Recommended Dose For Expansion Research Articles

Abstract PO3-18-06: First-in-human phase 1A study of RGT-419B, a next generation CDK4 inhibitor, in patients (pts) with hormone receptor positive (HR+) HER2- advanced/metastatic breast cancer (ABC) who progressed on prior CDK4/6 inhibitors (CDK4/6i)

Abstract Introduction: RGT-419B is a novel next generation CDK inhibitor. It has high potency against CDK4 with additional activity against CDK2 and selectivity against CDK6 to overcome resistance and reduce hematologic toxicity. In addition to anti-cancer activity in preclinical breast cancer models that are resistant to approved CDK4/6 inhibitors, we report the interim data from the first-in-human, multicenter trial of RGT-419B as a single agent in post-menopausal pts with HR+ HER2- ABC. Methods: Eligible pts received ≥2 lines of treatment and progressed on endocrine therapy (ET) and at least 1 line of an FDA approved CDK4/6i. Prior treatments of fulvestrant, other targeted agents and/or chemotherapy were allowed. Dose escalation of RGT-419B as oral (PO) monotherapy was administered in continuous 28-day cycles in 4 cohorts (25, 75,150 mg QD and 150 mg BID). A standard 3+3 design was employed to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). The primary objective was to assess safety and tolerability. The secondary objectives included pharmacokinetic (PK) assessment and exploratory efficacy. Results: At time of abstract submission, 12 eligible post-menopausal pts with HR+/HER2- ABC received RGT-419B. The median age was 64.8y (range 50-80y). All had prior palbociclib + ET (2 pts had abemaciclib or ribociclib after palbociclib); a majority received fulvestrant (67%) and prior chemotherapy (50%). Across the 4 cohorts (12 pts), the most observed treatment-emergent adverse events (TEAEs; all causality) with RGT-419B were nausea, reduced white blood cell counts (neutrophils and/or lymphocytes) and diarrhea. At data cutoff on June 30th 2023, there have been no CTCAE Grade 3 or higher treatment related AE (TRAEs). No ocular toxicity has been observed. No pts have discontinued treatment due to RGT-419B toxicity. Preliminary PK analyses for RGT-419B showed a dose-dependent increase of exposure at steady state with long half-life. Tumor assessments (RECIST v1.1) of pts in the first 3 cohorts treated with RGT-419B monotherapy (25-150 mg QD) showed partial responses in 2 pts (7 pts with measurable disease), 28.6% partial response (PR) (RECIST v. 1.1) and clinical benefit rate (CBR) 44%. Updated safety, PK and efficacy data will be presented. Conclusions: RGT-419B, with potent selective CDK4 activity, CDK2 activity and CDK6 selectivity, demonstrated a favorable safety and PK profile in an ongoing phase I study, with no grade 3 or higher TRAEs observed thus far. RGT-419B administered as once daily monotherapy also demonstrated preliminary evidence of efficacy as well. Dose expansions of RGT-419B as a single agent and in combination with ET in pts with HR+/HER2- ABC following prior CDK4/6i progression are planned. Citation Format: Seth Wander, Dave Valacer, Richard Zuniga, Heather Yeckes-Rodin, Christopher Perkins, Lisa Ge, Lili Yao, Jing Lin, Dawn Begley, Feifei Sun, Andie Zheng, Jing Han, Zhi (Julie) Xie, Aditya Bardia, Kevin Kalinsky. First-in-human phase 1A study of RGT-419B, a next generation CDK4 inhibitor, in patients (pts) with hormone receptor positive (HR+) HER2- advanced/metastatic breast cancer (ABC) who progressed on prior CDK4/6 inhibitors (CDK4/6i) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-06.

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity from a Phase I Study of Simlukafusp Alfa (FAP-IL2v) in Advanced/Metastatic Solid Tumors.

Simlukafusp alfa (FAP-IL2v), a tumor-targeted immunocytokine, comprising an interleukin-2 variant moiety with abolished CD25 binding fused to human immunoglobulin G1, is directed against fibroblast activation protein-α. This phase I, open-label, multicenter, dose-escalation and extension study (NCT02627274) evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of FAP-IL2v in patients with advanced/metastatic solid tumors. Participants received FAP-IL2v intravenously once weekly. Dose escalation started at 5 mg; flat dosing (≤25 mg) and intra-participant up-titration regimens (15/20 mg, 20/25 mg, 20/20/35 mg, 20/35/35 mg) were evaluated. Primary objectives were dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended expansion dose, and pharmacokinetics. Sixty-one participants were enrolled. DLTs included fatigue (flat dose 20 mg: n = 1), asthenia (25 mg: n = 1), drug-induced liver injury (up-titration regimen 20/25 mg: n = 1), transaminase increase (20/25 mg: n = 1), and pneumonia (20/35/35 mg: n = 1). Up-titration regimen 15/20 mg was the MTD and was selected as the recommended expansion dose. Increases in peripheral blood absolute immune cell counts were seen for all tested doses (natural killer cells, 13-fold; CD4+ T cells [including Tregs], 2-fold; CD8+ T cells, 3.5-fold), but without any percentage change in Tregs. Clinical activity was observed from 5 mg (objective response rate, 5.1% [n = 3]; disease control rate, 27.1% [n = 16]). Responses were durable (n = 3; 2.8 [censored], 6.3, and 43.4 months). FAP-IL2v had a manageable safety profile and showed initial signs of antitumor activity in advanced/metastatic solid tumors.

Abstract CT184: First-in-human trial of TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa (BA) in patients (pts) with advanced solid unresectable tumors

Abstract Introduction: M6223 is an intravenous (IV), fully human, antagonistic, anti-TIGIT antibody with an Fc-mediated effector region. In preclinical studies, M6223 combined with BA (a bifunctional fusion protein that simultaneously targets the TGF-β and PD-(L)1 pathways) enhanced antitumor efficacy compared to either agent alone. Methods: This first-in-human, dose escalation study of M6223 as monotherapy (M6223; Part 1A) or in combination with BA (M6223+BA; Part 1B) included pts with advanced solid tumors (aged ≥18 years, ECOG PS ≤1) (NCT04457778). In Part 1A, pts received M6223 at 10 mg, 30 mg, 100 mg, 300 mg, 900 mg, 1600 mg, 2400 mg (all Q2W) or M6223 2400 mg Q3W. In Part 1B, pts received M6223 at 300 mg, 900 mg, or 1600 mg, all in combination with BA 1200 mg (both Q2W, IV). Dose escalation decisions by the Safety Monitoring Committee were assisted by a Bayesian 2-parameter logistic regression model. Primary objectives were safety, tolerability, maximum tolerated dose (MTD), and recommended dose for expansion (RDE). Additional objectives included pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity. Results: At final analysis, 40 pts (21 male, age range 24-79 years) had received M6223 (Q2W: n=32; Q3W: n=8), and 18 pts (7 male, age range 34-80 years) had received M6223+BA. Overall, two dose-limiting toxicities were observed: a grade 3 adrenal insufficiency (M6223, 900 mg) and a grade 3 anemia (M6223+BA, 300 mg; unrelated to M6223). In the M6223 group, grade ≥3 TEAEs were observed in 14 (35.0%) pts and M6223-related grade ≥3 TEAEs in 2 (5.0%) pts. In the M6223+BA group, grade ≥3 TEAEs were observed in 14 (77.8%) pts and M6223-related grade ≥3 TEAEs in 4 (22.2%) pts. No MTD was identified. RDEs were 1600 mg Q2W or 2400 mg Q3W for M6223 monotherapy, and 1600 mg+1200 mg Q2W for M6223+BA. Half-life for the two monotherapy RDEs were 9.0 and 14.6 days, respectively, with moderate accumulation at the selected RDEs. Linear PK was observed for M6223 at 100-2400 mg Q2W and at 2400 mg Q3W; co-administration with BA did not change the PK profile of M6223. PD analyses in blood showed full and sustained TIGIT target occupancy, and depletion of suppressive Tregs at M6223 ≥900 mg. Paired biopsies in the M6223 group (900 mg Q2W, 1600 mg Q2W, 2400 mg Q3W; n=12) showed a trend of decrease in TIGIT+ and increase in CD226+ cells. Median overall survival was 7.6 months (95% CI: 4.9, 12.0) and median progression-free survival was 1.4 months (95% CI: 1.3, 1.8). No pt achieved an objective response (per RECIST v1.1); stable disease as the best response was observed in 13 (32.5%) pts in M6223 and 5 (27.8%) pts in M6223+BA. Conclusion: M6223 monotherapy and in combination with BA had a manageable safety profile, and RDEs for both mono- and combination therapy were defined. Further evaluation of M6223 is ongoing in combination with PD-L1 inhibitor avelumab (JAVELIN Bladder Medley; NCT05327530). Citation Format: Aung Naing, Meredith McKean, Anthony Tolcher, Anja Victor, Ping Hu, Keyvan Tadjalli Mehr, Thomas Kitzing, Daniel Holland, Emilia Richter, Lillian Siu. First-in-human trial of TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa (BA) in patients (pts) with advanced solid unresectable tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT184.

Abstract CT259: Results from monotherapy dose escalation of MDNA11, a long-acting IL-2 superkine, in a phase 1/2 trial show evidence of single-agent activity in advanced solid tumors

Abstract Background: MDNA11 is an albumin-fused ‘beta-enhanced not-alpha’ IL-2 agonist engineered to preferentially expand and activate CD8+ T and NK cells with minimal impact on Tregs. The ABILITY-1 (A Beta-only IL-2 ImmunoTherapY) is a global Phase 1/2 study evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of MDNA11, both as single agent and in combination with a PD-1 inhibitor, in pre-treated patients with advanced solid tumors. Method: The ABILITY-1 study (NCT05086692) comprises monotherapy dose escalation/evaluation with a modified 3+3 design (enrollment complete); monotherapy dose expansion (enrolling); combination with pembrolizumab dose escalation (enrolling) followed by combination expansion. Thirty participants were enrolled in the monotherapy cohorts (3, 10, 30, 60, 90, and 120 μg/kg, IV, Q2W): 23 in dose escalation and 7 in dose evaluation. To enhance tolerability, step-up dosing with 2 or 3 priming doses was implemented starting at 60 μg/kg. Primary endpoints were incidence and severity of adverse events (AEs) and secondary endpoints included PK, PD, and tumor response (RECIST 1.1 and iRECIST). Results: As of December 22, 2023, 30 patients were enrolled in dose-escalation/evaluation, comprising 16 melanoma, 3 NSCLC, 3 PDAC, 2 RCC, 2 sarcoma, 2 ovarian cancer, 1 tonsillar squamous cell carcinoma and 1 gastro-esophageal adenocarcinoma. No dose-limiting toxicities (DLTs) were observed. Most common treatment related AEs were infusion-related reactions (53.3%), primarily grade 1-2, encompassing pyrexia (43.3%), nausea (33.3%), chills (33.3%), hypotension (30%), and fatigue (26.6%) that resolved within 48-72 hours. PK analysis showed sustained dose-dependent increase in serum concentration of MDNA11 with repeat doses. PD evaluation showed robust and durable dose-dependent increase in lymphocyte counts without eosinophilia. Immune effector cells, particularly CD8+ T cells, showed durable expansion with evidence of activation markers (CD25, ICOS and OX40) peaking at the 90 μg/kg dose. Single-agent anti-tumor activity was evident among 26 evaluable patients with confirmed partial responses (PRs) in a PDAC (MSI-H) patient (60 μg/kg cohort) and a melanoma patient (90 μg/kg cohort) as well as 8 (30.7%) stable disease (SD) including 3 melanoma patients with durable SD (>6 months, >8 months, >1.5 years). Based on the combined safety, PK, PD and preliminary anti-tumor activity, a recommended dose for expansion (RDE) of 90 μg/kg (preceded by priming doses of 30 and 60 μg/kg; Q2W) was selected for the ongoing monotherapy dose expansion of the ABILITY-1 study. Conclusions: MDNA11 was well-tolerated with no DLTs observed at all dose levels up to 120 μg/kg. With study currently ongoing, single agent clinical activity was evident with an ORR of 7.7% and Clinical Benefit Rate (CBR) of 19.2% (2 PRs + 3 SDs > 6 months) in dose escalation to date. Monotherapy dose expansion at 90 μg/kg and combination dose escalation with pembrolizumab are enrolling. Citation Format: Victoria G. Atkinson, Jesus F. Antras, Philippe Bedard, Warren Brenner, Jacqueline Brown, Charlotte R. Lemech, Peter Lloyd, Kim Margolin, Matthen Mathew, John J. Park, Sajeve Thomas, Przemyslaw Twardowski, Humphrey Gardner, Amy Prawira, Melissa Coello, Walead Ebrahimimizadeh, Minh D. To, Rosemina Merchant, Sudhir Madduri Karanam, Arash Yavari, Lillian L. Siu, Hussein A. Tawbi, Paolo A. Ascierto. Results from monotherapy dose escalation of MDNA11, a long-acting IL-2 superkine, in a phase 1/2 trial show evidence of single-agent activity in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT259.

Abstract CT090: DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas

Abstract Background Neuroendocrine carcinomas (NECs) have limited treatment options. DLL3 is highly expressed in NECs and is a promising treatment target. In an ongoing phase 1 trial (NCT04429087), BI 764532, a DLL3/CD3 IgG-like T-cell engager, was tolerable with clinical activity in patients with DLL3-positive (+) tumors, including those with small cell lung cancer and other NECs. Purpose DAREON™-7 (NCT06132113), a phase 1, open-label, dose-escalation (Part A) and dose-expansion (Part B) trial, aims to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDE)/recommended phase 2 dose (RP2D), and the safety and efficacy of BI 764532 + platinum and etoposide in patients with DLL3+ NEC. Experimental design Part A: ~25 patients will receive intravenous BI 764532 (target dose after step-in dosing) plus carboplatin/etoposide (CE) until intolerable toxicity, or progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or for a maximum of 36 months. BI 764532 dose escalation will be guided by a Bayesian logistic regression model with overdose control. Part B: 2 cohorts (~15 patients each) will receive BI 764532 at the RDE/RP2D + CE or cisplatin/etoposide (carboplatin/etoposide or cisplatin/etoposide are the most-used standard of care [SOC] regimens). Key inclusion criteria: patients must have no prior systemic treatment for DLL3+ locally advanced or metastatic NEC (extrapulmonary or unknown primary) or large cell NEC of the lung except for 1 cycle of standard platinum/etoposide regimen as first-line treatment prior to entering the treatment period of the trial; patients with localized NEC or resectable disease who received prior adjuvant therapy can participate in the trial if they experienced a treatment-free interval of >6 months prior to the diagnosis of metastatic disease; and patients must have at least 1 measurable lesion as defined per RECIST v1.1. Patients must be adequate candidates to receive platinum/etoposide as the SOC treatment. Primary endpoints: occurrence of dose-limiting toxicities (DLTs) in the MTD evaluation (Part A) and on-treatment (Part B) periods. Secondary endpoints: occurrence of DLTs and adverse events during the on-treatment period (Part B), and efficacy measured by objective response and duration of response (Part B). Enrollment is ongoing. Citation Format: Jaume Capdevila, Timon Vandamme, Patricia Niccoli, Saori Mishima, Ken Kato, Yiyuan Ma, Ping Sun, Lijiang Geng, Ulrich M. Lauer. DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT090.

Abstract CT162: Trial in progress: A phase I, open-label, multicenter study of ZL-1218, an anti-CCR8 IgG1, as a single agent and as combination therapy with anti-PD-1 antibody to evaluate the safety, tolerability, and pharmacokinetics in subjects with advanced solid tumor

Abstract Background ZL-1218 is an anti-chemokine receptor 8 (CCR8) humanized IgG1 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. CCR8 demonstrates a preferential expression in tumor-associated Tregs over peripheral Tregs. Thus, targeting CCR8 may allow for specific depletion of intratumoral Tregs without impacting peripheral Tregs/other immune cells. ZL-1218 is intended to decrease the intratumoral Tregs by binding to both high- and low-expressing CCR8+ cells and eliciting potent ADCC activity. ZL-1218 blocked CCR8 ligand CCL1 from binding to CCR8, and reduced Treg recruitment by blocking chemotaxis of CCR8+ cells (unpublished data). Additionally, ZL-1218 demonstrated enhanced antitumor activity in preclinical models in combination with anti-PD-1. Methods This is a Phase I study of ZL-1218 as a single agent and in combination with pembrolizumab (P) to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity in subjects with advanced solid tumor malignancies. The study consists of Part 1 Dose Escalation and Part 2 Cohort Expansion. In Part 1, subjects will be treated with escalating doses of ZL-1218 alone and in combination with a fixed dose of P to identify the maximum tolerated dose (MTD) and/or the recommended expansion dose (RD). The Bayesian optimal interval (BOIN) design is used and adopted with overdose control. Upon progression in the single agent group, a subject may enroll into combination therapy of ZL-1218 with P. Subjects will start at their respective single agent dose or the cleared combination dose level, whichever is lower. Part 2 will explore the combination with pembrolizumab in subjects with selected tumor types, with or without prior CPI therapy. Major inclusion criteria include: (1) Subjects must have histologically confirmed and documented diagnosis of locally advanced unresectable/metastatic advanced solid tumor that is refractory/intolerant to standard treatment, or for which no standard treatment exists, and no greater than 3 prior lines of therapy in the relapse/refractory setting (2). Subjects must have at least one target lesion as defined by RECIST v1.1 on CT, PET/CT, or MRI scan. (3) Subjects must have a site of disease which is not previously irradiated and is safe and amenable to biopsy. Major exclusion criteria include: (1) Prior exposure to CCR8 inhibitor, or severe hypersensitivity (≥ Grade 3) to P and/or any of its excipients. (2) Subjects with symptomatic or uncontrolled brain metastasis requiring concurrent treatment, impaired major organ functions, active autoimmune disease, or active infections. Part 1 Dose Escalation is ongoing in the US and EU. Citation Format: Elena Garralda, Valentina Boni, David Vincente Baz, Arvind Chaudhry, Ignacio Gil Bazo, Martin Gutierrez, Jyoti Malhotra, Casal Guzman Alonso, Valentina Gambardella, Michael Chisamore, Renke Zhou, Maria Tea, Deborah Doroshow. Trial in progress: A phase I, open-label, multicenter study of ZL-1218, an anti-CCR8 IgG1, as a single agent and as combination therapy with anti-PD-1 antibody to evaluate the safety, tolerability, and pharmacokinetics in subjects with advanced solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT162.

First-in-Human Study of the Ataxia Telangiectasia and Rad3-Related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors.

Tuvusertib (M1774) is a potent, selective, orally administered ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. This first-in-human study (NCT04170153) evaluated safety, tolerability, maximum tolerated dose (MTD), recommended dose for expansion (RDE), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of tuvusertib monotherapy. Ascending tuvusertib doses were evaluated in 55 patients with metastatic or locally advanced unresectable solid tumors. A safety monitoring committee determined dose escalation based on PK, PD, and safety data guided by a Bayesian 2-parameter logistic regression model. Molecular responses (MR) were assessed in circulating tumor DNA samples. Most common grade ≥3 treatment-emergent adverse events were anemia (36%), neutropenia, and lymphopenia (both 7%). Eleven patients experienced dose-limiting toxicities, most commonly grade 2 (n = 2) or 3 (n = 8) anemia. No persistent effects on blood immune cell populations were observed. The RDE was 180 mg tuvusertib QD (once daily), 2 weeks on/1 week off treatment, which was better tolerated than the MTD (180 mg QD continuously). Tuvusertib median time to peak plasma concentration ranged from 0.5 to 3.5 hours and mean elimination half-life from 1.2 to 5.6 hours. Exposure-related PD analysis suggested maximum target engagement at ≥130 mg tuvusertib QD. Tuvusertib induced frequent MRs in the predicted efficacious dose range; MRs were enriched in patients with radiological disease stabilization, and complete MRs were detected for mutations in ARID1A, ATRX, and DAXX. One patient with platinum- and PARP inhibitor-resistant BRCA wild-type ovarian cancer achieved an unconfirmed RECIST v1.1 partial response. Tuvusertib demonstrated manageable safety and exposure-related target engagement. Further clinical evaluation of tuvusertib is ongoing.

Abstract C162: Assessment of the potential for QTc prolongation by the investigational ATR inhibitor tuvusertib in patients with advanced solid tumors using integrated nonclinical and clinical assessments

Abstract Background: Tuvusertib (M1774) is a potent, selective, orally administered inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR) with demonstrated antitumor activity in preclinical models. Tuvusertib is currently being evaluated in phase I and II trials as monotherapy and in combination with other DNA damage response inhibitors and immune checkpoint inhibitors. Assessment of an investigational agent’s potential to cause delayed ventricular repolarization (QTc prolongation) is essential in drug development. QTc prolongation is assessed using nonclinical studies and concentration-QTc (c-QTC) analysis of phase I clinical data across a wide dose range and/or a thorough QT/QTc (TQT) clinical study. Here, we assess tuvusertib’s potential to cause QTc prolongation by integrating nonclinical evaluations and clinical c-QTc analyses. Methods: Nonclinical evaluations included in vitro binding of tuvusertib to the ether-a-go-go-related gene (hERG) channel and telemetry of tuvusertib in male beagle dogs and minipigs. Pharmacokinetics-time-matched triplicate electrocardiograms were collected in patients with advanced solid tumors from the first-in-human (FIH) trial (NCT04170153) for tuvusertib 5−270 mg QD along with intermittent dosing regimens. Based on exploratory analyses, a linear mixed-effect model (Garnett C, et al. J Pharmacokinet Pharmacodyn 2018;45:383–97) was chosen to describe the relationship between tuvusertib plasma concentrations and selected heart rate (HR)-corrected QT using the Fridericia correction (QTcF). Results: In vitro hERG channel binding potency for tuvusertib 0.3–10.0 µM was calculated with a half-maximal inhibitory concentration (IC50) of 2.8 µM. Nonclinical telemetry studies showed no treatment effect on QT/QTc prolongation at doses of up to 3 mg/kg in male beagle dogs and minipigs. c-QTc analyses in 55 patients from the FIH trial revealed a small positive slope of drug effect (slope estimate [95% CI] = 0.00244 [0.000708, 0.00417] ms/(ng/mL)). This increase in model-predicted QTcF from baseline was not considered to be clinically meaningful (<20 ms threshold) at steady-state maximum concentration (Cmax) achieved with the recommended dose for expansion (RDE) of 180 mg QD 2w on/1w off (mean [upper bound of 95% CI] = 3.4 [5.5] ms) and up to 3 times the RDE (10.3 [16.5] ms). Concentration-HR modeling found no relationship between tuvusertib concentration and HR, suggesting the absence of an effect. Conclusions: Integrating nonclinical and clinical assessments revealed no clinically meaningful effect of tuvusertib on QTc at concentrations achieved with the RDE and up to 3-times higher concentrations. Citation Format: Jatinder Kaur Mukker, Timothy A. Yap, Anthony W. Tolcher, Johann S. de Bono, Ruth Plummer, Rohan Kulkarni, Han Witjes, Paul Matthias Diderichsen, Axel Krebs-Brown, Rainer Strotmann, Zoltan Szucs, Ioannis Gounaris, Karthik Venkatakrishnan. Assessment of the potential for QTc prolongation by the investigational ATR inhibitor tuvusertib in patients with advanced solid tumors using integrated nonclinical and clinical assessments [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C162.

Abstract B114: A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies

Abstract Background:KAZ954 (KAZ), a humanized immunoglobulin G1 monoclonal antibody, is a potent, selective inhibitor of anti-ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2). Preclinical data show that KAZ blocks the hydrolysis of adenosine triphosphate, enhances immune activation in the tumor microenvironment, and augments the efficacy of PDR001 (PDR, anti-PD-1), and NIR178 (NIR, adenosine A2aR inhibitor). Methods: This is an open-label, multicenter, dose-escalation (ESC)/expansion study (NCT04237649). We present the dose-ESC results of KAZ single-agent (SA) and with PDR or NIR in patients (pts) with advanced gastrointestinal (GI) malignancies. Dose ESC was guided by Bayesian logistic regression models and comprised 3 arms: (1) SA KAZ administered intravenously (IV) at 30, 50, 100, and 150 mg biweekly (Q2W) flat dosing; KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose; (2) KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose with PDR 400 mg IV every 4 weeks; and (3) KAZ 100 mg priming dose followed by 300 and 600 mg experimental dose with NIR 160 and 240 mg twice daily orally. Primary objectives were to evaluate safety and tolerability and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Secondary objectives were to assess antitumor activity and pharmacokinetics (PK). Tumor biopsies and blood samples were taken for biomarker analysis. Results: As of March 20, 2023, 77 pts were enrolled in ESC KAZ (n=43), KAZ+PDR (n=18), and KAZ+NIR (n=16) arms. Tumor types enrolled were microsatellite-stable colorectal cancer (37, 48%), pancreatic ductal adenocarcinoma (27, 35%), cholangiocarcinoma (10, 13%), and esophageal cancer (3, 4%). At data cutoff, 43 (100%), 15 (83.3%), and 11 (68.8%) pts discontinued treatment, and treatment-related adverse events (TRAEs) were reported in 37 (86%), 12 (66.7%), and 13 (81.3%) pts in KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. KAZ had an acceptable and manageable safety profile. Given the occurrence of cytokine release syndrome (CRS) observed with cycle 1 day 1 (C1D1), prophylactic premedication with acetaminophen, antihistamine, and corticosteroid, together with a priming dose on C1D1, was established as the recommended regimen to administer KAZ. Grade ≥3 TRAEs were reported in 9 pts(20.9%) in KAZ, most commonly CRS and decreased lymphocyte count (n=2 each); 7 pts(38.9%) in KAZ+PDR, most commonly lymphopenia and increased aspartate aminotransferase (n=2 each); and 2 pts(12.5%) in KAZ+NIR (asthenia and lymphopenia [n=1 each]). No MTDs were reached in any treatment arm explored. Although no objective responses were observed, 12(27.9%), 2(11.1%), and 2(12.5%) pts showed stable disease in the KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. Conclusions: KAZ was considered to be safe and well tolerated at all doses, and PK/PD analysis suggest effective ENTPD2 inhibition from a dose range of 150 to 1200 mg Q2W. Although a biologically active dose range was established, further dose-exploration studies are required to establish an RDE. Citation Format: Devalingam Mahalingam, Chia-Chi Lin, Philippe L. Bedard, Massimo Di Nicola, Zev Wainberg, Patricia LoRusso, Shubham Pant, Brigette B.Y. Ma, Wei-Peng Yong, Mia C. Weiss, Alessio Amatu, Kentaro Yamazaki, Lisa Nardi, Jong Bong Lee, Mike Roy, Anhthu Dang, Shu Yang, Bernard Pereira, Javier A. Otero, Teresa Macarulla. A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B114.

First-in-Human Dose-Escalation and -Expansion Trial with Sirpα Antibody BYON4228 in R/R B-Cell NHL

Introduction: Blocking of the immune checkpoint CD47-SIRPα promotes myeloid cell-mediated innate as well as adaptive immunity towards tumor cells. Antibodies in development are either directed against CD47 or SIRPα and in combination with tumor-targeting antibodies, checkpoint inhibitors, chemotherapeutics or other agents. The humanized SIRPα antibody BYON4228 (van Helden et al (2023) JITC 11: e006567) has been designed with three distinguishing characteristics compared to other CD47- or SIRPα-directed therapies which makes BYON4228 potentially best-in-class: 1.High specificity for SIRPα and no binding to SIRPγ on T cells which enables maximal contribution of T cells and therefore maximal anti-tumor immune response; 2.Silenced Fc backbone (IgG1-L234A/L235) which potentially results in reduced toxicity as confirmed in nonclinical studies showing no anemia or neutropenia in monkey; 3.Binding to both allelic forms of SIRPα (α 1 and α BIT) covering a broad patient population. Phase 1 clinical trial design: BYON4228.001 (NCT05737628) is the first-in-human clinical trial of BYON4228, in combination with rituximab, in relapsed or refractory (R/R) B-cell Non-Hodgkin's lymphoma (NHL). Part 1 (dose escalation) evaluates the safety, tolerability and Pharmacokinetics (PK) of, and receptor occupancy by BYON4228 to determine the maximum tolerated dose (MTD) or optimal biological dose (OBD) if the MTD is not reached, and recommended dose for expansion (RDE). A 28-day flat dose escalation schedule starting at 7 mg will be followed in a standard 3+3 design. Notably, only 1 cycle BYON4228 monotherapy will be given in each patient before combining with rituximab (375 mg/m 2 first cycle weekly administration; thereafter every 4 weeks for a total of 6 cycles). In part 2 (cohort expansion) BYON4228 + rituximab combination therapy will be given from cycle 1 onwards to further evaluate safety and efficacy in up to 24 additional diffuse large B cell lymphoma (DLBCL) patients and up to 24 patients with either marginal zone lymphoma (MZL) or follicular lymphoma (FL). This trial design of only 1 cycle monotherapy and swiftly moving into combination therapy not only allows to investigate PK and safety of BYON4228 but also efficacy of combination treatment with rituximab in a relevant therapeutic setting. Enrollment is ongoing in The Netherlands, United Kingdom, Italy and Spain since June 2023. Key inclusion criteria include, for part 1: B-cell NHL expressing CD20 by immunohistochemistry (IHC) or flow cytometry, R/R to at least 2 prior lines of therapy; for part 2, cohort A: Histologically confirmed DLBCL expressing CD20 R/R to front-line therapy, or second-line salvage regimens; for part 2, cohort B: Histologically confirmed MZL or FL (Grade 1-3a) expressing CD20, R/R to at least 2 prior lines of therapy. Autologous or allogeneic hematopoietic cell transplantation and autologous CAR-T cell therapy are allowed as prior lines. Key exclusion criteria include prior treatment with CD47- or SIRPα- targeting agents at any time; other anticancer therapy including investigational agents within 2 weeks or within at least 4 times the elimination half-life; Burkitt's lymphoma; history of active auto-immune disorders, active infections or uncontrolled systemic disease. Tumor response is determined according to Lugano and LYRIC criteria. An extensive biomarker program in the peripheral blood and bone marrow is included in the trial.

PHI-101 As a Potent Next-Generation FLT3 Inhibitor, Overcome Resistances in Previously Treated Patients with FLT3-ITD or TKD Acute Myeloid Leukemia: Results of a Phase Ia/Ib Clinical Trial

Background: The FLT3 receptor is mutated in about 30% of acute myeloid leukemia (AML) patients (pts) and has proven to be an attractive therapeutic target. The most prevalent alteration is internal tandem duplication (ITD) of the juxtamembrane domain, and several FLT3 inhibitors (e.g. gilteritinib, quizartinib, midostaurin) succeddfully target this mutation. However, patients frequently relapse due to resistance to these FLT3 inhibitors after initial clinical responses, often caused by the secondary mutations observed in the kinase domain (TKD) region. PHI-101, an orally bioavailable novel small molecule, is a next-generation FLT3 inhibitor that shows a potent anti-leukemic activity in primary AML samples harboring several FLT3-resistance mutations in preclinical studies. Global Phase I clinical trials with PHI-101 (NCT04842370) are currently underway in refractory or relapsed (R/R) AML pts. Study Design and Methods: The open-label, multicenter AML clinical trial consists of phase Ia, dose-escalation, and phase Ib, dose-expansion, utilizing oral PHI-101 tablets as a single-agent with R/R AML pts. If dose-escalation concludes with no dose-limiting toxicities (DLT), dose-expansion proceeds upon recommendation from the Safety Monitoring Committee (SMC). Response assessments with PHI-101 were reported according to 2017 ELN guidelines. The variant allelic frequency of mutations of FLT3 and other AML-related mutations was analyzed using NGS with bone marrow aspirates collected from pts before and after PHI-101 treatment. Blood samples were collected to evaluate pharmacokinetics (PK) and the plasma inhibitory assay (PIA) using FLT3-mutant cell lines. Together, these assessments were considered to determine the recommended dose for expansion (RDE) in phase Ib trials. Results: Phase Ia clinical trials of PHI-101 was designed to evaluate for safety and tolerability at five dose levels ranging from 40 mg to 200 mg. A total of 13 R/R AML pts were enrolled in the phase Ia and no DLTs were reported from daily doses of PHI-101 during the 28-day cycle. The target RDE at 160 mg was determined based on several considerations, including the PIA test achieving >85% inhibition of phosphor-FLT3, all available adverse events, PK data, and recommendation by the SMC. As of May 2023, with 6 pts enrolled in phase Ib, a total of 19 pts (5 FLT3-wild type (26.3%) and 14 FLT3 mutated (73.7%)), have been treated with PHI-101. Thirteen pts (68.4%) had more than 3 prior anti-leukemic treatments. Twelve of 13 pts (92%) assessed for the leukemic blast evaluation achieved clinical responses-4 pts with composite complete remissions [CRc, including complete remission with incomplete hematological recovery (CRi) and morphological leukemia free state (MLFS)] within 1 cycle of PHI-101 treatment. Ten pts were R/R following previous treatment with other FLT3 inhibitors (gilteritinib, quizartinib, midostaurin, or HM43239). 88 % of these pts achieved clinical responses including 3 CRc and 1 partial response (PR). Notably, all 5 R/R pts after gilteritinib treatment had clinical responses that included 2 with CRc. In addition, a patient with both FLT3-ITD and TKD (D835E and N676K) mutations who was resistant to 3 different FLT3 inhibitor treatments achieved PR and continued PHI-101 treatment for 6 cycles. Among pts who received 160 mg of PHI-101, 4 pts (57.1%) responded: 2 (28.6%) achieved CRi, 1(14.3%) achieved MLFS, and 1 (14.3%) achieved PR. Conclusion: In dose-escalating phase Ia clinical trials, PHI-101 was well tolerated at all dose levels with no DLTs. Phase Ib dose-expansion trials with 160 mg daily dosing are currently ongoing. PHI-101 has delivered CRcs at 120 mg and 160 mg. In this first-in-human, phase Ia/Ib trial of PHI-101, 92% of FLT3-wild or -mutated AML pts showed clinical responses even after having previously been treated with otherFLT3 inhibitors. More notably, 100% of pts who had relapsed after prior gilteritinib treatment showed clinical responses. The data from the clinical study of PHI-101to date demonstrates significant efficacy, particularly in R/R FLT3 mutant AML pts.

First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations

BackgroundWe investigated naporafenib (LXH254), a pan-RAF kinase inhibitor, with or without spartalizumab, in patients with advanced solid tumors harboring MAPK pathway alterations. MethodsThis first-in-human phase 1 study had two dose-escalation arms: single-agent naporafenib (starting at 100 mg once-daily [QD]) and naporafenib (starting at the recommended dose/regimen)/spartalizumab (400 mg every 4 weeks). The naporafenib/spartalizumab dose-expansion part enrolled patients with KRAS-mutated non-small cell lung cancer (NSCLC) and NRAS-mutated melanoma. The primary objectives were to establish the maximum tolerated doses (MTD)/recommended doses for expansion (RDE) and evaluate tolerability and safety. ResultsA total of 142 patients were included in the naporafenib dose-escalation (n = 87), naporafenib/spartalizumab dose-escalation (n = 12) and naporafenib/spartalizumab dose-expansion (n = 43) arms. The MTD/RDE of naporafenib was 600 mg twice-daily (BID). In naporafenib escalation, five patients experienced 7 dose-limiting toxicities: decreased platelet count (1200 mg QD); neuralgia, maculopapular rash, pruritus (600 mg BID); increased blood bilirubin, hyponatremia, peripheral sensory neuropathy (800 mg BID). No DLTs occurred in the naporafenib/spartalizumab arm: the RDE was established at 400 mg BID. The most common treatment-related adverse events were rash and dermatitis acneiform (each 24.1%; naporafenib), nausea and pruritus (each 33.3%; naporafenib/spartalizumab; escalation) and rash (39.5%; naporafenib/spartalizumab; expansion). Naporafenib reduced DUSP6 expression in tumors. Two partial responses (PRs) occurred in naporafenib escalation, and 1 complete response and 3 PRs in the naporafenib/spartalizumab NRAS-mutated melanoma and KRAS-mutated NSCLC arms, respectively. ConclusionsNaporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation.

Phase I/Ib, open-label, multicenter, dose-escalation study of the anti-TGF-β monoclonal antibody, NIS793, in combination with spartalizumab in adult patients with advanced tumors

BackgroundNIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-β). This first-in-human study investigated NIS793 plus spartalizumab treatment in patients with advanced solid tumors.MethodsPatients received...

First-in-human phase I/Ib study of NIZ985, a recombinant heterodimer of IL-15 and IL-15Rα, as a single agent and in combination with spartalizumab in patients with advanced and metastatic solid tumors

BackgroundPreclinically, interleukin-15 (IL-15) monotherapy promotes antitumor immune responses, which are enhanced when IL-15 is used in combination with immune checkpoint inhibitors (ICIs). This first-in-human study investigated NIZ985, a recombinant heterodimer...

1029P Dazostinag (TAK-676) alone and in combination with pembrolizumab (pembro) in patients (pts) with advanced or metastatic solid tumors: Preliminary safety, PK/PD, and anti-tumor activity in a phase I dose escalation study supporting a recommended dose for expansion (RDE)

1029P Dazostinag (TAK-676) alone and in combination with pembrolizumab (pembro) in patients (pts) with advanced or metastatic solid tumors: Preliminary safety, PK/PD, and anti-tumor activity in a phase I dose escalation study supporting a recommended dose for expansion (RDE)

A Phase 1/2, open label dose-escalation and expansion trial of NKT2152, an orally administered HIF2α inhibitor, to investigate safety, PK, PD and clinical activity in patients with advanced ccRCC

Abstract Background: Inactivation of the VHL gene leading to aberrant HIF2α activity is nearly universal in clear cell renal cell carcinoma (ccRCC). NKT2152 is a novel, potent, selective orally available HIF2α inhibitor optimized for enhanced PK exposure and sustained target inhibition which has demonstrated robust activity in both ccRCC cell line-derived and patient-derived xenograft RCC and other solid tumor models. This is a Phase 1/2 open label, multicenter, first in human study of NKT2152 in adults with advanced clear cell renal cell carcinoma (ccRCC) (NCT05119335). In Phase 1, up to ~60 patients will be enrolled according to a 3 + 3 design with backfill as permitted by the Safety Review Committee. The primary objective of phase 1 is to determine the recommended dose for expansion (RDE) based on the totality of clinical data. Phase 2 will enroll ~50 additional patients with the primary objective of determining investigator-assessed by RECIST v1.1. Key secondary objectives include safety, tolerability, PD effects, progression free survival, duration of response, and disease control rate. Exploratory objectives include evaluation of biomarkers predictive of tumor response. Adults who have advanced ccRCC without available standard therapy), ECOG PS 0-2, with measurable disease per RECIST 1.1 are eligible. Patients who have had prior HIF2a inhibitors, require supplemental oxygen, and with significant cardiac disease are excluded. Tumor assessments by CT or MRI are conducted every 8 weeks until 48 weeks, then every 12 weeks thereafter. Adverse events will be monitored and graded in severity using CTCAE v5.0. The Phase 1 study is currently actively accruing in the United States with Phase 2 dose expansion anticipated to start in Q3, 2023.

First-in-human phase 1 study of pimicotinib (ABSK021), a CSF-1R inhibitor, in patients with advanced solid tumors.

3100 Background: Colony-stimulating factor 1 (CSF-1) pathway is involved in the development of various types of cancer. Pimicotinib is an orally available, selective, potent small molecule CSF-1R inhibitor with significant pre-clinical anti-tumor activity. Here we present the results of the phase 1 trial. Methods: The escalation part employed a 3+3 design with a starting dose of 25 mg QD (28-day/ cycle) to determine the maximum tolerated dose (MTD) and the recommended dose for expansion (RDE). Additional pts with selected tumor types including pancreatic carcinoma, triple-negative breast cancer, lung cancer, and sarcoma were treated at RDE in the expansion part for further evaluation. Tenosynovial giant cell tumor (TGCT) cohorts were analyzed and reported separately. Results: As of December 31, 2022, 74 pts received at least one dose of pimicotinib at 25 mg (n=6), 50 mg (n=58), 75 mg (n=8), or 100 mg (n=2) QD. respectively. Median age was 59 y; 68.9% were female; 47.3% were white, 33.8% were Asian and 18.9% were African American. 74.3% were ECOG PS 1; 85.1% had metastasis; 67.6% had ≥3 lines of prior systemic anti-tumor therapies. Median duration of treatment was 49.5 days (range 4-377). Treatment-related adverse events (TRAEs), Grade ≥3 TRAEs, and serious TRAEs occurred in 74.3%, 21.6%, and 4.1% of pts, respectively. The most common TRAEs (≥20%) were serum enzyme elevations, including CPK, AST and LDH, which were all believed to be pimicotinib MOA related, with CPK increase (14.9%) being the only Grade ≥3 TRAE reported in ≥10% of pts. 3 pts (4.1%) reported serious TRAEs of ascites, blood bilirubin increase, and vaginal hemorrhage. After single and multiple dosing, pimicotinib plasma exposure increased slightly less than dose proportion. The rapid oral absorption (median tmax of 0.87 - 1.52 hrs) with moderate terminal t1/2 (mean t1/2 ranges: 43.6 - 63.5 hrs) suggested sustained drug exposure was achieved with a once daily dosing schedule. No dose adjustment was needed based on tested covariates including weight, age and race. Pimicotinib treatment led to a more than 85% reduction of non-classical monocytes (NCM) across all dose levels. Plasma CSF-1 levels were significantly increased from 25mg QD to 50mg QD and reached a plateau at 50mg QD, with ~40-fold maximal induction. Reduced CD163+ macrophages in skin and tumor tissues were seen at 50mg QD. All tested doses showed adequate inhibition of NCM, and CSF-1 change showed a positive correlation with plasma pimicotinib concentration. The MTD and RDE were determined as 75 mg QD and 50 mg QD. Conclusions: Tolerable safety profile and favorable PK/PD properties supported pimicotinib to be further evaluated in advanced solid tumors, including combinations. Clinical trial information: NCT04192344 .

First-in-human phase 1/2a study of a potent and novel CDK2-selective inhibitor PF-07104091 in patients (pts) with advanced solid tumors, enriched for CDK4/6 inhibitor resistant HR+/HER2- breast cancer.

3010 Background: PF-07104091 is a novel CDK2-selective inhibitor under investigation in pts with selected advanced or metastatic solid tumors. We present the first disclosure of data from the first-in-human, multicenter, phase 1 study of PF-07104091 monotherapy (NCT04553133). Methods: Pts with HR+/HER2- advanced/metastatic breast cancer (mBC) who received ≥ 2 lines of treatment for mBC including prior endocrine therapy (ET) + CDK4/6 inhibitors (CDK4/6i), and pts with other solid tumors, were included. Prior therapy with fulvestrant and chemotherapy was allowed for pts with mBC. PF-07104091 (75-500 mg) was given twice daily (BID) orally in 28-day cycles, following Bayesian design with overdose control, to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics and preliminary anti-tumor activity. Results: At data cut off (Aug 23, 2022), 35 pts with advanced solid tumors (n = 29 mBC) with median age 62y (range 32-80y), median 4 lines of prior systemic therapy (range 1–12) and ECOG PS 0 (20% pts) or 1 were enrolled. Of 29 pts with mBC, all had prior CDK4/6i, 25 (86.2%) prior fulvestrant, and 21 (72.4%) prior chemotherapy. Treatment-emergent adverse events (TEAEs) were observed in 34 pts (97.1%; 20 [57.1%] grade [G] ≥ 3). The most frequent TEAEs (all G≤3) were nausea (77.1%; 14.3% G3), diarrhea (48.6%; 8.6% G3), vomiting (48.6%; 2.9% G3), fatigue (45.7%; 20.0% G3) and anemia (45.7%; 8.6% G3). Dose-limiting toxicity occurred in 5 pts: 1 pt (G3 fatigue) at 300 mg BID; 2 pts (1 G3 nausea and G3 anorexia, 1 G3 nausea) at 375 mg BID, and 2 pts (1 G3 fatigue and 1 G3 diarrhea) at 500 mg BID. Steady-state PF-07104091 plasma exposures increased proportionally with dose. A trend of early decrease in ctDNA was observed. Further pharmacodynamic studies are ongoing. PF-07104091 300 mg BID was identified as the MTD and selected as the monotherapy RDE. Among 16 response evaluable mBC pts (all prior CDK4/6i+ET) with measurable disease at baseline, confirmed RECIST v1.1 partial responses were observed in 3 (18.8 %) pts (2 pts with duration of response > 6 months and 1 ongoing at data cut off), and stable disease in 6 (37.5%) pts. Disease control rate was 61.5% in mBC pts (response evaluable set, 95% CI: 40.6, 79.8). Conclusions: Treatment with PF-07104091 monotherapy was generally well tolerated and showed antitumor activity in heavily pretreated HR+ HER2- mBC pts who progressed on prior CDK4/6i. Dose expansions of PF-07104091 are ongoing as monotherapy in pts with ovarian cancer and in combination with fulvestrant in pts with breast cancer. Clinical trial information: NCT04553133 .

A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients (pts) with solid tumors: Safety and efficacy in patients with dedifferentiated liposarcoma (DDLPS).

11554 Background: Inactivation of p53 is a key mechanism which promotes tumor survival and proliferation. p53 inactivation can be due to mutations in TP53 or downregulation of wild-type (wt) p53 by the key negative regulator mouse double-minute 2 (MDM2). BI 907828 is a highly potent MDM2–p53 antagonist which has demonstrated preclinical antitumor activity, particularly in TP53-wt MDM2-amplified DDLPS models. In this phase I study (NCT03449381), BI 907828 monotherapy is being evaluated in pts with advanced solid tumors, including DDLPS. During dose escalation (phase Ia), BI 907828 had a manageable safety profile and the selected recommended dose for expansion (RDE) was 45 mg q3w. Here we report safety data in all pts who received the RDE of 45 mg q3w and present efficacy data in the subgroup of pts with DDLPS. Methods: In Phase Ia, pts received one of two BI 907828 dosing schedules: Arm A, day 1 of 21-day cycles (q3w); Arm B, days 1 and 8 of 28-day cycles. During Phase Ib (dose expansion), pts were enrolled to Cohort 1 ( TP53wt, MDM2-amplified sarcoma) or Cohort 2 (other TP53wt, MDM2-amplified solid tumors). Here we focus on Cohort 1 (received BI 907828 45 mg q3w). The primary endpoint (phase Ib) was progression-free survival (PFS). Secondary endpoints/objectives included overall response rate (ORR) and grade ≥3 treatment-related AEs (TRAEs). Results: As of December 22, 2022, a total of 137 pts had been enrolled; 72 (52.6%) were male, 77 (56.2%)/59 (43.1%) had ECOG PS 0/1, and the median number of prior systemic therapies was 2 (range, 0–11). In the 73 pts who received the RDE of 45 mg q3w, the most common any-grade TRAEs were nausea (74.0%) and fatigue (61.6%). 33 (45.2%) pts had grade ≥3 TRAEs; the most common were thrombocytopenia (23.3%), neutropenia (21.9%), anemia (11.0%), and leukopenia (11.0%). 22 (30.1%) pts had TRAEs leading to dose reductions and 6 (8.2%) had TRAEs leading to treatment discontinuation. 20 pts (27.4%) had serious AEs; the most common were nausea, pulmonary embolism (each 4.1%), sepsis, small intestine obstruction, vomiting, thrombocytopenia, and pyrexia (each 2.7%). 50/73 pts who received 45 mg q3w had advanced DDLPS; all had MDM2-amplified disease. Of the 42 evaluable DDLPS pts, 8 achieved a confirmed PR (ORR 19.0%; locally assessed) and a further 29 achieved a best response of stable disease (including 2 with unconfirmed PR), giving a disease control rate of 88.1%. Preliminary median PFS was 8.1 months. Conclusions: BI 907828 demonstrated a manageable safety profile overall and encouraging preliminary efficacy was seen in pts with advanced MDM2-amplified DDLPS; Phase Ib is ongoing. BI 907828 is also being evaluated versus doxorubicin as first-line treatment for pts with advanced DDLPS in the ongoing Phase II/III Brightline-1 study (NCT05218499), for which the FDA has granted a Fast Track Designation. Clinical trial information: NCT03449381 .

Abstract CT272: Pharmacodynamic and immunophenotyping analyses of ATR inhibitor M1774 in a Phase I study in patients with solid tumors (DDRiver Solid Tumors 301)

Abstract Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor with antitumor activity in preclinical models, was evaluated in Part A1 of an open-label, single-arm study (NCT04170153) for safety, tolerability, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). M1774 monotherapy in patients with advanced solid tumors was well-tolerated and the totality of evidence, including quantitative model-based analyses, suggested the recommended dose for expansion (RDE) as 180 mg QD 2 weeks on/1 week off.1 Here, we report findings of the M1774 PD and immunophenotyping analyses. Methods: M1774 PD was explored by assessing phosphorylation by ATR of CHK1 (p-CHK1) in tumor and of H2AX (γ-H2AX) in serial blood samples, stimulated ex vivo with the radiomimetic 4-Nitroquinoline N-oxide or Dimethyl sulfoxide as control. A flow cytometry quantitative assay was used to measure γ-H2AX in the CD45+ lymphocytes fraction. The effect of M1774 on the immunophenotype was explored by flow cytometry. Blood samples were collected at baseline, 3 and 24 hours after first M1774 administration on day 1 of cycle 1 for the γ-H2AX analysis, and on Days 1 and 15 of Cycles 1 and 2 before treatment for immunophenotyping. Results: Preclinical tumor tissue-blood bridging PD analyses in a mouse model demonstrated that the inhibition of γ-H2AX in lymphocytes highly correlated with inhibition of p-CHK1 in tumor. Clinical data of γ-H2AX levels and immunophenotyping were generated for the blood samples collected from the 55 participants of Part A1 of the study. Exploratory PK-PD analysis using γ-H2AX levels 3 h post-dose on day 1 across the doses predicted target inhibition >80% for doses ≥130 mg, suggesting target engagement. The levels of ɣ-H2AX at 24 h after first dose intake were variable and mean levels rebounded to baseline value. M1774 treatment did not cause any significant and consistent change in the levels of all explored immune cell subsets at the tested dose levels, including myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cells. Conclusions: PD analyses showed that M1774 efficiently inhibited ATR at the RDE without impacting the immunophenotype. 1TA Yap, et al. Ann Oncol. 2022; 33(suppl_7): S197-S224. Citation Format: Ruth Plummer, Anthony W. Tolcher, Timothy A. Yap, Giuseppe Sessa, Jatinder K. Mukker, Annick Seithel-Keuth, Christine Hicking, Zoltan Szucs, Ioannis Gounaris, Giuseppe Locatelli, Johann S. de Bono. Pharmacodynamic and immunophenotyping analyses of ATR inhibitor M1774 in a Phase I study in patients with solid tumors (DDRiver Solid Tumors 301) [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 CT272.