Found 2 Presentations For Request "M6620"
LBA60 - Randomized phase II (RP2) study of ATR inhibitor M6620 in combination with gemcitabine versus gemcitabine alone in platinum-resistant high grade serous ovarian cancer (HGSOC) (ID 1547)
- Panagiotis A. Konstantinopoulos (Boston, United States of America)
Abstract
Background
HGSOCs exhibit genomic instability and high replication stress due to universal loss of the G1/S checkpoint (via TP53 mutations), presence of homologous recombination alterations and induction via amplification of MYC and CCNE1 oncogenes. Based on in vitro and in vivo data, we hypothesized that addition of the selective ATR inhibitor M6620 to gemcitabine (gem) would demonstrate acceptable toxicity and superior efficacy in HGSOC.
Methods
We conducted a multicenter, open-label, RP2 study of gem/M6620 versus gem alone (1:1 randomization) in platinum resistant HGSOC. Randomization was stratified based on platinum free interval (PFI), (PFI≤3 months vs > 3 months). Primary endpoint was progression-free survival (PFS) while secondary endpoints included safety, objective response and clinical benefit rate. Unlimited prior lines but ≤1 prior regimen in the platinum resistant setting were allowed. Patients (pts) received gem 1000 mg/m2 IV on Days 1 and 8 with or without M6620 210 mg/m2 IV on Days 2 and 9 of a 21-day cycle until disease progression (PD) or intolerable toxicity. Pts on gem alone were allowed to crossover to gem/M6620 only if they developed PD by RECIST. In order to have 80% power to detect improvement of median PFS from 15 weeks with gem to 27.3 weeks with gem/M6620 (hazard ratio (HR) =0.55) with a one-sided alpha level of 0.1, 64 total pts were required.
Results
70 pts were randomized, 36 to gem and 34 to gem/M6620 arms. Kaplan-Meier estimated median PFS was 14.7 weeks in the gem alone versus 22.9 weeks in the gem/M6620 arm; gem/M6620 HR was 0.57 (90% CI, 0.33-0.997; 1-sided log-rank test p = 0.047). The benefit of addition of M6620 was observed mainly among pts stratified into the PFI≤3 months group (HR = 0.31; 90% CI, 0.13-0.77; 1-sided p = 0.013); insignificant PFS difference between the two arms was observed among pts with PFI>3 months (HR = 0.95; 90% CI, 0.46-1.97; 1-sided p = 0.45). No increase in treatment-related toxic effects was observed in the gem/M6620 arm.
Conclusions
Addition of the ATR inhibitor M6620 to gem in platinum resistant HGSOC met the primary endpoint of this RP2 trial without increasing toxicity. Further evaluation of gem/M6620 in this setting is warranted.
Clinical trial identification
NCI CTEP: 9944; NCT02595892.
Legal entity responsible for the study
National Cancer Institute (NCI).
Funding
National Cancer Institute (NCI).
Disclosure
P.A. Konstantinopoulos: Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Merck; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Tesaro; Advisory / Consultancy, Advisory Board: Vertex; Advisory / Consultancy, Advisory Board: Pfizer; Research grant / Funding (institution): Eli Lilly. R.T. Penson: Advisory / Consultancy, Advisory Board: AbbVie; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: AstraZeneca; Advisory / Consultancy, Advisory Board: Clovis; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Eisai; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Merck & Co; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Genentech/Roche; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Sanofi Aventis; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Vascular Biogenics; Advisory / Consultancy, Advisory Board: Sutro Biopharma; Advisory / Consultancy, Advisory Board: Mersana Therapeutics; Research grant / Funding (institution): Array Biopharma. L.R. Duska: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Cerulean; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Pfizer; Research grant / Funding (self), Research grant / Funding (institution): GlaxoSmithKline/Novartis; Research grant / Funding (institution): Morab; Honoraria (self), Research grant / Funding (institution): MorphoTek; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Aduro BioTech; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Ludwig; Research grant / Funding (institution): LEAP Therapeutics; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Inovio; Advisory / Consultancy: Cue Biopharma; Research grant / Funding (institution): Advaxis. M.A. Crispens: Advisory / Consultancy: AbbVie; Research grant / Funding (institution): AstraZeneca. A.B. Olawaiye: Advisory / Consultancy, Advisory Board: Clovis; Advisory / Consultancy, Advisory Board: Tesaro. M.T. McHale: Advisory / Consultancy: Eisai; Research grant / Funding (institution): Verastem. R.J. Schilder: Advisory / Consultancy, Consultant: Incyte; Advisory / Consultancy, Consultant: Immunogen; Advisory / Consultancy, Consultant: Celsion; Advisory / Consultancy, Consultant: Flatiron. G.I. Shapiro: Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Research grant / Funding (self): Merck KGaA/EMD-Serono; Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): Sierra Oncology; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy: Roche; Advisory / Consultancy: Bicycle Therapeutics; Advisory / Consultancy: Fusion Pharmaceuticals; Advisory / Consultancy: Cybrexa Therapeutics; Advisory / Consultancy: Astex; Advisory / Consultancy: Almac; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Angiex; Advisory / Consultancy: Daiichi Sankyo; Research grant / Funding (institution): Array Biopharma. U.A. Matulonis: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Myriad Genetics; Advisory / Consultancy: Clovis; Advisory / Consultancy: Merck; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Mersana; Advisory / Consultancy: Geneos; Advisory / Consultancy: Fuji Firm; Advisory / Consultancy: Immunogen; Advisory / Consultancy: Cerulean; Advisory / Consultancy: 2X Oncology. All other authors have declared no conflicts of interest.
1060TiP - Randomized, phase Ib/II study of M6620 + avelumab + carboplatin vs standard care (sc) in patients (pts) with platinum-sensitive poly (ADP-ribose) polymerase inhibitor-(PARPi)-resistant ovarian cancer (ID 5136)
- Susana Banerjee (London, United Kingdom)
Abstract
Background
Maintenance PARPis are standard of care for pts with recurrent ovarian cancer. Optimal treatment following PARPi resistance is currently unknown. PARPi-resistant recurrent ovarian cancer with expected platinum sensitivity is associated with high mutational load and homologous recombination deficiency. Ataxia telangiectasia and rad3-related (ATR) inhibition combined with immune checkpoint inhibition and DNA-damaging agents, such as carboplatin, has potential for activity following PARPi resistance by increasing DNA damage, immunologic cell death and potential immunological targets.
Trial design
NCT03704467 is an open-label, multicentre, international, 2-part study including participants with PARPi-resistant, recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer. Pts must have received ≥2 platinum-based tx (and responded to the last platinum-based tx); last platinum dose ≥ 6 months prior; ≥4 months PARPi maintenance tx before progression (PD) and known BRCA1/2 mutation status. Part A is a safety run-in, with dose de-escalation to find a recommended phase 2 dose (RP2D) of 3weekly carboplatin + M6620 (an ATR inhibitor) + avelumab (a programmed death ligand-blocking mAB; all iv). Planned starting doses are carboplatin AUC 5; M6620 90 mg/m2; avelumab 1600 mg. In Part B, pts will be randomized (stratified by BRCA gene status) to carboplatin + M6620 (at the RP2D from Part A) + avelumab or SC (platinum-based doublet ± bevacizumab; investigator’s choice). After completion of ≤ 6 triplet cycles in Part A/B, pts can receive avelumab maintenance tx (800 mg every 2 weeks) until PD, unacceptable toxicity, withdrawal of consent, death, or ≥ 12 months tx following confirmed complete response. The primary objective of Part B is progression-free survival. Secondary objectives for Part A/B include safety/tolerability; pharmacokinetics, immunogenicity, antitumor activity (BOR, duration of response, time to progression/subsequent tx). Planned enrolment: Part A 3–18 pts (modified 3 + 3 design); Part B ∼72 pts. Enrolment began in Nov 2018 and the first patient is enrolled.
Clinical trial identification
NCT03704467.
Editorial acknowledgement
Lisa Jolly, PhD, of Bioscript Science Macclesfield, UK, funded by Merck KGaA, Darmstadt, Germany.
Legal entity responsible for the study
Merck KGaA.
Funding
Merck KGaA.
Disclosure
S. Banerjee: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Tesaro; Honoraria (self): Clovis; Honoraria (self): Merck Serono; Honoraria (self): Nucana; Honoraria (self): Immunogen; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Gamamabs. I. Vergotte: Advisory / Consultancy: Advaxis, Inc.; Advisory / Consultancy: Eisai Inc.; Advisory / Consultancy: MSD Belgium; Advisory / Consultancy: Roche NV; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genmab; Advisory / Consultancy: F. Hoffmann-La Roche Ltd; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Millennium Pharmaceuticals; Advisory / Consultancy: Clovis Oncology Inc.; Advisory / Consultancy: AstraZeneca NV; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Research grant / Funding (institution): Oncoinvent AS; Advisory / Consultancy: Immunogen Inc; Advisory / Consultancy: Sotio; Research grant / Funding (institution): Amgen; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Stichting tegen Kanker; Travel / Accommodation / Expenses: Takeda Oncology; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Clovis; Travel / Accommodation / Expenses: Immunogen. N. Colombo: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD; Advisory / Consultancy: BIOCAD; Advisory / Consultancy: Takeda; Advisory / Consultancy: Lilly; Leadership role, Subject Editor: ESMO Clinical Guidelines; Non-remunerated activity/ies, Chair Scientific Committee: ACTO Onlus. R. Grisham: Advisory / Consultancy: Clovis; Advisory / Consultancy: Mateon. K.T. Mehr: Full / Part-time employment: Merck KGaA. M. Falk: Full / Part-time employment: Merck KGaA. F. Beier: Full / Part-time employment: Merck KGaA. M. Hennessy: Full / Part-time employment: EMD Serono. A. Schroeder: Full / Part-time employment: Merck KGaA. All other authors have declared no conflicts of interest.