- Emiliano Calvo (Madrid, Spain)
- Josep Tabernero (Barcelona, Spain)
16O - Phase I study of CC-90010, a reversible, oral BET inhibitor in patients (Pts) with advanced solid tumors (STs) and relapsed/refractory non-Hodgkin lymphoma (R/R NHL) (ID 158)
- Victor Moreno (Madrid, Spain)
- Victor Moreno (Madrid, Spain)
- Irene Braña (Barcelona, Spain)
- Juan M. Sepulveda Sanchez (Madrid, Spain)
- Maria Vieito Villar (Barcelona, La Coruña, Spain)
- Tatiana Hernández Guerrero (Madrid, Spain)
- Bernard Doger (Madrid, Spain)
- Omar Saavedra (Barcelona, Spain)
- Antonio Pinto (Naples, Italy)
- Carmelo Carlo Stella (Milan, Italy)
- Antoine Italiano (Bordeaux, CEDEX, France)
- Jean-Marie Michot (Villejuif, France)
- Gerardo Musuraca (Meldola, Italy)
- Rafael Sarmiento (Sevilla, Spain)
- Juan De Alvaro (Summit, NJ, United States of America)
- Marlene Zuraek (San Francisco, 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)
- Bishoy Hanna (Summit, NJ, United States of America)
- Zariana Nikolova (Boudry, Switzerland)
Abstract
Background
Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of genes involved in oncogenesis. CC-90010 is a potent BET inhibitor that showed preliminary antitumor activity in pts with advanced malignancies.
Methods
CC-90010-ST-001 is a phase I, first-in-human study of CC-90010 in pts with advanced STs and R/R NHL. Eleven dose levels and 4 dosing schedules (2 weekly [2 d on/5 d off; 3 d on/4 d off], 1 biweekly [3 d on/11 d off], and 1 monthly [4 d on/24 d off]) were evaluated. Primary objectives were safety, maximum-tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary objectives were to identify early antitumor activity, pharmacokinetics, and pharmacodynamics (PD).
Results
Of 69 pts enrolled in the dose escalation phase, 56 had advanced STs, 11 had gliomas, and 2 had R/R NHL. MTDs were 15 mg (2 d on/5 d off), 30 mg (3 d on/11 d off), and 45 mg (4 d on/24 d off). The RP2D was 45 mg (4 d on/24 d off). Median age was 57 y (range, 21–80) and 55% were men. Pts received a median of 4 (range, 1–9) prior systemic anticancer regimens. Six pts had dose-limiting toxicities occurring in all dosing schedules. The most common grade 3/4 treatment-related adverse events (AEs) were thrombocytopenia (13%), fatigue/asthenia (4%), and anemia (4%). Serious AEs occurred in 31 pts (45%); 8 (12%) had treatment-related serious AEs. One pt with progressive diffuse astrocytoma had a complete response (ongoing in cycle 14), 1 pt with endometrial carcinoma had a partial response, and 8 pts had stable disease >14 mo. Plasma exposures increased in an approximately dose-proportional manner across the dose range; the average terminal half-life (t1/2) at the RP2D was ∼60h. The monthly dosing schedule had the most profound suppression of the PD biomarker C-C motif chemokine receptor 1 (CCR1) 4 h after first and last dose of CC-90010.
Conclusion
CC-90010 showed promising antitumor activity in heavily pretreated pts with advanced STs and R/R NHL. The safety profile, long t1/2, and sufficient target engagement enabled less frequent dosing. These data provide the rationale for further exploration of CC-90010 alone and in combination with other agents.
Clinical trial identification
NCT03220347; EudraCT 2015-004371-79.
Editorial acknowledgement
Tisheeka Graham-Steed, PhD, MPH from Bio Connections, LLC.
Legal entity responsible for the study
Bristol-Myers Squibb.
Funding
Bristol-Myers Squibb.
Disclosure
V. Moreno: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Regeneron; Speaker Bureau/Expert testimony: Bayer/Loxo. I. Braña: Research grant/Funding (self): Celgene, A Bristol-Myers Squibb Company. J.M. Sepulveda Sanchez: Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: AbbVie; Advisory/Consultancy: Celgene, A Bristol-Myers Squibb Company; Advisory/Consultancy: GW Pharma; Speaker Bureau/Expert testimony: Astellas; Travel/Accommodation/Expenses: Ispen. M. Vieito Villar: Travel/Accommodation/Expenses: Roche. O. Saavedra: Travel/Accommodation/Expenses: Mundipharma; Travel/Accommodation/Expenses: Teva; Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Grunenthal; Travel/Accommodation/Expenses: Kyowakirin; Travel/Accommodation/Expenses: Boehringer-Ingelheim; Travel/Accommodation/Expenses: Debiopharm. A. Pinto: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: MDS; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self): Celgene, A Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy: Servier; Speaker Bureau/Expert testimony: EDO-Mundipharma; Travel/Accommodation/Expenses: Takeda. C. Carlo Stella: Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): Servier; Honoraria (self): Amgen; Honoraria (self), Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: ADC Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Geneta Science srl; Research grant/Funding (institution): Rhizen Pharma; Travel/Accommodation/Expenses: Takeda. G. Musuraca: Advisory/Consultancy: Servier. R. Sarmiento: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, A Bristol-Myers Squibb Company. M. Zuraek: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: BMS. T. Sánchez-Pérez: Full/Part-time employment: Celgene, A Bristol-Myers Squibb Company. 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. B. Hanna: Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: BMS. Z. Nikolova: Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, A Bristol-Myers Squibb Company. All other authors have declared no conflicts of interest.
Q&A (ID 261)
17O - A first-in-human phase I study of MORAb-202 in patients with folate receptor alpha-positive advanced solid tumors (ID 193)
- Jun Sato (Tokyo, Japan)
- Jun Sato (Tokyo, Japan)
- Toshio Shimizu (Tokyo, Japan)
- Yutaka Fujiwara (Tokyo, Japan)
- Kan Yonemori (Tokyo, Japan)
- Takafumi Koyama (Tokyo, Japan)
- Akihiko Shimomura (Shinjuku-ku, Japan)
- Kenji Tamura (Tokyo, Japan)
- Satoru Iwasa (Tokyo, Japan)
- Shunsuke Kondo (Tokyo, Japan)
- Kazuki Sudo (Tokyo, Japan)
- Hiroki Ikezawa (Tokyo, Japan)
- Maiko Nomoto (Tokyo, Japan)
- Ryo Nakajima (Tokyo, Japan)
- Takuma Miura (Tokyo, Japan)
- Noboru Yamamoto (Chuo-ku, Japan)
Abstract
Background
MORAb-202 is a novel antibody-drug conjugate consisting of farletuzumab (a humanized monoclonal antibody that binds to folate receptor alpha (FRA)) paired with a cathepsin B-cleavable linker to eribulin. Here we report preliminary results of part 1 (dose escalation part) from a first-in-human phase 1 study of MORAb-202 in patients (pts) with FRA-positive solid tumors.
Methods
Eligible pts have centrally confirmed FRA-positive solid tumors after failure of standard therapies and an ECOG PS of ≤1. MORAb-202 is administered IV once every 3 weeks. The primary objective is to evaluate the safety and tolerability and to identify the recommended dose. Secondary objectives include pharmacokinetics, pharmacodynamics, and efficacy.
Results
As of Sep 2, 2019, 22 pts were enrolled and treated with MORAb-202 across 5 dose cohorts in Part 1 (0.3 mg/kg: n=3 [2 endometrial and 1 ovarian], 0.45 mg/kg: n=3 [3 ovarian], 0.68 mg/kg: n=6 [3 non-small cell lung cancer (NSCLC), 2 ovarian, and 1 triple-negative breast cancer (TNBC)], 0.9 mg/kg: n=7 [4 ovarian, 1 endometrial, 1 NSCLC, and 1 TNBC], 1.2 mg/kg: n=3 [2 ovarian and 1 fallopian tube]); all completed > 1 cycle. Only one pt in the 0.9 mg/kg cohort experienced DLTs of Grade 3 alanine aminotransferase increased and Grade 3 gamma-glutamyl transferase increased. Treatment-emergent adverse events (TEAEs) occurred in 21 pts (95.5%). The most common TEAEs were leukopenia and neutropenia (50% each). TEAE of special interest was interstitial lung disease as adjudicated by an independent adjudication committee, observed in 5 pts, at Gr 1 (n=3) and Gr 2 (n=2). The overall response rate (ORR) was 45.5% (10/22 pts) with 1 complete response (CR) (ovarian) at 0.9 mg/kg and 9 partial responses (PRs) at 0.68 mg/kg (1 TNBC, 1 ovarian and 2 NSCLC), 0.9 mg/kg (2 ovarian), 1.2 mg/kg (2 ovarian) and 0.3 mg/kg (1 endometrial). ORR of ovarian at ≥ 0.9 mg/kg was 71.4% (5/7 pts). The disease control rate (CR+PR+stable disease) was 81.8% (18/22 pts).
Conclusion
MORAb-202 up to 1.2 mg/kg had manageable toxicity, with encouraging antitumor activity in pts with FRA-positive solid tumors. Expansion part in the dose range of 0.9 and 1.2 mg/kg is underway for ovarian cancer (including primary peritoneal carcinoma and fallopian tube carcinoma).
Clinical trial identification
NCT03386942.
Legal entity responsible for the study
Eisai Co. Ltd.
Funding
Eisai Co. Ltd.
Disclosure
T. Shimizu: Honoraria (self), Research grant/Funding (institution): Millenium-Takeda; Honoraria (self): Taiho Pharmaceuticals; Advisory/Consultancy: The Consortium on Harmonization of Institutional Requirements for Clinical Research (Chair) Joint Scientific Committee Review Member for Phase 1 Trials in Hong Kong; Advisory/Consultancy: KSAR China; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): 3D-Medicine; Research grant/Funding (institution): Chordia Therapeutics; Research grant/Funding (institution): Symbio Pharmaceuticals; Research grant/Funding (institution): Five Prime; Research grant/Funding (institution): PharmaMar; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Eisai. Y. Fujiwara: Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy: Daiichi-Sankyo. K. Yonemori: Advisory/Consultancy: Ono; Advisory/Consultancy: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: AstraZeneca. K. Tamura: Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Daiichi-Sankyo; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eli Lilly; Speaker Bureau/Expert testimony: Chugai; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): MSD; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Ono; Research grant/Funding (institution): Clovis Oncology. S. Iwasa: Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Lilly Japan; Honoraria (self), Research grant/Funding (institution): Chugai Pharma; Honoraria (self): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Bayer. S. Kondo: Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Esai; Research grant/Funding (institution): Ono; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Asran; Research grant/Funding (institution): MSD; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Boehringer Ingelheim. H. Ikezawa, M. Nomoto, R. Nakajima, T. Miura: Full/Part-time employment: Eisai Co. Ltd. N. Yamamoto: Research grant/Funding (institution): Daiichi-Sankyo; Honoraria (self), Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Kyowa-Hakko Kirin; Research grant/Funding (institution): Bayer; Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical Co., LTD; Research grant/Funding (institution): Takeda; Honoraria (self): Chugai; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): BMS; Advisory/Consultancy: Eisai; Advisory/Consultancy: Otsuka; Advisory/Consultancy: Takeda; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Cimic; Research grant/Funding (institution): Janssen Pharma; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Merck; Honoraria (self): Sysmex; Research grant/Funding (institution): GSK. All other authors have declared no conflicts of interest.
Q&A (ID 262)
18O - CC-90011 in patients (Pts) with advanced solid tumors (STs) and relapsed/refractory non-Hodgkin lymphoma (R/R NHL): Updated results of a phase I study (ID 168)
- 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)
- Marta López-Brea (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 is an oral, potent, selective, and reversible inhibitor of lysine-specific demethylase 1A. Prior results from the CC-900011-ST-001 study showed that CC-90011 was well tolerated and had promising preliminary antitumor activity in pts with advanced unresectable STs and R/R NHL. Here we present updated results with longer follow-up and additional pts.
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. Primary endpoints were safety, maximum tolerated dose, and/or recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy.
Results
Of 66 pts enrolled (50 in part A; 16 in part B), all but 1 pt had STs; 40 pts had neuroendocrine neoplasms (NENs). The primary objective of part A was met with an RP2D of 60 mg QW established. As of 13 Sept 2019, 6 pts remained on treatment. The primary reason for discontinuation was progressive disease (part A, 76%; part B, 63%). Thrombocytopenia was the most common treatment-related adverse event (AE; 47%) and the only serious AE reported in >1 pt in either part of the study; it was an on-target event that was reversible and easily managed. AEs led to discontinuation in 6% of pts in part A and 0 pts in part B; 1 pt in part B died of infection unrelated to CC-90011. Clinical benefit rate was 20% (95% CI, 10.0-33.7) in part A. One pt with NHL achieved a complete response (CR) and is ongoing in cycle 27 as of 13 Dec 2019; 3 pts had stable disease (SD) ≥20 cycles. Exposure increased proportional to dose. Negligible accumulation of exposure was observed with repeat dosing, and the terminal half-life was ∼60 h. Decreased levels of circulating neuroendocrine peptides and peripheral blood PD biomarkers indicated target engagement by CC-90011.
Conclusion
Results from this updated analysis show a consistent, well-tolerated safety profile and favorable PK and PD characteristics for CC-90011. Promising antitumor activity was observed in pts with advanced unresectable malignancies, including a durable CR in R/R NHL and prolonged SD in NENs. These data support further investigation of CC-90011.
Clinical trial identification
NCT02875223; EudraCT 2015-005243-13.
Editorial acknowledgement
Scarlett Geunes-Boyer, PhD from Bio Connections, LLC.
Legal entity responsible for the study
Bristol-Myers Squibb.
Funding
Bristol-Myers Squibb.
Disclosure
A. Hollebecque: Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: Amgen; Honoraria (self), Honoraria (institution): Eisai; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: Servier; Advisory/Consultancy, Travel/Accommodation/Expenses: Astra-Zeneca; Advisory/Consultancy: Incyte; Advisory/Consultancy: Debiopharm; Travel/Accommodation/Expenses: Lilly; Travel/Accommodation/Expenses: Medimmune. 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: Astra-Zeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Astellas; 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, 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; Research grant/Funding (institution): Menarini. R. Plummer: Advisory/Consultancy: Pierre Faber; Advisory/Consultancy: Genmab; Advisory/Consultancy: Bayer; Advisory/Consultancy: Octimet; Advisory/Consultancy, Licensing/Royalties: Clovis Oncology; Advisory/Consultancy: Novartis; Advisory/Consultancy: Karus Therapeutics; Advisory/Consultancy: Biosceptre; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy: Cybrexa; Advisory/Consultancy: Sanofi A; Honoraria (self): Ellipses; Research grant/Funding (self): Astra-Zeneca; Travel/Accommodation/Expenses: MSD. J. Capdevila: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Advanced Accelerator Applications; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Astra-Zeneca; Advisory/Consultancy: Sanofi; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Celgene, a Bristol-Myers Squibb Company. G. Curigliano: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Honoraria (self), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Honoraria (self): Novartis; Honoraria (self): Seagen; Advisory/Consultancy: BMS. V. Moreno: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Regeneron; Speaker Bureau/Expert testimony: Bayer/Loxo. F. De Braud: Advisory/Consultancy: Tiziana Life Sciences; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Celgene, A Bristol-Myers Squibb Company; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Servier; Advisory/Consultancy: Pharm Research Associated; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy, Speaker Bureau/Expert testimony: Ignyta; Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy: Octimet Oncology; Advisory/Consultancy: Incyte; Advisory/Consultancy: Teofarma; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: EMD Serono; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): Loxo Oncology; Research grant/Funding (institution): Tesaro; Speaker Bureau/Expert testimony: Astra-Zeneca; Speaker Bureau/Expert testimony: Gentili; Speaker Bureau/Expert testimony: Fondazione Menarini; Speaker Bureau/Expert testimony: MSD; 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; Speaker Bureau/Expert testimony: Biotechspert Ltd.; Speaker Bureau/Expert testimony: PriME Oncology. P. Martin-Romano: Research grant/Funding (institution), Non-remunerated activity/ies: Astra-Zeneca; Research grant/Funding (institution), Non-remunerated activity/ies: BMS; Research grant/Funding (institution), Non-remunerated activity/ies: Boehringer Ingelheim; Research grant/Funding (institution): Janssen Cilag; Research grant/Funding (institution), Non-remunerated activity/ies: Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution), Non-remunerated activity/ies: Pfizer; Research grant/Funding (institution), Non-remunerated activity/ies: Roche; Research grant/Funding (institution): Sanofi; Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: Johnson & Johnson; Non-remunerated activity/ies: Lilly; Non-remunerated activity/ies: Medimmune; Non-remunerated activity/ies: NH TherAGuiX. J. Parra-Palau: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, a Bristol-Myers Squibb Company. T. Sánchez-Pérez: Full/Part-time employment: Celgene, A Bristol-Myers Squibb Company. 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: Shareholder/Stockholder/Stock options, Full/Part-time employment: BMS; Licensing/Royalties: Pfizer. 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.
Q&A (ID 263)
19O - A phase Ib trial of CFI-402257 in combination with weekly paclitaxel in patients with advanced HER2-negative (HER2-) breast cancer (aBC) (ID 197)
- Philippe Bedard (Toronto, Ontario, Canada)
- Philippe Bedard (Toronto, Ontario, Canada)
- Mihaela Mates (Kingston, ON, Canada)
- Karen A. Gelmon (Vancouver, British Columbia, Canada)
- John Hilton (Ottawa, MA, Canada)
- Dongsheng Tu (Kingston, ON, Canada)
- Irene Li (Toronto, ON, Canada)
- Laleh Rastgou (Vancouver, Canada)
- Nancy Drummond-Ivars (Ottawa, Canada)
- Jackie Edwards (Kingston, ON, Canada)
- David Warr (Toronto, Canada)
- Caroline Lohrisch (Vancouver, Canada)
- Xinni Song (Ottawa, Canada)
- Amirrtha Srikanthan (Ottawa, Canada)
- Andrew Robinson (Kingston, ON, Canada)
- Linda Hagerman (Kingston, ON, Canada)
- Lesley K. Seymour (Kingston, Ontario, Canada)
- Moira Rushton (Kingston, Canada)
- David W. Cescon (Toronto, Canada)
Abstract
Background
CFI-402257 is a selective oral inhibitor of TTK protein kinase, a critical regulator of the mitotic spindle assembly checkpoint. TTK is overexpressed in breast cancer (BC); CFI-402257 has anti-proliferative and cytotoxic activity as monotherapy. Synergy has been identified between TTK inhibitors and taxanes; CFI-402257 enhances the antitumor activity of paclitaxel in BC xenograft models.
Methods
The primary objective was to establish the safety and recommended phase 2 dose (RP2D) of CFI-402257 combined with weekly paclitaxel. Patients with HER2-ve aBC with adequate organ function, PS 0-1, previously treated with > 1 non-taxane chemotherapy, not appropriate for endocrine therapy, were eligible. A 3+3 design was used with dose limiting toxicities (DLTs) assessed during cycle 1 (28 days). Starting dose CFI-402257 was 84mg on 2-day on, 5-day off schedule with paclitaxel 80mg/m2 day 1, 8, and 15. Safety assessments were performed weekly (CTCAE v5.0) and response (RECIST 1.1) every 2 cycles.
Results
13 patients received a total of 39 cycles at 3 dose levels (84mg, 112mg, 168mg). Median age was 51, 85% ER+/HER2-ve, 54% PS1, 50% ≥3 prior lines of chemotherapy, and 54% with ≥4 sites of metastatic disease. One grade 4 neutropenia DLT was seen at DL3; no related serious adverse events (AEs) were seen. The most frequent (≥30%) non-hematological AEs were alopecia (82%), diarrhea (55%), nausea (55%), fatigue (55%), vomiting (45%), sensory neuropathy (45%), headache (45%), constipation (45%), back pain (36%), and extremity pain (36%). Grade ≥3 hematological AEs were neutropenia (27%) and anemia (9%). The overall response rate for evaluable patients was 1/9 = 11.1%.
Conclusion
CFI-402257 and paclitaxel is well tolerated. Dose escalation is ongoing and the RP2D has not yet been defined. Updated safety and efficacy data will be presented at the meeting.
Clinical trial identification
NCT03568422.
Legal entity responsible for the study
Canadian Cancer Trials Group.
Funding
This study was coordinated by the Canadian Cancer Trials Group supported by SU2C Canada - Canadian Cancer Society Breast Cancer Dream Team Research Funding (SU2C-AACR-DT-18-15), with supplemental support from the Ontario Institute for Cancer Research, through funding provided by the Government of Ontario.
Disclosure
P. Bedard: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): BMS; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Servier; Research grant/Funding (institution): PTC Therapeutics; Research grant/Funding (institution): SignalChem LifeSciences; Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Nektar Therapeutics; Research grant/Funding (institution): Zymeworks. K.A. Gelmon: Advisory/Consultancy, Research grant/Funding (institution): AZ; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Oncothyreon; Advisory/Consultancy: Nanostring; Advisory/Consultancy: Merck; Advisory/Consultancy: Mylan; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Genomic Health; Advisory/Consultancy, Research grant/Funding (institution): BMS; Speaker Bureau/Expert testimony: Genentech. J. Hilton: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Lilly; Advisory/Consultancy: Puma; Advisory/Consultancy: Novartis; Advisory/Consultancy, Non-remunerated activity/ies, Data Monitoring Committee: BMS; Advisory/Consultancy: AZ. L.K. Seymour: Research grant/Funding (institution), For trial costs: University Health Network. D.W. Cescon: Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): GSK; Advisory/Consultancy: Novartis; Advisory/Consultancy: AZ; Advisory/Consultancy: Roche; Advisory/Consultancy: Puma; Advisory/Consultancy: Agendia; Advisory/Consultancy: Dynamo Therapeutics; Non-remunerated activity/ies, Patent holder (to institution) for biomarkers related to CFI-402257: University Health Network. All other authors have declared no conflicts of interest.