A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma

In relapsed/refractory Hodgkin lymphoma (R/R HL), immunotherapies such as the anti-programmed death-1 inhibitor pembrolizumab have demonstrated efficacy as monotherapy and are playing an increasingly prominent role in treatment. The CD30/CD16A-bispecific antibody AFM13 is an innate immune cell engager, a first-in-class, tetravalent antibody, designed to create a bridge between CD30 on HL cells and the CD16A receptor on natural killer cells and macrophages, to induce tumor cell killing. Early studies of AFM13 have demonstrated signs of efficacy as monotherapy for patients with R/RHL and the combination of AFM13 with pembrolizumab represents a rational new treatment modality. Here, we describe a phase 1b, dose-escalation study to assess the safety and preliminary efficacy of AFM13 in combination with pembrolizumab in patients with R/R HL. The primary objective was estimating the maximum tolerated dose; the secondary objectives were to assess safety, tolerability, antitumor efficacy, pharmacokinetics, and pharmacodynamics. In this heavily pretreated patient population, treatment with the combination of AFM13 and pembrolizumab was generally well tolerated, with similar safety profiles compared to the known profiles of each agent alone. The combination of AFM13 with pembrolizumab demonstrated an objective response rate of 88% at the highest treatment dose, with an 83% overall response rate for the overall population. Pharmacokinetic assessment of AFM13 in the combination setting revealed a half-life of up to 20.6 hours. This proof-of-concept study holds promise as a novel immunotherapy combination worthy of further investigation

Abstract C237: A phase I study of the alternating administration of ixabepilone and vinflunine every three weeks in patients with advanced cancer

Abstract Background: Vinflunine (VFL) is a new microtubule inhibitor of the vinca alkaloid class. VFL inhibits tubulin polymerization. Ixabepilone (IXA), a microtubule inhibitor, binds directly to -tubulin subunits, leading to suppression of microtubule dynamics. These agents have complementary mechanisms of action and relatively non-overlapping toxicities. This study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of an alternating regimen of VFL and IXA in patients (pts) with advanced cancer and to recommend a Phase 2 dose. Materials and Methods: This was an open-label Phase 1 doseescalation study of IXA and VFL in pts with advanced cancer. IXA was administered as a 3-hour infusion alternating every 3 weeks (wks) with VFL administered as a 20-minute infusion. A cycle was defined as 6 wks (42 days), with DLT assessment during Cycle 1. Doses started at 30 mg/m2 IXA and 250 mg/m2 VFL (IXA30+VFL250). VFL doses were first escalated to a maximum of 320 mg/m2. Once an intolerable dose or the maximum dose of VFL was reached, IXA was to be escalated with a maximum dose level of IXA 40 mg/m2. A standard 3+3 escalation design was used. The MTD was defined as the dose level below which ≥2/6 pts experienced a DLT. Results: This was the first clinical study to evaluate vinflunine and ixabepilone as an alternating regimen. Nine pts were enrolled and treated; 3 each at IXA30+VFL250, IXA30+VFL280, and IXA30+VFL320. Further enrollment and dose escalation was stopped when the study was closed due to termination of VFL development at BMS. The treated pts consisted of 8 males / 1 female, 3 with SCLC, 4 with NSCLC, and 2 with sarcomas. The majority of pts were white (8 of 9). Median Age was 63 years (range 38–85). ECOG performance status was 0 (n=1) or 1 (n=8). Adverse events were summarized by treatment. Of interest, 3 pts experienced grade 1 peripheral neuropathy (1 IXA, 2 VFL); 5 pts with grade 3/4 neutropenia (2 IXA, 2 VFL, 1 IXA/VFL); 2 pts with grade 2 constipation (2 VFL). Serious adverse events (SAEs) were reported in 3 of 9 treated pts. The SAEs of pyrexia grade 2, neutropenia grade 2, and leucopenia grade 3 were considered related to study drug in 1 patient. None of the SAEs or non-serious AEs led to discontinuation of study treatment. Two pts experienced progression of disease which resulted in death. Antitumor activity (as defined by RECIST and assessed by the investigator) was observed: confirmed partial response in 1 pt with NSCLC (IXA30+VFL320 dose level) and stable disease lasting from 2.5 to 9 months in 3 pts (2 with SCLC in IXA30+VFL250 and 1 with NSCLC in IXA30+VFL280). Conclusions: There were no DLTs observed in the dose levels examined and the MTD was not reached due to termination of study. The toxicity of the alternating regimen was manageable. Antitumor activity was observed in all dose cohorts. The alternating regimen of vinflunine and ixabepilone may warrant further investigation. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C237

Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein

International audienceThe PLZF gene was identified first by its fusion with the retinoic acid receptor alpha gene in the t(11;17) translocation associated with a retinoic acid resistant form of acute promyelocytic leukemia (APL). It encodes a krüppel-like zinc finger protein with a POZ domain shared with a subset of regulatory proteins including the BCL6 leukemogenic protein. PLZF, like BCL6, strongly represses transcription initiated from different promoters. Here we show that PLZF associates in vitro and in vivo with the Mad co-repressor mSin3A and the histone deacetylase HDAC1. Two domains in PLZF and the PAH1 structure of mSin3A mediate these interactions. Trichostatin A, a specific inhibitor of histone deacetylases, significantly reduces PLZF repression. These data strongly suggest that, like nuclear receptors and Mad, PLZF represses transcription by recruiting a histone deacetylase through the SMRT-mSin3-HDAC co-repressor complex. We also show that BCL6 associates with HDAC1 indicating that this type of regulation might be common to POZ/Zinc finger proteins involved in human leukemias. This work supports a role for deregulated histone deacetylation in the development of both lymphoid and myeloid neoplasia in human and suggests that targeted histone deacetylase inhibitors may be useful for treatment of certain types of malignancies

Identification of Mammalian Sds3 as an Integral Component of the Sin3/Histone Deacetylase Corepressor Complex

Silencing of gene transcription involves local chromatin modification achieved through the local recruitment of large multiprotein complexes containing histone deacetylase (HDAC) activity. The mammalian corepressors mSin3A and mSin3B have been shown to play a key role in this process by tethering HDACs 1 and 2 to promoter-bound transcription factors. Similar mechanisms appear to be operative in yeast, in which epistasis experiments have established that the mSin3 and HDAC orthologs (SIN3 and RPD3), along with a novel protein, SDS3, function in the same repressor pathway. Here, we report the identification of a component of the mSin3-HDAC complex that bears homology to yeast SDS3, physically associates with mSin3 proteins in vivo, represses transcription in a manner that is partially dependent on HDAC activity, and enables HDAC1 catalytic activity in vivo. That key physical and functional properties are also shared by yeast SDS3 underscores the central role of the Sin3-HDAC-Sds3 complex in eukaryotic cell biology, and the discovery of mSds3 in mammalian cells provides a new avenue for modulating the activity of this complex in human disease

A phase 1 study of BMS-275183, a novel oral analogue of paclitaxel given on a daily schedule to patients with advanced malignancies.

BMS-275183 is an oral C-4 methyl carbonate analogue of paclitaxel that has the same mechanism of action, stabilization of tubulin polymerization. The present study was designed to: (i) assess the safety and tolerability of BMS-275183, and (ii) determine a suitable Phase II dose of BMS-275183 when given on a continuous daily schedule to patients with advanced solid tumor(s).Clinical Trial, Phase IJournal ArticleMulticenter StudySCOPUS: ar.jinfo:eu-repo/semantics/publishe

Randomized Phase III Trial of Pegylated Liposomal Doxorubicin Versus Vinorelbine or Mitomycin C Plus Vinblastine in Women With Taxane-Refractory Advanced Breast Cancer

Purpose To compare the efficacy of pegylated liposomal doxorubicin (PLD) with that of a common salvage regimen (comparator) in patients with taxane-refractory advanced breast cancer. Patients and Methods Following failure of a first- or second-line taxane-containing regimen for metastatic disease, 301 women were randomly assigned to receive PLD (50 mg/m2 every 28 days); or comparator-vinorelbine (30 mg/m2 weekly) or mitomycin C (10 mg/m2 day 1 and every 28 days) plus vinblastine (5 mg/m2 day 1, day 14, day 28, and day 42) every 6 to 8 weeks. Patients were stratified before random assignment based on number of previous chemotherapy regimens for metastatic disease and presence of bone metastases only. Results Progression-free survival (PFS) and overall survival (OS) were similar for PLD and comparator (PFS: hazard ratio [HR], 1.26; 95% CI, 0.98 to 1.62; P = .11; median, 2.9 months [PLD] and 2.5 months [comparator]; OS: HR, 1.05; 95% CI, 0.82 to 1.33; P = .71; median, 11.0 months [PLD] and 9.0 months [comparator]). In anthracycline-naïve patients, PFS was somewhat longer with PLD, relative to the comparator (n = 44; median PFS, 5.8 v 2.1 months; HR, 2.40; 95% CI, 1.16 to 4.95; P = .01). Most frequently reported adverse events were nausea (23% to 31%), vomiting (17% to 20%), and fatigue (9% to 20%) and were similar among treatment groups. PLD-treated patients experienced more palmar-plantar erythrodysesthesia (37%; 18% grade 3, 1 patient grade 4) and stomatitis (22%; 5% grades 3/4). Neuropathy (11%), constipation (16%), and neutropenia (14%) were more common with vinorelbine. Alopecia was low in both the PLD and vinorelbine groups (3% and 5%). Conclusion PLD has efficacy comparable to that of common salvage regimens in patients with taxane-refractory metastatic breast cancer, thereby representing a useful therapeutic option