Jeffery A. Sosman

PURPOSE: Flavopiridol is the first cyclin-dependent kinase (cdk) inhibitor to enter clinical trials. Serum levels of flavopiridol obtained during phase I studies were sufficient to inhibit in vitro cancer cell growth. Because responses were observed in kidney cancer patients in the phase I trials, we performed a phase II trial of flavopiridol in this patient population. PATIENTS AND METHODS: Thirty-five minimally pretreated patients were accrued using a standard two-step mechanism. Flavopiridol (50 mg/m(2)/d) was administered by continuous infusion for 72 hours every 2 weeks, and response was evaluated every 8 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, at completion of drug infusion, and on day 7 of the first therapy cycle, and cell cycle parameters after phytohemagglutinin and interleukin-2 stimulation were assessed. RESULTS: There were two objective responses (response rate = 6%, 95% confidence interval, 1% to 20%). The most common toxicities were asthenia, occurring in 83% of patients (grade 3 or 4 in 9%), and diarrhea, occurring in 77% of patients (grade 3 or 4 in 20%). Also, nine patients (26%) experienced grade 3 or 4 vascular thrombotic events, including one myocardial infarction, two transient neurologic ischemic attacks, four deep venous thrombosis, and two pulmonary emboli. Cell cycle studies did not reveal any effect of flavopiridol on stimulated PBMCs. CONCLUSION: Flavopiridol, at the dose and schedule administered in this trial, is ineffective in metastatic renal cancer. In addition to the diarrhea observed in phase I studies, we also observed a higher incidence of asthenia and serious vascular thrombotic events than expected.

PURPOSE: Renal cell carcinoma is resistant to most chemotherapy, and only a minority of patients respond to immunotherapy. Its highly vascular nature suggests that antiangiogenesis therapy might be useful. We thus performed a phase II study of the fumigillin analog TNP-470 in previously treated patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Metastatic renal cell carcinoma patients with good organ function were entered onto the study through five separate institutions. There were no exclusion criteria for prior therapy. All patients were treated at a dose of 60 mg/m(2) of TNP-470 infused over 1 hour three times per week. RESULTS: Thirty-three patients were enrolled. Therapy was generally well tolerated, but asthenia, fatigue, vertigo, dizziness, sense of imbalance, and loss of concentration were common and severe enough to lead to therapy discontinuation in five patients. There was only one partial response of short duration (response rate, 3%, 95% confidence interval, 0% to 16%), but six patients (18%) remained on study for 6 or more months without toxicity or disease progression. CONCLUSION: Long-term therapy with TNP-470 has manageable toxicities and is feasible in patients with metastatic renal cell carcinoma but does not lead to any significant objective responses. Further studies in this population using TNP-470 schedules that produce more prolonged drug levels and clinical trial end points other than objective tumor regression may be indicated.

A physiological pharmacokinetic model was developed to describe the disposition of lycopene, delivered as a tomato beverage formulation in five graded doses (10, 30, 60, 90, or 120 mg), for a phase I study in healthy male subjects (five per dose). Blood was collected before dose administration (0 h) and at scheduled intervals until 672 h. Serum concentrations of carotenoids and vitamins were measured by high performance liquid chromatography analysis. The model was comprised of seven compartments: gastrointestinal tract, enterocytes, chylomicrons, plasma lipoproteins, fast-turnover liver, slow-turnover tissues, and a delay compartment before the enterocytes. As predicted, the percent absorption at the 10 mg dose (33.9 +/- 8.1%) was significantly greater than at the higher doses; however, the amount of lycopene absorbed (mg) was not statistically different (mean: 4.69 +/- 0.55 mg) between doses, suggesting a possible saturation of absorptive mechanisms. The slow-turnover tissue compartment served as a slow-depleting reservoir for lycopene, and the liver represented the fast-turnover pool. Independent of dose, 80% of the subjects absorbed less than 6 mg of lycopene. This may have important implications for planning clinical trials with pharmacological doses of lycopene in cancer control and prevention if absorption saturation occurs at levels that are already being consumed in the population.

Oncogene-induced senescence can provide a protective mechanism against tumour progression. However, production of cytokines and growth factors by senescent cells may contribute to tumour development. Thus, it is unclear whether induction of senescence represents a viable therapeutic approach. Here, using a mouse model with orthotopic implantation of metastatic melanoma tumours taken from 19 patients, we observed that targeting aurora kinases with MLN8054/MLN8237 impaired mitosis, induced senescence and markedly blocked proliferation in patient tumour implants. Importantly, when a subset of tumour-bearing mice were monitored for tumour progression after pausing MLN8054 treatment, 50% of the tumours did not progress over a 12-month period. Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response, which mediated senescence and a NF-κB-related, senescence-associated secretory phenotype (SASP). Blockade of IKKβ/NF-κB led to reversal of MLN8237-induced senescence and SASP. Results demonstrate that removal of senescent tumour cells by infiltrating myeloid cells is crucial for inhibition of tumour re-growth. Altogether, these data demonstrate that induction of senescence, coupled with immune surveillance, can limit melanoma growth.