Purpose: We studied the safety, clinical activity, and pharmacokinetics (PK) of AG-013736, an oral receptor tyrosine kinase inhibitor of vascular endothelial cell growth factor, platelet-derived growth factor, and c-Kit, in patients with advanced cancer. Patients and Methods: Patients received fixed doses of AG-013736 orally in 28-day cycles. In the first cohort, patients initially received two single test doses of AG-013736 (10 and 30 mg); subsequent dosing was determined by individual PK parameters. Doses in subsequent cohorts were assigned by using a traditional dose-escalation/de-escalation rule based on observed toxicities in the current and previous cohorts. PK analysis included evaluation of the effect of food and antacid. Results: Thirty-six patients received AG-013736 at doses ranging from 5 to 30 mg by mouth twice daily. The dose-limiting toxicities observed included hypertension, hemoptysis, and stomatitis and were seen primarily at the higher dose levels. The observed hypertension was manageable with medication. Stomatitis was generally tolerable and managed by dose reduction or drug holidays. AG-013736 was absorbed rapidly, with peak plasma concentrations observed within 2 to 6 hours after dosing. The maximum-tolerated dose and recommended phase II dose of AG-013736 is 5 mg, twice daily, administered in the fasted state. No significant drug interaction with antacid was seen. There were three confirmed partial responses and other evidence of clinical activity. Conclusion: In this study, we have demonstrated clinical activity and safety of AG-013736 in patients with advanced solid tumors and identified the dose for phase II testing. The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent.

Purpose: AT-101 binds and inhibits the antiapoptotic function of Bcl-2, Bcl-xL, Mcl-1, and Bcl-w and is a potent stimulator of proapoptotic proteins. In this multi-institution phase I/II trial, we evaluated the safety and efficacy of single-agent AT-101, in men with chemotherapy naïve, castrate-resistant prostate cancer (CRPC). Experimental Design: Patients with progressive CRPC were to be treated with escalating doses of AT-101 on a continuous daily basis until the maximally tolerated dose was achieved. At the recommended phase 2 dose, an additional 21 patients were planned to assess for preliminary evidence of efficacy. Results: Twenty-three patients were enrolled. The phase I starting dose was 30 mg/day on a continuous basis; however, ongoing trials with AT-101 showed increased gastrointestinal toxicity with this daily schedule when given for repetitive cycles. As a result, the phase II starting dose was chosen to be 30 mg/day for 21 of 28 days. The most frequent observed adverse events (any grade) were diarrhea (43.5%), fatigue (34.8%), nausea (21.7%), anorexia (21.7%), and small intestinal obstruction (21.7%). Due to the high incidence of grade 3 small intestinal obstruction (n = 5; 21.7%), a reduction in dose to 20 mg/day for 21 of 28 days was mandated for all patients. Two patients had a confirmed ≥50% posttherapy prostate-specific antigen decline. No objective responses (Response Evaluation Criteria in Solid Tumors) were observed. Conclusion: AT-101 administered at 20 mg/day for 21 of 28 days was well-tolerated. Evidence of single-agent clinical activity was observed with prostate-specific antigen declines in some patients. Further investigation of AT-101 in prostate cancer is warranted and trials combining AT-101 with androgen deprivation, as well as with docetaxel chemotherapy are ongoing.

Purpose: 2-Methoxyestradiol (2ME2; Panzem) is an endogenous, estradiol-17β metabolite that at pharmacologic doses exerts antimitotic and antiangiogenic activities. Studies with a 2ME2 capsule formulation showed limited oral bioavailability. We report the results of a phase I study using a NanoCrystal Dispersion formulation of 2ME2 (2ME2 NCD). Experimental Design: Patients with refractory solid tumors received 2ME2 NCD orally. Patients received drug either every 6 hours (part A) or every 8 hours (part B). Doses were escalated in successive cohorts until the maximum tolerated dose (MTD) was identified. The primary objective was identifying the MTD. Secondary objectives were to evaluate the plasma pharmacokinetics of 2ME2 and efficacy. Results: In part A, 16 patients received a median of 4 cycles of 2ME2 NCD. Dose-limiting toxicities (DLT) included fatigue (2), hypophosphatemia (2), increased alanine aminotransferase (1), and muscle weakness (1). Trough levels at steady-state reached the minimum effective concentration in all cohorts. The MTD was determined to be 1,000 mg orally every 6 hours. In part B, 10 patients received a median of 1 cycle. DLTs included elevated γ-glutamyltransferase (1), hyponatremia (1), fatigue (1), and anorexia (1). An MTD could not be defined for part B because 4 of 10 patients had DLTs at the initial dose level and dose reduction was not pursued. Thirteen patients had stable disease (A, 11; B, 2); there were no confirmed responses. Conclusion: For 2ME2 NCD, the MTD and recommended phase II regimen is 1,000 mg orally every 6 hours. Treatment was generally well-tolerated.

Purpose: To characterize proliferative changes in tumors during the sunitinib malate exposure/withdrawal using 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging. Patients and Methods: Patients with advanced solid malignancies and no prior anti-VEGF exposure were enrolled. All patients had metastatic lesions amenable to FLT PET/CT imaging. Sunitinib was initiated at the standard dose of 50 mg p.o. daily either on a 4/2 or 2/1 schedule. FLT PET/CT scans were obtained at baseline, during sunitinib exposure, and after sunitinib withdrawal within cycle #1 of therapy. VEGF levels and sunitinib pharmacokinetic (PK) data were assessed at the same time points. Results: Sixteen patients (8 patients on 4/2 schedule and 8 patients on 2/1 schedule) completed all three planned FLT PET/CT scans and were evaluable for pharmacodynamic imaging evaluation. During sunitinib withdrawal (change from scans 2 to 3), median FLT PET standardized uptake value (SUV_mean) increased +15% (range: −14% to 277%; P = 0.047) for the 4/2 schedule and +19% (range: −5.3% to 200%; P = 0.047) for the 2/1 schedule. Sunitinib PK and VEGF ligand levels increased during sunitinib exposure and returned toward baseline during the treatment withdrawal. Conclusions: The increase of cellular proliferation during sunitinib withdrawal in patients with renal cell carcinoma and other solid malignancies is consistent with a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI) withdrawal flare. Univariate and multivariate analysis suggest that plasma VEGF is associated with this flare, with an exploratory analysis implying that patients who experience less clinical benefit have a larger withdrawal flare. This might suggest that patients with a robust compensatory response to VEGFR TKI therapy experience early “angiogenic escape.” Clin Cancer Res; 17(24); 7634–44. ©2011 AACR.

Purpose: Docetaxel is standard of care for androgen-independent prostate cancer (AIPC). Doxercalciferol (1α-hydroxyvitamin D2) had modest activity in phase I/II trials. Preclinical data support combining vitamin D analogues with docetaxel to treat AIPC. Experimental Design: Chemotherapy-naive men with metastatic AIPC were randomized 1:1 to receive, on a 4-week cycle, docetaxel (35 mg/m² i.v., days 1, 8, and 15) with or without doxercalciferol (10 μg orally, days 1-28). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were progression-free survival, overall survival, objective response, and toxicity. Survival was analyzed as intent to treat. Results: Seventy patients were randomized. Median follow-up was 17.6 months (range, 3.3-45.2). PSA response rate was 46.7% [95% confidence interval (95% CI), 30-64] in the doxercalciferol arm and 39.4% (95% CI, 25-56) with placebo (P = 0.560). Median progression-free survival in the doxercalciferol arm was 6.17 months (95% CI, 4.20-10.7) versus 6.20 months (95% CI, 4.83-9.07) with placebo (P = 0.764). Median overall survival in the doxercalciferol arm was 17.8 months (95% CI, 14.9-23.6) versus 16.4 months (95% CI, 11.9-23.8) with placebo (P = 0.383). Twenty-four patients in the doxercalciferol arm and 23 in the placebo arm were evaluable for objective response. No complete responses were observed. Partial objective response rate was 12.5% with doxercalciferol versus 8.7% with placebo (P = 0.672). Rate of grade ≥3 toxicity was 46% with doxercalciferol versus 42% with placebo (P = 0.785). Conclusions: Daily doxercalciferol with weekly docetaxel did not enhance PSA response rate or survival. Toxicity was similar between arms. Despite the disappointing results of this study, other vitamin D analogues remain under active investigation.

PURPOSE: The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods: We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS: PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION: PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.