Browsing Over 173 Presentations
50O - A first-in-human first-in-class (FIC) trial of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with advanced solid tumours
- Ruth Plummer (Newcastle upon Tyne, GB)
- Ruth Plummer (Newcastle upon Tyne, GB)
- Sarah Halford (London, GB)
- Paul Jones (London, GB)
- Steve Wedge (Newcastle upon Tyne, GB)
- Sandra Hirschberg (London, GB)
- Gareth Veal (Newcastleupon Tyne, GB)
- Geoffrey Payne (London, GB)
- Maxine Chenard-Poirier (London, GB)
- Hector Keun (London, GB)
- Udai Banerji (Sutton, GB)
Abstract
Background
A key metabolic alteration in tumour cells is increased dependency on glycolysis, resulting in the production of lactate which is transported out of cells by MCTs. Inhibition of MCT-1 can constrain cancer cell growth in preclinical models. We report results on the phase I study of AZD3965, a FIC inhibitor of MCT-1.
Methods
Patients with advanced solid tumours were treated with oral (po) AZD3965 at total daily doses of 5-30mg given once (od) and twice daily (bd). Exclusion criteria included a history of retinal or cardiac disease due to preclinical toxicology findings in the eye and heart (which express MCT-1). The primary objectives were to determine the safety, dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of AZD3965. Intensive pharmacokinetic (PK) profiling was performed with subsequent modelling for receptor occupancy. Pharmacodynamic profiling included imaging to detect pH changes and tumour glucose uptake, and plasma/urine metabolomics.
Results
40 patients (24M:16F; median age 64.5 were treated at dose levels of 5, 10, 20, and 30mg od and 10 and 15mg bd. AZD3965 was well tolerated with nausea and fatigue (CTCAE Gr1-2) the most commonly reported side effects. A single DLT of cardiac troponin rise was observed at 20mg od. Asymptomatic, reversible retinal ERG changes were first observed at 20mg od, with DLTs observed at doses above 20mg od. PK data indicate exposures in the preclinical efficacy range. Metabolomic changes in urinary lactate and ketones correlate with on-target activity. A patient with undiagnosed tumour-associated lactic acidosis experienced a DLT with exacerbation of this following a single 10mg dose of AZD3965, again indicating target engagement.
Conclusions
The MCT1 inhibitor AZD3965 can be administered to patients at doses which engage the drug target, with a RP2D of 10mg bd po. Observed DLTs were primarily dose dependent, asymptomatic, reversible changes in retinal function, an expected on-target effect. Part 2 of the study is open to recruitment in patients with diffuse large B cell lymphoma, a tumour that predominantly expresses MCT1.
Legal entity responsible for the study
Cancer Research UK
Funding
Cancer Research UK
Disclosure
All authors have declared no conflicts of interest.
Q&A / Panel Discussion
10IN - Introduction and Metabolism interference or epigenetics treatment with special focus on haematological diseases
- Tak Mak (Toronto, CA)
- Tak Mak (Toronto, CA)
11IN - Genomic-guided trials in lymphoma
- Anas Younes (New York, US)
- Anas Younes (New York, US)
12IN - Genomic-guided metabolism drug development in myeloid diseases
- David Schenkein (Cambridge, US)
- David Schenkein (Cambridge, US)
Abstract
Background
Mutations in isocitrate dehydrogenase (IDH)1 or IDH2 are seen in ~15–20% of patients with acute myeloid leukemia (AML). Mutant IDH (mIDH) reduces α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), leading to histone hypermethylation and a block in myeloid differentiation. Ivosidenib (AG-120) and enasidenib (AG-221) are potent, selective, oral small molecule inhibitors of mIDH1 and mIDH2, respectively. Both have been shown preclinically to reduce aberrant 2-HG levels and promote myeloid differentiation, and as monotherapy are associated with robust overall response rates in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Enasidenib received full approval in the United States in Aug 2017 for the treatment of adult patients with R/R AML with an IDH2 mutation. A New Drug Application was recently submitted to the FDA for ivosidenib for the treatment of patients with R/R AML and an IDH1 mutation, based on evidence in patients showing clinical activity and observation of clinical benefit, including achievement of transfusion independence, and a decrease in the frequency of comorbidities such as febrile neutropenia and infections in responding patients. Additional data demonstrate that ivosidenib monotherapy results in deep IDH1 mutation clearance in a subset of patients with R/R AML and untreated AML who achieve clinical response. Tolerability and preliminary clinical activity data were also recently presented from two Phase 1 studies evaluating ivosidenib and enasidenib in combination with standard induction (7+3) chemotherapy or azacitadine in newly diagnosed AML patients. Independent clinical trials are currently underway for ivosidenib in mIDH1-positive malignancies in the solid tumor context. This presentation will focus on the discovery of these investigational medicines, as well as the promising clinical and translational results from the hematologic malignancy and solid tumor trials.
Legal entity responsible for the study
Agios Pharmaceuticals, Inc.
Funding
Agios Pharmaceuticals, Inc.
Disclosure
D. Schenkein: Agios: Full time employee, stock ownership, board of directors. Bluebird Bio: board of directors. Denali Therapeutics: board of directors.
13IN - Personalized therapy in adult acute lymphocytic leukemia: Path to the cure
- Elias Jabbour (Houston, US)
- Elias Jabbour (Houston, US)
Introduction
51P - Active immunotherapy with a VEGF targeted vaccine HeberSaVax: The road so far and the future ahead
- Mónica Bequet-Romero (Havana, CU)
- Mónica Bequet-Romero (Havana, CU)
- Yanelys M. Díaz (Cubanacán, Playa, CU)
- Javier S. Ramírez (Cubanacán, Playa, CU)
- Katty-Hind Selman-Housein (Havana, CU)
- Francisco Hernández-Bernal (Cubanacán, Playa, CU)
- Ana De la Torre Santos (Santa Clara, CU)
- Jesús Piñero (Santa Clara, CU)
- Cimara Bermúdez (Cubanacán, Playa, CU)
- Jorge V. Gavilondo Cowley (Cubanacán, Playa, CU)
- Marta Ayala Avila (Cubanacán, Playa, CU)
Abstract
Background
The vascular endothelial growth factor (VEGF) plays a central role in angiogenesis and immunosuppressive cascades inherent to tumor development. Success of drugs targeting this growth factor and their receptors signaling cascade built upon these facts. Such passive targeting of VEGF/VEGFR pathway had two major caveats: non-manageable side effects and the induction of resistance phenomena. To overcome some of these problems we design an active immunization approach based on the use of a functionally deficient VEGF 121 isoform as antigen. Herein we present preclinical and clinical development data of HeberSaVax vaccine (formerly known as CIGB-247).
Methods
Safety, antitumoral and immunological effects of HeberSaVax administration were analyzed in mouse, rats, rabbits, non-human primates and in two Phase I clinical trials. Formulations containing the adjuvants VSSP (Very Small Size Particles from Neisseria Meningitides) or Alum phosphate were used. Vaccine was administered once a week (VSSP) or bi-weekly (Alum Phosphate) for 8 weeks. Immune response was evaluated using direct and indirect ELISA methods and IFN-gamma ELISPOT.
Results
HeberSaVax administration inhibits implantation and growth of tumors and metastases favoring a significant increase in animals’ survival. In mice, rats, rabbits and on non-human primates the vaccine administration result in non-toxic induction of sustained antibody titers that specifically neutralized VEGF binding to VEGF receptors. Immunizations also induce VEGF specific cell mediated cytotoxicity. A total of 80 patients were included in the phase I/Ib clinical trials. Results indicated: a good safety profile that allows combining the vaccine with the existing arsenal for cancer therapy; the induction of specific humoral and cellular responses despite the advance stage of patient’s tumors and; an unexpected long term immune responses after 4 years of continuous treatment. As part of the trials three complete responses, one partial response and four stable diseases have been documented.
Conclusions
Altogether these results encourage further development of HeberSaVax vaccine for cancer therapy. Henceforth, a total of four Phase II/III clinical trials are planned to start in 2018 in specific localizations.
Clinical trial identification
RPCEC00000102 and RPCEC00000155
Legal entity responsible for the study
Center for Genetic Engineering and Biotechnology (CIGB)
Funding
Heber Biotec, and Chemo
Disclosure
All authors have declared no conflicts of interest.
52P - A novel rMVA combination immunotherapy triggers potent innate and adaptive immune responses against established tumors
- Jose Medina (Martinsried, DE)
- Jose Medina (Martinsried, DE)
- Maria Hinterberger (München, DE)
- Marco Testori (Martinsried, DE)
- Marlene Geiger (Martinsried, DE)
- Raphael Giessel (Martinsried, DE)
- Paul Chaplin (Martinsried, DE)
- Hubertus Hochrein (Martinsried, DE)
- Henning Lauterbach (Martinsried, DE)
Abstract
Background
Virus-based vaccines and appropriate costimulation enhance potent antigen-specific T cell immunity against cancer. In the present study we exploit both innate and adaptive immune responses triggered by a novel recombinant modified vaccinia virus Ankara (rMVA) encoding costimulatory CD40L against solid tumors in combination regimes to overcome tumor-induced resistance to immunotherapy.
Methods
Mice bearing tumors > 50 mm3 in volume were immunized intravenously and treated with monoclonal antibodies when indicated. Immune infiltrates were analyzed by flow cytometry. When indicated, immune populations were isolated to perform functional assays.
Results
Therapeutic treatment with rMVA-CD40L resulted in strong antitumor effects in unrelated established tumor models. Tumor infiltration was composed of non-exhausted, antigen-specific CD8+ T cells with proliferative capacity after rMVA-CD40L immunization. Strikingly, this antitumor effect was not entirely dependent on cross-presenting CD8α+ DC -induced CD8+ T cell expansion. Indeed, rMVA-CD40L-induced tumor control did not depend on cytosolic DNA sensor STING. Interestingly, rMVA-CD40L induced strong NK cell activation and thereby potent Antibody Dependent Cell Cytotoxicity (ADCC) against Tumor-Associated Antigen (TAA) targeting antibodies. Hence, the combination of TAA targeting antibodies and rMVA-CD40L resulted in increased therapeutic antitumor efficacy.
Conclusions
We describe a novel and translationally relevant therapeutic synergy between viral vaccination and CD40L costimulation. We connect CD40 ligation to cross-presenting CD8α+ DC -mediated expansion of non-exhausted CD8+ T cells in the tumor microenvironment. Taking advantage from intrinsic MVA-induced NK cell activation and further improved NK cell function by CD40 ligation, we show strengthened antitumor immune responses when both rMVA-CD40L-induced innate and adaptive immune mechanisms are exploited by combining immunotherapeutic regimes. This finding has a direct potential impact in clinical trials where TAA targeting antibodies are currently under evaluation.
Legal entity responsible for the study
Bavarian Nordic GmbH
Funding
Bavarian Nordic GmbH
Disclosure
J. Medina, M. Hinterberger, M. Testori, M. Geiger, R. Giessel, H. Hochrein, H. Lauterbach: Employee of Bavarian Nordic GmbH. P. Chaplin: CEO of Bavarian Nordic GmbH
53P - Impact of chronic hepatitis virus infection on the feasibility and efficacy for Asian patients with hepatocellular carcinoma in phase I clinical trials
- Takafumi Koyama (Tokyo, JP)
- Takafumi Koyama (Tokyo, JP)
- Shunsuke Kondo (Tokyo, JP)
- Toshio Shimizu (Tokyo, JP)
- YUTAKA Fujiwara (Tokyo, JP)
- Shigehisa Kitano (Tokyo, JP)
- Takahiro Ebata (Chiba, JP)
- Akihiko Shimomura (Tokyo, JP)
- Chigusa Morizane (Tokyo, JP)
- Takuji Okusaka (Tokyo, JP)
- Noboru Yamamoto (Tokyo, JP)
Abstract
Background
In Asia, chronic hepatitis B and C virus infections (CHVI) are major risk factors for liver fibrosis and hepatocellular carcinoma (HCC). Patients with advanced HCC have limited effective therapeutic options and are potential candidates for early phase clinical trials for new anti-cancer agents. The impact of CHVI on the feasibility and efficacy for patients with HCC in Phase I trials (P-Is) has not been reported or elucidated in Western countries.
Methods
We retrospectively analyzed the characteristics and outcomes of HCC patients participating in P-Is, with emphasis on CHVI. Patients testing positive for anti-hepatitis C virus (HCV) antibody or hepatitis B virus surface antigen (HBsAg) were diagnosed with CHVI.
Results
Eighty-five patients were enrolled in P-Is at our center. There were no significant differences in the clinical and laboratory variables, including the liver function test results, between the 46 (54%) CHVI-positive and 39 (46%) CHVI-negative patients in this study. The median time to treatment failure (TTF) and overall survivals (OS) from enrollment of the P-I were 60 days (95% confidence interval [CI]: 51–85) and 412 days (95% CI: 267–478), respectively. There is no significant difference between positive and negative for hepatitis virus in the best response based on the RECIST. The frequency of abnormal liver function test (LFT) adverse events (grade ≥ 3) was significantly different among CHVI-positive and -negative patients. No patient discontinued P-I treatment secondary to abnormal LFT results or developed reactivation of hepatitis virus, and no treatment-related mortality was observed. Multivariate analysis revealed that the number of prior systemic treatments significantly contributed to poor TTF (≥2; HR: 2.1, 95% CI: 1.3–3.6,
Conclusions
CHVI did not independently predict TTF and OS. Abnormal LFT adverse events could be related to CHVI but did not lead to discontinuation of P-I treatment. Thus, patients advanced HCC with CHVI can be enrolled in the P-Is.
Legal entity responsible for the study
N/A
Funding
Has not received any funding
Disclosure
All authors have declared no conflicts of interest.
54P - Identifying the oncogenic role of USP10 as the regulator of PTEN function in breast cancer
- Nishi Kumari (Singapore, SG)
- Nishi Kumari (Singapore, SG)
- Azad Saei (Singapore, SG)
- Charles R. Lalith (Singapore, SG)
- Violeta Serra (Barcelona, ES)
- Sudhakar Jha (Singapore, SG)
- Pieter Eichhorn (Singapore, SG)
Abstract
Background
The PI3K pathway is the most commonly activated signaling pathway in human cancer. The loss of PTEN further contributes to the tumorigenic impact of the active PI3K pathway, and have direct effect on prognosis of breast cancer. Although many small molecules are used in clinic to target the PI3K pathway, only minority of breast cancer patients respond to these drugs. This study identified the role of a deubiquitinating enzyme, USP10 in the regulation of PI3K pathway in breast cancer.
Methods
A genome wide RNAi screen targeting all known deubiquitinating enzymes was performed and level of phospho-AKT was assessed by western blotting. Significant hits of the screen were validated and mechanism of action in PTEN-mediated regulation of PI3K pathway and resistance to PI3K inhibitors in breast cancer has been investigated.
Results
We identified USP10 as a critical regulator of PI3K pathway. MAGI1 has been recently identified as PTEN interacting protein, and along with MEK1 functions to promote PTEN recruitment to the plasma membrane. We found USP10 as a part of complex between MEK1, MAGI1 and PTEN. Functionally, we demonstrated that USP10 stabilizes ITCH which is an E3 ligase for MEK1 resulting in degradation of MEK1 and decreased PTEN plasma membrane localization. We showed that downregulation of USP10 decreases activation of AKT, and results in decreased colony forming ability of breast cancer cells. Furthermore, expression analysis of USP10 revealed significantly higher levels of USP10 in breast cancer patients and its expression was correlated with the tumor progression and poorer overall survival in the breast cancer patients. Interestingly, we showed the upregulation of USP10 protein level in PI3K inhibitor resistant breast cancer cells as compared to their parental control and further depletion of USP10 resensitized these cells to PI3K inhibitors. In addition, positive correlation between USP10 and PTEN protein levels was observed in the PDX model of breast cancer patients who progressed after receiving PI3K inhibitor.
Conclusions
Overall, our results identify overexpression of USP10 as a potential mechanism for loss of PTEN functionality and PI3K pathway in breast cancer patients, and its possible involvement in resistance to PI3K inhibitors.
Legal entity responsible for the study
National University of Singapore
Funding
National University of Singapore
Disclosure
All authors have declared no conflicts of interest.
55P - Protein expression and clinical significance of the NEDDylation pathway in myelodysplastic syndrome
- Fatemeh Majidi (Düsseldorf, DE)
- Fatemeh Majidi (Düsseldorf, DE)
- Judith Strapatsas (Düsseldorf, DE)
- Simon K. Brille (Düsseldorf, DE)
- Iris Fey (Düsseldorf, DE)
- Frank Neumann (Cambridge, US)
- Allison Berger (Cambridge, US)
- Ulrich Germing (Düsseldorf, DE)
- Rainer Haas (Düsseldorf, DE)
- Norbert Gattermann (Düsseldorf, DE)
Abstract
Background
A phase I clinical trial of Pevonedistat (MLN4924), a NEDD8-activating enzyme inhibitor, in AML and MDS showed modest clinical activity as a single agent. A phase II trial with Pevonedistat plus Azacytidine versus single-agent Aza is ongoing. As yet, there is no data regarding activity or dysfunction of the NEDDylation pathway in MDS. We examined NEDDylation pathway protein expression and its prognostic relevance in MDS.
Methods
On a tissue microarray (TMA) with bone marrow biopsies from 119 MDS patients, 40 AML pts, and 11 normal controls, we established immunohistochemistry (IHC) for NEDD8, NAE1 and UBE2M. Semi-quantitative analysis was done according to Remmele-Stegner immunoreactive score (IRS) (0 to 12 points). Clinical follow-up was available for 116 pts.
Results
Of 96 evaluable MDS pts, 46 (39.7%) showed an abnormal karyotype. Ten patients who received disease-modifying treatment prior to biopsy were excluded from survival analysis. On IHC, 100% of 40 AMLs and 11 normal controls were clearly positive (IRS>4) for all three NEDDylation pathway proteins. MDS patients showed a different pattern. While NEDD 8 was positive in the majority (60.6%), NAE1 and UBE2M were expressed in only 30.8% and 29.4%, respectively. For each protein, expression was not correlated with MDS type (WHO 2016), IPSS-R risk group, overall survival or AML transformation. Patients with strong expression of all three proteins survived longer (51 vs. 26 months), but the difference did not reach statistical significance (p = 0.10). Low expression of NAE1 and UBE2M significantly correlated with the presence of karyotype anomalies (p = 0.01 and p = 0.02, respectively).
Conclusions
In contrast to AML, expression of NEDD8 conjugation pathway proteins was low in a substantial proportion of MDS patients. The significant association between low or absent expression of NAE1 and UBE2M, and the presence of karyotype anomalies, suggests that low NEDDylation pathway activity may contribute to chromosomal instability. Nevertheless, since NEDD8 increases DNMT3b-dependent DNA methylation, NEDDylation pathway inhibition may be useful to augment treatment with hypomethylating drugs or counteract resistance to this therapy.
Legal entity responsible for the study
Universitätsklinikum Düsseldorf
Funding
Takeda Pharmaceutical Company
Disclosure
F. Majidi, N. Gattermann: The current research project is funded by Takeda Pharmaceutical Company. All other authors have declared no conflicts of interest.