Journal: Investigational new drugs
Systemic chemotherapy using two-drug platinum-based regimens for the treatment of advanced stage non-small cell lung cancer (NSCLC) has largely reached a plateau of effectiveness. Accordingly, efforts to improve survival and quality of life outcomes have more recently focused on the use of molecularly targeted agents, either alone or in combination with standard of care therapies such as taxanes. The molecular chaperone heat shock protein 90 (Hsp90) represents an attractive candidate for therapeutic intervention, as its inhibition results in the simultaneous blockade of multiple oncogenic signaling cascades. Ganetespib is a non-ansamycin inhibitor of Hsp90 currently under clinical evaluation in a number of human malignancies, including NSCLC. Here we show that ganetespib potentiates the cytotoxic activity of the taxanes paclitaxel and docetaxel in NSCLC models. The combination of ganetespib with paclitaxel, docetaxel or another microtubule-targeted agent vincristine resulted in synergistic antiproliferative effects in the H1975 cell line in vitro. These benefits translated to improved efficacy in H1975 xenografts in vivo, with significantly enhanced tumor growth inhibition observed in combination with paclitaxel and tumor regressions seen with docetaxel. Notably, concurrent exposure to ganetespib and docetaxel improved antitumor activity in 5 of 6 NSCLC xenograft models examined. Our data suggest that the improved therapeutic indices are likely to be mechanistically multifactorial, including loss of pro-survival signaling and direct cell cycle effects resulting from Hsp90 modulation by ganetespib. Taken together, these findings provide preclinical evidence for the use of this combination to treat patients with advanced NSCLC.
Background BTH1677 is a beta glucan pathogen associated molecular pattern (PAMP) currently being investigated as a novel cancer therapy. Here, the initial safety and pharmacokinetic (PK) results of BTH1677 in healthy subjects are reported. Subjects and Methods In the Phase 1a single-dosing study, subjects were randomized (3:1 per cohort) to a single intravenous (iv) infusion of BTH1677 at 0.5, 1, 2, 4, or 6 mg/kg or placebo, respectively. In the Phase 1b multi-dosing study, subjects were randomized (3:1 per cohort) to 7 daily iv infusions of BTH1677 at 1, 2, or 4 mg/kg or placebo, respectively. Safety and PK non-compartmental analyses were performed. Results Thirty-six subjects (N = 24 Phase 1a; N = 12 Phase 1b) were randomized to treatment. No deaths or serious adverse events occurred in either study. Mild or moderate adverse events (AEs) occurred in 67 % of BTH1677-treated subjects in both studies. Treatment-related AEs (occurring in ≥10 % of subjects) included dyspnea, flushing, headache, nausea, paraesthesia, and rash in Phase 1a and conjunctivitis and headache in Phase 1b. BTH1677 serum concentration was linear with dose. Clearance, serum elimination half-life (t1/2) and volume of distribution (Vss) were BTH1677 dose-independent. In Phase 1b, area under the curve, t1/2, and Vss values were larger at steady state on days 6-30 versus day 0. Conclusions BTH1677 was well tolerated after single doses up to 6 mg/kg and after 7 daily doses up to 4 mg/kg.
Introduction The analysis of predictive factors of response may aid in predicting which patients with advanced renal cell carcinoma (RCC) would be good candidates for systemic treatments. Materials and methods The expression of several biomarkers was retrospectively analyzed using immunohistochemistry (IHC), as well as 2 analytical variables in 135 patients with advanced RCC treated with cytokines (CK) and/or new targeted drugs (NTD). Results 67 patients were treated solely with NTD and 68 with CK (23 also received NTD). Univariate analysis: HIF1α did not correlate significantly with response to these drugs. Overexpression of CAIX was associated with more responses (%) to NTD (64.7 vs. 21.1; p = 0.004) and CK (22.6 vs. 0; p = 0.038). PTEN demonstrated predictive value of response to sunitinib (70.8 vs. 34.1; p = 0.005). p21 was associated with a lower response to sunitinib (35.9 vs. 65.4; p = 0.025). Thrombocytosis was not significantly associated with response to NTD, although it was with CK (0 vs. 20; p = 0.017). Neutrophilia correlated with a lower response to NTD (29.6 vs. 57.5; p = 0.045), although not with CK. Multivariate analysis: Overexpression of CAIX was an independent predictor of significantly higher response to NTD and CK; OR = 8.773 (p < 0.001). Conclusions Our findings highlight the usefulness of CAIX in selecting patients with advanced RCC as candidates for systemic treatment. PTEN and p21 may be important in predicting response to sunitinib. Thrombocytosis and neutrophilia correlate well with response to CK and NTD, respectively.
Purpose This study investigated the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic (PK) profiles of DHP107, a novel oral paclitaxel containing neither Cremophor EL nor P-glycoprotein (P-gp) inhibitor. Patients and methods Patients with advanced solid tumors refractory to all standard treatments were administered a single oral dose of DHP107 on a dose-escalating schedule (60-600 mg/m(2)) during the first chemotherapy cycle, and intravenous paclitaxel 175 mg/m(2) during subsequent cycles. Cohorts of 3 patients were treated at each dose level provided no DLTs were observed. The pharmacokinetics of paclitaxel and its metabolites were investigated for oral DHP107 and intravenous paclitaxel. Results Thirty-four patients were enrolled. Dose-limiting toxicities were not observed, even at the highest dose level (600 mg/m(2)). Further dose escalation was not performed because pharmacokinetics did not increase proportionally at doses above 250 mg/m(2). The coefficient of variance of AUClast DHP107 ranged from 11.8 % to 34.0 %, comparable to 24.4 % of intravenous paclitaxel 175 mg/m(2). There were no grade 4 toxicities, whereas grade 3 toxicities included diarrhea (12.1 %), neutropenia (6.1 %) and fatigue (3.0 %). While no objective responses were observed, 11 patients (33.3 %) showed stable disease. Conclusions DHP107 was safe and feasible in patients with advanced malignancies. As exposure of paclitaxel plateau among patients receiving more than 250 mg/m(2) of DHP107, the dose escalation of DHP107 may be limited to 250 mg/m(2) in further clinical trials.
Acute lymphoblastic leukemia (ALL) is a potentially fatal disease that involves clonal expansion of early lymphoid progenitor cells. Much of drug development for ALL treatment involves targeting antigens of the clonal cell surface. Blinatumomab belongs to an emerging class of anti-cancer therapeutics referred to as bispecific T-cell engaging antibodies. The Food and Drug Administration approved its use in relapsed or refractory adult Philadelphia chromosome-negative B-cell precursor ALL in December of 2014.
The anti-cancer efficacy of methionine γ-lyase (MGL) from Clostridium sporogenes (C. sporogenes) is described. MGL was active against cancer models in vitro and in vivo. The calculated EC50 values for MGL were 4.4 U/ml for A549, 7.5 U/ml for SK-BR3, 2.4 U/ml for SKOV3, and 0.4 U/ml for MCF7 cells. The combination of doxorubicin (DOX) and MGL was more effective for A549 human lung cancer growth inhibition than either agent alone in vitro and in vivo. MGL reduced the EC50 of doxorubicin from 35.9 μg/mL to 0.01-0.265 μg/mL. The growth inhibitory effect of DOX + MGL on A549 xenografts in vivo was reflective of the results obtained in vitro. The inhibition rate of tumor growth in the combined arm was 57%, significantly higher than that in the doxorubicin (p = 0.033)-alone arm.
Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Methods This was a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors. A treatment cycle comprised 5 days of oral administration followed by 16 days of rest, for a total of 21 days (3-week cycle). Results Nineteen of 21 enrolled patients with confirmed metastatic disease received study medication. No DLTs occurred at the first 3 dose levels (6, 12, and 24 mg/m(2)/day). At the subsequent dose level (48 mg/m(2)/day), 2 of 3 patients developed DLTs. An intermediate level of 36 mg/m(2)/day was therefore investigated. Four patients were treated and two DLTs were observed. After further cohort expansion, the MTD and recommended phase II dose (RP2D) were determined to be 24 mg/m(2)/day. Disease stabilization, observed in several patients, was the best treatment response observed. Hematological toxicity (mostly thrombocytopenia and neutropenia) was the major DLT. Systemic exposure to NMS-1286937 increased with dose and was comparable between two cycles of treatment following oral administration of the drug. Conclusions This study successfully identified the MTD and DLTs for NMS-1286937 and characterized its safety profile.
Introduction This was an open-label, dose escalation (3 + 3 design), Phase I study of SOR-C13 in patients with advanced tumors of epithelial origin. Primary objectives were to assess safety/tolerability and pharmacokinetics. Secondary goals were to assess pharmacodynamics and efficacy of SOR-C13. Methods SOR-C13 was administered IV QD on days 1-3 and 8-10 of a 21-day cycle. Doses were 2.75 and 5.5 mg/kg (20-min infusion) and 1.375, 2.75, 4.13 and 6.2 mg/kg (90-min infusion). Toxicity was assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose limiting toxicity (DLT) was assessed within the first treatment cycle. Tumors were evaluated, using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, after two cycles. Results Twenty-three patients were treated. No drug-related serious adverse events occurred. DLTs occurred in six patients: asymptomatic, drug-related, transient Grade 2 hypocalcemia (4 patients), and unrelated Grade 3 anemia and Grade 3 atrial fibrillation, 1 patient each. Calcium and vitamin D supplementation eliminated further Grade 2 hypocalcemia. One Grade 3 treatment emergent adverse event, urticaria, was definitely related to SOR-C13. Four possibly drug-related, Grade 3 events (alanine aminotransferase and aspartate aminotransferase elevation, headache, and hypokalemia) were observed. Of 22 evaluable patients, 54.5% showed stable disease ranging from 2.8 to 12.5 months. The best response was a 27% reduction in a pancreatic tumor with a 55% reduction in CA19-9 levels at 6.2 mg/kg. Conclusion SOR-C13 was safe and tolerated up to 6.2 mg/kg. The Maximal Tolerated Dose (MTD) was not established. Stable disease suggested antitumor activity.
Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods Patients were randomized 2:1 to the BTH1677 arm (N=60; BTH1677, 4 mg/kg, weekly; cetuximab, initial dose 400 mg/m(2) and subsequent doses 250 mg/m(2), weekly; carboplatin, 6 mg/mL/min AUC (area-under-the-curve) by Calvert formula, once each 3-week cycle [Q3W]); and paclitaxel, 200 mg/m(2), Q3W) or Control arm (N=30; cetuximab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles; patients who responded or remained stable received maintenance therapy with BTH1677/cetuximab (BTH1677 arm) or cetuximab (Control arm). Investigator and blinded central radiology reviews were conducted. Efficacy assessments included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, time-to-progression and overall survival (OS); safety was assessed by adverse events (AEs). Potential biomarker analysis for BTH1677 response was also conducted. Results Compared to control treatment, the addition of BTH1677 numerically increased ORR by both investigator (47.8% vs 23.1%; p=0.0468) and central (36.6% vs 23.1%; p=0.2895) reviews. No other endpoints differed between arms. PK was consistent with previous studies. BTH1677 was well tolerated, with AEs expected of the backbone therapy predominating. Biomarker-positive patients displayed better ORR and OS than negative patients. Conclusions BTH1677 combined with cetuximab/carboplatin/paclitaxel was well tolerated and improved ORR as first-line treatment in patients with advanced NSCLC. Future patient selection by biomarker status may further improve efficacy ClinicalTrials.gov Identifier: NCT00874848.
The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia, including cell proliferation, survival, apoptosis, scattering and motility, invasion, and angiogenesis. MET over-expression (with or without gene amplification), aberrant autocrine or paracrine ligand production, and missense MET mutations are mechanisms that lead to activation of the MET pathway in tumors and are associated with poor prognostic outcome. We report here preclinical development of a potent, orally bioavailable, small-molecule inhibitor LY2801653 targeting MET kinase. LY2801653 is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a dissociation constant (K(i)) of 2 nM, a pharmacodynamic residence time (K(off)) of 0.00132 min(-1) and t(½) of 525 min. LY2801653 demonstrated in vitro effects on MET pathway-dependent cell scattering and cell proliferation; in vivo anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects. LY2801653 also maintained potency against 13 MET variants, each bearing a single-point mutation. In subsequent nonclinical characterization, LY2801653 was found to have potent activity against several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2 and against the serine/threonine kinases MKNK1/2. The potential value of MET and other inhibited targets within a number of malignancies (such as colon, bile ducts, and lung) is discussed. LY2801653 is currently in phase 1 clinical testing in patients with advanced cancer (trial I3O-MC-JSBA, NCT01285037).