To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib ...pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa).
Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m(2)/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m(2)).
A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m(2) (diarrhea, hypotension) occurring at an average 1-hour post-dose of >/= 75% 20S PI. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at >/= 50% 20S PI. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes.
The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.
To study the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate in androgen-independent prostate cancer (AIPC), alone and in combination with docetaxel, we designed a modular ...phase I trial. Our goals were to (1) evaluate the toxicity and maximum-tolerated dose of docetaxel with imatinib, and (2) evaluate the decline of prostate-specific antigen (PSA) induced by imatinib alone, and imatinib and docetaxel.
Twenty-eight men with AIPC and bone metastases were enrolled to receive imatinib 600 mg daily lead-in for 30 days, then imatinib 600 mg daily and one of six possible doses of docetaxel weekly for 4 weeks every 6 weeks.
During the imatinib lead-in module, one dose-limiting toxicity (DLT) event was observed, while two (7%) of 28 had PSA decline (both < 50%). With imatinib and docetaxel, cycle 1 DLT was found in three of 12 patients at docetaxel 30 mg/m(2), in three of four patients at docetaxel 45 mg/m(2), and in five of six patients at docetaxel 35 mg/m(2). DLTs (n = 40 total events) were principally fatigue (35%) and nausea (20%). Eight (38%) of 21 had PSA decline greater than 50%, and six (29%) of 21 had PSA decline less than 50%. Serial PSA declines beyond 18 months were observed. PDGFR-expressing tumor declined on serial bone marrow biopsies with combination therapy alone.
With imatinib 600 mg daily, the maximum-tolerated dose of docetaxel was determined to be 30 mg/m(2) weekly for 4 weeks every 6 weeks. Long-term responses were observed. The role of imatinib in modulating outcomes to docetaxel in AIPC is being tested in a randomized phase II trial.
Our
10-year translational study of the oral premalignant lesion (OPL) model
has advanced the basic understanding of carcinogenesis. Although
retinoids have established activity in this model, a ...substantial
percentage of our OPL patients progress to cancer, especially after
treatment is stopped. On the basis of our 10-year OPL study, we have
developed the first comprehensive tool for assessing cancer risk of OPL
patients. This cancer risk assessment tool incorporates
medical/demographic variables, epidemiological factors, and cellular
and molecular biomarkers.
Between 1988 and 1991, 70 advanced OPL patients were enrolled in a
chemoprevention trial of induction with high dose isotretinoin (1.5
mg/kg/day for 3 months) followed by 9 months of maintenance treatment
with either low dose isotretinoin (0.5 mg/kg/day) or β-carotene (30
mg/d; total treatment duration, 1 year). We assessed the relationship
between cancer risk factors and time to cancer development by means of
exploratory data analysis, logrank test, Cox proportional hazard model,
and recursive partitioning.
With a median follow-up of 7 years, 22 of our 70 patients (31.4%)
developed cancers in the upper aerodigestive tract following treatment.
The overall cancer incidence was 5.7% per year. The most predictive
factors of cancer risk are OPL histology, cancer history, and three of
the five biomarkers we assessed (chromosomal polysomy, p53 protein
expression, and loss of heterozygosity at chromosome 3p or 9p). In the
multivariable Cox model, histology ( P = 0.0003) and
the combined biomarker score of chromosomal polysomy, p53, and loss of
heterozygosity ( P = 0.0008) are the strongest
predictors for cancer development. Retinoic acid receptor β and
micronuclei were not associated with increased cancer risk.
We have demonstrated a successful strategy of comprehensive cancer risk
assessment in OPL patients. Combining conventional medical/demographic
variables and a panel of three biomarkers can identify high risk
patients in our sample. This result will need to be validated by future
studies. With the identification of high risk individuals, more
efficient chemoprevention trials and molecular targeting studies can be
designed.
Fluoropyrimidines are known to have modest activity in the treatment of metastatic renal cell carcinoma (RCC). Capecitabine is an orally administered prodrug that is converted to fluorouracil and is ...of potential use in the treatment of this disease. We conducted a Phase II clinical trial of capecitabine administered as a single agent to patients with metastatic RCC. The treatment consisted of 1250 mg/m
2 capecitabine orally, twice daily (2500 mg/m
2 per day) days 1–14, repeated every 21 days. There were 15 patients, including 13 men and 2 women, who underwent a total of 67 cycles (median 3.5; range 1–15). Nine patients had undergone prior systemic therapy consisting of interferon-α in 3, interleukin-2 in 1, interferon-α plus interleukin-2 in 4, and investigational therapy with bryostatin-1 in 1. There were 14 patients assessable for response (one withdrew), and no responses were seen. Median time to progression was 9 weeks (range 1–45). There were 3 patients (21%) who had stable disease for 18, 39, and 45 weeks. Hematologic toxicity was mild. Three patients had grade 3 or 4 gastrointestinal toxicity, and 3 required dose reductions. There were 2 early deaths, including 1 patient with pulmonary edema and 1 with hypotension. The study was terminated because there were no responses in the first 14 assessable patients, indicating that the response rate was likely to be less than 20%. We conclude that single-agent capecitabine has minimal activity for the treatment of metastatic RCC.
Irofulven (6-Hydroxymethylacylfulvene, MGI-114) is the first of a new class of anticancer compounds the acylfulvenes which are derived from the natural product, illudin S. Irofulven is a potent ...anticancer agent with activity against a broad range of human tumors in vitro and in vivo. Irofulven covalently binds to DNA, inhibits DNA synthesis and induces apoptosis. Clinical activity has been observed in phase I studies. Because disease stabilizations were observed in kidney cancer patients in the phase I trials, we performed a phase II trial of irofulven in this patient population. Twenty patients were accrued. Irofulven (11 milligrams per meter squared per day) was administered as a 5 minute intravenous infusion for 5 consecutive days, and response was evaluated every 8 weeks. There were no objective responses. The most common toxicities were nausea, emesis, and thrombocytopenia. Irofulven, at the dose and schedule administered in this trial, showed no effect in metastatic renal cell cancer.
Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for PC, ...many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9 × 10−7 and GAB2, p = 2.0 × 10−6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio HR = 1.13; 95% confidence interval CI = 0.94–1.36); whereas decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04–1.50). These results suggest that germline genetics may help inform and individualize the decision of AS—or the intensity of monitoring on AS—versus treatment for the initial management of patients with low-risk PC.
Genetic factors may distinguish who should receive active surveillance (AS) versus treatment following prostate cancer diagnosis. We undertook the first study to investigate this and report novel variants, genes, and risk scores associated with AS outcomes. These findings could help inform and individualize the decision of AS.
Background: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) ...patients. Methods: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91–0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. Results: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval CI = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T2 versus T1 = 1.77 95% CI = 1.35 to 2.31) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 95% CI = 1.00 to 9.71). Mortality was affected by tumor stage (HR for T2 versus T1 = 1.39 95% CI = 1.10 to 1.77), histology (HR for squamous versus nonsquamous = 1.31 95% CI = 1.03 to 1.68), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 95% CI = 1.11 to 17.29). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. Conclusions: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.
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