A phase 2 trial of sunitinib in patients with advanced non-clear cell renal cell carcinoma.

BACKGROUND: Sunitinib is a standard-of-care treatment in advanced clear cell renal cell carcinoma (ccRCC). Retrospective and expanded access data suggest sunitinib has activity in advanced non-clear cell renal cell carcinoma (nccRCC). OBJECTIVE: To prospectively determine the clinical efficacy and safety of sunitinib in patients with advanced nccRCC. DESIGN, SETTING, AND PARTICIPANTS: This is a single-arm phase 2 trial with a two-stage design. Eligibility criteria included pathologically confirmed nccRCC or ccRCC with ≥ 20% sarcomatoid histology, performance status 0-2, measurable disease, a maximum of two prior systemic therapies, and no prior treatment with tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptors. INTERVENTION: Patients received sunitinib 50mg daily on a 4-wk on, 2-wk off schedule. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end points were objective response rate (ORR) and progression-free survival (PFS). Secondary end points were safety and overall survival (OS). RESULTS AND LIMITATIONS: Fifty-seven patients were eligible (nccRCC histology: papillary, 27; chromophobe, 5; unclassified, 8; collecting duct or medullary carcinoma, 6; sarcomatoid, 7; and others, 4). Median PFS for 55 evaluable patients was 2.7 mo (95% confidence interval [CI], 1.4-5.4). Two patients with chromophobe and one patient with unclassified histology had a confirmed partial response (5% ORR). Median PFS for patients with papillary histology was 1.6 mo (95% CI, 1.4-5.4). Median PFS for patients with chromophobe histology was 12.7 mo (95% CI, 8.5-NA). Median OS for all patients was 16.8 mo (95% CI, 10.7-26.3). Treatment-emergent adverse events were consistent with sunitinib's mechanism of action. The nonrandomized design and small number of patients are limitations of this study. CONCLUSIONS: The differential response of chromophobe histology to sunitinib suggests a therapeutically relevant biological heterogeneity exists within nccRCC. The low ORR and short PFS with sunitinib in the other nccRCC subtypes underscore the need to enroll patients with these diverse tumors in clinical trials.

Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome.

PURPOSE: To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m(2) intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m(2) IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely. RESULTS: After a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival. CONCLUSION: The combination of vorinostat with idarubicin and cytarabine is safe and active in AML.

Impact of clinical and pathologic features on tumor-infiltrating lymphocyte expansion from surgically excised melanoma metastases for adoptive T-cell therapy.

PURPOSE: Clinical trials on adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) have shown response rates of over 50% in refractory melanoma. However, little is known how clinical and pathologic features impact TIL outgrowth isolated from metastatic melanoma tumors. EXPERIMENTAL DESIGN: We analyzed the impact of clinical and pathologic features on initial TIL outgrowth in 226 consecutive patients undergoing tumor resection. Successful initial TIL outgrowth was defined as ≥40 million viable lymphocytes harvested from all tumor fragments in a 5-week culture. To normalize for the different size of resected tumors and thus available tumor fragments, we divided the number of expanded TIL by the starting number of tumor fragments (TIL/fragment). RESULTS: Overall, initial TIL outgrowth was successful in 62% of patients, with patients ≤30 years of age (94%; P = 0.01) and female patients (71% vs. 57% for males; P = 0.04) having the highest rate of success. Systemic therapy 30 days before tumor harvest negatively impacted initial TIL outgrowth compared to patients who never received systemic therapy (47% vs. 71%, P = 0.02). Biochemotherapy within 0 to 60 days of tumor harvest negatively impacted the initial TIL outgrowth with a success rate of only 16% (P < 0.0001). CONCLUSION: Parameters such as age, sex, and the type and timing of prior systemic therapy significantly affect the success rate of the initial TIL outgrowth from tumor fragments for ACT; these parameters may be helpful in selecting patients for melanoma ACT.

3p22.1 and 10q22.3 deletions detected by fluorescence in situ hybridization (FISH): a potential new tool for early detection of non-small cell lung Cancer (NSCLC).

BACKGROUND: Our objective was to study the feasibility of detecting chromosomal deletions at 3p22.1 and 10q22.3 by fluorescent in situ hybridization (FISH) and to examine their distribution in different areas of the airway in patients with non-small cell lung cancer. METHODS: Brush biopsies from the mainstem bronchus on the normal side contralateral to the tumor (NBB) and mainstem bronchus on the tumor side (TBB) were obtained from 122 patients who underwent surgical resection. Touch preparations from the tumor (TTP), normal lung parenchyma, and bronchi adjacent to the tumor were also obtained. Two FISH assays using probes complementary to 3p22.1 and 10q22.3 were used to detect deletions. RESULTS: NBB showed a relatively low deletion rate of 3p22.1 and 10q22.3 compared with TTP (p < 0.0001). TBB showed a significantly higher rate of deletions compared with NBB but lower than TTP from the tumor (p < 0.05) for both 3p22.1 and 10q22.3. A significantly higher deletion rate was seen at TTP compared with normal lung parenchyma at both the 3p22.1 and 10 q22.3 (p < 0.0001). Correlations were seen between the deletion rates of TTP and TBB at 3p22.1 (rho = 0.61, p < 0.0001) and between TTP and bronchi adjacent to the tumor at 10q22.3 (rho = 0.64, p < 0.0001). CONCLUSION: Deletions of the 3p22.1 and 10q22.3 regions can be reliably detected by FISH. As one progresses from the contralateral normal bronchus to the bronchus on the side of tumor and the tumor itself, the percentage of chromosomal deletions increases in a statistically significant fashion. This suggests that, FISH analysis of bronchoscopic brushes may be useful for identifying patients at high risk for developing non-small cell lung cancer.

Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death.

Novel therapies are clearly needed for the treatment of gliomas, and strategies that involve combining oncolytic vectors with chemotherapy hold out significant hope for a more effective treatment of this malignancy. Whether chemotherapy acts directly on tumor cells by inducing cell arrest or cell death, or indirectly by blocking tumor angiogenesis, the resulting delay in tumor growth may provide the oncolytic virus with a wider window of opportunity to overcome the challenge imposed by the growth kinetics of the tumor. In this study we sought to determine whether the oncolytic adenovirus Delta-24-RGD, in combination with everolimus (RAD001), would result in an enhanced anti-glioma effect in vivo. Viability assays showed that Delta-24-RGD antitumoral activity is synergistically enhanced by combination with RAD001. Interestingly, combination treatment of Delta-24-RGD with RAD001 induced autophagy in vitro. We showed that Delta-24-RGD improved survival of tumor-bearing animals in a dose-dependent manner. A significant finding was that RAD001 enhanced the anti-glioma effect of Delta-24-RGD and resulted in the long-term survival of 80% of the experimental animals. Immunostaining of the treated tumors showed upregulation of Atg5, thereby indicating the therapeutic induction of autophagy. This is the first report showing that Delta-24-RGD plus RAD001 causes autophagic cell death, and dramatically increases long-term survival rates of glioma-bearing animals.

Use of Bayesian net benefit regression model to examine the impact of generic drug entry on the cost effectiveness of selective serotonin reuptake inhibitors in elderly depressed patients.

INTRODUCTION: Since their invention in the late 1980s and early 1990s, selective serotonin reuptake inhibitors (SSRIs) have become the primary form of pharmaceutical treatment for depression. As the patents of several top-selling SSRIs have expired or are soon to be expired, the SSRI market is expected to witness an increasing share of generic SSRIs. We explored the impact of generic drug entry on the cost effectiveness of SSRIs. METHOD: Using Medicare MarketScan claims data, we compared the cost effectiveness of sertraline, citalopram, escitalopram and fluoxetine with paroxetine in elderly depressed patients, before and after the entry of generic paroxetine. We followed users of SSRIs for 6 months, starting from the date of their first prescription of an SSRI. For each patient, we measured costs (C(i)) as total medical costs and quantified effectiveness (E(i)) as the avoidance of treatment failure, which was defined as having a break exceeding 45 days in the use of antidepressants. We then calculated individual net benefit as lambda x E(i)- C(i) and employed both net benefit and Bayesian net benefit regression models to examine the impact of generic paroxetine on the cost effectiveness of the other four SSRIs compared with paroxetine, while controlling for patients' sociodemographic characteristics, co-morbidities and patterns of medication switch. RESULTS: Deterministic analysis showed that paroxetine was dominated by most SSRIs prior to the availability of generic paroxetine, and that, after the entry of generic paroxetine, citalopram and escitalopram were dominated by paroxetine. Net benefit regression analysis found that, at a number of lambda values ($US1000, $US5000 and $US10,000), sertraline and escitalopram were more cost effective than paroxetine in the pre-generic-entry period but not in the post-entry period, although the difference in net benefit between the two SSRIs and paroxetine was not statistically significant in both periods. The Bayesian net benefit regression analysis reached similar conclusions. At lambda = $US5000, the probability that sertraline, citalopram, escitalopram or fluoxetine was more cost effective than paroxetine was 96.7%, 77.6%, 96.3% and 97.0%, respectively, in the pre-entry period in the pooled analysis. These probabilities reduced to 36.7%, 62.7%, 33.0% and 60.1%, respectively, in the post-entry period. The probabilities became 94.1%, 71.9%, 89.1% and 92.1% in analysis using the pre-entry data as a prior to update the post-entry data rather than using the pooled data. CONCLUSION: Using generic drug entry as an example, our study demonstrated the importance of including the economic life cycle of pharmaceuticals in cost-effectiveness analyses. Additionally, the proposed Bayesian framework not only preserves the advantages of the net benefit regression framework, but more importantly, it introduces the possibility of conducting probabilistic cost-effectiveness analyses with claims data.

Alterations in the mitochondrial displacement loop in lung cancers.

PURPOSE: Alterations of the noncoding displacement (D) loop of mitochondrial DNA are present in many cancers. These alterations include numerical changes in a homopolymeric C tract (PCT) at positions 303-309 and single base substitutions (SBS). We determined the frequency of D-loop alterations in lung cancer cell lines and tumors, and related them to clinicopathologic features. EXPERIMENTAL DESIGN: We sequenced the entire D-loop of 28 lung cancer cell lines [12 small cell lung cancer (SCLC) and 16 non-small cell lung cancer (NSCLC)] and matched B-lymphoblastoid cell lines. In 55 resected NSCLCs and corresponding nonmalignant lungs we determined the length of the PCT. RESULTS: In nonmalignant cell lines and tissues the most frequent PCT repeat number was seven (36 of 83; 43%) with a range of six to nine. Alterations, often multiple, were present in 17 of 28 (61%) of the cell lines, including 8 of 12 SCLC (67%) and 9 of 16 NSCLC (56%) lines. They consisted of SBS in 8 of 28 lines (29%), all of which were homoplasmic, and PCT changes in 14 of 28 (50%) lines, 8 of which were homoplasmic. Of interest, 95% (40 of 42) of the SBS were present within the two hypervariable regions in the D-loop. Because SBS were more frequent if PCT changes were present, only the PCT number was determined in resected samples. PCT changes were present in 11 of 55 (20%) of the NSCLC tumors. Changes were never noted in tumors when the PCT number in the nonmalignant tissue was seven, and only two tumor cell lines had changes when the PCT number in the matched lymphoblastoid cell line was seven. These changes were higher in squamous cell carcinomas (8 of 25; 32%) than in adenocarcinomas (3 of 30; 10%; P = 0.04) and in large tumors (T3 and T4; 7 of 20; 35%) compared with smaller tumors (T1 and T2; 4 of 35; 11%; P = 0.04). Smoking history, gender, age, and stage were not related to frequency of PCT change. CONCLUSIONS: Our findings indicate that D-loop alterations are frequent in lung cancers and their cell lines, and that these changes are weakly associated with certain clinical parameters. In tumors PCT changes were only present when the corresponding nonmalignant lung demonstrated a variation from the most common repeat number of seven.