Preliminary Clinical Activity Research Articles

Antitumor activity of the investigational B7-H3 antibody-drug conjugate, vobramitamab duocarmazine, in preclinical models of neuroblastoma

IntroductionB7-H3 is a potential target for pediatric cancers, including neuroblastoma (NB). Vobramitamab duocarmazine (also referred to as MGC018 and herein referred to as vobra duo) is an investigational duocarmycin-based antibody-drug...

Use of tamibarotene, a potent and selective RARα agonist, in combination with azacitidine in patients with relapsed and refractory AML with RARA gene overexpression

Tamibarotene-based therapy is a novel targeted approach for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with retinoic acid receptor alpha (RARA) gene overexpression. Approximately, 50% of higher-risk myelodysplastic syndrome (MDS) patients and approximately 30% of AML patients are positive for RARA overexpression using a blood-based biomarker test that measures RARA expression in peripheral blasts. A phase 2 study investigating the activity of tamibarotene in patients with RARA overexpression was conducted in patients with AML and MDS (NCT02807558). In 28 patients with R/R AML and RARA overexpression treated with tamibarotene in combination with azacitidine, the median overall survival was 5.9 months. In 21 response-evaluable patients, the complete remission/complete remission with incomplete hematologic recovery (CR/CRi) rate was 19%, and median time to initial CR/CRi was 1.2 months. The favorable safety profile and preliminary clinical activity support the development of combination therapies with tamibarotene in myeloid malignancies with RARA overexpression.

SAMETA: A Phase III study of savolitinib + durvalumab vs sunitinib and durvalumab monotherapy in patients with MET-driven, unresectable, locally advanced/metastatic papillary renal cell carcinoma

Abstract Background Papillary renal cell carcinoma (PRCC) is the most common subtype of non-clear cell renal cell carcinoma (RCC) and accounts for 10–15% of RCCs. Many PRCC cases are MET-driven, characterized by genomic abnormalities resulting in dysregulation of the MET signaling pathway, making these abnormalities a potential therapeutic target for treatment. The estimated prevalence of MET-driven status is 35−40% in PRCC. Savolitinib is an oral, potent and highly selective MET tyrosine-kinase inhibitor (TKI) demonstrating preliminary clinical activity in advanced solid tumors, including in MET-driven PRCC, defined as presence of any of the following molecular alterations, in the absence of co-occurring fumarate hydratase mutations: chromosome 7 gain, MET amplification, MET kinase domain variations, or hepatocyte growth factor amplification. In the Phase III SAVOIR study, in PRCC, savolitinib monotherapy showed encouraging efficacy vs the multi-targeted TKI, sunitinib. In addition, non-clinical studies suggest a possible synergistic anti-tumor effect of MET-inhibitors and programmed cell death-ligand (PD-L1) inhibitors, such as durvalumab; emerging data from the Phase I/II CALYPSO study investigating savolitinib plus durvalumab shows a notable efficacy signal in patients with MET-driven PRCC. Following these findings, the SAMETA study (NCT05043090) is designed to evaluate the efficacy and safety of savolitinib in combination with durvalumab vs sunitinib and durvalumab monotherapy in PRCC. Trial Schema In this open-label, three-arm, multi-center, Phase III study, adult patients with unresectable, MET-driven and locally advanced/metastatic PRCC are eligible. An estimated 200 patients (25 countries, 165 centers) will be randomized in a 2:1:1 ratio into three treatment arms (A–C) with stratification by International metastatic RCC database consortium risk group & PD-L1 expression tumor status. Arm A: oral savolitinib 600 mg once daily plus intravenous durvalumab 1500 mg every 4 weeks; Arm B: oral sunitinib 50 mg once daily for 4 consecutive weeks, followed by a sunitinib-free interval of 2 weeks every 6 weeks; Arm C: intravenous durvalumab 1500 mg every 4 weeks. Study treatment continues until RECIST 1.1 disease progression, or another discontinuation criterion is met. The primary endpoint is progression-free survival (by Blinded Independent Central Review; Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints include overall survival, objective response rate and duration of response. Safety (adverse events, vital signs, echocardiograms, hematology and biochemistry parameters) will also be reported. Current status The first patient was enrolled onto the study on 28 October 2021. At the early enrollment stage, during the biomarker pre-screening, approximately 29% of patients with PRCC who submitted a sample had eligible MET-driven status and of these patients with MET-driven PRCC, approximately 84% also met other eligibility criteria and were randomized.

Selected Articles from This Issue

Highlights| June 13 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2023 American Association for Cancer Research2023American Association for Cancer Research Clin Cancer Res (2023) 29 (12): 2171. https://doi.org/10.1158/1078-0432.CCR-29-12-HI Related Content A commentary has been published: Proinflammatory Macrophage Activation by the Polysialic Acid-Siglec-16 Axis Is Linked to Increased Survival of Patients with Glioblastoma A commentary has been published: SALVO: Single-Arm Trial of Ipilimumab and Nivolumab as Adjuvant Therapy for Resected Mucosal Melanoma A commentary has been published: Eganelisib, a First-in-Class PI3Kγ Inhibitor, in Patients with Advanced Solid Tumors: Results of the Phase 1/1b MARIO-1 Trial View more A commentary has been published: Clinical Importance of the lncRNA NEAT1 in Cancer Patients Treated with Immune Checkpoint Inhibitors View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record June 13 2023 Citation Selected Articles from This Issue. Clin Cancer Res 15 June 2023; 29 (12): 2171. https://doi.org/10.1158/1078-0432.CCR-29-12-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Eganelisib (IPI-549) is a first-in-class, potent, and highly selective phosphoinositide-3-kinase (PI3K)-γ inhibitor. Based on preclinical studies, PI3K-γ blockade reprograms myeloid cells to a proinflammatory phenotype, leading to immune activation in the tumor microenvironment and synergistic antitumor activity in combination with checkpoint inhibitors. In this study, Hong and colleagues present the data from MAcrophage Reprogramming in Immuno-Oncology-1 (MARIO-1), the first-in-human study of eganelisib as monotherapy and in combination with nivolumab in patients with advanced solid tumors. The overall safety profile was manageable both as monotherapy and combination therapy. Based on safety, preliminary clinical activity, pharmacokinetic, and pharmacodynamic results of this study, eganelisib doses of 30 mg and 40 mg daily are being investigated in combination with immune checkpoint inhibitors in phase II clinical trials. Checkpoint inhibitors have made tremendous improvements in outcomes for cutaneous melanoma both in the metastatic and adjuvant settings. For mucosal melanoma, which confers a worse prognosis, small... You do not currently have access to this content.

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

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

A novel anti-HER2 monoclonal antibody IAH0968 in HER2-positive, heavily pretreated solid tumors: Results from a phase Ⅰa/Ⅰb, first-in-human, open-label, single-center study.

e15098 Background: IAH0968 is an afucosylated anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody which possessing the same binding properties to HER2 as trastuzumab and improving antibody-dependent cellular cytotoxicity (ADCC) activity and superior anti-tumor efficacy. We present results from patients with advanced HER2 positive malignant solid tumors including trastuzumab resistant and ineffective patients to establish the recommended dose of IAH0968 for phase II trials, as well as to investigate the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of the drug. Methods: This was a single institution investigator-initiated phaseⅠa/Ⅰb study, using 3+3 design. The primary endpoint was safety, tolerability and preliminary clinical activity. Secondary endpoints included PK, recommended phase II dose, and anti-drug antibody (ADA). PK detection used ELISA to quantitatively determine blood drug concentration of IAH0968. Results: Eighteen pts were evaluable for safety and fifteen pts were suitable for efficacy analysis. The primary cancer sites included breast (8/18), colon (3/18), stomach (2/18), rectum (2/18), biliary tract (2/18), and pancreas (1/18). Median age was 54.2±9.7, ECOG 1/2 = 17/1, and 72.2% received anti-HER2 therapy in prior lines. Doses escalation were 6mg/kg (N = 3), 10mg/kg (N = 6), 15mg/kg (N = 5), and tolerable up to 20mg/kg (N = 4). Only one DLT was found at dosage 10mg/kg, and no MTD was reached. No ADA against IAH0968 was detected. The main PK parameters included mean T1/2 for doses 6~20 mg/kg ranging from 105 to 118 hours. The volume of distribution (Vz-obs) ranged from 4110.16 mL to 5395.64 mL. EC50 of ADCC activity of IAH0968 was 17.75~63.25 ×10-3 µg/mL. All grade treatment-related adverse events (TRAEs) occurred in 100% of pts, including grade 3 in 16.7%, and grade 4 in 5.6% of pts. The most common grade 3 TRAEs were hypokalemia (5.6%), arrhythmia (5.6%), QTC interval extension (5.6%), and infusion reaction (5.6%). The grade 4 TRAE was arrhythmia (5.6%). No serious TRAE or G5 were reported. 22.2% of pts had a TRAE leading to dose adjustment and 16.7% leading to discontinuation of IAH0968. After a median follow-up of 56.5 days (range, 0-479), objective response rate (ORR) was 13.3% (2/15), disease control rate (DCR) was 53.3% (8/15), and median progression-free survival (PFS) was 57.5 days (range, 42-236), with 4/15 responses ongoing. Conclusions: In heavily pretreated metastatic pts with HER2 positive, IAH0968 demonstrated promising clinical activity and tolerable safety profiles. IAH0968 will be further assessed in Phase Ⅱ study in combination treatment. Clinical trial information: NCT04934514 .

HB-300, a novel arenavirus-based cancer immunotherapy in patients with metastatic castration-resistant prostate cancer.

TPS5108 Background: Prostate cancer is the most frequent type of malignant neoplasia in men. Immunotherapy targeting self-antigens in prostate cancer is evolving and requires overcoming multiple mechanisms that mediate immune tolerance. Sipuleucel-T, a cell-based therapy recognizing prostatic acid phosphatase (PAP) protein, is approved for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and induced PAP-specific T cell responses correlating with overall survival (OS). Poxvirus vectors encoding prostate-specific antigen (PSA) increased PSA-specific T cell levels and were associated with OS benefit, although not confirmed in a Phase 3 study. Arenaviral vectors used in preclinical tumor models could overcome self-tolerance by inducing strong self-antigen specific CD8 T cell responses. In humans, arenaviral vectors encoding HPV16 E7E6 fusion protein (HB-200) induced unprecedented E6E7-specific CD8 T cell levels in patients with recurrent/metastatic HPV16+ cancers. Preliminary clinical activity and favorable safety and tolerability were observed in these heavily pre-treated, checkpoint inhibitor-resistant patients (ref: Fu et al. ASCO 2022; NCT04180215). It is therefore hypothesized that HB-300, a live-attenuated arenaviral vector therapy encoding the self-antigens PAP and PSA, will induce substantially stronger T cell responses in prostate cancer patients than previously tested active immunization approaches. Methods: This is a Phase 1/2 open-label clinical study of HB-300 in ~ 70 patients with advanced mCRPC. A 3+3 Dose Escalation will be followed by a dose-expansion to confirm the recommended Phase 2 dose (RP2D). HB-300 consists of HB-302 (Pichinde virus based) alternating with HB-301 (LCMV based) vectors, administered IV every 3 weeks (Q3W) for 5 doses then Q6W. The program’s entry into the clinic with a mini dose-escalation was supported by the submission of a data master file along with the HB-300 Investigational New Drug application, based on arenavirus vector platform data collected in the HB-200 program. Trial inclusion criteria include male participants age ≥ 18; documented mCRPC (adenocarcinoma without neuroendocrine or small cell features); receipt of at least 1 androgen deprivation therapy and no prior chemotherapy regimens (docetaxel in the castration-sensitive setting is allowed); ≥1 measurable lesion; ECOG PS 0-1. Exclusions are uncontrolled pain or symptoms; active auto-immune disease; immunosuppression; active central nervous system or liver metastasis; and active infection. Phase 1 primary objectives include safety/tolerability and determination of RP2D, secondary objectives include preliminary efficacy, and exploratory assessments include antigen-specific T cell response and circulating tumor cell analysis. Clinical trial# NCT05553639. Clinical trial information: NCT05553639 .

STAR-121: A phase 3, randomized study of domvanalimab (DOM) and zimberelimab (ZIM) in combination with chemotherapy vs pembrolizumab (pembro) and chemotherapy in patients with untreated metastatic non-small cell lung cancer (mNSCLC) with no actionable gene alterations.

TPS9141 Background: Although immune checkpoint inhibitors have improved clinical outcomes in mNSCLC, the majority of patients will experience progression and shorter survival. Thus, an urgent need exists for more effective treatment options in mNSCLC. DOM is an anti-TIGIT IgG1, Fc-silent monoclonal antibody designed to inhibit the interaction between TIGIT and its ligand, CD155, thereby reducing immunosuppression of T cells and natural killer cells and promoting antitumor activity. ZIM is an anti–PD-1 IgG4 monoclonal antibody with demonstrated antitumor activity in vivo and preliminary clinical activity in multiple tumor types. Preliminary studies have shown that dual blockade of TIGIT and PD-(L)1 increases antitumor activity relative to PD-(L)1 inhibition. In ARC-7, a randomized phase 2 study in PD-L1–high, first-line NSCLC, DOM and ZIM in combination recently demonstrated a higher objective response rate (ORR) and longer median progression-free survival (PFS) than ZIM monotherapy. We hypothesize that DOM and ZIM in combination with chemotherapy will improve clinical outcomes in patients with untreated mNSCLC without EGFR or ALK aberrations regardless of PD-L1 expression. Methods: STAR-121 is a phase 3, global, open-label, randomized study to evaluate the safety and efficacy of DOM and ZIM plus chemotherapy vs pembro plus chemotherapy as first-line therapy for patients with mNSCLC with no EGFR or ALK aberrations or other known actionable gene alterations. Approximately 720 patients will be randomized into 3 groups (A, B, or C) in a 4:4:1 ratio and stratified by baseline PD-L1 tumor proportion score ( < 50% vs ≥50%), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Eligible patients are aged ≥18 with untreated mNSCLC with no EGFR or ALK aberrations. Group A will receive DOM 1200 mg + ZIM 360 mg + platinum-doublet chemotherapy (PT), group B will receive pembro 200 mg + PT, and group C will receive ZIM 360 mg + PT. DOM, ZIM, and pembro will be administered until disease progression (PD) as assessed by blinded independent central review (BICR) per RECIST 1.1 or intolerable toxicity or for up to 35 doses. Study treatment will be administered IV every 3 weeks. PT will be chosen by investigators based on tumor histology and administered for the first 4 cycles, after which, pemetrexed can be continued for patients with nonsquamous histology until PD or intolerable toxicities. The primary endpoints are PFS by BICR and overall survival. Key secondary endpoints are ORR and duration of response by BICR, safety, and quality of life. This study is currently enrolling globally. Clinical trial information: NCT05502237 .

A first-in-human, open-label, phase I trial of daily oral PCLX-001, an NMT inhibitor, in patients with relapsed/refractory B-cell lymphomas and advanced solid tumors.

e15094 Background: Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, regulates multiple membrane-bound signal transduction pathways driving cancer cell biology. This modification is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2. Aberrant NMT expression has been identified in cancer cells and inhibition of myristoylation represents a novel anticancer treatment strategy. PCLX-001 is an oral, highly bioavailable, small molecule NMT inhibitor with strong affinity for both NMT1 and NMT2 proteins (IC50 of 5nM and 8nM, respectively). In vitro, hematologic cancer cell lines were exquisitely sensitive to PCLX-001. PCLX-001 regressed subcutaneous tumors in xenograft models derived from lymphoma cell lines, as well as in a refractory DLBCL patient derived xenograft model. PCLX-001 also demonstrated anticancer activity in multiple solid tumor xenograft models. Based on pre-clinical data, we hypothesized that PCLX-001 would be safe, tolerable, and active as a novel oral cancer therapeutic. Methods: Patients with relapsed/refractory B-cell lymphomas and advanced solid tumors are being enrolled in a multicenter, open label, standard phase I dose escalation design to determine feasibility, maximum tolerated dose (MTD), and pharmacokinetics of PCLX-001 monotherapy. Seven dose levels are being studied: 20 mg, 40 mg, 70 mg, 100 mg, 140 mg, 200 mg, and 280 mg. Dose limiting toxicity (DLT) is defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, Gr 4 ANC ≥ 7 days, febrile neutropenia, or clinically significant > Gr 3 non-hematologic toxicity. Results: Eighteen evaluable patients (3 relapsed B-cell lymphoma; 15 advanced solid tumor) have been accrued through dose level six (200 mg cohort) without DLT. No attributable Gr 3 or 4 toxicities have been identified. Noncompartmental pharmacokinetic (PK) analyses demonstrate rapid oral absorption, a terminal half-life of approximately 10 hours, rapid achievement of steady state, and no induction of metabolism. PCLX-001 trough plasma concentrations at higher dose cohorts exceed the EC90 required to inhibit cultured cancer cells. Conclusions: PCLX-001 is safe and well tolerated up to the 200 mg daily dose. Our results support the ongoing development of PCLX-001 as an oral daily therapy for the treatment of patients with cancer. Updated study results will be presented, summarizing the safety, MTD, and PK outcomes in PCLX-001 treated patients. Preliminary clinical activity will be determined in 20 patient dose expansion cohorts of relapsed/refractory B-cell lymphomas, and selected advanced solid tumors following the identification of PCLX-001 MTD. Clinical trial information: NCT04836195 .

Concurrent durvalumab plus chemoradiation therapy followed by durvalumab in Chinese patients with unresectable stage III non-small cell lung cancer: CRUISER study.

e20576 Background: Concurrent chemoradiation therapy (CRT) followed by durvalumab consolidation therapy has demonstrated significant survival benefit for unresectable stage III non-small cell lung cancer (NSCLC) in PACIFIC trial. However, there are still 20%-30% patients who have disease progression (PD) or intolerable toxicity. This prospective study aimed to evaluate safety and clinical activity of concurrent durvalumab plus CRT followed by durvalumab in unresectable stage III NSCLC (NCT04982549). Methods: This is a single-arm, open-label, multicenter phase II clinical trial and planned to enroll 35 patients with unresectable stage III NSCLC of any PD-L1 expression level and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All of patients will receive concurrent durvalumab 1500mg every 4 weeks plus SoC CRT followed by durvalumab monotherapy 1500mg every 4 weeks until PD or unacceptable toxicity. One cycle of induction durvalumab plus chemotherapy is allowed before radiotherapy upon investigator discretion. The primary endpoint is the incidence of grade ≥3 immune-mediated adverse event (AE). Here we report the preliminary clinical activity and safety of a preplanned interim analysis of this study. Results: By September 2022, 28 patients finished concurrent durvalumab plus CRT treatment and were included for analysis. 21 (75%) of 28 patients had radiographic tumor evaluation and entered the consolidation treatment stage, 7 (25%) patients discontinued treatment without radiographic tumor evaluation because of intolerable AE (5 patients) or withdrawing from the study (2 patients). 20 (71.4%) of 28 patients received one cycle induction therapy of durvalumab plus chemotherapy. The median age of these 28 patients was 64 years old, 26 (92.9%) of 28 patients with ECOG performance status of 1, and 14 (50%) of 28 patients were squamous carcinoma. Disease stage was IIIA (42.9%, 12/28), IIIB (39.3%, 11/28) and IIIC (17.9%, 5/28), with most of them (89.3%, 25/28) had N2/N3 lymphatic metastasis. 19 (90.5%) of 21 patients achieved objective response. Median interval from enrollment to the first radiological evaluation was 112 days. Grade ≥3 treatment-related adverse event (TRAEs) occurred in 13(46.4%) of 28 patients, including six (21.4%) possibly related to durvalumab. Conclusions: The interim results from CRUISER study showed promising clinical activity and manageable toxicity of durvalumab plus concurrent CRT followed by durvalumab for unresectable stage III NSCLC. The survival outcome and biomarker exploration will be analyzed upon data maturity. Phase 3 PACIFIC-2 study investigating clinical outcome of concurrent durvalumab plus CRT in unresectable NSCLC is ongoing. Clinical trial information: NCT04982549 .

Phase 1 trial of KT‐333, a STAT3 degrader, in patients with relapsed or refractory lymphomas, large granular lymphocytic leukemia and solid tumors

Background: KT-333 is a first-in-class, potent, highly selective, heterobifunctional small molecule degrader of the signal transducer and activator of transcription 3 (STAT3) protein. Aberrant activation of STAT3 resulting from activating mutations or deregulated cytokine signaling is known to underlie a variety of malignancies including peripheral T-cell lymphomas (PTCL), cutaneous T-cell lymphoma (CTCL), and large granular lymphocytic leukemia (LGL-L). However, selective targeting of STAT3 has been a therapeutic challenge. In preclinical xenograft studies, treatment with KT-333 resulted in durable tumor regressions in STAT3-dependent T cell lymphomas. Pharmacokinetic (PK) and pharmacodynamic (PD) analysis demonstrated that STAT3 degradation of >90% in tumor for 48 h is required for anti-tumor efficacy. Methods: The ongoing multicenter Phase 1a/1b study evaluates the safety, tolerability, PK, PD and preliminary clinical activity of KT-333 administered as a weekly IV infusion in 28-day cycles. The Phase 1a will identify the recommended phase 2 dose based on dose limiting toxicity (DLT) observed in Cycle 1. Eligible patients include those with advanced solid tumors and relapsed or refractory B- and T-cell lymphomas, Hodgkin’s lymphoma, and LGL leukemia. Serial blood samples are collected in Cycle 1 and Cycle 2 to measure KT-333 plasma concentrations and STAT3 protein expression in PBMCs (using targeted mass spectrometry). STAT3 degradation and the impact on tumor biology is measured in patients with accessible tumors. Results: As of February 3, 2023, seven patients have been treated in the first two dose levels (DLs) in Phase 1a, including patients with CTCL and PTCL with median age of 65 (range 57, 74) and performance status of 0 (n = 1) and 1 (n = 6). No DLTs have been observed and no patients have discontinued KT-333 due to an adverse event. The most common adverse events are Grade 1 and 2 and include constipation, fatigue, abdominal pain, dizziness, and nausea. PD data in blood demonstrated robust and sustained STAT3 degradation with mean maximum decrease of PBMC STAT3 levels after dosing on Days 1 and 8 of 66% in DL1 (n = 4) and 70% in DL2 (n = 2). PK results were in line with the modeled predictions. Conclusion: The emerging clinical data suggest that KT-333 is a potent degrader of STAT3 as demonstrated in PBMCs at doses that are well tolerated. These data provide the first evidence of STAT3 targeted protein degradation in humans and point to the potential of heterobifunctional degraders for targeting previously undruggable targets. It is projected that higher doses of KT-333 will achieve the predicted degradation profile in tumors that may translate into clinical benefit in patients with STAT3-dependent T cell malignancies. Accrual into the study is ongoing, and analyses from additional patients will be presented at the meeting. The research was funded by: Kymera Therapeutics Keywords: Aggressive T-cell non-Hodgkin lymphoma, Cutaneous non-Hodgkin lymphoma, Therapeutics and Clinical Trials in Lymphoma Conflicts of interests pertinent to the abstract. A. Olszewski Consultant or advisory role: Schrodinger, Genmab Research funding: Genentech, Schrodinger, PrecisionBio, Adaptive biotechnologies Z. Epstein-Peterson Honoraria: OncLive Research funding: Kymera, Viracta, Amgen R. Perea Employment or leadership position: Kymera Stock ownership: Kymera; Pfizer A. Gollerkeri Employment or leadership position: Kymera Stock ownership: Kymera, Pfizer J. Dey Employment or leadership position: Kymera Therapeutics Stock ownership: Kymera Therapeutics C. Klaus Employment or leadership position: Kymera Therapeutics Stock ownership: Kymera Therapeutics S. Agarwal Employment or leadership position: Kymera Stock ownership: Kymera J. Gollob Employment or leadership position: Kymera Stock ownership: Kymera A. Shastri Consultant or advisory role: Janssen Pharmaceuticals, Gilead Sciences, Rigel Pharmaceuticals and Kymera Therapeutics Honoraria: NACE & PeerView. Research funding: Kymera Therapeutics

Preclinical characterization of a novel anti-CD39/TGFβ-trap bispecific antibody that aims to modulate tumor microenvironment.

e14523 Background: Adenosine and TGF-β are two key immune suppressors in tumor microenvironment (TME) that cause broad immune suppression resulting in resistance to current CPI immunotherapies. Cancer cells, and other cell types within TME, frequently express TGFβ, which inhibits CD8+ T and Th1 cells and promotes epithelial–mesenchymal transition. We have designed a bi-specific targeting molecules blocking the two inhibitory pathways, aiming to create an immune-friendly TME. Methods: We have created a bifunctional antibody–ligand trap called ES014 that comprises an antibody targeting CD39 fused to a TGFβ receptor II ectodomain sequence. ES014 molecule could simultaneously disable CD39 to prevent extracellular ATP from degradation and neutralize autocrine/paracrine TGFβ in the vicinity of target cells. The immunological function of ES014 was studied in series of in vitro immuno-assays. The in vivo efficacy of ES014 was investigated in human PBMC engrafted models. The effects of ES014 on immune cells were also analyzed using malignant pleural effusions (MPE) collected from lung cancer patients. The pharmacokinetics (PK), pharmacodynamics (PD) and safety profile were assessed in cynomolgus monkeys after intravenous administration of ES014. Results: The bispecific antibody, ES014 exhibited synergistic effects in T cell activation and suppression of Treg differentiation. ES014 activates dendritic cells, macrophages and natural killer cells by maintaining extracellular ATP level and neutralizing the immune-suppressive effects of TGFβ. Interestingly, ES014 demonstrated a unique mechanism by protecting effector T cells from activation induced cell death (AICD), which was not observed with TGFβ receptor or anti-CD39 antibody alone, or the combination of the two. The ES014 molecule is effective in inhibiting tumor progression in a PD-1 antibody-unresponsive in vivo model. Treatment of ES014 in malignant pleural effusions (MPE) collected from lung cancer patients led to the switch of M2 to M1 macrophage as indicated by increased CD86 expression and decreased CD163 expression on CD11b+ cells. Importantly, more CD8+ T cells were maintained with ES014 treatment in MPE as compared to control, resulting in significant reduction of cancer number. ES014 was well tolerated in cynomolgus monkeys, and a phase I clinical study is ongoing to investigate the safety, tolerability, PK, PD and preliminary clinical activity of ES014 in patients with advanced solid tumors. Conclusions: ES014 is a first-in-class molecule that simultaneously targeting CD39 and TGFβ. ES014 counteracts TGFβ-mediated differentiation of Tregs and adenosine-induced immune tolerance, and protected effector T cells from AICD. Treatment of ES014 resulted in significant anti-tumor effects in ex vivo and in vivo efficacy models. A single agent activity of ES014 is therefore expected in clinical trials.

Preliminary results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with metastatic BRAF V600E mutated colorectal cancer (CRC) in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies (GI cancers).

3557 Background: The RAS/MAPK pathway (including BRAF) is dysregulated in a broad range of cancers including CRC, resulting in downstream activation of ERK1/2. Metastatic CRC with BRAF V600E mutation (BRAF V600E mCRC) has dramatically worse survival than non-BRAF V600E mutated CRCs, and novel therapies are needed. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK. The combination of a BRAF plus EGFR inhibitor (EC) is approved for the treatment of pts with BRAF V600E mCRC; however, only 20% of pts experience an objective response. ERAS-007 alone or in combination with EC showed promising in vitro and in vivo activity in BRAF V600E CRC models to support the combinatorial clinical benefit of ERAS-007+EC in BRAF V600E mCRC. Methods: HERKULES-3 is a Phase 1b/2 study to assess the safety, tolerability, PK, and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety and tolerability of escalating doses of ERAS-007 + EC in pts with BRAF V600E CRC. Prior BRAF inhibitor and EGFR inhibitor treatment is neither required nor excluded to be enrolled in this study. Results: As of 30 November 2022, 12 patients were dosed with ERAS-007 twice daily-once a week (BID-QW) (75 and 100 mg; n = 10) or once daily once a week (QW) (150 mg; n = 2) in combination with EC (300 mg oral daily + 500 mg/m2 intravenous infusion once every 2 weeks). The treatment-emergent AEs (TEAEs) occurring in ≥20% of pts were fatigue (50%), headache (42%), constipation, diarrhea, nausea, dermatitis acneiform (33% each), and vomiting (25%). No TEAEs led to ERAS-007 discontinuation or death. Grade ≥3 TEAEs were reported in 3 pts (25%). Grade ≥3 treatment-related AEs reported in ≥ 2 patients (17%) include hypertension, headache, confusional state, and skin toxicity. Three pts (25%) died due to disease progression. No DLTs were reported. Out of 4 efficacy evaluable EC naïve pts, one confirmed partial response (PR) and one unconfirmed PR were observed. Evaluation of PK is ongoing and preliminary data will be presented. Conclusions: ERAS-007+EC in pts with BRAF V600E CRC shows acceptable preliminary safety/tolerability and evidence of clinical activity. The highest dose of ERAS-007 evaluated and cleared by the safety review committee to date is 100 mg BID-QW when combined with EC. Observed PK, toxicity, and preliminary activity support continued evaluation of this combination in pts with BRAF V600E CRC. Clinical trial information: NCT05039177 .

Preliminary results from ERAS-007 plus palbociclib (palbo) in patients (pts) with KRAS/NRAS mutant (m) colorectal cancer (CRC) or KRASm pancreatic ductal adenocarcinoma (PDAC) in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies (GI cancers).

3558 Background: The RAS/MAPK pathway is dysregulated in a broad range of cancers including CRC and PDAC, resulting in downstream activation of ERK1/2. ERAS-007 is a novel, orally bioavailable inhibitor of ERK. Palbo is an oral CDK4/6 inhibitor that inhibits cellular proliferation, an essential feature of tumor growth. Both in vitro & in vivo data exploring the combination of ERAS-007 and palbo in a panel of CRC and pancreatic CDX and/or PDX models have shown promising activity to support the potential combinatorial clinical benefit in RASm CRC and PDAC pts. Methods: HERKULES-3 is a Phase 1b/2 study to assess safety, tolerability, PK, and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety, tolerability, and PK of escalating doses of ERAS-007 twice daily-once a week (BID-QW) (75, 100 mg) in combination with palbo once daily (QD) (75, 100, 125 mg) in pts with KRASm/NRASm CRC or KRASm PDAC. Results: As of 30 November 2022, 30 pts were dosed with the combination of palbo and ERAS-007. Treatment emergent AEs (TEAEs) occurring in ≥20% pts were diarrhea (40%), nausea (40%), anemia (33%), vision blurred (27%), fatigue (23%), and neutrophil count decreased (20%). ERAS-007 treatment related AEs (TRAEs) were reported in 19 pts (63%), with the most frequently reported as diarrhea (40%), nausea (33%), and vision blurred (27%). Grade (Gr) ≥3 TEAEs were reported in 12 pts (40%), including 3 related to ERAS-007 (neutrophil count decreased, diarrhea and dermatitis acneiform). Neutrophil count decreased and anemia were the only Gr 3 events reported in ≥2 pts. No Gr 4 events were reported. Two Gr 5 events unrelated to any drugs (hemorrhage intracranial and malignant pleural effusion) and one Gr 5 event (anemia) related to palbo were reported. Two pts discontinued ERAS-007 due to TEAEs (Gr 5 malignant pleural effusion and Gr 2 neutrophil count decreased). Three pts reported 4 DLTs: 1 pt at 75mg ERAS-007 & 125mg palbo (Gr 3 maculopapular rash & Gr 4 sepsis), 1 pt at 100mg ERAS-007 & 100mg palbo (Gr 3 dermatitis acneiform), and 1 pt at 100mg ERAS-007 & 125mg palbo (Gr 3 thrombocytopenia). Based on preliminary PK, no clinically relevant PK interactions were identified between ERAS-007 and palbo. The evaluation of clinical activity is ongoing. Conclusions: ERAS-007 in combination with palbo in pts with KRASm/NRASm CRC or KRASm PDAC shows expected preliminary safety with reversible and manageable AEs. The highest dose evaluated and cleared by the safety review committee to date is ERAS-007 100 mg BID-QW in combination with the approved monotherapy dose of palbo 125 mg QD. Clinical trial information: NCT05039177 .

Phase 1/1b study of SY-5609, a selective and potent CDK7 inhibitor, in advanced solid tumors and in 2L/3L pancreatic ductal adenocarcinoma (PDAC) in combination with gemcitabine +/- nab-paclitaxel.

3080 Background: SY-5609 is an oral, highly selective and potent noncovalent inhibitor of CDK7, a key regulator of cell cycle progression and transcription. In this Phase 1 FIH study (NCT04247126), the single agent (SA) continuous daily dosing (CDD) regimen maximum tolerated dose (MTD) was 3 mg/day. Subsequently, enhanced tolerability was demonstrated using an intermittent 7 day on/7 day off (7/7) schedule at higher dose levels (Sharma 2021). SY-5609 preclinical data and early clinical activity provided the rationale for evaluating SY-5609 + gemcitabine (gem) +/- nab-paclitaxel (np) in PDAC. Herein, we present data from the ongoing SA dose escalation and SY-5609 + gem +/- nab-paclitaxel (np) safety lead-ins (SLIs). Methods: The 7/7 schedule was used to further evaluate SA escalation in pts with select solid tumors. In the PDAC combination SLIs, SY-5609, starting with a dose of 4 mg, is escalated using the 7/7 schedule in combination with biweekly gem (1000 mg/m2) +/- np (125 mg/m2). Evaluations included safety, clinical activity (RECIST v1.1), PK, and induction of peripheral blood PD marker POLR2A (Papadopoulos 2020). Results: As of 13 Jan 2023, 87 pts have been enrolled (70 SA, 14 SY-5609 + gem, 3 SY-5609 + gem/np), including 30 pts across the 4, 5, 6, 7, and 10 mg SA 7/7 cohorts included in the safety summary. MTD for the 7/7 schedule has not been reached. The 15 mg SA cohort is now enrolling. Most SA 7/7 AEs were low-grade; AEs included (>20%) nausea, diarrhea, fatigue, anorexia, and thrombocytopenia. No new safety signals were observed in the SY-5609 4 mg and 5 mg + gem and SY-5609 4 mg + gem/np cohorts; 1 pt (SY-5609 5 mg + gem) had a DLT of Gr3 diarrhea. The 10 mg + gem cohort is now enrolling. Most SY-5609 + gem +/- np AEs were low grade. AEs in the SLIs were consistent with the safety profile of either SY-5609 or gem +/- np and included (>20%) fatigue, anorexia, nausea, abdominal pain, and constipation. In the SA cohorts (response-evaluable, n=29), 100% (3/3) of pts in the 10 mg 7/7 cohort had stable disease (SD) as the best response, compared to 19% (5/26) SD rate in 4 to 7 mg SA 7/7 cohorts. Disease control rate in the combination SLIs (response-evaluable, n=11) was 45% (5/11), including 1 confirmed partial response (4 mg + gem) in a patient with liver metastases who had a reduction in CA 19-9 from 60,357 U/mL to 968 U/mL, and SD in 4 pts (3 in 5 mg + gem, 1 in 4 mg + gem/np). SA and SLI PK data support an emerging exposure-activity relationship. POLR2A PD marker data from SA and SLI cohorts correlate with exposure. Conclusions: To date, intermittent dosing of SY-5609 on the 7/7 schedule has acceptable tolerability alone and in combination with gem +/- np. Encouraging preliminary clinical activity and the emerging exposure-activity relationship supports the ongoing escalation of SY-5609 in SA and combination SLI cohorts; updated results will be presented. Clinical trial information: NCT04247126 .

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

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

Abstract CT253: Phase 1/2 study of the safety, pharmacokinetics, and preliminary clinical activity of BT7480 in patients with nectin-4 associated advanced malignancies

Abstract Background: Bicycles are a novel class of synthetic molecules formed by using a central scaffold to constrain short linear peptides into a stabilized bi-cyclic structure, which can then be readily conjugated to other molecules. BT7480 is a trimeric first-in-class Bicycle tumor-targeted immune cell agonist (Bicycle TICA) comprised of two unique bicyclic peptides: one that binds to Nectin-4 and two identical Bicycles that bind and agonize CD137. The resulting multi-specific molecule stimulates an immune response in the presence of both Nectin-4-expressing tumor cells as well as CD137-expressing immune cells. Nectin-4, a cell adhesion molecule overexpressed on the surface of tumor cells and CD137, a costimulatory receptor expressed on immune cells, are co-expressed in a variety of solid tumors including lung, head and neck, breast, ovarian, and bladder. Co-ligation of Nectin-4 and CD137 by BT7480 is hypothesized to induce oligomerization and activation of CD137, resulting in a tumor-localized costimulatory signal. A favorable preclinical profile supported the initiation of this first-in-human study to investigate the safety and efficacy of BT7480 in patients with solid tumors associated with Nectin-4 expression (NCT05163041). Methods: This is a phase 1/2, open-label, multicenter study to assess safety, clinical activity, and pharmacokinetics (PK) and pharmacodynamics (PD) of BT7480. Patients must have an advanced malignancy associated with Nectin-4 expression that is not eligible for standard therapy. Additional key criteria include ≥18 years of age, ECOG of 0 or 1, adequate organ function, and no prior therapy with a CD137-targeted agent. Patients are treated at one of the escalating doses (3+3 design) by weekly IV infusion in a 4-week cycle. Primary objectives are to assess safety (phase 1) and clinical activity per RECIST v1.1 (phase 2). Secondary objectives include assessment of PK parameters, measurement of anti-drug antibodies, and evaluation of CD137 target engagement in blood. Key exploratory objectives include evaluating pharmacogenomics, ctDNA, and biomarkers in blood and tumors associated with pharmacological activity, including signals of immune activations and target expression. PK and PD analyses will be performed to support dose escalation decisions and to further the understanding of safety and clinical activity signals as a result of treatment with BT7480. This study is actively recruiting. Citation Format: Thomas R. Evans, Afshin Dowlati, Juanita S. Lopez, Mohammed M. Milhem, Jordi Rodón Ahnert, Alexander Spira, Richard D. Carvajal, Matthew Zibelman, Sebastien J. Hazard, Amy Dickson, Lei Xu, Heather Cohen, Justin Bader, Kristen Hurov, Rajiv Sharma, Dominic Smethurst, Kyriakos P. Papadopoulos. Phase 1/2 study of the safety, pharmacokinetics, and preliminary clinical activity of BT7480 in patients with nectin-4 associated advanced malignancies [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 CT253.

Abstract CT025: NMS-03592088, a novel, potent FLT3, KIT and CSF1R inhibitor with activity in FLT3 positive acute myeloid leukemia patients with prior FLT3 inhibitor experience

Abstract Background: FLT3 mutations occur in approximately 30% of AML patients and are associated with aggressive disease. Despite the approval of midostaurin and gilteritinib, the prognosis for FLT3+ patients with relapsed or refractory disease is poor. NMS-088 is a novel, potent FLT3, KIT and CSF1R inhibitor with superior preclinical activity compared with approved FLT3 inhibitors in different FLT3-driven models. In addition, NMS-088 is active on FLT3 resistance mutation F691L. Dose escalation results from a Phase I/II study to establish safety, dose selection and preliminary clinical activity for NMS-088 in patients with R/R AML and CMML are described. Methods: In the Phase I 3+3 escalations, NMS-088 is administered daily for 21 of 28 days (schedule A) or continuously (schedule B). Patients must have R/R AML or CMML unsuitable for standard therapy. The primary objective is the MTD or MAD as assessed by DLTs. Secondary endpoints include safety, PK and ELN response. Results: as of January 26, 44 R/R AML or CMML patients were treated at doses from 20 to 360 mg/day in A or from 120 to 250 mg/day in B. Median age was 64 yrs, 41 pts had AML and 3 pts had CMML, median number of prior lines was 2 (range 1 to 10). FLT3 mutations were present in 24 out of 41 AML pts (20 FLT3-ITD, 2 FLT3 D835 and 2 FLT3-ITD and D835). The majority of pts with FLT3+ AML had received prior FLT3 inhibitors (86.4%). NMS-088 showed manageable safety with no MTD characterized. One pt had DLT (abnormal posture, decreased activity, dyspnea G3 and eyelid ptosis G1) at 360 mg in A (at day 21) and one pt had DLT (eyelid ptosis G3) at 180 mg in B (at day 29), both suggestive for myasthenic syndrome. Three additional pts experienced possible myasthenic syndrome at doses ≥ 180 mg. Overall the most frequent treatment emergent related adverse events (≥10%) were nausea (any grade 20.5%), vomiting (13.6%), asthenia (11.4%). Discontinuations due to related AEs were as follows: 2 DLT pts per protocol, 2 pts due to nausea (G1; day 161 at 270 mg) and myasthenia gravis (G3; day 39 at 300 mg in a pt with baseline AChR antibodies). There was a dose-dependent trend for response. A total of 5 out of 12 evaluable pts with FLT3+ AML treated at dose ≥ 300 mg achieved a response with 2 CRi, 1 CRi/MLFS and 2 MLFS. Remarkably, all these pts had received prior midostaurin and 2 pts received both midostaurin and gilteritinib. Two pts with response withdrew from treatment to receive HSCT (DoR 1.0+ mos each). For other responding pts DoR was 1.3, 2.8 and 7.9 mos. Conclusions: NMS-088 showed clinical efficacy in pts with FLT3+ R/R AML, including pts who have failed prior FLT3 inhibitors. Together with the manageable safety observed, these results warrant further development of this drug including potential as a novel valuable therapeutic option for pts who have exhausted available treatments. The trial is currently opened for enrollment (NTC03922100). Citation Format: Antonio Curti, Alessandro Rambaldi, Chiara Cattaneo, Roberto Cairoli, Matteo Della Porta, Patrizia Chiusolo, Federico Lussana, Marta Ubezio, Valentina Mancini, Isabel Cano, Carmen Besliu, Christian Hove Claussen, Rosalinda Gatto, Patrizia Crivori, Elena Colajori, Alessio Somaschini, Cristina Davite, Antonella Isacchi, Elena Ardini, Lisa Mahnke, Pau Montesinos. NMS-03592088, a novel, potent FLT3, KIT and CSF1R inhibitor with activity in FLT3 positive acute myeloid leukemia patients with prior FLT3 inhibitor experience [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 CT025.

Abstract CT235: A phase I/II clinical study of an oncolytic adenovirus expressing the immunostimulatory transgenes TMZ-CD40L and 4-1BBL in advanced solid malignancies

Abstract There is a need for therapeutics with novel mechanisms-of-action for patients with advanced solid malignancies. In this first completed part of LOKON002, a phase I/II (NCT03225989) clinical study, the safety and clinical response to LOAd703 in combination with standard-of-care (SoC), or conditioning gemcitabine chemotherapy, was investigated. LOAd703 is an oncolytic adenovirus of serotype 5/35 modified to express two immunostimulatory transgenes, trimerized membrane-bound CD40L and 4-1BBL. In the completed part I (phase I and IIa) of the study, eligible patients with advanced pancreatic-, colorectal-, biliary- and ovarian cancer, were treated with increasing doses of LOAd703 (5 × 1010, 1 × 1011 and 5 × 1011 viral particles) using a standard 3+3 design. LOAd703 was administered intratumorally (ultrasound-guided) for up to 8 bi-weekly injections. The maximum tolerated dose tested was further evaluated in an extended dose cohort to confirm safety and assess preliminary clinical activity, and to select the best two indications for the part II of the study. Twenty-eight patients were enrolled in part I presented herein. Fifteen of these received LOAd703 combined with SoC, and thirteen in combination with conditioning gemcitabine. The most frequently reported treatment- or procedure-related adverse events were fever (82% of patients), chills (54%) and fatigue (43%). Four patients developed transient cytokine release syndrome. Twenty-five patients fulfilled the criteria to be evaluable for efficacy, which required receiving at least 3 doses of LOAd703 and results from a CT scan week 9. Partial response (PR) was achieved in two patients with pancreatic cancer treated at the highest LOAd703 dose level in combination with gemcitabine and nab-paclitaxel. One of the PRs was achieved at week 25, and the patient received one additional month of chemotherapy per protocol. This patient remained treatment-free for 17 months before chemotherapy was restarted due to progression, and was still alive at last follow-up 34 months after the study registration date. The other PR was achieved at week 17, two weeks after the last LOAd703 injection; disease progression was evident at week 33 and OS was 21 months. Three patients experienced stable disease for a minimum of 25 weeks. This included a patient with advanced ovarian cancer who showed SD at least until week 40, and had an OS of 40 months. No association between adverse events and response was identified. Anti-adenoviral antibody levels (IgG), which increased in all patients, could not be related to indices of clinical benefit. Based on the safety of LOAd703 at all dose levels studied, as well as evidence of objective clinical activity in patients with advanced pancreatic cancer, further disease-directed studies of intratumoral administration of LOAd703 are warranted. Citation Format: Amanda Hahn, Sandra Irenaeus, Jessica Wenthe, Emma Eriksson, Aglaia Schiza, Hanna Dahlstrand, Ulla Olsson-Strömberg, Johan Krause, Anders Sundin, Linda Sandin, Justyna Leja Jarblad, Maria Gustafsson Liljefors, Eric Rowinsky, Angelica Loskog, Gustav J. Ullenhag. A phase I/II clinical study of an oncolytic adenovirus expressing the immunostimulatory transgenes TMZ-CD40L and 4-1BBL in advanced solid malignancies [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 CT235.

Phase I Trial of Combination Therapy With Avelumab and Cabozantinib in Patients With Newly Diagnosed Metastatic Clear Cell Renal Cell Carcinoma.

Combination immunotherapy is now considered the standard first-line therapy for patients with metastatic clear cell renal cell carcinoma (mccRCC) after multiple clinical trials demonstrated improved overall survival compared with single-agent tyrosine kinase inhibitors. Cabozantinib modulates critical components of the immune system, such as decreasing regulatory T cells and increasing T-effector cell populations, and is approved for the treatment of mRCC. Avelumab is a human IgG1 monoclonal antibody that binds to programmed death-ligand 1 protein and inhibits the interaction with PD-1. This phase I trial assessed the safety and clinical activity of avelumab and cabozantinib combination therapy in mccRCC. This study was a phase I, 3+3 dose escalation clinical trial. The primary endpoint was the safety and identification of the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR) and radiographic progression-free survival (rPFS). There were 3 dose cohorts: cabozantinib 20, 40, and 60 mg/day, each combined with avelumab (10 mg/kg intravenously every 2 weeks). An additional 3 patients were included in the final dose cohort as a confirmation of the RP2D. No dose modifications were allowed for avelumab, but dose delays were permitted. Both dose reductions and holds were allowed for cabozantinib. Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was used to determine ORR, and treatment beyond progression was allowed. Twelve patients with newly diagnosed mccRCC were enrolled from July 2018 until March 2020. Three patients were enrolled in the 20 and 40 mg cohorts each, and 6 were enrolled in the 60 mg cohort. The International Metastatic RCC Database Consortium (IMDC) risk categories for these patients were: 4 patients (favorable risk), 6 patients (intermediate risk), and 2 patients (poor risk). No dose-limiting toxicities (DLTs) were observed in any cohort. Six patients developed serious adverse events related to study treatment after the DLT window period. Immune-related adverse events (iRAEs) were reported in 11 patients; fatigue and diarrhea were the most common (each with n = 4, 33.3%), followed by maculopapular rash and hand-foot syndrome (each with n = 3, 25%). Dose reductions were required in 5 of 6 patients in the cabozantinib 60 mg cohort after the DLT period. One patient discontinued avelumab due to irAE (nephritis), while none discontinued cabozantinib due to toxicity. The ORR was 50%, with one complete response (CR) and 5 partial responses (PR). The disease control rate (CR + PR + stable disease) was noted in 92% of the patients. Radiological PFS survival rate at 6 and 12 months was reported in 67.7% and 33.5% of patients, respectively. Combination therapy with avelumab and cabozantinib is safe and showed preliminary clinical activity in mccRCC. Even though the DLT was not met in any of the 3 cohorts, the recommended RP2D dose for the combination is cabozantinib 40 mg/day due to a high incidence of grade 2 toxicity for cabozantinib 60 mg/day after the DLT period. (ClinicalTrials.gov Identifier: NCT03200587).