Tumor Doubling Time Using CT Volumetric Segmentation in Metastatic Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy with an overall unfavorable prognosis. Clinicians treating patients with ACC have noted accelerated growth in metastatic liver lesions that requires rapid intervention compared to other metastatic locations. This study measured and compared the growth rates of metastatic ACC lesions in the lungs, liver, and lymph nodes using volumetric segmentation. A total of 12 patients with metastatic ACC (six male; six female) were selected based on their medical history. Computer tomography (CT) exams were retrospectively reviewed and a sampling of ≤5 metastatic lesions per organ were selected for evaluation. Lesions in the liver, lung, and lymph nodes were measured and evaluated by volumetric segmentation. Statistical analyses were performed to compare the volumetric growth rates of the lesions in each organ system. In this cohort, 5/12 had liver lesions, 7/12 had lung lesions, and 5/12 had lymph node lesions. A total of 92 lesions were evaluated and segmented for lesion volumetry. The volume doubling time per organ system was 27 days in the liver, 90 days in the lungs, and 95 days in the lymph nodes. In this series of 12 patients with metastatic ACC, liver lesions showed a faster growth rate than lung or lymph node lesions.

Long-term outcomes in patients with advanced adrenocortical carcinoma after image-guided locoregional ablation or embolization.

BACKGROUND: To evaluate outcomes and survival rates in patients with metastatic adrenocortical carcinoma (ACC) who were treated with image-guided locoregional treatments (IGLTs). PURPOSE: To evaluate the overall survival (OS) and clinical impact of IGLT in the management of patients with advanced metastatic ACC. METHODS: Retrospective review of 39 patients treated with IGLT between 1999 and 2018 was performed. Short- and long-term efficacy of treatments were defined based upon imaging and clinical data. Subgroup survival analysis was performed on patients with metastatic disease at diagnosis (N = 17) and compared with the same stage group from the most recent National Cancer Database (NCDB) report. Statistical analysis was performed using Cox proportional hazards model. RESULTS: Treatments were performed at different anatomic sites including liver (N = 46), lung (N = 14), retroperitoneum (N = 5), bone (N = 4), subcutaneous (N = 2), and intracaval (N = 1). Radiofrequency, microwave, cryoablation, or a combination of two modalities (45, 18, 3, 3, respectively) were used in 69 ablation sessions. Intra-arterial procedures were performed in 12 patients in 18 treatment cycles (range 1-3 per patient). As of a 2019 analysis, 11 patients were alive with a mean follow-up of 169 months (range 63-292 months) from diagnosis. Two- and 5-year OS rates for all patients were 84.5% and 51%, respectively, and 76.5% and 59% for patients with metastatic disease at diagnosis (N = 17). This compares favorably with an NCDB report of 35% 5-year survival rate for patients with metastatic disease. Female gender and longer time from diagnosis to first IGLT were found to be predictors of prolonged survival with hazard ratios of 0.23 (p < 0.001) and 0.66 (p = 0.001), respectively. CONCLUSION: IGLT may be associated with prolonged life expectancy in select patients with metastatic ACC.

Metastatic and recurrent adrenocortical cancer is not defined by its genomic landscape.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14-17 month median overall survival. We asked whether tumors from patients with advanced or metastatic ACC would offer clues as to putative genes that might have critical roles in disease progression or in more aggressive disease biology. METHODS: We conducted comprehensive genomic and expression analyses of ACCs from 43 patients, 30 female, and 42 from metastatic sites, including deep sequencing, copy number analysis, mRNA expression and microRNA arrays. RESULTS: Copy number gains and losses were similar to that previously reported for ACC. We identified a median mutation rate of 3.38 per megabase (Mb). The mutational signature was characterized by a predominance of C > T, C > A and T > C transitions. Only cancer genes TP53 (26%) and beta-catenin (CTNNB1, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes MEN1 and PRKAR1A were found in low frequency-4.7 and 2.3%, respectively. The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer. Specifically, amongst the 38 genes that were mutated in more than 9% of samples, only four were represented in Tier 1 of the 576 COSMIC Cancer Gene Census (CCGC). Thus, 82% of genes found to have mutations likely have no role in the etiology or biology of ACC; while the role of the other 18%, if any, remains to be proven. Finally, the transcript length for the 38 most frequently mutated genes in ACC is statistically longer than the average of all coding genes, raising the question of whether transcript length in part determined mutation probability. CONCLUSIONS: We conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients-with very little in the way of genomic aberration to explain differences in biology. With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.

Phase I/II Trial of Vandetanib and Bortezomib in Adults with Locally Advanced or Metastatic Medullary Thyroid Cancer.

LESSONS LEARNED: Vandetanib at a dose of 300 mg orally every day plus bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 could be administered safely.Assessing outcomes in 17 patients with medullary thyroid cancer, investigators considered the combination to be more difficult to administer than single-agent vandetanib and that achieving better outcomes was unlikely. Consequently, a planned phase II study was terminated early. BACKGROUND: The proto-oncogene RET (REarranged during Transfection) has a critical role in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib (V), a multitargeted tyrosine kinase inhibitor approved for the treatment of MTC, is thought to inhibit RET in MTC. Supported by preclinical studies demonstrating that bortezomib (B) administration lowered RET mRNA and protein levels, we conducted a phase I study in advanced solid tumors of vandetanib in combination with bortezomib. The goal was to establish an RP2D (recommended phase II dose) for the combination of vandetanib plus bortezomib, a regimen envisioned as a dual strategy for targeting RET in MTC. METHODS: Patients with advanced solid tumors were treated with escalating doses of bortezomib or vandetanib to assess the safety and tolerability of daily oral vandetanib and intravenous (IV) bortezomib administered on days 1, 4, 8, and 11 of a 28-day cycle. Intrapatient dose escalation was allowed. RESULTS: Twenty-two patients were enrolled and received escalating mg/m2 bortezomib and mg vandetanib (number of patients) at initial doses of 1 and 100 (3), 1.3 and 100 (6), 1.3 and 200 (6), and 1.3 and 300 (7), respectively. Patients received a median of four cycles of bortezomib/vandetanib (range: 1-10), with 13 patients escalating to 1.3/200 and 10 to 1.3/300. G3 toxicities occurring in more than one patient included hypertension (24%), fatigue (19%), thrombocytopenia (10%), diarrhea (10%), and arthralgia (10%). There were no drug-related G4/5 toxicities. There was one dose-limiting toxicity, G3 thrombocytopenia, at bortezomib/vandetanib doses of 1.3/200 in cycle 2 that resolved without intervention. Four patients with a diagnosis of MTC (27%) had a partial response (PR). CONCLUSION: The MTD of the combination was established as bortezomib, 1.3 mg/m2 IV days 1, 4, 8, and 11 with vandetanib 300 mg p.o. daily. RECIST responses were observed in patients with a diagnosis of MTC.

A Phase II Multi-Center Study of Bevacizumab in Combination with Ixabepilone in Subjects with Advanced Renal Cell Carcinoma.

LESSONS LEARNED: Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development. BACKGROUND: Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule-stabilizing agent approved for the treatment of breast cancer, is active in taxane-sensitive and -resistant cells. In this single-arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC. METHODS: We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)-approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m2 ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days. After 6 cycles, the treatment interval could be extended to every 28 days. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and the toxicity of the combination. RESULTS: The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2-54). The median follow-up was 36.4 months (range 23.5-96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9-10.6) and the median OS was 15.0 months (95% CI, 11.3-28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%). CONCLUSION: The combination of ixabepilone and bevacizumab was well tolerated, with modest activity in second - or later-line mRCC, but it is not recommended as a therapy without further clinical development. Alternative combinations with these agents could be explored in future studies.

Adrenocortical Cancer: A Molecularly Complex Disease Where Surgery Matters.

The development of new therapies has lagged behind for rare cancers without defined therapeutic targets. Adrenocortical cancer is no exception. Mitotane, an older agent considered "adrenolytic," is used both to control symptoms in advanced disease and as adjuvant therapy after surgical resection. Molecular characterization of adrenocortical cancer has deepened our understanding of this genetically complex disease while identifying subgroups whose importance remains to be determined. Unfortunately, such studies have yet to demonstrate a therapeutic target for drug development, and to date, no targeted therapy has achieved meaningful outcomes. Consequently, first-line therapy for metastatic disease remains a combination regimen of etoposide, doxorubicin, and cisplatinum established in a randomized clinical trial. In addition to evaluating recent studies in adrenocortical cancer, we raise one critical clinical issue-the risk of peritoneal dissemination following laparoscopic resection of adrenocortical cancer. In a retrospective case series of 267 patients referred to the NCI for the treatment of recurrent or advanced adrenocortical cancer, we found extensive peritoneal dissemination in 25 of the 45 patients (55.6%) who had undergone laparoscopic resection, compared with only 7 of the 222 patients (3%) who had undergone an open resection (P < 0.0001). Although this has been debated in the literature, our data argue for an end to laparoscopic resection of adrenocortical cancers to avoid peritoneal dissemination, a complication of laparoscopy that is uniformly fatal. Clin Cancer Res; 22(20); 4989-5000. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "ENDOCRINE CANCERS REVISING PARADIGMS".

Phase II Clinical Trial of Ixabepilone in Metastatic Cervical Carcinoma.

LESSONS LEARNED: Accrual to cervical cancer studies remains a puzzling challenge given the lack of options and the dismal prognosis of this disease. The majority of patients referred for a trial such as this have very advanced disease that is difficult to manage.The observation of 4 partial responses among the 41 patients indicates that ixabepilone has some activity but not sufficient for further development without greater understanding of mechanisms of sensitivity and resistance. BACKGROUND: Ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Preclinical data have shown that ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of ixabepilone in previously treated mCC. METHODS: Patients with histologically confirmed mCC and at least one prior cisplatin-containing regimen were treated with ixabepilone [6 mg/m(2) per day for 5 days] every 21 days. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were response rate, rate of tumor growth, overall survival (OS), and safety. Levels of glu-terminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot. RESULTS: In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four patients (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for taxane-naïve, and 2.03 for taxane-pretreated patients (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43%), sensory neuropathy (21%), and fatigue (60%). Bowel fistulas were observed in 7% of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated. CONCLUSION: Ixabepilone was well tolerated but showed very modest activity in second- or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC.

Brain metastasis in patients with adrenocortical carcinoma: a clinical series.

INTRODUCTION: Adrenocortical carcinoma (ACC) is a heterogeneous and rare disease. At presentation or at the time of a recurrence, the disease commonly spreads to the liver, lungs, lymph nodes, and bones. The brain has only rarely been reported as a site of metastases. OBJECTIVE: The aims of this report were to describe the clinical characteristics of patients with ACC who developed brain metastasis and were evaluated at the National Cancer Institute. METHODS: We describe the history and clinical presentation of six patients with ACC and metastatic disease in the brain. Images of the six patients and pathology slides were reviewed when available. RESULTS: The median age at the time of the diagnosis of ACC was 42 years. The median time from the initial diagnosis until the presentation of brain metastasis was 43 months. As a group the patients had previously received multiples lines of chemotherapy (median of three), and they presented with one to three metastatic brain lesions. Four patients underwent metastasectomy, one had radiosurgery, and one had both modalities. Two patients are still alive, three died, between 2 and 14 months after the diagnosis of brain metastases, and one was lost to follow-up. CONCLUSION: Patients with advanced ACC can rarely present with metastasis to the brain, most often long after the initial diagnosis. Timely diagnosis of brain metastasis with appropriate intervention after discussion in a multidisciplinary meeting can improve the prognosis in this particular scenario.

The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer.

CONTEXT: Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis in need of more effective treatment options. Published evidence indicates many ACCs express the vascular endothelial growth factor receptor (VEGFR), suggesting inhibiting vascular endothelial growth factor signaling could potentially impact tumor growth. OBJECTIVE: The objective of the study was to determine the antitumor efficacy of axitinib (AG-013736), a potent, selective inhibitor of VEGFR1, -2, and -3. DESIGN: This was a phase II, open-label trial using a two-stage design. PATIENTS: Thirteen patients with metastatic ACC previously treated with at least one chemotherapy regimen with or without mitotane participated in the study. INTERVENTION: Starting axitinib dose was 5 mg orally twice daily. Dose escalations were permitted if the administered dose was tolerable. RESULTS: Thirteen patients were enrolled. Dose escalation was possible in seven patients, but the majority could not tolerate a dose higher than the starting 5 mg, twice-daily dose for prolonged periods of time. All patients experienced known grade 1/2 toxicities, and 10 of 13 patients had at least one grade 3/4 adverse event. No patient tumor could be scored as a Response Evaluation Criteria in Solid Tumors response, although the growth rate on therapy compared with that prior to starting axitinib was reduced in 4 of the 13 patients. The median progression-free survival was 5.48 months, and the median overall survival was longer than 13.7 months. CONCLUSION: Axitinib has limited effectiveness in ACC. Together with 48 patients previously reported who received either sorafenib or sunitinib, a total of 61 ACC patients have now been treated with a VEGFR tyrosine kinase inhibitor without an objective Response Evaluation Criteria in Solid Tumors response. Future trials in ACC should look to other targets for possible active agents.

Role of radiotherapy in adrenocortical carcinoma.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare and highly malignant tumor usually diagnosed in an advanced stage. Radiation therapy has been a poorly studied and underutilized therapeutic option. METHODS: This retrospective analysis reviewed treatment courses for 14 patients with pathologically confirmed ACC treated between 1997 and 2012. Two patients were treated adjuvantly following surgery, and 12 were treated with palliative intent. Patients presented with stage II (n = 4), stage III (n = 7), and stage IV (n = 3) disease. Patients had a mean age of 51.5 years. Ten patients received chemotherapy before radiotherapy (RT), and 12 patients received surgery before RT, before receiving radiation at a mean of 17.8 months after diagnosis. RESULTS: In total, 20 sites were treated, 2 of which were in an adjuvant setting, and 18 of which were for palliative indications in 12 patients as follows: (1) pain/neuropathy (n = 10), (2) prophylactic treatment of asymptomatic recurrences (n = 3), and (3) prevention of imminent metastatic complications (n = 2), hemoptysis (n = 1), severe mass effect (n = 1), and brain metastasis (n = 1). Sites were treated to a median dose of 36.3 Gy (range, 17.5-60 Gy) in a median of 2.5 Gy/fraction (range, 1.8-4 Gy). At a mean follow-up of 22.0 months for the 2 patients given adjuvant RT, 1 patient did not have a local recurrence during a 14.3-month period of follow-up, and the other had a local recurrence 14.5 months after RT. At a mean follow-up of 11.3 months for the 12 patients receiving palliative RT, 10 patients had either a clinical or radiographic response. Of the courses of palliative RT that had adequate radiographic follow-up, 4 treatments (27%) resulted in a partial response. Eleven treatments (73%) that were able to be evaluated resulted in clinical improvement. Acute Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicities observed in 7 patients included 3 grade 1, 4 grade 2, and 1 grade 3. No patient had acute toxicity of grade 4 or greater or any Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late toxicity of grade 1 or greater. DISCUSSION: This report is one of the largest to date examining the role of modern radiation techniques in the management of ACC. We conclude that radiation can be effective in the management of metastatic ACC, palliating local symptoms, and preventing complications from large metastases. Radiation should be considered as an option in multimodality management of ACC patients.

Combination chemotherapy in advanced adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. METHODS: We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. RESULTS: For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. CONCLUSIONS: Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).

A phase II clinical trial of ixabepilone (Ixempra; BMS-247550; NSC 710428), an epothilone B analog, in patients with metastatic renal cell carcinoma.

PURPOSE: Ixabepilone (Ixempra; BMS-247550) is an epothilone B analog and nontaxane microtubule-stabilizing compound with clinical activity in a range of solid tumors. This phase II study was conducted to assess the efficacy and safety of ixabepilone in patients with metastatic renal cell carcinoma. EXPERIMENTAL DESIGN: Patients with metastatic renal cell carcinoma who had measurable disease and had not received previous cytotoxic or targeted therapy were treated with 6 mg/m(2) ixabepilone i.v. daily for 5 days every 3 weeks. Levels of Glu-terminated and acetylated tubulin, markers of microtubule stabilization, were assessed by Western blot. VHL gene mutation status was determined by sequencing. RESULTS: Eighty-seven patients received a total of 590 cycles, with a median of 5 cycles (range, 1-29). The overall response rate was 13% (Response Evaluation Criteria in Solid Tumor). One patient had a complete response, 10 patients had partial responses, and 59 patients had stable disease. The median duration of response was 5.5 months. The median overall survival of renal cell carcinoma Motzer grade 0 and 1 patients with clear cell histology was 19.25 months. Treatment-related adverse events were primarily alopecia, gastrointestinal toxicity, neuropathy, and fatigue. Biopsies were done at baseline and after five doses of ixabepilone. Microtubule target engagement was achieved in 84.6% to 92.3% of patients evaluated. No correlation was identified between the target engagement, VHL gene mutation status, and clinical response. CONCLUSION: Ixabepilone can cause tumor regression in some patients with metastatic renal cell carcinoma and could be considered in combination regimens with other therapies.

Other paradigms: growth rate constants and tumor burden determined using computed tomography data correlate strongly with the overall survival of patients with renal cell carcinoma.

In solid tumors, where curative therapies still elude oncologists, novel paradigms are needed to assess the efficacy of new therapies and those already approved. We used radiologic measurements obtained in patients with metastatic renal cell carcinoma enrolled in a phase II study of the epothilone B analog, ixabepilone (Ixempra), to address this issue. Using a novel 2-phase mathematical equation, we used the radiologic measurements to estimate the concomitant rates of tumor regression and growth (regression and growth rate constants). Eighty-one patients were enrolled on the ixabepilone trial at the time of this analysis. Growth rate constants were determined using computed tomography measurements obtained exclusively while a patient was enrolled on study. The growth rate constants of renal cell carcinomas treated with ixabepilone were significantly reduced compared with those of tumors in patients who received placebo in a previous trial. Furthermore, a correlation with overall survival was found for both the growth rate constant and the initial tumor burden; and this correlation was even stronger when both the growth rate constant and the initial tumor burden were combined. The readily amenable mathematical model described herein has potential applications to many tumor types that can be assessed with imaging modalities. Because the growth rate constant seems to be a surrogate for survival, assessment could aid in the evaluation of relative efficacies of different therapies and perhaps in assessing the potential individual benefit of an experimental therapy.

Science, technology, and innovation: nursing responsibilities in clinical research.

Clinical research is a systematic investigation of human biology, health, or illness involving human beings. It builds on laboratory and animal studies and often involves clinical trials, which are specifically designed to test the safety and efficacy of interventions in humans. Nurses are critical to the conduct of ethical clinical research and face clinical, ethical, and regulatory challenges in research in many diverse roles. Understanding and addressing the ethical challenges that complicate clinical research is integral to upholding the moral commitment that nurses make to patients, including protecting their rights and ensuring their safety as patients and as research participants.

A phase I study of the P-glycoprotein antagonist tariquidar in combination with vinorelbine.

PURPOSE: P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. EXPERIMENTAL DESIGN: Patients first received tariquidar alone to assess effects on the accumulation of (99m)Tc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. RESULTS: Twenty-six patients were enrolled. Vinorelbine 20 mg/m(2) on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver (99m)Tc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased (99m)Tc-sestamibi retention in a majority of tumor masses visible by (99m)Tc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. CONCLUSIONS: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.

Is there room for improvement in adverse event reporting in the era of targeted therapies?

The Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, and its predecessors, the Common Toxicity Criteria (CTC) versions 1.0 and 2.0, were developed under the direction of the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI) in an effort to provide standard language for reporting adverse events that occur in NCI-sponsored clinical trials. Each successive version of the CTC has improved the accuracy, precision, and completeness of the criteria in an effort to standardize reporting. We believe that the current version of the CTCAE cannot adequately code the subacute adverse events that commonly occur with today's targeted therapies.

A Phase I clinical trial of ixabepilone (BMS-247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days.

BACKGROUND: The epothilones are a novel class of microtubule-stabilizing agents. Ixabepilone (BMS-247550; NSC 710428) is a semisynthetic analog of the natural product epothilone B. The authors conducted a Phase I study by administering ixabepilone to patients as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days. METHODS: Twenty-six patients were enrolled and received ixabepilone at a starting dose of 8 or 10 mg/m(2) per day for 3 consecutive days. RESULTS: One hundred and nineteen cycles were administered to 26 patients. The maximum-tolerated dose was 8 mg/m(2) per day of ixabepilone administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days. The dose-limiting toxicity (DLT) was neutropenia. Other nonhematologic Grade 3 toxicities included fatigue (3 cycles), hyponatremia (1 cycle), anorexia (1 cycle), ileus (1 cycle), stomatitis (1 cycle), and emesis (1 cycle). Prolonged disease stabilization was observed in patients with mesothelioma, ovarian carcinoma, and renal cell carcinoma. CONCLUSIONS: The recommended Phase II dose of ixabepilone on the daily schedule for 3 days was 8-10 mg/m(2) per day. Neutropenia was the DLT. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.

Treatment of recurrent cervical adenocarcinoma with BMS-247550, an epothilone B analog.

OBJECTIVE: The incidence of recurrent cervical adenocarcinoma is rising relative to the squamous subtype. There are limited therapeutic options for women with advanced cervical adenocarcinoma. Only a few chemotherapy agents have demonstrated activity in this disease. This report describes results with BMS-247550, an epothilone B analog that stabilizes microtubules, with activity in previously treated adenocarcinoma of the cervix. METHOD: We present two women with recurrent cervical adenocarcinoma with metastases to the lung. Both women were treated previously with paclitaxel and were enrolled in a phase I study with BMS-247550. Both women had partial responses to BMS-247550 with a decrease in tumor size and CA-125 levels. CONCLUSIONS: The demonstration of a response to BMS-247550, especially after additional chemotherapy had been administered, is encouraging, albeit preliminary. The ultimate role of BMS-247550 and multiagent chemotherapy in the treatment of adenocarcinoma of the cervix should be further investigated.

Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days.

PURPOSE: The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. PATIENTS AND METHODS: Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both. RESULTS: One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 +/- 6.0 hours, the volume of distribution at steady-state was 798 +/- 375 L, and the clearance was 712 +/- 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer. CONCLUSION: The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.

Increased 99mTc-sestamibi accumulation in normal liver and drug-resistant tumors after the administration of the glycoprotein inhibitor, XR9576.

99mTc-sestamibi, a substrate of the multidrug transporter P-glycoprotein (Pgp), has been used as a functional imaging agent for the multidrug resistance-1 (MDR1) phenotype. In vitro, retention of (99m)Tc-sestamibi by cells that overexpress Pgp can be enhanced by the addition of Pgp inhibitors. XR9576 (Tariquidar) is a potent and selective noncompetitive inhibitor of Pgp that is active at 25-80 nM. A Phase I trial of XR9576 in combination with vinorelbine (Navelbine) was conducted in 26 patients with metastatic cancers. A (99m)Tc-sestamibi scan was obtained at baseline followed 48-96 h later by a second scan 1-3 h after the administration of XR9576. Time activity curves and areas under the curves (AUCs) were obtained for tumor, liver, lung, and heart, and tissue:heart AUC ratios were calculated. XR9576 enhanced (99m)Tc-sestamibi accumulation and retention in the liver of all but two patients with a mean change of +128%. Furthermore, in 13 of 17 patients with tumor masses visible by (99m)Tc-sestamibi, the tumor:heart (99m)Tc-sestamibi AUC(0-3 h) increased after the administration of XR9576, with increases of 36-263% seen in 8 patients. We conclude that in vivo administration of XR9576 inhibits (99m)Tc-sestamibi efflux in both the normal liver and in drug resistant tumors. This study provides convincing evidence of the existence of XR9576-inhibitable (99m)Tc-sestamibi efflux in a large fraction of drug resistant tumors. One can predict that efflux of Pgp substrates also occurs in these tumors. XR9576 provides an efficient way to inhibit this efflux and offers the potential to increase drug exposure in human cancer.