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.
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).
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.
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.
NCT02875223; EUDRACT 2015-005243-13.
Writing and editorial assistance were provided by Yaeko Hiyama, PhD, of Bio Connections LLC, funded by Bristol-Myers Squibb Company.
Celgene, a Bristol-Myers Squibb Company.
Celgene, a Bristol-Myers Squibb Company.
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.
SCC244 is a novel potent and highly selective c-MET inhibitor, which displayed high antitumor activity and desirable pharmacokinetic (PK) profile in preclinical models. This first-in-human phase I study was designed to evaluate the safety, PK, and preliminary efficacy of SCC244. Here, we reported the results from phase Ia part of the study.
Escalating doses of SCC244 (from 100 mg to 400 mg), using a conventional 3+3 escalation scheme, were administered orally once daily in advanced NSCLC pts regardless of c-MET status.
At the data cut-off date of Aug 21, 2020, a total of 19 pts were enrolled to 4 dose levels (3 at 100 mg, 3 at 200 mg, 7 at 300 mg, and 6 at 400 mg). The most common (≥ 20%) any grade treatment-related adverse events included oedema peripheral (36.8%）, decreased appetite (36.8%), headache (31.6%), dizziness (31.6%), vomiting (31.6%), nausea (31.6%), bilirubin conjugated increased (26.3%) and asthenia (26.3%). Only one pt at 400 mg (1 of 6 pts) had experienced dose-limiting toxicity: grade 3 vomiting. The maximum tolerated dose was not reached. 300 mg QD was selected as recommended phase II dose (RP2D) for further study. The Cmax was reached in approximately 2 to 3 hours; SCC244 exposure (AUC0-24h and Cmax) increased approximately in a dose-proportional manner; the mean (range) of T1/2 was 34.8 (12.4-64.1) hours; the mean (range) of Rac (AUC) was 3.4 (1.5-5.9), Rac (Cmax) was 3 (1.2-5.4). In total of 17 evaluable pts, two pts achieved confirmed partial response (PR) per RECIST 1.1. One pt at 300 mg achieved confirmed PR with a duration of response (DOR) of 7.3 months. Exploratory analysis showed that this pt carried c-MET ex14 skipping mutation. Another pt at 200mg, who had disease progression after the fourth lines of anti-EGFR therapy, achieved confirmed PR with a DOR of 11.1 months, and was found to be c-MET IHC 3+.
This first-in-human study of the c-MET selective inhibitor SCC244 demonstrated a tolerable and manageable safety profile, linear PK, and encouraging preliminary anti-tumor activity. The long T1/2 supports once daily dosing. Studies with SCC44 in patients with METex14 skipping mutation in NSCLC are ongoing to further explore the safety and efficacy in larger populations.
NCT03466268.
Haihe Biopharma Co., Ltd.
Haihe Biopharma Co., Ltd.
M-H. Sun, Y. Li: Full/Part-time employment: Haihe Biopharma Co., Ltd. All other authors have declared no conflicts of interest.
IL-12 is a strong driver of a TH1 immune response, but systemic recombinant IL-12 is poorly tolerated clinically. MEDI1191 (IL-12 mRNA) is a lipid nanoparticle (LNP)-formulated therapy developed for intratumoral (IT) injection, designed to drive local IL-12 production and induce anenestic anti-tumor activity. In preclinical models, IT IL-12 mRNA induces a potent TH1-mediated antitumor response, that is further enhanced by PD-L1 blockade.
This phase I, multicenter, open-label, dose-escalation (part 1) and expansion (part 2) study evaluates the safety and efficacy of MEDI1191 IT in sequential or concurrent combination with durvalumab 1500 mg Q4W IV in advanced solid tumors with superficial and deep-seated lesions. Patients (pts) who have progressed on at least 1 line of standard systemic therapy were eligible, including IO naïve or pre-treated pts. Primary endpoints for part 1 are safety and to identify the maximum tolerated dose and a pharmacodynamic active dose. Secondary endpoints for part 1 include efficacy (disease control rate, duration of response, time to response, PFS, and OS), pharmacokinetics and immunogenicity. Here we will be presenting preliminary data that needs further validation.
From May 2019 to December 2020, 10 pts were enrolled across three dose escalation cohorts in part 1 in pts with superficial lesions. 6 out of 10 were IO-pretreated pts. No DLT, AESI, ≥ G3 TRAE or TR-SAE were reported. To date, two partial responses have been observed, both pts had received IO therapies and had PD-L1 negative tumors, including one pt with melanoma with tumor shrinkage of both injected and non-injected lesions following 2 doses of MEDI1191 and prior to durvalumab. Preliminary pharmacodynamic analysis indicate that MEDI1191 induced transient elevation in serum levels of IL-12; and concordant changes in IFN-g and CXCL10.
Sequential combination of IT MEDI119 with IV durvalumab was well tolerated and showed encouraging preliminary antitumor and pharmacodynamic activity including in IO pre-treated pts, consistent with the expected mechanism of action. The study is active and recruiting.
NCT03946800.
AstraZeneca.
AstraZeneca.
O. Hamid: Research grant/Funding (self): Moderna. M. Hellman: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca. B. Carneiro, V. Subbiah: Research grant/Funding (self): AstraZeneca. T. Marron: Advisory/Consultancy: AstraZeneca. J. Eyles, V. Dubois, B. Ridgway, O. Hamid, A. Gasco Hernandez: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.
PIK3CA mutations are among the most frequent alterations in solid tumors, identified in 12% of ovarian cancer (OC), 27%-36% of breast cancer (BC), and 42% of cervical cancer. Targeting PI3Kα may be effective in those cancers harboring PIK3CA mutation. Here, we report the results from an ongoing phase Ia/Ib study of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors.
This phase Ia trial had 2 parts: dose escalation and dose expansion. Pts with or without PIK3CA mutant were eligible for dose-escalation, but only pts with PIK3CA mutation were eligible for dose-expansion.
At data cut-off (31 Oct 2020), 39 pts had been enrolled (19 from dose escalation at 1-60 mg and 20 from dose expansion at 20-40 mg) including 4 pts with OC, 8 pts with BC. The most common (≥ 20%) any grade treatment-related adverse events included hyperglycemia (84.6%), decreased appetite (30.8%), nausea (30.8%), diarrhea (28.2%), weight decrease (25.6%), and vomiting (23.1%). Hyperglycemia was generally manageable with anti-hyperglycemic medications. Three pts had experienced dose-limiting toxicity (DLT): grade 3 hyperglycemia at 40 mg and 60 mg dose level, and grade 3 nausea at 60 mg dose level. Thus, the 40 mg dose was considered to be RP2D. AUC0-24h and Cmax increased in a dose-proportional manner. Median Tmax was 2-4 hours and half-life (t1/2) was about 20 hours. In 18 evaluable pts with PIK3CA hotspot mutations, 4 pts achieved best overall response. One OC pt (PIK3CA E545A mutation) who had received 2 lines of platinum-based chemotherapy achieved complete response (CR) per RECIST 1.1, and the duration of response had lasted more than 10 months as of data cut-off. Other 3 pts with partial response (PR) were found in 1 OC pt (PIK3CA E545K mutation), 1 BC pt (PIK3CA E545K mutation), and 1 gastric cancer (PIK3CA E542K mutation). In addition, 1 colorectal cancer pt (PIK3CA status unknown) in dose escalation part also achieved PR.
CYH33 demonstrates a manageable safety profile and linear pharmacokinetic characteristics. An encouraging preliminary anti-tumor efficacy in certain tumor types harboring PIK3CA mutation was observed.
NCT03544905.
Haihe Biopharma Co., Ltd.
Haihe Biopharma Co., Ltd.
Q-Q. Yu, Y-W. Du: Full/Part-time employment: Haihe Biopharma Co., Ltd. All other authors have declared no conflicts of interest.