Umang Swami

Eribulin—A review of preclinical and clinical studies

Eribulin mesylate is a non-taxane, structurally simplified, completely synthetic, halichondrin B derivative with an end poisoning, microtubule inhibitory action. Preclinical studies have demonstrated activity in various cancer cell lines and synergistic action with gemcitabine, epirubicin, trastuzumab, cisplatin, docetaxel and vinorelbine. Eribulin has recently been approved by United States Food and Drug Administration as a third line therapy for metastatic breast cancer patients, who have previously been treated with an anthracycline and a taxane. It has also advanced to phase II trials in non-small cell lung cancer, pancreatic, prostate, bladder, head and neck cancers, sarcomas and ovarian and other gynecological tumors. Combination trials with carboplatin, gemcitabine, pemetrexed, cisplatin, and erlotinib are currently ongoing. Eribulin potentially has a low incidence of peripheral neuropathy. The predominant side effects are neutropenia and fatigue, which are manageable. This article reviews the available information on eribulin with respect to its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism, preclinical studies and clinical trials.

Abstract C216: Phase 1, first‐in‐human, dose‐escalation study of EZN‐2208, a novel anticancer agent, in patients (pts) with advanced malignancies

Background: SN38, the active moiety of irinotecan, is a potent topoisomerase I inhibitor. Thus far, SN38 itself has not been used as an anticancer drug in humans due to its poor solubility in any pharmaceutically acceptable formulation. EZN‐2208 (PEG‐SN38) is a water‐soluble, polyethylene glycol drug conjugate of SN38 that is active in preclinical models of solid tumors/lymphoma, including an in vivo CPT‐11‐resistant tumor model. EZN‐2208 accumulates in tumors, where it releases SN38. EZN‐2208 also down‐modulates mRNA of hypoxia‐inducible factor‐1α (HIF‐1α) target genes, and has been shown to have anti‐angiogenic and anti‐apoptotic effects. Methods: Pts with advanced solid tumors were enrolled to determine the safety, tolerability, pharmacokinetics (PK), maximum tolerated dose (MTD), recommended dose, and preliminary evidence of antitumor activity of EZN‐2208 administered as a 1‐h IV infusion every 3 weeks. Dose escalation (3+3) was based on drug‐related toxicities observed during the first cycle. Plasma concentrations of EZN‐2208 and SN38 were determined by HPLC using fluorescence detection. PK parameters were estimated using a noncompartmental model analysis. Results: 39 pts (59% women; median age = 58 y [24‐78 y]) received EZN‐2208 either without first‐cycle G‐CSF per the original protocol (n=27) or with first‐cycle G‐CSF per protocol amendment (n=12) after the dose‐limiting toxicity (DLT) was found to be neutropenic fever. Pts received EZN‐2208 doses of 1.25 mg/m2 (n=3), 2.5 mg/m2 (n=3), 5.0 mg/m2 (n=5), 10 mg/m2 (n=10), 16.5 mg/m2 (n=6), 16.5 mg/m2 with G‐CSF (n=6), and 25 mg/m2 with G‐CSF (n=6). All pts had received previous treatment (median number of prior regimens = 3 (1–11). Tumor types included colorectal cancer (CRC) (n=14); breast, head & neck, and pancreatic cancers (n=3 each); ovarian, thyroid, and uterine cancers (n=2 each); cholangiocarcinoma (n=1); and anal, esophageal, fallopian tube, gallbladder, gastric, hepatocellular, SCLC, unknown primary, and vulvar cancers (n=1 each). Pts received 1 to 7 treatment cycles. The DLT was Grade 3 to 4 febrile neutropenia, which was reported in 2 pts who received 16.5 mg/m2 EZN‐2208 without G‐CSF and in 2 pts who received 25 mg/m2 EZN‐2208 with G‐CSF. Adverse events (AEs) were mostly Grade 1 or 2. The most common AEs (>20% of pts) considered likely related to study drug were fatigue (41%), nausea (36%), alopecia and diarrhea (33% each), neutropenia (23%), and vomiting (21%). Only 1 of all 39 pts had Grade 3 diarrhea in Cycle 1. Prolonged stable disease (>90 days), sometimes associated with tumor shrinkage (), was observed as best response (duration on study) for 9 pts with colorectal (214+ [K‐RAS mutation], 148, 127, 127, 111 days), breast (135 days ↓), uterine (130 days ↓), cholangiocarcinoma (129 days ↓), and head and neck (262+ days) cancers. The 5 pts with mCRC had received prior irinotecan. Conclusions: EZN‐2208, a novel agent, was well tolerated in previously treated pts with advanced malignancies. No cumulative toxicities were reported. DLT was neutropenic fever, in distinction to the DLT of irinotecan. The MTD and recommended dose of EZN‐2208 for this regimen is 10 mg/m2 without G‐CSF and 16.5 mg/m2 with G‐CSF. For some pts, the duration of EZN‐2208 was longer than for their prior therapy. This study is closed to accrual; final results, including PK, will be presented at the meeting. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C216.

Clinical outcome and prognostic markers for patients with gynecologic malignancies in phase 1 clinical trials: A single institution experience from 1999 to 2010

OBJECTIVES There is a scarcity of outcome data regarding phase 1 trials for patients with gynecologic malignancy. The objective of this study was to assess toxicity, clinical benefit and prognosticators in gynecologic oncology patients participating in phase 1 trials. METHODS All phase 1 oncology trials conducted at Albert Einstein Cancer Center from 1999 to 2010 were reviewed and extracted for relevant demographic and clinical data concerning patients with gynecologic malignancy. Cox-proportional and logistic regression modeling were used for multivariate analysis. RESULTS 120 distinct patients with gynecologic malignancy participated in 41 trials, constituting 30.6% of all phase 1 patients enrolled in the same time period. The median age is 59 years. Out of the 184 patients enrolled, 160 individual responses were evaluable. Seventeen DLT events (9.2%) occurred, including 1 (0.5%) treatment-related mortality. There were 27.2%≥ grade 3 hematologic and 24.4% non-hematologic toxicity. Eighty patients had stable disease (SD, 50%), including 21.9% with SD ≥ 4 months, 11 (6.3%) with partial response (PR), and 3 (1.9%) achieving complete response (CR). The clinical benefit rate (CBR=SD+CR+PR) was 58.1%. Albumin (Alb)≤ 3.5 g/dL and abnormal ANC were independent negative prognosticators of survival. We also found a continuous correlation between changes in Albumin (p=0.02) and LDH (p=0.02) and odds of achieving CBR≥4month. CONCLUSIONS Our clinical outcome and safety data suggested that phase 1 trials may be a reasonable option for patients with advanced and recurrent gynecologic cancer. The potential prognosticators identified should be further validated in larger trials.