PI3K δ plays an essential role in B-cell development and function. And SHC014748M is a small-molecule inhibitor of PI3K with high selectivity to δ isoform. Thus, we evaluated the safety, tolerability, efficacy and pharmacokinetics of SHC014748M capsules in patients with relapsed or refractory inert B-cell malignancies in this study.
This trial included two phases: dose-escalation phase and dose-expansion phase. 3 subjects with iNHL(indolent non-Hodgkin Lymphoma) were respectively assigned into five dose levels (50-250mg). 12 patients were enrolled in the 150mg QD and 12 in the 200mg QD. The primary outcomes were safety, tolerability, and pharmacokinetics of SHC014748M Capsules in Patients. The secondary outcome was ORR (Overall Response Rate).
39 patients were enrolled in the study, including 23(59.0%) with follicular lymphoma, 11 (28.2%) with chronic lympho cytic leukemia/small lymphocytic lymphoma, 2 (5.1%) with Marginal Zone Lymphoma, and 3 (7.7%) with Waldenstrom Macroglobulinemia. The median age was 55 and 30 were males. The mean lines of prior systemic therapy was 2.23. Dose Limited Toxicity did not occur in all dose groups. Common adverse events included neutropenia (45.5%), blood lactate dehydrogenase increased (38.2%), platelet count decreased (25.5%), anemia (21.8%) and fatigue (23.6%). Severe (Grade≥3) adverse reaction included neutropenia (16.4%), diarrhea (7.3%) , pneumonitis (5.5%), rash (5.5%) and anemia (5.5.%). Tmax was 1.3 ∼ 2.2 h and T1/2 was 14.1 ∼ 22.1 h after taking orally SHC014748M capsule for 28 days. The overall ORR across all groups (50-250 mg QD) was 59.0%, with 66.7% (CR 6.7%, PR 60.0%) in 200 mg QD. For patients with follicular lymphoma, the ORR reached at 72.7% (CR 9.0%, PR 63.7%) in 200mg QD.
Oral administration of SHC014748M capsules in Patients with iNHL were highly effective and safe in Chinese patients. And the results of phase I study suggested patients with FL administered at 200mg should be explored in additional studies.
NCT03588598.
The authors.
Nanjing Sanhome Pharmaceutical CO., LTD.
All authors have declared no conflicts of interest.
Immune rejection of tumors is contingent to the development of a specific immune response and presence of a favorable TME. We aimed to evaluate the immune priming effect of TG4001, an HPV E6/E7 vaccine based on a recombinant Modified Vaccinia Ankara combined with avelumab, an anti-PD-L1 monoclonal antibody, in HPV+ cancers (NCT03260023).
34 patients (pts) with recurrent/ metastatic HPV16+ anal (15), oropharyngeal (8), cervical (6) or vulvar/vaginal (5) cancer were administered 5·107 pfu SC weekly for 6 weeks (wks), every 2 wks up to month 6, and then every 12 wks in combination with avelumab IV at 10mg/kg every 2 wks. Tissue and PBMC samples were collected at baseline and day (D) 43. T cell responses against HPV antigens were measured using ex-vivo IFNγ-ELISPOT on PBMCs; PD-L1 expression and CD3 and CD8+infiltrate were evaluated by immunostaining of tumor, and changes in gene expression were measured using nanostring.
7 pts achieved partial response and 1 achieved complete response according to RECIST 1.1. 7/11 pts evaluable for ELISPOT developed reactive T cells against E6, E7 or both after vaccination. The patient with complete response had an intense T cell response against E6 and E7 at D43. Reanalysis of this patient after 6 months showed that the T cell response was maintained, consistent with sustained disease control. At baseline, higher level of PD-L1 expression was seen in clinical responders vs. non-responders as well as higher CD3 (median: 470 vs. 200/mm2) and CD8 cell (median: 238 vs 92 /mm2) infiltrates. Infiltrates tended to increase during treatment and, at day 43, were accompanied by strong changes of the tumor transcriptomic profile, involving increase in expression of effector T cell activation cascades such as CD3G, IL21R and IFNG (respectively, 13-fold, 17-fold and 9-fold versus baseline). The Immunosign gene signature was applied as an index of “cold” or “hot” TME profile. 57% of pts had “hot” TME profile at baseline versus 100% at D43.
TG4001 and PD-L1 blockade with avelumab led to the development of specific immunity and TME transformations in HPV+ cancer pts potentially leading to clinical benefit.
NCT03260023.
Transgene SA.
Transgene, Merck Serono.
C. Le Tourneau: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: MSD; Advisory/Consultancy: BMS; Advisory/Consultancy: Celgene; Advisory/Consultancy: GSK; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Rakuten; Advisory/Consultancy: Nanobiotix; Advisory/Consultancy: Roche. P. Cassier: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Roche/Genentech; Honoraria (self), Travel/Accommodation/Expenses: Amgen; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Serono; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Blueprint Medicines; Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Abbvie; Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS; Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Toray Industries; Research grant/Funding (institution): Transgene; Research grant/Funding (institution): Loxo; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Innate Pharma; Research grant/Funding (institution): Janssen. F. Rolland: Advisory/Consultancy: Pfizer; Advisory/Consultancy: BMS; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: MSD. J-M. Limacher: Honoraria (self), Advisory/Consultancy: AstraZeneca; Shareholder/Stockholder/Stock options: Odimma SA. A. Tavernaro: Shareholder/Stockholder/Stock options, Full/Part-time employment: Transgene. H. Makhloufi: Full/Part-time employment: Transgene. K. Bendjama: Full/Part-time employment: Transgene. J-P. Delord: Advisory/Consultancy: Novartis; Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): MSD. All other authors have declared no conflicts of interest.
mUM is a historically treatment-refractory tumor with high expression of gp100 and 12 month (mo) OS rate of 43% (Khoja L, et al.
We conducted a Ph2 study of tebe in mUM pts. HLA-A*0201+ pts were treated at 24 centers with a regimen of QW iv dosing (20μg C1D1; 30μg C1D8; 68μg C1D15). 1° objective was ORR by RECIST 1.1 using independent central review (ICR). 2° objectives included safety, OS and PFS.
127 pts were treated (50% male; 70% ECOG 0, 58% LDH >ULN). All pts received ≥1 prior therapy in metastatic setting (34% ≥2 lines; 45% LDT; 73% immunotherapy (65% anti PD1, 31% anti CTLA4)). ORR (all PRs) was 5% (95% CI: 1.8%, 10.0%); median duration of response 8.7 mos. 45% pts achieved stable disease. Of pts with evaluable tumors (n=116), 44% had reduction in target lesions (TL) including immune-related responses. With median follow-up of 19.6 mos, median OS (mOS) was 16.8 mos (95% CI: 12.9, 21.3). 12 mo OS rate was 62%, 18 mo was 45%. 12 mo OS rate of pts with any TL reduction was 86%. Median PFS was 2.8 mos. Most common treatment related AEs (TRAEs) were generally cutaneous (gp100+ melanocytes) or cytokine mediated (T cell activation) and included pyrexia (80%), pruritus (67%), and chills (64%) with Grade ≥3 TRAE of rash maculo-papular (13%), hypotension (8%), increased aspartate aminotransferase (AST), and hypophosphatemia (5% each). TRAEs decreased in frequency and severity after first 3 doses. 86% pts experienced cytokine release syndrome (CRS) by ASTCT criteria (Lee DW, et al.
While the 1° endpoint of ORR was 5%, 44% pts had reduction in TL. 12 mo OS rate (62% all pts, 86% in pts with TL reduction) was promising. Related AEs were generally predictable, manageable, decreased in frequency and severity over first few doses and were consistent with proposed MoA. Tebe is being evaluated in a randomised pivotal trial with 1° endpoint of OS.
NCT02570308.
Immunocore Ltd.
Immunocore Ltd.
J.J. Sacco: Advisory/Consultancy, Research grant/Funding (institution): Immunocore; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): MSD; Advisory/Consultancy: Delcath; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Speaker Bureau/Expert testimony: Pierre Fabre; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Replimune. R. Carvajal: Advisory/Consultancy: Castle Biosciences; Advisory/Consultancy, Research grant/Funding (institution): Immunocore; Advisory/Consultancy: InxMed; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: PureTech Health; Advisory/Consultancy, Research grant/Funding (institution): Regeneron; Advisory/Consultancy: Sanofi Genzyme; Advisory/Consultancy: Sorrento Therapeutics; Advisory/Consultancy: Trisalus; Shareholder/Stockholder/Stock options: Aura Biosciences; Shareholder/Stockholder/Stock options: Chimeron; Shareholder/Stockholder/Stock options: Rgenix; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Corvus; Research grant/Funding (institution): Ideaya; Research grant/Funding (institution): Iovance; Research grant/Funding (institution): Mirati; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Roche. M. O. Butler: Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (institution), Safety Review Committee: Adaptimmune; Advisory/Consultancy, Safety Review Committee: GSK; Advisory/Consultancy, Research grant/Funding (institution): Immunocore; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Sun Pharma; Research grant/Funding (self): Takara Bio; Research grant/Funding (institution): Regeneron; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): OncoSeq. A.N. Shoushtari: Honoraria (self), Research grant/Funding (institution): Immunocore; Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self): Castle Biosciences; Licensing/Royalties: UpToDate; Research grant/Funding (institution): Xcovery; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer. J. C. Hassel: Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy: MSD; Advisory/Consultancy: Pierre Fabre; Honoraria (self), Research grant/Funding (institution): BMS; Advisory/Consultancy: Sun Pharma; Honoraria (self), Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Immunocore; Research grant/Funding (institution): Philogen; Research grant/Funding (institution): Sensitize; Research grant/Funding (institution): LIipomerit; Research grant/Funding (institution): Regeneron. A. Ikeguchi: Research grant/Funding (institution): Dynavax; Research grant/Funding (institution): Immunocore; Research grant/Funding (institution): Merck; Research grant/Funding (institution): GSK/Sarah Cannon; Research grant/Funding (institution): Neon Therapeutics/Sarah Cannon. L. Hernandez-Aya: Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy: Castle Bioscience; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Regeneron; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Immunocore; Research grant/Funding (institution): Merck-EMD; Research grant/Funding (institution): Corvus; Research grant/Funding (institution): Polynoma; Research grant/Funding (institution): Genentech. P. Nathan: Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Advisory/Consultancy, Research grant/Funding (institution): Immunocore; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Incyte; Advisory/Consultancy: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy: 4SC; Non-remunerated activity/ies, Uveal melanoma lead: EORTC Melanoma Group; Non-remunerated activity/ies, UK Uveal Melanoma Lead: International Rare Cancer Initiative. O. Hamid: Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Aduro; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Akeso Bio; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution): Array/Pfizer; Advisory/Consultancy: Beigene; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution): BMS; Advisory/Consultancy: Caris; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Genentech; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): GSK; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Immunocore; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Incyte; Advisory/Consultancy: Janssen; Advisory/Consultancy: Jounce; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Nextcure; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Regeneron; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Sanofi; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (self): Tempus; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Zelluna; Research grant/Funding (self): Arcus; Research grant/Funding (self), Research grant/Funding (institution): CytomX; Research grant/Funding (self), Research grant/Funding (institution): Exelixis; Research grant/Funding (self), Research grant/Funding (institution): Iovance; Research grant/Funding (self), Research grant/Funding (institution): Moderna; Research grant/Funding (self), Research grant/Funding (institution): Torque; Research grant/Funding (institution): Arcus. J.M. Piulats Rodriguez: Research grant/Funding (institution): Immunocore. M. Rioth: Advisory/Consultancy: Health Advances. D.B. Johnson: Advisory/Consultancy, Research grant/Funding (institution): Array Biopharma; Advisory/Consultancy, Research grant/Funding (self): BMS; Advisory/Consultancy: Catalyst; Advisory/Consultancy: Iovance; Advisory/Consultancy: Janssen; Advisory/Consultancy: Merck; Advisory/Consultancy: Novartis; Research grant/Funding (self): Incyte; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Immunocore; Non-remunerated activity/ies, Melanoma Guideline Committee: NCCN; Non-remunerated activity/ies, Scientific Selection Committee: ASCO; Non-remunerated activity/ies, Immunotherapy Toxicity Guidleines: SITC. J. J. Luke: Honoraria (self), Research grant/Funding (institution): Abbvie; Honoraria (self): Aligos; Honoraria (self), Research grant/Funding (institution): Array; Honoraria (self): Bayer; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS; Honoraria (self): Checkmate; Honoraria (self): Cstone; Honoraria (self): Eisai; Honoraria (self), Research grant/Funding (institution): EMD Serono; Honoraria (self): KSQ; Honoraria (self), Travel/Accommodation/Expenses: Janssen; Honoraria (self), Research grant/Funding (institution): Merck; Honoraria (self), Travel/Accommodation/Expenses: Mersana; Honoraria (self): Novartis; Honoraria (self): Partner; Honoraria (self): Pfizer; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Actym; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Alphamab Oncology; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Arch Oncology; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Kanaph; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Mavu; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Onc.AI; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Pyxis; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Tempest; Research grant/Funding (institution): Agios; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Corvus; Research grant/Funding (institution): Immatics; Research grant/Funding (institution): Incyte; Non-remunerated activity/ies: 7 Hills; Research grant/Funding (institution), Non-remunerated activity/ies: Springbank; Advisory/Consultancy: RefleXion; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Ribon; Advisory/Consultancy: Rubius; Advisory/Consultancy: Silicon; Advisory/Consultancy: Tesaro; Advisory/Consultancy: Werewolf; Advisory/Consultancy: Xilio; Advisory/Consultancy, Research grant/Funding (institution): Xencor; Research grant/Funding (institution): Kadmon; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Tizona; Travel/Accommodation/Expenses: Pyxis. E. Espinosa: Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Sanofi; Non-remunerated activity/ies, Vice-President: Grupo Espanol Melanoma. S. Leyvraz: Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy: Immunocore. H.M. Goodall: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Immunocore. C. Holland: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Immunocore. S. Abdullah: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Immunocore. T. Sato: Advisory/Consultancy, Research grant/Funding (institution): Immunocore.
Intravenous (IV) administration of IPI and NIVO has low activity in patients (pts) with recurrent glioblastoma (rGB). IT administration of IPI and NIVO was safe in cohort C1 and C2 of the GlITIpNi phase I clinical trial (Schwarze et al. ASCO 2020, abstract #2534). In C3 and C4, IT administration of IPI and NIVO was followed by repeated IC and IV administrations of NIVO.
Pts with resectable rGB were recruited in C4; pts with non-resectable rGB in C3 (biopsy only). IT administration (in the brain tissue lining the resection cavity) of IPI (5 mg) plus NIVO (10 mg), was followed by IC-NIVO (through an Ommaya reservoir) at a dose of 1, 5 or 10 mg Q2w plus IV-NIVO (10mg) Q2w (max 12x). Cerebrospinal fluid (CSF) was collected prior to each drug administration for biochemical/cytological analysis, and concentration measurements of IPI and NIVO. NGS (RNA/DNA) was performed on resected tissue.
32 pts (23 male; med age 55y [38-77]; IDH1 R132H mutation [n=2], 1p/19q LOH [n=1]) diagnosed with rGB were enrolled (C3 [n=17], C4 [n=15]). After a median FU of 37w (1-82w), study treatment is ongoing in 2 pts. All pts received the predefined IT dose of IPI and NIVO. Median number of IC/IV NIVO administrations in C3 and C4 were respectively 5 [1-12] and 4 [1-12]. Most frequent AEs were fatigue (n=27), headache (n=17), fever (n=9), and seizures (n=5). Bacterial colonization of the Ommaya reservoir requiring removal and antibiotic therapy occurred in 4 pts. There were no G5 AEs. In C3, 1 pt has an ongoing PR after 83w (best response was PD in all other 15 evaluable pts); 11 pts have died (due to PD; median OS is 38w [95% CI 9-61]). In C4, 3 pts remain relapse-free after 30, 31 and 32w; 5 pts have died (all due to PD; median OS not reached). In 5 (C3) and 6 (C4) pts, elevated protein levels as well as lymphocytic pleocytosis were documented. There was no evidence for accumulation of NIVO in the CSF during therapy. Cytokine, cfDNA analysis of CSF and NGS on tumor tissue are ongoing.
IT administration of NIVO and IPI followed by IC/IV administration of NIVO was feasible and sufficiently safe to warrant further investigation in pts with rGB.
NCT03233152.
Department of Medical Oncology, Universitair Ziekenhuis Brussel.
Stichting Tegen Kanker.
J.K. Schwarze: Travel/Accommodation/Expenses: Merck Sharp & Dohme; Travel/Accommodation/Expenses: Amgen. G. Awada: Research grant/Funding (institution): Pfizer; Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Astellas. B. Neyns: Research grant/Funding (institution): Roche; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: EtheRNA; Advisory/Consultancy: CryoStorage; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Merck-Serono. All other authors have declared no conflicts of interest.