Compressing drug development timelines in oncology using phase '0' trials.

The optimal evaluation of molecularly targeted anticancer agents requires the integration of pharmacodynamic assays into early clinical investigations. Phase '0' trials conducted under the new Exploratory Investigational New Drug Guidance from the US Food and Drug Administration can provide a platform to establish the feasibility of assays for target modulation in human samples, evaluate biomarkers for drug effects and provide pharmacokinetic data. Phase 0 trials could facilitate rational drug selection, identify therapeutic failures early, and might compress timelines for anticancer drug development. We expect that such trials will become a routine part of early-phase oncological drug development in the future.

Under-representation of racial minorities in prostate cancer studies submitted to the US Food and Drug Administration to support potential marketing approval, 1993-2013.

BACKGROUND: US Food and Drug Administration (FDA) approval of new drugs depends on results from clinical trials that must be generalized to the US population. However, racial minorities are frequently under-represented in clinical studies. The enrollment of racial minorities was compared in key clinical studies submitted to the FDA in the last 10 years in support of potential marketing approval for prostate cancer (PCa) prevention or treatment. METHODS: Patient demographic data were obtained from archival data sets of large registration trials submitted to the FDA to support proposed PCa indications. Six countries/regions were analyzed: the United States, Canada, Australia, Europe, the United Kingdom, and Eastern Europe. Background racial demographics were collected from national census data. RESULTS: Seventeen key PCa clinical trials were analyzed. These trials were conducted in the past 20 years, comprising 39,574 patients with known racial information. Most patients were enrolled in the United States, but there appeared to be a trend toward increased non-US enrollment over time. In all countries, racial minorities were generally under-represented. There was no significant improvement in racial minority enrollment over time. The United States enrolled the largest nonwhite population (7.1%). CONCLUSIONS: Over the past 20 years, racial minorities were consistently under-represented in key PCa trials. There is a need for effective measures that will improve enrollment of racial minorities. With increased global enrollment, drug developers should aim to recruit a patient population that resembles the racial demographics of the patient population to which drug use will be generalized upon approval.

The statistics of phase 0 trials.

The PD-driven phase 0 trial is a new form, designed to be a first-in-man study, often of a new agent, conducted to assess drug effect on a molecular target, by means of a pharmacodynamic (PD) assay, in a very small number (10-15) of patients. Such a study is meant to be a proof of principle trial to determine whether the agent yields the PD effect predicted by pre-clinical studies. The dosage is meant to be pharmacologically active, but is neither toxic nor likely to yield clinical benefit. Such a trial may be used to serve as a very early test of an agent's biologic effect, allowing for early weeding out of ineffective agents, or as an early means of determining the most promising of competing analogue agents. This manuscript will present designs for such PD-driven studies that are statistically efficient and rigorous, focusing on non-comparative trials. The phase 0 trial promises to become an increasingly important tool for facilitating and speeding the development of new therapeutic agents, particularly in oncology.

Improving the quality of abstract reporting for phase I cancer trials.

PURPOSE: Conference abstracts of phase I trials (P1T) communicate important anticancer drug development information. Our objectives were to determine elements essential for good P1T abstract reporting, to assess the quality of P1T abstracts submitted to American Society of Clinical Oncology (ASCO) meetings, and to propose reporting guidelines. EXPERIMENTAL DESIGN: A survey of developmental therapeutics experts established elements of P1T reporting quality, and a scoring system was generated. All P1T abstracts published in ASCO Annual Proceedings from 1997 to 2006 were reviewed, and the scoring system was applied. RESULTS: A survey was distributed twice to 69 experts, with a response rate of 39% (27 of 69). Experts rated 37 elements using a five-point scale, and elements with mean ratings over 3.75 were included in the final scoring system. One thousand six hundred and eighty three P1T abstracts were reviewed. A positive and linear association was observed between average expert rating of the elements and the proportion of P1T abstracts including those elements (Spearman correlation coefficient, rho = 0.60, P < 0.001). The median for all 1,683 abstracts was 62.5% (range, 25-95%; SD, 12.3%). Year of presentation was found to be significantly associated with higher quality scores (rho = 0.20, P < 0.001), with later years possessing better quality scores. The quality score was statistically significant as a predictor of type of presentation (odds ratio, 1.10; 95% confidence interval, 1.02-1.19 per 10% increase; P = 0.014), with oral presentations having the highest scores. CONCLUSIONS: The quality of P1T abstract reporting at ASCO has improved over time, although there is room for optimization. The quality of P1T abstract reporting may be enhanced using guidelines derived from our expert consensus.

Designing phase 0 cancer clinical trials.

Phase 0 trials are designed primarily to evaluate the pharmacodynamic and/or pharmacokinetic properties of selected investigational agents before initiating more traditional phase I testing. One of the major objectives of phase 0 trials is to interrogate and refine a target or biomarker assay for drug effect in human samples implementing procedures developed and validated in preclinical models. Thus, close collaboration between laboratory scientists and clinical investigators is essential to the design and conduct of phase 0 trials. Given the relatively small number of patients and tissue samples, showing a significant drug effect in phase 0 trials requires precise and reproducible assay procedures and innovative statistical methodology. Furthermore, phase 0 trials involving limited exposure of a study agent administered at low doses and/or for a short period allow them to be initiated under the Food and Drug Administration exploratory investigational new drug guidance with less preclinical toxicity data than usually required for traditional first-in-human studies. Because of the very limited drug exposure, phase 0 trials offer no chance of therapeutic benefit, which can impede patient enrollment, particularly if invasive tumor biopsies are required. The challenges to accrual are not insurmountable, however, and well-designed and executed phase 0 trials are feasible and have great potential for improving the efficiency and success of subsequent trials, particularly those evaluating molecularly targeted agents.

Treatment of recurrent metastatic colon cancer in the age of modern adjuvant therapy.

The treatment of patients with metastatic colon cancer has evolved tremendously over the past 10 years, with improved overall survival (OS) rates as a result of the advent of several important agents. Following the results of important adjuvant trials, the incorporation of oxaliplatin into the adjuvant setting has significantly increased the disease-free survival and OS rates in patients who undergo curative resection. However, still a significant number of patients will present with recurrent disease after being treated with oxaliplatin-containing chemotherapy regimens. Herein, we present approaches to the chemotherapeutic management of such patients with a review of the literature.

Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies.

PURPOSE: MS-275 is a histone deacetylase inhibitor that has shown potent and unique anticancer activity in preclinical models. The aims of this phase I trial were to determine the dose-limiting toxicities and maximum tolerated dose of oral MS-275 in humans administered with food on a once weekly schedule and to study the pharmacokinetics of oral MS-275. EXPERIMENTAL DESIGN: Patients with refractory solid tumors and lymphoid malignancies were treated with oral MS-275 on a once weekly schedule for 4 weeks of a 6-week cycle. Samples for pharmacokinetic and pharmacodynamic analyses were collected during cycle 1. Protein acetylation in subpopulations of peripheral blood mononuclear cells was measured using a multivariable flow cytometry assay. RESULTS: A total of 22 patients were enrolled, and 19 were considered evaluable for toxicity. The maximum tolerated dose was 6 mg/m(2). No National Cancer Institute Common Toxicity Criteria grade 4 toxicities were observed. Dose-limiting grade 3 toxicities were reversible and consisted of hypophosphatemia, hyponatremia, and hypoalbuminemia. Non-dose-limiting grade 3 myelosuppression was also observed. The mean terminal half-life of MS-275 was 33.9 +/- 26.2 and the T(max) ranged from 0.5 to 24 h. Although there was considerable interpatient variability in pharmacokinetics, the area under the plasma concentration versus time curve increased linearly with dose. CONCLUSIONS: MS-275 is well tolerated at a dose of 6 mg/m(2) administered weekly with food for 4 weeks every 6 weeks. Drug exposure increases linearly with dose, and protein acetylation increased in all the subpopulations of peripheral blood mononuclear cells following MS-275 administration.

Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura.

PURPOSE: The DNA methylation paradox, manifested as derepression of cancer-testis antigens, and silencing of tumor suppressors during malignant transformation, provides the rationale for the utilization of chromatin remodeling agents for cancer therapy. A phase I trial was done to examine pharmacokinetics, toxicities, and gene expression mediated by 5-aza-2'-deoxycytidine (DAC) in patients with thoracic malignancies. EXPERIMENTAL DESIGN: Thirty-five patients with cancers refractory to standard therapy received continuous 72-hour DAC infusions using a phase I dose-escalation schema. Each full course of therapy consisted of two identical 35-day cycles. Plasma DAC levels were evaluated by liquid chromatography-mass spectrometry techniques. Quantitative reverse transcription-PCR, methylation-specific PCR, and immunohistochemical techniques were used to evaluate NY-ESO-1, MAGE-3, and p16 expression in tumor biopsies. Long oligonucleotide arrays were used to evaluate gene expression profiles in laser-captured tumor cells before and after DAC exposure. RESULTS: Thirty-five patients were evaluable for toxicities; 25 were evaluable for treatment response. Myelosuppression constituted dose-limiting toxicity. The maximum tolerated dose of DAC was 60 to 75 mg/m(2) depending on the number of prior cytotoxic chemotherapy regimens. No objective responses were observed. Plasma DAC concentrations approximated thresholds for gene induction in cultured cancer cells. Target gene induction was observed in 36% of patients. Posttreatment antibodies to NY-ESO-1 were detected in three patients exhibiting NY-ESO-1 induction in their tumor tissues. Complex, heterogeneous gene expression profiles were observed in pretreatment and posttreatment tissues. CONCLUSION: Prolonged DAC infusions can modulate gene expression in primary thoracic malignancies. These findings support further evaluation of DNA-demethylating agents alone or in combination with other regimens targeting induced gene products for the treatment of these neoplasms.

Phase I study of bryostatin 1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (non-Hodgkin's) lymphoma.

PURPOSE: Preclinical studies suggested that bryostatin 1 might potentiate the therapeutic effects of fludarabine in the treatment of hematologic malignancies. We undertook a phase I study to identify appropriate schedules and doses of bryostatin 1 and fludarabine to be used in phase II studies. EXPERIMENTAL DESIGN: Patients with chronic lymphocytic leukemia (CLL) or indolent lymphoma received fludarabine daily for 5 days and a single dose of bryostatin 1 via a 24-hour continuous infusion either before or after the fludarabine course. Doses were escalated in successive patients until recommended phase II doses for each sequence were identified on the basis of dose-limiting toxic events. RESULTS: Bryostatin 1 can be administered safely and tolerably with full dose fludarabine (25 mg/m(2)/d x 5). The recommended bryostatin 1 phase II dose is 50 microg/m(2) for both sequences, bryostatin 1 --> fludarabine and fludarabine --> bryostatin 1. The combination is active against both CLL and indolent lymphomas with responses seen in patients who had been previously treated with fludarabine. Correlative studies do not support the hypothesis that bryostatin 1 potentiates fludarabine activity through down-regulation of protein kinase C in target cells. CONCLUSIONS: Bryostatin 1 can be administered with full dose fludarabine, and the combination is moderately active in patients with persistent disease following prior treatment. In view of the activity of monoclonal antibodies such as the anti-CD20 monoclonal antibody rituximab in the treatment of CLL and indolent lymphomas, the concept of combining bryostatin 1 and fludarabine with rituximab warrants future consideration.

Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08.

PURPOSE: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib. EXPERIMENTAL DESIGN: Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response. RESULTS: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by approximately 68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages. CONCLUSIONS: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.

Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms.

PURPOSE: To define the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol administered as a daily 1-hour infusion every 3 weeks. PATIENTS AND METHODS: Fifty-five patients with advanced neoplasms were treated with flavopiridol at doses of 12, 17, 24, 30, 37.5, and 52.5 mg/m(2)/d for 5 days; doses of 50 and 62.5 mg/m(2)/d for 3 days; and doses of 62.5 and 78 mg/m(2)/d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of flavopiridol with these schedules. RESULTS: Dose-limiting neutropenia developed at doses >/= 52.5 mg/m(2)/d. Nonhematologic toxicities included nausea, vomiting, diarrhea, hypotension, and a proinflammatory syndrome characterized by anorexia, fatigue, fever, and tumor pain. The median peak concentrations of flavopiridol achieved at the MTDs on the 5-day, 3-day, and 1-day schedule were 1.7 micro mol/L (range, 1.3 to 4.2 micro mol/L), 3.2 micro mol/L (range, 1.7 to 4.8 micro mol/L), and 3.9 micro mol/L (1.8 to 5.1 micro mol/L), respectively. Twelve patients had stable disease for >/= 3 months, with a median duration of 6 months (range, 3 to 11 months). CONCLUSION: The recommended phase II doses of flavopiridol as a 1-hour infusion are 37.5 mg/m(2)/d for 5 days, 50 mg/m(2)/d for 3 days, and 62.5 mg/m(2)/d for 1 day. Flavopiridol as a daily 1-hour infusion can be safely administered and can achieve concentrations in the micromolar range, sufficient to inhibit cyclin-dependent kinases in preclinical models. Further studies to determine the optimal schedule of flavopiridol as a single agent and in combination with chemotherapeutic agents are underway.

Innovative approaches to the clinical development of DNA methylation inhibitors as epigenetic remodeling drugs.

The most extensively studied inhibitors of DNA methylation are the cytidine analogs 5-azacytidine (5-aza-CR; azacitidine) and 5-aza-2'- deoxycytidine (5-aza-CdR; decitabine). Despite decades of nonclinical and clinical research, there remains considerable interest in finding innovative and better ways to use these DNA methyltransferase (DNMT) inhibitors. A mounting body of data supports the role of methylation in silencing genes involved in tumor growth and resistance. This information has fueled further nonclinical and clinical research on ways to use inhibitors of methylation to restore normal gene expression and function. As such, recent clinical strategies have shifted from simply evaluating cytotoxic effects to exploring and optimizing the ability of these agents to restore or reactivate gene expression and putative targets. This article considers innovative approaches to develop and evaluate inhibitors of DNA methylation as epigenetic remodeling agents for the treatment of cancer. These include optimization of dose and schedule, restoration or enhancement of sensitivity to other treatment modalities, and combinations with other agents including histone deacetylase inhibitors.

Effects of alpha1-acid glycoprotein on the clinical pharmacokinetics of 7-hydroxystaurosporine.

OBJECTIVE: UCN-01 (7-hydroxystaurosporine) is a small molecule cyclin-dependent kinase modulator currently under clinical development as an anticancer agent. In vitro studies have demonstrated that UCN-01 is strongly bound to the acute-phase reactant alpha (1)-acid glycoprotein (AAG). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of UCN-01 in patients. EXPERIMENTAL DESIGN: Pharmacokinetic data were obtained from a group of 41 patients with cancer receiving UCN-01 as a 72-hour i.v. infusion (dose, 3.6 to 53 mg/m(2)/day). RESULTS: Over the tested dose range, total drug clearance was distinctly nonlinear (P = 0.0076) and increased exponentially from 4.33 mL/hour (at 3.6 mg/m(2)/day) to 24.1 mL/hour (at 54 mg/m(2)/day). As individual values for AAG increased, values for clearance decreased in a linear fashion (R(2) = 0.264; P = 0.0008), although the relationship was shallow, and the data showed considerable scatter. Interestingly, no nonlinearity in the unbound concentration (P = 0.083) or fraction at the peak plasma concentration of UCN-01 was apparent (P = 0.744). CONCLUSION: The results suggest the following: (1) that extensive binding to AAG may explain, in part, the unique pharmacokinetic profile of UCN-01 described previously with a small volume of distribution and slow systemic clearance, and (2) that measurement of total UCN-01 concentrations in plasma is a poor surrogate for that of the pharmacologically active fraction unbound drug.

Phase I study of low-dose suramin as a chemosensitizer in patients with advanced non-small cell lung cancer.

PURPOSE: Our preclinical studies have shown that acidic and basic fibroblastic growth factors confer broad spectrum chemoresistance and that low concentrations (10-50 microM) of suramin, a nonspecific fibroblastic growth factor inhibitor, enhance the antitumor activity of paclitaxel in vivo. The present Phase I study evaluated low-dose suramin in combination with paclitaxel/carboplatin in advanced non-small cell lung cancer patients. EXPERIMENTAL DESIGN: Patients received suramin followed by paclitaxel (175-200 mg/m(2)) and carboplatin area under the concentration-time curve of 6 mg/ml/min, every 3 weeks. The initial suramin dose for the first cycle was 240 mg/m(2), and the doses for subsequent cycles were calculated based on the 72-h pretreatment plasma concentrations. The recommended suramin dose would yield plasma concentrations of 10-20 microM at 48 h in >or=5 of 6 patients. RESULTS: Fifteen patients (11 stage IV, 4 stage IIIB, 9 chemonaive, and 6 previously treated) received 85 courses. The most common toxicities were neutropenia, nausea/vomiting, malaise/fatigue, and peripheral neuropathy. No treatment-related hospitalizations, adrenal dysfunction, or episodes of sepsis occurred. The initial suramin dose resulted in the targeted concentrations of 10-20 microM at 48 h in 5 of the first 6 patients treated but also resulted in peak concentrations > 50 microM in all patients. Dividing the suramin dose to be administered in two doses, 24 h apart, yielded the target concentrations and avoided undesirable peak concentrations. Discernable antitumor activity occurred in 7 of 10 patients with measurable disease, including 2 with prior chemotherapy. The median time to tumor progression is 8.5 months (range, 3-27+ months) for 12 evaluable patients. CONCLUSIONS: Low-dose suramin does not increase the toxicity of paclitaxel/carboplatin combination. The suramin dose can be calculated based on clinical parameters. Because of the preliminary antitumor activity observed, efficacy studies in chemonaive and chemorefractory patients are under way.

Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B-cell malignancies.

PURPOSE: Bryostatin 1 activates protein kinase C (PKC) with short-term exposure and results in depletion of PKC with prolonged exposure. Preclinical in vitro and in vivo studies demonstrate synergistic activity and increased tumor apoptosis in B-cell malignancies when a prolonged infusion of bryostatin 1 is followed by vincristine. EXPERIMENTAL DESIGN: We embarked on a Phase I trial of bryostatin 1 as a 24-h continuous infusion followed by bolus vincristine in patients with refractory B-cell malignancies other than acute leukemias. Twenty-four evaluable patients were enrolled. RESULTS: The dose-limiting toxicity was myalgia. The MTD and recommended Phase II dose of bryostatin 1 was 50 microg/m2/24 h followed by vincristine 1.4 mg/m2 (maximum total dose of 2 mg) repeated every 2 weeks. Significant antitumor activity was observed in this relapsed population, including patients who had failed high-dose chemotherapy. This included 5 durable complete and partial responses and 5 patients with stable disease lasting > or =6 months (range, 6-48+ months). Median time to response was 8 months. Correlative studies demonstrated a progressive increase in serum interleukin-6 with bryostatin 1 infusion followed by an additional increase after vincristine. Flow cytometry for detection of apoptosis in B and T cells showed an initial decrease in apoptotic frequency in CD5+ cells within 6 h of bryostatin 1 infusion compatible with its known increase in PKC activity in the majority of patients followed by a return to baseline or overall increase in apoptotic frequency after completion of infusion. All (5 of 5) patients who had an overall increase in apoptotic frequency in CD5+ cells achieved either a clinical response or prolonged stable disease. Four of these 5 patients did not have the initial decrement in apoptosis at 6 h. CONCLUSIONS: Given the lack of myelosuppression and early evidence of clinical efficacy, additional exploration of this regimen in non-Hodgkin's lymphoma and multiple myeloma is warranted.

A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms.

PURPOSE: To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations. METHODS: Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1-2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels. Daily perifosine "maintenance" doses of 50, 100, 150, 200 and 250 mg for levels 1 through 5, respectively, commenced on days 2 or 3 and continued for a total of 21 days. No treatment was given for days 22-27. The pharmacokinetics of perifosine with these schedules was characterized. RESULTS: Dose-limiting diarrhea developed at or above dose level 4. The MTD and recommended phase II dose was dose level 3B, with a loading dose of 900 mg on day 1 divided into two doses of 450 mg administered 6 h apart and a maintenance dose of 150 mg on day 2 through 21. On subsequent cycles, the loading dose was reduced to 300 mg. Non-gastrointestinal toxicities included three episodes of gout or gout-like syndromes observed at doses above the MTD. The median peak plasma concentration of perifosine achieved at the MTD was approximately 8.3 µg/mL. Four patients had stable disease ranging from 167 to 735 days. CONCLUSIONS: Perifosine given according to a loading and maintenance schedule can safely sustain concentrations of drug, approaching concentrations achieved in preclinical models with evidence of anti-tumor effect.

Assessment of audit methodologies for bias evaluation of tumor progression in oncology clinical trials.

As progression-free survival (PFS) has become increasingly used as the primary endpoint in oncology phase III trials, the U.S. Food and Drug Administration (FDA) has generally required a complete-case blinded independent central review (BICR) of PFS to assess and reduce potential bias in the investigator or local site evaluation. However, recent publications and FDA analyses have shown a high correlation between local site evaluation and BICR assessments of the PFS treatment effect, which questions whether complete-case BICR is necessary. One potential alternative is to use BICR as an audit tool to detect evaluation bias in the local site evaluation. In this article, the performance characteristics of two audit methods proposed in the literature are evaluated on 26 prospective, randomized phase III registration trials in nonhematologic malignancies. The results support that a BICR audit to assess potential bias in the local site evaluation is a feasible approach. However, implementation and logistical challenges need further consideration and discussion.

Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas.

PURPOSE: Batracylin (daniquidone), an ATP-insensitive topoisomerase I/II inhibitor, demonstrated wide interspecies variation in preclinical models consistent with formation of a toxic metabolite, N-acetyl-batracylin, following metabolism by N-acetyl-transferase 2 (NAT2). To minimize exposure to this toxic metabolite, this first-in-human study was conducted in patients with advanced refractory solid tumors or lymphomas demonstrated to have a slow NAT2 acetylator genotype. The objectives were to determine the safety, maximum tolerated dose (MTD), and pharmacokinetics of batracylin and its metabolites. METHODS: Based on the MTD for rats, the most sensitive species, the starting dose was 5 mg/day for 7 days in 28-day cycles. Dose escalation followed accelerated titration design 4B, with restaging performed every 2 cycles. RESULTS: Thirty-one patients were enrolled. Treatment was well tolerated; one patient experienced grade 3 toxicity (lymphopenia). Dose escalation was stopped at 400 mg/day due to grade 1 and 2 hemorrhagic cystitis. No objective responses were observed, but prolonged disease stabilization was observed in 2 patients, one with peritoneal mesothelioma (8 cycles) and another with adrenocortical cancer (18 cycles). Across an 80-fold range of doses, the ratios of systemic exposures for batracylin and N-acetyl batracylin were near 1. CONCLUSIONS: Pharmacogenetically selected patients reached a dose that was 20-fold higher than the MTD in rats and 70 % of the MTD in mice. This genotype-guided strategy was successful in safely delivering batracylin to patients. However, due to unexpected cystitis, not preventable by hydration, and in the absence of a stronger signal for antitumor activity, further development of batracylin has been stopped.

Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors.

BACKGROUND: The triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic Acid (CDDO, previously RTA 401) is a multifunctional molecule that controls cellular growth and differentiation. While CDDO is capable of activating the transcription factor peroxisome proliferator activator receptor-γ (PPARγ), its apoptotic effects in malignant cells have been shown to occur independently of PPARγ. A phase I dose-escalation study was conducted to determine the toxicity, the maximum tolerated dose, and the pharmacokinetics and pharmacodynamics of CDDO, administered as a 5-day continuous infusion every 28 days in patients with advanced cancers. METHODS: An accelerated titration design was followed, with one patient per cohort entered, and doses ranging from 0.6 to 38.4 mg/m(2)/h. Pharmacokinetics of CDDO was assessed and cleaved poly (ADP-ribose) polymerase (c-PARP), as a marker of apoptosis, was measured in peripheral blood mononuclear cells to assess drug effect. RESULTS: Seven patients, one patient per dose level up to dose level 7 (38.4 mg/m(2)/h), were enrolled and received a total of 11 courses of treatment. Cmax increased proportionally with dose. Preclinically determined efficacious blood level (1 µM) of drug was attained at the highest dose level. One patient, at dose level 6, experienced grade 2 mucositis, nausea, vomiting, and anorexia. Four patients developed thromboembolic events subsequently considered as dose-limiting toxicity. No antitumor activity was noted. CONCLUSION: A causal relationship of observed thromboembolic events to CDDO was considered possible but could not be established.

Phase I trial of fenretinide lym-x-sorb oral powder in adults with solid tumors and lymphomas.

BACKGROUND: The synthetic retinoid fenretinide (N-(4-hydroxyphenyl)retinamide, 4-HPR) has shown promising anticancer activity in preclinical studies, but its limited oral bioavailability has hindered clinical assessment. A novel lipid matrix, Lym-X-Sorb (LXS), was evaluated to improve fenretinide bioavailability and attain higher plasma concentrations. PATIENTS AND METHODS: Adults with refractory malignancies were administered fenretinide/LXS oral powder in 2 divided doses over 24 h for 7 consecutive days every 21 days in a standard phase I dose-escalation study with pharmacokinetic analysis. RESULTS: The principal toxicities observed were diarrhea, reversible night blindness, and allergic reaction. The maximum tolerated dose regimens were 1,000 mg/m(2)/day divided into 2 daily doses for 7 days, every 21 days, and 800 mg/m(2)/day divided into 3 daily doses for 7 consecutive days, every 21 days. CONCLUSION: Better fenretinide formulations are needed to improve adult patient acceptability and compliance and to achieve the consistent systemic exposures associated with activity in preclinical models.