Background

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.

Methods

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).

Results

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.%). T_max was 1.3 ~ 2.2 h，and T_1/2 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.

Conclusions

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.

Clinical trial identification

NCT03588598

Background

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).

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

NCT03260023

Background

mUM is a historically treatment-refractory tumor with high expression of gp100 and 12-month (mo) OS rate of 43% (Khoja L, et al. Ann Oncol. 2019; 30(8):1370-1380). Tebe is a bispecific consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells (melanocytes and melanoma). An intra-patient escalation regimen evaluated in phase1 of the current study identified 68 µg as the phase 2 dose (Sato T et al. J. Clin. Oncol. 2018; 36(15_suppl): 9521).

Methods

We conducted a phase 2 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 [LR-E1] [HG2] C1D15+). Primary objective was ORR by RECIST 1.1 using independent central review (ICR). Secondary objectives included safety, OS and PFS.

Results

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. Biol Blood Marrow Transplant. 2019; 25(4): 625-638); 3% Grade 3; 1% Grade 4. There were no grade 5 TRAEs.

Pts who developed rash within 7 days of tebe start (64%) had superior mOS, 22.5 mos vs other pts, 10.3 mos.

Conclusions

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.

Clinical trial identification

NCT02570308

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

ClinicalTrials.gov: NCT03233152