A phase I dose-ranging study of the pharmacokinetics, pharmacodynamics, safety, and tolerability of AVN944, an IMPDH inhibitor, in healthy male volunteers.

A phase I study of AVN944, an inosine monophosphate dehydrogenase (IMPDH) inhibitor, was carried out to assess its safety, tolerability, pharmacokinetics, and pharmacodynamics. Healthy male volunteers (N = 25) participated in this double-blind, randomized, placebo-controlled trial. Sixteen received oral doses ranging from 25 to 250 mg on 3 separate occasions at intervals of 3 or 6 days after overnight fasting. Six participants received two 100-mg doses, and 2 participants received 2 placebo doses, one with food and the other after fasting overnight. Clinical and laboratory parameters, including excretion of AVN944 and thiocyanate and IMPDH inhibition, were made at intervals for 48 hours postdosing. There were 13 mild and 2 moderate but no serious adverse events. One mild and 1 moderate event could be treatment related. AVN944 disappeared rapidly from plasma, but clearance decreased at doses > 50 mg. Food reduced absorption, with a geometric mean Cmax ratio of 33% and a geometric mean AUC0-infinity ratio of 44%. Urinary excretion was negligible. AVN944 doses > 100 mg showed definite IMPDH inhibition lasting at least 4 to 6 hours. AVN944, when administered orally to healthy volunteers, is well tolerated, absorbs better with fasting, and exhibits a pharmacodynamic profile that suggests potential for significant anticancer activity.

A phase II study of the safety and efficacy of the multidrug resistance inhibitor VX-710 combined with doxorubicin and vincristine in patients with recurrent small cell lung cancer.

BACKGROUND: Tumors with multidrug resistance (MDR) frequently up-regulate efflux proteins, including MDR-associated protein (MRP-1) and P-glycoprotein (Pgp). MDR represents an obstacle to successful chemotherapy treatment and is reversible in Pgp- or MRP-1-expressing cells by the inhibitor VX-710. A Phase II study was designed to evaluate VX-710 in combination with doxorubicin and vincristine in patients with sensitive, recurrent small cell lung cancer (SCLC). METHODS: Eligible patients had recurrent SCLC after a response to first-line chemotherapy. Stage 1 safety evaluation was completed with planned expansion if 9 responses were confirmed in the first 35 patients. Patients were treated every 21 days until progression or intolerable adverse events (AEs). RESULTS: Thirty-six patients were enrolled from 1998 to 2000. Neutropenia was the major toxicity, occurring in 26 of 36 patients (72%). Neutropenia was more severe (30% vs 20% grade 4) and developed earlier (58% vs 38% in Cycle 1) among the 15 patients who were enrolled prior to an amendment that required neutropenia prophylaxis. Four patients died on study: 2 from infections likely related to therapy and 2 from cancer progression. Seven of 36 patients (19%) had partial responses; 6 patients sustained responses through 6 cycles of treatment, with 1 response lasting 3 years. Three additional patients had unconfirmed responses, and 4 patients had stable disease. The median survival was 6 months. No correlative (99m)Tc-sestamibi uptake in tumor tissue was observed with the addition of VX-710 in this study. CONCLUSIONS: The addition of VX-710 to doxorubicin and vincristine therapy did not significantly enhance antitumor activity or survival. Although there were durable responses, criteria were not met to proceed with Stage 2 expansion.

The Aurora kinase inhibitor VX-680 induces endoreduplication and apoptosis preferentially in cells with compromised p53-dependent postmitotic checkpoint function.

VX-680 is a potent inhibitor of Aurora kinases that induces the accumulation of cells with > or =4N DNA content, followed by cell death. Here, we define the role of p53 and p21(Waf1/Cip1) in cell cycle perturbations following exposure to VX-680. Endoreduplication and apoptosis in response to VX-680 are limited in A549 and MCF-7 cells expressing wild-type p53, and markedly enhanced in cells lacking p53, including those engineered to express the HPV16-E6 oncoprotein or short interfering RNA pools targeting p53. In contrast, endoreduplication and apoptosis occur in the p53 wild-type cell lines, RKO and U2OS. The difference in response to VX-680 among these cell lines correlates with the timing of induction of p21(Waf1/Cip1) and its ability to inhibit cyclin E-cdk2 activity. In A549 cells, VX-680 induces the expression of p53 and p21(Waf1/Cip1) within 24 hours, with consequent inhibition of cyclin E-cdk2, and reduction of retinoblastoma protein phosphorylation, limiting endoreduplication. In RKO and U2OS cells, the induction of p21(Waf1/Cip1) is delayed and associated with higher residual cyclin E-cdk2 kinase activity and retinoblastoma protein phosphorylation, followed by progressive endoreduplication and apoptosis. Abrogation of p21(Waf1/Cip1) expression by short interfering RNA targeting in A549 cells results in a substantial increase in the degree of endoreduplication, whereas inducible expression of p21(Waf1/Cip1) in p53-negative NCI-H1299 cells inhibits VX-680-induced endoreduplication and cell death. These data suggest that the integrity of the p53-p21(Waf1/Cip1)-dependent postmitotic checkpoint governs the response to Aurora kinase inhibition. Although cells with intact checkpoint function arrest with 4N DNA content, those with compromised checkpoint function are more likely to undergo endoreduplication followed by eventual apoptosis.

Safety and efficacy of the MDR inhibitor Incel (biricodar, VX-710) in combination with mitoxantrone and prednisone in hormone-refractory prostate cancer.

PURPOSE: VX-710 (biricodar, Incel) restores drug sensitivity to cells expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1). MRP1 is expressed in a high proportion of prostate tumors while P-gp expression is variable. Since mitoxantrone (M) and prednisone (P) are substrates for MDR transporters, we initiated a study to evaluate the safety, pharmacokinetics, and efficacy of VX-710 plus M/P in patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Eligible patients had progressive HRPC (defined as new lesions, new disease-related pain, or 50% increase in PSA within 6 weeks of entry), testosterone <30 ng/ml, no prior chemotherapy, ECOG performance status of 0-3, and adequate organ function. Patients received VX-710 (120 mg/m(2) per h) as a 72-h continuous intravenous infusion with intravenous bolus mitoxantrone (12 mg/m(2)) administered 4 h after VX-710 was started and prednisone (5 mg twice daily) administered throughout the study treatment. Endpoints included serum PSA response, PSA response duration, time to PSA progression, pain reduction, and quality of life measures. RESULTS: Enrolled in the study were 40 patients and 184 courses of VX-710 plus M/P were administered. Intensive pharmacokinetics, which were performed on six patients who received one cycle of M/P alone, followed by VX-710 plus M/P for all other cycles, showed that VX-710 did not alter mitoxantrone clearance. VX-710 blood concentration at the time of mitoxantrone administration averaged 4.52 microg/ml. VX-710 plus M/P was well tolerated. Transient nausea/vomiting and mild neutropenia were the principal treatment toxicities. Five patients experienced an uncomplicated febrile neutropenic episode (12%), three had severe nausea/vomiting, and two experienced transient moderate to severe ataxia. Of the 40 patients, 12 (30%, 95% confidence interval 16-44%) had a reduction in PSA of >/=50% and 9 of the 12 patients (23% overall, 95% CI 10-35%) achieved a reduction in PSA of >/=80% that was sustained for the duration of treatment with M/P plus VX-710. The median time to PSA progression was 41 weeks (95% CI 34-68 weeks). Of the 40 patients, 15 completed treatment with stable disease and 13 had progressive disease with increasing serum PSA during study treatment. Median survival was 48 weeks for the intent-to-treat population of 40 patients. CONCLUSIONS: The addition of VX-710 to M/P therapy did not appear to increase the proportion of patients with significant serum PSA reductions compared to M/P alone. However, the duration of PSA response observed for the 12 PSA responders suggests that MDR inhibition may benefit some patients with HRPC. In addition to MRP1 or P-gp expression, other mechanisms of drug resistance are probably associated with the relative insensitivity of HRPC to cytotoxic therapy.

A phase II study of the MDR inhibitor biricodar (INCEL, VX-710) and paclitaxel in women with advanced ovarian cancer refractory to paclitaxel therapy.

PURPOSE: Incel (biricodar, VX-710) restores drug sensitivity to P-glycoprotein (MDR1) and multidrug-resistance-associated protein (MRP1) expressing cells. This phase II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus paclitaxel in women with advanced ovarian cancer refractory to prior paclitaxel therapy. EXPERIMENTAL DESIGN: Eligible patients had paclitaxel-refractory disease defined as progressive disease after a minimum of two cycles of paclitaxel (weekly or 3-week schedule) or relapsed disease within 4 months of prior paclitaxel therapy. Patients received 80 mg/m(2) paclitaxel over 3 h starting 4 h after initiation of a 24-h continuous intravenous infusion of 120 mg/m(2)/h VX-710. Cycles were repeated every 3 weeks. RESULTS: Fifty patients received treatment and 45 were evaluable for response. VX-710 + paclitaxel therapy was generally well tolerated. Myelosuppression was the principal toxicity, with a median Cycle 1 nadir absolute neutrophil count of 0.27 x 10(9) cells/L and a 47% overall incidence of Grade 4 neutropenia. Mild to moderate peripheral neuritis or neuropathy was the primary nonhematologic toxicity, affecting 62% of patients. Other nonhematologic toxicities were generally mild to moderate and reversible. Paclitaxel area under the concentration-versus-time curve (AUC) (16 +/- 5.3 microg x h/mL) during the first treatment cycle was comparable to standard 175 mg/m(2) paclitaxel administered over 3 h. Of the 3 patients who achieved partial responses, 2 had progressed during prior paclitaxel therapy. Twelve patients maintained stable disease and 14/45 (31%) of patients had CA-125 reductions of 50-90% for up to 24 weeks. The median time-to-disease progression was 10 weeks for the intent-to-treat population and 20.7 weeks for the CA-125 responders. CONCLUSIONS: The results suggest that VX-710 with paclitaxel has modest activity in paclitaxel-resistant ovarian cancer. Further research is warranted in less heavily treated patients.

Safety and efficacy of the multidrug resistance inhibitor Incel (biricodar; VX-710) in combination with paclitaxel for advanced breast cancer refractory to paclitaxel.

PURPOSE: VX-710 (biricodar, Incel) restores drug sensitivity to P-glycoprotein (MDR1) and multidrug resistance-associated protein (MRP1)-expressing cells. This Phase II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus paclitaxel in women with locally advanced or metastatic breast cancer who were refractory to prior paclitaxel therapy. EXPERIMENTAL DESIGN: Eligible patients had paclitaxel-refractory disease defined as progressive disease after a minimum of two cycles of paclitaxel (weekly or 3-week schedule) or relapsed/progressive disease within 6 months of prior paclitaxel therapy. Patients received 80 mg/m(2) paclitaxel over 3 h starting 4 h after initiation of a 24-h continuous i.v. infusion of 120 mg/m(2)/h VX-710. Cycles were repeated every 3 weeks. RESULTS: Thirty-seven patients received study treatment and 35 were evaluable for response. VX-710 + paclitaxel therapy was generally well tolerated. Myelosuppression was the principal toxicity, with a median nadir ANC cycle 1 of 0.76 x 10(9) cells/liter and a 40% overall incidence of Grade 4 neutropenia. Nonhematological side effects (asthenia, paresthesia, headache, myalgia, nausea, and diarrhea) were generally mild to moderate and reversible. Paclitaxel AUC (16.8 +/- 5.0 microg x h/ml) and clearance (5.1 +/- 1.3 liters/h/m(2)) during the first treatment cycle were comparable with standard 175 mg/m(2) paclitaxel administered in a 3-h schedule. Four patients achieved partial responses (three of the four had progressive disease on prior paclitaxel) with a mean response duration of 5.5 months. CONCLUSIONS: The 11.4% (4 of 35) objective response rate observed in this study suggests that VX-710 can resensitize a subgroup of paclitaxel-refractory patients to paclitaxel. The safety and pharmacokinetics of the VX-710/pacitaxel regimen support further evaluation in breast cancer patients with initial paclitaxel therapy to prevent emergence of the MDR phenotype in recurrent disease.

Safety and efficacy of the multidrug-resistance inhibitor biricodar (VX-710) with concurrent doxorubicin in patients with anthracycline-resistant advanced soft tissue sarcoma.

PURPOSE: Incel (biricodar, VX-710) restores drug sensitivity to P-glycoprotein and multidrug resistance-associated protein-1-expressing cells. This Phase I/II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus doxorubicin in patients with inoperable, locally advanced or metastatic, anthracycline-resistant/refractory, soft tissue sarcoma. EXPERIMENTAL DESIGN: In Phase I, i.v. bolus doxorubicin at 60, 75, or 67.5 mg/m(2) was administered 8 h after initiation of a 72-h continuous i.v. (CIV) infusion of VX-710 (120 mg/m(2)/h) to cohorts of patients to establish a maximum tolerated dose. For efficacy evaluations in Phase II, eligible patients had inoperable, locally advanced or metastatic, anthracycline-resistant/refractory soft tissue sarcoma; < or =225 mg/m(2) cumulative prior doxorubicin; and adequate hematological, liver, and kidney function. Cycles were repeated every 3 weeks. RESULTS: Fourteen patients were enrolled in Phase I. Myelosuppression was the dose-limiting toxicity with 75 and then 67.5 mg/m(2) doxorubicin, and the maximum tolerated dose was established at 60 mg/m(2) with VX-710, 120 mg/m(2)/h, 72-h CIV. VX-710 had no apparent effect on doxorubicin pharmacokinetics. Twenty-nine patients enrolled in Phase II were treated with VX-710, 120 mg/m(2)/h 72-h CIV, and 60 mg/m(2) doxorubicin. Among 26 evaluable patients, minimal activity was noted among 11 patients with gastrointestinal stromal tumors (GISTs); however, in 15 patients with anthracycline-resistant sarcomas of other histologies, 2 achieved partial responses and 7 patients had disease stabilization with an overall median progression-free interval of 3.4 months. CONCLUSION: Anthracycline resistance in GISTs appears to be independent of P-glycoprotein or multidrug resistance-associated protein-1 resistance mechanisms. However, the combination of VX-710 and doxorubicin resulted in objective responses or disease stabilization in patients with strictly defined anthracycline-refractory non-GIST sarcomas, which warrants further evaluation.