Estimation of renal cell carcinoma treatment effects from disease progression modeling.

To improve future drug development efficiency in renal cell carcinoma (RCC), a disease-progression model was developed with longitudinal tumor size data from a phase III trial of sorafenib in RCC. The best-fit model was externally evaluated on 145 placebo-treated patients in a phase III trial of pazopanib; the model incorporated baseline tumor size, a linear disease-progression component, and an exponential drug effect (DE) parameter. With the model-estimated effect of sorafenib on RCC growth, we calculated the power of randomized phase II trials between sorafenib and hypothetical comparators over a range of effects. A hypothetical comparator with 80% greater DE than sorafenib would have 82% power (one-sided α = 0.1) with 50 patients per arm. Model-based quantitation of treatment effect with computed tomography (CT) imaging offers a scaffold on which to develop new, more efficient, phase II trial end points and analytic strategies for RCC.

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis.

The effects of sorafenib--an oral multikinase inhibitor targeting the tumour and tumour vasculature--were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with > or =25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with > or =25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had > or =25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had > or =25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor.

The Ras-Raf-MEK-ERK signalling pathway is frequently dysregulated in human malignancies, as is angiogenesis and the vascular endothelial growth factor receptor (VEGF/VEGFR) pathway. These kinases are therefore important anticancer targets. The novel, oral treatment sorafenib (BAY 43-9006), has been shown to be an inhibitor of VEGFR, Raf and platelet-derived growth factor in clinical trials against a variety of cancers, with the greatest activity to date observed in metastatic renal cancer. Although side-effects with this targeted therapy are usually not dose-limiting, they frequently involve the skin, and consist of a maculopapular rash, palmar-plantar dysaesthesia, alopecia and xerosis. In this report, we present two patients in whom treatment with sorafenib resulted in inflammation of actinic keratosis, which in some cases progressed to invasive squamous cell carcinoma. This side-effect is of clinical importance, as early recognition is critical for early treatment and may represent a source of additional morbidity to these patients.

Thymidylate synthase expression and response to neoadjuvant chemotherapy in patients with advanced head and neck cancer.

BACKGROUND: Thymidylate synthase (TS), an essential enzyme in DNA synthesis, is a target for the fluoropyrimidines, an important group of antineoplastic agents used widely in the treatment of head and neck cancer. PURPOSE: We evaluated relationships between the level and/or pattern of tumor TS expression and response to fluorouracil (5-FU)-based neoadjuvant chemotherapy in patients with advanced head and neck cancer. METHODS: Tumor specimens from 86 patients were available for this retrospective analysis. The patients were enrolled in four consecutive phase II studies that tested combinations of 5-FU, leucovorin, and cisplatin with or without added methotrexate plus piritrexim or interferon alfa-2b (IFN alpha-2b). TS protein expression in the tumors was assessed by use of the TS 106 monoclonal antibody and standard immunohistochemical staining techniques. TS immunostaining was classified according to its level of intensity (TS 0-1 = low, TS 2 = intermediate, and TS 3 = high) and according to its extent (focal pattern = less than 25% of tumor cells positive; diffuse pattern = greater than or equal to 25% of tumor cells positive). Data from 79 patients were available for an analysis of tumor TS expression and patient/tumor characteristics; 70 patients were assessable for their response to neoadjuvant chemotherapy. RESULTS: There was a statistically significant association between the level of tumor TS expression and the degree of tumor differentiation; a higher proportion of patients whose tumors exhibited TS 0-1 immunostaining had undifferentiated or poorly differentiated tumors than patients whose tumors exhibited TS 2 or TS 3 immunostaining (P = .04, Jonckheere-Terpstra trend test). Among the 70 patients who were assessable for response to neoadjuvant chemotherapy, TS 3 tumor immunostaining was associated with a lower rate of complete response (i.e., complete disappearance of clinically detectable disease for a minimum of 4 weeks from time of initial determination) than was TS 2 or TS 0-1 immunostaining, but this association was not statistically significant (P = .09, exact trend test); among the 39 patients who were treated with regimens that included 5-FU, leucovorin, cisplatin, and IFN alpha-2b, this inverse association between TS immunostaining intensity and response was statistically significant (P = .02, exact trend test). Tumor TS immunostaining intensity and overall survival were not found to be associated. Patients with tumors exhibiting a focal pattern of TS immunostaining have experienced significantly longer survival than patients with tumors exhibiting a diffuse pattern; for the 53 patients with diffuse tumor TS immunostaining, the median survival was 24.7 months, whereas the median survival has not yet been reached for the 22 patients with focal tumor TS immunostaining (P = .04, two-tailed logrank test). However, the survival advantage for the focal versus diffuse TS immunostaining pattern was limited to patients whose tumors also exhibited a TS 3 level of immunostaining intensity. CONCLUSIONS AND IMPLICATIONS: Characterization of tumor TS expression may be of value in identifying patients with advanced head and neck cancer who would benefit from fluoropyrimidine-based neoadjuvant chemotherapy.

Amonafide: An active agent in the treatment of previously untreated advanced breast cancer--a cancer and leukemia group B study (CALGB 8642).

Amonafide is a new imide derivative of naphthalic acid. The drug had demonstrated significant activity in preclinical studies and some activity in Phase I trials. The drug is extensively metabolized and detected in plasma and urine. Its toxicity has previously been correlated to the formation of an active metabolite, N-acetyl-amonafide. Amonafide was chosen for inclusion in the Cancer and Leukemia Group B (CALGB) master metastatic breast cancer protocol. CALGB 8642 randomizes previously untreated metastatic breast cancer patients either to one of several Phase II agents given for up to four cycles and then followed by standard cyclophosphamide-doxorubicin-5-fluorouracil, or to immediate treatment with standard cyclophosphamide-doxorubicin-5-fluorouracil. The end point of CALGB 8642 is to assess the difference in survival, toxicity, and overall response when limited exposure to Phase II agents precedes standard chemotherapy. This report deals only with amonafide as a Phase II agent. Comparisons with the cyclophosphamide-doxorubicin-5-fluorouracil arm will not be addressed. Patients had to have histologically documented measurable breast cancer and a performance status of 0-1. Patients could not have had prior chemotherapy for metastatic disease. Prior adjuvant chemotherapy was permitted. Patients could not have visceral crisis. Amonafide was given at 300 mg/m2/day i.v. for 5 days, and repeated at 21-day intervals for a maximum of four cycles. Escalation and reduction in dose was mandated dependent on hematotoxicity or lack thereof. Toxicity was primarily hematological and bimodal: 32% had grade 3 or 4 leukopenia and 24% had grade 3 or 4 thrombocytopenia; 22% had no leukopenia and 44% had no thrombocytopenia. The response rate was 18%, including one complete response. When response was analyzed by hematological toxicity, there was a 35.7% response if patients had leukopenia grade 3/4 (versus 8.3%, P = 0.08). There was a 50% response if patients had thrombocytopenia grade 3/4 (versus 7.1%, P = <0.01). We conclude that amonafide is somewhat active in previously untreated breast cancer patients. There may be a steep dose-response curve, based on the significant correlation between myelosuppression and response. Rates of responses in patients adequately dosed (i.e., with significant hematotoxicity) with amonafide ranged from 35 to 50%. Further studies will incorporate individualized dosing based on pretreatment acetylator phenotyping.

5-Fluorouracil, hydroxyurea and escalating doses of iododeoxyuridine with concomitant radiotherapy for malignant gliomas: a clinical and pharmacologic analysis.

BACKGROUND: Iododeoxyuridine (IUdR) is a known radiation enhancer, and interacts biochemically with 5-fluorouracil (5-FU) and hydroxyurea (HU). PATIENTS AND METHODS: IUdR was added to the previously studied regimen of continuous infusion 5-FU at 300 mg/m2/day for 5 days, HU 500 mg every 12 hours for 11 doses and radiotherapy 200 cGy/day for 5 days, all administered for 7 consecutive weeks to patients with malignant glioma. IUdR was administered as 5-day continuous intravenous infusion during weeks 1 and 4. The IUdR dose was changed in cohorts of patients. IUdR plasma concentrations were determined during weeks 1 and 4, and IUdR incorporation into the DNA of granulocytes was measured on weeks 2 and 5. RESULTS: Two patients treated at the initial IUdR dose of 500 mg/m2/day developed grade 3 or 4 myelosuppression and mucositis. Additional dose levels of IUdR tested were 250 mg/m2/day and 125 mg/m2/day; at the latter dose, severe or life-threatening toxicity was seen in only 3 of 8 patients treated. IUdR incorporation into DNA of granulocytes was 10.5(+/- 2.3)% at an IUdR dose of 500 mg/m2/day but decreased to 0.76(+/- 0.3)% at 125 mg/m2/day. Similarly, IUdR plasma concentrations decreased from 436 (+/- 114) ng/ml to 99 (+/- 29) ng/ml. CONCLUSIONS: The addition of IUdR to 5-FU and HU results in significant systemic toxicity necessitating limitation of the IUdR dose to 125 mg/m2/day. There is a significant biochemical interaction between IUdR, 5-FU and HU leading to increased IUdR incorporation into DNA and to substantial clinical toxicity. Further clinical studies to exploit this interaction at more feasible schedules may be useful.

Five-day infusion of fluorodeoxyuridine with high-dose oral leucovorin: a phase I study.

Fluorodeoxyuridine (FUdR) interferes with cellular metabolism by inhibiting thymidylate synthase. Therefore, we sought to modulate its activity with leucovorin (LV) and to identify the maximally tolerated dose given as a 5-day continuous intravenous infusion in combination with oral administration of LV at a dose of 100 mg every hour for four doses immediately preceding the start of the FUdR infusion and then every 4 h for the entire duration of FUdR treatment. Patients were evaluated at six FUdR dose levels ranging from 0.1 to 0.375 mg/kg per day. Severe or life-threatening mucositis was first observed in two of six patients treated at 0.25 mg/kg daily. Further escalation of the dose to 0.3 mg/kg per day resulted in grade 2 mucositis in four of six patients and in grade 3 mucositis in two cases. A dose of 0.375 mg/kg daily resulted in grade 3 toxicity in all three patients treated. Other types of toxicities included skin rash and hand-foot syndrome, but no hematologic toxicities were observed. Stable disease was observed in 11 of 24 evaluable patients, including 3 subjects with renal cell carcinoma. Our recommended dose for phase II trials is 0.3 mg/kg FUdR per day.

Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration.

The clinical formulation of leucovorin calcium (leucovorin, LV) is a mixture of stereoisomers [(6R,S)-5-formyltetrahydrofolate], which have been shown to differ significantly in plasma clearance and route of elimination after intravenous administration; the (6S) isomer is rapidly converted to 5-CH3 tetrahydrofolate (5-CH3 THF), and the (6R) isomer is slowly eliminated by renal excretion. The relative importance of (6S) LV and 5-CH3 THF in expanding reduced folate pools in tumor cells is unknown, but it is known that high concentrations of (6R) LV can support growth of folate-depleted cells and thus have the potential to interfere with the biological activity of the (6S) isomer. To examine the pharmacokinetics of the LV isomers and metabolites, we administered 1,000 mg of LV to five normal subjects as a 2-hour intravenous infusion and in divided oral 100-mg doses given over 24 hours. Plasma and urine samples were analyzed by reverse phase followed by chiral high-performance liquid chromatography. Following intravenous administration, peak plasma concentrations of (6R) LV, (6S) LV, and 5-CH3 THF were 148 +/- 32, 59.1 +/- 22, and 17.8 +/- 17 microM, respectively. During oral administration of LV, virtually no (6S) LV appeared in the plasma. Steady-state plasma concentrations of (6R) LV and 5-CH3 THF were approximately 1.5 +/- 0.23 and 2.8 +/- 0.41 microM, respectively. Intravenous administration of LV resulted in an area under the curve (AUC) for (6R) LV that was more than four times that of the biologically active (6S) folates, whereas oral administration produced an AUC for (6S) reduced folates [(6S) LV and 5-CH3 THF] that was approximately twice that of (6R) LV. After administration of high doses of LV intravenously, conversion of (6S) LV to 5-CH3 THF was saturable, as indicated by the prolonged (6S) LV half-life of 58 minutes and the slow (6S) LV clearance of 119.2 +/- 38 mL/min, compared with previously reported data for administration of low doses. This study illustrates that intravenous administration of LV produces equivalent AUCs of (6S) LV and 5-CH3 THF but a substantially higher AUC for (6R) LV. Oral administration over 24 hours results in an AUC of 5-CH3 THF equivalent to that obtained after intravenous dosing in the presence of only small amounts of (6R) LV. The optimal route of LV administration will ultimately be determined by ongoing studies of the cellular pharmacology of LV that will determine if high concentrations of (6R) LV interfere with the biological activity of the (6S) reduced folates.