitro models. CONCLUSIONS: At the current doses and schedule, flavopiridol does not have cytotoxic activity in NSCLC, although protracted periods of disease stability were observed with an acceptable degree of toxicity.

Phase I trial of the colloidal dispersion formulation of 9-amino-20(S)-camptothecin administered as a 72-hour continuous intravenous infusion.

The camptothecins are a class of potent cytotoxic anticancer agents that interact with the nuclear enzyme topoisomerase I to produce lethal DNA strand cleavages. 9-Amino-20(S)-camptothecin (9AC) was introduced into Phase I clinical trials in dimethylacetamide and polyethylene glycol 400 in a 10 mM phosphoric acid vehicle for i.v. solubility. A lyophilized colloidal dispersion (CD) of 9AC for reconstitution with 20% dextrose in normal saline was developed as an alternative formulation. Patients (ages 25-75 years) with normal liver and kidney function, Eastern Cooperative Oncology Group performance status < or = 2, and up to two prior chemotherapy regimens were treated. The initial infusion rate was 37.5 micrograms/m2/h as a 72-h continuous infusion (2.7 mg/m2 total dose). Patient cohorts were treated with escalating infusion rates until grade 4 hematological or other grade 3 toxicity developed. Pharmacokinetic sampling was performed on all patients, and 9AC lactone concentrations in plasma were determined by a high-performance liquid chromatographic assay. Twenty-five patients received a total of 65 courses of 9AC CD at doses from 2.70 to 4.65 mg/m2. The dose-limiting toxicity was neutropenia, with little nonhematological toxicity. Nonlinear regression analysis of pooled patient data yielded a total plasma clearance of 30.3 +/- 4.5 liters/h/m2, a half-life of 22.5 +/- 8.5 h, a mean residence time of 9.7 +/- 3.5 h, and a steady-state volume of distribution of 325 +/- 145 liters/m2. Although no objective responses were seen, 9 of 25 patients exhibited stable disease for 2-6 months. The plasma pharmacokinetics of 9AC lactone in cancer patients were comparable between the 9AC CD and soluble formulations. The dosing regimen recommended for Phase II trials of the 9AC CD formulation is 54.2 micrograms/m2/h, given as a 72-h continuous i.v. infusion every 3 weeks.

Phase I and pharmacokinetic study of ecteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies.

Ecteinascidin 743 (ET-743) is a cytotoxic tetrahydroisoquinoline alkaloid that covalently binds to DNA in the minor groove. The in vitro chemosensitivity of cancer cells to ET-743 is markedly enhanced by prolonging the duration of exposure to the drug. A Phase I study of ET-743 given as a 72-h continuous i.v. infusion every 21 days was performed. Characteristics of the 21 adult patients with refractory solid tumors enrolled in the study were as follows: (a) 12 men; (b) 9 women; (c) median age, 59 years; (d) Eastern Cooperative Oncology Group performance status < or = 1, 20 patients; and (e) two prior regimens of chemotherapy, 7 patients. Dose limiting toxicity (DLT) was defined by typical criteria, except that grade 3 transaminitis did not constitute a DLT. There were no DLTs in the six patients evaluated at the first two dose levels of 600 and 900 microg/m2. Reversible grade 4 transaminitis occurred in two of nine patients after treatment with the first cycle of therapy at the third dose level of 1200 microg/m2. Another patient experienced grade 4 rhabdomyolysis, renal failure requiring hemodialysis, grade 4 neutropenia, and grade 3 thrombocytopenia during the second cycle of therapy with this dose. The maximum tolerated dose was 1200 microg/m2, and an additional six patients were enrolled at an intermediate dose level of 1050 microg/m2. This well-tolerated dose was established as the recommended Phase II dose. The disposition of ET-743 was distinctly biexponential, and a departure from linear pharmacokinetic behavior was evident at the 1200-microg/m2 dose level. Pharmacokinetic parameters determined at 1050 microg/m2 were (mean +/- SD): maximum plasma concentration, 318 +/- 147 pg/ml; initial disposition phase half-life, 9.0 +/- 10.3 min; terminal phase half-life, 69.0 +/- 56.7 h; and total plasma clearance, 28.4 +/- 22.5 liters/h/m2. Prolonged systemic exposure to concentrations of the agent that are cytotoxic in vitro were achieved. Toxicity of the drug is clearly schedule-dependent, because increasing the duration of infusion from 3 or 24 h to 72 h results in decreased myelosuppression and comparable hepatotoxicity. Although there were no objective responses to therapy, clear evidence of antitumor activity was observed in a patient with epithelioid mesothelioma, as confirmed by positron emission tomography studies. A Phase II trial to assess the efficacy of ET-743 against this highly refractory neoplasm has been initiated on the basis of this observation. The therapeutically optimal administration schedule remains to be established, inasmuch as there have been indications of activity against a variety of tumors during Phase I studies when the drug was infused over times ranging from 1 to 72 h. Characterizing the pharmacokinetics of ET-743 during the course of Phase II trials and Phase I combination studies is recommended to assure that this promising new anticancer drug can be used with an acceptable margin of safety.

A phase II study of weekly paclitaxel in elderly patients with advanced non-small cell lung cancer.

PURPOSE: Our aim was to evaluate the efficacy, toxicity, and pharmacokinetic behavior of single-agent paclitaxel given weekly to elderly patients with lung cancer. EXPERIMENTAL DESIGN: Previously untreated patients with stage IIIB/IV non-small cell lung cancer were eligible for the study if they were at least 70 years of age and had preserved organ function. Paclitaxel was administered over 1 h at a dose of 90 mg/m(2) for 6 consecutive weeks on an 8-week cycle. The pharmacokinetics of paclitaxel were assessed during the first and sixth week of therapy in a subgroup of eight patients. RESULTS: A total of 35 patients (median age, 76 years; range, 70-85) were enrolled. The overall response rate was 23%. Median time to failure was 5.2 months, whereas the median survival time was 10.3 months. Survival rates after 1 and 2 years were 45 and 22%, respectively. Grade 3/4 toxicities included neutropenia (5.8%), hyperglycemia (17.6%), neuropathy (5.8%), and infection (8.8%). Two patients died from treatment-related toxicity. There was no significant difference (P = 0.18) between the total body clearance of paclitaxel on the first (17.4 +/- 2.9 liters/h/m(2), mean +/- SD) and sixth (15.8 +/- 4.1 liters/h/m(2)) week of therapy. CONCLUSION: Paclitaxel administered as a weekly 1-h infusion at a dose of 90 mg/m(2) is a safe and effective therapy for elderly patients with advanced non-small cell lung cancer. Its pharmacokinetics in elderly patients do not appear to differ from historical data for younger patients, and there was no suggestion of a change in drug clearance after repeated weekly dosing.

A Phase I study of continuous infusion doxorubicin and paclitaxel chemotherapy with granulocyte colony-stimulating factor for relapsed epithelial ovarian cancer.

A Phase I study of paclitaxel and doxorubicin administered as concurrent 96-h continuous i.v. infusion was performed to determine the maximum tolerated dose (MTD), principal toxicities, and pharmacokinetics of this combination in women with relapsed epithelial ovarian cancer. The paclitaxel dose was fixed at 100 mg/m2 (25 mg/m2/day for 4 days). The dose of doxorubicin was escalated from 30 mg/m2 (7.5 mg/m2/day for 4 days) in increments of 10 mg/m2 until dose-limiting toxicity was observed. All patients received granulocyte colony-stimulating factor 5 microg/kg/day prophylactically. Apparent steady-state plasma levels of both drugs were determined in the final cohort of patients treated at the MTD. A total of 17 patients received 52 cycles of therapy. The median age was 58 years, and all patients had previously received one to five different regimens (median, 2) of chemotherapy, including both platinum and paclitaxel. The treatment was tolerated well, with grade 1-2 nausea being the most frequent side effect (73% of cycles). Anemia, neutropenia, thrombocytopenia, and mucositis became dose limiting at the fourth dose level, defining the MTD of doxorubicin in this regimen as 50 mg/m2. There were four partial responses and one complete response in 15 evaluable patients. Apparent steady-state plasma concentrations (mean +/- SD) of paclitaxel and doxorubicin in the three patients treated at the MTD were 33.9 +/- 12.5 nM and 15.7 +/- 1.3 nM, respectively. Paclitaxel and doxorubicin by continuous infusion is a well-tolerated and active chemotherapy regimen for recurrent ovarian cancer.

Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia.

On the basis of the data suggesting that adolescents and young adult patients with acute lymphoblastic leukemia (ALL) have improved outcomes when treated on pediatric protocols, we assessed the feasibility of treating adult patients aged 18-50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E. coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18-50 years were enrolled at 13 participating centers. Seventy-eight patients (85%) achieved a complete remission (CR) after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival (DFS) for the patients achieving a CR was 69% (95% confidence interval (CI) 56-78%) and the 4-year overall survival (OS) for all eligible patients was 67% (95% CI 56-76%). The 4-year DFS for the 64 patients who achieved a CR and were Philadelphia chromosome negative (Ph-) was 71% (95% CI 58-81%), and for all 74 Ph- patients the 4-year OS was 70% (95% CI 58-79%). We conclude that a pediatric-like treatment strategy for young adults with de novo ALL is feasible, associated with tolerable toxicity, and results in improved outcomes compared with historical regimens in young adult patients with ALL.

Disappearance of endogenous luteinizing hormone is prolonged in postmenopausal women.

Pituitary secretion of LH is increased after menopause, but it is not known whether changes in LH clearance also contribute to elevated serum levels. To determine whether the disappearance of endogenous LH is decreased in postmenopausal women (PMW), compared with normal cycling women, GnRH receptor blockade was used to inhibit endogenous secretion of LH and the glycoprotein free alpha-subunit (FAS), and the decline of serum levels was monitored. The NAL-GLU GnRH antagonist ([Ac-D-2Nal1,D-4ClPhe2, D-3Pal3,Arg5,D-4-p-methoxybenzoyl-2-aminobutyric acid6,D-Ala10]GnRH) was administered s.c., at doses of 5, 15, 50, and 150 microg/kg, to 15 euthyroid PMW in 21 studies. Blood was sampled every 10 min, for 4 h before and 8 h after a single sc injection of the GnRH antagonist, followed by hourly samples, ending at 20 h after injection. Results of the maximally suppressive doses (50 and 150 microg/kg) were compared with those of 24 normal cycling women in the early follicular phase and late follicular phase or early luteal phase, and 8 women at the midcycle surge (MCS), who also received these doses of the GnRH antagonist. The best fit curve describing the decay of hormone serum levels after maximal GnRH receptor blockade was determined by nonlinear regression analysis. The elimination of both LH and FAS, after GnRH receptor blockade, exhibited apparent first-order kinetics characterized by a single exponential phase. No differences were seen in percent suppression or half-lives (t1/2) of LH or FAS, between the 50- and 150-microg/kg antagonist doses, in any of the subject populations; and percent suppression of LH was similar across all groups. The t1/2 of LH was prolonged in PMW (139 +/- 35 min, mean +/- est. SD), in comparison with both the MCS (78 +/- 20 min; P < 0.0005) and other cycle stages (57 +/- 28 min; P < 0.0001). However, the disappearance of FAS was not different in PMW, compared with MCS or other cycle stages (t1/2 = 51 +/- 26, 41 +/- 12, and 41 +/- 19 min, respectively). Our conclusions were: 1) Disappearance of endogenous LH after GnRH receptor blockade is significantly prolonged in PMW, compared with the MCS or other cycle stages; 2) The disappearance of FAS is not altered in PMW, suggesting that differences in the disappearance of LH relate to LH microheterogeneity rather than systemic factors.

Quantitative analysis of the novel depsipeptide anticancer drug Kahalalide F in human plasma by high-performance liquid chromatography under basic conditions coupled to electrospray ionization tandem mass spectrometry.

Kahalalide F (KF) is a novel cyclic depsipeptide anticancer drug, which has shown anticancer activity both in vitro and in vivo especially against human prostate cancer cell lines. To characterize the pharmacokinetics of KF during a phase I clinical trial in patients with androgen refractory prostate cancer, a method was developed and validated for the quantitative analysis of KF in human plasma using high-performance liquid chromatography (HPLC) coupled to positive electrospray ionization tandem mass spectrometry (ESI-MS/MS). Microbore reversed-phase liquid chromatography (LC) performed with mobile phases containing trifluoroacetic acid, an additive commonly used for separating peptides, resulted in substantial suppression of the signal for KF on ESI-MS/MS. An alternative approach employing a basic mobile phase provided an excellent response for KF when detected in the positive ion mode. Plasma samples were prepared for LC MS/MS by solid-phase extraction on C(18) cartridges. The LC separation was performed on a Zorbax Extend C(18) column (150 x 2.1 mm i.d., particle size 5 micro m) with acetonitrile -10 mM aqueous ammonia (85 : 15, v/v) as the mobile phase, at a flow-rate of 0.20 ml min(-1). A butyric acid analogue of KF was used as the internal standard. The lower limit of quantitation (LLQ) using a 500 micro l sample volume was 1 ng ml(-1) and the linear dynamic range extended to 1000 ng ml(-1). The inter-assay accuracy of the assay was -15.1% at the LLQ and between -2.68 and -9.05% for quality control solutions ranging in concentration from 2.24 to 715 ng ml(-1). The inter-assay precision was 9.91% or better at these concentrations. The analyte was stable in plasma under all relevant conditions evaluated and for a period of 16 h after reconstituting plasma extracts for LC analysis at ambient temperature.

Dose-dependent pharmacokinetics of rapamycin-28-N,N-dimethylglycinate in the mouse.

Rapamycin-28-N,N-dimethylglycinate methanesulfonate salt (RG), synthesized as a potential water-soluble prodrug to facilitate parenteral administration of the antineoplastic macrolide rapamycin (RA), is active against intracranially implanted human glioma in mice. Preclinical pharmacokinetic studies to evaluate the prodrug were conducted in male CD2F1 mice treated with 10, 25, 50 and 100 mg/kg doses of RG by rapid i.v. injection. The plasma concentration of RG decayed in a distinctly triphasic manner following treatment with the 100 mg/kg dose; however, prodrug disposition was apparent biexponential at each of the lower doses. RG exhibited dose-dependent pharmacokinetics, characterized by an increase in the total plasma clearance from 12.5 to 39.3 ml.min-1.kg-1 for dosage escalations in the range 10-50 mg/kg, while clearance values at doses of 50 and 100 mg/kg were similar. The terminal rate constants decreased linearly as the dose was increased from 10 to 100 mg/kg, eliciting an apparent prolongation of the biological half-life from 2.1 to 4.8 h. There was also a sequential increase in the steady state apparent volume of distribution from 1.73 to 8.75 l/kg. These observations are consistent with saturable binding of RG to plasma proteins while binding to tissue remains linear. Nevertheless, conversion to RA appeared to represent a prominent route of RG elimination. The molar plasma concentration of RA exceeded that of the prodrug within 30-90 min after i.v. treatment and declined very slowly thereafter, with plasma levels sustained between 0.1 and 10 microM for 48 h at each of the doses evaluated. Thus, RG effectively served as a slow release delivery system for RA, implying the possibility of maintaining therapeutic plasma levels of the drug from a more convenient dosing regimen than a continuous infusion schedule. The present findings, coupled with the demonstrated in vivo activity of RG against human brain tumor models, warrant its continued development as a much needed chemotherapeutic agent for the treatment of brain neoplasms.

Plasma pharmacokinetics and bioavailability of 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea after intravenous and oral administration to mice and dogs.

PURPOSE: Chloroethylnitrosoureas are among the most widely used chemotherapeutic agents for the treatment of brain tumors. SarCNU (1-(2-chloroethyl)3-sarcosinamide-1-nitrosourea) is an investigational nitrosourea analogue that has shown greater antitumor activity and a more favorable toxicity profile than 1,3-bis(2-chloroethyl)-1-nitrosourea in preclinical studies. The purpose of the present study was to characterize the plasma pharmacokinetics and oral bioavailability of SarCNU in mice and dogs treated by intravenous infusion and gastric intubation. METHODS: SarCNU was administered to mice by i.v. injection or orally at doses ranging from 10 to 100 mg/kg. Plasma samples were obtained from groups of five animals at each time-point at intervals ranging from 3 min to 2.5 h after dosing. A group of three male beagle dogs were treated with Sar CNU 10 mg/kg given both by i.v. infusion and orally in a crossover design. The concentration of SarCNU in plasma was measured by high-performance liquid chromatography. RESULTS: During the initial 90 min after i.v. injection to mice, SarCNU was eliminated from plasma in a monoexponential manner with a mean half-life of 9.8 +/- 0.8 min. The total plasma clearance was 47.3 +/- 8.7 ml/min per kg and the apparent volume of distribution was 0.7 +/- 0.1 l/kg. SarCNU exhibited linear pharmacokinetic behavior following both i.v. and oral administration of doses ranging from approximately 10 to 100 mg/kg. Peak plasma levels provided by a dose of 100 mg/kg given by the i.v. and oral routes were 142.4 microg/ml (0.5 min) and 27.8 microg/ml (9.8 min), respectively. The mean oral bioavailability of the drug was 57.3 +/- 12.6% in mice. In comparison, the disposition of SarCNU in dogs after rapid i.v. injection was biexponential, with half-lives of 5.4 +/- 8.4 min and 40.8 +/- 9.0 min for the initial and terminal disposition phases, respectively. Mean values of the total plasma clearance and apparent volume of distribution were 17.8 +/- 1.8 ml/min per kg and 1.1 +/- 0.3 l/kg, respectively. The Cmax was 18.5 +/- 6.5 microg/ml after i.v. injection and 8.5 0.4 microg/ml after oral administration of a 10 mg/kg dose. Oral bioavailability of the drug in dogs (71.7 +/- 21.2%) was greater than that observed in mice. CONCLUSIONS: SarCNU exhibited linear and consistent pharmacokinetics in mice and dogs with very good oral bioavailability in both species. These findings support the rationale for evaluating SarCNU given by the oral route of administration in phase I clinical trials.

Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent.

The plasma pharmacokinetics of the anti-tumor antibiotic geldanamycin (GM: NSC 122750), a naturally occurring benzoquinoid ansamycin, was characterized in mice and a beagle dog. Concentrations of GM well above 0.1 microgram/ml, which was typically effective against neoplastic cell lines responsive to the drug in vitro, were achieved in the plasma of the mice and the dog treated by i.v. injection. However, the systemic duration of the drug was relatively short. Plasma levels decayed below 0.1 microgram/ml within 3-4 h after administration of the apparent maximum tolerated doses, which were approximately 20 mg/kg for the mice and 4 mg/kg for the dog. The drug exhibited linear pharmacokinetic behavior within the dose ranges studied. However, there were significant interspecies differences in its disposition. Whereas the mean biological half-life of GM was slightly longer in the mice (77.7 min) than in the dog (57.9 min), its mean residence time in the dog (46.6 min) was more than twofold greater than that observed in the mice (20.7 min). Nevertheless, the drug was cleared from plasma much faster by the dog (49.4 ml/min per kg) than by the mice (30.5 ml/min per kg). These apparent anomalies were principally associated with differences in the relative significance of the terminal phase upon overall drug disposition. The liver appeared to be the principal target organ of acute drug toxicity in the dog. Doses of 2.0 and 4.2 mg/kg both produced elevations in serum levels of the transaminases and other indicators of liver function characteristic of acute hepatic necrosis. Additional effects included symptoms of minor gastrointestinal toxicity and alterations in serum chemistry parameters consistent with less severe nephrotoxicity. Drug-related toxicity appeared to be reversible. In consideration of the potential for acute hepatotoxic reactions to GM, as well as to the other benzoquinoid ansamycins based upon structural analogy, additional pharmacological and therapeutic information is required to ascertain whether these compounds are viable candidates for clinical development.

Phase I clinical trial of 7-cyanoquinocarcinol (DX-52-1) in adult patients with refractory solid malignancies.

PURPOSE: A phase I study of the antitumor antibiotic 7-cyanoquinocarcinol, DX-52-1, was conducted in patients with refractory solid malignancies. This study sought to determine the maximum tolerated dose and principal toxicities of this agent and to characterize its pharmacokinetic behavior. METHODS: Patients were required to have adequate bone marrow, renal and hepatic function. DX-52-1 was administered by i.v. continuous infusion over a 6-h period each week for four consecutive weeks followed by a 2-week rest period, which constituted one cycle of treatment. RESULTS: Initial dose levels were 3, 6, and 10 mg/m2. An intermediate dose level of 8 mg/m2 was added after acceptable toxicity was observed at the 6 mg/m2 dose level, but dose-limiting toxicities, including life-threatening ones, were seen at the 10 mg/m2 dose level in all three patients. The maximum tolerated dose (MTD) was subsequently determined to be 6 mg/m2. Because a clear pattern of toxicities was not initially evident, a larger than usual number of additional patients (16) were enrolled at the MTD to better distinguish toxicities due to the study drug from those secondary to the patients' underlying malignancies. Even at the MTD, the drug was poorly tolerated, with gastrointestinal toxicities (abdominal pain, nausea, vomiting and increased liver function tests) predominating and dose-limiting. Pharmacokinetic studies revealed that the mean maximum plasma concentration of DX-52-1 in patients evaluated at the MTD (138.8 +/- 59.3 ng/ml, n = 19) was considerably lower than the concentrations required for cytostatic or cytotoxic activity against sensitive human tumor cell lines in vitro. Further, the weekly dose intensity of the most efficacious treatment schedule identified during in vivo antitumor efficacy studies was 60 times greater than the 6 mg/m2 weekly dose tolerated by cancer patients. None of the 33 patients participating in this study, including the 22 patients evaluated at the MTD, had any response to treatment. CONCLUSION: Given the poor tolerability, the inability to achieve drug levels necessary to inhibit in vitro or in vivo tumor growth, and the lack of any responses in our study, DX-52-1, as given by this schedule, does not appear to warrant further investigation in phase II studies.