Summary Sitravatinib (MGCD516) is an oral inhibitor of several closely related oncogenic tyrosine kinase receptors that include VEGFR-2 (vascular endothelial growth factor receptor-2), AXL, and MET (mesenchymal-epithelial transition). The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also assessed. Overall, 48 patients (RCC n = 38, CRPC n = 10) received ≥ 1 dose of sitravatinib. Both cohorts were heavily pretreated (median number of prior systemic therapies: RCC cohort 3, CRPC cohort 6). In the RCC cohort, ORR was 25.9%, P = 0.015 (null hypothesis [ORR ≤ 10%] was rejected). Responses were durable (median duration 13.2 months). Median PFS was 9.5 months and median OS was 30.0 months. No objective responses were seen in the CRPC cohort; median PFS and OS were 5.8 months and 10.1 months, respectively. Across both cohorts, diarrhea (72.9%), fatigue (54.2%), and hypertension (52.1%) were the most frequent all-cause treatment-emergent adverse events (TEAEs). Diarrhea and vomiting (both, 6.3%) were the most frequent serious TEAEs considered related to study treatment. Sitravatinib demonstrated an acceptable safety profile and promising clinical activity in patients with clear cell RCC refractory to prior angiogenesis inhibitor therapy. Strong indicators for clinical activity were not seen in patients with CRPC and bone metastases. Clinical trial registration :ClinicalTrials.gov NCT02219711.
Abstract Background: Combining proteasome inhibition with HDAC inhibition has recently been shown to provide synergistic anti-tumor activity in preclinical and clinical studies. A proposed mechanism centers around inhibition of both of the major protein disposal mechanisms of the cell, resulting in near complete lack of ability of the tumor to dispose of normal pro-apoptotic and growth inhibitory peptides. The bi-cyclic structure of NPI-0052 is not polypeptide based as are other proteasome inhibitors, leading to rapid, broad and prolonged inhibition of all 3 proteolytic sites, with unique proteasome inhibition, toxicology and efficacy profiles. Preclinical studies indicated marked synergy with a number of HDAC inhibitors in solid tumor and hematologic malignancy models. Materials and Methods: Patients with melanoma, pancreatic carcinoma and NSCLC having failed standard therapies were given NPI-0052 intravenously on a weekly (Days 1, 8 and 15) schedule dose escalation, in combination with vorinostat 300 mg orally on the first 16 days of each 28 day cycle. A 3+3 design was used with the dose of NPI-0052 escalated from 0.15 mg/m2 to 0.7 mg/m2. In addition to standard safety laboratory studies, proteasome inhibition and pharmacokinetics are also assayed in blood on Day 1 and multiple subsequent time points. Results: 20 patients have been enrolled into this study. There has not been an indication of increased toxicity with the combination, and the dose of NPI-0052 has been escalated to and is currently being administered at the full single agent dose without dose limiting toxicity. Pharmacokinetic data indicate a short half life of NPI-0052 (<15 min) and large volumes of distribution (Vz =73.9 ± 44.7 L and Vss=80.7 ± 53.6 L), which do not seem to be dose dependent. The PK parameters of vorinostat were in agreement with published data (T1/2 of 1.69 ± 0.86 hours and Vz/F of 1040.1±458.3L). Co-administration of Vorinostat with NPI-0052 therefore does not appear to affect the kinetics of either drug. Proteasome inhibition assays demonstrate dose dependent inhibition of the chymotrypsin-like proteasome activity of up to 78%. The majority of the patients enrolled have had metastatic melanoma. Seven of 14 evaluable patients have demonstrated regressions in tumor measurements. Conclusions: The combination of full dose NPI-0052 with vorinostat is tolerable and has not resulted in unexpected safety findings (of note the toxicity profile is dissimilar to that reported with other proteasome inhibitors, in not inducing neutropenia, thrombocytopenia or peripheral neuropathy). Pharmacokinetic and pharmacodynamic results were likewise consistent with what are expected from prior data with each drug. Enrollment continues to further characterize the combination at the recommended phase 2 dose. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A107.
MHC class II molecules carry the restriction determinants (RDs) for antigen presentation to antigen-specific Th lymphocytes. This restriction of T cell activation endows those molecules with a key role in the induction and regulation of antigen-specific immune responses. Moreover, class II molecules are the products of class II immune response (Ir) genes. The polymorphism of these Ir genes leads to genetically controlled differences in immuneresponsiveness between different individuals. An important human example is leprosy, in which HLA class II-linked Ir genes determine the immune response against Mycobacterium leprae, the causative organism of the disease. Since the immune response against M. leprae is entirely dependent on Th cells, the HLA class II-linked Ir gene products may well regulate the immune response by controlling the presentation of M. leprae antigens to Th cells. We therefore have investigated the HLA class II RD repertoire of M. leprae-reactive Th cell clones (TLC) by means of extensive panel and inhibition studies with fully class II-typed allogeneic APCs and well-defined HLA class II-specific mAbs. The TLC studied (n, 36) proliferated specifically towards M. leprae, produced IFN-gamma upon activation, and had the CD3+CD4+CD8- phenotype. The results show in the first place that the majority of the RDs for M. leprae reside on DR and not on DP or DQ molecules. This indicates a major role for DR molecules in the immune response to M. leprae and suggests that these molecules are the main products of M. leprae-specific Ir genes. Furthermore, since the expression of DR molecules is much stronger than that of DP and DQ molecules, these findings suggest that the localization of RDs for M. leprae on class II molecules correlates with the quantitative expression of these molecules. The observation that the RDs on DR molecules coded by a DR4 haplotype were situated only on those DR molecules that are known to be highest in expression can be explained in the same way. Second, four distinct RDs related with but not identical to the Dw13 allodeterminant were carried by the DR+DRw53- (alpha beta 1) molecules of a DR4Dw13 haplotype. Since the known amino acid residue differences between the allelic DR4 related Dw beta 1 chains cannot explain the observed RD-polymorphism, this observation suggests that multiple distinct RDs unique for the DR4Dw13 haplotype are expressed by these molecules. Only 2 of 36 TLC were not restricted by DR.(ABSTRACT TRUNCATED AT 400 WORDS)
2575 Background: MGCD516 is an oral, potent small molecule inhibitor of a closely related spectrum of RTKs including RET, TRK family, DDR2, MET, AXL and split RTKs (VEGFR, PDGFR and KIT). MGCD516 has demonstrated antitumor activity in nonclinical cancer models harboring genetic alterations of MGCD516 targets including rearrangement of RET or NTRK or CHR4q12 amplification. Methods: Study objectives include evaluation for safety, pharmacokinetics (PK), pharmacodynamics (PD), the maximum tolerated dose (MTD) and clinical activity of MGCD516 in patients (pts) with advanced solid tumors. Eligible pts received a single dose for PK profiling followed by continuous daily dosing (QD) in 21 day cycles. Results: 32 unselected pts (14 men/18 women; median age 62 years; range 27-85) with advanced solid tumors were treated in escalating dose cohorts of 10, 20, 40, 80, 110, 150 or 200mg MGCD516. At 80mg, 1 of 6 evaluable pts experienced a DLT (Grade 3 palmar plantar erythrodysesthesia). At 200mg, 3 DLTs were observed among 3 evaluable pts (intolerable Grade 2 neuropathy, fatigue and stomatitis in 1 pt each), demonstrating 200mg exceeded the MTD. Treatment-related AEs ( > 15% of pts; Grade1-3) included hypertension, fatigue, diarrhea, nausea and decreased appetite. One treatment-related Grade 4 AE (febrile neutropenia) was reported. Prolonged stable disease (SD) has been observed in multiple pts including 3 pts with at least 17 weeks SD and 1 pt with 35 weeks SD. Preliminary PK data show that exposure increased dose proportionally with doses up to 200mg. At 150mg, the Cavg and AUC0-24 values at steady state (90.7 ng/mL and 2.18 μg·h/mL, resp.) exceed plasma exposure projections required for inhibition of key RTK targets and antitumor efficacy in nonclinical tumor models. Preliminary clinical PD data indicate dose dependent inhibition of the VEGF and MET pathways. Conclusions: The Phase 1b dose for MGCD516 was established at 150mg QD. MGCD516 shows favorable PK characteristics, on-target PD effects and is associated primarily with constitutional or GI-related AEs. Phase 1b enrollment began November 2015. Pts with NSCLC or other solid tumors with specific genetic alterations in MGCD516 target RTK genes are being enrolled. Clinical trial information: NCT02219711.
The diketopiperazine NPI-2358 is a synthetic analog of NPI-2350, a natural product isolated from Aspergillus sp., which depolymerizes microtubules in A549 human lung carcinoma cells. Although structurally different from the colchicine-binding site agents reported to date, NPI-2358 binds to the colchicine-binding site of tubulin. NPI-2358 has potent in-vitro anti-tumor activity against various human tumor cell lines and maintains activity against tumor cell lines with various multidrug-resistant (MDR) profiles. In addition, when evaluated in proliferating human umbilical vein endothelial cells (HUVECs), concentrations as low as 10 nmol/l NPI-2358 induced tubulin depolymerization within 30 min. Furthermore, NPI-2358 dose dependently increases HUVEC monolayer permeability--an in-vitro model of tumor vascular collapse. NPI-2358 was compared with three tubulin-depolymerizing agents with vascular-disrupting activity: colchicine, vincristine and combretastatin A-4 (CA4). Results showed that the activity of NPI-2358 in HUVECs was more potent than either colchicine or vincristine; the profile of CA4 approached that of NPI-2358. Altogether, our data show that NPI-2358 is a potent anti-tumor agent which is active in MDR tumor cell lines, and is able to rapidly induce tubulin depolymerization and monolayer permeability in HUVECs. These data warrant further evaluation of NPI-2358 as a vascular-disrupting agent in vivo. Currently, NPI-2358 is in preclinical development for the treatment of cancer.
6152 NPI-0052 is a potent, structurally novel, small molecule proteasome inhibitor isolated from the fermentation broth of a Salinosporasp. NPI-0052 shares a common bicyclic γ-lactam-β-lactone ring structure with Omuralide and PS-519, two known 20S proteasome inhibitors. NPI-0052 specifically inhibits all three major proteolytic activities of purified human 20S proteasome with EC50 values ranging from 3 nM to 400 nM. Furthermore, NPI-0052 demonstrates potent anti-tumor activity against a panel of human tumor cell lines. Among the tested cell lines, NPI-0052 is the most active against the multiple myeloma (MM) cell lines. The effects of NPI-0052 were also investigated on MM cells freshly isolated from patients relapsing after multiple prior therapies including Dexamethasone, Velcade® (Bortezomib) and Thalidomide. Results from DNA fragmentation assays demonstrated that NPI-0052 induces apoptosis in patient MM cells refractory to conventional and Bortezomib therapies. In contrast, NPI-0052 did not affect the viability of normal human peripheral blood mononuclear cells. When analyzed in vivo, NPI-0052 inhibits the chymotrypsin-like activity of murine whole blood 20S proteasomes in a dose-dependent manner after oral or i.v. administration. The effect of NPI-0052 on the 20S proteasome activity in whole blood cells was also evaluated after repeated oral dosing. The weights of the mice were monitored to access tolerability of the dosing schedules. These studies showed that twice weekly oral dosing of NPI-0052 at 0.25 mg/kg and 0.5 mg/kg for up to seven consecutive treatment resulted in minimal body weight loss, while a sustained inhibition of the 20S proteasome was established. Treatment of MM tumor bearing mice with NPI-0052 at 0.25 mg/kg or 0.5mg/kg was very well tolerated and resulted in significant inhibition of MM tumor growth, prolonged survival and a high percentage of tumor cures in these mice. In summary, NPI-0052 inhibits all three major protease-like activities of the 20S proteasome and induces apoptosis of patient MM cells resistant to conventional and Bortezomib therapies in vitro. NPI-0052 is orally active, inhibits MM tumor growth, prolongs survival and resulted in tumor cured in vivo.
Terpenoids constitute a large family of natural steroids that are widely distributed in plants and insects. We investigated the effects of a series of diterpenes structurally related to acanthoic acid in macrophage functions. We found that diterpenes with different substitutions at the C4 position in ring A are potent activators of liver X receptors (LXRα and LXRβ) in both macrophage cell lines from human and mouse origin and primary murine macrophages. Activation of LXR by these diterpenes was evaluated in transient transfection assays and gene expression analysis of known LXR-target genes, including the cholesterol transporters ABCA1 and ABCG1, the sterol regulatory element-binding protein 1c, and the apoptosis inhibitor of macrophages (Spα). Moreover, active diterpenes greatly stimulated cholesterol efflux from macrophages. It is interesting that these diterpenes antagonize inflammatory gene expression mainly through LXR-dependent mechanisms, indicating that these compounds can activate both LXR activation and repression functions. Stimulation of macrophages with acanthoic acid diterpenes induced LXR-target gene expression and cholesterol efflux to similar levels observed with synthetic agonists 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)-amino]propyloxy]phenylacetic acid hydrochloride (GW3965) and N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide [T1317 (T0901317)]. These effects observed in gene expression were deficient in macrophages lacking both LXR isoforms (LXRα,β–/–). These results show the ability of certain acanthoic acid diterpenes to activate efficiently both LXRs and suggest that these compounds can exert beneficial effects from a cardiovascular standpoint through LXR-dependent mechanisms.
