Dose-limiting Toxicity Grade Research Articles

Lisavanbulin (BAL101553), a novel microtubule inhibitor, plus radiation in patients with newly diagnosed, MGMT promoter unmethylated glioblastoma.

Lisavanbulin (BAL101553) is a small, lipophilic, oral microtubule destabilizer with promising antitumoral activity observed in preclinical glioblastoma (GBM) models. This multicenter phase 1 study sought to determine the MTD of oral Lisavanbulin in combination with standard RT (60 Gy/30 fractions) but without temozolomide in patients with newly diagnosed MGMT promoter unmethylated GBM (uGBM). Dose escalation followed a modified 3 + 3 design. Secondary objectives included estimation of OS and PFS and pharmacokinetic analysis. Twenty-six patients with uGBM (median age, 63 years, 42.3% male, 61.5% with gross total resection, median Karnofsky performance status 80) were enrolled; 2 tumors had an IDH1 mutation. Predefined dose levels of Lisavanbulin, administered daily concomitantly with RT, were: 4mg (5 pts), 6mg (5 pts), 8mg (7 pts), 12mg (5 pts), and 15mg (4 pts). The initial starting dose was 8mg. Due to grade 4 aseptic meningoencephalitis in the first patient, the dose was decreased to 4mg. Dose escalation resumed and continued to 15mg with dose-limiting toxicities of grade 2 confusion and memory impairment observed at 12mg. Avanbulin exposures increased in a relatively dose-proportional manner with increasing oral dose of Lisavanbulin from 4 to 15mg. Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15mg daily.

A phase I/II study of nanoliposomal irinotecan and carboplatin in patients with advanced or metastatic, poorly differentiated gastroenteropancreatic neuroendocrine carcinoma characterized by tissue and liquid next-generation sequencing.

52 Background: For locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), standard chemotherapy typically incorporates etoposide or irinotecan plus platinum agents. Herein, we initiate a phase I/II trial to apply Nal-IRI in combination with carboplatin as the 1st line treatment in patients with GEP-NECs to define the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). Methods: In the phase I part, traditional 3+3 design was applied. Enrolled patients would receive escalating dose of 60 (level -1), 80 (starting dose, level 0) or 100 (level 1) mg/m2 salt-form nal-IRI plus carboplatin AUC=4 with maximum total dose of 600 mg on D1, every 21 days as a cycle. DLTs were evaluated during the first one cycle of treatment with tumor assessment every 6 weeks. Prophylaxis G-CSF was not allowed in the first cycle Paired testing of tissue (TBx) and liquid biopsy (LBx) was done by Illumina TSO500 platform before treatment. The second LBx would be repeated for confirmed partial responders when progression. Results: Totally 6 GEP-NEC patients with primary sites of colon in three, and each one in esophagus, ampulla of Vater and pancreas were enrolled to level 0. One patient had DLT of grade 4 neutropenia lasting for 3 days even under salvage G-CSF. Treatment-related adverse events showed grade 3/4 neutropenia (33.4%), grade 2 anemia (16.7%), grade 3 fatigue (16.7%), and grade 2 skin rash (16.7%). Four patients achieved confirmed partial response and 2 patients got stable disease, with the objective response rate of 66.7% (95% confidence interval: 22%-96%). After the data and safety monitoring board meeting, level 0 was decided as RP2D but not escalation to level 1 because of acceptable toxicity profiles and promising efficacies. Comprehensive genomic profiling showed that driver mutations were identified in three cases including two harboring BRAFV600E mutation and one with KRASG12D mutation. The other three cases lacking driver mutation showed frequent copy number alteration including 1 with MDM2 amplification (copy number 27) and a wild-type TP53. Homologous recombination deficiency (HRD), as determined by GIS score, was identified in a colon GEP-NEC who remained to be HRD-positive at progression but a higher TMB (from 4.7 to 10.2 Muts/Mb) and a higher BRAFV600E mutation allele frequency (from 24.1% to 43.6%) in tumor tissue, compared to the baseline profiling. Conclusions: Based on current data, the RP2D is 80 mg/m2 of nal-IRI (salt-form) and carboplatin of AUC=4, every 3 weeks. The extension phase II study in GEP-NEC is ongoing. Clinical trial information: NCT05385861 .

H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive (ER+), HER2 negative (–) breast cancer (BC).

1015 Background: H3B-6545 is a novel selective ER covalent antagonist (SERCA) that inactivates wild-type and mutant ERα. This phase 1/2 study aimed to identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and characterize safety and efficacy of H3B-6545 in women with advanced/metastatic ER+, HER2– BC. Methods: This multicenter, open-label study included dose-escalation [ph1] and -expansion [ph2] phases. Females (postmenopausal or concurrently receiving a luteinizing hormone-releasing hormone agonist) with ER+, HER2–BC who had disease progression on standard therapy were eligible. Prior therapy must have included a minimum of 2 hormonal therapies (HTs), or 1 HT + 1 chemotherapy, or 1 HT + a CDK4/6 inhibitor. H3B-6545 was administered orally QD at doses of 100-600 mg. The MTD was the highest dose at which ≤1 of 6 patients (pts) had a dose-limiting toxicity (DLT). In ph2, efficacy of the RP2D was examined. The primary endpoints were determination of RP2D (ph1) and efficacy (ph2; including objective response rate [ORR], duration of response [DOR], and progression-free survival [PFS] per RECIST v1.1 by investigator, and overall survival [OS]). Safety and PK were secondary endpoints. Results: At data cutoff (30 Nov 22), 151 pts received ≥1 dose of H3B-6545 during ph1 or ph2. Pts had a median (m [range]) of 2 (1-7) prior endocrine- and 1 (1-6) non-endocrine–containing therapies; 90.1% of pts received prior CDK4/6 inhibitors. During ph1, DLTs of grade (G) 3 rash (n=1) and G 3 fatigue (n=1) were observed at 600 mg; thus, 450 mg was determined to be the MTD/RP2D. In the full analysis set (N=151), 100% and 50.3% of pts had any grade and G ≥3 treatment-emergent adverse events (TEAEs), respectively. TEAEs leading to drug interruption, dose reduction, and withdrawal occurred in 38.4%, 20.5%, and 8.6% of pts, respectively. Nausea (45.7% [2.0% G ≥3]), sinus bradycardia (44.4% [0% G ≥3]), and diarrhea (41.1% [1.3% G ≥3]) were the most common TEAEs. QT prolongation occurred in 9.9% [3.3% G ≥3] of pts. Among 94 response-evaluable pts treated at 450 mg, ORR was 20.2% (95% CI 12.6–29.8) and clinical benefit rate (CBR) was 41.5% (95% CI 31.4–52.1); mPFS (95% CI) was 5.06 (3.15–7.26) months. Among all pts treated at 450 mg (n=115), mOS (95% CI) was 21.52 (16.56–25.46) months. Plasma concentration of H3B-6545 increased as dose increased. Additional results are shown (Table). Conclusions: H3B-6545 had a low rate of G ≥3 TEAEs and showed clinically meaningful antitumor activity in heavily pretreated female patients with ER+, HER2– BC. Clinical trial information: NCT03250676 . [Table: see text]

Abstract CT057: Phase 1/2 trial of trametinib + ceritinib in patients with unresectable melanoma

Abstract Background: In advanced melanoma, treatment options after progression on immunotherapy are limited, particularly for patients with BRAF-WT tumors. MEK-inhibitors have been explored, with limited clinical efficacy. Our pre-clinical data demonstrated efficacy of the tyrosine kinase inhibitor ceritinib in NRAS-mutant and BRAF-mutant melanoma cells lines. There was synergy observed combining the MEK inhibitor trametinib with ceritinib (compared to trametinib alone) in BRAF-WT melanoma xenografts, with dual suppression of MAPK and mTOR signaling (Verduzco et al, Mol Cancer Ther 2018) Further, in our anti-PD-1 resistant mouse melanoma models, combination of ceritinib and trametinib was highly effective when administered subsequent to anti-PD1. (Phadke et al, Cancer Immunol Res 2021) Methods: We conducted a phase 1/2 trial of ceritinib monotherapy and then combination of trametinib with ceritinib in patients with advanced melanoma after failure of anti-PD-1 (and prior BRAF/MEK inhibitors if eligible.) Primary objective was to identify the maximum tolerated dose (MTD) of this combination, with secondary objectives of tumor response (RECIST 1.1) and progression-free (PFS) and overall survival (OS). In the initial phase 2 portion to explore single-agent activity, patients received oral ceritinib monotherapy at 450 mg daily (QD). In the subsequent phase 1 portion, patients started at dose level (DL)1 of 300 mg PO QD ceritinib + 2mg PO QD trametinib, with a BOIN design to guide dose escalation in cohort sizes of 3. DL 2 was 450 mg + 2 mg QD, while DL -1 was 300 mg + 1.5 mg QD of the combination. Tumor biopsies and blood samples were obtained on day 1 and day 15. Results: We enrolled 28 patients with unresectable/metastatic melanoma. Median age was 66, 10 female, 26 stage IV, 11 NRAS-mutant, 4 BRAF V600-mutant, with median 3 prior lines of prior therapy. There was no objective response observed to ceritinib monotherapy in 11 patients; prolonged stable disease of 6 and 8 months was seen in 2 pts. Median PFS was 2.1 months (95% CI 1.91, NA); median OS was 7.3 months (95% CI 2.4, NA). Two patients had grade 3 AST/ALT elevation; there were no unexpected toxicities. Of the 17 patients on the combination regimen, 12 received DL1. Dose-limiting toxicities of grade 3 rash and grade 2 glaucoma led to de-escalating to DL -1 for other patients. Overall, most frequent grade 3/4 toxicities were grade 3 rash (n=3), grade 3 hypertension (n=2), and grade 3 ALT/AST elevation (n=2). MTD was determined at DL -1 of 1.5 mg trametinib + 300 mg ceritinib QD. Two patients had partial response (12%), both NRAS-mutant; 6 had SD (3 lasting ≥6 months). Median PFS was 3.1 months (95% CI 1.94, 6.18) with median OS of 7.8 months (95% CI 5.1, 13.2). Overall, patients with immediate prior line of anti-PD-1 before trial treatment had a trend toward improved OS (10.2 months vs 5.1 months; p=0.21); no differences were seen based on NRAS or BRAF-status. Conclusions: Ceritinib does not appear to have meaningful single agent activity in treatment-refractory advanced melanoma. Efficacy of the combination with trametinib is modest, and the inability to dose-escalate the combination due to overlapping toxicities such as rash may have contributed. Analyses from baseline and on-treatment tumor biopsies, including immunohistochemistry and single cell RNA seq to explore drug effect on mTOR and MAPK pathways as well as immune infiltration, are ongoing and will be presented. Citation Format: Zeynep Eroglu, Vivien Yin, Joseph Markowitz, Andrew Brohl, Ahmad A. Tarhini, Wenyi Fan, Deanryan De Aquino, Ann Chen, Uwe Rix, Nikhil I. Khushalani, Keiran Smalley. Phase 1/2 trial of trametinib + ceritinib in patients with unresectable melanoma [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 CT057.

Abstract CT115: A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in a hematologic malignancies cohort

Abstract Background: Mutations in genes encoding RNA splicing factors such as SF3B1, SRSF2, U2AF1, and ZRSR2, are common genetic aberrations in many forms of myeloid neoplasms. CTX-712 is a first-in-class, orally available, highly potent, and selective small molecule inhibitor of CDC2-like kinase (CLK), a key regulator of RNA splicing. Preclinical data show that CTX-712 demonstrated anti-proliferative activity in in-vitro and in-vivo models derived from hematologic malignancies. A phase I study of CTX-712 was conducted to evaluate the safety and the preliminary efficacy of CTX-712 in patients with relapsed or refractory acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS). Methods: The objectives of this cohort were to evaluate the dose-limiting toxicity (DLT), safety, pharmacokinetic (PK)/pharmacodynamic (PD) profiles, and preliminary efficacy of CTX-712 in patients with hematologic malignancies. A 3+3 design was used in two dose levels (70 mg and 105 mg twice a week (TW)) based on the safety data from the previous dose escalation cohort in patients with solid tumors. Results: As of data cutoff on November 20, 2023, a total of 14 patients (12 AML and 2 MDS) were enrolled in 70 mg TW (n=8) and 105 mg TW dose levels (n=6). DLT of Grade 4 pneumonia was observed in 1 of 3 DLT-evaluable patients in the 105 mg TW group. In the 70 mg TW group, no DLT was observed in 6 DLT-evaluable patients. Among the safety analysis population (n=14), median treatment duration was 76 days (Range 15-974 days). At data cutoff, treatment was ongoing in 1 patient and discontinued in 13 patients. The common any-grade adverse events (AEs) (≥30%) were diarrhea (57.1%) and nausea (42.9%). The most common Grade 3 or higher AE were white blood cell count decreased and tumor lysis syndrome (14.3%). In AML patients (n=12), complete remission (CR) was observed in 3 patients (25.0%), and CR with incomplete hematologic recovery (CRi) was observed in 1 patient (8.3%). The median time to remission was 67 days (Range 29-113 days), and the median duration of response was 281 days (Range 56-924 days). In MDS patients (n=2), CR was observed in 1 patient (50.0%). PK/PD profiles of the hematologic malignancies dose escalation cohort were comparable with those of the solid tumor cohort at the same dosage. Conclusions: CTX-712 demonstrated a manageable and tolerable safety profile and showed anti-tumor efficacy in patients with hematologic malignancies. Currently, a Phase I/II Study of CTX-712 in relapsed/refractory AML and higher risk MDS is ongoing using a new tablet formulation in the United States. Clinical trial information: jRCT2080224127 Citation Format: Hisayuki Yokoyama, Noriko Fukuhara, Koji Ando, Hiroatsu Iida, Takahiro Yamauchi, Suguru Fukuhara, Koji Izutsu, Yasushi Tanoue, Maki Yamamoto, Hirokazu Tozaki, Eiji Takahara, Shingo Shoji, Akio Mizutani, Daisuke Morishita, Robert W. Oda, Hiroshi Miyake, Noboru Yamamoto. A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in a hematologic malignancies cohort [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 CT115.

Abstract CT256: Results from KEYNOTE-B98: A phase 1b/2 study of pembrolizumab plus investigational agents in patients with anti-PD-(L)1-refractory extensive-stage small-cell lung cancer (ES-SCLC)

Abstract Background: Anti-PD-L1 plus chemotherapy is a recommended first-line (1L) treatment option for ES-SCLC. However, most patients (pts) relapse and effective second-line (2L) treatment options are limited. Pembrolizumab (pembro) has demonstrated antitumor activity in previously treated ES-SCLC. The KEYNOTE-B98 study (NCT04938817) evaluated pembro in combination with investigational agents as 2L therapy for anti-PD-(L)1-refractory ES-SCLC. We present initial results from this study. Methods: This randomized, phase 1b/2, multicenter, open-label, platform study enrolled adult pts with confirmed ES-SCLC (stage IV per AJCC v8.0) that progressed ≤12 wk of last anti-PD-(L)1 dose given as part of 1L platinum-based therapy, measurable disease per RECIST v1.1, and ECOG PS of 0-1. Pts were randomized 1:1:1:1 to: (A) MK-1308A (coformulation of quavonlimab [anti-CTLA4] 25 mg + pembro 400 mg) Q6W, (B) MK-1308A Q6W + lenvatinib 20 mg QD, (C) MK-1308A Q6W + MK-4830 (anti-ILT4) 800 mg Q3W, and (D) MK-4280A (coformulation of favezelimab [anti-LAG3] 800 mg + pembro 200 mg) Q3W. A safety lead-in was performed for the first 21 days of treatment in cohort C in ≤10 pts evaluable for dose-limiting toxicities (DLTs), followed by efficacy evaluation. Pts in safety lead-in were not randomized. Primary endpoints were safety (DLTs in safety lead-in phase, AEs, and discontinuations due to AEs) and ORR per RECIST v1.1 by BICR. Secondary endpoints were PFS and DOR per RECIST v1.1 by BICR. Results: 76 pts received ≥1 dose of study treatment: cohort A, n = 19; B, n = 20; C, n = 17; D, n = 20. Median follow-up at data cutoff (Jul 3, 2023) was 12.9 (range, 5.9-21.8) mo. During safety lead-in, 1 pt had a DLT of grade 3 arthralgia. Treatment-related AEs (TRAEs) occurred in 12 pts (63%; grade 3/4, n = 2, 11%) in cohort A, 17 (85%; grade 3/4, n = 6, 30%) in cohort B, 12 (71%; grade 3/4, n = 1, 6%) in cohort C, and 15 (75%; grade 3/4, n = 4, 20%) in cohort D; none were grade 5. 1 pt (5%) in cohort A, 3 (15%) in cohort B, 0 in cohort C, and 2 (10%) in cohort D had TRAEs that led to treatment discontinuation. Confirmed ORR (95% CI) was 5% (0%-26%; 1 PR) in cohort A, 25% (9%-49%; 5 PR) in cohort B, 0% (0%-20%) in cohort C, and 0% (0%-17%) in cohort D. Median (range) DOR was not reached (9.4+ to 9.4+ mo) in group A and 3.9 (2.0-3.9) mo in group B. Median (95% CI) PFS was 1.4 (1.2-2.6) mo, 3.9 (1.7-5.3) mo, 1.2 (0.8-1.4) mo, and 2.6 (1.4-4.0) mo in cohorts A-D, respectively. Conclusions: In the KEYNOTE-B98 study of anti-PD-(L)1-refractory ES-SCLC, no new safety signals were identified for the pembro-based combinations investigated. Modest antitumor activity was observed with MK-1308A ± lenvatinib, but no activity for MK-1308A + MK-4830 or for MK-4280A. This study provided proof-of-concept for the feasibility of platform trials in 2L ES-SCLC. Further investigation of new compounds and combinations is needed in this population. Citation Format: Alejandro Navarro, Myung-Ju Ahn, James Stevenson, Nir Peled, Talia Shentzer Kutiel, Florian Huemer, Dong-Wan Kim, Maria Jove Casulleras, Adnan Khattak, Dariusz Kowalski, Natasha B. Leighl, Filippo de Marinis, Carolin Lips, Jiaxin Niu, Mo Huang, Bin Zhao, Hazem El-Osta, Taofeek Owonikoko. Results from KEYNOTE-B98: A phase 1b/2 study of pembrolizumab plus investigational agents in patients with anti-PD-(L)1-refractory extensive-stage small-cell lung cancer (ES-SCLC) [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 CT256.

Sequential Therapy with Ropeginterferon Alfa-2b and Anti-Programmed Cell Death 1 Antibody for Inhibiting the Recurrence of Hepatitis B-Related Hepatocellular Carcinoma: From Animal Modeling to Phase I Clinical Results.

Hepatocellular carcinoma (HCC) usually recurs after curative surgical resection. Currently, no approved adjuvant therapy has been shown to reduce HCC recurrence rates. In this study, the in vivo effect of sequential combination treatment with recombinant mouse interferon-alpha (rmIFN-α) and an anti-mouse-PD1 antibody on hepatitis B virus (HBV) clearance in mice was evaluated. A Phase I clinical trial was then conducted to assess the safety, tolerability, and inhibitory activity of sequential therapy with ropeginterferon alfa-2b and nivolumab in patients with HCC recurrence who underwent curative surgery for HBV-related HCC. The animal modeling study showed that HBV suppression was significantly greater with the rmIFN-α and anti-PD1 sequential combination treatment in comparison with sole treatment with rmIFN-α or anti-PD1. In the Phase I study, eleven patients completed the sequential therapy with ropeginterferon alfa-2b every two weeks for six doses at 450 µg, followed by three doses of nivolumab every two weeks up to 0.75 mg/kg. A notable decrease in or clearance of HBV surface antigen was observed in two patients. The dose-limiting toxicity of grade 3 alanine transaminase and aspartate aminotransferase increases was observed in one patient. The maximum tolerated dose was then determined. To date, no HCC recurrence has been observed. The treatment modality was well tolerated. These data support the further clinical development of sequential combination therapy as a post-surgery prophylactic measure against the recurrence of HBV-related HCC.

Abstract C164: A phase 1 dose-escalation study of PRT2527, a cyclin-dependent kinase 9 (CDK9) inhibitor, in adult patients with advanced solid tumors: An updated analysis

Abstract Introduction: CDK9 has emerged as a key dependency due to its role in regulation of transcription elongation in many “transcription-addicted” cancers. We report updated phase 1 results from an ongoing, open-label, multicenter, dose-escalation study of PRT2527 (NCT05159518), an investigational, potent, and highly selective CDK9 inhibitor being evaluated in patients (pts) with advanced solid tumors. Methods: Enrolled adult pts had selected sarcomas, castration-resistant prostate cancer (CRPC), HR+/HER2– breast cancer (BC), non-small cell lung cancer (NSCLC), or MYC-amplified solid tumors that were relapsed or refractory to prior systemic treatment. Pts received intravenous PRT2527 (3, 6, 12, 15, or 18 mg/m2) once weekly (QW; 21-day cycle) using a Bayesian optimal interval design (n=3-6 per dose level); prophylactic anti-emetic and growth factor support was not required. Primary objectives were to evaluate dose-limiting toxicities (DLTs) and establish the maximum tolerated dose and recommended phase 2 dose of PRT2527. Secondary objectives were safety/tolerability, pharmacokinetics, and antitumor activity. Results: At data cutoff (May 18, 2023), 29 pts with CRPC (38%), BC (17%), sarcoma (31%), pancreatic cancer (7%), and NSCLC (3%) were treated across 5 dose levels; 5 and 9 pts received 15 mg/m2 QW in dose escalation and confirmation, respectively. Seven pts had MYC amplification. Four pts were ongoing; 1 pt with chondrosarcoma received treatment for >55 weeks. Two DLTs of grade 4 neutropenia were observed during dose escalation in the 15 and 18 mg/m2 QW cohorts. Overall, 100% of pts experienced all-cause, any-grade adverse events (AEs); the most frequent (≥15%) were nausea (45%), vomiting (38%), neutropenia (35%), fatigue (24%), and diarrhea (21%). Grade ≥3 all-cause and treatment-related AEs were reported in 48% and 21% of pts, respectively. Treatment-related grade ≥3 AEs were neutropenia (17%), anemia, leukopenia, thrombocytopenia, nausea, and pneumonia staphylococcal (3% each). Two deaths were reported while on study (sepsis and unknown cause; a third death occurred 38 days after the end of treatment); all were deemed unrelated to treatment. Four pts had dose reductions due to treatment-related AEs. Two pts required growth factor support for neutropenia. Eight (28%) pts had a best response of stable disease. Dose-dependent inhibition of CDK9 transcriptional targets was observed in all cohorts. A mean decrease of 76% (standard deviation [SD], 13%, n=8) in MCL1 and 77% (SD, 11%, n=8) in MYC mRNA was achieved 2 hours post infusion of the 15 mg/m2 QW dose; by 4 hours, MYC mRNA levels had rebounded to baseline levels (n=9) while MCL1 levels remained suppressed with a 60% (SD, 25%; n=9) inhibition. Conclusions: In adults with solid tumors, PRT2527 demonstrated favorable tolerability, with manageable neutropenia and gastrointestinal events. Doses of 12 and 15 mg/m2 QW showed optimal target inhibition as predicted by the preclinical model. PRT2527 will be investigated as a combination therapy and in hematological malignancies. Citation Format: Manish R. Patel MD, Astrayee Basu-Mallick MD, Filemon Dela Cruz MD, Douglas Orr MD, Alex Spira MD, PhD, Guru P. Sonpavde MD, Pooja Ghatalia MD, Christine Lihou BSc, Neelesh Sharma MD, PhD, Peggy Scherle PhD, William Sun PhD, Sri Sahasranaman, Jason T. Henry MD. A phase 1 dose-escalation study of PRT2527, a cyclin-dependent kinase 9 (CDK9) inhibitor, in adult patients with advanced solid tumors: An updated analysis [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 C164.

TIM-3 Inhibitor Sabatolimab for Patients with Acute Myeloid Leukemia (AML) with Measurable Residual Disease (MRD) Detected after Allogeneic Stem Cell Transplantation (AlloSCT): Preliminary Findings from the Phase Ib/II Stimulus-AML2 Study

Introduction: AlloSCT is a potentially curative treatment for patients (pts) with AML. However, MRD persistence after transplantation has been identified as a risk factor for relapse. In this regard, the graft-versus-leukemia (GvL) effect is well recognized as one of the leading mechanisms of disease control after transplantation. Sabatolimab is a novel immunotherapy that targets the immuno-myeloid regulator TIM-3 on both immune cells and leukemic blasts, and may have the potential to enhance the GvL effect. STIMULUS-AML2 (NCT04623216) is a Phase Ib/II, open-label, multicenter study of sabatolimab alone or in combination with azacitidine as pre-emptive therapy in pts with AML who are in complete remission (CR) with positive MRD (MRD+) after alloSCT. Here we report preliminary data from the safety run-in of sabatolimab monotherapy at two dose levels (400 mg or 800 mg intravenous [IV] every four weeks [Q4W]). Methods: Eligible pts for the safety run-in were adults (≥18 years [y]) with de novo or secondary AML, who achieved CR post-alloSCT but were MRD+ by local assessment at any time ≥Day (D) 60 after alloSCT (protocol amended from MRD+ D100-365 post alloSCT; March 24, 2022) and ≥2 weeks after immunosuppressive medications had been tapered off. MRD was assessed locally at baseline by polymerase chain reaction (PCR; 12 pts: NPM1 and/or WT1, 8; IDH2, 2; other, 2), multiparameter flow cytometry (MFC; 6 pts), both PCR and MFC (1 pt), and CD34+ chimerism (2 pts). In this safety run-in, adult pts received sabatolimab monotherapy at 400 mg or 800 mg IV on D1 of every 28-day cycle. The primary endpoint was incidence of treatment-emergent dose-limiting toxicity (DLT), including acute graft-vs-host disease (GvHD) and chronic GvHD during the first 2 cycles. Results: A total of21 pts were enrolled in the safety run-in (10 at 400 mg; 11 at 800 mg). Median age was 59 years. At AML diagnosis, across cohorts, 8, 9 and 4 pts had favorable, intermediate, and adverse genetic risk (European LeukemiaNet 2017), respectively. At data cut-off (April 26, 2023), 3 pts were still ongoing in the 400 mg cohort and 7 had discontinued due to disease relapse. At 800 mg, 4 pts were ongoing and 7 had discontinued (5 due to relapse, 1 due to adverse event [AE], 1 due to new therapy) ( Table 1). Across cohorts, there was 1 DLT of grade (G) 3 myocarditis after the first infusion of sabatolimab 800 mg, which recovered/resolved on the same day and sabatolimab was then withdrawn. An overview of safety is shown in Table 2. Any G and G≥3 AEs occurred in 16 (76.2%) and 8 (38.1%) pts, respectively. There were no cases of GvHD or immune-related AEs, 2 cases of G≥3 neutropenia and 1 case of G≥3 thrombocytopenia. G3 neutropenia and G3 thrombocytopenia in the same pt at 400 mg were considered treatment related and the patient later relapsed. At 400 mg, 2 pts experienced serious AEs (SAEs) after the DLT observation period (>3 cycles) and 2 pts at 800 mg had SAEs during the DLT period (G3 myocarditis [1 pt] and disease relapse with central nervous system involvement [1 pt]). There were 5 deaths, all at 400 mg and due to study indication (AML). As a preliminary indicator of efficacy, 7 pts were still on treatment and in CR at data cut-off. At 400 mg, 2 pts and 1 pt had received 14 and 15 cycles of treatment (>1 y), respectively. At 800 mg, 1 pt had received 5, 1 pt 6, and 2 pts 7 cycles. At 400 mg, 7 pts relapsed: 2 pts after cycle 1, 2 pts after cycle 2, 1 pt each after cycles 3, 4 and 7. At 800 mg, 5 pts relapsed: 1 pt after cycle 1, 2 pts after cycle 2, 1 pt after cycle 3 and 1 pt after cycle 5. Conclusions: In adult pts with AML who are in hematological CR with MRD+ after alloSCT, sabatolimab 400 mg and 800 mg monotherapies were well tolerated. Cytopenias occurred at low rates, were generally G1-2 and mostly related to imminent relapse. Importantly, there were no cases of GvHD reported or any immune-related AEs commonly seen with checkpoint inhibitors. Preliminary efficacy was promising with 30% of the pts at 400 mg still in CR after more than 1 y on treatment (available longer-term follow-up >1 y), and data may suggest a delayed onset of relapse. A dose expansion cohort at 800 mg opened for enrollment June 30, 2023. Adults will be randomized to sabatolimab as monotherapy or in combination with azacitidine, and preliminary efficacy on the prevention of hematological relapse will be evaluated. Adolescents (12-17 y) will also be enrolled to evaluate the safety of sabatolimab monotherapy. This study is sponsored by Novartis.

A Phase 1 Study of the Oral CDK9 Inhibitor Voruciclib in Relapsed/Refractory (R/R) B-Cell Lymphoma (NHL) or Acute Myeloid Leukemia (AML)

Background: The anti-apoptotic protein Mcl-1 contributes to the pathophysiology of certain B-cell malignancies and AML, and dependence on Mcl-1 is associated with resistance to venetoclax. Efforts to target Mcl-1 through direct inhibition have faced challenges due to cardiovascular toxicities. Voruciclib, a potent oral CDK9 inhibitor (CDK9i), was shown to indirectly downregulate Mcl-1 protein levels and synergize with venetoclax in preclinical models in lymphoid and myeloid malignancies. In solid tumors, voruciclib maximum tolerated dose (MTD) was defined as 350 mg with continuous daily dosing, and 600 mg when used on days 1-14 on a 21-day cycle. This phase 1 study is the first to evaluate the safety, dose-limiting toxicities (DLT), preliminary efficacy, pharmacokinetics, and pharmacodynamics of voruciclib in R/R hematologic malignancies (NCT03547115). Methods: Patients (pts) with relapsed B-cell NHL, CLL, or AML aged ≥18 years who had ECOG performance status ≤1, disease progression after standard therapies, adequate hepatic and renal function, and no prior CDK9i were eligible. The study followed a 3+3 design and DLTs were assessed in Cycle 1. Voruciclib was administered daily continuously at a starting dose of 50 mg on a 28-day cycle (Cohort I). After 2 DLTs were observed at 100 mg in AML pts, dosing was changed to daily on days 1-14 on a 28-day cycle (Cohort II). Also, pts with prior allogeneic transplant were excluded and dose escalation (100, 150, 200 mg) proceeded separately in AML and B-cell malignancies. Disease response was assessed by investigators using the Lugano, 2008 iwCLL, and 2017 ELN criteria. Results: 40 pts were enrolled: 21 AML, 19 NHL (9 DLBCL, 3 CLL, 3 MCL, 3 FL and 1 MZL). Cohort I enrolled 16 pts, 8 each at 50 mg and 100 mg. Cohort II enrolled 24 pts (17 AML and 7 B-cell malignancies), including 6 at 100 mg, 7 at 150 mg, and 11 at 200 mg. Dose escalation in Cohort II did not reach the MTD and was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition. Median age was 70 years (range 40-90), 72.5% of pts were ≥65 years, and 77.5% had ECOG performance status = 1. Pts had a median of 3 prior therapies (range, 1-8). Median duration on drug was 5 weeks (range 1-22). Drug-related serious adverse events (AEs) were reported in Cohort I only. Two pts with AML had a DLT of Grade (Gr) 3 interstitial pneumonitis at 100 mg; both had had allogeneic transplant and active graft versus host disease, one of whom also had a concurrent Gr 3 differentiation syndrome. One pt with DLBCL at 50 mg had Gr 3 hypoxemic respiratory failure in Cycle 4. In Cohort II, no DLTs were observed and there were no non-hematologic Gr 3-5 drug-related AEs. In the overall population, the most common AEs were diarrhea (30%), nausea (25%), anemia (22.5%), fatigue (22.5%), constipation (17.5%), dizziness (15%) and dyspnea (15%) [Table 1). One pt with AML had Gr 3 hyperbilirubinemia. There was no evidence of drug-related neutropenia in pts with NHL. No significant cardiovascular AEs were observed. One pt with AML in Cohort I achieved a morphologic leukemia-free state. At 200 mg, 5 of 10 AML pts (50%) had stable disease. Voruciclib pharmacokinetics was dose proportional, mean accumulation ratio was 2.4, mean T max was 4 hours, and at 200 mg, steady state C max was 925 ng/mL and mean C trough was 442 ng/mL (~1 microM). Analysis of Mcl-1 protein expression in normal lymphocytes by flow cytometry showed a trend of decrease in on-treatment samples compared to pre-treatment. Consistent with this, RNA-Seq analysis of 3 paired CLL samples confirmed rapid (after 6 hours) downregulation of Mcl-1 mRNA transcript in the malignant B-cells. Furthermore, scRNA-Seq analysis of 2 longitudinal AML samples demonstrated downregulation of MYC transcriptional program and oxidative phosphorylation in circulating AML blasts, both evident 24 hours after start of voruciclib and ongoing at C1D15. Conclusions: Voruciclib at doses up to 200 mg administered on 14 consecutive days on a 28-day cycle was well tolerated, with no DLTs observed, and no cardiovascular toxicities. There was no significant myelosuppression in pts with B-cell malignancies. As the safety profile suggested non-overlapping toxicities with venetoclax, the study is now evaluating voruciclib in combination with venetoclax in pts with R/R AML to exploit dual inhibition of Bcl-2 and Mcl-1.

Phase 1/1b open-label, dose-escalation study of fruquintinib in patients with advanced solid tumors in the United States

SummaryThis open-label, phase 1/1b study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of fruquintinib in United States (U.S.) patients to confirm the recommended phase 2 dose (RP2D) established in China. Patients with advanced solid tumors who had progressed on approved systemic therapy, were enrolled into 2 successive dose escalation cohorts, fruquintinib 3 mg (n = 7) or 5 mg (n = 7), orally, once daily (QD), 3 weeks on and 1 week off (3/1) with a 3 + 3 design followed by a dose expansion cohort at the RP2D 5 mg dose (n = 6). PK samples were collected on Days 1, 14, and 21 (Cycle 1). One of 6 dose-limiting toxicity (DLT)-evaluable patients in the 3 mg cohort had a DLT of grade 4 hypertension; there were no DLTs in the 5 mg cohort. The RP2D was confirmed to be 5 mg QD 3/1. All 20 patients experienced a treatment-emergent adverse event; grade ≥ 3 in 5 (71.4%; 3 mg dose) and 12 (92.3%; 5 mg dose) patients. Two patients had a confirmed partial response. After single and multiple doses, median peak plasma concentrations occurred at 2 h post-dose. Steady-state was achieved after 14 days of QD dosing with systemic exposure four-fold higher than that after a single dose. Fruquintinib was well tolerated, and the safety and PK profile at the 5 mg RP2D in U.S. patients with advanced solid tumors was consistent with dose-finding studies in China. Preliminary anticancer activity was observed. This study is registered at Clinicaltrials.gov NCT03251378.

Repurposing the FDA-approved anthelmintic pyrvinium pamoate for pancreatic cancer treatment: study protocol for a phase I clinical trial in early-stage pancreatic ductal adenocarcinoma

BackgroundRecent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical...

Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results

The T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel) consists of single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors. The primary objectives were to evaluate safety and determine the recommended phase 2 dose (RP2D). Secondary objectives included efficacy. Thirty-two patients received gavo-cel at increasing doses either as a single agent (n = 3) or after lymphodepletion (LD, n = 29). Dose-limiting toxicities of grade 3 pneumonitis and grade 5 bronchioalveolar hemorrhage were noted. The RP2D was determined as 1 × 108 cells per m2 after LD. Grade 3 or higher pneumonitis was seen in 16% of all patients and in none at the RP2D; grade 3 or higher cytokine release syndrome occurred in 25% of all patients and in 15% at the RP2D. In 30 evaluable patients, the overall response rate and disease control rate were 20% (13% confirmed) and 77%, respectively, and the 6-month overall survival rate was 70%. Gavo-cel warrants further study in patients with mesothelin-expressing cancers given its encouraging anti-tumor activity, but it may have a narrow therapeutic window. ClinicalTrials.gov identifier: NCT03907852.

A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation

PurposeAberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug resistance often develops due to aberrant or compensatory mechanisms. Herein, we sought to determine the feasibility and safety of neratinib and trametinib in patients with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation and KRAS mutation.MethodsPatients with actionable somatic mutations or amplifications in ERBB genes or actionable KRAS mutations were enrolled to receive neratinib and trametinib in this phase I dose escalation trial. The primary endpoint was determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary endpoints included pharmacokinetic analysis and preliminary anti-tumor efficacy.ResultsTwenty patients were enrolled with a median age of 50.5 years and a median of 3 lines of prior therapy. Grade 3 treatment-related toxicities included: diarrhea (25%), vomiting (10%), nausea (5%), fatigue (5%) and malaise (5%). The MTD was dose level (DL) minus 1 (neratinib 160 mg daily with trametinib 1 mg, 5 days on and 2 days off) given 2 DLTs of grade 3 diarrhea in DL1 (neratinib 160 mg daily with trametinib 1 mg daily). The treatment-related toxicities of DL1 included: diarrhea (100%), nausea (55.6%) and rash (55.6%). Pharmacokinetic data showed trametinib clearance was significantly reduced leading to high drug exposures of trametinib. Two patients achieved stable disease (SD) ≥ 4 months.ConclusionNeratinib and trametinib combination was toxic and had limited clinical efficacy. This may be due to suboptimal drug dosing given drug–drug interactions.Trial registration ID: NCT03065387.

First-in-human study of ABBV-011, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate, in patients with small cell lung cancer.

3002 Background: Small cell lung cancer (SCLC) has a dismal prognosis and new therapies are urgently needed. SEZ6 is a transmembrane protein expressed in SCLC tumors that may be used as a therapeutic target. ABBV-011 is an antibody-drug conjugate (ADC) targeting SEZ6 with a calicheamicin payload, which has shown antitumor activity in preclinical models of SCLC. Preliminary results from the monotherapy dose-escalation and -expansion cohorts of the first-in-human ABBV-011 study are presented. Methods: Phase 1, open-label, multicenter study (NCT03639194) of ABBV-011 alone or in combination with budigalimab, a programmed cell death 1 inhibitor. Primary objectives were to assess the safety and tolerability and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose of ABBV-011. Adults (≥18 years) with relapsed/refractory SCLC (1–3 lines of prior therapy) were enrolled. Dose escalation was guided by Bayesian continual reassessment method. ABBV-011 was administered intravenously at doses from 0.3 to 2.0 mg/kg once every 3 weeks. Dose expansion was conducted in SEZ6-selected patients. Results: At data cutoff on August 22, 2022, 99 patients were treated with ABBV-011 monotherapy. Median age was 63 years (range, 41–79), 50% of patients were male, and 68% had received ≥2 prior therapies. ABBV-011 ADC pharmacokinetics were approximately dose-proportional with an elimination half-life of 4.6 days across the dose range of 0.3–2.0 mg/kg. In dose escalation (n=26), 1 patient had a dose-limiting toxicity of grade (G) 3 fatigue at 2.0 mg/kg. We report safety and efficacy results for 40 patients in the dose-expansion 1.0-mg/kg ABBV-011 cohort. Median duration of treatment was 12 weeks (range, 1.9–63.3). Treatment-emergent adverse events (TEAEs) occurred in 39 (98%) patients, the most frequent being fatigue (48%), nausea (45%), anorexia (38%), thrombocytopenia (38%), and vomiting (35%). G3 TEAEs occurred in 18 (45%) patients, the most frequent being fatigue, thrombocytopenia, and neutropenia (10% each); 1 G4 TEAE of dyspnea was reported. Seven patients died due to malignant neoplasm/disease progression (n=6) or respiratory distress (n=1); none were related to ABBV-011. Hepatotoxicity was observed, including G≥2 TEAEs of hyperbilirubinemia (18%), increased gamma-glutamyltransferase (8%), ascites (5%), veno-occlusive liver disease (3%), and portal hypertension (3%). Confirmed objective response rate was 25% (10 partial responses [PR]), with median duration of response of 4.2 months (95% CI: 2.6, 6.7). Clinical benefit rate (CBR) was 65% (10 PR and 16 stable disease) and CBR lasting >12 weeks was 43%. The median progression-free survival was 3.5 months. Conclusions: The MTD was not reached and ABBV-011 was well tolerated at 1.0 mg/kg with promising antitumor activity observed. Further evaluation of ABBV-011 is ongoing. Clinical trial information: NCT03639194 .

First-line lenvatinib plus pembrolizumab plus chemotherapy versus chemotherapy in advanced/metastatic gastroesophageal adenocarcinoma (LEAP-015): Safety run-in results.

411 Background: LEAP-015 (NCT04662710) is a randomized, open-label, 2-part, phase 3 study of the safety and efficacy of lenvatinib + pembrolizumab + chemotherapy as a first-line treatment for advanced/metastatic gastroesophageal adenocarcinoma. We report findings from part 1, the safety run-in, of LEAP-015. Methods: Eligible patients had untreated, HER2-negative, locally advanced unresectable or metastatic gastroesophageal adenocarcinoma, measurable disease per RECIST v1.1, and ECOG performance status 0 or 1. In part 1, patients received induction with IV pembrolizumab 400 mg Q6W (×2) + oral lenvatinib 8 mg QD + investigator choice of chemotherapy (capecitabine + oxaliplatin [CAPOX] Q3W ×4 or 5-fluorouracil + leucovorin + oxaliplatin [mFOLFOX6] Q2W ×6) and consolidation with pembrolizumab 400 mg Q6W for ≤16 doses + lenvatinib 20 mg QD; dose-limiting toxicities (DLTs), defined as selected prespecified grade ≥3 adverse events (AEs) or any-grade thromboembolic events, were evaluated for 21 days after the first dose of study intervention. If ≥3 DLTs occurred in either oxaliplatin-containing regimen, then enrollment in part 2 may be delayed to allow for the examination of safety data and to consider design changes. In part 1, the primary end point was safety and tolerability in all patients. Preliminary efficacy was also assessed in part 1. Objective response and disease control rate were assessed per RECIST version 1.1 by blinded independent central review. Results: In part 1, 15 pts received ≥1 dose of lenvatinib + pembrolizumab + chemotherapy. 1 DLT of grade 3 asthenia occurred in the CAPOX cohort and 1 DLT of grade 4 neutropenia occurred in the FOLFOX cohort. Median time from first dose to data cutoff (Oct 13, 2021) was 7 mo (range, 7-9). Treatment-related AEs occurred in 14 patients (93%), with grade 3/4 events in 8 patients (53%). 4 patients (27%) discontinued any drug because of a treatment-related AE, and no patient discontinued all drugs because of a treatment-related AE. No patients died because of a treatment-related AE. No grade ≥3 immune-mediated AEs or infusion reactions occurred. Objective response was reported in 11 of 15 patients (73%; 95% CI, 45-92) who received ≥1 dose of treatment. Disease control rate was reported in 14 of 15 patients (93%; 95% CI, 68-100) who received ≥1 dose of treatment. Conclusions: In the safety run-in of LEAP-015, lenvatinib + pembrolizumab + chemotherapy was associated with a manageable safety profile in the first-line treatment of advanced/metastatic gastroesophageal adenocarcinoma. Preliminary antitumor activity was observed for lenvatinib + pembrolizumab + chemotherapy. Part 2 will evaluate the efficacy and safety of lenvatinib + pembrolizumab + chemotherapy versus chemotherapy in this same patient population and patient accrual is ongoing. Clinical trial information: NCT04662710 .

A First-in-Human Phase I Study of CTX-712 in Patients with Advanced, Relapsed or Refractory Malignant Tumors - Hematologic Malignancies Dose Escalation Cohort

Background: Mutations of RNA splicing factors, including SF3B1, SRSF2, U2AF1, and ZRSR2, are implicated in the pathogenesis of various cancers, such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), most likely via abnormal RNA splicing. CTX-712 is a first-in-class, orally available, highly potent, and selective small-molecular inhibitor of CDC2-like kinase (CLK), a key regulator of the RNA splicing process. Preclinical data show that CTX-712 demonstrated anti-proliferative activity on various in vitro and in vivo models derived from not only solid tumors but also hematologic malignancies. Based on these results, a phase I study of CTX-712 was conducted to determine the recommended dose (RD) in solid tumors and hematologic malignancies. While therapeutic agents have been developed to target RNA splicing factor abnormalities, no such agents have been developed to be standard care until now. We report the interim data from the dose escalation cohort of relapsed or refractory AML and MDS, including preliminary efficacy results of CTX-712. Methods: The objectives of this cohort are to evaluate the maximum tolerated dose, dose- limiting toxicity (DLT), safety, pharmacokinetic/pharmacodynamic profiles, and preliminary efficacy of CTX-712 and to determine the RD for the next phase in patients with hematologic malignancies. A 3+3 design is used for finding the RD. An initial CTX-712 dose of 105 mg twice a week was used based on the safety information of the preceding solid tumor dose escalation cohort. Results: As of April 28, 2022, a total of 6 patients (5 AML and 1 MDS) were enrolled in the initial 105 mg twice-a-week dosing cohort. Three of the 6 patients were considered non-evaluable for DLT analysis (2 patients received less than 75% of the dose in cycle 1 due to tumor lysis syndrome, 1 patient discontinued treatment due to disease progression before completing cycle 1). A DLT of Grade 4 pneumonia was observed in 1 of 3 DLT-evaluable patients. Based on these safety profiles, the safety monitoring committee recommended to suspend the 105 mg twice-a-week dosing cohort and to initiate a 70 mg twice-a-week dosing cohort. Among the safety analysis population (N=6), with a median treatment duration of 114 days (Range 15-609 days), the common any-grade adverse events (AEs) (≥30%) were nausea (100%), diarrhea, hypotension (66.7%), vomiting, blood creatinine increased, pyrexia, insomnia (50.0%), fatigue, malaise, amylase increased, tumour lysis syndrome, dysgeusia, nail discoloration, dry skin, rash, and oedema (33.3%). The most common Grade 3 or higher AE was tumour lysis syndrome (33.3%). In the AML patients (N=5), complete remission (CR) was observed in two patients (40.0%), and CR with incomplete hematologic recovery (CRi) was observed in one patient (20.0%). The median time to remission is 56 days (Range 29-57 days), and the median duration of response is 56 days (Range 49+-532 days). In the MDS patient (N=1), CR was observed. Pharmacokinetic/pharmacodynamic profiles of the hematologic malignancies cohort were comparable with those of the solid tumor cohort in the same dosage. Conclusions: Assessment of CTX-712 safety profile for hematologic malignancies is ongoing. CTX-712 showed preliminary anti-tumor efficacy for both AML and MDS. Clinical trial information: JapicCTI-184188

1223P First-line lenvatinib (Len) + pembrolizumab (Pembro) + chemotherapy (Chemo) vs chemo in advanced/metastatic gastroesophageal adenocarcinoma: LEAP-015 safety run-in

LEAP-015 (NCT04662710) is a randomized, open-label, 2-part, phase III study of the safety and efficacy of len + pembro + chemo as a first-line treatment for advanced/metastatic gastroesophageal adenocarcinoma. We report findings from part 1, the safety run-in, of LEAP-015. Eligible patients (pts) had untreated, HER2-negative, locally advanced unresectable or metastatic gastroesophageal adenocarcinoma, measurable disease per RECIST v1.1, and ECOG performance status 0 or 1. In part 1, pts received induction with IV pembro 400 mg Q6W (×2) + oral len 8 mg QD + investigator choice of chemo (capecitabine + oxaliplatin [CAPOX] Q3W ×4 or 5-fluorouracil + leucovorin + oxaliplatin [mFOLFOX6] Q2W ×6) and consolidation with pembro 400 mg Q6W for ≤16 doses + len 20 mg QD; dose-limiting toxicities (DLTs), defined as selected prespecified grade ≥3 adverse events (AEs) or any-grade thromboembolic events, were evaluated for 21 days after the first dose of study intervention. If ≥3 DLTs occurred in either oxaliplatin-containing regimen, then enrollment in part 2 was delayed to allow for examination of safety data and to consider design changes. In part 1, the primary end point was safety and tolerability in all pts. In part 1, 15 pts received ≥1 dose of len + pembro + chemo. 1 DLT of grade 3 asthenia occurred in the CAPOX cohort and 1 DLT of grade 4 neutropenia occurred in the FOLFOX cohort. Median time from first dose to data cutoff (Oct 13, 2021) was 7 mo (range, 7-9). Treatment-related AEs occurred in 14 pts (93%), with grade 3/4 treatment-related AEs in 8 pts (53%). 4 pts discontinued any drug because of a treatment-related AE and no pt discontinued all drugs because of a treatment-related AE. No pt died because of a treatment-related AE. No grade ≥3 immune-mediated AEs or infusion reactions occurred. In the safety run-in of LEAP-015, len + pembro + chemo was associated with a manageable safety profile in the first-line treatment of advanced/metastatic gastroesophageal adenocarcinoma. Part 2 is currently enrolling and will evaluate the efficacy and safety of len + pembro + chemo vs chemo in this same pt population.

460MO Preliminary results from a phase I study using the bispecific, human epidermal growth factor 2 (HER2)-targeting antibody-drug conjugate (ADC) zanidatamab zovodotin (ZW49) in solid cancers

ZW49 is a novel ADC comprised of a HER2-targeting bispecific antibody (directed against 2 non-overlapping HER2 epitopes) attached to a proprietary auristatin toxin with a protease-cleavable linker. The results from this ongoing, first-in-human, dose escalation (DE) and dose expansion (DX) study (NCT03821233) are presented. DE: In a 3+3 design, patients (pts) with HER2+ cancers were dosed with ZW49 IV QW (3 weeks on, 1 off; 1-1.75 mg/kg), Q2W (1-2 mg/kg) or Q3W (2-3 mg/kg). DX: Pts with centrally confirmed HER2+ cancers and measurable disease received ZW49 at the recommended dose(s)(RD[s]) determined in DE. Primary endpoints are safety and tolerability assessments; secondary endpoints include response assessments per RECIST v1.1. As of 10 Mar 2022, 76 pts (DE [51] and DX [25]; female: 58%; median age: 59 years [range, 24-83]) have been treated with ZW49. Overall, the most common histologies were gastric (28%) and breast (22%) cancers; 70% received prior HER2-targeted therapy; median number of prior metastatic therapies was 3 (range: 1-16). A RD of 2.5 mg/kg was identified for the Q3W schedule. One dose-limiting toxicity of Grade [Gr] 2 keratitis > 14 days was observed in 1 pt and resolved to Gr 1 (2.5 mg/kg Q3W DX cohort). 68 (89%) pts had treatment-related adverse events (TRAEs); majority were Gr 1 or 2 in severity. The most common TRAEs (≥ 20% pts) included keratitis (42%), alopecia (25%), and diarrhea (21%). 7 (9%) pts had Gr ≥ 3 TRAEs, including 2 Gr 4 events (infusion-related reaction [1 pt] and decreased neutrophil count [1 pt]). Serious TRAEs were reported in 3 pts, leading to 1 discontinuation (D/C); 2 other pts had D/C due to TRAE. No interstitial lung disease nor TR deaths were reported. Among 29 response-evaluable pts treated with ZW49 at 2.5 mg/kg Q3W, the confirmed objective response rate across multiple cancer types was 28% and disease control rate was 72%. ZW49 has a manageable safety profile with encouraging single-agent antitumor activity in heavily pretreated pts with HER2+ cancers. Enrollment continues at 1.75 mg/kg QW in DE and 1.5 mg/kg QW in DX.

First-in-human/phase I trial of PE0116 (4-1bb Ig G4 McAb) as single agent in patients with solid tumors progressed after lines of therapies in China.

2640 Background: The 4-1BB co-stimulatory protein is an important modulator of the adaptive T Cell immune responses, and potentially a vital target for immunotherapies in oncology. HE0116 is a humanized agonist antibody to 4-1BB that promotes proliferation and activation of T cells. The FIH/phase Ia/Ib study was conducted to establish a maximum tolerated dose, identify dose-limiting toxicities (DLTs) and to assess safety, tolerability, and pharmacokinetics of HE0116 as single agent in patients with solid tumors who have progressed on standard of care (SoC) and experimental therapies. Methods: Patients (pts) with histologically confirmed solid tumors who progressed after prior SoC and experimental therapies were enrolled. A Fibonacci 3+3 design was employed for the phase 1a dose escalation of 9 dose levels. HE0116 was administered intravenously once in first 28-day cycle for PK analysis and DLT assessment. Pts continued HE0116 treatment every 3 weeks until experiencing an intolerable toxicity, disease progression or withdrawing consent. Results: As of January 25, 2022, 19 pts were enrolled in the dose-escalation phase). All pts had progressed on multiple lines of therapies, including but not limited to, chemotherapy, hormonal therapy, or/and immunotherapy. As defined in study protocol, pts received HE0116 intravenously at least once at six dose levels: 0.03 mg/kg (n = 1), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3), 1 mg/kg (n = 4), 2 mg/kg (n = 3), and 3 mg/kg (n = 5). One DLT of Grade (g) 4 platelets decrease was reported at 3 mg/kg, thus 3 new pts were added at this dose. The grade1 and grade2 HE0116 related adverse events (AEs) per CTCAE v5 that occurred ( < 10% frequency) were ALT and AST increase, platelet decrease, WBC decrease, anemia, hypokalemia, hyponatremia, hypoalbuminemia, hypothyroidism, or bone pain. Three SAE were reported: 1 g2 ascites, 1 g4 dyspnea, 1 g2 fever. To date there was one iPR at 1 mg/kg for a pt with advanced ovarian cancer with liver met after 6 cycles of treatment, and 4 iSD (1 in 2 mg/kg, 3 in 3 mg/kg) were recorded. Conclusions: HE0116 administrated intravenously every 3 weeks is well tolerated with minimal toxicities. Preliminary data are very encouraging as single agent HE0116 showed durable responses with 1 iPR, 4 iSD in several difficult to treat late-stage cancer pts. Dose escalation is ongoing as per study protocol. Phase II in select patient populations, and clinical investigation of the combination of HE0116 with CTLA-4 or PD-1 are warranted. Clinical trial information: CTR20201794.