Clinical Activity In Phase Research Articles

Identification of immune biomarkers in treatment-naive patients with metastatic pancreatic cancer treated with the GSK-3 inhibitor elraglusib (9-ING-41) in combination with gemcitabine/nab-paclitaxel in the 1801 phase 2 study.

e16331 Background: Elraglusib (9-ING-41), a potent and selective GSK-3 inhibitor, is a targeted anticancer agent with clinical activity in phase 1 trial and undergoing clinical development for the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC). Elraglusib (9-ING-41) displayed immune-modulatory activity in preclinical models and modulation of serum cytokine profile in clinical specimens. Here, we investigated the correlation between plasma levels of cytokines/chemokines/soluble cell receptors/growth factors (CCSG) and clinical outcomes of patients with mPDAC treated with elraglusib and gemcitabine/nab-paclitaxel (GnP) in an exploratory study. Methods: CCSGs were evaluated in the pre-dose plasma samples of patients with newly diagnosed mPDAC enrolled in the 1801 phase 2 study (NCT03678883) treated with GnP (n = 13) or elraglusib/GnP (n = 32). Using a Luminex immunoassay, 40 CCSGs were screened as predictive biomarkers of median overall survival (mOS) in the elraglusib/GnP arm using 5-fold cross-validation and maximally selected rank statistic cutpoint determination. A subset of CCSGs (n = 10) was remeasured using an MSD immunoassay with greater sensitivity. Maximally selected rank statistic cutpoint determinations were conducted using MSD results for elraglusib/GnP samples with mOS and median progression free survival (mPFS). P values < 0.05 were considered statistically significant. Results: Luminex screening revealed several CCSGs significantly stratified elraglusib/GnP patients by mOS. IL-6 and IL-8 were identified as top candidates with stable and significant results on cross-validation. Using the MSD assay, both were confirmed to stratify elraglusib/GnP patients by OS and extended to analyze PFS. Low level of IL-8 conferred a better OS prognosis (HR: 0.0919, 95%, CI: 0.0205-0.411, P < 0.001) than low IL-6 (HR: 0.205, 95%, CI: 0.063-0.665, P = 0.005) in the elraglusib/GnP treated patients. Correlations with mPFS were similar in the elraglusib/GnP patients for IL-6 (HR: 0.248, 95% CI: 0.072-0.848, P = 0.02) and IL-8 (HR: 0.297, 95%, CI: 0.111-0.743, P = 0.01). Conclusions: Preliminary results of our exploratory study identified low plasma levels of IL-6 and IL-8 prior to elraglusib/GnP treatment as potential predictive biomarkers associated with improved outcomes in previously untreated patients with mPDAC. The 1801 Part 3 Arm B clinical trial recruitment has been completed. We plan to analyze additional pre-dose plasma samples obtained from approximately 200 patients by April 2024. These will be analyzed using interim OS data available by April 2024 and included in the final presentation. Clinical trial information: NCT03678883 .

SB221: A proof-of-concept study to assess the combination of SON-1010 (IL12-FHAB) and atezolizumab in patients with platinum-resistant ovarian cancer.

TPS5629 Background: Recombinant interleukins (rIL) have had limited clinical success due to inefficient tumor targeting and short PK, requiring frequent dosing that leads to aberrant immunostimulation and toxicity. IL-12 potently activates T and NK cells to produce IFNγ and kill tumor cells, yet dosing strategies have failed to provide adequate therapeutic benefit in humans. We developed a novel platform that delivers immunomodulator(s) linked to a fully-human albumin binding (FHAB) domain (Cini, Front Immunol 2023). Single-chain native IL-12 genetically linked to the FHAB provides enhanced tumor targeting and retention through albumin binding to over-expressed FcRn, GP60, and SPARC in the tumor microenvironment (TME), with an improved PK profile, a dose-sparing effect that decreases the toxicity risk, and a broader therapeutic index. Tumor growth inhibition in an immunologically ‘cold’ B16-F10 mouse melanoma model showed the efficacy of IL12-FHAB compared with rIL-12, resulting in significant increases in activated NK, NKT, Th1, and cytotoxic CD8 T cells. SON-1010 is being studied clinically as monotherapy (study SB101) in advanced solid tumors and in healthy volunteers (study SB102) (Chawla, AACR 2023). Atezolizumab (Tecentriq), an anti-PD-L1 immune checkpoint inhibitor (ICI), has shown preliminary clinical activity in Phase 1 studies of patients with platinum-resistant ovarian cancer (PROC) (Liu, Gyn Onc 2019; Moroney, Clin Canc Res 2020). SON-1010 may ‘warm up’ the TME to improve ICI effectiveness in these immunologically-active tumors that have high levels of SPARC. Methods: Study SB221 is a Phase 1b/2a multicenter, dose-escalation and proof-of-concept study to assess the safety, tolerability, PK, PD, and efficacy of SON-1010 administered SC, either alone or in combination with a fixed dose of atezolizumab given IV (NCT05756907). The study is designed in Part 1 to rapidly establish the maximum tolerated dose (MTD) of the combination in patients with advanced solid tumors with up to 5 dose-escalation groups and to expand the dataset using patients with PROC to establish the Recommended Phase 2 Dose (RP2D). Once the likelihood of efficacy is shown in a Simon 2-stage design, this will be followed in Part 2 by an assessment of the potential for improved efficacy of the combination in patients with PROC over SON-1010 alone or the standard of care (SOC). The first dose-escalation cohorts have been enrolled and additional sites are being added to help with recruitment of patients with PROC. Combination of SON-1010 with an ICI offers a unique opportunity to use this extended PK version of IL-12 to augment the potential for tumor control in PROC, which represents a significant unmet medical need. Clinical trial information: NCT05756907 .

INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH RESIDUAL OR RECURRENT GRADE 2 GLIOMA WITH AN IDH1/2 MUTATION

Abstract AIMS Current treatments grade 2 gliomas are not curative and can be associated with short- and long-term toxicities. Vorasidenib (VOR), an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes, has shown a tolerable safety profile and preliminary clinical activity in phase 1 studies. METHOD In the phase 3 INDIGO study (NCT04164901), patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumor size. Key eligibility criteria included: age ≥12; KPS >80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI). RESULTS As of 06 Sep2022, 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Median PFS by BIRC was 27.7 mos with VOR and 11.1 with PBO (HR, 0.39; 95% CI, 0.27, 0.56; 1-sided P=0.000000067). Median TTNI was not reached with VOR and 17.8 mos with PBO (HR, 0.26; 95% CI, 0.15, 0.43; 1-sided P=0.000000019). All-grade adverse events (AEs) occurring in >20% pts receiving VOR vs PBO were alanine aminotransferase increased, COVID-19, fatigue, aspartate aminotransferase increase, headache, diarrhea, nausea. Common grade ≥3 AEs (>5%): ALT increased (9.6% vs 0%). CONCLUSIONS VOR significantly improved PFS by BIRC versus PBO with a manageable safety profile. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved.

KS02.6.A INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE III STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH RESIDUAL OR RECURRENT GRADE 2 GLIOMA WITH AN IDH1/2 MUTATION

Abstract BACKGROUND Grade 2 gliomas are slowly progressive, malignant brain tumours with a poor long-term prognosis. Current treatments (surgery followed by observation or adjuvant radiation and chemotherapy) are not curative and can be associated with short- and long-term toxicities. Mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in approximately 80% and 4% of grade 2 gliomas, respectively, and are a disease-defining characteristic in the World Health Organization (WHO) 2021 definition. Vorasidenib (VOR) - an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes - has shown a tolerable safety profile and preliminary clinical activity in Phase I studies. MATERIAL AND METHODS In this randomized, double-blind, placebo (PBO)-controlled Phase III study (NCT04164901), patients (pts) were randomized 1:1 to receive VOR 40 mg daily or PBO daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumour size. Key eligibility criteria included: age ≥12; Karnofsky performance scale (KPS) >80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI). RESULTS As of 6 Sep 2022 (2nd planned interim analysis data cutoff), 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Of the 331 pts: median age: 40.4 years (range, 16-71); KPS =100: 53.5%; histological subtype: oligodendroglioma (172) and astrocytoma (159); median time from last surgery until randomization: 2.4 years. Two hundred twenty-six (68.3%) pts remained on treatment (VOR: 131; PBO: 95). PFS by BIRC was statistically significant in favour of the VOR arm (HR 0.39, 95% CI 0.27-0.56; P=0.000000067). Median PFS: VOR: 27.7 months (mo); PBO: 11.1 mo. TTNI was statistically significant in favour of the VOR arm (HR 0.26, 95% CI 0.15-0.43; P=0.000000019). Median TTNI: PBO: 17.8 mo; VOR: not reached. All reported P values are one sided. All-grade adverse events (AEs) occurring in >20% pts receiving VOR vs PBO were alanine aminotransferase (ALT) increased (38.9 vs 14.7%); COVID-19 (32.9 vs 28.8%); fatigue (32.3 vs 31.9%); aspartate aminotransferase increase (28.7 vs 8.0%); headache (26.9 vs 27.0%); diarrhoea (24.6 vs 16.6%); nausea (21.6 vs 22.7%). Common grade ≥3 AEs (>5%): ALT increased (9.6% vs 0%). CONCLUSION This is the first prospective, randomized Phase III study of a targeted therapy in grade 2 mIDH glioma. VOR significantly improved PFS by BIRC, compared with PBO, with a manageable safety profile. These data demonstrate the clinical benefit of VOR in this pt population for whom chemotherapy and radiotherapy are being delayed.

INDIGO: A global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation.

LBA1 Background: Grade 2 gliomas are slowly progressive, malignant brain tumors with a poor long-term prognosis. Current treatments (surgery followed by observation or adjuvant radiation and chemotherapy) are not curative and can be associated with short- and long-term toxicities. Mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in approximately 80% and 4% of grade 2 gliomas, respectively, and are a disease defining characteristic in the World Health Organization (WHO) 2021 definition. Vorasidenib (VOR) – an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes has shown a tolerable safety profile and preliminary clinical activity in phase 1 studies. Methods: In this randomized, double-blind, placebo-controlled phase 3 study (NCT04164901) patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumor size. Key eligibility criteria included: age ≥12; KPS >80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI). Results: As of 6Sep2022 (2nd planned interim analysis data cutoff), 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Of the 331 pts: median age: 40.4 years (range, 16 to 71); KPS =100: 53.5%; histological subtype: oligodendroglioma: 172 and astrocytoma: 159; median time from last surgery until randomization: 2.4 years. Two hundred twenty-six (68.3%) pts remained on treatment (131VOR; 95PBO). PFS by BIRC was statistically significant in favor of the VOR arm (HR, 0.39; 95% CI, (0.27, 0.56); P=0.000000067). Median PFS: VOR: 27.7 mos; PBO: 11.1 mos. TTNI was statistically significant in favor of the VOR arm (HR, 0.26; 95% CI, (0.15, 0.43); P=0.000000019). Median TTNI: PBO: 17.8 mos; VOR: not reached. All reported P values are one-sided. All-grade adverse events (AEs) occurring in >20% pts receiving VOR vs PBO were alanine aminotransferase increased (38.9% vs 14.7%), COVID-19 (32.9% vs 28.8%), fatigue (32.3% vs 31.9%), aspartate aminotransferase increase (28.7% vs 8.0%), headache (26.9% vs 27.0%), diarrhea (24.6% vs 16.6%), nausea (21.6% vs 22.7%). Common grade ≥3 AEs (>5%): ALT increased (9.6% vs 0%). Conclusions: This is the first prospective, randomized phase 3 study of a targeted therapy in grade 2 mIDH glioma. VOR significantly improved PFS by BIRC compared with PBO with a manageable safety profile. These data demonstrate the clinical benefit of VOR in this pt population for whom chemotherapy and radiotherapy are being delayed. Clinical trial information: NCT04164901 .

Phase II study of telomelysin (OBP-301) in combination with pembrolizumab in gastroesophageal (GEA) adenocarcinoma.

4052 Background: OBP-301 is a novel, replication-selective adenoviral construct that incorporates the human telomerase reverse transcriptase gene (hTERT) promoter, which is highly expressed in tumors but not in normal, differentiated adult cells, to regulate expression of the early adenoviral genes, E1A and E1B. OBP-301 has been evaluated as a single agent, and demonstrated immune responses and clinical activity in phase I studies. We examined OBP-301 in combination with pembrolizumab in a multicenter phase II study as a novel mechanism to improve immunotherapy in advanced gastric cancer. Methods: Eligible patients had advanced GEA that had progressed on at least 2 lines of prior therapy for incurable, advanced disease. Patients were required to have adequate end-organ function, measurable disease by RECIST 1.1, and a PD-L1 CPS > 1. Patients received OBP-301 at 2x1012 viral particles via direct tumor injection every two weeks x 4 injections as well as pembrolizumab 200 mg IV every 3 weeks. The primary endpoint was objective response rate (ORR). The null hypothesis that the ORR is < 15% was tested against the Ha ORR > 30%. We used a Simon two-stage design, requiring 3 or more responses in 18 patients in the first stage to proceed to stage two. The study was closed after successfully completing stage one of the Simon’s two stage design to formally examine OBP-301 + pembrolizumab in an immunotherapy (IO) refractory GEA population. Tissue was collected for single cell RNA Sequencing to examine the tumor immune microenvironment pre- and post-OBP-301 injections. Results: From May 2019 to Oct 2022, we enrolled 16 patients, median age 65 (range 43-81), male n = 13. OBP-301 direct tumor injection was well tolerated, median OBP-301 injections 3 (range 1-5). Toxicity attributed to OBP-301 included grade 2 fatigue/weakness (25%), grade 2 fever (18.7%), and a single incidence each of grade 2 nausea, anemia, grade 3 melena, and grade 4 diabetes mellitus (6.25%). We observed 3 patients (19%) with a partial response (PR), thereby meeting the Simon two-stage threshold. The responses were durable; two patients with PR are currently without evidence of disease (one completed 2 years of pembrolizumab, one underwent resection of primary tumor after 15 months), and the 3rd patient is now in month 12 of treatment. Further, one patient with brain metastases demonstrated regression of metastatic disease following progression on immunotherapy alone. All patients were mismatch repair proficient. Conclusions: OBP-301 viral particle injection into the tumor is feasible and safe. OBP-301 with pembrolizumab has encouraging activity in GEA, with durable responses and demonstration of activity in immunotherapy refractory disease. Single Cell RNA Sequencing data of the pre- and post-injection immune effects of OBP-301 will be presented. A formal phase II study of OBP-301 + pembrolizumab in IO refractory GEA patients is underway. Clinical trial information: NCT03921021 .

Abstract 2800: Pharmacokinetics, bioavailability, and pharmacodynamics of oral triapine

Abstract Background: Locally advanced cervical cancer accounts for most deaths from disease. Standard of care includes treatment with cisplatin-based chemoradiation with a 70% response rate. The addition of intravenous (IV) triapine to chemoradiation has shown promising clinical activity in phase 1 and 2 studies but comes with a more intensive treatment regimen. An ongoing phase 1 trial has finished the escalation phase, and we report the pharmacokinetics (PK) and pharmacodynamics (PD) of oral (PO) triapine. Methods: This phase 1 study followed a 3+3 design for dose escalation of oral triapine, starting with initial dose of 100 mg five days a week for five weeks combined with external beam pelvic radiation and weekly IV cisplatin. PK was determined by LC-MS/MS, and PD included methemoglobin levels at 4 h post dose. Within patient PK variability after IV and PO dosing and PO bioavailability were calculated. Results: PK data were available for 10 patients at 100 (the MTD) and 150 mg. PO parameter values were Tmax 1.3 h, t1/2 1.4 h, CL/F 104 L/h, and Vz/F 214 L. There was no discernable difference between triapine exposure at 100 vs. 150 mg PO (Cmax 520 (2.5) vs. 344 (1.9) µg/L; AUC 1209 (2.53) vs. 1034 (1.41) µg/L•h), and between patient variability at each dose level was substantial. The correlation of PO Vz/F vs Cl/F was high at R2=0.86, suggesting that the apparent clearance and volume variability is primarily due to variability in the oral bioavailability F. PO within patient variability of Cmax and AUC was also large at 43% and 55%. IV PK was less variable with lower geometric standard deviations across all parameters, including within patients where variability of Cmax and AUC was modest at 10 and 12% coefficient of variation, respectively. Oral bioavailability was estimated at 66%. We found a non-significant trend of smoking almost doubling triapine oral clearance from 68 to 156 L/h (p=0.056). There was no apparent relationship between occurrence of DLT and either IV or PO triapine AUC. Methemoglobin levels directly correlated with triapine exposure expressed as AUC or Cmax. Conclusions: Triapine PK parameter values for PO and IV administration and PO bioavailability values observed in this trial were comparable to previous reports. Correlation of methemoglobin with exposure highlights the importance of optimizing triapine exposure. Additional data may support the exploration of a dose specific to current smokers. Citation Format: Jan H. Beumer, Sarah Behr, Holly Gallion, John Vargo, Frederick Ueland, Haider Mahdi, Brian Orr, Eugenia Girda, Susan Christner, Edward Chu, Charles Kunos, Percy S. Ivy, Sarah Taylor. Pharmacokinetics, bioavailability, and pharmacodynamics of oral triapine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2800.

Abstract P2-24-04: The ER antagonist giredestrant induces profound chromatin remodeling including activation of cis-regulatory elements bound by FOXA1 and GATA3 in HR+ breast cancer models

Abstract The progression of HR+ breast cancers is governed by ER signaling which makes the development of optimized ER-targeting agents a high priority. Among current therapeutics, selective ER antagonists and degraders (SERDs) have emerged as a particularly attractive class. Fulvestrant is the only SERD that is currently approved, but its clinical potential is hypothesized to be somewhat limited by poor physicochemical properties, dosage and exposure. We identified giredestrant as an orally bioavailable, highly potent non-steroidal ER antagonist, immobilizer and degrader with robust anti-proliferative activity. Giredestrant is currently being evaluated in phase III clinical trials for the treatment of ER+ breast cancer, after showing evidence of clinical activity in phase I and II trials. Here, we set out to investigate the impact of giredestrant on the transcriptome and chromatin landscape of ER+ breast cancer cells in vitro and in vivo. RNA-seq data from MCF-7 cells in vitro and three patient-derived xenograft (PDX) models in vivo showed that giredestrant inversely regulates the RNA levels of E2-regulated genes. Transcriptome wide, the expression of genes affected by giredestrant are strongly correlated (r2=0.8) with those affected by siRNA-mediated silencing of ESR1, consistent with on-target ER antagonism. Performing ATAC-seq in the three PDX models, including one ESR1 mutant model, reveals that giredestrant reduces accessibility in up to 18,173 chromatin regions that are associated with genes induced by E2. These regions are also enriched in the ER binding motif. In addition, we found up to 17,127 chromatin regions with increased accessibility upon giredestrant treatment. These regions are associated with genes suppressed by E2, and are enriched in the FOXA1 binding motif. To probe giredestrant’s role in functional modulation of cis-regulatory elements (CREs), we performed ChIP-seq targeting FOXA1 and GATA3, as key pioneer factors for ER, as well as ER itself and H3K27ac as a marker of active enhancers in MCF-7 cells. We identified 3,195 regions with significantly reduced H3K27ac signals that also exhibit significant reduction of both ER and FOXA1 binding upon giredestrant treatment, indicating that giredestrant deactivates these CREs concomitantly with suppressing ER and FOXA1 binding. ChIP-seq analysis further revealed 2,292 regions with a significant increase in H3K27ac signals upon giredestrant treatment. Interestingly, the GATA3 motif was identified as the most enriched motif in these activated CREs. Further, GATA3 and FOXA1 ChIP-seq signals were stronger in the activated CREs compared to the deactivated ones. Similar profiling of both tamoxifen, an approved selective ER modulator (SERM), as well an GNE-858, a SERM from the same chemical series as giredestrant, showed their epigenetic effects to be highly distinct from those observed for giredestrant, suggesting that the high degree of chromatin remodeling is likely related to giredestrant’s mechanism of action. Our studies here show that giredestrant profoundly alters ER binding and remodels the chromatin landscape, thus changing the transcriptional profile of cells in a manner that is associated with an anti-proliferative response. While deactivation of CREs with ER binding is perhaps in line with expectations, giredestrant treatment also leads to the activation of a number of regions associated with pioneer factors, potentially through their redistribution. This raises the question of the functional consequences of CRE activation and if this is relevant for the anti-proliferative effects of giredestrant. Citation Format: Musaddeque Ahmed, Jane Guan, Wei Zhou, Xiaosai Yao, Ciara Metcalfe, Marc Hafner. The ER antagonist giredestrant induces profound chromatin remodeling including activation of cis-regulatory elements bound by FOXA1 and GATA3 in HR+ breast cancer models [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-24-04.

EP08.01-081 A Phase I Dose-Escalation Study of HBM4003, an anti-CTLA-4 Heavy Chain Only Monoclonal Antibody, in Combination with Pembrolizumab

Combination therapy with ipilimumab plus PD-1 inhibitors has shown promising efficacy in various tumor types, demonstrating higher rates of response than either agent alone. HBM4003 is a fully human heavy chain only monoclonal antibody targeting CTLA-4, which has been engineered to deplete Treg cells and enhanced antibody-dependent cellular cytotoxicity. HBM4003 has shown preliminary clinical activity in phase (Ph) I trial in patients (pts) with advanced solid tumors. Pembrolizumab is a humanized immunoglobulin G4 monoclonal antibody against PD-1 and has been approved by FDA in various indications.

317 Characterization of pharmacokinetics, pharmacodynamics, tolerability and clinical activity in phase I studies of the novel allosteric tyrosine kinase 2 (TYK2) inhibitor NDI-034858

Tyrosine kinase 2 (TYK2) is an obligate mediator of signaling via IL-23, IL-12 and the type I interferon receptors, and is a validated therapeutic target in psoriasis and psoriatic arthritis. NDI-034858 is a novel, oral, allosteric, investigational TYK2 inhibitor with high selectivity for TYK2 over JAK1, JAK2, and JAK3 kinases. NDI-034858 was studied in multiple placebo-controlled Phase I studies. These included two trials in healthy volunteers receiving single ascending doses (six dose groups, N = 5-6 per group; versus placebo, N = 12) and multiple ascending doses (four dose groups, N = 6 per group; versus two placebo groups, N = 4 per group) for 2 weeks. NDI-034858 was also studied in patients with moderate to severe psoriasis treated daily for 4 weeks (three dose groups, N = 21 total; versus placebo, N = 5). Across the studies, the pharmacokinetic parameters of NDI-034858 were calculated. Pharmacodynamic effect was tested in a cytokine-induced ex vivo assay using whole blood samples, which demonstrated that exposure to NDI-034858 correlated with activity. No serious adverse events or deaths were observed in the studies, and treatment emergent adverse events were as expected for inhibition of TYK2. Exploratory efficacy endpoint analysis in patients with moderate to severe psoriasis using the Psoriasis Area and Severity Index (PASI) score suggested improvement in the disease. These data support further development of NDI-034858. Phase 2b trials in psoriasis and psoriatic arthritis are ongoing.

Lentiviral interferon: A novel method for gene therapy in bladder cancer

Interferon alpha (IFNα) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNα have shown clinical efficacy treating bacillus Calmette-Guerin (BCG)-unresponsive bladder cancer (BLCA). However, transient transgene expression and adenoviral immunogenicity may limit therapeutic activity. Lentiviral vectors can achieve stable transgene expression and are less immunogenic. In this study, we evaluated lentiviral vectors expressing murine IFNα (LV-IFNα) and demonstrate IFNα expression by transduced murine BLCA cell lines, bladder urothelium, and within the urine following intravesical instillation. Murine BLCA cell lines (MB49 and UPPL1541) were sensitive to IFN-mediated cell death after LV-IFNα, whereas BBN975 was inherently resistant. Upregulation of interleukin-6 (IL-6) predicted sensitivity to IFN-mediated cell death mediated by caspase signaling, which when inhibited abrogated IFN-mediated cell killing. Intravesical therapy with LV-IFNα/Syn3 in a syngeneic BLCA model significantly improved survival, and molecular analysis of treated tumors revealed upregulation of apoptotic and immune-cell-mediated death pathways. In particular, biomarker discovery analysis identified three clinically actionable targets, PD-L1, epidermal growth factor receptor (EGFR), and ALDHA1A, in murine tumors treated with LV-IFNα/Syn3. Our findings warrant the comparison of adenoviral and LV-IFNα and the study of novel combination strategies with IFNα gene therapy for the BLCA treatment.

Level of Evidence for FDA Drug Approvals in Pivotal Clinical Trials of Hematological Malignancies

BACKGROUND Clinical trials are integral to improve treatment outcomes for patients with hematological malignancies. Although early phase (I/II) clinical trials may provide evidence of clinical efficacy, the main goal for early phase trials is to assess safety signal. Results of phase III clinical trials provide the strongest evidence to support the use of new cancer medications. The Food and Drug Administration (FDA) is responsible to ensure appropriate control and supervision of pharmaceutical drugs. METHODS On the basis of publicly available study protocols and FDA reviews, the authors reviewed the level of evidence in 52 clinical trials supporting 49 drug approvals from 2016 to 2020. Data cut point was May 2020. These trials resulted in approval of medications to treat leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, myeloproliferative neoplasms and multiple myeloma. RESULTS A total of 52 clinical trials were assessed in the 5 years period. Phase III trials supported 61.5% while earlier phase trials supported 36.5% of subsequent FDA hematological malignancies approvals. The level of evidence to support FDA approvals improved with time with 50% of approvals in 2016 and 2017 supported by phase III clinical trials compared to 69% in 2019. Approvals were based on early phase trials in mantle cell lymphoma (100%), chronic myeloid leukemia (100%), diffuse large B cell lymphoma (100%), classic Hodgkin's lymphoma (67%) and acute myeloid leukemia (56%). Phase III trials enrolled 87% of the patients (14238 from16429 patients). Eighteen drug approvals (37% of all approvals) were based on 13% of the total number of patients in the studied period. CONCLUSIONS Level of evidence to support drug approvals in hematological malignancies was based on early phase trials in more than a third of the times. Although early phase studies are appropriate for safety signals, further clinical activity assessment should be done to support the use of new drugs to treat hematological malignancies. Previous successful early phase studies failed to show clinical activity in phase III studies. Despite the fact that use of new approved drugs based on early phase studies evidence may be needed, patients and healthcare providers should be aware of such possibility when using newly approved medications. Figure Disclosures Ramos: Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Kuur Therapeutics: Research Funding.

Abstract 1573: Association between TGF-β signaling and HMGA2, a potential biomarker for bintrafusp alfa in triple negative breast cancer

Abstract Background: Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor, to function as a TGF-β “trap”, fused to a human IgG1 antibody blocking PD-L1, which has shown early evidence of clinical activity in phase 1 studies in patients with advanced solid tumors. We recently reported high expression of HMGA2 in patients with triple negative breast cancer (TNBC) who experienced disease control (response or stable disease) with bintrafusp alfa treatment compared with those who had progressive disease, suggesting that HMGA2 may predict response to bintrafusp alfa in this indication. HMGA2 is a transcriptional regulator whose expression is upregulated by TGF-β signaling and is known to be an important factor in mediating TGF-β–induced epithelial–mesenchymal transition (EMT). The purpose of this study was to evaluate the association between HMGA2 expression and TGF-β signaling in TNBC and the effect of bintrafusp alfa on HMGA2/TGF-β signaling. Methods: The syngeneic murine 4T1 tumor model was utilized for this study because it closely mimics human stage IV TNBC, has high baseline levels of HMGA2 expression, and bintrafusp alfa directly modulates canonical TGF-β signaling and induces antitumor activity in this model. Results: Tumors from mice treated with isotype control, anti–PD-L1, anti–PD-L1(mut)/TGF-β trap (trap control), or bintrafusp alfa were analyzed by RNAseq and both bintrafusp alfa or trap control treatment decreased HMGA2 expression relative to anti–PD-L1 or isotype control treatment. In isotype control-treated 4T1 tumors Spearman's rho correlation coefficient showed that 29% (26/89) of the TGF-β signaling-related genes significantly correlated with HMGA2 expression, indicating that there is a strong association between HMGA2 and TGF-β signaling. In bintrafusp alfa-treated tumors, the association of HMGA2 and TGF-β signaling was even stronger, with 55% (49/89) of TGF-β signaling-related genes significantly associated with HMGA2, suggesting that there is a relationship between HMGA2, TGF-β signaling, and bintrafusp alfa pharmacodynamic effects in this TNBC model. Analysis of individual TGF-β signaling-related genes from this signature showed significant correlation between HMGA2 expression and the expression of TGF-β receptors, ligands, collagen, and EMT-related genes. Furthermore, both bintrafusp alfa and trap control treatment significantly reduced expression of these HMGA2-correlated TGF-β signaling-related genes relative to anti–PD-L1 or isotype control treatment in the 4T1 model, suggesting that HMGA2 is associated with TGF-β-related signaling more strongly in the presence of TGF-β sequestration. Conclusions: Taken together, these observations warrant further analysis of the potential link between HMGA2 and bintrafusp alfa antitumor efficacy. Citation Format: Tsz-Lun Yeung, George Locke, Adam Lazorchak, Guozhong Qin, Huakui Yu, Jin Qi, Bo Marelli, Molly Jenkins, Alex Rolfe, Laureen S. Ojalvo, Isabelle Dussault, Yan Lan. Association between TGF-β signaling and HMGA2, a potential biomarker for bintrafusp alfa in triple negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1573.

Prexasertib: an investigational checkpoint kinase inhibitor for the treatment of high-grade serous ovarian cancer

ABSTRACT Introduction Patients with high-grade serous ovarian cancer (HGSOC) have a poor prognosis, and current chemotherapy regimens for treating advanced disease are far from satisfactory. Prexasertib (LY2606368) is a novel checkpoint kinase inhibitor (CHK) under investigation for the treatment of HGSOC. Data from a recent phase II trial showed promising efficacy and safety results for treating wild-type BRCA HGSOC. Areas covered This article reviews the available data on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of prexasertib in the treatment of HGSOC. Expert opinion Until now, prexasertib demonstrated clinical activity in phase I and II clinical trial for treating wild-type BRCA HGSOC, whereas its promising efficacy as monotherapy and combined with olaparib in BRCA-mutated HGSOC has been preliminary evidenced only in phase I studies. Compared to other drugs of the same class, prexasertib showed a better tolerability profile, causing moderate hematological toxicity. Further studies are needed to confirm efficacy and safety profiles of prexasertib in combined regimens. New early clinical trials may investigate prexasertib administered with programmed cell death ligand 1 (PD-L1) and PI3 K inhibitors due to the preclinical evidence of a synergic action.

Selection of the Recommended Phase 2 Dose for Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1.

Bintrafusp alfa, a first‐in‐class bifunctional fusion protein composed of the extracellular domain of the TGF‐βRII receptor (TGF‐β “trap”) fused to a human IgG1‐blocking PD‐L1, showed a manageable safety profile and clinical activity in phase I studies in patients with heavily pretreated advanced solid tumors. The recommended phase 2 dose (RP2D) was selected based on integration of modeling, simulations, and all available data. A 1,200‐mg every 2 weeks (q2w) dose was predicted to maintain serum trough concentration (Ctrough) that inhibits all targets of bintrafusp alfa in circulation in > 95% of patients, and a 2,400‐mg every 3 weeks (q3w) dose was predicted to have similar Ctrough. A trend toward an association between exposure and efficacy variables and a relatively stronger inverse association between clearance and efficacy variables were observed. Exposure was either weakly or not correlated with probability of adverse events. The selected intravenous RP2D of bintrafusp alfa is 1,200 mg q2w or 2,400 mg q3w.

The AUGMENT study: Lenalidomide in indolent lymphoma … balance the imbalance!

AbstractFollicular lymphoma is the most common form of indolent Non-Hodgkin Lymphoma and characterized by repeated relapses. Follicular lymphoma (FL) tissue was found to have association between malignant cells and benign immune cells represented in the surrounded microenvironment. Lenalidomide, an immunomodulator, is affecting this microenvironment and demonstrated relevant clinical activity in phase III trials in patients with FL lymphoma. The AUGMENT trial resulted in a better PFS with lenalidomide and rituximab than rituximab and placebo in patients with relapsed/refractory FL and marginal zone lymphoma. However, there are some concerns around the study. The following article is discussing some of these concerns.

Approach to Richter transformation of chronic lymphocytic leukemia in the era of novel therapies.

Chronic lymphocytic leukemia (CLL) has a highly variable clinical course. About 2-10% of CLL patients develop aggressive histological transformation, most commonly to diffuse large B cell lymphoma (DLBCL), historically called Richter transformation (RT). Clinical features suggestive of RT include elevated LDH and non-specific symptoms such as fever, weight loss, and lymphadenopathy. 18-fluorodeoxyglucose (18-FDG) uptake is increased on PET scan (standardized uptake value max most commonly ≥10). PET/CT study can identify optimal site for excisional biopsy, which is the gold standard for RT diagnosis, as well as aid in disease staging and prognostication. In addition to clinical prognostic features such lactate dehydrogenase level, platelet count, and performance status, important predictors of poor outcome in RT are TP53 disruption and clonal relationship of DLBCL to underlying CLL. Chemoimmunotherapy constitutes the standard treatment for RT, followed by stem cell transplant (SCT) in eligible patients. However, the majority of patients do not proceed to allogeneic SCT, either due to inadequate disease control with initial therapy, poor performance status, or lack of donor availability. Overall outcome is dismal. Some novel agents under investigation, particularly PD-1 inhibitors, are showing clinical activity in Phase I and II trials. An ongoing incidence of RT has been noted in studies of previously treated patients receiving targeted therapies such as ibrutinib and venetoclax; the frequency of RT in patients initially treated with novel agents rather than chemoimmunotherapy will be important to determine with longer follow-up. This review focuses on the development, clinicopathologic features, and treatment of RT in the context of novel therapies.

Abstract P4-13-19: Poziotinib, an oral, irreversible pan-HER inhibitor, demonstrates promising clinical activity in metastatic HER2 positive breast cancer patients

Abstract Background: Poziotinib is a novel, oral, irreversible pan-HER inhibitor that has been studied in two completed Phase 1 clinical trials in patients with advanced solid tumors (HM-PHI-101; HM-PHI-102) and is currently being studied in several Phase 2 clinical trials. Preclinical studies have shown poziotinib to be more potent in vitro than other EGFR- and HER2-directed tyrosine kinase inhibitors. This study collates the clinical experience of poziotinib in patients with advanced HER2 positive breast cancer from the two completed Phase 1 trials. Results: The maximum tolerated dose (MTD) and safety of poziotinib were evaluated in HM-PHI-101 (once daily, Day 1-14 q3 weeks) and in HM-PHI-102 (continuous dosing). The Dose Limiting Toxicity (DLT) was diarrhea in both studies. Anti-diarrheal medicine was allowed, but prophylactic anti-diarrheal therapy was not used. The most frequently reported Grade 3 AE was diarrhea (40%). The MTD for intermittent dosing of poziotinib was 24 mg and the MTD for continuous dosing was 16 mg. The Dose Limiting Toxicity (DLT) was diarrhea in both studies. Anti-diarrheal medicine was allowed, but prophylactic anti-diarrheal therapy was not used. In total, 10 patients with HER2 positive metastatic breast cancer were treated in the two trials (median age 56.5, range 30-69). These patients were heavily pretreated (median number of previous treatment regimens 5, range 3-9), and all patients had failed treatment with both trastuzumab and lapatinib. The Overall Response Rate (ORR) in these breast cancer patients was 60% and Clinical Benefit Rate (CBR) was 80%. The median duration of response was 32.5 weeks (range 18 - 56 weeks). Two patients in the early dose cohorts of 1 or 2mg had progressive disease. The median progression free survival (PFS) was 28 weeks (6, 6, 12, 17, 25, 31, 37, 49, 57, and 98 weeks). Conclusions: Poziotinib showed very promising clinical activity in Phase 1 patients with metastatic HER2 positive breast cancer, who had been heavily pretreated and failed two prior HER2-directed therapies. The ORR in this patient population was 60% and the CBR was 80% in these two early dose finding studies. The AEs observed in these studies was consistent with other pan-HER and EGFR inhibitors. While the majority of DLT cases involves diarrhea, toxicity of other adverse events was relatively tolerable. An intermittent dosing schedule seemed appropriate for poziotinib. Multiple Phase 2 studies with poziotinib are ongoing in patients with breast cancer and other solid tumors. Citation Format: Im S-A, Kim J-H, Lee K-H, Kim SH, Oh D-Y, Kim Y-J, Han S-W, Kim T-Y, Kim T-Y, Jung J, Bang Y-J. Poziotinib, an oral, irreversible pan-HER inhibitor, demonstrates promising clinical activity in metastatic HER2 positive breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-19.

Abstract OT3-01-10: A prospective, open-label, single-arm, multi-center, phase II exploratory study to evaluate the efficacy and safety of poziotinib (NOV120101) in patients with HER2-positive metastatic breast cancer who have received at least two prior HER2-directed regimens

Abstract Background: Poziotinib is a novel, oral, irreversible pan-HER inhibitor that has shown promising clinical activity in Phase 1 studies of patients (pts) with advance HER2 positive breast cancer who have failed at least 2 prior lines of HER2-directed therapy. A Phase 2 study of poziotinib was initiated in Korea in March 2015 in pts with HER2+ metastatic breast cancer. This phase 2 study is designed to seek accelerated approval for poziotinib for the treatment of metastatic breast cancer in Korea. Trial Design: Prospective Phase 2, open-label, single-arm, multi-center study in pts with recurrent, Stage IV breast cancer with HER2-overexpression who had received at least 2 prior HER2-directed regimens Eligibility Criteria: Histologically confirmed breast cancer patients, at least 19 years of age, with confirmed HER2 positive evaluable tumors (per RECIST, 1.1) who have adequate hematologic, renal, and hepatic function and have failed at least two HER2-directed regimens that included a taxane-containing anticancer chemotherapy, with a life expectancy of at least 12 weeks. Specific Aims: The Primary Efficacy Endpoint of the study was Progression-Free Survival (PFS). The Secondary Efficacy Endpoints included: PFS rate at 12 weeks post-dose; Objective Response Rate (ORR) including Complete Response (CR) and Partial Response (PR) rates; Disease Control Rate (DCR) including CR, PR, and Stable Disease (SD); Duration of Disease Control; Overall Survival (OS); Time to Progression (TTP); Time to Objective Response and Duration of Objective Response. The Exploratory Endpoints included: Population Pharmacokinetic (PK) Profile and Exploratory Genomic and Biomarker Analyses. Statistical Methods: In the randomized, multicenter, 2-arm, open-label study of trastuzumab emtansine (TH3RESA18), the median PFS was shown to be 3.3 months in subjects with optimal treatment per Investigator's Choice. This ongoing study with poziotinib expects a median PFS of 4.5 months based on data from a previous Phase 1 study of poziotinib (NOV120101). Based on the following assumptions, a 5% one-sided significance level, and 80% power, and 2 months of accrual and 12 months of follow-up, 66 subjects will be required. Accounting for a 10% drop-out rate, a total of 74 subjects will be recruited into this ongoing Phase 2 study. Present Accrual and Target Accrual: 17 patients enrolled as of May 20, 2015 with a total target enrollment of 74 patients Contact information: ClinicalTrials.gov Identifier: NCT02418689. Citation Format: Park Y-H, Jung KH, Sohn JH, Lee KS, Lee KH, Kim J-H, Kim J-Y, Jung J, Han H, Park W-Y, Im S-A. A prospective, open-label, single-arm, multi-center, phase II exploratory study to evaluate the efficacy and safety of poziotinib (NOV120101) in patients with HER2-positive metastatic breast cancer who have received at least two prior HER2-directed regimens. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-10.

Phase Ib trial of cabazitaxel and tasquinimod in men with heavily pretreated metastatic castration resistant prostate cancer (mCRPC): The CATCH trial.

190 Background: Cabazitaxel resistance develops within a few months of treatment initiation in most men with mCRPC in post-docetaxel, and thus combination therapy with other active agents may improve outcomes. Tasquinimod is an oral immunomodulatory agent with anti-angiogenic and anti-tumor in preclinical models of PC and clinical activity in phase II and III trials. Methods: We conducted a phase I dose escalation trial of cabazitaxel plus tasquinimod in men with mCRPC. Cabazitaxel was dosed at 25 mg/m2 every 3 weeks with low dose prednisone and PEG-filgrastim support, and tasquinimod dose levels included 0.25, 0.5, and 1.0 mg, using a 3 week within-patient dose escalation for dose levels 2 and 3, starting all patients at 0.25 mg once daily. The primary objective was to define the recommended phase II dose (RP2D) based on safety and dose limiting toxicity. Preliminary efficacy (PSA decline, PFS) and pharmacokinetic interactions were key secondary objectives. Results: We enrolled 25 men with mCRPC who had failed docetaxel across 3 dose levels. Median PSA at entry was 220 ng/dl. The RP2D was 0.5 mg tasquinimod based on excess DLTs (2 of 3 men) observed at dose level 3 (1.0 mg) including grade 3 sensory neuropathy and grade 3 atrial fibrillation). Dose level 2 was expanded to 14 men, where 3 DLTs were observed: grade 3 fatigue, grade 4 febrile neutropenia, and grade 3 liver function test abnormalities. The proportion of men with a > 30% PSA decline was 63% (95% CI: 41%, 81%). The median composite PFS was 8.5 months (95% CI 4.2-16.4 months) based on 12 PFS events. The median number of cycles of cabazitaxel was 6 (range 1-13), with 6 men receiving > 10 cycles. Best overall RECIST responses (CR+PR) were observed in 3 men (12%), stable disease in 12 (48%). No unexpected adverse events were observed and no pharmacokinetic interactions were observed. Conclusions: The RP2D was cabazitaxel 25 mg/m2 with prednisone and PEG-filgrastim every 3 weeks with tasquinimod 0.25 mg once daily for 3 weeks followed by 0.5 mg. Preliminary evidence of efficacy over cabazitaxel alone is based on observed PSA response and PFS data, and a substantial number of men were progression free beyond 10 cycles with good tolerability. Clinical trial information: NCT01513733.