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Purpose: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts., Methods: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208)., Results: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients., Conclusion: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.

Purpose: Children with low-grade glioma often require long-term therapy and suffer from treatment morbidity. Although targeted agents are promising, tumor targets often encompass normal developmental pathways and long-term effects of inhibition are unknown. Lenalidomide is an immunomodulatory agent with wide-ranging properties. Phase I studies indicated greater tolerability of lenalidomide in children compared with adults and a potential dose-response effect., Patients and Methods: We performed a phase II trial of lenalidomide in children with pilocytic astrocytomas and optic pathway gliomas who failed initial therapy. Primary objectives included determination of objective response rate of children randomly assigned to regimen A, low-dose (20 mg/m 2 /dose), or regimen B, high-dose (115 mg/m 2 /dose) lenalidomide, and assessment for early progression. Secondary objectives included estimation of event-free survival, overall survival, incidence of toxic events, and assessment of plasma lenalidomide concentrations. Lenalidomide was administered once daily × 21 days of each 28-day cycle for each regimen., Results: Seventy-four eligible patients were enrolled (n = 37, each arm). The predefined activity level of interest was achieved for both arms. Four objective responses were observed in each arm, and the number of early progressors was low. Eighteen patients completed 26 cycles of therapy (regimen A, n = 12; regimen B, n = 6). The median number of cycles was 14 (range, 2-26) for regimen A and 11 for regimen B (range, 1-26). Of 74 eligible patients who received study drug, 30 required dose reduction for toxicity (regimen A, n = 6; regimen B, n = 24) and 16 discontinued because of toxicity (regimen A, n = 2; regimen B, n = 14)., Conclusion: Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration. Low-dose (20 mg/m 2 /dose administered once daily × 21 days of each 28-day cycle) lenalidomide appears to have better tolerability with comparable activity.

Purpose: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances., Patients and Methods: Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS)., Results: Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC., Conclusion: CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.

Purpose Abiraterone acetate (AA) is a standard of care for metastatic castration-resistant prostate cancer (CRPC). Despite a large food effect, AA was administered under fasting conditions in its pivotal trials. We sought to test the hypothesis that low-dose AA (LOW; 250 mg with a low-fat meal) would have comparable activity to standard AA (STD; 1,000 mg fasting) in patients with CRPC. Patients and Methods Patients (n = 72) with progressive CRPC from seven institutions in the United States and Singapore were randomly assigned to STD or LOW. Both arms received prednisone 5 mg twice daily. Prostate-specific antigen (PSA) was assessed monthly, and testosterone/dehydroepiandrosterone sulfate were assessed every 12 weeks with disease burden radiographic assessments. Plasma was collected for drug concentrations. Log change in PSA, as a pharmacodynamic biomarker for efficacy, was the primary end point, using a noninferiority design. Progression-free survival (PFS), PSA response (≥ 50% reduction), change in androgen levels, and pharmacokinetics were secondary end points. Results Thirty-six patients were accrued to both arms. At 12 weeks, there was a greater effect on PSA in the LOW arm (mean log change, -1.59) compared with STD (-1.19), and noninferiority of LOW was established according to predefined criteria. The PSA response rate was 58% in LOW and 50% in STD, and the median PFS was approximately 9 months in both groups. Androgen levels decreased similarly in both arms. Although there was no difference in PSA response or PFS, abiraterone concentrations were higher in STD. Conclusion Low-dose AA (with low-fat breakfast) is noninferior to standard dosing with respect to PSA metrics. Given the pharmacoeconomic implications, these data warrant consideration by prescribers, payers, and patients. Additional studies are indicated to assess the long-term efficacy of this approach.

Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points. Results Between June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The cediranib intermittent schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of eight), pulmonary embolism (two of eight), pulmonary hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus intermittent cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab increased cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. Two partial responses (≥15 months and ≥ 11 months) and eight stable diseases ≥ 4 months (median, 8 months [4 to 14.5 months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses (≥ 5 to ≥ 8 months) and three stable diseases ≥ 4 months (4 to ≥ 8 months) were seen in 12 evaluable patients who received durvalumab plus cediranib, for a 50% response rate and a 75% disease control rate. Response to therapy was independent of PD-L1 expression. Conclusion To our knowledge, this is the first reported anti-PD-L1 plus olaparib or cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent cediranib are tolerable and active. Phase II studies with biomarker evaluation are ongoing.

Purpose Kaposi's sarcoma (KS) is a multicentric tumor caused by Kaposi's sarcoma-associated herpesvirus. Unmet needs include therapies that are oral, anthracycline sparing, and deliverable in resource-limited settings. We evaluated pomalidomide, an oral immune modulatory agent, in patients with symptomatic KS. Methods The primary objectives were to assess tolerability, pharmacokinetics, and activity. Initial dosage level was 5 mg once per day for 21 days per 28-day cycle, with a de-escalated level of 3 mg if not tolerable, and aspirin 81 mg once per day thromboprophylaxis. HIV-infected patients required controlled viremia with either persistent KS despite 3 months of antiretroviral therapy (ART) or progressive KS despite 2 months of ART. Evaluations included tumor response and health-related quality of life (HRQL). Results Twenty-two patients were treated; 15 (68%) were HIV infected, 17 (77%) had advanced (T1) disease, and 19 (86%) previous KS therapy excluding ART. All were treated with 5 mg because no dose-limiting toxicities occurred. Over 156 cycles, the grade 3/4 adverse events possibly attributable to therapy were neutropenia (23 cycles, 10 patients), infection (1 cycle), and edema (1 cycle). Sixteen patients responded (73%; 95% CI, 50% to 89%): nine of 15 HIV-infected patients (60%; 95% CI, 32% to 84%) and all seven HIV-uninfected patients (100%; 95% CI, 59% to 100%). Median time to response was 4 weeks (range, 4 to 36 weeks). HRQL showed no impairment during therapy and improved satisfaction with appearance at end therapy ( P = .03). Significant increases in CD4 + and CD8 + cells were seen in patients with and without HIV, together with a transient increase in Kaposi's sarcoma-associated herpesvirus viral load at week 4 ( P = .05). Conclusion Pomalidomide is well tolerated and active in KS regardless of HIV status. Responses were rapid, with improved self-reported outcomes, and occurred in advanced and heavily pretreated disease. Correlative studies support, at least in part, an immunologic mechanism of activity.

Purpose: Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy., Patients and Methods: We performed a first in-human trial of Escherichia coli-produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer., Results: Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients., Conclusion: IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration., (© 2014 by American Society of Clinical Oncology.)

Purpose: Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT., Patients and Methods: A cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays., Results: Three SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P < .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene-gene interaction (P(interaction) = .041)., Conclusion: Genetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer.

Purpose: While disclosing a cancer diagnosis to a patient is common practice, how it is disclosed and the impact it has on the patient are poorly understood. We examined how cancer diagnoses were first given to patients and the impact of different aspects of disclosure on patient satisfaction., Patients and Methods: We provided a self-administered questionnaire to a total of 460 oncology patients of the National Cancer Institute (NCI) being treated at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD., Results: Of the 437 patients who completed the survey, 54% were told their diagnosis in-person in the physician's office, 18% by phone, and 28% in the hospital. Forty-four percent of patients reported discussions of 10 minutes or fewer, 53% reported discussions lasting longer than 10 minutes, and 5% could not remember. Treatment options were not discussed for 31% of those who could clearly remember. Higher mean satisfaction scores were associated with diagnoses revealed in person rather than over the phone (68.2 +/- 1.6 v 47.2 +/- 3.7), diagnoses revealed in a personal setting rather than an impersonal setting (68.9 +/- 1.6 v 55.7 +/- 2.8), discussions lasting longer than 10 minutes rather than fewer than 10 minutes (73.5 +/- 1.9 v 54.1 +/- 2.4), and inclusion of treatment options rather than exclusion (72.0 +/- 1.9 v 50.7 +/- 3.2; P < .001 for each aspect)., Conclusion: Physicians should disclose a cancer diagnosis in a personal setting, discussing the diagnosis and treatment options for a substantial period of time whenever possible.

PURPOSE We previously demonstrated that thalidomide appears to add to the activity of docetaxel in metastatic castration-resistant prostate cancer (CRPC). Phase II studies combining docetaxel with bevacizumab have had substantial antitumor activity. We hypothesized that the combination of docetaxel plus these antiangiogenic drugs with different targets would have substantial clinical activity. To explore safety and efficacy, this was tested in mice and in human patients. PATIENTS AND METHODS Preclinical efficacy of the combination therapy was evaluated in PC3 xenograft mice. Sixty patients with progressive metastatic CRPC received intravenous docetaxel and bevacizumab plus oral thalidomide and prednisone. The primary end point was a prostate-specific antigen (PSA) decline of > or = 50%. Secondary end points included time to progression, overall survival, and safety. Results In the mouse model, combination therapy of docetaxel, bevacizumab, and thalidomide inhibited tumor growth most effectively. In the clinical trial, 90% of patients receiving the combination therapy had PSA declines of > or = 50%, and 88% achieved a PSA decline of > or = 30% within the first 3 months of treatment. The median time to progression was 18.3 months, and the median overall survival was 28.2 months in this group with a Halabi-predicted survival of 14 months. While toxicities were manageable, all patients developed grade 3/4 neutropenia. CONCLUSION The addition of bevacizumab and thalidomide to docetaxel is a highly active combination with manageable toxicities. The estimated median survival is encouraging, given the generally poor prognosis of this patient population. These results suggest that definitive clinical trials combining antiangiogenic agent combinations with docetaxel are warranted to improve treatment outcomes for patients with metastatic CRPC.

PURPOSE Romidepsin (depsipeptide or FK228) is a member of a new class of antineoplastic agents active in T-cell lymphoma, the histone deacetylase inhibitors. On the basis of observed responses in a phase I trial, a phase II trial of romidepsin in patients with T-cell lymphoma was initiated. PATIENTS AND METHODS The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or Sézary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens. Results Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months. CONCLUSION The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.

Purpose: Sorafenib inhibits Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab is a monoclonal antibody targeted against VEGF. We hypothesized that the complementary inhibition of VEGF signaling would have synergistic therapeutic effects., Patients and Methods: Patients had advanced solid tumors, Eastern Cooperative Oncology Group performance status of 0 to 1, and good end-organ function. A phase I dose-escalation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level [DL] 1) or 10 mg/kg (DL2) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD)., Results: Thirty-nine patients were treated. DL1 was the MTD and administered in cohort 2 (N = 27). Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22+ months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization >or= 4 months (median, 6 months; range, 4 to 22+ months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/d at a median of four cycles (range, one to 12 cycles)., Conclusion: Combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.

Purpose: To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone., Methods: A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data., Results: The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group., Conclusion: PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.

Purpose: The objective of this study was to define the maximum-tolerated dose (MTD), the recommended phase II dose, the dose-limiting toxicity, and determine the pharmacokinetic (PK) and pharmacodynamic profiles of MS-275., Patients and Methods: Patients with advanced solid tumors or lymphoma were treated with MS-275 orally initially on a once daily x 28 every 6 weeks (daily) and later on once every-14-days (q14-day) schedules. The starting dose was 2 mg/m2 and the dose was escalated in three- to six-patient cohorts based on toxicity assessments., Results: With the daily schedule, the MTD was exceeded at the first dose level. Preliminary PK analysis suggested the half-life of MS-275 in humans was 39 to 80 hours, substantially longer than predicted by preclinical studies. With the q14-day schedule, 28 patients were treated. The MTD was 10 mg/m2 and dose-limiting toxicities were nausea, vomiting, anorexia, and fatigue. Exposure to MS-275 was dose dependent, suggesting linear PK. Increased histone H3 acetylation in peripheral-blood mononuclear-cells was apparent at all dose levels by immunofluorescence analysis. Ten of 29 patients remained on treatment for > or = 3 months., Conclusion: The MS-275 oral formulation on the daily schedule was intolerable at a dose and schedule explored. The q14-day schedule is reasonably well tolerated. Histone deacetylase inhibition was observed in peripheral-blood mononuclear-cells. Based on PK data from the q14-day schedule, a more frequent dosing schedule, weekly x 4, repeated every 6 weeks is presently being evaluated.

Purpose: We conducted a phase I study of a 30-minute hepatic artery infusion of melphalan via a percutaneously placed catheter and hepatic venous hemofiltration using a double balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an activated charcoal filter and then to the systemic circulation. The purpose of the study was to demonstrate feasibility in an initial cohort and subsequently determine the maximum tolerated dose and dose-limiting toxicity of melphalan., Patients and Methods: The initial cohort (n = 12) was treated with 2.0 mg/kg of melphalan before dose escalation to 3.5 mg/kg (n = 16). Total hepatic drug delivery, systemic levels, and percent filter efficiency were determined. Patients were assessed for hepatic and systemic toxicity and response., Results: A total of 74 treatments were administered to 28 patients. Twelve patients with primary and metastatic hepatic tumors received 30 treatments (mean, 2.5 per patient) at an initial melphalan dose of 2.0 mg/kg. At 3.5 mg/kg, a dose-limiting toxicity (neutropenia and/or thrombocytopenia) was observed in two of six patients. Transient grade 3/4 hepatic and systemic toxicity was seen after 19% and 66% of treatments, respectively. An overall radiographic response rate of 30% was observed in treated patients. In the 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses., Conclusion: Delivery of melphalan via this system is feasible, with limited, manageable toxicity and evidence of substantial antitumor activity; 3 mg/kg is the maximum safe tolerated dose of melphalan administered via this technique.

Purpose: To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics., Patients and Methods: Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained., Results: The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor., Conclusion: Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients., (Copyright 2004 American Society of Clinical Onocology)

Purpose: Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC). We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC., Methods: Seventy-five patients with chemotherapy-naïve metastatic AIPC were randomly assigned to receive either docetaxel 30 mg/m(2) intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25); or docetaxel at the same dose and schedule, plus thalidomide 200 mg orally each day (n = 50). Prostate-specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline, and time to progression., Results: After a median potential follow-up time of 26.4 months, the proportion of patients with a greater than 50% decline in PSA was higher in the docetaxel/thalidomide group (53% in the combined group, 37% in docetaxel-alone arm). The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group (P =.32). At 18 months, overall survival in the docetaxel group was 42.9% and 68.2% in the combined group. Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group., Conclusion: In this randomized phase II trial, the addition of thalidomide to docetaxel resulted in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC. After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses, the combination regimen was well tolerated. Larger randomized trials are warranted to assess the impact of this combination.

Purpose: Interest in the use of herbal products has grown dramatically in the Western world. Recent estimates suggest an overall prevalence for herbal preparation use of 13% to 63% among cancer patients. With the narrow therapeutic range associated with most anticancer drugs, there is an increasing need for understanding possible adverse drug interactions in medical oncology., Methods: In this article, a literature overview is provided of known or suspected interactions of the 15 best-selling herbs in the United States with conventional allopathic therapies for cancer., Results: Herbs with the potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome p450 isozymes) and/or the drug transporter P-glycoprotein include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), St John' s wort (Hypericum perforatum), and kava (Piper methysticum). All of these products participate in potential pharmacokinetic interactions with anticancer drugs., Conclusion: It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care.

Purpose: To determine the predictive value of urinary levels of two angiogenic factors, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMPs), in a longitudinal study to determine their correlation with 1-year progression-free survival in patients with cancer., Patients and Methods: VEGF and MMP levels were measured in the urine of 65 cancer patients at first evaluation, during therapy, and at follow-up (n = 242); normalized by creatinine levels; and compared with 16 healthy controls. The correlation of initial levels and trends of VEGF and MMPs with 1-year progression-free survival was assessed using two-sample tests and stepwise logistic regression., Results: Urinary VEGF levels at presentation were different between patients with local-regional cancer and normal controls, and between patients with metastatic prostate cancer and local-regional disease (P =.04 and.01, respectively). Similar results were found with MMP measurement (P =.03 and.0001, respectively). Of those patients subsequently treated with radiation, VEGF levels at presentation between patients with no evidence of disease (NED) after radiation and those who had persistent or recurrent disease after radiotherapy were also different (P =.039). The comparison between angiogenic factor levels taken at least 1 month postradiotherapy and the last level taken during treatment was the strongest predictor of patient 1-year progression-free survival (P =.004). Similarly, the overall MMP trend was also significantly associated with 1-year progression-free survival, as was the individual MMP-2 trend (P =.004 and.001, respectively). Stepwise logistic regression revealed that the VEGF trend comparing postradiation levels with last level taken during treatment was an independent predictor of progression-free survival (P =.02)., Conclusion: This small exploratory study suggests that the angiogenic urinary trends of VEGF and MMPs may be useful predictive markers for progression-free survival in cancer patients after the completion of radiotherapy.

Purpose: Carboxyamidotriazole (CAI) is a cytostatic inhibitor of nonvoltage-operated calcium channels and calcium channel-mediated signaling pathways. It inhibits angiogenesis, tumor growth, invasion, and metastasis. We hypothesized that CAI would promote disease stabilization lasting >/= 6 months in patients with relapsed ovarian cancer., Patients and Methods: Patients with epithelial ovarian cancer, good end-organ function, measurable disease, and three or fewer prior regimens were eligible. Oral CAI was given daily using a pharmacokinetic-dosing approach to maintain plasma concentrations between 2 and 4 microg/mL. Radiographic imaging to assess response was performed every 8 weeks. Positive outcome included stabilization or improvement of disease lasting >/= 6 months. Plasma vascular endothelial growth factor (VEGF), interleukin (IL)-8, and matrix metalloproteinase (MMP)-2 were measured., Results: Thirty-six patients were assessable for primary end point analysis, and 38 were assessable for toxicity. Forty-four percent of patients had three prior regimens, more than 50% had four or more disease sites, and 48% had liver metastases. Thirty-three patients reached the targeted concentration range during the first cycle. Eleven patients (31%) attained the >/= 6-month outcome end point, with one partial response (8 months) and three minor responses (8, 12+, and 13 months). Median time to progression was 3.6 months (range, 1.6 to 13.3 months). CAI was well tolerated, with mostly grade 1 to 2 toxicity. Grade 3 events included fatigue (5%), vomiting (2%), neutropenic fever (2%), and neutropenia (2%). There were no grade 4 adverse events. No associations between VEGF, IL-8, and MMP-2 with CAI concentration or clinical outcome were observed., Conclusion: CAI is a potential agent for additional study in the stabilization of relapsed ovarian cancer. Given a limited toxicity profile, it may have utility as a maintenance therapeutic agent for this disease.

Purpose: The use of thalidomide as an antiangiogenic agent has met with only limited success in the treatment of malignant gliomas. On the basis of preclinical data demonstrating synergistic antitumor activity when antiangiogenic agents are combined with cytotoxic agents, we explored the clinical activity of the combination of thalidomide and carmustine (BCNU) in patients with recurrent high-grade gliomas., Patients and Methods: Patients with a histologic diagnosis of high-grade glioma and radiographic evidence of tumor progression after standard surgery, radiation, and chemotherapy were eligible for the study. Patients received BCNU 200 mg/m2 on day 1 of every 6-week cycle, and 800 mg/d of thalidomide that was escalated to a maximal dose of 1,200 mg/d as tolerated., Results: A total of 40 patients (38 with glioblastomas, two with anaplastic gliomas) were accrued to the study. The combination of thalidomide and BCNU was well tolerated; mild myelosuppression and mild to moderate sedation were the most common side effects. The median progression-free survival (100 days) and the objective radiographic response rate (24%) for patients with glioblastoma compared favorably with data from historical controls., Conclusion: This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials.

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.

Purpose: To evaluate (1) whether there were racial differences in the androgen receptor gene CAG repeat length and in clinical or laboratory attributes of prostate cancer at the time of diagnosis; (2) whether there were differences in race, Gleason score, prostate-specific antigen (PSA) level, and stage at diagnosis by androgen receptor gene CAG repeat length; and (3) whether sociodemographic, clinical, and laboratory based factors might be associated with advanced-stage prostate cancer. To our knowledge, our study is the first to report on CAG repeat lengths in a cohort of prostate cancer patients, which includes large numbers of African-American men., Methods: CAG repeat lengths on the androgen receptor gene were evaluated for 151 African-American and 168 white veterans with prostate cancer. The chi(2) test, t test, and logistic regression analyses were used to evaluate the associations between CAG repeat lengths and race, stage, histologic grade, and PSA levels at diagnosis., Results: The mean age of the cohort at the time of diagnosis was 68.7 years. At presentation, 42.0% had stage D prostate cancer, 26.5% had Gleason scores of 8 to 10, and 53.0% had PSA levels >/= 10 ng/dL. Mean androgen receptor gene CAG repeat length for white veterans was 21.9 (SD, 3.5) versus 19.8 (SD, 3.2) for African-American veterans (P =.001). Men with shorter CAG repeats were more likely to have stage D prostate cancer (P =.09) but were not more likely to have a higher PSA concentration or Gleason score., Conclusion: In this cohort of men with prostate cancer, short CAG repeat length on the androgen receptor gene was associated with African-American race and possibly with higher stage but not with other clinical or pathologic findings.

Purpose: Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and are overexpressed in Kaposi's sarcoma (KS) cells. The primary aim was to define the safety and toxicity of the MMP inhibitor COL-3 in patients with AIDS-related KS. Secondary aims were to evaluate tumor response, pharmacokinetics, and changes in blood levels of MMP-2, MMP-9, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF)., Patients and Methods: COL-3 was administered orally once daily, and doses were escalated in cohorts of three to six subjects. Patients with symptomatic visceral KS or severe tumor-associated edema were excluded. Antiretroviral therapy was permitted but not required. Study end points were grade 3 or 4 toxicity or progressive KS. Serial blood specimens were obtained for pharmacokinetics and levels of MMP-2, MMP-9, VEGF, and bFGF., Results: Eighteen patients received COL-3 in dosing cohorts of 25, 50, and 70 mg/m(2)/d. Prior KS therapy was reported by 17 patients (94%). COL-3-related grade 3 or 4 adverse events were reported by six patients and included photosensitivity, rash, and headache. There was one complete response and seven partial responses, for an overall response rate of 44%, with a median response duration of 25+ weeks. The median COL-3 half-life was 39.3 hours (range, 4.1 to 251.1 hours). There was a significant difference between responders and nonresponders with respect to the change in MMP-2 serum levels from baseline to minimum value on treatment (P =.037)., Conclusion: COL-3 administered orally once daily to patients with AIDS-related KS is reasonably well tolerated. The most common adverse event was dose-related photosensitivity. Antitumor activity was noted. Further evaluation of COL-3 for the treatment of KS is warranted.

Purpose: To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV)., Patients and Methods: Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed., Results: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m(2)/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. Therefore, nine patients received drug on the initial 2-week schedule, and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m(2)/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m(2)/d for 3 days included mean total plasma concentration of 36.4 microM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period ( > 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G(2) checkpoint., Conclusion: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.

Purpose: PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion., Patients and Methods: Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion. Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833., Results: In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (C(pss)) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received a paclitaxel dose of 35 mg/m(2)/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non-small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma., Conclusion: PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent. This in turn will facilitate dosing to achieve comparable CPss and AUCs.

Purpose: To determine the feasibility of an organ preservation regimen consisting of infusional paclitaxel administered concurrently with radiotherapy to patients with locally advanced head and neck squamous cell carcinoma (HNSCC)., Patients and Methods: Thirty-three previously untreated patients with stage III or IV tumors were enrolled onto the study. Paclitaxel was administered as a 120-hour continuous infusion every 3 weeks during the course of radiation therapy. Sixteen patients received a paclitaxel dose of 105 mg/m(2), and 17 patients received 120 mg/m(2). Radiation was delivered in a standard format at 1.8 Gy/d to a total dose of 70.2 to 72 Gy., Results: Three months after therapy, a 76% complete response (CR) at the primary site and a 70% overall CR was achieved. At 36 months, locoregional control was 55.7%, overall survival was 57.8%, and disease-free survival was 51.1%. The median survival duration for all 33 patients was greater than 50 months at the time of this report. Local toxicities including mucositis, dysphagia, and skin reactions were severe but tolerable. All patients retained functional speech, and all but four patients were swallowing food 3 months after treatment. Steady-state plasma concentrations for paclitaxel were not achieved during a 120-hour infusion, suggesting a nonlinear process. Tumor volume quantified by pretreatment computerized tomography imaging was associated with likelihood of response and survival., Conclusion: Paclitaxel administered as a 120-hour continuous infusion in combination with radiotherapy is a feasible and promising treatment for patients with advanced HNSCC.

Purpose: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors., Patients and Methods: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug., Results: Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042)., Conclusion: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.

Purpose: To assess the toxicity and activity of oral thalidomide in Kaposi's sarcoma (KS) in a phase II dose-escalation study., Patients and Methods: Human immunodeficiency virus (HIV)-seropositive patients with biopsy-confirmed KS that progressed over the 2 months before enrollment received an initial dose of 200 mg/d of oral thalidomide in a phase II study. The dose was increased to a maximum of 1,000 mg/d for up to 1 year. Anti-HIV therapy was maintained during the study period. Toxicity, tumor response, immunologic and angiogenic factors, and virologic parameters were assessed., Results: Twenty patients aged 29 to 49 years with a median CD4 count of 246 cells/mm(3) (range, 14 to 646 cells/mm(3)) were enrolled. All patients were assessable for toxicity, and 17 for response. Drowsiness in nine and depression in seven patients were the most frequent toxicities observed. Eight (47%; 95% confidence interval [CI], 23% to 72%) of the 17 assessable patients achieved a partial response, and an additional two patients had stable disease. Based on all 20 patients treated, the response rate was 40% (95% CI, 19% to 64%). The median thalidomide dose at the time of response was 500 mg/d (range, 400 to 1,000 mg/d). The median duration of drug treatment was 6.3 months, and the median time to progression was 7.3 months., Conclusion: Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted.

Purpose: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas., Patients and Methods: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria., Results: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival., Conclusion: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.

Purpose: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters., Result: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point., Conclusion: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.

Purpose: We conducted a phase I trial of the cyclin-dependent kinase inhibitor, flavopiridol (National Service Center [NSC] 649890), to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacology of flavopiridol given as a 72-hour infusion every 2 weeks., Patients and Methods: Seventy-six patients with refractory malignancies with prior disease progression were treated with flavopiridol, with first-cycle pharmacokinetic sampling., Results: Forty-nine patients defined our first MTD, 50 mg/m2/d x 3 with dose-limiting toxicity (DLT) of secretory diarrhea at 62.5 mg/kg/d x 3. Subsequent patients received antidiarrheal prophylaxis (ADP) to define a second MTD, 78 mg/m2/d x 3 with DLT of hypotension at 98 mg/m2/d x 3. Other toxicities included a proinflammatory syndrome with alterations in acute-phase reactants, particularly at doses >50 mg/ m2/d x 3, which in some patients prevented chronic therapy every 2 weeks. In some patients, ADP was not successful, requiring dose-deescalation. Although approximately 70% of patients displayed predictable flavopiridol pharmacology, we observed unexpected interpatient variability and postinfusion peaks in approximately 30% of cases. At the two MTDs, we achieved a mean plasma flavopiridol concentration of 271 nM (50 mg/m2/d x 3) and 344 nM (78 mg/m2/d x 3), respectively. One partial response in a patient with renal cancer and minor responses (n=3) in patients with non-Hodgkin's lymphoma, colon, and renal cancer occurred., Conclusion: The MTD of infusional flavopiridol is 50 mg/m2/d x 3 with dose-limiting secretory diarrhea at 62.5 mg/m2/d x 3. With ADP, 78 mg/m2/d x 3 was the MTD, with dose-limiting hypotension at 98 mg/m2/d x 3. Based on chronic tolerability, 50 mg/m2/d x 3 is the recommended phase II dose without ADP. Antitumor effect was observed in certain patients with renal, prostate, and colon cancer, and non-Hodgkin's lymphoma. Concentrations of flavopiridol (200 to 400 nM) needed for cyclin-dependent kinase inhibition in preclinical models were achieved safely.

Purpose: To investigate the antitumor activity and safety of paclitaxel in patients with advanced human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS)., Patients and Methods: Twenty-nine patients with advanced HIV-associated KS were enrolled. The patients were overall quite immunosuppressed (median CD4 count, 15 cells/microL). Paclitaxel was initially administered at 135 mg/m2 over 3 hours every 3 weeks without filgrastim support; the dose was increased as tolerated to a maximum of 175 mg/m2. Patients who failed to respond or progressed could then receive filgrastim support or paclitaxel administered over 96 hours., Results: Of 28 assessable patients, 20 had major responses (18 partial responses [PRs], one clinical complete response [CR], and one CR), for a major response rate of 71.4% (95% confidence interval [CI], 51.3% to 86.8%). Each of the five patients with pulmonary KS responded, as did all four assessable patients who had previously received anthracycline therapy for KS. Of six patients who went on to receive a 96-hour infusion of paclitaxel, five had major responses. Neutropenia was the most frequent dose-limiting toxicity; possible novel toxicities included late fevers, late rash, and eosinophilia. Two patients developed an elevated creatinine concentration and one cardiomyopathy., Conclusion: Paclitaxel has substantial activity against advanced HIV-associated KS as a single agent, even in patients with pulmonary involvement or who had previously received anthracyclines. Further research is needed to define the optimal treatment schedule and its role vis-a-vis the other available therapies for this disease.

Purpose: Cytostatic agents targeted against angiogenesis and tumor cell invasive potential form a new class of investigational drugs. Orally administered carboxyamidotriazole (CAI) (NSC609974) is both antiangiogenic and antimetastatic. An encapsulated micronized powder formulation has been developed to optimize CAI administration. A phase I dose escalation trial with pharmacokinetic analysis has been performed., Patients and Methods: Twenty-one patients with refractory solid tumors and good end organ function and performance status were enrolled onto the study. Patients received a test dose followed 1 week later by daily administration of CAI in the encapsulated micronized formulation at doses of 100 to 350 mg/m2. Patients remained on CAI until disease progression or dose-limiting toxicity. Plasma samples were taken to characterize the pharmacokinetic parameters of this formulation of CAI., Results: All patients were assessable for toxicity and 18 were assessable for pharmacokinetics and response analysis. Grade 1 and 2 gastrointestinal side effects were observed in up to 50% of patients. Dose-limiting toxicity was observed in both patients treated at 350 mg/m2/d, consisting of reversible grade 2 to 3 cerebellar ataxia (n = 1) and confusion (n = 1). One minor response (MR) was observed in a patient with renal cell carcinoma and another nine patients had disease stabilization (MR + SD = 47%). Pharmacokinetic analysis demonstrated reduced bioavailability (58% reduction) compared with the PEG-400 liquid formulation previously reported., Conclusion: The better toxicity profile of encapsulated micronized CAI with similar frequency of disease stabilization and ease of administration compared with the liquid or gelatin capsule, suggests that the micronized formulation is a preferable formulation for subsequent studies. A dose of 300 mg/m2/d is proposed for phase II investigations.

Purpose: To assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer., Patients and Methods: Patients with stage D2 and poor-prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 micrograms/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone., Results: Fifty patients were entered onto the study: 48 with stage D2 and two with stage D1 disease. The median age was 59 years (range, 42 to 79) and 31 patients had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable soft tissue disease. Forty-one (82%) had severe disease. The overall response rate in 49 assessable patients was three complete responses (CRs) and 30 partial responses (PRs) for an overall response rate of 67%. Eighteen patients have died. The median survival time has not been reached, with a median potential follow-up duration of 44 months. Grade 3 to 4 toxicity was seen in 38% of patients and was predominantly hematologic and reversible., Conclusion: The high response rate and prolonged survival in a poor-prognosis group of patients with metastatic prostate cancer warrant a phase III randomized comparison of this regimen versus hormonal therapy alone. Toxicity was moderate and reversible.

Purpose: To describe pharmacologic variables correlated with the development of neurologic toxicity in patients treated with suramin., Methods: Eighty-one patients were treated with suramin in a phase I study. The rate of drug infusion was continuously adjusted to maintain a preassigned plasma suramin concentration (175, 215, or 275 micrograms/mL) for a fixed duration (2 to 8 weeks)., Results: Eight patients developed grade III/IV neurologic motor impairment (predominantly motor axonal polyneuropathy). All were treated at the 275-micrograms/mL concentration. One patient treated at the 215-micrograms/mL concentration developed grade II motor dysfunction. In addition, seven of nine patients had sensory symptoms. Pharmacologic variables associated with the development of polyneuropathy included total cumulative suramin dose, duration of exposure to plasma concentrations greater than 200 micrograms/mL, and area under the curve (AUC) greater than 200 micrograms/mL., Conclusion: Significant neurologic toxicity can result from therapy with suramin, even when dosing is designed to avoid exposure to plasma concentrations greater than 350 micrograms/mL. Future clinical trials of suramin should be designed in such a way as to limit the total cumulative dose to < or = 157 mg/kg given over a period of > or = 8 weeks, limit the period of exposure to plasma suramin concentrations greater than 200 micrograms/mL to < or = 25 days, and limit the AUC greater than 200 micrograms/mL to < or = 48,000 mg.h/AL.