Single-agent Efficacy Research Articles

TiNivo-2: A phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor.

TPS4605 Background: Tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (aRCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile (Rini et al Lancet Oncol 2020). Tivozanib was approved by the FDA on March 10, 2021, for the treatment of patients with aRCC who had progressed on 2 or more prior systemic therapies. Tivozanib was combined with Nivolumab in the phase 1b/2 TiNivo trial (NCT03136627), showing an objective response rate of 56%, disease control rate of 96%, median PFS of 18.9 months and a tolerable safety profile (Albiges et al Ann Oncol. 2021). Methods: TiNivo-2 (NCT04987203) is a phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following 1-2 lines of therapy including an immune checkpoint inhibitor. Eligibility criteria include age >18 years, clear cell RCC, ECOG PS 0-1, and disease progression during or following at least 6 weeks of treatment with ICI for RCC. Subjects will be stratified by IMDC risk category and whether ICI was received in most recent line of treatment or not. Subjects will receive tivozanib 1.34 mg orally once daily for 21 consecutive days followed by 7 days off, on the monotherapy arm, and tivozanib 0.89 mg at the same schedule in addition to nivolumab 480mg intravenously every 4 weeks on the combination arm. Study assessments include CT scan or MRI of the chest, abdomen, and pelvis every 8 weeks following Cycle 1 Day 1 for 2 years and every 12 weeks thereafter until disease progression is confirmed by independent radiology review (IRR). The primary objective is to compare the progression-free survival (PFS) of tivozanib in combination with nivolumab to tivozanib. A sample size of 326 subjects, with 191 events will provide at least 80% power to detect a 50% improvement in PFS, 12 mos v. 8 mos, as assessed by an IRR. Secondary endpoints include assessment of overall survival (OS), objective response rate (ORR), and duration of response (DoR), as well as safety and tolerability. Exploratory endpoints are to assess the quality of life (FKSI-DRS and EORTC QLQ C-30) and to investigate the pharmacokinetics of tivozanib. TiNivo-2 is actively enrolling and planning to open at 190 sites in the United States, and the European Union. Clinical trial information: NCT04987203.

A Multicenter Randomized Phase II Study of Single Agent Efficacy and Optimal Combination Sequence of Everolimus and Pasireotide LAR in Advanced Thyroid Cancer.

Simple SummaryPrior clinical studies showed modest activity for single agent everolimus and somatostatin analogues in different subtypes of thyroid cancer; the combination of everolimus and somatostatin analogue was synergistic in preclinical models of thyroid cancer. This randomized trial showed that the combination was more effective than a single agent and the sequence of single agent everolimus followed by the delayed combination of everolimus and pasireotide-LAR achieved the best efficacy and was the optimal combination strategy.Purpose: Aberrant mTOR pathway and somatostatin receptor signaling are implicated in thyroid cancer and offer potential therapeutic targets. We assessed the clinical efficacy of everolimus and Pasireotide long-acting release (LAR) in radioiodine-refractory differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC). Patients and methods: Adults with progressive MTC and DTC untreated or treated with no more than one systemic agent were eligible. The trial was designed to establish the most promising regimen and the optimal combination sequence. Patients were randomized to start treatment with single agent everolimus (10 mg QD; Arm A), pasireotide-LAR (60 mg intramuscular injection, Q4 weeks; Arm B), or the combination (Arm C). At initial progression (PFS1), patients on Arm A or B switched to the combination and continued until progression (PFS2). Efficacy was measured by RECIST criteria. Results: Study enrolled 42 patients: median age 65 years; female 17 (40.5%); White 31 (73.8%), African American 6 (14.3%), others 5 (11.9); DTC 32 (76.2%); MTC 10 (23.8%). There was no objective response by RECIST criteria across the three arms. Median and 1-year PFS1 rates were 8.3, 1.8, 8.1 months and 49.9%, 36.4%, 25.0% for Arms A, B, C, respectively. Median and 1-year PFS2 rates were 26.3, 17.5, 8.1 months and 78.4%, 70.0%, 25% for Arms A, B, C, respectively. The most frequent adverse events were anemia, stomatitis, fatigue, hyperglycemia, and hypercholesterolemia. Conclusions: The combination of everolimus and pasireotide-LAR showed promising efficacy over single agent. The delayed combination of everolimus and pasireotide-LAR following progression on single agent everolimus appeared intriguing as a combination strategy.

One-Year Efficacy and Safety of Omidenepag Isopropyl in Patients with Normal-Tension Glaucoma.

Purpose: To retrospectively evaluate the 1-year efficacy and safety of single-agent of omidenepag isopropyl in patients with normal-tension glaucoma (NTG). Methods: One hundred patients (100 eyes) newly administered omidenepag isopropyl were enrolled. Intraocular pressure (IOP) was compared at baseline and 3, 6, 9, and 12 months after administration. The mean deviation values at baseline and 12 months measured using the Humphrey visual field test (30-2 Swedish Interactive Threshold Algorithm standard) were compared. Adverse reactions and dropouts were observed. Results: IOP significantly decreased from 15.5 ± 2.7 mmHg at baseline to 13.3 ± 2.5 mmHg after 3 months, 13.7 ± 2.3 mmHg after 6 months, 13.9 ± 2.4 mmHg after 9 months, and 13.7 ± 2.3 mmHg after 12 months (P < 0.0001). There was no significant difference in the mean deviation values at baseline (-3.66 ± 3.49 dB) and after 12 months (-3.41 ± 3.80 dB). Adverse reactions occurred in 9 patients (9.0%): conjunctival hyperemia (n = 6), eye pain (n = 1), iritis (n = 1), and blepharitis (n = 1). Twenty-one patients (21.0%) discontinued administration because of changes in medication (n = 7), interruption of visits (n = 5), adverse reactions (n = 4), and others. Conclusions: After administering omidenepag isopropyl, the IOP in patients with NTG decreased within 1 year, visual fields were maintained, and safety was satisfactory. Omidenepag isopropyl can be used as the first-line medication for patients with NTG.

Selected Articles from This Issue

Despite the proven benefits of antibody-based therapies for HER2-amplified cancers, there remains an urgent need for novel therapeutic approaches to combat acquired and innate drug resistance. Here, O'Brien and colleagues demonstrate that tucatinib, a small molecule inhibitor of HER2, has selective activity in HER2-driven cancers. Tucatinib showed single agent and combined efficacy with trastuzumab and inhibitors of CDK4/6 in cell line xenograft models. The selective nature of tucatinib make it an ideal combination partner for HER2-based therapies. Data presented here provide insight into the optimal patient selection and combination strategies for the expanded clinical development of tucatinib.Head and neck squamous cell carcinoma (HNSCC) is a common cancer with limited treatment options. Recent clinical trials in patients with HRAS-mutant HNSCC have shown the efficacy of tipifarnib, a farnesyl transferase inhibitor (FTI) that blocks a required posttranslational modification of HRAS and other proteins. Here, Javaid and colleagues have validated HRAS as a key therapeutic target of tipifarnib and identified multiple signaling pathways that could cause treatment resistance. Combining FTI with an ERK inhibitor blocked compensatory signaling changes, enhancing the efficacy of FTI and showing that this combination could be a promising treatment strategy for patients with HRAS-mutant HNSCC.Pancreatic ductal adenocarcinoma (PDAC) is the most RAS-addicted of all cancers and development of anti-RAS therapies is a major priority. RRSP-DTB is an engineered biologic with specific RAS proteolytic activity. Vidimar and colleagues conducted a study to assess in vitro RAS degradation and in vivo activity of RRSP-DTB in RAS-driven PDAC models. As a single agent, RRSP-DTB effectively degraded RAS in cells and engaged RAS in mice leading to nearly complete regression of PDAC patient-derived xenografts without development of resistance. These results support further study of RRSP-DTB as an unprecedented RAS biodegrader for RAS-addicted tumors.Clinical outcomes in FLT3-mutant acute myeloid leukemia (AML) remain exceedingly poor due to FLT3 tyrosine kinase inhibitor (TKI) resistance. FF-10101 is the first covalent FLT3 inhibitor and recently completed phase I clinical evaluation. Here, Ferng and colleagues profile FF-10101 against a panel of FLT3 TKI resistance-mutations and off-target resistance mechanisms. FF-10101 suppresses all clinically described on-target mutations but not those that compromise covalent binding to FLT3. FF-10101 also exhibits activity in an in vitro model of cytokine-driven TKI resistance. Thus, FF-10101 shows the potential to benefit AML patients already treated with existing FLT3 TKIs or patients harboring certain FLT3 mutations.

The Irreversible FLT3 Inhibitor FF-10101 Is Active Against a Diversity of FLT3 Inhibitor Resistance Mechanisms.

Small-molecule FLT3 inhibitors have recently improved clinical outcomes for patients with FLT3-mutant acute myeloid leukemia (AML) after many years of development, but resistance remains an important clinical problem. FF-10101 is the first irreversible, covalent inhibitor of FLT3 which has previously shown activity against FLT3 tyrosine kinase inhibitor resistance-causing FLT3 F691L and D835 mutations. We report that FF-10101 is also active against an expanded panel of clinically identified FLT3 mutations associated with resistance to other FLT3 inhibitors. We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single-agent efficacy when used in patients with FLT3-mutant AML.

Comparison of Clinical Effects of Temozolomide Single Agent and Combined Doxorubicin in the Treatment of Glioma.

In this article, we have compared and analyzed the clinical effects of temozolomide single agent and combined doxorubicin in the treatment of glioma. To evaluate this, a total of 70 patients diagnosed with glioma in our hospital from July 2019 to July 2020 were randomly divided into two groups, the observation group and the control group, with 35 patients in each group. The control group received temozolomide capsules orally. The observation group was treated with temozolomide single agent and doxorubicin. After treatment, the clinical efficacy, adverse reactions, and KPS score of the two groups were observed. After treatment, the total response rate of the control group was 31.43%, and the total response rate of the observation group was 62.86%. The difference between the two groups was statistically significant (P < 0.05). Before treatment, there was no significant difference in KPS scores between the two groups (P > 0.05). After treatment, the KPS scores of both groups were improved, and the KPS scores of the observation group and the control group were significantly better, with statistical significance (P < 0.05). In the observation group, 17 cases had adverse reactions, including 10 cases of nausea and vomiting, 2 cases of leucopenia, and 5 cases of thrombocytopenia, with a total incidence of 48.57%. In the control group, there were 31 cases of adverse reactions, including 22 cases of nausea and vomiting, 6 cases of leucopenia, and 4 cases of thrombocytopenia, with a total incidence of 91.43%. The difference between the two groups was statistically significant (P < 0.05). The efficacy of temozolomide single agent and combined doxorubicin in the treatment of glioma was significant. Moreover, it can significantly improve clinical efficacy, reduce the incidence of adverse reactions, and improve the health status of patients, which is worthy of further clinical application.

TiNivo-2: A phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor.

TPS405 Background: Tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (aRCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile (Rini et al. Lancet Oncol 2020; 21:95-104). Tivozanib was approved by the FDA on March 10, 2021, for the treatment of patients with aRCC who had progressed on 2 or more prior lines of therapy. Tivozanib was combined with Nivolumab in the TiNivo trial (NCT03136627), showing an objective response rate of 56%, disease control rate of 96%, median PFS of 18.9 months and a favorable safety profile (Albiges et al. Ann Oncol. 2021 Jan;32(1):97-102). Methods: TiNivo-2 (NCT04987203) is a phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following 1-2 lines of therapy including an immune checkpoint inhibitor. Eligibility criteria include age &gt;18 years, clear cell RCC, ECOG PS 0-1, and disease progression during or following at least 6 weeks of treatment with ICI for RCC. Subjects will be stratified by IMDC risk category and whether ICI was received in most recent line of treatment or not. On both arms, subjects will receive Tivozanib 1.34 mg orally once daily for 21 consecutive days followed by 7 days off. In the combination arm, subjects will also receive Nivolumab 480mg intravenously every 4 weeks. Study assessments include CT scan or MRI of the chest, abdomen, and pelvis every 8 weeks following Cycle 1 Day 1 for 2 years and every 12 weeks thereafter until disease progression is confirmed by independent radiology review. The primary objective is to compare the progression-free survival (PFS) of tivozanib in combination with nivolumab to tivozanib. A sample size of 326 subjects, with 191 events will provide at least 80% power to detect a 50% improvement in PFS, 12 mos v. 8 mos, as assessed by an IRR. Secondary endpoints include assessment of overall survival (OS), objective response rate (ORR), and duration of response (DoR), as well as safety and tolerability. Exploratory endpoints are to assess the quality of life (FKSI-DRS and EORTC QLQ C-30) and to investigate the pharmacokinetics of tivozanib. TiNivo-2 is actively enrolling and planning to open at 190 sites in the United States, and the European Union. Clinical trial information: NCT04987203.

Abstract OT2-11-01: EMBER-3: A randomized phase 3 study of LY3484356, a novel, oral selective estrogen receptor degrader vs investigator’s choice of endocrine therapy of either fulvestrant or exemestane, in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer previously treated with endocrine-based therapy

Abstract Background: The estrogen receptor (ER) is the key therapeutic target for ER-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Novel degraders of ER may overcome resistance to available endocrine therapy (ET) while providing consistent oral bioavailability and convenience of administration. LY3484356 is a novel, orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties resulting in sustained inhibition of ER-dependent gene transcription and -cell growth. In the phase 1a/b EMBER trial, LY3484356 monotherapy demonstrated a favorable safety profile with pharmacokinetic (PK) exposures that exceeded fulvestrant. LY3484356 also showed single agent efficacy in patients with ER+, HER2- metastatic breast cancer (MBC), including in patients with baseline ESR1 mutations and fulvestrant- and/or CDK4/6 inhibitor- refractory disease1. Trial Design: EMBER-3 is a randomized, open-label, global phase 3 study comparing LY3484356 versus investigator’s choice of ET (fulvestrant or exemestane), in patients with ER+, HER2- locally advanced or MBC. Approximately 500 patients will be randomized 1:1 to receive LY3484356 (400 mg PO QD continuously in 28-day cycles) or investigator’s choice of ET (dosed per label). Males and pre-menopausal women will receive concomitant treatment with a GnRH agonist. Eligibility criteria: Eligible patients are adult males and females (pre- or post-menopausal) with ER+, HER2- locally advanced or MBC who have received prior treatment with an aromatase inhibitor, alone or in combination with a CDK4/6 inhibitor. No other prior therapy for advanced disease is permitted. Patients must have evaluable disease (measurable or non-measurable bone only). Study endpoints: The primary endpoint is investigator-assessed progression-free survival (PFS) per RECIST v1.1. Secondary endpoints include BIRC-assessed PFS, overall survival, objective response rate, duration of response, clinical benefit rate, safety and tolerability, PK and patient reported outcomes. Recruitment for the EMBER-3 study begins in Q3 2021. Reference: 1Jhaveri et al. J Clin Oncol 2021 39:15_suppl, 1050 Citation Format: Komal Jhaveri, Nadia Harbeck, Philippe Aftimos, Sung-Bae Kim, Xavier Pivot, Cristina Saura, Giuseppe Curigliano, Monica Casalnuovo, Xuejing Aimee Wang, Suzanne R.L. Young, Lillian Smyth, Joyce O'Shaughnessy. EMBER-3: A randomized phase 3 study of LY3484356, a novel, oral selective estrogen receptor degrader vs investigator’s choice of endocrine therapy of either fulvestrant or exemestane, in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer previously treated with endocrine-based therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-01.

Abstract P5-17-13: Selective CDK8/CDK19 inhibitor RVU120 demonstrates efficacy against hormone-independent breast cancer cells in vitro and in vivo

Abstract Breast cancer (BC) is a complex and heterogenous disease, and various approaches have been used to classify BC into several subtypes to improve diagnostic and therapeutic outcomes. One of the features of BC is deregulated transcription, which allows for classification of the disease based on gene expression signature into four basic types: Luminal A, Luminal B, HER2-enriched, and triple negative (TNBC)/basal-like. Novel therapeutic approaches targeting oncogenic transcriptional programs may represent a promising strategy, in particular for TNBC, where the lack of common genetic alterations has so far limited the development of targeted therapies. The CDK8 module of the mediator complex represents an effective therapeutic target across multiple hematologic malignancies and solid tumors. CDK8 module of mediator functions as a master coordinator of transcription, bridging enhancers and core promoters. Meta-analysis of transcriptomic data revealed that higher CDK8 expression and its paralog CDK19 is associated with shorter relapse-free survival (RFS) in all molecular subtypes of BC. Our analysis of curated TCGA data revealed that &amp;gt;15% of all BC have alterations in either CDK8 or CDK19. Increased expression of CDK8 in BC can be partially attributed to copy number gains and amplifications. High CDK8 expression was inversely correlated with the expression of estrogen receptor (ER) and positively correlated with occurrence of TP53 mutations. In order to identify whether increased expression of CDK8/19 in BC could be associated with increased sensitivity to pharmacological inhibition of both kinases, we have interrogated a panel of BC cell lines representing various subtypes with RVU120 - a specific, selective inhibitor of CDK8/CDK19, currently being tested in a first-in-human Phase Ib clinical trial. The highest sensitivity to RVU120 in clonogenic assays has been observed for TNBC and ER-/PR-/HER2+ cells with high STAT3 phosphorylation levels. In contrast, neither RVU120 nor other CDK8 inhibitors were able to inhibit mitogenic effect of estrogen, confirming differential efficacy in hormone - independent BC. Detailed transcriptional profiling of responder cells revealed high enrichment of TNF/NFKB and STAT target genes (signatures associated with inflammatory phenotypes) and SOX4 target genes (signatures associated with invasiveness and stemness). Non-responder cells were characterized by enrichment of transcriptional signatures of ER activity. Efficacy of RVU120 in TNBC cells has been corroborated in a three-dimensional (3D) spheroid viability assay that could predict in vivo efficacy of RVU120 in tested xenograft models and recapitulated using other chemically non-related CDK8 inhibitors, indicating a class effect. Single agent efficacy of RVU120 has been confirmed in subcutaneous TNBC xenograft models in vivo at well tolerated doses. These studies provide rationale for further development of RVU120 in TNBC patients. Citation Format: Tomasz Rzymski, Aniela Gołas, Milena Mazan, Urszula Pakulska, Magdalena Masiejczyk, Agata Stachowicz, Justyna Martyka, Michał Combik, Katarzyna Wiklik, Kristina Goller, Marta Obacz, Elżbieta Adamczyk, Krzysztof Brzózka. Selective CDK8/CDK19 inhibitor RVU120 demonstrates efficacy against hormone-independent breast cancer cells in vitro and in vivo [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-13.

A multicenter phase Ib/II study of liposomal-irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) with nivolumab as second-line therapy for patients with advanced biliary tract cancer (BilT-03).

438 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy and treatment beyond first-line platinum doublet remains largely investigational. The immunomodulatory properties of conventional cytotoxic therapy, particularly in regard to the upregulation of PD-L1 expression rendering tumor cells less sensitive to T cell-mediated lysis, rapid emergence of chemotherapy resistance, and known modest efficacy of single agent anti-PD-1 antibody in BTC provide a rationale for combination chemoimmunotherapy. We conducted a multi-center, phase Ib/II, single-arm study to investigate the role of liposomal-irinotecan, 5FU and LV in combination with nivolumab as second-line therapy in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed unresectable or metastatic BTC after progression or intolerance of first-line systemic therapy, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease or chronic steroid use. The limited phase Ib portion evaluated 10 pts to determine the recommended phase 2 dose (RP2D) based on the probability of dose-limiting toxicity (DLT) rate &lt;30% during days 1-29. Study treatment included 5FU 2400 mg/m2 over 46 hrs, LV 400 mg/m2, liposomal-irinotecan 70 mg/m2 at dose level 0 along with nivolumab 240 mg every 2 wks for up to 2 yrs in absence of disease progression or unacceptable toxicity. The primary endpoint was median progression-free survival (PFS) rate with an alternative and null hypothesis of 5.0 mo and 2.9 mo (two-sided alpha 0.05, power 80%), respectively. Secondary endpoints included best overall response rate (ORR) per immune related (ir)RECIST, median overall survival (OS), 75th percentile estimates of PFS and OS, and safety. Exploratory objectives include biomarker analysis using include targeted panel exome/transcriptome and immune cell subsets in tissue. Results: 30 eligible pts (60% men, 83% Caucasian) including 10 pts in phase Ib and 20 pts in phase II with a median age of 63.5 yrs (range 36-75) were enrolled across 4 US sites between June 2019 and July 2021. In phase Ib, one pt experienced DLT (grade 3 enterocolitis); RP2D was confirmed at dose level 0. All 30 pts were included in study reported outcomes with a median follow-up time of 10.7 mo. Median PFS was 4.2 mo (95% CI, 1.9-10.2) and failed to reject the null hypothesis. Median OS was 7.5 mo (95% CI, 5.8-21.4). The 75th percentile estimates for PFS and OS are 10.2 mo (95% CI, 5.4-NE) and 21.4 mo (95% CI, 7.8-21.4). ORR estimates and toxicity data are pending and will be presented at the meeting. Conclusions: The observed median PFS is insufficient to reject the null hypothesis. The 75th percentile estimates for PFS and OS are suggestive of prolonged benefit with chemoimmunotherapy in a small fraction of patients with BTC. Clinical trial information: NCT03785873.

XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is associated with extensive dysregulation of the epigenome and epigenetic regulators, such as bromodomain and extraterminal motif (BET) proteins, have been suggested as potential targets for therapy. However, single-agent BET inhibition has shown poor efficacy in clinical trials, and no epigenetic approaches are currently used in PDAC. To circumvent the limitations of the current generation of BET inhibitors, we developed the compound XP-524 as an inhibitor of the BET protein BRD4 and the histone acetyltransferase EP300/CBP, both of which are ubiquitously expressed in PDAC tissues and cooperate to enhance tumorigenesis. XP-524 showed increased potency and superior tumoricidal activity than the benchmark BET inhibitor JQ-1 invitro, with comparable efficacy to higher-dose JQ-1 combined with the EP300/CBP inhibitor SGC-CBP30. We determined that this is in part due to the epigenetic silencing of KRAS invitro, with similar results observed using ex vivo slice cultures of human PDAC tumors. Accordingly, XP-524 prevented KRAS-induced, neoplastic transformation invivo and extended survival in two transgenic mouse models of aggressive PDAC. In addition to the inhibition of KRAS/MAPK signaling, XP-524 also enhanced the presentation of self-peptide and tumor recruitment of cytotoxic T lymphocytes, though these lymphocytes remained refractory from full activation. We, therefore, combined XP-524 with an anti-PD-1 antibody invivo, which reactivated the cytotoxic immune program and extended survival well beyond XP-524 in monotherapy. Pending a comprehensive safety evaluation, these results suggest that XP-524 may benefit PDAC patients and warrant further exploration, particularly in combination with immune checkpoint inhibition.

Discovery and Lead Optimization of Benzene-1,4-disulfonamides as Oxidative Phosphorylation Inhibitors.

Inhibition of oxidative phosphorylation (OXPHOS) is a promising therapeutic strategy for select cancers that are dependent on aerobic metabolism. Here, we report the discovery, optimization, and structure-activity relationship (SAR) study of a series of novel OXPHOS inhibitors. The hit compound, benzene-1,4-disulfonamide 1, was discovered in a phenotypic screen selective for cytotoxicity in a galactose-containing medium. Our multi-parameter optimization campaign led to the discovery of 65 (DX3-235), showing nanomolar inhibition of complex I function and adenosine triphosphate (ATP) production in a galactose-containing medium resulting in significant cytotoxicity. Importantly, 64 (DX3-234), a close analogue of 65, is well tolerated in mice and shows significant single agent efficacy in a Pan02 syngeneic pancreatic cancer model, suggesting that highly potent and selective OXPHOS inhibitors can be useful for the treatment of pancreatic cancer.

Checkpoint Inhibitors in Multiple Myeloma: Intriguing Potential and Unfulfilled Promises.

Simple SummaryMultiple myeloma (MM) is a hematological malignancy caused by aberrations in the plasma cell development, resulting in uncontrolled production of plasma cells and or monoclonal proteins. Currently, several treatments are centered around immune-based therapies including immunomodulatory agents, monoclonal antibodies, cellular therapies, and stem cell transplantation. We review the biologic rationale, efficacy, side effects, and limitations of immune-checkpoint inhibitors (ICIs), which have been successful in several solid organ malignancies such as melanoma, kidney, and lung cancers. Recent clinical trials evaluating ICIs as monotherapy and in combination with approved pharmaceutical drugs in MM, have thus far remained underwhelming due to excessive side effects and lack of efficacy in aggressive and advanced cases. There may be a role for ICIs in early forms of MM and preventing recurrence once achieving remission. Side effect mitigation and improved efficacy to combat resistance are needed prior to profoundly impacting the current MM landscape. Clinical studies to answer these questions are ongoing, and we eagerly await this data to determine if ICIs will become a permanent fixture in MM.Immune dysregulation and alteration of the bone marrow microenvironment allowing plasma cells to escape immune surveillance are well-known factors associated with the proliferation of clonal plasma cells and development of multiple myeloma (MM). Whilst immunotherapeutic approaches are now commonplace in a wide spectrum of malignancies, this aberration of myeloma development gives rise to the biological rationale for the use of immune checkpoint inhibitors (ICIs) in MM. However, the initial experience with these agents has been challenging with limited single agent efficacy, significant toxicity, and side effects. Herein, we review the biological and immunological aspects of MM and ICIs. We discuss the basic biology of immune checkpoint inhibitors, mechanisms of resistance, and drug failure patterns, review the published clinical trial data for ICIs in MM, and look towards the future of ICIs for MM treatment.

RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors.

Ataxia telangiectasia and Rad3-related (ATR) kinase protects genome integrity during DNA replication. RP-3500 is a novel, orally bioavailable clinical-stage ATR kinase inhibitor (NCT04497116). RP-3500 is highly potent with IC50 values of 1.0 and 0.33 nmol/L in biochemical and cell-based assays, respectively. RP-3500 is highly selective for ATR with 30-fold selectivity over mammalian target of rapamycin (mTOR) and more than 2,000-fold selectivity over ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and phosphatidylinositol 3-kinase alpha (PI3Kα) kinases. In vivo, RP-3500 treatment results in potent single-agent efficacy and/or tumor regression in multiple xenograft models at minimum effective doses (MED) of 5 to 7 mg/kg once daily. Pharmacodynamic assessments validate target engagement, with dose-proportional tumor inhibition of phosphorylated checkpoint kinase 1 (pCHK1) (IC80 = 18.6 nmol/L) and induction of phosphorylated H2A.X variant histone (γH2AX), phosphorylated DNA-PK catalytic subunit (pDNA-PKcs), and phosphorylated KRAB-associated protein 1 (pKAP1). RP-3500 exposure at MED indicates that circulating free plasma levels above the in vivo tumor IC80 for 10 to 12 hours are sufficient for efficacy on a continuous schedule. However, short-duration intermittent (weekly 3 days on/4 days off) dosing schedules as monotherapy or given concomitantly with reduced doses of olaparib or niraparib, maximize tumor growth inhibition while minimizing the impact on red blood cell depletion, emphasizing the reversible nature of erythroid toxicity with RP-3500 and demonstrating superior efficacy compared with sequential treatment. These results provide a strong preclinical rationale to support ongoing clinical investigation of the novel ATR inhibitor, RP-3500, on an intermittent schedule as a monotherapy and in combination with PARP inhibitors as a potential means of maximizing clinical benefit.

Avelumab as neoadjuvant therapy in patients with urothelial non-metastatic muscle invasive bladder cancer: a multicenter, randomized, non-comparative, phase II study (Oncodistinct 004 - AURA trial)

IntroductionCisplatin-based neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for patients with non-metastatic muscle invasive bladder cancer (MIBC). Unfortunately, many patients are not candidates to receive cisplatin due to renal impairment. Additionally, no predictive biomarkers for pathological complete response (pCR) are currently validated in clinical practice. Studies evaluating immune checkpoint inhibitors in the peri-operative setting are emerging with promising results. Clinical trials are clearly required in the neoadjuvant setting in order to improve therapeutic strategies.Methods and analysisOncodistinct 004 – AURA is an ongoing multicenter phase II randomized trial assessing the efficacy and safety of avelumab single-agent or combined to different NAC regimens in patients with non-metastatic MIBC. Patients are enrolled in two distinct cohorts according to their eligibility to receive cisplatin-based NAC. In the cisplatin eligible cohort, patients are randomized in a 1:1 fashion to receive avelumab combined with cisplatin-gemcitabine or with dose-dense methotrexate-vinblastine-doxorubicin-cisplatin. In the cisplatin ineligible cohort, patients are randomized at a 1:1 ratio to paclitaxel-gemcitabine associated to avelumab or avelumab alone. Primary endpoint is pCR. Secondary endpoints are pathological response and safety.Ethics and disseminationThe study is approved by ethics committee from all participating centers. All participants provide informed consent prior inclusion to the study. Once completed, results will be published in peer-reviewed journals.Trial registration numberClinicalTrials.gov (NCT03674424).

CTNI-17. A PHASE 1 WITH DOSE EXPANSION/PHASE 2 STUDY OF SELINEXOR IN COMBINATION WITH STANDARD OF CARE THERAPY FOR NEWLY DIAGNOSED OR RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary brain tumor with median overall survival of 15 months and 5-7 months for patients with newly diagnosed or recurrent disease (nGBM or rGBM), respectively. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export which blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing cancer cell death. Increased XPO1 expression in gliomas is associated with higher pathological grade and poorer prognosis. Consistent with these data, selinexor inhibited tumor growth and prolonged survival in an animal model of GBM. Importantly, selinexor showed encouraging intra-tumoral penetration and single-agent efficacy in rGBM (KING study). The current trial tests the hypothesis that adding selinexor to standard therapy will improve clinical outcomes for patients with nGBM or rGBM. METHODS To facilitate the successful development of new therapies, consensus recommendations are to use biomarker enrichment and flexible design that allows expansion of promising cohorts. Accordingly, this phase 1a dose finding study is followed by a phase 1b dose expansion (and ultimately by a 1:1 randomized phase 2 efficacy exploration trial) to independently evaluate: radiation + selinexor in nGBM with unmethylated MGMT promoter (Arm A), radiation + temozolomide + selinexor for nGBM with methylated MGMT promoter (Arm B), and lomustine + selinexor in rGBM (Arm C). Bevacizumab or TTField + selinexor in rGBM (Arms D &amp; E, respectively) are being considered. The Phase 1a primary endpoint is maximum tolerated dose/recommended phase 2 dose. The phase 1b primary endpoint is PFS at 3 months against historic controls. The phase 1b dose expansion is included to evaluate preliminary efficacy before launching into a randomized phase 2 trial. Patient quality of life during the trial will be objectively measured using digital devices (e.g. smartwatch/customized smartphone app). We are currently enrolling patients nationwide. Clinical Trial Registration number: NCT04421378.

SEL24/MEN1703 Inhibits PIM/FLT3 Downstream Target in Acute Myeloid Leukemia (AML) Patients: Results of the Pharmacodynamics (PD) Assay and Genomic Profiling in the First-in-Human Diamond-01 Trial

SEL24/MEN1703 Inhibits PIM/FLT3 Downstream Target in Acute Myeloid Leukemia (AML) Patients: Results of the Pharmacodynamics (PD) Assay and Genomic Profiling in the First-in-Human Diamond-01 Trial

ALL-440: Promising Safety and Efficacy Results from an Ongoing Phase 1/2 Study of Pembrolizumab in Combination with Blinatumomab in Patients (pts) with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

<h3>Background:</h3> Blinatumomab, a bispecific anti-CD19/CD3 antibody, demonstrated single-agent efficacy with 42% CR/CRh in R/R B-ALL. Upregulation of immune inhibitory molecules has been shown to confer resistance to blinatumomab. Here, we set out to test the combination of pembrolizumab and blinatumomab in a phase 1/2 trial (NCT03512405). <h3>Methods:</h3> Pts [≥18 years old (yo); ECOG <1] with CD19+ R/R B-ALL received blinatumomab 9 mcg/day on days 1–7 and 28 mcg/day on days 8–28 in cycle 1 and on days 1–28 in subsequent cycles. Pembrolizumab was given on day 15 (schedule A) or day 22 (schedule B) in cycle 1 and on days 1 and 22 in subsequent cycles. Cycle length was 42 days, except 35 days for cycle 1 in schedule A. We completed the schedule A phase 1 portion with primary objectives of safety, tolerability, and recommended phase 2 dose (RP2D) using the "3+3" design. <h3>Results:</h3> As of February 1, 2021, 7 pts were enrolled to phase 1, with one unevaluable. Six treated and evaluable pts received a median of 2 (1–5) cycles of treatment. At baseline, the median age was 51 yo (29–74) with median 2 (2–4) prior lines of regimens and median 29% (0–83) BM blasts. Two pts had extramedullary disease. In cycle 1, all 6 pts experienced grade (gr) 1–2 cytokine release syndrome. Neurologic toxicities were all reversible with only 1 ≥ gr3 AE. All-non-hematologic gr3 toxicities, were reversible. No dose-limiting toxicity, ≥ gr4 non-hematologic toxicity, or treatment-related deaths were seen. Five of 6 evaluable pts (83%) achieved MRD-negative CR after a median of 1 (1–2) cycle. Three pts in CR received alloHCT, all engrafted. With a median follow-up of 2.8 (1.1–9.6) months, 4 CRs are ongoing (1 post-transplant), and 5 of 6 pts are still alive at the data cut-off. <h3>Conclusions:</h3> The combination of pembrolizumab and blinatumomab in phase 1 of this study in pts with B-ALL was deemed safe with a manageable side effect profile and encouraging anti-leukemic activity. The study is now open for phase 2 with the primary objective of overall response rate.

Structure-Guided Optimization Provides a Series of TTK Protein Inhibitors with Potent Antitumor Activity.

TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast cancer (TNBC) cell lines (8: TTK IC50 = 3.0 nM; CAL-51 IC50 = 84.0 nM). Inspired by previously described potent tricyclic TTK inhibitor 6 (TTK IC50 = 0.9 nM), we embarked on a structure-enabled design and optimization campaign to identify an improved series with excellent potency, TTK selectivity, solubility, CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model. These efforts culminated in the discovery of 25 (TTK IC50 = 3.0 nM; CAL-51 IC50 = 16.0 nM), which showed significant single-agent efficacy when dosed iv in a TNBC xenograft model without body weight loss.

Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma

HDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%–35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.