Browsing Over 131 Presentations
Big data, Artificial Intelligence and clinical trials (ID 67)
- Emiliano Calvo (Madrid, Spain)
- Emiliano Calvo (Madrid, Spain)
39P - Effect of dose level of the selective FGFR2 inhibitor alofanib on toxicity, pharmacokinetics and preliminary efficacy: A phase Ib study in patients with advanced gastric cancer (RPT835GC1B) (ID 256)
- Ilya Tsimafeyeu (Moscow, Russian Federation)
- Ilya Tsimafeyeu (Moscow, Russian Federation)
- Vasily Kazey (Moscow, Russian Federation)
- Nadezhda Dragun (Saint-Petersburg, Russian Federation)
- Dmitry Reznikov (Saint-Petersburg, Russian Federation)
- Evgenia Gavrilova (Saint-Petersburg, Russian Federation)
- Svetlana Gorbacheva (Moscow, Russian Federation)
- Aiyyna Nikiforova (Saint-Petersburg, Russian Federation)
- Mikhail Byakhov (Reutov, Russian Federation)
- Sergei Tjulandin (Moscow, Russian Federation)
Abstract
Background
FGFR2 molecular changes was observed in gastric cancer at a frequency of 4-15% and associated with shorter progression-free survival (PFS) and overall survival (OS). Alofanib (RPT835) is a novel selective inhibitor that binds allosterically to the extracellular domain of FGFR2.
Methods
The aim of this phase Ib study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, preliminary efficacy and pharmacokinetics (PK) of alofanib administered intravenously daily for 5 days weekly. Patients with advanced or metastatic gastric adenocarcinoma resistant to standard therapy were enrolled in 5 dose levels: 50, 100, 165, 250, and 350 mg/m2, using a 3 + 3 design.
Results
To date, 13 patients have been enrolled in the trial. The MTD was not reached. All patients have not experienced any DLT within the 28-day DLT-assessment window. Intravenous alofanib was safe. There were no correlations between dose level and toxicity. Three grade 3 adverse events (ALT/AST increased at 50 mg/m2, diarrhea at 165 mg/m2, and hyponatremia at 350 mg/m2) were reported. One patient discontinued treatment due to drug related grade 3 uncontrolled diarrhea. Grade 1-2 adverse events included fatigue, diarrhea, nausea, anemia, thrombocytopenia, increased alkaline phosphatase, and reactions immediately after intravenous injections (facial flushing, dizziness, weakness, sweating, and sinus tachycardia). Grade 1 hyperphosphatemia was founded in 25% of cases. Of the 12 assessed patients, 1 (8%) partial response at 50 mg/m2 and 8 (67%) stable diseases at 50-250 mg/m2 were recorded. After a median follow-up of 4.5 months, the median PFS and OS was not reached. PK parameters have increased with dose. PK values (Cmax, AUC, and t1/2) did not correlate with response, PFS and OS (all P>0.1).
Conclusions
Administration of alofanib by intravenous route as single agent was safe and demonstrated promising antitumor activity in heavily pretreated patients with metastatic gastric cancer. The MTD has not been reached up to 350 mg/m2. PK profiles did not correlate with toxicity and efficacy of alofanib. The study is ongoing.
Clinical trial identification
NCT04071184.
Legal entity responsible for the study
Ministry of Health, Russian Federation.
Funding
Skolkovo Foundation.
Disclosure
N. Dragun, D. Reznikov, E. Gavrilova: Full/Part-time employment: Ruspharmtech LLC. All other authors have declared no conflicts of interest.
Live Q&A (ID 326)
- Alex A. Adjei (Rochester, NY, United States of America)
- Lee M. Ellis (Houston, TX, United States of America)
- Matteo Lambertini (Genoa, Italy)
- Alex A. Adjei (Rochester, NY, United States of America)
- Lee M. Ellis (Houston, TX, United States of America)
- Matteo Lambertini (Genoa, Italy)
Live Q&A and discussion (ID 21)
- Philippe Bedard (Toronto, Ontario, Canada)
- Philippe Bedard (Toronto, Ontario, Canada)
- Patricia Lorusso (New Haven, CT, United States of America)
- Bissan Al-Lazikani (Sutton, United Kingdom)
- Emile Voest (Amsterdam, Netherlands)
- Rene Bernards (Amsterdam, Netherlands)
- Nicola Valeri (Sutton, United Kingdom)
Multispecific IgGs (ID 56)
- Pablo Umana (Schlieren, Zurich, Switzerland)
- Pablo Umana (Schlieren, Zurich, Switzerland)
7O - Updated results from phase I study of CC-90011 in patients (pts) with solid tumours (STs), including neuroendocrine neoplasms (NENs), and relapsed/refractory non-Hodgkin lymphoma (R/R NHL) (ID 234)
- Antoine Hollebecque (Villejuif, France)
- Antoine Hollebecque (Villejuif, France)
- Johann S. De Bono (London, United Kingdom)
- Stefania Salvagni (Bologna, Italy)
- Ruth Plummer (Newcastle-upon-Tyne, Tyne and Wear, United Kingdom)
- Patricia Niccoli (Marseille, France)
- Jaume Capdevila (Barcelona, Spain)
- Giuseppe Curigliano (Milan, Italy)
- Victor Moreno (Madrid, Spain)
- Filippo De Braud (Milan, Italy)
- Sonia Gonzalez de Villambrosía (Santander, Spain)
- Patricia Martin-Romano (Villejuif, France)
- Eric Baudin (Villejuif, CEDEX, France)
- Marina Arias (Summit, NJ, United States of America)
- Juan De Alvaro (Summit, NJ, United States of America)
- Josep Parra-Palau (Summit, NJ, United States of America)
- Tania Sánchez-Pérez (Summit, NJ, United States of America)
- Ida Aronchik (Summit, NJ, United States of America)
- Ellen Filvaroff (Summit, NJ, United States of America)
- Manisha Lamba (Summit, NJ, United States of America)
- Zariana Nikolova (Boudry, Switzerland)
Abstract
Background
CC-90011, an oral, potent, selective, and reversible inhibitor of lysine-specific demethylase 1A, was well tolerated and showed antitumor activity in the first-in-human CC-90011-ST-001 study of pts with advanced unresectable STs and R/R NHL. Here, we present updated results with longer follow-up.
Methods
Pts in this phase I, dose-escalation (part A) and -expansion (part B) study received CC-90011 once/wk (qw) in 28-d cycles (Cs). Primary endpoints were safety, maximum tolerated dose, and recommended phase II dose (RP2D). The key secondary endpoint was preliminary efficacy, and exploratory endpoints included pharmacokinetics and pharmacodynamics (PD).
Results
As of 11 Sept 2020, 67 pts were enrolled, 50 in part A (27 with NENs, 1 with R/R NHL) and 17 in part B (16 with NENs, 1 with R/R NHL). Thrombocytopenia, an on-target toxicity, was the most common treatment-emergent adverse event (AE; 46% in part A, 71% in part B), the only serious AE reported in >2 pts in either part of the study, and successfully managed with dose modification. AEs led to discontinuation in 3 pts, all in part A. There were no deaths due to treatment-related AEs. Longer follow-up confirmed the good tolerability of CC-90011. The clinical benefit rate was 20% (95% CI, 10.0-33.7) in part A and 41% (95% CI, 18.4-67.1) in part B. As of 25 Nov 2020, 2 pts in part A (1 with solitary fibrous tumor [SFT] and 1 with R/R NHL) and 2 pts in part B (both with bronchial NENs) remained on treatment. In part A, the pt with R/R NHL achieved a complete response (CR; ongoing in C39), a pt with SFT achieved a partial response (PR) in C36 (ongoing in C42), and 5 pts with NENs had stable disease (SD)≥9 Cs, including 1 with SD ≥32 Cs. In part B, 3 pts with NENs had SD≥9 Cs, including 2 ongoing in C21 and C27. CC-90011 target engagement was indicated by decreased levels of chromogranin A and MMD in pts’ peripheral blood. PD marker changes at RP2D (60 mg qw) were consistent in part A and part B.
Conclusions
CC-90011 was well tolerated and demonstrated promising antitumor activity, including a durable CR in R/R NHL, a PR in SFT, and prolonged SD in NENs. These data support further investigation of CC-90011 as monotherapy and in combination with other therapies.
Clinical trial identification
NCT02875223; EUDRACT 2015-005243-13.
Editorial acknowledgement
Writing and editorial assistance were provided by Yaeko Hiyama, PhD, of Bio Connections LLC, funded by Bristol-Myers Squibb Company.
Legal entity responsible for the study
Celgene, a Bristol-Myers Squibb Company.
Funding
Celgene, a Bristol-Myers Squibb Company.
Disclosure
A. Hollebecque: Honoraria (self), Honoraria (institution), Shareholder/Stockholder/Stock options: BMS; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Honoraria (self), Honoraria (institution): Eisai; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: Servier; Advisory/Consultancy: Gritstone Oncology; Advisory/Consultancy: QED Therapeutic; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Incyte; Advisory/Consultancy, Travel/Accommodation/Expenses: Lilly; Advisory/Consultancy: Debiopharm; Travel/Accommodation/Expenses: Roche. J.S. de Bono: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sierra Oncology; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Genmab; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: GSK; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Serono; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Menarini Silicon Biosystems; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Orion; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Taiho; Research grant/Funding (institution): Cellcentric; Research grant/Funding (institution): Celgene a Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Astellas; Licensing/Royalties: My institution has commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income); Leadership role: CI/PI of many industry sponsored clinical trials. R. Plummer: Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer; Speaker Bureau/Expert testimony: Tesaro; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Octimet; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Karus Therapeutics; Advisory/Consultancy: Biosceptre; Advisory/Consultancy: Cybrexa; Advisory/Consultancy: Ellipses; Advisory/Consultancy: CV6 Therapeutics; Advisory/Consultancy: Astex Therapeutics; Advisory/Consultancy: Sanofi Aventis; Travel/Accommodation/Expenses: MSD. G. Curigliano: Speaker Bureau/Expert testimony: priME; Speaker Bureau/Expert testimony: Accademia Nazionale di Medicina; Speaker Bureau/Expert testimony: Medscape; Honoraria (self): Ellipsis; Advisory/Consultancy: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Merck; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Samsung. V. Moreno: Advisory/Consultancy: BMS; Advisory/Consultancy: Bayer; Advisory/Consultancy: Pieris; Advisory/Consultancy: Janssen. F. De Braud: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Speaker Bureau/Expert testimony: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Gentili; Speaker Bureau/Expert testimony: Fondazione Menarini; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony: Ignyta; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Speaker Bureau/Expert testimony: Noema S.r.l.; Speaker Bureau/Expert testimony: ACCMED; Speaker Bureau/Expert testimony: Dephaforum S.r.l.; Speaker Bureau/Expert testimony: Nadirex; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Biotechspert Ltd.; Speaker Bureau/Expert testimony: priME Oncology; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy: Tiziana Life Sciences; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Celgene, a Bristol-Meyers Squibb Company; Advisory/Consultancy: Servier; Advisory/Consultancy: Pharm Research Associated; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Octimet Oncology; Advisory/Consultancy: Incyte; Advisory/Consultancy: Teofarma; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: EMD Serono; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): Loxo Oncology; Research grant/Funding (institution): Tesaro. P. Martin-Romano: Research grant/Funding (institution), Non-remunerated activity/ies, Non-financial support (drug supplied): AstraZeneca; Research grant/Funding (institution), Non-remunerated activity/ies, Non-financial support (drug supplied): BMS; Research grant/Funding (institution), Non-remunerated activity/ies, Non-financial support (drug supplied): Boehringer Ingelheim; Research grant/Funding (institution): Janssen Cilag; Research grant/Funding (institution), Non-remunerated activity/ies, Non-financial support (drug supplied): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution), Non-remunerated activity/ies, Non-financial support (drug supplied): Pfizer; Research grant/Funding (institution), Non-remunerated activity/ies, Non-financial support (drug supplied): Roche; Research grant/Funding (institution): Sanofi; Non-remunerated activity/ies, Non-financial support (drug supplied): Bayer; Non-remunerated activity/ies, Non-financial support (drug supplied): Johnson & Johnson; Non-remunerated activity/ies, Non-financial support (drug supplied): Lilly; Non-remunerated activity/ies, Non-financial support (drug supplied): MedImmune; Non-remunerated activity/ies, Non-financial support (drug supplied): NH TherAGuiX. E. Baudin: Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Ipsen; Speaker Bureau/Expert testimony, Non-remunerated activity/ies, Other Relationship: AAA; Non-remunerated activity/ies, Other Relationship: Pfizer; Speaker Bureau/Expert testimony: Hutchinson Pharma. J. Parra-Palau: Honoraria (self), Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene/BMS. T. Sánchez-Pérez: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene/BMS. I. Aronchik: Shareholder/Stockholder/Stock options, Full/Part-time employment: BMS. E. Filvaroff: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: BMS; Shareholder/Stockholder/Stock options: Amgen; Shareholder/Stockholder/Stock options: Gilead; Shareholder/Stockholder/Stock options: Genentech/Roche. M. Lamba: Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer; Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene (now part of Bristol-Myers Squibb); Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb. Z. Nikolova: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, A Bristol-Myers Squibb Company. All other authors have declared no conflicts of interest.
24P - miR-17-5p: A potential activator of natural killer cells through tuning STAT3/H19/ULBP2 axis in breast cancer (ID 313)
- Yousra A. ZeinElAbdeen (New Cairo, Egypt)
- Yousra A. ZeinElAbdeen (New Cairo, Egypt)
- Raghda A. Soliman (Cairo, Egypt)
- Rana A. Youness (Cairo, Egypt)
Abstract
Background
Natural killer (NK) cells are the first native invaders against malignancy. NK cells activity is regulated by an array of activating and inhibitory receptors present on their surface. UL-16 binding proteins (ULBP 1-6) are ligands expressed by malignant cells to be detected by NKG2D activating receptor and consequent eradication of transformed cells by NK cells. Breast cancer (BC) patients experience a shedding of ULBP2 ligand in an attempt to evade immune surveillance process exhibited by NK cells. Yet, the mechanism behind the de-regulation of ULBP2 in BC is still to be explored. Crosstalk between different classes of non coding RNAs (ncRNAs) is the current research hotspot. Our research group has recently highlighted a harmonic interplay between several microRNAs and long ncRNAs regulating the immunogenic profile of BC cells. However, the ncRNAs circuit regulating ULBP2 in BC has yet to be identified. Therefore, the aim of this study is to identify the ncRNA circuit regulating ULBP2 in BC cells.
Methods
BC patients were recruited (n=30). Bioinformatic analysis was performed. MDA-B-231 cells are cultured and transfected by different oligonucleotides using lipofection technique. RNA was extracted using biozol, reverse transcribed and amplified and quantified using q-RT-PCR. BC cells transfected with ncRNAs are functionally analyzed using MTT, colony forming and migration assays. Statistical analysis was done using GraphPad 9.0.
Results
In silico analysis revealed a potential targeting capacity of miR-17-5p to STAT3, H19. Moreover, miR-17-5p and H19 were found to target ULBP2. Screening showed an under-expression of miR-17-5p in BC tissues and an up-regulation of STAT3 and H19. miR-17-5p mimics and H19 siRNAs repressed BC hallmarks. Ectopic expression of miR-17-5p mimics resulted in a repression of STAT3, H19 and induction of ULBP2 levels. Knocking down of STAT3 repressed H19 levels and induced ULBP2. Consquently, H19 siRNAs induced ULBP2 levels.
Conclusions
This study showed miR-17-5p/STAT3/H19 as a vital regulatory axis for ULBP2 in BC cells. The current evidence also supports the nomination of miR-17-5p as a potential therapeutic option for BC patients counteracting the immune intolerance phenomena exhibited by BC cells.
Legal entity responsible for the study
German University in Cairo.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Live Q&A and discussion (ID 8)
- Andrea Alimonti (Bellinzona, Switzerland)
- Andrea Alimonti (Bellinzona, Switzerland)
Oncolytics, radiation and other combinations (ID 43)
- Kevin J. Harrington (London, United Kingdom)
- Kevin J. Harrington (London, United Kingdom)
5P - Anti-GD2 chimeric antigen receptor & TRAIL modified mesenchymal progenitors as novel strategy against Ewing’s sarcoma (ID 217)
- Giulia Golinelli (Modena, Italy)
- Giulia Golinelli (Modena, Italy)
- Giulia Grisendi (Modena, Italy)
- Massimiliano Dall'Ora (Modena, Italy)
- Giulia Casari (Modena, Italy)
- Malvina Prapa (Modena, Italy)
- Carlotta Spano (Medolla (MO), Italy)
- Rebecca Talami (Modena, Italy)
- Federico Banchelli (Modena, Italy)
- Massimo Dominici (Modena, Italy)
Abstract
Background
Ewing’s sarcoma (ES) is an aggressive and rare malignancy that primarily afflicts children and young adults. Patients with metastases have the worst prognosis. We have previously demonstrated that locally delivered mesenchymal stromal/stem cells (MSCs) can control ES growth releasing tumor necrosis factor-related apoptosis inducing ligand (TRAIL). However, considering the nature of the disease, new MSC strategies for metastatic ES are needed, accounting that ES can express high levels of the disialoganglioside GD2. To optimize the MSC affinity for tumors, we recently developed a bi-functional (BF) strategy where MSCs expressing TRAIL were further modified by a truncated anti-GD2 chimeric antigen receptor (GD2 tCAR). Here, anti-GD2 BF MSCs delivering a soluble variant of TRAIL (sTRAIL) were challenged in several in vitro and in vivo models, including a metastatic ES xenotransplant.
Methods
Co-expression in MSCs of GD2 tCAR together with sTRAIL was obtained by lentiviral vectors. The BF MSC binding to GD2-positive ES cells was verified in a cell-to-cell interaction assay. Cytotoxicity by BF MSCs was assessed by 2D and 3D cocultures. Tumor targeting and killing by BF MSCs was then investigated in a metastatic ES xenotransplant by in vivo imaging and ddPCR.
Results
In vitro data demonstrated both tumor affinity and killing of BF MSCs. The in vivo model closely mimicking the disseminated ES, with lung and liver as the main metastatic sites, demonstrated that MSCs were able to counteract ES growth in the lung with a significant reduction in tumor signal. As for the liver, a slight though not significant antitumor effect was observed. Evidence on engraftment of BF MSCs into ES metastatic sites was also provided indicating that GD2 tCAR ameliorated the tumor targeting of BF MSCs.
Conclusions
Our work represents the first attempt to target metastatic ES by MSCs delivering an anticancer molecule. With the limitation of a monotherapy approach, BF MSCs promise to pave the way for an improved therapeutic delivery of TRAIL to treat metastatic ES and other deadly GD2-positive malignancies.
Legal entity responsible for the study
University of Modena and Reggio Emilia.
Funding
This work was supported in part by grants from the Association ASEOP and from MIUR “Dipartimenti Eccellenti” 2017.
Disclosure
G. Golinelli: supported by an AIRC fellowship for Italy Grant. G. Grisendi, C. Spano, G. Casari: Honoraria (self): Rigenerand Srl. M. Dominici: Honoraria (self), Advisory/Consultancy, Leadership role: Rigenerand Srl. All other authors have declared no conflicts of interest.
40P - Phase I study of the safety, pharmacokinetics and pharmacodynamics of escalating doses followed by dose expansion of selinexor in Asian patients with advanced solid tumour malignancies (ID 284)
- Jing Shan Ho (Singapore, Singapore)
- Jing Shan Ho (Singapore, Singapore)
- Valerie Heong (Singapore, Singapore)
- Wei Peng Yong (Singapore, Singapore)
- Ross Soo (Singapore, Singapore)
- Cheng Ean Chee (Singapore, Singapore)
- Andrea Wong (Singapore, Singapore)
- Yee Liang Thian (Singapore, Singapore)
- Raghav Sundar (Singapore, Singapore)
- Anil Gopinathan (Singapore, Singapore)
- Soo Chin Lee (Singapore, Singapore)
- Boon Cher Goh (Singapore, Singapore)
- Hongmei Xu (Newton, AL, United States of America)
- David SP Tan (Singapore, Singapore)
Abstract
Background
This study was conducted to evaluate the tolerability of selinexor and to establish the recommended phase II dose in an Asian population.
Methods
We investigated 4 dosing schedules. Schedule 1: twice a week dosing at 40mg/m2 in a 28-day cycle. Schedule 2: once weekly at 50mg/m2 in a 28-day cycle. Schedule 3: twice a week dosing at 40mg/m2, 2 out of 3 weeks in a 21-day cycle. Schedule 4: 3 times a week dosing at 20mg/m2 in a 28-day cycle. Adverse events were graded with the NCI Common Terminology Criteria for Adverse Events v 4.03. Pharmacodynamic assessments: nuclear-cytoplasmic localisation of p27, XPO1 cargo proteins including ki67, apoptag, cleaved caspase 3, and c-myc pre and post selinexor. Pharmacokinetic assessments were conducted in 19 individuals at doses between 40-60mg/m2.
Results
The safest dosing was 40mg/m2 (equivalent 60mg) with no DLTs. The schedule with a 1-week drug holiday was the most tolerable for our patients. G3 adverse events included fatigue (8%), hyponatremia (23%), vomiting (5%), thrombocytopenia (5%), anemia (2%). Selinexor had a rapid oral absorption with median Tmax of 2 h with no PK accumulation after multiple doses of tested regimens. Complete responses were noted in 2 lymphoma patients. Partial responses were noted in 3 DLBCL patients, 1 Hodgkins lymphoma and thymic carcinoma. Stable disease was seen in 12 colorectal cancer patients, 3 pancreatic cancer patients, 2 thymic carcinoma patients, 1 each for ovarian cancer, hepatocellular carcinoma, cholangiocarcinoma, lung cancer, breast cancer, tongue cancer and grey zone lymphoma. An exploratory analysis on 36 colorectal cancer cases with known RAS pathway mutational status showed a median progression free survival of 86 vs 50 days, p=0.09, log-rank in RAS mutant compared to wildtype patients.
Conclusions
Selinexor is tolerated by Asian patients at 60mg twice a week. A 1-week drug holiday was needed as our patients could not tolerate the continuous dosing regimens because of persistent G3 fatigue, anorexia and hyponatremia. Exploratory analyses of colorectal cancer patients alluded to a clinical benefit that selinexor may have significant activity in RAS pathway activated tumors.
Legal entity responsible for the study
The authors.
Funding
This study was supported by grant funding from Karyopharm and the National Medical Research Council Singapore, National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative.
Disclosure
H. Xu: Shareholder/Stockholder/Stock options: Karyopharm. All other authors have declared no conflicts of interest.
Emerging preclinical and clinical data with novel antibody drug conjugates in various tumour types (ID 349)
- Giuseppe Curigliano (Milan, Italy)
- Giuseppe Curigliano (Milan, Italy)