- Emiliano Calvo (Madrid, Spain)
- Ruth Plummer (Newcastle upon Tyne, Tyne and Wear, United Kingdom)
438O - METEOR-1: A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours (ID 3410)
- Lillian L. Siu (Toronto, Ontario, Canada)
Abstract
Background
PRMT5 is an enzyme that methylates arginines in proteins important for tumor growth and development. GSK3326595 is a potent and selective PRMT5 inhibitor that demonstrates efficacy in multiple tumor models. METEOR-1 is a phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of GSK3326595 in adults with solid tumors.
Methods
Eligible participants (pts) were >18 years with advanced or metastatic solid tumors. Pts were enrolled in a modified toxicity probability interval design. Safety, tolerability, PK, PD, and efficacy data were used to identify the recommended phase 2 dose (RP2D).
Results
Fifty-four pts with a median age of 60 (range 21 – 81) received at least one dose of drug. The most common tumor types were adenoid cystic carcinoma (ACC; n = 14 [26%]), colorectal cancer (n = 9 [17%]), and breast cancer (n = 3 [6%]). Dosing proceeded from 12.5 mg to 600 mg once daily (QD), and from 50 mg to 200 mg twice daily. Median time on treatment was 1.8 months (range 1 day to 18.7 months). Overall, 48 pts (89%) experienced at least one adverse event (AE) that was deemed treatment-related. The most common related AEs were fatigue (n = 21 [39%]), anemia (n = 17 [31%]), nausea (n = 17 [31%]), alopecia (n = 15 [28%]), and dysgeusia (n = 14 [26%]). Grade 3/4 related AEs included anemia (n = 8 [15%]), thrombocytopenia, neutropenia, and fatigue (each n = 4 [7%]). There were no Grade 5 related AEs. Twenty-two pts (41%) had ≥1 dose reduction. GSK3326595 Cmax and AUC were dose-dependent after single and repeat dosing. PD analyses showed robust target engagement, as measured by dimethylated arginine in plasma and tumor samples. Clinical activity was observed in several tumor types, with partial responses in patients with HPV+ cervical cancer (1 response/1 subject) and ACC (3 responses/14 subjects). Durable stable disease was achieved in bladder cancer and other tumors. 400 mg QD was selected as the RP2D.
Conclusions
This is the first study evaluating a PRMT5 inhibitor. Overall, AEs were common but manageable. Patients with multiple tumor types responded to therapy. Part 2 of the study is open for subjects with predefined solid tumors and non-Hodgkin’s lymphoma.
Clinical trial identification
NCT02783300.
Legal entity responsible for the study
GlaxoSmithKline.
Funding
GlaxoSmithKline.
Disclosure
L.L. Siu: Advisory / Consultancy: Merck (compensated), Pfizer (compensated), Celgene (compensated), AstraZeneca/Medimmune (compensated), Morphosys (compensated), Roche (compensated), GeneSeeq (compensated), Loxo (compensated), Oncorus (compensated), Symphogen (compensated), Seattle Geneti; Research grant / Funding (institution): Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks; Shareholder / Stockholder / Stock options, Spouse: agios. D.W. Rasco: Research grant / Funding (institution): gsk. S. Postel Vinay: Research grant / Funding (institution): Boehringer Ingelheim, Roche and Merck KGaA; Advisory / Consultancy: Merck KGaA; Travel / Accommodation / Expenses: AstraZeneca; Leadership role, Principal/sub-investigator of clinical trials: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol. P. Martin Romano: Research grant / Funding (institution): AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-remunerated activity/ies, Drug supplied: AstraZeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche; Non-remunerated activity/ies, Courses, trainings for: AstraZeneca, Roche. J.L. Egger: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. S.A. Gorman: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. R. Parasrampuria: Full / Part-time employment: GlaxoSmithKline. K. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. B.E. Kremer: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. M.M. Gounder: Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self): Epizyme, Tracon, Amgen, Daiichi Sankyo, Springwork Therapeutics, Bayer, Karyopharm. All other authors have declared no conflicts of interest.
439O - A first in human, phase I trial of NP137, a first-in-class antibody targeting netrin-1, in patients with advanced refractory solid tumors (ID 3777)
- Philippe Cassier (Lyon, France)
Abstract
Background
Netrin-1, a dependence receptor ligand, is overexpressed in many cancers and leads to resistance to cell death. In preclinical studies, targeting netrin-1 with the humanized anti-netrin-1 antibody NP137 inhibits tumor growth and metastasis.
Methods
Adults with advanced, refractory solid tumors received NP137 IV Q2W, starting at 1 mg/kg. Dose was escalated using a rapid titration design followed by a model-based design with 3-6 pts per cohort; Additional patients (pts) were enrolled in 4 biomarker cohorts, at dose levels that had been declared safe, starting at 6 mg/kg, and underwent paired biopsies for pharmacodynamics (PD) purposes.
Results
Nineteen pts were enrolled in 7 dose levels (1 to 20 mg/kg). No DLTs were observed but 11 (58%) had infusion related reactions (IRR) of grade 1-2 severity, all at doses of 4 mg/kg and above. Twenty-three pts were enrolled in the biomarker cohorts (up to 6 pts per cohort), and 18 (78%) experienced IRR. To date, 9 of 42 pts (21%) experienced at least one grade ≥ 3 drug related AE and 9 pts had at least one related SAEs (total of 14 SAEs including 10 IRRs and ischemic stroke, back pain, hyponatremia, pneumonia, n = 1 each). Among 36 pts with at least one follow-up RECIST 1.1 assessment, 1 pt with endometrial carcinoma had a confirmed PR (> 6 months to date, >50%, 14mg/kg) and 6 pts had SD at 3 months including one long-lasting SD over 1 year (cervical carcinoma, 6mg/kg) with a shrinkage > 30% in an irradiated lesion. To date, 3 pts are still on treatment (median duration: 43.0 days [7.0; 476.0]). Serum NP137 concentrations had biphasic disposition characteristic of both target and non-target-mediated clearances. PK data up to 5 consecutive cycles showed no evidence of NP137 accumulation. No ADAs were noted. RNAseq data on paired biopsies suggests that NP137 triggers a shift toward a more epithelial phenotype. Based on available data, 14mg/kg Q2W was selected as the RP2D. Recruitment in the extension phase is ongoing in gynecological tumors.
Conclusions
NP137 was well-tolerated, with mild to moderate IRR as the most frequent treatment-related AEs and showed encouraging signs of clinical activity. Updated data will be presented at the meeting.
Clinical trial identification
NCT02977195.
Legal entity responsible for the study
Centre Léon Bérard.
Funding
Netris Pharma.
Disclosure
P. Cassier: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Abbvie; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. Y. Courbebaisse: Full / Part-time employment: Netris Pharma. S. Depil: Advisory / Consultancy: Cellectis; Advisory / Consultancy: Netris Pharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: PDCLine Pharma; Advisory / Consultancy: Erytech; Advisory / Consultancy: Servier. J. Delord: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Roche/Genentech; Advisory / Consultancy: EMD Serono; Research grant / Funding (self): AstraZeneca. I.L. Ray-Coquard: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astr-Zeneca; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: PharmaMar; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GenMab. B. Ducarouge: Full / Part-time employment: Netris Pharma. P. Mehlen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netris Pharma. J. Blay: Non-remunerated activity/ies, uncompensated scientific advice: Netris Pharma. All other authors have declared no conflicts of interest.
440O - Phase I study of the arginase inhibitor INCB001158 (1158) alone and in combination with pembrolizumab (PEM) in patients (Pts) with advanced/metastatic (adv/met) solid tumours (ID 1621)
- Aung Naing (Houston, TX, United States of America)
Abstract
Background
Arginase (Arg), an enzyme secreted by myeloid-derived suppressor cells and neutrophils in the tumor milieu, suppresses T-cell activity via arginine depletion. This phase 1 study is evaluating 1158, an oral small molecule Arg inhibitor, as monotherapy (MT) and in combination (CT) w/ the PD-1 inhibitor PEM in checkpoint inhibitor (CPI) refractory and naïve adv/met solid tumors.
Methods
Dose escalation of 1158 MT and CT w/ PEM (200 mg Q3W) was followed by tumor expansion cohorts to evaluate safety/activity at the recommended phase 2 dose (RP2D) using a Simon 2 Stage design. Primary objective is safety/tolerability. Data cutoff: April 23, 2019.
Results
73 pts were enrolled in MT/CT dose escalation, 68 across 3 MT expansion cohorts (colorectal carcinoma [CRC], non-small cell lung cancer, basket) and 94 to date across 8 CT expansion cohorts (4 CPI refractory, 4 CPI naïve). Median age was 63 yrs (32-92), w/ median 3 prior therapies (1-11). No maximum tolerated dose of 1158 was reached up to 150 mg BID; RP2D was 100 mg BID. Plasma arginase inhibition was seen at all doses as were dose-related elevations in plasma arginine. Clinically significant urea cycle inhibition (on-target toxicity), defined as concomitant rise in urine orotic acid and plasma ammonia, was not seen. Immune-related adverse events (irAEs) in MT were G3 colitis and G2 malaise (1 each). Overall frequency/severity of irAEs for CT was similar to PEM MT. AEs were generally manageable and reversible. CRC expansion cohorts are most mature; MT CRC and CT MSS CRC cohorts met response criteria to advance to Simon Stage 2. Partial responses were seen in efficacy evaluable MSS CRC pts in MT and CT with overall response (ORR)/disease control rate (ORR + stable disease) of 3%/28% (n = 32) and 6%/37% (n = 35), respectively. Other expansion cohorts are ongoing in Stage 1.
Conclusions
Early data indicate that 1158 MT and CT w/ PEM was well tolerated and showed responses as MT and CT in pretreated MSS CRC pts. Updated safety and efficacy data will be presented.
Clinical trial identification
NCT02903914 Posted to clinicaltrials.gov: September 16, 2016.
Editorial acknowledgement
Medical writing support was provided by Ingrid Koo, PhD, and funded by Calithera Biosciences and Incyte Corporation.
Legal entity responsible for the study
Calithera Biosciences, Inc., and Incyte Corp.
Funding
Calithera Biosciences, Inc., and Incyte Corp.
Disclosure
A. Naing: Research grant / Funding (institution): NCI; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Healios Onc. Nutrition; Research grant / Funding (institution): Atterocor; Research grant / Funding (institution): Amplimmune; Research grant / Funding (institution), Travel / Accommodation / Expenses: ARMO Biosciences; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Incyte; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): CytomX Therapeutics; Research grant / Funding (institution): Neon Therapeutics; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): TopAlliance Bioscences; Research grant / Funding (institution): Kymab, PsiOxus; Spouse / Financial dependant: Immune Deficiency Foundation. T. Bauer: Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Leap Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy, Research grant / Funding (institution): Moderna; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Loxo; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Immunogen; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Phosplatin Therapeutics; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Koltan Pharmaceuticals; Research grant / Funding (institution): Principa Biopharma; Research grant / Funding (institution): Peleton; Research grant / Funding (institution): Immunocore; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Alleron Therapeutics; Research grant / Funding (institution): Bristol-Meyer Squibb; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Onyx, Sanofi, Boehringer-Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance Bioscience, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Foundation Medicine, ARMO Biosciences. K.P. Papadopoulos: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): ARMO Biosciences; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Curegenix; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): 3D Medicines; Research grant / Funding (institution): Formation Biologics; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Syros Pharmaceuticals; Research grant / Funding (institution): Mersana, OncoMed, MabSpace Biosciences, Jounce Therapeutics. O. Rahma: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Merck; Advisory / Consultancy: Celgene; Advisory / Consultancy: Five Prime; Advisory / Consultancy: GFK; Advisory / Consultancy: Defined Health INC; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Puretech; Advisory / Consultancy: Leerink; Advisory / Consultancy: PRMA Consulting; Licensing / Royalties, Patent pending: Methods of using Pembrolizumab and trebananib: Patent; Speaker Bureau / Expert testimony: BMS. F. Tsai: Shareholder / Stockholder / Stock options: Salarius Pharmaceuticals; Advisory / Consultancy: Tempus Lab; Licensing / Royalties: Caremission LLC. E. Garralda: Advisory / Consultancy, Research grant / Funding (institution): F. Hoffmann-La Roche; Advisory / Consultancy: Ellipses Pharma; Advisory / Consultancy: Neomed Therapeutics1 Inc; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Janssen Global Services; Speaker Bureau / Expert testimony: Bristol-Meyers Squibb; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Research grant / Funding (institution), Travel / Accommodation / Expenses: Glycotope; Travel / Accommodation / Expenses: Menarini; Research grant / Funding (self), Scitron Project - VHIÓS Technology Platform to study tumor clonal evolution and Resistance to Immune and Targeted Therapies.: Novartis; Research grant / Funding (institution): Principia Biopharma Inc; Research grant / Funding (institution): Lilly, S.A; Research grant / Funding (institution): Novartis Farmacéutica, S.A; Research grant / Funding (institution): Genentech, Inc; Research grant / Funding (institution): Loxo Oncology; Research grant / Funding (institution): Symphogen A/S; Research grant / Funding (institution): Incyte Biosciences International, Pharma Mar S.A.U., Kura Oncology Inc, Macrogenics Inc, Pierre Fabre Medicameng, Cellestia Biotech, Menarini Ricerche Spa, Blueprint Medicines Corporation, Beigene USA Inc, Sierra Oncology Inc, Genmab B.V.; Non-remunerated activity/ies, ImCORE Translational Committee Member since 2017: Roche/Genentech; Non-remunerated activity/ies: ESMO, SEOM, AACR, ASCO, Cancer Core Europe; Leadership role: ESMO Women For Oncology - W40. J. Naidoo: Honoraria (self): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Roche/Genentech; Research grant / Funding (institution): Merck. M.K. Gibson: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Non-remunerated activity/ies, Author: NCCN. I. Rybkin: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): ARMO Biosciences; Research grant / Funding (institution): Beyond Spring Pharmaceutical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Mirati Therapeutical Inc.; Research grant / Funding (institution): Nilogen, Inc.; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Polaris Group; Research grant / Funding (institution): Syndax Inc.; Research grant / Funding (institution): Xcovery Inc.; Research grant / Funding (institution): BerGenBio AS; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Amgen. D.F. McDermott: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Array BioPharm; Advisory / Consultancy, Research grant / Funding (institution): Genentech BioOncology; Advisory / Consultancy, Research grant / Funding (institution): Alkermes, Inc.; Advisory / Consultancy: Jounce Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): X4 Pharma; Advisory / Consultancy, Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Eli Lilly and Company; Research grant / Funding (institution): Prometheus Laboratories. M. de Miguel: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Incyte/INC Research; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Menarini; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pharmamar; Research grant / Funding (institution): Roche. Y. Jenkins: Shareholder / Stockholder / Stock options, Full / Part-time employment: Calithera Biosciences; Spouse / Financial dependant: Second Genome. H. Kallender: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. S. Gogov: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. E. Kuriakose: Shareholder / Stockholder / Stock options, Full / Part-time employment: Calithera Biosciences, Inc. M. Pishvaian: Speaker Bureau / Expert testimony: Sirtex; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Celgene; Speaker Bureau / Expert testimony: Caris; Advisory / Consultancy: Rafael; Advisory / Consultancy, Research grant / Funding (institution): ARMO; Advisory / Consultancy: Eisai; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Merrimack; Shareholder / Stockholder / Stock options: Perthera; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Fibrogen; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Bavarian Nordic, Novartis, Pfizer, BMS, Abbvie, Halozyme, Karyopharm, Bayer, Regeneron, Curegenix, Calithera, Pharmacyclics. All other authors have declared no conflicts of interest.
Invited Discussant 438O, 439O and 440O (ID 6667)
- Christophe Massard (Villejuif, CEDEX, France)
441O - A platform trial with a registry study for rare cancers: MASTER KEY project (ID 1777)
- Shoko N. Noda (Tokyo, Japan)
Abstract
Background
Rare cancers have had a challenge in establishing standard therapies for patients compared to major cancers, due to the lack of basis for clinical studies and investigations. We started a biomarker driven basket/umbrella trial using a “master protocol”, called the MASTER KEY Project, which aims to find more efficient ways to evaluate treatments for rare cancers.
Methods
The project opened in April 2017 and consists of a prospective registry study part and a multiple clinical trials part. Patients with advanced rare cancers (annual incidence <6 / 100,000 population)/cancers of unknown primary/rare tissue subtypes of common cancers, undergoing a molecular diagnostic testing are enrolled. The primary objective of the registry study is to collect consecutive data on biomarker, patient background, and prognosis to build a database highly reliable for use as historical control data in future clinical trials. Sub-studies are placed under a “master protocol”, and each sub-study will enroll patients with the appropriate biomarker, regardless of tumor type.
Results
As of Feb. 2019, 515 patients were enrolled in the project, and 493 were available for their backgrounds. Most frequent cancer types were: soft tissue sarcomas (33.7%), neuroendocrine tumors (7.3%), tumors of CNS (5.9%), salivary gland tumors (4.5%), etc. 346 patients had next generation sequencing testing results. The most common alterations were TP53 (32.4%), KRAS (10.4%), PIK3CA (9.5%), MDM2 (5.2%), CDK42 (4.9%), CDKN2A (4.9%), and RB1 (4.9%). 278 patients already had 6 months follow-up, and 116 patients received 181 systemic chemotherapy regimens after enrollment. Of those regimens, 25 were biomarker-based therapies, and median progression free survival was 8.1 months compared to 4.8 months with other cytotoxic chemotherapy regimens (Hazard ratio 0.61; 95% confidential interval 0.32-1.07).
Conclusions
MASTER KEY Project is one of the largest platform trials focused only on rare cancers. The project provided the chance for rare cancer patients to receive biomarker-based treatment, and it showed better prognosis. This is a continuous project aimed to accelerate treatment development for rare cancers, with clinical trials directed towards new drug approvals.
Clinical trial identification
UMIN000027552.
Legal entity responsible for the study
The authors.
Funding
Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Kyorin Pharmaceutical, Novartis Parma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Taiho Pharmaceutical and Takeda Pharmaceutical.
Disclosure
All authors have declared no conflicts of interest.
442O - Therapeutic drug monitoring of oral anticancer drugs - preliminary results of a prospective study (ID 2651)
- Steffie L. Groenland (Amsterdam, Netherlands)
Abstract
Background
Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK). Even though exposure has been linked to efficacy and toxicity for many of these drugs, they are still dosed using a one-size-fits-all approach. Consequently, individual patients (pts) have a high probability to be either underdosed or overdosed, potentially leading to decreased antitumor efficacy or increased toxicity. Therapeutic drug monitoring (TDM), which is personalised dosing based on measured drug levels, can be used to address these problems and thereby optimize treatment outcomes.
Methods
This prospective clinical study (www.trialregister.nl, NL6695) evaluates the feasibility, tolerability and efficacy of TDM of oral anticancer drugs. In total, 600 pts will be included for 23 different drugs. Pts starting regular treatment with one of these drugs at the approved dose are included. PK sampling is performed 4, 8, and 12 weeks after start of treatment and every 12 weeks thereafter. Drug concentrations are measured and trough concentrations (Cmin) are estimated. In case of Cmin below the predefined target and acceptable toxicity, a PK-guided intervention is recommended. This may include emphasizing compliance, adaptations in concomitant medication (due to drug-drug interactions), concomitant intake with food, splitting intake moments or dose increments.
Results
In total, 274 pts were included (trametinib (n = 43), abiraterone (n = 38), enzalutamide (n = 35), imatinib (n = 33), pazopanib (n = 23), other (n = 102)), of whom 246 pts had available PK data. 83 pts (34%) were underdosed and had ≥ 1 PK samples below the predefined target. In 48 of 246 pts (20%) a PK-guided intervention was performed, which was successful (i.e. target attainment without additional toxicities) in 39 pts (81%). In 35 pts, a PK-guided intervention could not be performed, due to toxicity (17 pts), logistical reasons (13 pts) or lack of physician adherence (5 pts).
Conclusions
This prospective study shows that PK-guided dose optimization of oral anticancer drugs is feasible in clinical practice. A PK-guided intervention was recommended in 20% of the patients and resulted in target attainment without additional toxicities in 81% of these patients.
Clinical trial identification
NL6695; release date: 6 December 2017.
Legal entity responsible for the study
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital.
Funding
Unrestricted research grant of Novartis, Pfizer and Roche.
Disclosure
S.L. Koolen: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. D.J.A.R. Moes: Advisory / Consultancy: Sandoz; Advisory / Consultancy, Research grant / Funding (institution): Chiesi Pharmaceuticals. I.M.E. Desar: Research grant / Funding (institution): Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Eisai. D.J. Touw: Advisory / Consultancy: Sanguin; Research grant / Funding (institution): Chiesi Pharmaceuticals. N.P. van Erp: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Gilead. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Honoraria (institution), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier. N. Steeghs: Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Incyte. All other authors have declared no conflicts of interest.
Invited Discussant 441O and 442O (ID 6669)
- Christophe Le Tourneau (Paris, France)