Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma.

BACKGROUND: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. RESULTS: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma. CONCLUSION: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier NCT00112372.

Enhanced antitumor activity of 6-hydroxymethylacylfulvene in combination with irinotecan and 5-fluorouracil in the HT29 human colon tumor xenograft model.

6-Hydroxymethylacylfulvene (MGI-114) is a semisynthetic analogue of the toxin illudin S, a product of the Omphalotus mushroom. MGI-114 induces cytotoxicity in a variety of solid tumors in vivo, including the refractory HT29 human colon cancer xenograft. In this study, the potential application of MGI-114 in the treatment of colon cancer was further explored by evaluating the activity of MGI-114 in combination with irinotecan (CPT-11) and 5-fluorouracil (5FU). Groups of 9 nude mice bearing HT29 xenografts were treated with either single agent MGI-114, CPT-11, or 5FU, or MGI-114 in combination with CPT-11 or 5FU. MGI-114 was administered at doses of 3.5 and 7 mg/kg i.p. daily on days 1 through 5, and CPT-11 and 5FU were administered at doses of 50 and 100 mg/kg i.p. on days 1, 12, and 19. In the single agent studies, MGI-114, CPT-11, and 5FU all resulted in decreased final tumor weights compared with vehicle-treated controls (P<0.05), but only MGI-114 at 7 mg/kg produced partial responses. When MGI-114 at 3.5 mg/kg was combined with CPT-11, significant decrements in final tumor weights occurred compared with monotherapy with the same doses of MGI-114 and CPT-11 (P< or =0.001). Also, administration of the low-dose combination (MGI-114 at 35 mg/kg and CPT-11 at 50 mg/kg) resulted in final tumor weights similar to those achieved after administration of high-dose MGI-114 as a single agent. Moreover, the combination of MGI-114 and CPT-11 produced partial responses in nearly all of the animals, with some animals achieving complete responses. The outcome with the combination of MGI-114 and 5FU was less striking, with fewer partial responses and no complete responses. These results suggest enhanced activity when MGI-114 is combined with CPT-11, and clinical trials to further evaluate this combination regimen are planned.

Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies.

PURPOSE: To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized. RESULTS: Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 +/- 0.62 microg/mL; clearance rate, 6.33 +/- 6.41 L/h; elimination half-life, 24.4 +/- 14.6 hours; volume of distribution, 136. 4 +/- 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 +/- 0.12 microg/h/mL). CONCLUSION: The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.

Phase I and pharmacokinetic study of BMS-184476, a taxane with greater potency and solubility than paclitaxel.

PURPOSE: To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474. RESULTS: Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean +/- SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 +/- 89 mL/min/m2, 402 +/- 231 L/m2, and 40.8 +/- 21.8 hours, respectively. CONCLUSION: The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.

Phase I and pharmacokinetic study of irofulven, a novel mushroom-derived cytotoxin, administered for five consecutive days every four weeks in patients with advanced solid malignancies.

PURPOSE: To evaluate the toxicity and pharmacologic behavior of the novel mushroom-derived cytotoxin irofulven administered as a 5-minute intravenous (IV) infusion daily for 5 days every 4 weeks to patients with advanced solid malignancies. PATIENTS AND METHODS: In this phase I trial, 46 patients were treated with irofulven doses ranging from 1.0 to 17.69 mg/m(2) as a 5-minute IV infusion (two patients received a 1-hour infusion) daily for 5 days every 4 weeks. The modified continual reassessment method was used for dose escalation. Pharmacokinetic studies were performed on days 1 and 5 to characterize the plasma disposition of irofulven. RESULTS: Forty-six patients were treated with 92 courses of irofulven. The dose-limiting toxicities on this schedule were myelosuppression and renal dysfunction. At the 14.15-mg/m(2) dose level, renal dysfunction resembling renal tubular acidosis occurred in four of 10 patients and was ameliorated by prophylactic IV hydration. The 17.69-mg/m(2) dose level was not tolerated because of grade 4 neutropenia and renal toxicity, whereas the 14.15-mg/m(2) dose level was not tolerable with repetitive dosing because of persistent thrombocytopenia. Other common toxicities included mild to moderate nausea, vomiting, facial erythema, and fatigue. One partial response occurred in a patient with advanced, refractory metastatic pancreatic cancer lasting 7 months. Pharmacokinetic studies of irofulven revealed dose-proportional increases in both maximum plasma concentrations and area under the concentration-time curve, while the agent exhibited a rapid elimination half-life of 2 to 10 minutes. CONCLUSION: Given the results of this study, the recommended dose of irofulven is 10.64 mg/m(2) as a 5-minute IV infusion daily for 5 days every 4 weeks. The preliminary antitumor activity documented in a patient with advanced pancreatic cancer and the striking preclinical antitumor effects of irofulven observed on intermittent dosing schedules support further disease-directed evaluations of this agent on the schedule evaluated in this study.

Oral paclitaxel and concurrent cyclosporin A: targeting clinically relevant systemic exposure to paclitaxel.

Oral paclitaxel is not inherently bioavailable because of the overexpression of P-glycoprotein by intestinal cells and the significant first-pass extraction by cytochrome P450-dependent processes. This study sought to simulate the toxicological and pharmacological profile of a clinically relevant schedule of paclitaxel administered on clinically relevant i.v. dosing schedules in patients with advanced solid malignancies using oral paclitaxel administered with cyclosporin A, an inhibitor of both P-glycoprotein and P450 CYP3A. Nine patients were treated with a single course of oral paclitaxel in its parenteral formulation at a paclitaxel dose level of 180, 360, or 540 mg. Cyclosporin A was administered at a dose of 5 mg/kg p.o. 1 h before and concurrently with oral paclitaxel. Blood sampling was performed to evaluate the pharmacokinetics of paclitaxel, 6-alpha-hydroxypaclitaxel, 3-p-hydroxypaclitaxel, and cyclosporin A. The pharmacokinetic behavior of paclitaxel was characterized using both compartmental and noncompartmental methods. Model-estimated parameters were used to simulate paclitaxel concentrations after once daily and twice daily oral administration of paclitaxel and cyclosporin A. Aside from an unpleasant taste, the oral regimen was well tolerated, and there were no grade 3 or 4 drug-related toxicities. The systemic exposure to paclitaxel, as assessed by maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) values, did not increase as the dose of paclitaxel was increased from 180 to 540 mg, and there was substantial interindividual variability (4-6-fold) at each dose level. Mean paclitaxel Cmax values approached plasma concentrations achieved with clinically relevant parenteral dose schedules, averaging 268+/-164 ng/ml. AUC values averaged 3306+/-1977 ng x h/ ml, which was significantly lower than AUC values achieved with clinically relevant i.v. paclitaxel dose schedules. However, computer simulations using pharmacokinetic parameters derived from the present study demonstrated that pharmacodynamically relevant steady-state plasma paclitaxel concentrations of at least 0.06 microM would be achieved after protracted once daily and twice daily dosing with oral paclitaxel and cyclosporin A. Paclitaxel metabolites were detectable in three patients, and the 6-alpha-hydroxypaclitaxel: paclitaxel and 3-p-hydroxypaclitaxel:paclitaxel AUC ratios averaged 0.63 and 0.86, respectively; these values were substantially higher than values reported in patients treated with i.v. paclitaxel. Oral paclitaxel was bioavailable in humans when administered in combination with oral cyclosporin A 5 mg/kg 1 h before and concurrently with paclitaxel treatment, and plasma paclitaxel concentrations achieved with this schedule were biologically relevant and approached concentrations attained with clinically relevant parenteral dose schedules. However, treatment of patients with oral paclitaxel using a single oral dose administration schedule failed to achieve sufficiently high systemic drug exposure and pharmacodynamic effects. In contrast, computer simulations demonstrated that clinically relevant pharmacodynamic effects are likely to be achieved with multiple once daily and twice daily oral paclitaxel-cyclosporin A dosing schedules.

A phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine dye analog MKT 077.

This Phase I study was performed to evaluate the tolerability and pharmacokinetic behavior of MKT-077, a water soluble rhodacyanine dye analogue, which partitions into tumor cell mitochondria where it is thought to act as a metabolic poison, leading to G1 arrest and apoptosis. Thirteen patients with advanced solid malignancies were treated with MKT-077 administered as a 30-min i.v. infusion weekly for 4 weeks every 6 weeks at doses ranging from 42 to 126 mg/m2/week. The principal toxicity was renal magnesium wasting, which was dose-limiting (grade 3) in one patient at each of the 84- and 126-mg/m2 dose levels. The other three patients at the 126-mg/m2 dose level developed grade 2 hypomagnesemia, which was cumulative in nature, improved with i.v. magnesium supplementation, and was controlled in two patients by the administration of prophylactic magnesium before and after treatment with MKT-077. Given the requirement for extensive monitoring of serum magnesium levels, dose escalation >126 mg/m2 was not considered feasible. Thus, the recommended dose for disease-oriented studies with this schedule of MKT-077 is 126 mg/m2/week. Pharmacokinetic studies revealed a prolonged terminal half-life (37 +/- 17 h) and a large volume of distribution (685 +/- 430 liters/m2). Clearance averaged 39 +/- 13 liters/h/m2. Peak MKT-077 plasma concentrations (1.2 +/-0.31 to 6.3 +/- 5.3 microg/ml) exceeded the IC50 concentrations required for human CX-1 colon, MCF-breast, CRL-1420 pancreas, EJ bladder, and LOX melanoma tumor cell lines in vitro (0.15-0.5 microg/ml). These results indicate that at the recommended dose level of 126 mg/m2/week of MKT-077, the toxicity profile was consistent with the preferential accumulation of the agent within tumor cell mitochondria, and biologically relevant plasma concentrations were achieved.

A phase I and pharmacological study of the farnesyl protein transferase inhibitor L-778,123 in patients with solid malignancies.

This Phase I study was performed to assess the feasibility of administering L-778,123, a peptidomimetic farnesyl protein transferase (FPTase) inhibitor, as a continuous i.v. infusion for 7 days every 3 weeks and to determine the recommended dose for subsequent disease-directed trials. This study also sought to characterize the pharmacological behavior of L-778,123 and to determine whether the desired biological effect, inhibition of protein farnesylation, could be detected and assessed during treatment. Patients with advanced solid malignancies were treated with L-778,123 as a continuous i.v. infusion for 7 days every 3 weeks at doses ranging from 35 to 1120 mg/m(2)/day. On the basis of preclinical studies, toxicity assessments included cardiac telemetry, electrocardiograms, and electroretinograms in addition to more routine safety monitoring laboratory tests. Plasma sampling was performed to characterize the pharmacokinetics of L-778,123, and peripheral blood mononuclear cells (PBMCs) were sampled to detect and monitor the inhibitory effects of L-778,123 on the prenylation of HDJ2, a chaperone protein that undergoes farnesylation. Twenty-five patients received 51 complete courses of L-778,123. An unacceptably high incidence of dose-limiting toxicities, consisting of grade 4 thrombocytopenia, significant prolongation of the QT(c) interval, and profound fatigue, was observed at the 1120 mg/m(2)/day dose level. At the next lower L-778,123 dose level, 560 mg/m(2)/day, seven new patients had no unacceptable toxicity. Instead, myelosuppression was mild to moderate and QT(c) prolongation was negligible. Pharmacokinetics were linear, and L-778,123 plasma concentrations at steady-state (mean, 8.09 +/- 3.11 microM at 560 mg/m(2)/day) exceeded IC(50) values (range, 0.07-5.35 microM) required for growth inhibition and cytotoxicity in preclinical studies. The systemic clearance of L-778,123 averaged 106.4 +/- 45.6 ml/min/m(2), and the terminal half-life of elimination was 2.8 +/- 1.0 h. L-778,123 inhibited HDJ2 prenylation for the duration of the drug infusion in a dose-dependent manner, but seemed to plateau above 560 mg/m(2)/day. At the 560 mg/m(2)/day dose level, the mean percentage of HDJ2 protein in its unprenylated form increased from 1.41% +/- 1.71% (pretreatment) to 28.76% +/- 6.10% (day 4) and 30.86 +/- 4.96 (day 8) and declined to 2.28% +/- 2.11% one week after drug discontinuation (day 16). L-778,123 administered as a continuous 7-day i.v. infusion for 7 days every 21 days is well tolerated at doses of 560 mg/m(2)/day and results in biologically relevant concentrations and consistent inhibition of HDJ2 prenylation in PBMCs. Although the relationship between drug-related inhibition of HDJ2 prenylation in PBMCs and both prenylation of relevant proteins and growth inhibition in tumor cells is unknown, serial analyses of HDJ2 prenylation provide a pharmacodynamic marker of protein prenylation that may be useful in optimizing the development of drugs targeting FPTase.

A Phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies.

Temozolomide (TMZ) is an oral imidazotetrazinone that is spontaneously converted to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) at physiological pH. MTIC methylates DNA at the O6 position of guanine, although this lesion may be repaired by the enzyme O6-alkylguanine-DNA alkyltransferase (AGAT). In this study, TMZ was combined with cisplatin (CDDP), because both agents have single-agent activity against melanoma and other tumor types. Additionally, CDDP has been shown to inactivate AGAT, and subtherapeutic concentrations of CDDP have been shown to increase the sensitivity of leukemic blasts to TMZ. This Phase I study sought to determine the toxicities, recommended dose, and pharmacological profile of the TMZ/CDDP combination. Patients were treated with oral TMZ daily for 5 consecutive days together with CDDP on day 1 (4 h after TMZ) every 4 weeks at the following TMZ (mg/m2/day)/CDDP (mg/m2) dose levels: 100/75, 150/75, 200/75, and 200/100. Plasma samples were obtained on days 1 and 2 to evaluate the pharmacokinetic parameters of TMZ alone and in combination with CDDP. Fifteen patients received a total of 44 courses of TMZ/CDDP. The principal toxicities of the regimen consisted of neutropenia, thrombocytopenia, nausea, and vomiting, which were intolerable in two of six new patients treated at the 200/100 mg/m2 dose level. Of five patients receiving 17 courses at the next lower dose level (200/75 mg/m2), none experienced dose-limiting toxicity. Antitumor activity was observed in patients with non-small cell lung cancer, squamous cell carcinoma of the tongue, and leiomyosarcoma of the uterus. Pharmacokinetic studies of TMZ revealed the following pertinent parameters (mean +/- SD): time to maximum plasma concentration (Tmax) = 1.1+/-0.6 h (day 1) and 1.7+/-0.9 h (day 2); elimination half-life (t1/2) = 1.74+/-0.22 h (day 1) and 2.35+/-0.70 h (day 2); and clearance (Cl(s)/F) = 115+/-27 ml/min/m2 (day 1) and 141+/-109 ml/min/m2 (day 2). TMZ drug exposure, described by the area under the plasma concentration-time curve (AUCinfinity) and the maximum plasma concentration (Cmax), was similar on days 1 and 2. On the basis of these results, the recommended doses for Phase II clinical trials are TMZ 200 mg/m2/day for 5 days with 75 mg/m2 CDDP on day 1, every 4 weeks. The addition of CDDP did not affect the tolerable dose of single-agent TMZ (200 mg/m2/day x 5 days), nor did it substantially alter the pharmacokinetic behavior of TMZ.

Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay.

PURPOSE: This study was performed to evaluate the activity of the multitargeted antifolate (MTA or LY231514) against a broad range of human tumors taken directly from patients. MATERIALS AND METHODS: Human tumor colony-forming units were treated with MTA at concentrations of 0.1, 1.0, and 10 microg/ml in 1-h exposure studies. The responses of a limited number of specimens were also evaluated concurrently in 1-h exposures to cisplatin, fluorouracil, irinotecan, and/or paclitaxel. RESULTS: Of 358 specimens plated in the 1-h exposure studies, 148 (41%) were evaluable. Overall, responses were observed in 3% of specimens (4/144) at 0.1 microg/ml, 11% (17/148) at 1.0 microg/ml, and 23% (33/141) at 10 microg/ml. In this range of concentrations achievable clinically, there was a significant concentration-response relationship. At 10 microg/ml in the 1-h exposure studies, the response rate in colorectal cancer specimens was 32% (9/28), and the response rate in non-small-cell lung cancer was 25% (6/24). Responses were also observed in several chemoresistant tumors, including renal cell carcinoma, hepatocellular carcinoma, mesothelioma, and pancreatic carcinoma. The activity of MTA was not completely cross-resistant with that of cisplatin, fluorouracil, irinotecan, and paclitaxel. CONCLUSIONS: MTA demonstrated in vitro activity against a spectrum of tumors, including several tumors generally considered chemoresistant.

G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer.

Rigorous quality control steps, termed checkpoints, tightly regulate progression through the cell cycle. DNA-damaging chemotherapy and radiation activate functional cellular checkpoints. These checkpoints can facilitate DNA repair and promote cell death in unrepaired cells. There are at least three DNA damage checkpoints - at G1/S, S, and G2/M - as well as a mitotic spindle checkpoint. Most cancer cells harbour mutations in tumour suppressors and/or oncogenes, which impair certain cell checkpoints. Inhibiting the remaining cell checkpoints - particularly after exposure of cancer cells to chemotherapy and/or radiation - allows cell death, a strategy now being employed in cancer therapeutics. With our increasing knowledge of cell cycle regulation, many compounds have been developed to inhibit specific checkpoint components, particularly at the G2/M transition. One such target is checkpoint kinase-1 (Chk1). We review here the molecular framework of the cell cycle, the rationale for targeting Chk1, the preclinical concepts related to the development of Chk1 inhibitors, and the efficacy and safety results from Chk1 inhibitors now in phase I/II trials.