Overall Response Of Stable Disease Research Articles

Abstract PS17-08: A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies

Abstract Background The combination of an aromatase inhibitor with a CDK4/6 inhibitor is the mainstay of first-line endocrine therapy (ET) for locally advanced or metastatic HR+/HER2− breast cancer (LA/mBC). Management of recurrent disease in the post-CDK4/6 inhibitor setting includes additional lines of ET single agent or in combination with a targeted agent. For patients with HR+/HER2− LA/mBC tumors, fulvestrant monotherapy as the second- or third-line therapy has limited activity with a median PFS of 1.9-3.6 months. Effective targeted treatments for these patients are needed to maintain quality of life, improve survival, and delay the initiation of cytotoxic chemotherapy. Methods This ongoing single arm, open-label global study (NCT04851613) is to evaluate the efficacy and safety of the combination therapy of afuresertib (a pan-AKT inhibitor) plus fulvestrant in patients with HR+/HER2− LA/mBC. Eligible patients must have received 1-2 prior lines of ET. Patients may have prior treatment of CDK4/6 inhibitors (up to 1 therapy), and/or up to 1 line of chemotherapy. Patients received afuresertib (125 mg PO, QD) in combination with fulvestrant (500 mg IM; Day 1 and 15 in Cycle 1, and Day 1 in subsequent 28-day cycles). The safety of the initial treatment doses of the combination therapy was evaluated in the first 6 patients during the Cycle 1 safety run-in period. Radiographic assessment per RECIST 1.1 was performed every 8 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included safety and tolerability of the combination therapy and pharmacokinetic characterization. Results Twenty patients (1 male and 19 females, 3 in the US and 17 in China) were enrolled between May 2022 and April 2023. As of the data cut-off date of May 26th, 2023, 10 patients had discontinued the study treatment (9 due to disease progression, 1 due to patient’s withdrawal of consent) and 10 patients were still in treatment. Of the 19 patients who had at least one post-baseline tumor assessment, 4 patients observed confirmed Partial Response (cPR), 12 had best overall response of Stable Disease, and 3 had Progressive Disease (PD). The Disease Control Rate is 84%. Of the 15 patients who had at least 2 tumor assessments or who discontinued treatment early due to PD, the confirmed ORR is 26.7% (4 cPR). No dose modification was required during the safety run-in. The most common treatment-emergent adverse events (TEAEs, > 20% of patients) of all grades were hyperglycemia (50%), diarrhea (45%), ALT/AST increase (40%), nausea (35%), rash (35%), hypercholesterolemia (35%), and anemia (30%), the majority of which were Grade 1. Grade 3 AEs were reported in 4 patients, including diarrhea (1 patient), WBC increase (1 patient), creatine phosphokinase increase (1 patient), and ALT/AST increase and rash (1 patient). No SAE or TEAE >= Grade 4 were reported. No patient discontinued treatment due to TEAE. Conclusions The preliminary data from the combination therapy of afuresertib plus fulvestrant has shown promising efficacy with a well-tolerated safety profile in patients with HR+/HER2− LA/mBC who progressed on 1-2 prior lines of standard of care therapies. These results support further evaluation of this combination therapy in this patient population in an upcoming phase III study. Citation Format: Binghe Xu, Pin Zhang, Tao Sun, Ying Wang, Zhongsheng Tong, Sneha Phadke, Trevor Feinstein, Pengfei Guo, Jing Qu, Xiaoyu Wang. A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-08.

Abstract CT146: AZD0466 in patients with advanced non-Hodgkin lymphoma: Efficacy and safety in an open-label phase 1 trial

Abstract Background Overexpression of pro-survival proteins Bcl-2 and Bcl-xL have been associated with poor prognosis in patients with non-Hodgkin lymphoma (NHL). AZD0466 is a drug-dendrimer conjugate consisting of the dual Bcl-2/Bcl-xL inhibitor AZD4320 covalently conjugated to a pegylated poly-L-lysine dendrimer, which allows for gradual release by hydrolysis. Preclinically, AZD0466 monotherapy has demonstrated efficacy in xenograft models of diffuse large B-cell lymphoma (DLBCL). Here, we report results from a Phase 1 trial (NCT05205161) of AZD0466 in relapsed/refractory (R/R) advanced B-cell NHL (B-NHL). Methods Eligible patients were ≥18 years old and had received 2-5 prior lines of therapy. AZD0466 was administered intravenously, with a dose ramp-up on days 1 and 4 of a 28-day cycle, and weekly administration of the target dose from day 8. The primary objective of the dose escalation phase was to assess the safety and tolerability of AZD0466 in patients with R/R B-NHL and to identify the maximum tolerated dose and recommended phase 2 dose. Preliminary efficacy was evaluated using Lugano 2014 criteria. Secondary objective was evaluation of pharmacokinetic (PK) parameters for the study drug. Results As of November 02, 2023, 7 patients (DLBCL n=5, follicular lymphoma n=1, marginal zone lymphoma (MZL) n=1; median age, 57 [26−79] years) had received AZD0466 at 600 mg (n=3), 1200 mg (n=3), or 2400 mg (n=1). All patients experienced adverse events (AEs). AEs possibly related to AZD0466 were reported in 6 patients, most common: platelet count decrease (57.1%), neutropenia/neutrophil count decrease (42.9%), and hypophosphatemia (28.6%). Grade ≥3 AEs possibly related to AZD0466 were reported in 4 patients: 2 Grade 3 and 1 Grade 4 neutropenia/neutrophil count decrease, and 2 AEs that led to treatment discontinuation (Grade 3 platelet count decrease and dose-limiting Grade 3 troponin increase). Among 6 evaluable patients across all dose levels, 1 patient with MZL treated at 1200 mg had an objective response (partial response). Another 3 patients had a best overall response of stable disease and 2 patients had progressive disease. One patient discontinued the study prior to disease assessment. AZD4320 exposure was dose-proportional, with PK profiles similar to studies with other hematologic malignancies. As a surrogate of Bcl-xL on-target activity, transient thrombocytopenia with moderate platelet count recovery prior to the next dose was observed in most patients, in line with preclinical modeling. Pharmacodynamic modulation based on cleaved caspase-3 induction by AZD0466 was observed at 1200 and 2400 mg. Conclusion AZD0466 ≤1200 mg was clinically well tolerated but evidence of asymptomatic myocardial injury was observed at 2400 mg. The study was terminated due to similar findings in a concurrent trial (D8241C00001; NIMBLE). With an objective response observed at the 1200 mg dose level, further development of agents targeting Bcl-2/xL in NHL is warranted with efforts to reduce the cardiotoxicity profile. Citation Format: Geoffrey Chong, Franck Morschhauser, Alex Herrera, Ki-Seong Eom, Tae Min Kim, Michael Wang, Connor Hall, Fathima Zumla Cader, Kaitlyn Beyfuss, Patricia Cheung, Wei Quan, Shringi Sharma, Yotvat Marmor, Jamal Saeh, Jose Mariz. AZD0466 in patients with advanced non-Hodgkin lymphoma: Efficacy and safety in an open-label phase 1 trial [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 CT146.

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

Purpose5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU.Patients and methodsNUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity.ResultsFifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival.ConclusionNUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies.Trial registrationClinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240.

Safety, tolerability, pharmacokinetics, and antitumor activity of adavosertib in Japanese patients with advanced solid tumors: A phase I, open-label study

IntroductionWe aimed to assess the safety, pharmacokinetic profile, and antitumor activity of adavosertib monotherapy in Japanese patients with advanced solid tumors. Materials and methodsThis was a single-center, open-label, phase I study with two consecutive cohorts (250 mg and 200 mg cohorts). Patients received adavosertib at 250 mg or 200 mg, orally once daily for 5 days on and 2 days off for Weeks 1 and 2 of a 21-day cycle. ResultsDose-limiting toxicities (Grade 3 febrile neutropenia) occurred in 2/6 patients in the 250 mg cohort. None of the three patients in the 200 mg cohort developed dose-limiting toxicities. The most frequent treatment-emergent adverse event was nausea (250 mg: 83.3 %; 200 mg: 100.0 %). Median time to peak drug concentration was 4.03 and 2.08 h after the first dose and 2.82 and 1.90 h after multiple dosing in the 250 and 200 mg cohorts, respectively; respective mean terminal elimination half-lives were 7.36 and 7.30 h (first dose) and 10.55 and 8.88 h (multiple dosing). Systemic exposure increased in a slightly more than dose-proportional manner. No RECIST v1.1 response was observed. Disease control rate was 0 % and 33.3 % in the 250 and 200 mg cohorts, respectively. One patient (33.3 %) in the 200 mg cohort showed a best overall response of stable disease at ≥ 8 weeks; the rest showed progressive disease. ConclusionsAdavosertib 200 mg once daily was well tolerated in this patient population and no safety concerns were raised. Exposure increased in a slightly more than dose-proportional manner and limited antitumor activity was shown. Trial registrationClinicalTrials.gov, NCT04462952

Preliminary Results from a Phase 1 Dose Escalation Study of FHD-286, a Novel BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, Administered As an Oral Monotherapy in Patients with Advanced Hematologic Malignancies

The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its adenosine triphosphate (ATP)-dependent chromatin remodeling activity, BAF complexes regulate the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. FHD-286 is a first-in-class, orally administered compound that potently and selectively inhibits the ATPase components of the BAF complexes, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). In preclinical models, acute myeloid leukemia (AML) cell lines were highly sensitive to BAF inhibition. FHD-286-C-002 (NCT04891757) is a multicenter, open-label, Phase 1 dose escalation study designed to determine the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose and/or the recommended phase 2 dose(s), as well as to evaluate the preliminary clinical activity of FHD-286, in patients with advanced hematologic malignancies. Patients with relapsed or refractory (R/R) AML or myelodysplastic syndrome (MDS) failing all available standard therapies were eligible to receive FHD-286 doses ranging from 2.5 mg once daily (QD) to 10 mg QD on a continuous dosing regimen. Patients had regularly scheduled assessments to evaluate safety, pharmacokinetics (PK), pharmacodynamics, preliminary clinical activity, and exploratory biomarkers. As of 02 Aug 2022, 40 patients with a median age of 65.5 years (range 25 to 84) with R/R AML (36 patients) or MDS (4 patients) had received at least 1 dose of FHD-286. 67.5% of patients had received ≥3 prior lines of therapy for AML/MDS/other antecedent hematologic disorder, with 22.5% having received ≥5 prior lines. 32.5% of patients had prior hematopoietic stem cell transplant. 65% of patients had adverse risk genetics by 2017 ELN recommendations. 85% of patients experienced a treatment-related adverse event (TRAE) of any grade; the most common (≥20% of patients) were dry mouth (27.5%), increased blood bilirubin (22.5%), and alanine aminotransferase (ALT) increased and rash (20% each). 50% of patients experienced a Grade ≥3 TRAE, the most common of which was increased blood bilirubin (12.5%); stomatitis, ALT increased, differentiation syndrome (DS), and hypocalcemia occurred in 7.5% (each). 2 DLTs were reported: Grade 3 hyperbilirubinemia in 1 patient receiving 5 mg QD and Grade 3 muscular weakness in 1 patient receiving 10 mg QD. Treatment-related DS of any grade was investigator-reported in 4 patients (10%). An independent adjudication committee determined that the rate of suspected DS was 15% (6 patients). 16 patients (15 AML; 1 MDS) had a best overall response of stable disease. Markers of myeloid differentiation with neutrophil recovery and reductions in bone marrow and/or peripheral blasts have been observed in a subset of patients in the study who had a broad range of cytogenetic backgrounds, including patients with enhancer-driven leukemias such as MECOM and KMT2A. Preliminary PK analysis indicates that FHD-286 appears to have a long half-life, at a minimum of &amp;gt;24 hours, and that plasma concentrations of FHD-286 increase with increasing dose. Exploratory flow cytometry assessment of markers of differentiation, hematopoietic stem cell identity, and apoptosis suggested dose-dependent target engagement. Additionally, exploratory sequencing analysis on bone marrow blasts revealed comprehensive impacts on AML-specific expression pathways and stemness genes in response to FHD-286. An exposure-response analysis using the percentage of peripheral blasts showed a trend toward lower blast count with higher FHD-286 area-under-the-curve. Enrollment into the single-agent dose escalation phase of the study is complete. Based on nonclinical, translational, and single-agent clinical data, FHD-286 in combination with decitabine or low-dose cytarabine is being evaluated in the combination dose escalation phase of the study.

Undetectable MRD Status in Patients with R/R CLL/SLL with Stable Disease after Lisocabtagene Maraleucel Treatment: Exploratory Analysis of the TRANSCEND CLL 004 Study

Background:For patients (pts) with R/R CLL/SLL after failure of Bruton tyrosine kinase inhibitor (BTKi) and B-cell lymphoma 2 inhibitor (BCL2i)-based treatment, there is no established standard of care and therefore there is a high unmet therapeutic need. The phase 1/2 TRANSCEND CLL 004 study (NCT03331198) investigated the efficacy and safety of lisocabtagene maraleucel(liso-cel) monotherapy, an autologous CD19-directed CAR T cell therapy, in pts with heavily pretreated R/R CLL/SLL and ≥ 2 previous lines of therapy, including a BTKi. The primary analysis demonstrated durable CR/CR with incomplete marrow recovery (CRi) per 2018 International Workshop on CLL (iwCLL 2018) criteria, high undetectable MRD (uMRD; 10 − 4 sensitivity) rates, and a manageable safety profile in pts who received liso-cel (Siddiqi T, et al. Lancet 2023). All evaluable responders (CR/CRi/PR) achieved blood uMRD status. Among evaluable pts with stable disease (SD), uMRD status was associated with longer median PFS (6.4 months) versus MRD-positive (MRD+) status (PFS, 2.8 months). This exploratory analysis aimed to better understand potential variables associated with achieving uMRD in pts who had SD with liso-cel. Methods: Among 96 pts in the full efficacy set who were treated with liso-cel at dose level 1 (50 × 10⁶ CAR + T cells) or 2 (100 × 10⁶ CAR + T cells), 80 pts were evaluable for peripheral blood MRD. Peripheral blood MRD status was assessed by next-generation sequencing (NGS; clonoSEQ) assay; uMRD was defined as &amp;lt; 10 −4 (&amp;lt; 1 CLL cell per 10,000) at 1 or more postinfusion time points. Additional exploratory analysis leveraged sample-level MRD results defined by total clonal cells/total nucleated cells assessed by NGS. Cellular kinetics were analyzed in peripheral blood samples by qPCR to detect the liso-cel transgene. Correlative analysis studies of baseline markers of tumor burden (sum of the product of diameters; CD19 + cells/μL; percent CLL cells in bone marrow biopsies or aspirates) with liso-cel expansion were evaluated by MRD status. Statistical analyses were performed using the Wilcoxon signed-rank test. Results:Of the 80 pts who were evaluable for peripheral blood MRD, 34 had a best overall response of SD, 19 of whom achieved uMRD and 15 who were MRD+. Greater liso-cel expansion parameters (median maximum expansion and area under the curve from 0-28 days postinfusion) were observed in all pts, including those with SD, who achieved uMRD versus MRD+ status ( P &amp;lt; 0.0001), suggesting that higher liso-cel expansion after infusion was associated with achievement of uMRD independent of iwCLL 2018 response. Regardless of baseline tumor burden, pts with higher liso-cel expansion achieved uMRD after liso-cel treatment. A positive association between tumor burden and liso-cel expansion in pts with SD and uMRD was also observed. In contrast, pts with SD who were MRD+ had lower liso-cel expansion and trends of higher baseline disease burden. Liso-cel expansion in pts with SD and uMRD clustered with the responders, who all achieved uMRD status (in those evaluable for MRD). Notably, 4 pts with SD and uMRD had a durable disease control of &amp;gt; 22 months. We wanted to further understand the relationship between uMRD and durable disease control. Given that the median PFS of pts with SD and uMRD was 6 months, we evaluated the association between tumor burden and liso-cel expansion in pts who had a PFS of ≤ 6 months or &amp;gt; 6 months. Although no clear association was observed with liso-cel expansion and tumor burden within these 2 groups, 4 out of 5 pts with SD and uMRD with longer disease control (PFS &amp;gt; 6 months) had a &amp;gt; 98% decrease in sample-level MRD from Month 1 to Month 3. In contrast, in pts with SD and uMRD with PFS ≤ 6 months, 5 out of 7 pts had a &amp;gt; 70% increase in sample-level MRD from Month 1 to Month 3. Conclusions:In this exploratory analysis of pts with R/R CLL who had SD by iwCLL 2018 criteria after liso-cel treatment, greater liso-cel expansion, regardless of baseline tumor burden, correlated with blood uMRD status. Additionally, those with a PFS &amp;gt; 6 months achieved deeper clearance of blood sample-level MRD within 3 months of treatment versus those with a PFS ≤ 6 months, suggesting that MRD kinetics may identify pts with SD who can achieve durable disease control despite not achieving a response per iwCLL 2018 criteria. Further investigation is needed to better understand which subsets of pts with CLL who had SD may derive clinical benefit from liso-cel.

Recommended phase 2 dose (RP2D) for abemaciclib in combination with irinotecan (IRN) and temozolomide (TMZ) in pediatric patients with relapsed/refractory solid tumors (JPCS Part A).

10039 Background: There remains an unmet need to improve outcomes for pediatric patients (pts) with relapsed/refractory solid tumors. Abemaciclib is an orally administered, selective cyclin-dependent kinase (CDK) 4 &amp; 6 inhibitor approved for breast cancer. Based upon preclinical data and the role of CDK4 &amp; 6 in multiple pediatric solid tumor types, we hypothesized that abemaciclib in combination with IRN and TMZ would demonstrate clinical activity to support further pediatric development. This Phase 1b study aimed to determine the RP2D of abemaciclib in combination with IRN and TMZ in this pt population. Methods: This dose escalation study was part A of study JPCS (NCT04238819), and enrolled pts ≤18 years, weighing ≥10 kg, with a body-surface area ≥0.5 m2, and with relapsed/refractory solid tumors, including CNS tumors, that progressed on standard treatment or experienced disease recurrence. IRN (50 mg/m2) and TMZ (100 mg/m2) were administered on days 1-5 of 21-day cycles and remain the same for all dose levels, while abemaciclib was tested on four dose levels: 55, 70, 90, and 115 mg/m2 twice daily (BID). The starting dose was 70 mg/m2 BID for abemaciclib. The maximum tolerated dose was defined as the highest dose level at which &lt; 33% of pts experienced a dose-limiting toxicity (DLT) during Cycle 1. The primary objective, determination of the abemaciclib RP2D, was defined based on the totality of safety, tolerability, and pharmacokinetic (PK) results, and confirmed in an expansion cohort. Secondary objectives included safety and response assessments. Results: At the data cut-off of 13 June 2022, a total of 20 pts received abemaciclib at 70 mg/m2 (n = 7) or 55 mg/m2 (n = 13). The most frequent diagnoses (≥3 pts) were medulloblastoma (n = 4), malignant glioma (n = 3), and rhabdomyosarcoma (n = 3). At the starting dose of 70 mg/m2, DLTs were experienced by 3 pts (neutropenia [n = 3; 43%]; gamma glutamyltransferase increased [n = 1; 14%]). The dose was de-escalated to 55 mg/m2, at which one pt (8%) experienced a DLT (thrombocytopenia). High grade adverse events (AEs) were mostly hematological. Discontinuations due to AEs occurred in 2 pts (29%) at 70 mg/m2 and 0 pts at 55 mg/m2. Five pts (71%) at 70 mg/m2 and 4 pts (31%) at 55 mg/m2 achieved a best overall response of stable disease; 1 pt (8%) at 55 mg/m2 achieved a complete response (rhabdomyosarcoma). No partial responses were observed. PK concentrations of abemaciclib at 55 mg/m2 achieved average plasma abemaciclib concentrations of ~150 ng/mL and the abemaciclib Ctrough concentrations appeared reasonably constant over time at ~100 ng/mL. PK concentrations of IRN and TMZ were as expected. Conclusions: The RP2D of abemaciclib is 55mg/m2 BID in combination with IRN and TMZ. This combination appears tolerable with plasma concentrations within the range associated with efficacy in adult studies. Clinical trial information: NCT04238819 .

Effect of bispecific B7H3 x CD19 CAR T cells on host CD19 expression and CAR T cell engraftment.

10043 Background: Our experience of B7H3 chimeric antigen receptor T cells (CAR-T) revealed modest engraftment (max 4.9 cells/uL) and no objective responses on first infusion. Previous CD19 CAR T cell trials have revealed that host B Cell CD19 can drive robust engraftment and persistence even in the absence of malignant CD19 expression. We therefore developed a bispecific B7H3xCD19 CAR T cell with the intent of using host CD19 expression to drive better engraftment of the B7H3-targeting CAR. Methods: Young patients with relapsed/refractory solid tumors (R/RST) were enrolled onto a Phase 1 trial (NCT04483778) to examine the safety of autologous T cells lentivirally transduced to express either or both scFV-IgG4hinge-CD28tm-4-1BB-zeta B7H3-specific and CD19-specific CARs. The B7H3 CAR construct contained the methotrexate resistance/selection cassette DHFRdm and the tracking/suicide construct EGFRt and the CD19 CAR construct containing the tracking/suicide construct HER2tg, allowing for differential CAR tracking. CAR T cells were cultured in low-dose methotrexate to select for B7H3 containing CAR T cells and limit exposure to monospecific CD19 CAR T cells. All patients received lymphodepleting fludarabine and cyclophosphamide prior to infusion of cryopreserved CAR-T at the prescribed dose level. The maximal tolerated dose or biologically effective dose (BED) was determined based upon observed toxicity through day 28 from initial CAR-T infusion and using a 3+3 statistical design. Results: 11 subjects (age 5-23, median 18 years) enrolled and received dose level (DL) 0B (0.5 x 106 TOTAL CAR-T/kg, n = 7) or DL1B (1 x 106 TOTAL CAR-T cells/kg, n = 4). One subject experienced dose limiting toxicities at DL1 of transaminitis, hyponatremia, worsening of a pericardial effusion and hypoxia. Most common toxicities were cytokine release syndrome (CRS) (n = 4, maximum CTCAE grade 2).No occurrence of ICANS was noted. Maximum total circulating CAR-T expansion on first infusion was 796.3 cells/uL and max B7H3 expansion was 374.2 cells/uL with 7/11 continuing with ongoing detection of CAR T cells in the peripheral blood at time of last follow up (21 days to 8 months). CAR engraftment was predominated by the B7H3 CAR single expressing CAR T cells in all subjects. All subjects developed B cell aplasia which is ongoing in 10/11 subjects at time of last check (range of 21 days to 8 months). Best overall response of Stable Disease was observed in 2 of the 11 subjects infused. Conclusions: B7H3xCD19 CAR T cells robustly engraft and expand in patients with R/RST and are safe, but despite ongoing detection of the CAR T cells, no objective responses were observed. It is likely that additional measures will be required to enhance the activity of CAR-T cells to achieve objective responses. STRIvE-02 Arm C will explore the addition of pembrolizumab post bispecific CAR infusion to evaluate the effect of PD1 blockade on anti-tumor activity. Clinical trial information: NCT04483778 .

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

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

Phase 1 efficacy and pharmacodynamic results of exicorilant + enzalutamide in patients with metastatic castration-resistant prostate cancer.

145 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease with significant morbidity. Androgen receptor (AR) signaling is a key driver of tumor growth in mCRPC, and AR-targeted therapies are the mainstay for patients (pts) with locally advanced or metastatic disease. Enzalutamide (ENZA) is commonly used, but resistance typically develops within 1–2 years. The glucocorticoid receptor (GR) can substitute for the AR, providing a tumor escape pathway (Arora et al. Cell 2013). In the 22Rv1 CRPC xenograft model, the selective GR modulator exicorilant (EXI) combined with ENZA reduced tumor growth, supporting the hypothesis that dual antagonism of GR + AR may block this escape pathway. Safety and pharmacokinetics from the first study of EXI + ENZA in pts with mCRPC (NCT03437941) were previously presented (Linch et al. ESMO 2022). Here, we report efficacy and pharmacodynamic (PD) results from the same study. Methods: Segment 1 (Seg 1) of this phase 1 study evaluated open-label, fasting, BID dosing of EXI (140 or 180 mg) + ENZA 160 mg QD. Segment 2 (Seg 2) tested QD dosing of EXI with food in a double-blind design: All pts received EXI 240 mg + ENZA and were randomized 3:1 to EXI titration (to 280 mg followed by 320 mg) or to remain on EXI 240 mg + placebo. Efficacy assessments included radiographic response and changes in prostate-specific antigen (PSA) levels. PSA was collected prior to study entry and PSA doubling times were calculated before and during treatment. PD analyses included baseline (BL) tumor GR expression and modulation of GR target genes in whole blood. As not all pts enrolled in Seg 1 were ENZA naïve, efficacy data are reported for Seg 2 only. Data cutoff date: July 7, 2022. Results: 39 pts were enrolled (Seg 1: 14, irrespective of prior ENZA exposure; Seg 2: 25, on a stable ENZA dose with rising PSA, defined as a 25% increase over nadir and absolute value &gt;1 ng/mL). In Seg 2, there were no radiographic responses, 18 pts had a best overall response of stable disease per PCWG3, and 1 pt achieved a PSA response (≥50% PSA reduction from BL). BL tumor GR expression was detectable in all assessed tumors. PD analyses demonstrated EXI modulation of GR target genes, such as CDKN1C. Comparable PD effects were observed across EXI doses (240–320 mg QD). While BL 24-h urinary free cortisol (UFC) for most pts was within the normal range, improvements in PSA doubling times after treatment with EXI + ENZA were predominantly observed in pts with higher BL UFC ( P&lt;0.05). Conclusions: This study did not include an ENZA-alone arm and was thus not designed to assess the contribution of EXI to the efficacy of the EXI + ENZA combination. In heavily pretreated pts with prior ENZA exposure, 1 PSA response and no radiographic responses were observed. PD analysis confirmed systemic GR modulation. Instances of PSA doubling time improvements were observed in pts with relatively higher UFC. Clinical trial information: NCT03437941 .

STRIVE-02: A first-in-human phase 1 trial of systemic B7H3 CAR T cells for children and young adults with relapsed/refractory solid tumors.

10011 Background: B7H3 (CD276) has limited expression in normal tissues and high cell-surface expression in pediatric solid malignancies providing rationale for immunologic therapeutic targeting. We present a first-in-human experience of B7H3 chimeric antigen receptor T cells (CAR-T) for children and young adults (CYA) with relapsed or refractory solid tumors (R/RST). Methods: CYA patients with R/RST were enrolled onto a Phase 1 trial (NCT04483778) to examine the safety of autologous T cells genetically modified to express scFV-IgG4hinge-CD28tm-4-1BB-zeta B7H3-specific CAR with the methotrexate resistance/selection cassette DHFRdm and the tracking/suicide construct EGFRt. All patients received lymphodepleting fludarabine and cyclophosphamide prior to infusion of cryopreserved CAR-T at the prescribed dose level. The maximal tolerated dose or biologically effective dose (BED) was determined based upon observed toxicity through day 28 from initial CAR-T infusion and using a 3+3 statistical design. Results: Sixteen subjects (age 11-24, median 17 years) enrolled and received dose level (DL) 1 (0.5 x 106 CAR-T/kg, n = 3) or DL2 (1 x 106 CAR-T cells/kg, n = 6). No dose limiting toxicity was observed following first infusion, most common toxicities were fatigue and cytokine release syndrome (CRS) (n = 2, maximum CTCAE grade 2). Maximum circulating CAR-T expansion on first infusion was 4.98 cells/uL (range 0.23-4.98 cells/uL) with median persistence of 28 days (range 14-90). Best overall response of Stable Disease was observed in 3 of the 9 subjects infused. Given observed expansion and persistence, DL2 was determined to be the BED. A second infusion at DL2 in one subject demonstrated CAR T expansion to 1590 cells/uL (86% of circulating CD3 cells) with CTCAE grade 2 CRS and transient dose limiting CTCAE grade 4 liver enzyme elevation. A partial metabolic response on FDG-PET by PERCIST criteria was observed in this subject at Day 28. Conclusions: B7H3 CAR T cells are safe and demonstrate anti-tumor activity in CYA with R/RST. CAR-T cell expansion and persistence may be necessary to achieve objective responses. STRIvE-02 Arm B will explore dual expression of CD19 CAR with B7H3 CAR, using lymphocytic CD19 expression to drive CAR expansion and persistence. Clinical trial information: NCT04483778.

A phase 1/2 multicenter investigator-initiated trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

5048 Background: Dickkopf-1 (DKK1) is a secreted Wnt signaling modulator that is upregulated in prostate cancers with low androgen receptor (AR) expression and co-occurring mutations in Wnt signaling family genes. DKN-01, a potent humanized monoclonal antibody (IgG4) with neutralizing activity against DKK1, delays prostate cancer growth in pre-clinical DKK1-expressing models in an NK cell dependent manner. These data provided the rationale for a prospective clinical trial testing DKN-01 in patients with mCRPC and elevated DKK1. Here, we report the safety and efficacy results of the phase 1 dose escalation cohorts. Methods: This is an investigator-initiated parallel-arm non-randomized phase 1/2 clinical trial testing DKN-01 alone or in combination with docetaxel 75 mg/m2 for men with mCRPC who progressed on ≥1 AR signaling inhibitor. Eligible patients who had progressed on or were intolerant of docetaxel were assigned to the monotherapy cohort whereas taxane-naïve patients were assigned to the DKN-01 plus docetaxel combination cohort. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was safety, characterized by dose-limiting toxicity (DLT). A secondary endpoint of the study was to correlate anti-tumor activity, DKK1 expression (cutoff H-score ≥ 1), and clinical evidence of aggressive variant prostate cancer (AVPC). Results: 13 pts were enrolled in the completed phase 1 portion of this study – 7 patients in the monotherapy cohort and 6 patients in the combination cohort. No DLTs were observed at DKN-01 300mg or 600mg dose levels as monotherapy or in combination with docetaxel. No treatment-related serious adverse events occurred in either cohort. A best overall response of stable disease occurred in 2 out of 7 patients in the monotherapy cohort. In the combination cohort, all 5 evaluable patients had a partial response (PR) – 3 confirmed and 2 unconfirmed. All evaluable combination patients had ≥ 50% reduction in either PSA or CEA. Confirmed PRs in the combination cohort were observed in both DKK1 low (DKK1 H-score &lt; 1) and high expressing tumors (H-score ≥1), including in 2 out of 3 patients with AVPC. Conclusions: DKN-01 600mg was well tolerated and selected as the recommended phase 2 dose as monotherapy and in combination with docetaxel. DKN-01 in combination with docetaxel showed promising clinical activity in prostate cancers regardless of DKK1 expression and was particularly promising in patients with AVPC. Further accrual into the phase 2 portion of this study is ongoing alongside preclinical and correlative studies aiming to investigate the mechanism of action of this combination therapeutic strategy. Clinical trial information: NCT03837353.

Abstract P2-13-25: A phase I dose-escalation study of DHES0815A, a HER2-targeting antibody-drug conjugate with a DNA monoalkylator payload, in patients with HER2-positive breast cancer

Abstract Background: Despite the success of multiple HER2-targeted agents in HER2+ breast cancer (BC), resistance remains a challenge and novel therapies are needed. DHES0815A is a THIOMABTM antibody-drug conjugate consisting of a humanized IgG1 anti-HER2 monoclonal antibody (mAb) conjugated to the DNA alkylating agent PBD-MA. The reduced potency of PBD-MA compared to PBD dimers and the stability of the conjugation site and linker were designed to improve tolerability, whereas the binding of the mAb to a HER2 epitope distinct from trastuzumab and pertuzumab was designed to enable combination therapy with existing HER2 therapies. Methods: This first-in-human, Phase I, open-label, multicenter, dose escalation study used a 3+3 dose escalation design to assess the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of DHES0815A in patients with metastatic HER2-positive BC refractory to established therapies (NCT03451162). DHES0815A (0.6-6.0 mg/kg) was administered intravenously every 3 weeks (Q3W) until intolerable toxicity or disease progression. Results: A total of 14 patients were treated with DHES0815A; all had ≥3 prior lines of therapy. Thirteen patients discontinued treatment due to progressive disease (43%), adverse events (AE; [29%]) symptomatic deterioration (14%) or other (7%); 1 patient remains on treatment. DHES0815A was initially well-tolerated for doses up to 2.4 mg/kg. At 4.0 mg/kg and 6.0 mg/kg, the first dose was also well-tolerated with no dose limiting toxicities, however, following 3 or more cycles at 4.0 mg/kg or 2 or more cycles at 6.0 mg/kg, safety events involving skin, eyes, and lung emerged. Skin events were reported in 50% of patients (all doses) and related events occurring in n≥2 patients included pruritus (36%), rash (36%), and skin hyperpigmentation (21%). Ocular toxicities were reported in 57% and related events occurring in n≥2 patients included photophobia (21%), conjunctivitis, eye pain, and dry eye (each 14%). Lung toxicities were reported in 36% of patients; events occurring in n≥2 included pneumonitis (14%). Other related skin, ocular, and pulmonary events occurring in 1 patient (7%) included palmar-plantar erythrodysaesthesia, macular rash, blurred vision, eyelid edema, periorbital edema, blepharitis, punctate keratitis, wheezing, allergic rhinitis, and pneumothorax. Most events were grade 1 or 2 although 3 patients experienced grade 3 ocular events (blepharitis, eye pain, photophobia). Due to these AEs, DHES0815A dose was decreased to 2.4 mg/kg Q3W for all enrolled patients and accrual was stopped. All 5 patients receiving doses of 4.0 mg/kg and 6.0 mg/kg discontinued due to AEs. At lower doses, 1 patient receiving 2.4 mg/kg developed grade 2 rash at Cycle 21 and 1 patient receiving 1.2 mg/kg developed grade 1 rash, pruritis, and skin hyperpigmentation between Cycles 28-30. Nonlinear PK of antibody-conjugated PBD-MA (acPBD-MA) was observed due to target mediated drug disposition at 0.6, 1.2, and 2.4 mg/kg; PK approached linear at 4.0 mg/kg. Minimal systemic exposure of unconjugated PBD-MA was observed. Overall, 1 patient (7%) in the 1.2 mg/kg cohort achieved a confirmed complete response. As of 10Jun21, this patient remains on study after more than 32 months on treatment. Ten patients (86%) showed a confirmed best overall response of stable disease (86%). Conclusion: Despite some anti-tumor activity observed with DHES0815A, development in HER2-positive BC has been discontinued due to safety concerns and the narrow therapeutic window. Toxicities observed in skin, lung, and eyes are clinically apparent only after repeated dose administration. If future exploration of PBD-MA-based constructs is performed in the clinic, close monitoring for delayed toxicities is warranted. Citation Format: Ian Krop, Erika Hamilton, Kyung Hae Jung, Shanu Modi, Kevin M Kalinsky, Gail Phillips, Rong Shi, Sharareh Monemi, Michael Mamounas, Ola Saad, Voleak Choeurng, Renee Commerford, Eunpi Cho, Alexander Ungewickell, Patricia LoRusso. A phase I dose-escalation study of DHES0815A, a HER2-targeting antibody-drug conjugate with a DNA monoalkylator payload, in patients with HER2-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-25.

An analysis of the use of targeted therapies in patients with advanced Merkel cell carcinoma and an evaluation of genomic correlates of response.

BackgroundThe use of targeted therapy remains a treatment consideration for some patients with advanced Merkel cell carcinoma (MCC). However, supportive data on the use of targeted therapy approaches are limited. Thus, we sought to evaluate the responsiveness of targeted agents in patients with advanced MCC.MethodsAn institutional MCC database identified patients who were treated with targeted therapy. For the purpose of this study, targeted therapy was defined as any multi‐targeted tyrosine kinase inhibitor or inhibitor of the PI3K‐pathway. Clinical benefit was defined as complete response, partial response, or stable disease (SD) ≥6 months. A subset of patient samples underwent next‐generation sequencing (NGS), Merkel cell polyomavirus testing, and PD‐L1/PD‐1 expression testing.ResultsNineteen patients with MCC treated with targeted therapy were identified, 21 targeted therapy regimens were evaluable for response in 18 patients. Four of twenty‐one (19%) of evaluable regimens were associated with clinical benefit with the best overall response of SD. The durations of SD were 13.6 months (59 weeks), 9.7 months (42 weeks), 7.6 months (33 weeks), and 7.2 months (31 weeks). Of the four patients who derived clinical benefit, three were treated with pazopanib alone and one was treated with pazopanib plus everolimus. No difference in the rate of clinical benefit between molecular disease subtypes was detected nor was associated with any specific genomic alteration.ConclusionIn our series, targeted agents elicited a disease control rate of 19% in patients with advanced MCC, with a best overall response of SD. Pazopanib alone or in combination exhibited a rate of disease control of 36% (4 of 11 with SD ≥6 months).

A phase 1 study evaluating preliminary safety, pharmacokinetic and pharmacodynamic of pemigatinib in Chinese patients with advanced malignancy.

e15051 Background: Dysregulation of fibroblast growth factor receptor (FGFR) is strongly associated with establishment and progression of cancer. Pemigatinib is a selective FGFR1–3 inhibitor that are active in a targeted manner against cancers with activated FGFR pathway. The study was aimed at evaluating the tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) of pemigatinib in Chinese patients (pts) with advanced malignancy. Moreover, potential efficacy of pemigatinib was explored in a broad spectrum of FGFR alteration in variety of cancer types. Methods: In this phase 1 study, Chinese patients with advanced, recurrent or metastatic malignancy that were histologically or cytologically confirmed and harboring FGF/ FGFR 1-3 variation were enrolled. Pemigatinib was self-administered orally at 13.5 mg QD on a 3-week cycle (2-weeks-on/1-week-off schedule). Adverse events and other safety factors were monitored throughout the study. Blood samples were obtained at prespecified time points for PK and PD analysis and efficacy was assessed every 9 weeks per RECIST v1.1 guideline. Results: As of Jan 31, 2021, 12 patients with 5 different cancer types (colorectal cancer (4 pts), gastric and gastroesophageal junction carcinoma (3 pts), cholangiocarcinoma (2 pts), esophageal carcinoma (2 pts) and breast cancer (1pts)) were enrolled. Documented FGF/ FGFR1-3 alterations were FGFR amplification (6), FGFR point mutation (5), FGFR2 fusion (2) and FGF alteration (4) with 2 subjects had more than one alteration types. All the subjects were failed to at least 1 line of prior standard therapy. All patients had at least 1 treatment related adverse events (TRAE) and the most common ones were hyperphosphatemia (100%), decreased appetite (50%) and diarrhea (33.3%). Two patients (16.7%) reported ≥ grade 3 TRAEs, which were hyponatremia (8.3%) and proteinuria (8.3%). There were no TEAEs leading to death or treatment discontinuation. Among 11 efficacy evaluable patients, 2 of them had partial responses (PR) as evaluated by investigators with 1 cholagiocarcinoma harboring FGFR2 point mutation (p.F276C) and the other esophageal carcinoma carrying FGFR1 mutation (p.A354V). 3 patients had a best overall response of stable disease (SD). The objective response rate (ORR) was 16.7% (95%CI: 2–48%) and disease control rate was 41.7% (95%CI: 15–72%). Conclusions: Pemigatinib had an acceptable and manageable toxicity and demonstrated a possible anti-cancer benefit in Chinese patients with advanced malignancy that accompanied with FGF/FGFR1-3 aberrance. A significant implication of the data is that it extended the population that potentially benefit from pemigatinib other than FGFR2 fusion/rearrangement. Clinical trial information: NCT04258527.

Safety, pharmacokinetic and pharmacodynamic results from dose escalation of SAR439459, a TGFβ inhibitor, as monotherapy or in combination with cemiplimab in a phase 1/1b study.

2510 Background: SAR439459 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. In preclinical models, combining SAR439459 with an anti-PD-1 showed improved anti-tumor activity compared to single agent. Here we report preliminary results of SAR439459 ± cemiplimab in a first in human study. Methods: This is an open-label study (dose escalation and expansion) of SAR439459 ± cemiplimab administered intravenously in adult patients with advanced solid tumors to determine safety and tolerability, the maximum tolerated dose (MTD) and/or maximum administered dose (MAD) of SAR439459 ± cemiplimab, pharmacokinetics (PK); pharmacodynamic (PD) and preliminary clinical benefit. In Part 1A, SAR439459 (0.05-15 mg/kg) was administered as monotherapy Q2W in an adaptive Bayesian design with overdose control. In Part 1B, SAR439459 doses cleared from monotherapy were administered in combination with fixed dose of cemiplimab (3 mg/kg Q2W or 350 mg Q3W) in a 3+3 design. Results: As of 31 January 2020, 28 (1A) and 24 (1B) patients with ECOG performance status of 0-1 with a median age of 60.5 and 63 years respectively were enrolled. In Part 1A, 25 patients (89.3%) had at least one treatment emergent adverse event (TEAE) and 15 (53.5%) experienced grade (G)≥ 3 events. In Part 1B, 22 patients (91.7%) had at least one TEAE and 14 (58.3%) experienced G ≥ 3 events. Dose-limiting toxicities (DLTs) were evaluable in 24 and 21 patients respectively. In 1A, 2 DLTs were reported in 2 of 8 evaluable patients in dose level (DL) 4: G5 brain stem hemorrhage in a patient on concomitant low molecular weight heparin treatment and G3 myocardial infarction in a patient with diabetes, chronic kidney disease, chronic obstructive pulmonary disease, and hypertension. In 1B, 1 of 6 evaluable patients in DL5 had DLTs (G3 ALT and AST increase). MTD was not reached in either part. Ten patients had best overall response of stable disease: 6 in 1A and 4 in 1B. The PK of SAR439459 was dose proportional over the dose range tested with no evidence of cemiplimab effect on SAR439459 PK, when given in combination. Treatment with SAR439459 ± cemiplimab led to rapid reduction in total plasma TGFβ level in all dose levels tested and induced CD8 &amp; NK cells expansion and Th1 cytokines production, suggesting peripheral T cell activation. Preliminary results from paired tumor biopsies collected from patients treated with SAR439459 ± cemiplimab in expansion showed trend of TGFβ signaling pathway inhibition and conversion from excluded to inflamed tumor-immune phenotype. Conclusions: SAR439459 ± cemiplimab showed an acceptable tolerability profile overall. MTD was not reached. Peripheral and tumor target engagement and modulation of key immune cells was observed in treated patients. Dose expansion cohorts are currently enrolling selected solid tumor patients. Funding: Sanofi. Clinical trial information: NCT03192345.

Phase 1, 2 trial of concurrent anti-PD1 and stereotactic radiosurgery for melanoma and non-small cell lung cancer brain metastases (NCT02858869).

2022 Background: The safety and efficacy of concurrent pembrolizumab (anti-PD1) and stereotactic radiosurgery (SRS) for brain metastases (BM) is unknown. Methods: Patients with melanoma or NSCLC, 1-10 brain metastases, ≥ 1 extra-cranial lesion, age ≥ 18, and ECOG 0-1 were treated with anti-PD1 every 3 weeks. SRS was administered 1-2 days after starting anti-PD1. SRS used three different radiation arms: Arm A used 6 Gray (Gy) in 5 fractions (fx), Arm B used 9 Gy in 3 fx, and Arm C used 18-21 Gy in single fx. Primary endpoint was grade 3 CNS toxicity at 3 months (CTCAE v 4.0). Secondary endpoints were overall survival (OS), local control (LC) within the SRS field, intra-cranial progression free survival (IC-PFS), extra-cranial progression free survival (EC-PFS), rate of extra-cranial clinical benefit, and immunological changes. OS, LC, IC-PFS, and EC-PFS were estimated using the Kaplan-Meier method, and covariates were compared using log-rank tests. 95% confidence intervals for 6-month and 12-month were estimated using Greenwood’s formula. Results: 25 patients were treated from 2016 until 2020. The mean age was 61. The mean number of CNS lesions was 2.7. The mean number of extra-cranial lesions was 2.5. Six were enrolled on Arm A, 12 on Arm B, and 7 on Arm C. 21 had melanoma. 4 had NSCLC. Of the melanoma, 8 were BRAF-, 10 were BRAF+, and 3 had unknown mutation status. 12 patients (48%) had progressed on prior immunotherapy and/or other oncological therapies. The trial met its primary endpoint, with no grade 3 CNS toxicity at 3 months. Two patients (8%) experienced ≥ Grade 3 anti-PD1 related toxicity, and no grade 5 toxicity was noted. The median OS was 32.8 months. The 6 and 12 month OS were 79.1% (56.5-90.8%) and 67.8% (43.3-83.5%), respectively. The 1 year OS was similar between previously treated and treatment naïve patients (71.8% vs. 65.6%), suggesting some role for SRS in overcoming therapy resistance. However, with longer follow-up, the OS trended worse (p=0.07) for previously treated patients. LC was 95.7% (72.9-99.4%) at 6 and 12 months. IC-PFS at 6 months was 69.1% (45.8-83.9%), and at 12 months was 57.5% (33.7-75.5%). The EC-PFS at 6 and 12 month was 54.5% (32.1-72.4%) and 43.6% (22.3-63.2%), respectively. Clinical benefit, which was defined as a best overall response of stable disease or better according to RECIST 1.1, occurred in 12 patients (48%). No outcome differences were noted amongst the three different SRS arms. 70% of the patients demonstrating early activation (within 3 weeks of starting SRS/anti-PD1) of CD8+PD1+Ki67+ T cells demonstrated a clinical benefit. 100% of patients that failed to show early activation of CD8+PD1+Ki67+ T cells progressed. Conclusions: Concurrent pembrolizumab (Anti-PD-1) and SRS is safe and effective. Early activation of CD8+PD1+Ki67+ T cells correlates with improved outcome. Further trials testing pembrolizumab and SRS are justified. Clinical trial information: NCT02858869.

First-in-human phase 1 dose escalation study of HX009, a novel recombinant humanized anti-PD-1 and CD47 bispecific antibody, in patients with advanced malignancies.

2517 Background: HX009 is a novel humanized antibody fusion protein which binds to CD47 and PD-1 concurrently. HX009 significantly inhibited tumor growth in mouse xenograft models. In Cynomolgus monkeys, the highest non-severely toxic dose in repeat dose testing was 15mg/kg. HX009-I-01 (ClinicalTrials.gov：NCT04097769) is a first-in-human study evaluating the safety and efficacy of HX009 in subjects with advanced malignancies. Here we report the preliminary results from this study. Methods: The study is being conducted in Australia at 3 sites. The study design follows a 3+3 dose-escalation scheme, enrolling cohorts of at least 3 subjects (except the first dose level) sequentially until MTD or the maximum dose is reached. HX009 is administered as single agent every 2 weeks via intravenous infusion. The 7 dose levels planned are: 0.1mg/kg (1 subject), 0.3mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 5mg/kg, 7.5mg/kg. All AEs are graded using NCI CTCAE v5.0. Efficacy assessments are per RECIST 1.1. Blood samples are obtained for pharmacokinetics (PK) and for immunogenicity assessments by the development of Antidrug Antibodies. Results: As of the January 22 2021 cutoff date, 21 patients (12M/9F) with a median age of 69.0 years (range 38-86) have received dose levels of 0.1-7.5 mg/kg. Patients with the following tumor types have been enrolled: colorectal cancer (7), squamous cell carcinoma (3), endometrial cancer (2), breast cancer (3), malignant epithelioid mesothelioma (1), gallbladder cancer (1), pancreatic cancer (1), glioblastoma(1), ovarian cancer (1), gastroesophageal junction adenocarcinoma (1). Patients had received a median of 3 (range 1-9) prior anti-cancer regimens. Treatment-related AEs have been reported in 10 (47.6%) patients to date. Most AEs are grade 1 or 2. The most frequent treatment-related AEs include nausea (n = 2, G1), rash (n = 2, G1), vomiting (n = 2, G1), and decreased appetite (n = 2, G1). Only 1 treatment-related SAE of pneumonitis. One treatment-related anemia (G2), and no thrombocytopenia. No DLT was observed in all 7 dose levels. Among 18 patients who have had at least one post-baseline tumor assessments, partial responses (PR) have been achieved in 3 patients with the following tumor types (dose level): gallbladder adenocarcinoma (1mg/kg), triple negative breast cancer (5mg/kg), metastatic squamous cell carcinoma of head and neck (5mg/kg). In addition, there are 6 patients with best overall response of stable disease. As of the data cutoff date, 6 patients are still receiving treatment. Updated clinical and PK results will be presented at the meeting. Conclusions: HX009, on an every 2 weeks dosing schedule, up to 7.5 mg/kg, is well-tolerated, without any DLT to date. Antitumor activity was seen at 1 mg/kg and 5 mg/kg cohorts with objective responses in multiple tumor types; Further investigation in phase Ib/II studies is warranted. Clinical trial information: NCT04097769.

A phase 1 study of TAK-164, an anti-guanylyl cyclase C (GCC) antibody-drug conjugate (ADC), in patients (pts) with advanced gastrointestinal (GI) cancers expressing GCC.

3050 Background: TAK-164 is a second-generation ADC comprising a human IgG1 monoclonal antibody targeting GCC conjugated to a DNA-damaging alkylating agent by a peptide linker. TAK-164 demonstrated cytotoxic and antitumor activity in GCC-expressing cells and xenograft mouse models. This first-in-human study investigated the safety, pharmacokinetics (PK), and preliminary efficacy of TAK-164. Methods: Adult pts with GCC-positive, advanced/metastatic GI cancers received TAK-164 intravenously on day 1 of a 21-day cycle (Q3W). Dose escalation proceeded based on cycle 1 safety data via a Bayesian model of modified toxicity probability interval starting at 0.004 mg/kg. Results: Thirty-one pts were enrolled. Median age was 58 years (range 32–72), 58.1% of pts were female and 64.5% had colon carcinoma. The median number of prior lines of therapy was 4 (range 2–9). TAK-164 was given at 0.004 (n = 1), 0.008 (n = 1), 0.016 (n = 1), 0.032 (n = 5), 0.064 (n = 7), 0.12 (n = 7), 0.16 (n = 2), 0.19 (n = 3), 0.25 (n = 3) and 0.32 mg/kg (n = 1). No pts had dose-limiting toxicities (DLT) in cycle 1 up to 0.32 mg/kg. Three pts had adverse events (AEs) after cycle 1 considered to be DLTs: 1 pt receiving 0.19 mg/kg (grade 3 pyrexia and grade 5 hepatic failure) and 2 pts receiving 0.25 mg/kg (1 pt had grade 3 nausea, and grade 4 platelet count decrease and neutrophil count decrease; 1 pt had grade 4 hepatic failure and grade 4 platelet count decrease). Dosing was capped at 0.19 mg/kg due to hepatic toxicity and the recommended phase 2 dose (RP2D) was determined as 0.064 mg/kg based on safety and tolerability beyond cycle 1. Overall, pts received a median of 2 (range 1–8) treatment cycles. TAK-164-related treatment-emergent AEs (TEAEs) reported in 77.4% of pts included platelet count decrease (58.1%), fatigue (38.7%), and anemia (32.3%). TAK-164-related grade ≥3 TEAEs reported in 32.3% of pts included platelet count decrease (12.9%), alanine aminotransferase increase, aspartate aminotransferase increase, fatigue, and anemia (all 9.7%). Three pts discontinued due to TAK-164-related TEAEs. There was a dose-dependent increase in TAK-164 maximum plasma concentration and exposure over the range 0.016–0.32 mg/kg, with no meaningful accumulation in PK with repeat Q3W dosing. One pt receiving TAK-164 0.19 mg/kg showed γH2AX induction via immunohistochemistry in a post-treatment biopsy, demonstrating target engagement. One pt with low baseline GCC expression who received 5 cycles of TAK-164 0.008 mg/kg had an unconfirmed partial response at cycle 4; 11 of 25 (44.0%) evaluable pts had a best overall response of stable disease. Conclusions: TAK-164 appeared to have a manageable safety profile up to 0.064 mg/kg in pts with advanced GI cancers; hepatic toxicity was identified as a potential risk. The RP2D was determined as 0.064 mg/kg but was considered insufficient to derive significant clinical benefit. Clinical trial information: NCT03449030.

Abstract CT032: A phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies

Abstract Background: While PD-1/L1 blockade is an effective therapeutic approach for many patients with solid and hematologic malignancies, it is not sufficient to induce tumor regressions in the majority of patients. Optimal T cell responses require T cell receptor activation and co-stimulation, which can be provided via ligation of tumor necrosis factor receptor family members, such as OX40. Binding of OX40 by OX40L in the presence of a recognized antigen promotes CD4+ and CD8+ T cell expansion, enhances memory responses and inhibits regulatory T cell function. mRNA-2416 is a novel mRNA-based lipid nanoparticle therapeutic agent that expresses the wild type human OX40L. Preclinical in vivo anti-tumor activity of a murine mRNA-2416 surrogate and synergy with anti-PD-L1 antibodies in syngeneic cancer models are observed (unpublished). Here we present the findings of a first-in-human study of mRNA-2416 monotherapy delivered intratumorally in solid tumor patients with accessible lesions. Methods: This study tested the safety and efficacy of mRNA-2416 administered every 2 weeks for up to 12 doses in a standard 3+3 phase 1 dose escalation in patients with locally advanced, recurrent or metastatic solid malignancy or lymphoma. Tumor biopsies were collected pre- and post-treatment and evaluated by quantitative immunofluorescence (QIF) and RNA sequencing to characterize OX40L expression and immune response following treatment. Results: As of November 13, 2019, 39 patients have been treated at 4 dose levels from 1-8 mg. mRNA-2416 was generally well-tolerated with no DLTs. 6 out of 39 patients experienced grade 3 treatment related AEs. Out of 14 patients with best overall response of stable disease by RECIST, 6 had stable disease for ≥ 14 weeks, and 4 had tumor shrinkage in the injected lesions. Analyses of paired biopsies from injected lesions by QIF showed increased OX40L protein expression as well as elevated T cell scores post-treatment. Activation of a pro-inflammatory gene expression response post-treatment was observed in many cases, including increased cytolytic activity scores, elevated PD-L1 expression, and stimulation of a T cell-inflamed gene expression profile predictive of anti-PD-1/L1 response. These findings were observed in patients with long duration on study or tumor shrinkage. Conclusion: Intratumoral mRNA-2416 is tolerable at all dose levels studied when given as monotherapy and analyses of tumor post-treatment demonstrate increased OX40L protein expression, elevated PD-L1 levels and pro-inflammatory activity. Taken together with the observation of preclinical in vivo synergy with PD-L1 blockade, these data support the evaluation of a combination of intratumoral mRNA-2416 with the anti-PD-L1 inhibitor durvalumab in solid tumors, which is ongoing in part B of this study. Citation Format: Antonio Jimeno, Shilpa Gupta, Ryan Sullivan, Khanh T. Do, Wallace L. Akerley, Ding Wang, Deanna Teoh, Kurt Schalper, Sima J. Zacharek, Jing Sun, Andressa S. Laino, Joshua Frederick, Honghong Zhou, William Randolph, Stephanie Pascarella, Lisa Johansen, Pamela S. Cohen, ROBERT S. MEEHAN, Todd M. Bauer. A phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT032.