Monotherapy Dose Research Articles

Abstract CT103: A phase 1 first-in-human study of MEM-288 oncolytic virus in solid tumors including non-small cell lung cancer (NSCLC): impact on tumor and systemic T cell immunity

Abstract Background: MEM-288 is a conditionally-replicative oncolytic adenovirus expressing human IFNβ and a recombinant membrane-stable form of CD40L (MEM40). Preclinical studies show MEM-288 induces robust dendritic cell-mediated systemic T cell responses capable of inhibiting abscopal tumor growth as monotherapy and synergizes with immune checkpoint inhibitors (ICI). Methods: Safety, antitumor and immunologic activity of MEM-288 are being evaluated in this Phase 1, multicenter, open-label trial (NCT05076760). Pts with select solid tumors including NSCLC (a) refractory to standard therapy and (b) with a tumor lesion deemed feasible for biopsy and MEM-288 intratumoral injection are eligible. The primary objective is to determine a recommended phase 2 dose of MEM-288 monotherapy across 3 dose levels (DL1-3) spanning 1e10 to 1e11 viral particles by intratumoral injection once every 3 weeks, for up to 6 injections, using a BOIN design. Secondary objectives include efficacy assessment (including response rate of injected and non-injected tumors assessed separately). Tumor biopsies immediately prior to the 1st and 2nd injections, and peripheral blood at serial timepoints, are used to explore biomarkers and anti-tumor immune responses. Results: As of Jan 2023, the study is ongoing with the DL3 high-dose cohort completing accrual. 11 pts (10 NSCLC and 1 pancreatic) enrolled and received ≥1 dose of MEM-288 (n=3 DL1, n=5 DL2, n=3 DL3). No dose limiting toxicities have been reported to date and no pts have discontinued treatment due to toxicity. Treatment-related adverse events observed in >1 pt include grade 1 injection site reaction (45%) and chills (18%). Of 7 pts evaluable for response, 3 had shrinkage of injected tumor (range -40 to -54%), and multiple pts also had stabilization or shrinkage of distal non-injected lesions with best RECIST response in uninjected tumors as 2 SD and 5 PD. After a single MEM-288 injection, biopsies show decreased tumor cell percentage concomitant with substantial increases in overall CD8+ T cells, increased T clonotype diversity in both tumor and peripheral blood, and increased TCF1+ stem-like CD8+ T cells that are strongly associated with response to ICIs. Plasma cytokine analysis showed increases in IFNγ and of IFN-inducible cytokines and chemokines, supportive of stimulation of systemic response after MEM-288. Of note, a pt with strong stimulation of tumor and systemic T cell immunity after MEM-288 had a subsequent CR (ongoing >6 months) to docetaxel + ramucirumab following prior treatment failure with platinum doublet + ICI received before MEM-288. Conclusions: Preliminary safety, antitumor and immune response data are encouraging. Updated results and immune data will be presented. An expansion arm is planned with combination MEM-288 and anti-PD1 antibody in pts with advanced NSCLC refractory to ICI. Citation Format: Andreas N. Saltos, Christy Arrowood, Georgia Beasley, James Ronald, Ghassan El-Haddad, Uzma Khan, Luiziane Guerra-Guevara, Steven Wolf, Lin Gu, Xiaofei F. Wang, Dana Foresman, Xiaoqing Yu, Mark J. Cantwell, Scott J. Antonia, Amer A. Beg, Neal E. Ready. A phase 1 first-in-human study of MEM-288 oncolytic virus in solid tumors including non-small cell lung cancer (NSCLC): impact on tumor and systemic T cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT103.

Abstract CT110: Safety and anti-tumor activity of a novel Treg depleter RG6292, as a single agent and in combination with atezolizumab in patients with solid tumors

Abstract Background RG6292 is the first anti-human CD25 antibody developed to specifically deplete human Tregs while preserving IL-2R STAT5 signaling and Teff activity. Methods Patients with advanced/metastatic solid tumors and without standard treatment options were enrolled in dose escalation studies and received RG6292 i.v. Q3W as monotherapy (S1: NCT04158583) or in combination with atezolizumab 1200 mg Q3W (S2: NCT04642365) until disease progression or unacceptable toxicities to determine the maximum tolerated dose (MTD) and/or optimal biological dose, safety and preliminary clinical activity. DLT window was 4 weeks and dose increments were determined by a Bayesian-based continuous reassessment method (CRM) with overdose control. Adverse events (AEs) were graded by NCI CTCAE v5.0. Tumors were assessed by RECIST 1.1 every 8 weeks in the first year and then every 12 weeks. Results As of 27th May, 2022, 76 patients have been treated with RG6292 monotherapy (dose ranging from 0.3 - 165 mg). Six DLTs were reported, including rash, papular rash, rash macular-papular, AST elevation and ALT elevation. MTD is 165 mg. Seventy-five patients (99%) experienced at least one AE. The most common AEs were pruritus (32%), rash (29%) and fatigue (29%). Thirty-five patients (46%) experienced grade ≥ 3 AEs and 2 patients discontinued from study treatment due to AEs. Fourteen patients (18%) experienced grade ≥ 3 TRAEs. No AEs led to a fatal outcome. Median treatment duration was 43 days. Twenty-three patients have SD as best overall response. Forty-eight patients have been treated with RG6292 (dose ranging from 0.3 - 160 mg) in combination with atezolizumab. Two DLTs were reported, including immune system disorder and maculopapular rash. MTD has not been reached. Forty-seven patients (98%) experienced at least one AE. The most common AEs reported were pruritus (44%), rash (33%) and fatigue (33%). Twenty patients (42%) experienced grade ≥3 AEs and 2 patients discontinued from study treatment due to AEs. Five patients (10%) experienced grade ≥3 TRAEs. No AEs led to a fatal outcome. Median treatment duration was 54 days. Pruritus and rash were expected AEs and easily managed withtopical steroids or short course, low dose systemic steroids. Two patients have PR and 19 patients have SD as best overall response. Conclusion RG6292 is well tolerated and has a manageable safety profile as a single agent and in combination with atezolizumab. The preliminary safety and clinical activity from dose-escalation warrant further investigation of RG6292. Citation Format: Valentina Gambardella, Michael Ong, Maria Esperanza Rodriguez Ruiz, Jean-Pascal Machiels, Miguel Fernandez de Sanmamed, Josep Maria Tabernero, Anna Spreafico, Daniel J Renouf, Stephen J Luen, Rachel Galot, Bernard Doger de Speville Uribe, Emiliano Calvo Aller, Aung Naing, Samira Curdt, Eva Rossmann, Tamara Tanos, Kevin Smart, Maria Amann, Yuying Xie, Gabriel Schnetzler, Christophe Boetsch, Vaios Karanikas, Theresa Kolben, Linxinyu Xu, Kristoffer S Rohrberg. Safety and anti-tumor activity of a novel Treg depleter RG6292, as a single agent and in combination with atezolizumab in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT110.

Abstract CT133: Trial in progress: a multicenter phase 1/1b dose escalation study of WTX-124 as a monotherapy and in combination with pembrolizumab in patients with selected advanced or metastatic solid tumors

Abstract Background: High-dose recombinant human IL-2 (HD IL-2) is an FDA-approved therapy that produces durable complete remissions in a subset of patients with advanced or metastatic cutaneous melanoma and renal cell carcinoma. However, the clinical benefit of HD IL-2 is counterbalanced by life-threatening toxicities such as capillary leak syndrome. WTX-124 is an engineered cytokine prodrug composed of a wild-type IL-2 fused via proprietary cleavable linkers to an inactivation domain and to a half-life extension domain. In the circulation and in normal tissues, WTX-124 is designed to remain inactive and not bind to high- (αβγ) and intermediate-affinity (βγ) IL-2 receptors. In contrast, proteolytic activation of WTX-124 in the tumor microenvironment (TME) is expected to liberate the IL-2 cytokine to stimulate antitumor immune responses. Preclinical data show that WTX-124 is activated by a range of dissociated human tumors in vitro but not by normal human cells or by patient serum. Moreover, WTX-124 demonstrates potent antitumor activity in multiple murine syngeneic tumor models with substantial expansion and activation of tumor-infiltrating lymphocytes. In the MC38 model, WTX-124 has a large therapeutic window of >19-fold compared to ~3-fold for recombinant human IL-2. Methods: This first-in-human, open-label phase 1/1b trial is investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity of WTX-124 administered as a monotherapy or in combination with the anti-PD-1 antibody pembrolizumab to patients with advanced or metastatic solid tumors (NCT05479812). All patients must have ≥ 1 measurable lesion per RECIST 1.1 and a tumor type for which immune checkpoint inhibitor (ICI) therapy is indicated. Dose escalation uses a modified toxicity probability interval-2 study design with WTX-124 administered intravenously (IV) every two weeks in 28-day cycles. If the safety of WTX-124 as a monotherapy is established in the first three cohorts, the study will then initiate dose escalation of WTX-124 in combination with pembrolizumab 400mg IV every six weeks. Dose expansion is anticipated to include four arms that will enroll patients with either advanced or metastatic cutaneous melanoma or renal cell carcinoma to receive WTX-124 monotherapy or combination therapy (N=20 patients per arm). Patients with melanoma assigned to the WTX-124/pembrolizumab combination arm may be naïve to all prior systemic therapy for advanced disease, but all other patients in expansion must have previously received a standard of care ICI regimen. Pre- and on-treatment tumor biopsies, archival tumor tissue, and blood samples will be used to investigate multiple exploratory biomarkers. As of January 12, 2023, WTX-124 monotherapy dose escalation is proceeding. Citation Format: Ildefonso Ismael Rodriguez-Rivera, Justin C. Moser, Mateusz Opyrchal, Brendan Curti, Mehmet A. Bilen, Saero Park, Marissa Bruno, Paul Windt, Kulandayan K. Subramanian, Sameer S. Chopra, Randi Isaacs. Trial in progress: a multicenter phase 1/1b dose escalation study of WTX-124 as a monotherapy and in combination with pembrolizumab in patients with selected advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT133.

Abstract CT052: A phase 1/2 randomized study of imvotamab monotherapy and in combination with loncastuximab tesirine in relapsed/refractory non-Hodgkin lymphomas

Abstract Background: Recent advances in the treatment of non-Hodgkin lymphoma (NHL) have transformed the landscape and provided significant benefits to patients. Novel agents that target CD19 and CD20 on B cells, such as bispecific T-cell engagers and chimeric antigen receptor T-cell (CAR-T) therapy, have demonstrated benefit for patients in the relapsed and refractory setting. However, these agents can often be associated with significant toxicity and there is a need for new therapies that can provide clinical benefit with a superior safety profile. Imvotamab is a novel CD20 x CD3 bispecific antibody utilizing an IgM backbone. This allows targeting of up to 10 CD20 binding sites for every CD3 site. In preclinical models, imvotamab demonstrated encouraging antitumor activity and stimulated T-cells in a more physiologic manner than IgG-based antibodies, which may reduce adverse events typically associated with T-cell engagers and CAR-T, such as CRS and neurotoxicity. Loncastuximab tesirine is a CD19-targeting antibody-drug conjugate approved by the US FDA and EMA for relapsed DLBCL after 2 lines of systemic therapy. Loncastuximab tesirine has shown activity in both DLBCL and FL. Combining therapies such as loncastuximab tesirine, which targets CD19 and induce apoptosis of cancer cells, with imvotamab’s ability to eliminate CD20+ tumor cells by engagement with T-cells, may improve treatment outcomes among patients with NHL via synergistic mechanisms of action. Methods: This study is a Phase 1/2, multicenter, single-arm clinical trial of imvotamab as monotherapy and in combination with loncastuximab tesirine for patients with relapsed/refractory NHL. Phase 1a Dose Escalation is complete with no DLTs or neurotoxicity AEs up to 1000mg dose titration. Phase 1b Combination will evaluate imvotamab and loncastuximab tesirine in patients with R/R 2nd line or later NHL. Phase 2 monotherapy Dose Selection is currently ongoing. The Phase 2 component randomizes patients at two different dose levels (100 mg and 300 mg plateau dose) in two separate indications (R/R DLBCL and R/R FL). Patients receive weekly dosing on Day 1, 8, and 15 of each 21- day cycle. Dosing begins at 15 mg and is increased weekly for 3-4 weeks to reach the plateau dose. Patients then stay at the plateau dose until disease progression or unacceptable toxicity. Patients who achieve a response by Week 12 may switch to a less frequent dosing interval of every 3 weeks. Primary endpoints include frequency and severity of adverse events and objective response rate (ORR) based on Lugano criteria. Correlative biomarker studies will evaluate the relationship of clinical benefit with blood and tissue biomarkers. The study is currently open with patients enrolling in Phase 2 at time of submission. Phase 1b Combination is expected to begin enrollment in the first quarter of 2023. Clinical trial information: NCT04082936. Citation Format: Catherine Diefenbach, Won Seog Kim, Chan Cheah, Ajay K. Gopal, Philippe Armand, Ian Flinn, Gareth P. Gregory, Sung-Soo Yoon, Loretta Nastoupil, Jennifer Lue, Vincent Ribrag, Javier Briones, Antonio Salar-Silvestre, Anna Sureda-Balari, Matthew Ku, Hans Cruz, Paul Thaler, Ibrahim Qazi, Rachel Wei, Maya Leabman, Genevive Hernandez, Iris Sison, Elizabeth Budde. A phase 1/2 randomized study of imvotamab monotherapy and in combination with loncastuximab tesirine in relapsed/refractory non-Hodgkin lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT052.

Abstract CT094: Phase I dose-escalation study evaluating the safety and tolerability of ginisortamab (UCB6114), a first-in-class anti-gremlin-1 monoclonal antibody (mAb), as monotherapy in advanced solid tumors

Abstract Effective treatment for gastrointestinal (GI) cancers is a significant unmet need. Gremlin-1, secreted by cancer-associated fibroblasts, downregulates bone morphogenetic proteins (BMP), members of the transforming growth factor β superfamily, resulting in tumor stemness, hyperproliferation, and invasiveness. Ginisortamab, a fully human IgG4P mAb, neutralizes gremlin-1, thus restoring BMP signaling. Preclinical studies showed that ginisortamab binds to gremlin-1 and has antitumor activity in several mouse models, including GI cancers. Here we report the initial findings from Part A (monotherapy dose escalation) of the first-in-human study. ONC001 (NCT04393298) is an ongoing multi-part, multicenter, nonrandomized, open-label, Phase I/II study assessing the safety, PK/PD, and antitumor activity of intravenous (IV) ginisortamab as monotherapy or in combination with selected standard of care regimens in patients (pts) with advanced solid tumors. ONC001 includes 3 dose escalation modules (Parts A-C) and a dose adaptation module (Part A1). To be eligible for Part A, pts had to be aged ≥18 years (y) with advanced disease, resistant or refractory to standard therapy, with ECOG PS ≤1. We present the primary (safety, tolerability), secondary (PK/PD), and exploratory (antitumor activity) endpoints, as well as the monotherapy RP2D from Part A. At data cutoff (June 20, 2022), 25 pts received ≥1 dose of ginisortamab (median [range] age: 64 [37-74] y; 68% male; 88% White; 36% had >3 lines of prior therapy). The most common tumor type enrolled was colorectal adenocarcinoma (44%). Ginisortamab was escalated using a modified rolling 6 design through 5 levels (100, 250, 500, 1000, and 2000 mg IV Q2W) in 28-day cycles. No DLTs, Grade ≥3 AEs related to ginisortamab, or serious related AEs were observed; the 2000 mg dose was deemed safe for further development. Temporary treatment interruption and study discontinuation due to AEs unrelated to ginisortamab occurred in 7 (28%) and 2 pts (8%), respectively. Ginisortamab PK aligned with expectations from preclinical models for an IgG4 mAb, allowing favorable dosing intervals. Confirmation of target occupancy was demonstrated by increases in total circulating gremlin-1. Antidrug antibody formation was not observed. The best overall response of stable disease was observed in 7/24 pts (29%); 4 pts had a reduction of the sum of the dimensions of their target lesions relative to baseline. Favorable safety and PK/PD data at the maximum dose of 2000 mg and preliminary antitumor activity were observed with the first-in-class anti-gremlin antibody ginisortamab. These data support further evaluation of the efficacy and safety of ginisortamab monotherapy at 2000 mg Q2W, or in combination with standard of care regimens (FOLFOX, trifluridine/tipiracil) in advanced solid tumors. Citation Format: Debashis Sarker, Sarah Blagden, Natalie Cook, Thomas R. Evans, Ruth Plummer, Angelos Angelakas, Saira Bashir, Salma El Badri, Leonidas Mavroeidis, Cienne Morton, Abdul (Moe) Muhith, Mark White, Rupert Dixon, Elodie Garric, Joanne Mann, Ivan Matthews, Udai Banerji. Phase I dose-escalation study evaluating the safety and tolerability of ginisortamab (UCB6114), a first-in-class anti-gremlin-1 monoclonal antibody (mAb), as monotherapy in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT094.

Abstract CT127: A phase 1 study to assess BDTX-1535, an oral EGFR inhibitor, in patients with glioblastoma or non-small cell lung cancer

Abstract Background: The epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in many cancers, including glioblastoma (GBM) and non-small cell lung cancer (NSCLC). EGFR tyrosine kinase activity driven by common EGFR mutations can be inhibited by small molecules, however, resistance to available agents may be driven by mutations in the EGFR active kinase site or other regions. BDTX-1535 is an orally available, highly potent, selective, irreversible inhibitor of EGFR mutations, including extracellular variants and amplifications commonly expressed in GBM and inhibits the uncommon EGFR mutations found in NSCLC, including the C797S mutation acquired following 3rd generation EGFR inhibitor therapy. Preclinical data demonstrated the ability of BDTX-1535 to cross the blood-brain barrier and produce sustained inhibition of EGFR signaling. Preclinical studies suggest that BDTX-1535 has potential to be clinically active in suppressing tumor growth in patients with GBM and NSCLC with or without CNS metastases, including a potential survival benefit. Methods: BDTX-1535-101 (NCT05256290) is Phase 1, open-label, multicenter study to assess the safety, tolerability, PK, CNS penetrance, and preliminary antitumor activity of BDTX-1535 in recurrent GBM (rGBM) or locally advanced or metastatic NSCLC with or without CNS disease. The Monotherapy Dose Escalation portion will evaluate BDTX-1535 in patients with either rGBM expressing EGFR alterations or locally advanced/metastatic NSCLC harboring sensitizing EGFR mutations with or without CNS disease. Patients with rGBM must have previously received available standard therapy of surgical resection followed by chemoradiotherapy and/or temozolomide (TMZ). Eligible NSCLC patients must have EGFR mutated NSCLC that has progressed following standard of care EGFR inhibitor therapy. Once a provisional recommended Phase 2 dose (RP2D) has been established, BDTX-1535 monotherapy will be explored in the following Dose Expansion cohorts to further evaluate safety, PK, and preliminary assessment of efficacy: 1) rGBM with confirmed EGFR alterations, 2) NSCLC with uncommon EGFR mutations following EGFR inhibitor therapy; 3) NSCLC with acquired EGFR resistance mutation following a 3rd generation EGFR inhibitor in 1L setting. NSCLC patients may enroll with or without CNS metastases and must not be known to express excluded resistance mutations such as EGFR T790M or MET. BDTX-1535 will also be studied in combination with TMZ to assess safety, tolerability, and a recommended combination dose for the treatment of patients with rGBM harboring EGFR mutations or variants. Enrollment was initiated in 2022 and dose escalation is ongoing. Dose Expansion cohorts are expected to open in 2023. For additional information, please contact BDTX_1535_101_Study@bdtx.com Citation Format: Melissa Johnson, Jason Henry, Alex Spira, James Battiste, Iyad Alnahhas, Manmeet Ahluwalia, Minal Barve, Jeffrey Edenfield, DoHyun Nam, Sudharshan Eathiraj, Julio Hajdenberg, Sergey Yurasov, Helena Yu, Patrick Wen. A phase 1 study to assess BDTX-1535, an oral EGFR inhibitor, in patients with glioblastoma or non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT127.

Abstract 5668: Using clinical utility index (CUI) to determine the optimal biological dose of a nonfucosylated anti-TIGIT antibody: A proposed alternative to maximum tolerated dose (MTD)

Abstract SEA-TGT is a human nonfucosylated monoclonal antibody (mAb) targeting the T cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) protein. TIGIT is an immunoregulatory receptor expressed on activated and memory T cells, Tregs, and NK cells. TIGIT binding to CD155 and CD112 on tumor cells drives an inhibitory signal resulting in decreased T cell functionality. TIGIT targeting has been reported to release these inhibitory signals, drive Treg depletion, augment CD8+ T cell generation, and promote anti-tumor responses. SGNTGT-001 (NCT04254107) is a phase 1 clinical trial that evaluated the safety and tolerability of SEA-TGT as monotherapy in solid tumors and lymphomas at doses ranging from 0.01 to 6 mg/kg. Because an MTD was not identified in dose escalation, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints were measured to assess biological activity and inform dose selection. The biological activity of SEA-TGT as monotherapy was compared across different dose levels using a clinical utility index (CUI), which mathematically integrated multiple clinically-meaningful PK and PD endpoints into a single readout. PD endpoints included NK and CD8+ T cell proliferation, maintenance of overall peripheral CD8+ T cell numbers, depletion of peripheral regulatory T cells, and peripheral target engagement. The PK endpoint was pharmacokinetic linearity. Surrogates of predicted tumor efficacy metrics included tumor target engagement and formation of the TIGIT:SEA-TGT:Fc receptor gamma (FcγRIIIa) trimer complexes in the tumor. An increase in the CUI score, representing an increase in biological activity, was observed during dose escalation, with an apparent plateau between the 0.3 and 6.0 mg/kg levels. Based on safety signals at 6 mg/kg and PK variability at lower doses, 1 and 3 mg/kg were of most interest for further evaluation. Both 1 and 3 mg/kg represented biologically active dose levels as they showed PK and PD activity that were within desirable ranges and had similarly high overall CUI scores relative to all doses evaluated. Dose selection for SEA-TGT was based on biological activity as assessed via PK/PD endpoints and integrated into a CUI model. Based on the totality of clinical data and the CUI results from monotherapy dose escalation from SGNTGT-001, the SEA-TGT dose of 1 mg/kg was determined to be the lowest biologically active dose with acceptable safety and tolerability. Citation Format: Gabriela Patilea-Vrana, John Harrold, Joseph A. Ware, Shaparak Lonning, Hun Lee, Lisa Brooks, Haley Neff-LaFord, William D. Hanley, Andres Forero-Torres. Using clinical utility index (CUI) to determine the optimal biological dose of a nonfucosylated anti-TIGIT antibody: A proposed alternative to maximum tolerated dose (MTD). [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 5668.

Phase 1 study of oral selective estrogen receptor degrader (SERD) amcenestrant (SAR439859), in Japanese women with ER-positive and HER2-negative advanced breast cancer (AMEERA-2)

BackgroundThis AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.MethodsIn this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed.ResultsNo DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported.ConclusionsAmcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer.Trial registrationClinical trial registration NCT03816839.

Brexpiprazole augmentation in a clozapine-resistant young schizophrenic patient: a successful case report.

IntroductionAlthough clozapine is considered the most effective drug for Treatment Resistant Schizophrenia (TRS), only 40% of patients treated will meet clinical response. Literature reviews and meta-analytic data offer no definite conclusions about the most effective clozapine augmentation strategies. Nevertheless, it has been suggested that the lack of evidence should not discourage clinicians from trying out new strategies in individual patients. Brexpiprazole is a novel 5-HT and DA modulator antipsychotic that exhibits partial agonism to D2/D3 and 5HT1A receptors, antagonism to 5HT2A and α-1B/2C receptors and represents a promising new drug in the pharmacotherapy of schizophrenia for both acute and maintenance treatment. In current literature there is no evidence of experiences in brexpiprazole augmentation for clozapine resistant patients.ObjectivesThis case report describes a successful clinical experience of brexpiprazole augmentation in a complicated case of clozapine resistant paranoid schizophrenia with consistent negative symptoms, the clinical evolution and metabolic improvement consequent to this therapy combination.MethodsIn a 27 male TRS patient, sequentially treated with adequate doses of risperidone, cariprazine, aripiprazole and olanzapine monotherapy, prescribed for adequate time, clozapine treatment was started, with a gradual titration from 25 to 300 mg/day, without significant clinical response on both positive and negative symptoms. Successively was introduced fluoxetine, from 10 to 30 mg/day, with no relevant clinical improvement. After 2 months of pharmacological stabilization with clozapine and fluoxetine described dosages, brexpiprazole was introduced starting from 1 mg/day and rapidly increasing till 4 mg/day.ResultsAfter 6 weeks of treatment, PANSS positive and negative subscales showed a significant decrease, respectively from 28 to 17 and from 42 to 20, while general psychopathology subscale decreased from 66 to 34. Negative sub-items with major improvement were those regarding blunted affect, emotional withdrawal, poor rapport, and passive/apathetic social withdrawal. Brexpiprazole augmentation also allowed to slowly decrease (in 6 months) clozapine dose till actual 150 mg/day, with a significant improvement in general tolerability and a slow decline in metabolic parameters (BMI from 36.5 to 30.3; fasting glucose from 112 to 92 mg/dL; total cholesterol from 248 to 182 mg/dL; total triglycerides from 392 to 198 mg/dL).ConclusionsIn this case report brexpiprazole augmentation in a clozapine resistant young schizophrenic patient was an effective strategy with significant symptoms improvement, in particular in PANSS general psychopathology and PANSS negative subscales. The consequent clozapine dose reduction contribute to the slow decrease in metabolic parameters considered.Disclosure of InterestNone Declared

Abstract GS3-03: GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study

Abstract Background: ARV-471 is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC®) protein degrader that targets wild-type and mutant ER. ARV-471 is being evaluated in patients with ER+/HER2- locally advanced or metastatic breast cancer in a first-in-human phase 1/2 study (NCT04072952). In the phase 1 dose escalation, ARV-471 monotherapy (dose range: 30–700 mg total daily dose) showed a manageable safety profile in patients who had previously received endocrine therapy and a cyclin-dependent kinase (CDK) 4/6 inhibitor. The clinical benefit rate (CBR; rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26–56) in 47 evaluable patients. The phase 2 expansion portion of the study (VERITAC) evaluated 2 doses of ARV-471.Methods: In VERITAC, ARV-471 monotherapy was administered at doses of 200 mg once daily (QD) or 500 mg QD to patients with ER+/HER2- locally advanced/metastatic breast cancer who had received ≥1 prior endocrine therapy for ≥6 months, ≥1 CDK4/6 inhibitor, and ≤1 chemotherapy regimen. The primary endpoint of CBR was evaluated in patients enrolled ≥24 weeks prior to the data cutoff. Results: As of June 6, 2022, 71 patients received ARV-471 (200 mg QD [n=35]; 500 mg QD [n=36]) in VERITAC. Across all treated patients, 69 (97.2%) were female and median age was 60 y (range: 41–86). Patients had received a median of 4 prior regimens in all settings (range: 1–10); 100% had prior CDK4/6 inhibitors, 78.9% had prior fulvestrant, and 73.2% had prior chemotherapy. ARV-471 was well tolerated at both doses, with most treatment-related adverse events (TRAEs) grade 1/2; the most common TRAEs were fatigue and nausea (Table). In all, 3 patients (1 in the 200 mg QD cohort and 2 in the 500 mg QD cohort) discontinued ARV-471 due to treatment-emergent adverse events (TEAEs); 3 patients had ARV-471 dose reductions due to TEAEs (all from 500 mg QD to 400 mg QD). CBR was 37.1% (95% CI: 21–55) in 35 evaluable patients treated at 200 mg QD and 38.9% (95% CI: 23–57) in 36 evaluable patients treated at 500 mg QD. CBR in evaluable patients with mutant ESR1 in the 200 mg QD (n=19) and 500 mg QD (n=22) cohorts was 47.4% (95% CI: 24–71) and 54.5% (95% CI: 32–76), respectively. Conclusions: In the phase 2 VERITAC expansion cohorts of patients with ER+/HER2- locally advanced/metastatic breast cancer and prior CDK4/6 inhibitor treatment, ARV-471 monotherapy showed evidence of clinical activity based on CBR, which was further enhanced in the subgroup with ESR1 mutations. The manageable AE profile observed in the phase 1 portion of the study was maintained during cohort expansion at doses of 200 mg QD and 500 mg QD. Additional analyses are ongoing.Table. TRAEs reported in ≥10% of patients overall aNo grade 3/4 TRAE occurred in >1 patient. AST=aspartate aminotransferase Citation Format: Anne F. Schott, Sara Hurvitz, Cynthia Ma, Erika Hamilton, Rita Nanda, George Zahrah, Natasha Hunter, Antoinette R. Tan, Melinda Telli, Jesus Anampa Mesias, Rinath Jeselsohn, Pamela Munster, Haolan Lu, Richard Gedrich, Cecile Mather, Janaki Parameswaran, Hyo S. Han. GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study [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 GS3-03.

Abstract P2-24-07: Combination of complete estrogen receptor antagonist, OP-1250, and CDK4/6 inhibitors enhances tumor suppression and inhibition of cell cycle-related gene expression

Abstract OP-1250, a complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD), is currently in Phase I/II clinical trials for the treatment of estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. OP-1250 has previously demonstrated efficacy in both estrogen receptor 1 (ESR1) wild-type and Y537S mutant breast cancer xenograft models. Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are a standard first-line treatment for ER+ advanced or metastatic breast cancer in combination with endocrine therapy. To characterize OP-1250 efficacy in this setting, we explored the combination of OP-1250 with CDK4/6 inhibitors palbociclib and ribociclib in ER+/HER2- breast cancer preclinical models, and profiled the transcriptional changes associated with single agent and combination therapy. OP-1250 and CDK4/6 inhibitors were tested alone and in combination in ESR1 wild-type MCF7 and ESR1 Y537S mutant ST941 xenograft models. Higher doses of OP-1250 and either CDK4/6 inhibitor, when given as a monotherapy, suppress tumor growth and increase animal survival, while lower doses of the compounds display a modest or minimal effect on tumor growth or survival. In combination, lower doses of OP-1250 and either CDK4/6 inhibitor result in significantly greater tumor growth suppression (both xenograft models), tumor regression (MCF7) and animal survival (ST491) than each compound individually. RNA sequencing revealed substantially more gene expression changes with combination treatment than monotherapy. In particular, pathways associated with cell cycle progression displayed greater changes with combination treatment, similar to what was observed with a much higher dose of monotherapy. This study supports the clinical evaluation of OP-1250 in combination with CDK4/6 inhibitors (palbociclib or ribociclib) and provides additional context to mechanisms of combination efficacy. OP-1250 is currently being evaluated in a Phase Ib clinical trial in combination with palbociclib and a study including evaluation of the combination of OP-1250 with ribociclib is planned to initiate in Q3 2022. Citation Format: Alison D. Parisian, Gopinath S. Palanisamy, Fabian Ortega, Judevin L. Sapugay, William J. Bodell, David Kulp, Peter Kushner, Cyrus Harmon. Combination of complete estrogen receptor antagonist, OP-1250, and CDK4/6 inhibitors enhances tumor suppression and inhibition of cell cycle-related gene expression [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 P2-24-07.

Abstract OT3-08-01: A phase 1 trial of LOXO-783, a potent, highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor in PIK3CA H1047R-mutant advanced breast cancer (aBC) and other solid tumors (PIKASSO-01, trial in progress)

Abstract Background: Phosphoinositide 3-kinase alpha (PI3Kα) H1047R mutations are activating oncogenic events that occur in ~15% of breast cancers (BC). Available PI3Kα inhibitors target both wild-type (WT) and mutant PI3Kα and, as a result, their efficacy may be limited by on-target WT PI3Kα-mediated toxicities, including hyperglycemia, skin rash, and diarrhea. LOXO-783 is an oral, potent and highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor. Preclinically, LOXO-783 is highly selective for PI3Kα H1047R over WT PI3Kα and other PI3K isoforms and induces single-agent tumor regressions in ER+, HER2- PI3Kα H1047R-mutant BC models without causing hyperglycemia or increases in plasma insulin/C-peptide. LOXO-783 also demonstrates brain penetration in vivo with dose-dependent tumor growth inhibition in brain metastasis models. This trial investigates LOXO-783 alone and in combination with other anticancer therapies in patients with PIK3CA H1047R-mutant aBC and other solid tumors. Trial Design: This global, first-in-human phase 1a/b study of LOXO-783 includes dose escalation of LOXO-783 monotherapy followed by dose expansion of LOXO-783 alone and in combination with other anticancer therapies (Table). Monotherapy dose escalation will be evaluated using a modified toxicity probability interval-2 (mTPI-2) design. In dose expansion (Parts A-E), each combination cohort will include a safety lead-in of 3-6 patients. Men and premenopausal women with ER+ aBC must receive concomitant treatment with a GnRH agonist. An optional pharmacodynamic (PD) biomarker sub-study will be conducted at select dose levels during dose escalation in patients with ER+, HER2- aBC with soft tissue disease amenable to safe repeat tumor biopsies. Eligibility criteria: Eligible patients must have PIK3CA H1047R-mutant aBC or other solid tumors with measurable disease or non-measurable bone-only disease (aBC patients only). In dose escalation, patients may have received up to 5 prior regimens. In dose expansion, prior therapy requirements are outlined in the Table below. Key exclusion criteria include prior inhibitor(s) of PI3K/AKT/mTOR (except in dose escalation or in select patients with prior intolerance of these inhibitors), colorectal cancer, endometrial cancer with concurrent PI3K/AKT/mTOR and/or RAS/RAF alterations and diabetes mellitus (DM) requiring medication (except in Part C). Study objectives: Recommended phase 2 dose (RP2D) determination; safety and tolerability assessment, PK and PD evaluation, objective response rate and clinical benefit rate assessment per RECIST v1.1. Recruitment is ongoing (PIKASSO-01, NCT05307705). Table. Dose Expansion (Phase 1b) Citation Format: Dejan Juric, Komal Jhaveri, Muralidhar Beeram, Erika Hamilton, Vincent Chau, Matthew P. Hanley, Shiyao Liu, Lillian M. Smyth, Funda Meric-Bernstam. A phase 1 trial of LOXO-783, a potent, highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor in PIK3CA H1047R-mutant advanced breast cancer (aBC) and other solid tumors (PIKASSO-01, trial in progress) [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 OT3-08-01.

Abstract OT3-22-01: First-in-human global multi-center study of RLY-2608, a pan mutant and isoform selective PI3Kα inhibitor, as a single agent in advanced solid tumor patients and in combination with fulvestrant in patients with advanced breast cancer

Abstract Background: Targeting constitutively active mutant kinases with selective small molecule inhibitors is a key therapeutic pillar of precision oncology. Phosphatidylinositol-4,5bisphosphate-3 kinase, catalytic subunit alpha (PIK3CA) mutations leading to oncogenic activation of PI3Kα represent the largest opportunity for this approach in solid tumors. However, there is no selective inhibitor that targets mutant PI3Kα in the clinic. Toxicity related to non-selective inhibition of WT PI3Kα (hyperglycemia) and other PI3K isoforms limits the tolerability, dosing and efficacy of the orthosteric inhibitor, alpelisib, the only approved solid tumor PI3K inhibitor. RLY-2608, a novel oral allosteric PI3Kα inhibitor, is uniquely designed to overcome these limitations via mutant- and isoform-selective PI3Kα inhibition for greater target coverage, improved tolerability and antitumor activity. We initiated a first-in-human (FIH), study to evaluate the clinical activity of RLY-2608 as a single agent in advanced solid tumor patients (pts) with PI3KCA mutations and in combination with fulvestrant in pts with PIK3CA mutant, HR+, HER2- metastatic breast cancer (MBC). Methods: This is a global, multi-center, dose escalation/expansion study (NCT05216432) of RLY2608 as a single agent in adults who have advanced solid tumors and are refractory, intolerant, or declined standard therapy and RLY-2608 in combination with fulvestrant in previously treated pts with HR+/HER2- MBC. Eligibility criteria include presence of PI3KCA mutation (blood or tumor) per local assessment, ECOG performance status 0-1, measurable or evaluable disease per RECIST 1.1 and no prior PI3K inhibitor (except combination group 2). RLY-2608 is administered on a continuous schedule with 4-week cycles. Adverse events (AEs) per CTCAE v5, PK, biomarkers (mutant ctDNAs and insulin pathway markers) and anti-tumor activity are assessed serially. Dose escalation employs a Bayesian Optimal Interval design to identify MTD and RP2D. Following dose escalation, pts will be treated with RLY-2608 at the MTD/RP2D in a monotherapy dose expansion with 5 groups (N=75, 15 each): 1. Clear cell ovarian carcinoma 2. Head and neck squamous cell carcinoma 3. Cervical cancer 4. Other solid tumors 5. PI3KCA double mutations. In addition, two expansion cohorts will enroll patients with HR+/HER2- MBC treated with RLY-2608 and fulvestrant combination (N = 30, 15 each): 1. No prior PI3K therapy 2. Intolerant to PI3K inhibitors. The primary endpoints are MTD/RP2D and AE profile for single agent and combination; key secondary endpoints are PI3KCA genotype in blood and tumor, PK, biomarkers, and overall response rate. US enrollment began December 2021 and ex-USA startup is under way. Citation Format: Andreas Varkaris, Erika Hamilton, Jason Henry, Alexander I. Spira, Alison M. Schram, Julia E. McGuinness, Gege Tan, Xiaoyan Li, Tamieka Hunter, Ramin Samadani, Alison Timm, Djuro Karanovic, Vivek Subbiah, Cesar A. Perez. First-in-human global multi-center study of RLY-2608, a pan mutant and isoform selective PI3Kα inhibitor, as a single agent in advanced solid tumor patients and in combination with fulvestrant in patients with advanced breast cancer [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 OT3-22-01.

BT8009-100: A phase I/II study of novel bicyclic peptide and MMAE conjugate BT8009 in patients (pts) with advanced malignancies associated with nectin-4 expression, including urothelial cancer (UC).

498 Background: BT8009 is a Bicycle Toxin Conjugate (BTC), a novel class of chemically synthesized molecules comprising a small (~2 kDa) bicyclic peptide targeting Nectin-4 tumor antigen linked to cytotoxin MMAE via a valine-citrulline cleavable linker. BTCs represent a unique therapeutic class, distinct from ADCs and with pharmacokinetic properties analogous to small molecules. Presented are the monotherapy dose escalation results of the ongoing Phase I/II clinical trial of BT8009 (NCT04561362). Methods: In the Part A 3+3 dose escalation portion of the study, BT8009 monotherapy was administered weekly (2.5, 5, 7.5 mg/m2) or every other week (7.5, 10 mg/m2) of a 28-day cycle, or on days 1 and 8 of a 21-day cycle (7.5 mg/m2). Primary objectives were to assess safety of the monotherapy and define maximum tolerated and recommended Phase II dose(s) (RP2D). Key secondary objectives were antitumor activity per RECIST v1.1 and PK parameters. Results: At time of the 20 Sept 2022 data cut-off, 49 pts had received BT8009 (24 pts with UC): weekly (7 pts at 2.5 mg/m2, 20 pts at 5 mg/m2, 5 pts at 7.5 mg/m2); biweekly (5 pts at 7.5 mg/m2, 7 pts at 10 mg/m2); and days 1+8 of a 21-day cycle (5 pts at 7.5 mg/m2). Two RP2Ds have been determined: 5 mg/m2 given weekly on a 28-day cycle and 7.5 mg/m2 given on days 1+8 of a 21-day cycle. Median age was 66 y, 59% pts were male, and median prior lines of therapy was 3 (range 1-15). Most common treatment-related adverse events of any grade experienced by ≥15% of pts were nausea, fatigue, diarrhea, decreased appetite, alopecia, asthenia, pyrexia, and neutrophil count decreased/neutropenia; majority were mild to moderate in severity. One DLT (G3 asthenia) was reported at the 7.5 mg/m2 weekly dose level and 1 DLT (G4 sepsis) at the 10 mg/m2 biweekly dose level. Treatment-related SAEs occurred in 5 pts. No pt discontinued treatment due to an AE. No treatment-related deaths occurred. Of 8 efficacy evaluable pts with UC treated with a RP2D of 5 mg/m2, there was 1 complete response, 3 partial responses (PR), and 3 stable diseases (SD), for an ORR of 50% and clinical benefit rate of 75% (CR+PR+SD≥16 wks). Median duration of response has not yet been reached, but as of 20 Sept 2022 was at least 11 months. Both plasma BT8009 and MMAE exhibited linear pharmacokinetics, with short half-life for BT8009 (<1 h) and longer half-life for MMAE (37-46 h). Conclusions: BT8009 was well tolerated and demonstrated promising preliminary antitumor activity. Evaluation of BT8009 as monotherapy at RP2D(s) and in combination with an immune checkpoint inhibitor will be explored during the expansion phase of this trial; cohorts will include pts with renal impairment to support further development in cis-ineligible pts, pts with previously untreated cis-ineligible metastatic UC, pts with refractory UC, and tumor-specific cohorts outside of bladder cancer. Clinical trial information: NCT04561362 .

Cost-effectiveness analysis of initial treatment with single-pill combination antihypertensive medications.

Hypertension guidelines recommend initiating treatment with single pill combination (SPC) antihypertensive medications, but SPCs are used by only one-third of treated hypertensive US adults. This analysis estimated the cost-effectiveness of initial treatment with SPC dual antihypertensive medications compared with usual care monotherapy in hypertensive US adults.The validated BP Control Model-Cardiovascular Disease (CVD) Policy Model simulated initial SPC dual therapy (two half-standard doses in a single pill) compared with initial usual care monotherapy (half-standard dose when baseline systolic BP < 20 mmHg above goal and one standard dose when ≥20 mmHg above goal). Secondary analyses examined equivalent dose monotherapy (one standard dose) and equivalent dose dual therapy as separate pills (two half-standard doses). The primary outcomes were direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) over 10 years from a US healthcare sector perspective.At 10 years, initial dual drug SPC was projected to yield 0.028 (95%UI 0.008 to 0.051) more QALYs at no greater cost ($73, 95%UI -$1 983 to $1 629) than usual care monotherapy. In secondary analysis, SPC dual therapy was cost-effective vs. equivalent dose monotherapy (ICER $8 000/QALY gained) and equivalent dose dual therapy as separate pills (ICER $57 000/QALY gained). At average drug prices, initiating antihypertensive treatment with SPC dual therapy is more effective at no greater cost than usual care initial monotherapy and has the potential to improve BP control rates and reduce the burden of CVD in the US.

A phase 1/2 open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of OTX-2002 as a single agent and in combination with standard of care in patients with hepatocellular carcinoma and other solid tumor types known for association with the MYC oncogene (MYCHELANGELO I).

TPS627 Background: MYC, or c-MYC, is a master regulator of gene expression that controls cell growth and proliferation. Dysregulation of MYC is frequently identified in various cancer types, including hepatocellular carcinoma (HCC), where it is overexpressed in up to 70% viral and alcohol-related disease.1 While MYC represents an attractive therapeutic target, it has historically been considered undruggable due to a lack of a structured binding pocket and its tightly autoregulated expression. OTX-2002 is a first-in-class, engineered and programable mRNA therapeutic called Omega Epigenomic Controllers (OECs) that modulates MYC gene expression pre-transcriptionally by creating epigenetic marks at two different structural and regulatory elements within the insulated genomic domain where MYC resides. In vitro studies have demonstrated that downregulation of MYC through OTX-2002 led to loss of viability in HCC cells while sparing normal hepatocytes. In HCC xenograft mouse models, OTX-2002 demonstrated anti-tumor activity as monotherapy and in combinations with standard of care therapies in HCC.2 Methods: OTX-2002 is being evaluated in an open-label, non-randomized, phase 1/2 study (MYCHELANGELO I) in patients with HCC and other advanced solid tumor types (NCT05497453). The study consists of two parts. Part 1 dose escalation explores ascending doses of intravenous OTX-2002 monotherapy given every 2 weeks to identify dose limiting toxicities, maximum tolerated dose, and recommended dose for expansion (RDE) in patients with HCC and other solid tumors using a classic 3+3 design. Upon identification of the RDE, a monotherapy expansion in advanced HCC patients is planned to explore the preliminary anti-tumor activity of OTX-2002. Part 2 will evaluate OTX-2002 in combination with HCC standard of care in the same HCC population as that of Part 1 expansion. The safety of OTX-2002 at the selected dose in combination with a tyrosine kinase inhibitor or immune checkpoint inhibitor will be evaluated in a safety run-in; expansion will follow to identify the preliminary anti-tumor activity of the combinations. Key eligibility criteria for HCC patients include: 1) Barcelona Clinical Liver Cancer (BCLC) stage B or C disease, 2) Child-Pugh A liver function, 3) received at least 1 prior systemic therapy. The MYCHELANGELO I study began enrollment in August 2022, and Part 1 dose escalation is ongoing in the US.

Phase I study of Minnelide and paclitaxel combination chemotherapy in refractory gastric cancer (GC).

414 Background: Minnelide is a prodrug that rapidly releases the active compound triptolide when exposed to phosphatases in the bloodstream. Triptolide is a diterpene that has been shown to inhibit tumor cell proliferation and induce apoptosis in various cancer types. The anti-tumor effect of triptolide is the result of inhibition of heat shock protein (HSP) 70 expression. In GC Minnelide inhibits Sp1 to decrease HSP70 and induce cell death in preclinical data. Methods: This phase 1 trial was designed to determine the maximum tolerated dose (MTD) of Minnelide monotherapy and the MTD of Minnelide in combination with paclitaxel in refractory GC patients. There were 6 cohorts tested in this trial: cohort A: Minnelide 1 mg qd D1-21, q 28 days; cohort B: Minnelide 1.25 mg qd D1-21, q 28 days; cohort C: 1.5 mg qd D1-21, q 28 days; cohort D: Minnelide 0.25 mg D1-21 + weekly paclitaxel 60 mg/m2 on D1, D8, D15; cohort E: Minnelide 0.5 mg qd D1-21+ weekly paclitaxel 80 mg/m2 on D1, D8, D15; cohort F: Minnelide 0.75 mg qd D1-21+ weekly paclitaxel 80 mg/m2 D1, D8, D15. Results: From Feb 2021 to Sep 2022, 23 GC patients were enrolled (cohort A – C, N=10; cohort D-F, N=12). All patients had metastatic disease at the time of study enrollment. 20 of 23 patients received the study treatment as &gt;= 3rd-line (range, 2 – 6th line). In all, 3 patients had HER2 positive GC and 10 patients had PDL1 + tumor. In the monotherapy cohorts, there were no DLTs observed, and the regimen was tolerated well. One patient achieved confirmed PR which lasted for 6 months. For the combination arm (cohort D-F), there were no DLTs observed. Of the 11 patients who were evaluable for treatment response, there were 1 PR, 5 SDs and 5 PDs. Two of five patients who achieved stable disease had durable stable disease for &gt; 6 months on study treatment. In the combination cohorts, the most common adverse events of any grade were neutropenia; however, there was no neutropenic fever or treatment related mortality. Conclusions: Minnelide in combination with weekly paclitaxel demonstrated promising anti-tumor activity with durable responses in refractory AGC. Clinical trial information: Underreview .

Trials in progress: A phase 1, open-label, pharmacokinetic, safety and tolerability study of PF-07265807 (selective TAM kinase inhibitor) alone or with sasanlimab in patients with advanced or metastatic solid tumors.

TPS270 Background: Inhibition of Mer Proto-oncogene tyrosine kinase (MERTK) and AXL may lower the threshold for immune activation thereby promoting anti-tumor activity. PF-07265807 (ARRY-067) is a selective small-molecule inhibitor of the tumor-associated macrophage kinases MERTK and AXL. In preclinical models, PF-07265807 plus anti-programmed cell death protein 1 (anti-PD-1) antibodies show antitumor activity that results in long-term cures and resistance to tumor re-challenge. Sasanlimab is a monoclonal antibody to PD-1 administered subcutaneously (300 mg every 4 wk or equivalent); it has an acceptable safety profile and is being tested in a Phase 3 trial in non-muscle invasive bladder cancer. This first-in-human study will evaluate safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of PF-07265807 alone and with sasanlimab in patients (pts) with selected advanced or metastatic solid tumors. Study design of PF-07265807 monotherapy dose escalation (Part 1) was presented at ASCO 2021 (TPS2671). Here, we describe dose escalation (Part 2) and dose expansion (Part 4) cohorts for the doublet combination of PF-07265807 + sasanlimab. Methods: This is a Phase 1, open-label, multi-center study (NCT04458259) of PF-07265807. Adult pts with selected advanced or metastatic solid tumors who are intolerant or resistant to standard therapy will enroll into doublet therapy dose escalation (Part 2). Pts who are anti-PD-1/PD-L1 treatment naïve with intermediate tumor mutational burden (defined as ≥6 and &lt; 16 microsatellite stable) colorectal cancer (CRC) or PD-L1+ (defined as combined positive score ≥1) gastric cancer will enroll into doublet therapy dose expansion cohorts (Part 4). Other key eligibility criteria: measurable or non-measurable disease by RECIST 1.1; ECOG PS 0–2; adequate bone marrow, renal and liver function; and resolved acute effects of any prior therapy. Each cycle will be 21 days. Treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. The doublet maximum tolerated dose (MTD) will be guided by a Bayesian analysis of dose limiting toxicity (DLT) data for doublet therapy (Part 2). The recommended phase 2 dose (RP2D) will then be determined via holistic data review with/without the MTD identification. Primary endpoints in Part 2 include the incidence of DLTs, adverse events and laboratory abnormalities. After doublet MTD/RP2D is identified in Part 2, the preliminary anti-tumor activity of PF-07265807 + sasanlimab will be explored in Part 4. Primary endpoints in Part 4 include objective response and complete response rates; secondary endpoints include disease control rate and response duration, adverse events and laboratory abnormalities. The study began in Q4 2020 and is recruiting pts. Clinical trial information: NCT04458259 .

P749 Crohn’s disease stricture response and resolution with adalimumab therapy demonstrated with intestinal ultrasound. The STRIDENT randomised trial

Abstract Background Transmural healing is a treatment goal in the management of Crohn’s disease, and intestinal ultrasound (IUS) is potentially a sensitive, non-invasive and reproducible means to assess the response to treatment. Methods The STRIDENT (Stricture Definition and Treatment) study was a randomised controlled trial of standard dose monotherapy adalimumab versus intensive high-dose adalimumab combined with a thiopurine. Crohn’s disease patients with symptomatic intestinal strictures were randomised 2:1 to high dose adalimumab induction (160mg weekly for 4 weeks) with 40mg fortnightly maintenance plus thiopurine, with possible dose escalation at 4 and 8 months, versus standard dose adalimumab monotherapy. The primary endpoint was clinical response, defined as a reduction in the Obstructive Symptom Score (OSS) of ≥1, at 12 months. IUS was performed at baseline, 4, 8 and 12 months. IUS endpoints included stricture resolution (normalisation of pre-stenotic dilation (&amp;lt;2.5cm); reduced stricture bowel wall thickness (BWT ≥25% reduction); reduced colour doppler blood flow (inflammation, Limberg score ≤1) and normalisation of BWT (≤3mm). Patients with good quality baseline IUS and IUS-visible strictures were included for analysis. Results 77 patients underwent therapy randomisation. Of 63 patients with IUS-visible strictures 43 (68%) were in the intensive arm. Primary outcome was achieved by 32 (74%) patients in the intensive and 14 (70%) in the standard arms. Stricture resolution was seen in 1/5 non-responders and 18/45 responders. Median BWT reduced from 6.4mm (IQR 5.2-7.3mm) at baseline to 4.9mm (IQR 3-6mm) at 12 months (P&amp;lt;0.001). Clinical responders had significant reduction in median BWT from 6.0mm (IQR 4.5-7.1) at baseline to 4.3mm (IQR 3-5.7) at 12 months (P&amp;lt;0.001). There was no significant reduction in BWT at 4, 8 or 12 months in non-responders (P=0.26, P=0.29, P=0.26 respectively). BWT &amp;gt;3mm at 12 months occurred more often in non-responders than responders (P&amp;lt;0.05). Stricture resolution was seen in 13/36 in the intensive arm and 6/14 standard arm (P=0.75). The intensive arm had significant reduction in median BWT from 6.6mm (IQR 5.5-7.4mm) at baseline to 5.1mm (IQR 3-6.4mm) at 12 months (P&amp;lt;0.001). There was no significant reduction in BWT at 4, 8 or 12 months in the standard arm (P=0.75, P=0.42, P=0.09 respectively). There was no significant difference in BWT&amp;gt;3mm between trial arms at 12 months (P=1). Conclusion Stricture resolution and bowel wall thickness normalisation were demonstrated on intestinal ultrasound in stricturing Crohn’s disease patients treated with adalimumab therapy. Adalimumab therapy is associated with clinical improvement, and transmural improvement and healing, in patients with Crohn’s disease strictures.

Lung Immune Therapy Evaluation (LITE) Risk, a Novel Prognostic Model for Patients With Advanced Non-Small Cell Lung Cancer Treated With Immune Checkpoint Blockade

Introduction/BackgroundImmune checkpoint inhibitors (ICI) have revolutionized non-small cell lung cancer (NSCLC). We aimed to identify baseline characteristics, that are prognostic factors for overall survival (OS) in patients with NSCLC treated with ICI monotherapy, in order to derive the Lung Immune Therapy Evaluation (LITE) risk, a prognostic model. Materials and MethodsMulti-center observational cohort study of patients with advanced NSCLC that received ≥1 dose of ICI monotherapy. The training set (n=342) consisted of patients with NSCLC who received first line ICI. The test set (n=153) used for external validation was a discrete cohort of patients who received second line ICI. 20 candidate prognostic factors were examined. Penalized Cox regression was used for variable selection. Multiple imputation was used to address missingness. ResultsThree baseline characteristics populated the final model: ECOG (0, 1 or ≥2), lactate dehydrogenase>upper limit of normal, and derived neutrophil to lymphocyte ratio ≥3. Patients were parsed into 3 risk groups; favorable (n=146, risk score 0-1), intermediate (n=101, risk score 2) and poor (n=95, risk score ≥3). The c-statistic of the training cohort was 0.702 and 0.694 after bootstrapping. The test cohort c-statistic was 0.664.The median OS for favorable, intermediate and poor LITE risk were; 28.3 months, 9.1 months and 2.1 months respectively. Improving LITE risk group was associated with improved OS, intermediate vs favorable HR 2.08 (95%CI 1.46-2.97, P < .001); poor vs favorable HR 5.21 (95%CI 3.69-7.34, P < .001). ConclusionA simple prognostic model, utilizing accessible clinical data, can discriminate survival outcomes in patients with advanced NSCLC.