Phase I/II study of bevacizumab with BKM120, an oral PI3K inhibitor, in patients with refractory solid tumors (phase I) and relapsed/refractory glioblastoma (phase II).

BACKGROUND: Current bevacizumab-based regimens have failed to improve survival in patients with recurrent glioblastoma. To improve treatment efficacy, we evaluated bevacizumab + BKM120, an oral pan-class I PI3K inhibitor, in this patient population. METHODS: A brief phase I study established the optimal BKM120 dose to administer with standard-dose bevacizumab. BKM120 60 mg PO daily + bevacizumab 10 mg/kg IV every 2 weeks in 28-day cycles was then administered to patients with relapsed/refractory glioblastoma in the phase II portion. RESULTS: Eighty-eight patients enrolled (phase I, 12; phase II, 76). In phase I, BKM120 80 mg PO daily produced dose limiting toxicity in 3 of 6 patients; a BKM120 dose of 60 mg PO daily was established as the maximum tolerated dose. In phase II, the median progression-free survival (PFS) was 4.0 months (95% CI 3.4, 5.4), PFS at 6 months was 36.5%, and the overall response rate was 26%. Forty-two patients (57%) experienced one or more serious treatment related toxicities. The most common CNS toxicities included mood alteration (17%) and confusion (12%); however, these were often difficult to classify as treatment- versus tumor-related. CONCLUSIONS: The efficacy seen in this study is similar to the efficacy previously reported with single-agent bevacizumab. This regimen was poorly tolerated, despite the low daily dose of BKM120. Further development of this combination for the treatment of glioblastoma is not recommended.

MB0 and MBI Are Independent and Distinct Transactivation Domains in MYC that Are Essential for Transformation.

MYC is a transcription factor that is essential for cellular proliferation and development. Deregulation or overexpression of MYC occurs in a variety of human cancers. Ectopic expression of MYC causes hyperproliferation and transformation of cells in culture and tumorigenesis in several transgenic mouse models. Deregulation of MYC can also induce apoptosis through activation of p53 and/or ARF tumor suppressors as a safeguard to prevent tumorigenesis. MYC binds to thousands of genomic sites and regulates hundreds of target genes in a context-dependent fashion to mediate these diverse biological roles. The N-terminal region of MYC contains several conserved domains or MYC Boxes (MB), which influence the different MYC transcriptional and biological activities to varying degrees. However, the specific domains that mediate the ability of MYC to activate transcription remain ill defined. In this report, we have identified a new conserved transactivation domain (TAD), MB0, which is essential for MYC transactivation and target gene induction. We demonstrate that MB0 and MBI represent two distinct and independent TADs within the N-terminal 62 amino acids of MYC. In addition, both MB0 and MBI are essential for MYC transformation of primary fibroblasts in cooperation with activated RAS, while MB0 is necessary for efficient MYC-induced p53-independent apoptosis.

A phase II trial of carboplatin and weekly topotecan in the first-line treatment of patients with extensive stage small cell lung cancer.

BACKGROUND: Carboplatin and topotecan are commonly used in the treatment of small cell lung cancer (SCLC); however, there are no data for this combination in the first-line setting using weekly topotecan. In this multicenter, community-based phase II trial, we evaluated carboplatin and weekly topotecan in the previously untreated patients with extensive stage SCLC. METHODS: This trial was designed to achieve an objective response rate (ORR) of 70% (alpha = 0.05; beta = 0.20); secondary aims were to assess time to progression, toxicity, and overall survival (OS). Patients with Eastern Cooperative Oncology Group performance status 0 to 1, measurable disease, and adequate organ function were eligible. TREATMENT: carboplatin area under the concentration-time curve = 5 (intravenous) on day 1 and topotecan 4 mg/m(2) (intravenous) on days 1 and 8, every 21 days for up to six cycles, with restaging every 6 weeks (per RECIST). RESULTS: Between June 2006 and November 2008, 61 patients were enrolled. The median follow-up is 40 weeks (range 27-109 weeks). Patient characteristics were as follows: median age 67 years (range 40-84 years); male, 53%; and Eastern Cooperative Oncology Group performance status 0, 28%. Complete responses were seen in two patients and partial responses in 33 patients; ORR was 57% (95% confidence interval [CI] 44-70). Stable disease was seen in 12 patients (20%), and progressive disease was seen in two patients (3%). The median time to progression was 5.5 months (95% CI 4.0-6.3 months). The median OS was 8.5 months (95% CI 7.2-11.4 months). One-year OS was 29%. Grade 3/4 toxicity in >5%: neutropenia (66%), thrombocytopenia (48%), leukopenia (40%), anemia (30%), fatigue (13%), dehydration (8%), infection (8%), and pain (7%). CONCLUSIONS: The ORR achieved with carboplatin and weekly topotecan was less than the anticipated rate of 70%; however, it was comparable with historical rates seen with other platinum doublets in the first-line extensive stage SCLC setting. This regimen was generally well tolerated, with myelosuppression as its primary toxicity.

Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial.

PURPOSE: To compare the results of empiric first-line therapy with paclitaxel/carboplatin/etoposide (PCE) versus gemcitabine/irinotecan, both followed by single-agent gefitinib, in patients with carcinoma of unknown primary site. PATIENTS AND METHODS: Patients with previously untreated carcinoma of unknown primary site were randomized to receive either PCE or gemcitabine/irinotecan. Responding and stable patients continued treatment for 4 to 6 cycles. Patients with no evidence of tumor progression at that time received single-agent gefitinib until tumor progression. The trial was designed to detect an improvement in the 2-year survival rate from 20% to 30%. RESULTS: Between September 2003 and July 2008, 198 patients entered this multicenter, community-based trial. Because of slow accrual, the trial was stopped short of its target accrual of 320 patients. Clinical characteristics were comparable for patients receiving PCE (N = 93) and gemcitabine/irinotecan (N = 105). PCE and gemcitabine/irinotecan produced similar 2-year survival (15% vs. 18%), median survival (7.4 months vs. 8.5 months), median progression-free survival (3.3 months vs. 5.3 months), and response rate (18% vs. 18%). Grade 3/4 neutropenia, thrombocytopenia, anemia, febrile neutropenia, and red blood cells transfusions were more common with PCE; diarrhea was more common with gemcitabine/irinotecan. The median duration of gefitinib maintenance was 3 months, suggesting no role as a maintenance therapy in this setting. DISCUSSION: The PCE and gemcitabine/irinotecan regimens have comparable efficacy in the first-line treatment of patients with carcinoma of unknown primary site. Gemcitabine/irinotecan is the preferable regimen, due to its favorable toxicity profile. However, the moderate efficacy of both regimens underscores the need for novel treatment approaches in this patient population.