Prolonged Stable Disease Research Articles

A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours

BackgroundGartisertib is an oral inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), a key kinase of the DNA damage response. We aimed to determine the safety and tolerability of gartisertib ± carboplatin in patients with advanced solid tumours.MethodsThis phase I open-label, multicenter, first-in-human study comprised four gartisertib cohorts: A (dose escalation [DE]; Q2W); A2 (DE; QD/BID); B1 (DE+carboplatin); and C (biomarker-selected patients).ResultsOverall, 97 patients were enroled into cohorts A (n = 42), A2 (n = 26), B1 (n = 16) and C (n = 13). The maximum tolerated dose and recommended phase II dose (RP2D) were not declared for cohorts A or B1. In cohort A2, the RP2D for gartisertib was determined as 250 mg QD. Gartisertib was generally well-tolerated; however, unexpected increased blood bilirubin in all study cohorts precluded further DE. Investigations showed that gartisertib and its metabolite M26 inhibit UGT1A1-mediated bilirubin glucuronidation in human but not dog or rat liver microsomes. Prolonged partial response (n = 1 [cohort B1]) and stable disease >6 months (n = 3) did not appear to be associated with biomarker status. Exposure generally increased dose-dependently without accumulation.ConclusionGartisertib was generally well-tolerated at lower doses; however, unexpected liver toxicity prevented further DE, potentially limiting antitumour activity. Gartisertib development was subsequently discontinued.ClinicalTrials.govNCT02278250.

METRO-PD1: Phase 1 study of nivolumab in combination with metronomic chemotherapy in children and adolescents with relapsing/refractory solid tumors

BackgroundThis multicenter Phase I study (NCT03585465) evaluated nivolumab in combination with 3 metronomic chemotherapy (MC) regimens in children with refractory/relapsing solid tumors. Objectives: To evaluate the feasibility and safety of the three regimens MethodsPatients aged < 18 years were enrolled. Nivolumab was combined with cyclophosphamide and vinblastine (arm A), capecitabine (arm B), or cyclophosphamide, vinblastine and capecitabine (arm C). Arm A and B were allocated sequentially. Arm C opened only if A and B were deemed safe. Dose-limiting toxicities (DLTs) were evaluated over the first two cycles. Patients were evaluable if they received > 2 cycles and > 70% of the planned dose. PopulationSixteen patients were enrolled, 3 in arm A, 6 in arm B, and 7 in arm C. Median age was 11.5 years (range, 5–19). Patients previously received a median of 3.5 (range, 1–4) lines of systemic treatment, 14 patients had surgery and 11 had radiotherapy. ResultsMedian number of cycles was 2 (1−24), median treatment duration was 56 days (18−714). In arm C, median number of cycles was 4 with median treatment duration of 95 days. No DLT was observed. Grade 3 adverse events (AE) and serious AE were observed in 8 patients (50%) and 1 patient (6%), respectively, over the first 2 cycles. No grade 4 AE occurred. The 6-month PFS and OS were 12% and 44%, respectively, in the whole population. Prolonged stable disease was observed in a high-grade glioma and an atypical teratoid rhabdoid tumor. ConclusionArm C appears safe. A randomized phase II trial evaluating the addition of nivolumab to the triple MC is ongoing.

Abstract B049: Phase II study of NUC-3373, leucovorin, irinotecan (NUFIRI) + bevacizumab vs FOLFIRI + bevacizumab for the second-line treatment of patients with advanced/metastatic colorectal cancer (NuTide:323)

Abstract Background: NUC-3373 is a phosphoramidate transformation of fluorodeoxyuridine monophosphate (FUDR-MP) designed to replace fluoropyrimidines, such as 5-FU. Fluoropyrimidines predominantly exert their activity via FUDR-MP, which inhibits thymidylate synthase (TS). NUC-3373 has been designed to overcome the shortcomings that limit the clinical utility of 5-FU, such as inefficient conversion to FUDR-MP, generation of toxic metabolites, and a lengthy administration schedule due to poor pharmacokinetic (PK) properties. Promising data have been observed in the NuTide:302 study where heavily pre-treated patients (pts) received NUC-3373 (± leucovorin, LV) or NUC-3373 + LV + irinotecan (NUFIRI), and second-line pts received NUFIRI + bevacizumab (NUFIRI-bev). NUC-3373 was well-tolerated in all combinations. Prolonged stable disease was observed in heavily pre-treated pts, with tumour shrinkages as well as periods of progression-free survival (PFS) longer than those achieved on prior lines. Methods: NuTide:323 is a Phase II, open-label, randomised study of NUFIRI-bev vs FOLFIRI-bev in pts with advanced/metastatic CRC who have previously received ≥2 months of a first-line fluoropyrimidine and oxaliplatin-containing regimen or have relapsed within 6 months of completing adjuvant fluoropyrimidine and oxaliplatin. Pts with measurable disease, ECOG 0-1 and wildtype BRAF are eligible. Pts with MSI-H or dMMR are ineligible. 171 pts will be randomised (1:1:1) to either 1500 mg/m2 NUC-3373 + LV Q1W or 1500 mg/m2 NUC-3373 + LV Q2W, both with 180 mg/m2 irinotecan and 5 mg/kg bevacizumab Q2W or FOLFIRI-bev Q2W. NUC-3373 will be administered over 2 h (vs 46 h for 5-FU). Randomisation is stratified by RAS status, prior bevacizumab and duration of prior line of therapy. Primary objectives are to compare the PFS of NUFIRI-bev to FOLFIRI-bev and determine the optimal NUFIRI-bev dosing schedule. Secondary objectives are to compare the efficacy and safety of NUFIRI-bev to FOLFIRI-bev, and assess the PK of NUFIRI-bev. NuTide:323 is being conducted at 65 sites in Europe and the USA. Clinical trial information: NCT05678257 Citation Format: Richard H Wilson, Kristen K Ciombor, Andrew L Coveler, Janet S Graham, Benjamin L Schlechter, Thomas J George, Elena Élez, TR Jeffry Evans, Jordan Berlin, Aimery de Gramont, Fiona G McKissock, Elisabeth Oelmann, Jeffrey D Bloss, Giulia Martini, Jaafar Bennouna, Dominik P Modest, Julien Taieb, Josep Tabernero. Phase II study of NUC-3373, leucovorin, irinotecan (NUFIRI) + bevacizumab vs FOLFIRI + bevacizumab for the second-line treatment of patients with advanced/metastatic colorectal cancer (NuTide:323) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B049.

Abstract LB_C12: Alisertib and pembrolizumab in Rb-deficient head and neck squamous cell carcinomas (HNSCC)

Abstract Preclinical studies demonstrate that cancers with retinoblastoma (Rb) loss are dependent upon Aurora kinases for survival. Additionally, our lab demonstrated that human papilloma virus (HPV)+ cancer cells, in which the viral E7 leads to Rb degradation, undergo apoptosis and immunogenic cell death when treated with the Aurora kinase A inhibitor alisertib (Ali) supporting the clinical combination of pembrolizumab (P) and Ali. All patients received 200mg P every 21d in combination with Ali. Ten advanced solid tumor patients were treated in the phase I portion with the recommended phase II Ali dose of 40mg PO BID for 7d every 21d. There were no objective responses, but one phase I patient previously treated with P remains on therapy with stable disease (SD) for &amp;gt;2 years. The phase II study enrolled 14 patients with immunotherapy- and platinum- resistant HPV+ HNSCC. There were no objective responses, but 7 patients had SD: 3 of them for &amp;gt;10 months. PDL1 expression did not correlate with progression free survival (PFS, p=0.59). The median OS has not been reached. The median PFS was 1.4 months. Toxicities were as expected. Ali caused cytopenias that lead to dose reductions in 2 patients on the phase II trial at cycles 13 and 16. P had to be discontinued in one patient due to elevated liver function tests. Pharmacokinetic (PK) analysis for Ali was performed on cycle 1, d1 and d7 in 12 phase II patients. On d7, PK parameters increased with an accumulation index of 1.54. With limited sampling over the dosing interval, the mean values were: Cmax of 688 and 1300 ng/mL; ahalf-life 4.6 and 7.7 hours; estimated trough concentration at end of dosing period C12 of 278 and 512 ng/mL; and area under the concentration-time curve (AUC0-12) of 3754 and 9738 ng*h/mL on d1 and d7 respectively. These values were similar to prior findings with Ali indicating no drug interactions with P. Cell-free plasma was collected at baseline and every 2 cycles then subjected to a multiplex assay using antibody-coated beads and a fluorescent detection system for simultaneous quantification of 20 immune markers. Higher levels of IL-17 and pronounced increases in the levels of TH2 cytokines IL-10 and IL-4 along with the pro-inflammatory cytokine IL-1β in the in the pretreatment plasma correlated with poor outcome. Levels of cytokines representative of TH1 responses (e.g., IL-12, IFNγ) were not different between those 3 patients with prolonged SD vs. others. Analysis of the HPV ctDNA, ELISpot, and multi-color flow cytometry for phenotypic and functional characterization of lymphocyte/myeloid cells are underway and will be presented. Although there were no objective responses, the combination of Ali and P was well tolerated and led to prolonged SD in patients who had previously progressed on immunotherapy supporting our hypothesis that Aurora A inhibition can reverse immunotherapy resistance in Rb-deficient HNSCC. Additionally, an imbalance of cytokine response favoring TH2 and TH17 over TH1 immunity predicts poor outcome in HPV+ HNSCC patients treated with Ali and P. Citation Format: Faye M Johnson, Madison P O'Hara, J Jack Lee, Yun Qing, Hai Tran, Soma Ghosh, Lacin Yapindi, Peixin Jiang, Alexandre Reuben, George Blumenschein, Jagannadha Sastry. Alisertib and pembrolizumab in Rb-deficient head and neck squamous cell carcinomas (HNSCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C12.

A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better

BackgroundStimulating inflammatory tumor associated macrophages can overcome resistance to PD-(L)1 blockade. We previously conducted a phase I trial of cabiralizumab (anti-CSF1R), sotigalimab (CD40-agonist) and nivolumab. Our current purpose was to study the activity and cellular effects of this three-drug regimen in anti-PD-1-resistant melanoma.MethodsWe employed a Simon’s two-stage design and analyzed circulating immune cells from patients treated with this regimen for treatment-related changes. We assessed various dose levels of anti-CSF1R in murine melanoma models and studied the cellular and molecular effects.ResultsThirteen patients were enrolled in the first stage. We observed one (7.7%) confirmed and one (7.7%) unconfirmed partial response, 5 patients had stable disease (38.5%) and 6 disease progression (42.6%). We elected not to proceed to the second stage. CyTOF analysis revealed a reduction in non-classical monocytes. Patients with prolonged stable disease or partial response who remained on study for longer had increased markers of antigen presentation after treatment compared to patients whose disease progressed rapidly. In a murine model, higher anti-CSF1R doses resulted in increased tumor growth and worse survival. Using single-cell RNA-sequencing, we identified a suppressive monocyte/macrophage population in murine tumors exposed to higher doses.ConclusionsHigher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options.Trial registrationClinicalTrials.gov Identifier: NCT03502330.

CTNI-29. A PHASE 2 STUDY TO EVALUATE EFFICACY AND SAFETY OF ACT001 AND TEMOZOLOMIDE COMBINATION TREATMENT IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME

Abstract BACKGROUND Han Chinese patients with rGBM were randomly assigned to one of three cohorts in this phase 2 open label study: Arm A (ACT001, 400mg, BID), B (ACT001 and temozolomide combination) and C (TMZ or CCNU). Study endpoints include 1-year OS rate, PFS (by iRANO) and AE incidence. RESULTS 7, 6 and 6 patients were enrolled to Arms A, B and C respectively including one patient in Arm C with a mutant IDH1 (R132H). The median age was 52 years (range: 34-68) and male to female ratio 11/8. In addition to 7 SAEs, 189 TEAEs were reported in this interim analysis including 49 and 70 chemo-related AEs in Arm B and Arm C. Post enrollment MRI scans were performed in 6,6 and 4 patients in Arms A, B and C respectively. Despite the lack of objective response and difference in 1-year OS, a prolonged PFS lasting at least 12 months was noted in 3 patients including the patient with mutant IDH1 in Arm C (23 months and ongoing) and two patients in Cohort B (19 and 22 months, both ongoing) who were sensitive to TMZ in first line treatment as shown by at least 12-month interval between TMZ initiation and first relapse. Among 18 patients with wild type IDH, the prolonged stable disease was restricted to combination Arm whereas either the four patients with positive MGMT methylation or two patients with a similar history of sensitivity to first line TMZ treatment didn’t have such prolonged stable disease after being treated with TMZ or ACT001 alone during this study. CONCLUSIONS ACT001 restored sensitization of rGBM patients to TMZ treatment in sub-group of patients likely due to reduced DNA repair capacity by ACT001 treatment. Further study is warranted to evaluate the effect of ACT001 and TMZ combination in phase 2b study.

CTNI-03. EFFICACY OF WSD0922-FU IN OSIMERTINIB-RESISTANT NSCLC WITH CENTRAL NERVOUS SYSTEM (CNS) METASTASES – UPDATES FROM THE DOSE ESCALATION COHORT OF A FIRST-IN-HUMAN PHASE 1 CLINICAL TRIAL (MC1914)

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent HGA and NSCLC. Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR aberrant HGA were enrolled and treated across six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles) to determine the maximum tolerated dose (MTD). 25 patients (17 HGA, 8 NSCLC) were enrolled (median age = 57 years; 24% female; 36% ECOG 0). All patients with HGA received prior radiation and temozolomide. All patients with NSCLC had previous disease progression on EGFR inhibitor therapy (prior osimertinib 88%). The median duration of WSD0922-Fu exposure among all patients was 55 days (range 3 to &amp;gt;279 days) [NSCLC median = 131 days; HGA median = 51 days]. Common treatment-related adverse events are comparable to other EGFR inhibitors (fatigue, acneiform rash, diarrhea, nausea, pruritis). At Cycle 1 Day 15 for patients treated at MTD (160 mg twice daily), the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Among patients with NSCLC treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses. Intracranial and extracranial efficacy was concordant. Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Expansion cohorts are in progress to optimize WSD0922-Fu dose and schedule for future phase 2 development.

The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling.

Imetelstat shows activity in patients with myeloproliferative neoplasms, including primary myelofibrosis (PMF) and essential thrombocythemia. Here, we describe a case of prolonged disease stabilization by imetelstat treatment of a high-risk PMF patient enrolled into the clinical study MYF2001. We confirmed continuous shortening of telomere length (TL) by imetelstat treatment but observed emergence and expansion of a KRAST58I mutated clone during the patient's clinical course. In order to investigate the molecular mechanisms involved in the imetelstat treatment response, we generated induced pluripotent stem cells (iPSC) from this patient. TL of iPSC-derived hematopoietic stem and progenitor cells, which was increased after reprogramming, was reduced upon imetelstat treatment for 14 days. However, while imetelstat reduced clonogenic growth of the patient's primary CD34+ cells, clonogenic growth of iPSC-derived CD34+ cells was not affected, suggesting that TL was not critically short in these cells. Also, the propensity of iPSC differentiation toward megakaryocytes and granulocytes was not altered. Using human TF-1MPL and murine 32DMPL cell lines stably expressing JAK2V617F or CALRdel52, imetelstat-induced reduction of viability was significantly more pronounced in CALRdel52 than in JAK2V617F cells. This was associated with an immediate downregulation of JAK2 phosphorylation and downstream signaling as well as a reduction of hTERT and STAT3 mRNA expression. Hence, our data demonstrate that imetelstat reduces TL and targets JAK/STAT signaling, particularly in CALR-mutated cells. Although the exact patient subpopulation who will benefit most from imetelstat needs to be defined, our data propose that CALR-mutated clones are highly vulnerable.

A phase I study of the ceramide nanoliposome in patients with advanced solid tumors

PurposeCeramide is a sphingolipid metabolite that deactivates multiple oncogenic signaling pathways and promotes cell death. In-vivo data demonstrate single-agent anti-cancer activity and enhanced efficacy with combination strategies. This phase I dose-escalation trial evaluated Ceramide nanoLiposomes (CNL) in patients with advanced solid tumors and no standard treatment option.MethodsThe primary objective was to establish the maximum tolerated dose. Secondary objectives included determining the recommended phase II dose, the safety and tolerability, the pharmacokinetic profile and preliminary anti-tumor efficacy.Results15 patients with heavily pretreated metastatic disease enrolled. Safety data were analyzed for all patients, while pharmacokinetic data were available for 14 patients. There were no grade 3 or higher treatment-related adverse events. The maximum tolerated dose was not reached and there were no dose-limiting toxicities. The most common grade 1 or 2 treatment-related adverse events included headache, fatigue, constipation, nausea and transaminitis. The maximum concentration and area under the curve increased with dose. Clearance was consistent between doses and was observed mainly through the liver without significant hepatotoxicity. The half-life ranged from 20 to 30 h and the volume of distribution was consistent with a lipophilic drug.ConclusionsCNL exhibited an encouraging safety profile and pharmacokinetic parameters, with some signals of efficacy including prolonged stable disease in 1 patient with refractory pancreatic cancer. Pre-clinical data indicate potential synergy between CNL and multiple systemic therapies including chemotherapy, targeted therapy, and immunotherapy. Future studies are planned investigating CNL in combination strategies. Trial registrationThis study is registered under ClinicalTrials.gov ID: NCT02834611.

Evaluation of prevalence and outcomes of serial tyrosine kinase inhibitor use in pediatric patients with advanced solid tumors.

Multitargeted tyrosine kinase inhibitors (mTKIs) are increasingly utilized in the treatment of pediatric sarcomas and other solid tumors. It is unknown whether serial treatment with multiple TKIs provides a benefit and which patients are most likely to benefit from mTKI rechallenge. We performed a retrospective cohort study of pediatric cancer patients who received serial mTKI therapy off-study between 2007 and 2020 as either monotherapy or combination therapy. We report patient characteristics, clinical outcomes, dosing patterns, and treatment-associated toxicity. The study cohort included 25 patients. The overall prevalence of serial mTKI therapy among all patients treated for sarcoma at our institution was 3.7%, and the response rate to second mTKI was 9%. Median 6-month progression-free survival (PFS) and overall survival (OS) from start of second mTKI were 42.1% (95% CI: 20.4%-62.5%) and 79.1% (95% CI: 57.0%-90.8%), respectively. Patients who had received 4months or more (n=11) of therapy with first mTKI had significantly longer PFS versus those who received less than 4months (n=11; p=.001). Thirty-three percent of patients discontinued second mTKI due to toxicity. Six (40%) of 15 patients who discontinued the first mTKI due to progression had either a partial response or stable disease on the second mTKI. We observed a low response rate to mTKI rechallenge. However, we identified patients who had been treated with first mTKI for ≥4months as more likely to have prolonged stable disease with second mTKI. Several patients had a response or stable disease on the second mTKI despite having progressed on the first mTKI. Though toxicity was common, only a minority of patients discontinued the second mTKI due to toxicity.

Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer.

O6-methylguanine DNA methyltransferase (MGMT)-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has MGMT silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer. Patients with advanced colorectal cancer were screened for MGMT promoter hypermethylation using methylation-specific PCR of archival tumor. Eligible patients received TMZ 75 mg/m2 days 1-7 with olaparib 150 mg twice daily every 21 days. Pretreatment tumor biopsies were collected for whole-exome sequencing (WES), and multiplex quantitative immunofluorescence (QIF) of MGMT protein expression and immune markers. MGMT promoter hypermethylation was detected in 18/51 (35%) patients, 9 received study treatment with no objective responses, 5/9 had stable disease (SD) and 4/9 had progressive disease as best response. Three patients had clinical benefit: carcinoembryonic antigen reduction, radiographic tumor regression, and prolonged SD. MGMT expression by multiplex QIF revealed prominent tumor MGMT protein from 6/9 patients without benefit, while MGMT protein was lower in 3/9 with benefit. Moreover, benefitting patients had higher baseline CD8+ tumor-infiltrating lymphocytes. WES revealed 8/9 patients with MAP kinase variants (7 KRAS and 1 ERBB2). Flow cytometry identified peripheral expansion of effector T cells. Our results indicate discordance between MGMT promoter hypermethylation and MGMT protein expression. Antitumor activity seen in patients with low MGMT protein expression, supports MGMT protein as a predictor of alkylator sensitivity. Increased CD8+ TILs and peripheral activated T cells, suggest a role for immunostimulatory combinations. TMZ and PARP inhibitors synergize in vitro and in vivo in tumors with MGMT silencing. Up to 40% of colorectal cancer is MGMT promoter hypermethylated, and we investigated whether TMZ and olaparib are effective in this population. We also measured MGMT by QIF and observed efficacy only in patients with low MGMT, suggesting quantitative MGMT biomarkers more accurately predict benefit to alkylator combinations.

The highs and lows of serous ovarian cancer.

Low-grade serous ovarian cancer was initially described as a distinct type of rare epithelial ovarian cancer 20 years ago; however, only recently have physicians begun to leverage the understanding of the clinical behavior and molecular profile of this disease for treatment. The use of routine next-generation sequencing has allowed a deeper understanding of the molecular drivers of this disease and shown how molecular alterations in mitogen-activated protein kinase pathway genes such as KRAS and BRAF can affect overall prognosis and disease behavior. The use of targeted therapies, including MEK inhibitors, BRAF kinase inhibitors, and other investigational targeted therapies are changing the way this disease is viewed and treated. In addition, endocrine therapy can provide prolonged disease stability with generally mild toxicity, as well as promising response rates in recent studies examining combination therapy with CDK 4/6 inhibitors in the upfront and recurrent setting. Once seen merely as a chemo-resistant form of ovarian cancer, recent studies have worked to harness the unique features of low-grade serous ovarian cancer to provide individualized treatment options for patients with this disease.

TRLS-12. INTRAVENTRICULAR B7-H3 CAR T CELLS FOR DIFFUSE INTRINSIC PONTINE GLIOMA: INTERIM ANALYSIS OF BRAINCHILD-03 ARM C

Abstract BACKGROUND BrainChild-03 is a first-in-human phase 1 clinical trial delivering repeated intraventricular B7-H3 CAR T cells to children with central nervous system (CNS) tumors without lymphodepleting chemotherapy. METHODS We report on the ongoing Arm C for patients with diffuse intrinsic pontine glioma (DIPG), currently enrolling at the highest Dose Regimen (10x10^7 B7-H3CARs/dose). Primary endpoints are feasibility and safety. Secondary endpoints are disease response and correlatives of CAR-T activity. RESULTS 19 patients have enrolled. All had successful CAR-T manufacturing. 17 patients were treated; 13 received sufficient doses for safety evaluation (4 doses/8 weeks) without a dose limiting toxicity (DLT). One patient had a DLT (pontine hemorrhage 8 days post-initial dose). The 5 unevaluable patients include: 2 on protocol not yet evaluable, 2 left the study due to rapid progression, and 1 did not meet eligibility to initiate treatment. Overall, patients have received 134 doses (median: 8/patient, range: 1-36). Adverse events include headache (93%), nausea/vomiting (79%), and fever (57%). Cytokine release syndrome (CRS) or immune effort cell-associated neurotoxicity syndrome (ICANS) have not occurred. Of 14 evaluable patients, 8 enrolled after progression, including some with metastases. Patients with progressive DIPG at enrollment have a median survival of 278 days post-initial dose (3/8 alive). Patients who enrolled before progression have a median overall survival of 207 days (6/6 alive) with 1 patient still receiving protocol therapy after 18 months (36 doses). We have found localized CSF circulating CAR T cells and cytokine elevations supporting local immune activation. CSF mass spectrometry shows modulation of B7-H3 and immune analytes (CD14, CD163, CSF-1, CXCL13). CONCLUSION Repeated intraventricular B7-H3 CAR T dosing has been feasible for children with DIPG, even after progression, with evidence of local immune activation. Tolerability and prolonged stable disease suggest the potential for clinical benefit allowing for future cellular enhancements and combinations.

Phase 1 study of indenoisoquinoline LMP744 in adults with relapsed solid tumors and lymphomas.

3022 Background: Indenoisoquinolines (IIQ) are non-camptothecin inhibitors of topoisomerase 1 (TOP1) that have improved characteristics over camptothecin TOP1 inhibitors. IIQs demonstrate better chemical stability, produce more persistent DNA breaks induced by trapping DNA-TOP1 cleavage complexes, induce DNA breaks at different sites than camptothecins, and are not substrates for cellular export proteins. We present data from a trial of LMP744 (NSC 706744), which was the most efficacious IIQ in a canine lymphoma trial, designed to establish the safety, efficacy, and maximum tolerated dose (MTD) of LMP744. Methods: We conducted a multicenter phase 1 trial in adult patients (pts) with dose escalations following design 3 of the Simon accelerated titration designs. LMP744 was administered intravenously daily on d1-5 in 28-day cycles (C), starting at dose level (DL) 1 (6 mg/m2/d). Responses and adverse events (AEs) were defined by RECIST 1.1 and CTCAE v4.0, respectively. Plasma concentrations were determined by LC-MS/MS with a validated assay over a range of 1-3,000 ng/mL. Paired biopsies (baseline and C1D2) were analyzed for DNA damage response markers (γH2AX, pNBS1, and Rad51) by IFA. Results: A total of 36 pts were enrolled, median age was 61 years (range 35-81), median prior lines of systemic treatment was 5 (range 2-10) and 26 pts (72%) had received prior TOP1 inhibitor therapy. One pt on DL6 (190 mg/m2/d) experienced a dose-limiting toxicity (DLT) of grade 3 hypokalemia during C1, reverting the study to a 3+3 design. MTD was established at DL6. Of 24 patients evaluable for response, 1 pt with small cell lung cancer on DL6 achieved a partial response (PR), remaining on treatment for 7C. 17 pts had stable disease (including 1 pt with an unconfirmed PR), and 6 had progressive disease. Median duration of response among pts with SD was 4.5C (range 1-28). A total of 6 pts on DL6 with colorectal cancer (n=4, all had received prior irinotecan), mesothelioma (n=1), and low-grade appendiceal mucinous neoplasm (n=1) remained on study for &gt;6C. Treatment-related grade 3/4 AEs included leukopenia (n=9), anemia (n=4), dehydration (n=2), neutropenia (n=2) and nausea (n=2). Pharmacokinetic (PK) data for the first 17 patients suggests dose-linear PK, best fit to a 2-compartment model. Approximate half-life, clearance, central and peripheral volume values were 30 h, 90 L/h, 200 L, and 2500 L, respectively. Induction of γH2AX and Rad51 was measured in the pt with PR. Conclusions: The MTD of LMP744 was established at 190 mg/m2/d on d1-5 in a 28d C. The single agent activity of LMP744 in this heavily pretreated population was limited; however, 4 colorectal cancer pts had prolonged stabilization of disease with prior progression on irinotecan. Analyses of secondary and exploratory correlatives are ongoing. Clinical trial information: NCT03030417 .

A single-institution pediatric and young adult interventional oncology collaborative: Novel therapeutic options for relapsed/refractory solid tumors.

Pediatric interventional oncology (PIO) is a growing field intended to provide additional or alternative treatment options for pediatric patients with benign or malignant tumors. Large series of patients treated uniformly and subjected to rigorous endpoints for efficacy are not available. We designed a collaborative initiative to capture data from pediatric patients with benign and malignant tumors who underwent a therapeutic interventional radiology procedure. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was utilized as a measure of radiologic response and data were collected regarding improvement in pain and functional endpoints. Cumulative incidence of progressive disease was calculated using both the treated site and the patient as the analytic unit. Forty patients, 16 with malignant tumors and 24 with benign tumors, underwent a total of 88 procedures. Cryo- and radiofrequency ablation were the most frequently utilized techniques for both cohorts of patients. A complete or partial response, or prolonged disease stability, were achieved in approximately 40% of patients with malignant tumors and 60% of patients with benign tumors. No patients had progressive disease as their best response. Resolution of pain and improved mobility with return-to-baseline activity were demonstrated across patients from both cohorts. Only minor complications were experienced. Interventional radiology-guided interventions can serve as an alternative or complementary approach to the treatment of benign and malignant tumors in pediatric patients. Prospective, multi-institutional trials are required to adequately study utility, treatment endpoints, and durability of response.

First-in-human phase 1 trial of the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of WSD0922-Fu: Initial report from dose escalation cohort.

3109 Background: WSD0922-Fu is an oral, central nervous system (CNS)-penetrant, small molecule, ATP non-competitive, reversible EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). We report initial results of a first-in-human phase 1 dose-escalation trial (NCT04197934) in patients with EGFR aberrant recurrent HGA and NSCLC. Methods: Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR mutant and/or EGFR amplified HGA were enrolled. WSD0922-Fu was orally administered, and dose escalated in cohorts based on a standard 3+3 design to determine the maximum tolerated dose (MTD). Toxicities were graded per CTCAE v5.0 and preliminary efficacy was based on modified RANO criteria or RECIST 1.1 as appropriate. Results: 25 patients (17 HGA, 8 NSCLC) were enrolled and treated in six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles). The median age was 57 years (range 39-75 years). 24% were female and 36% were ECOG 0. For patients with HGA, all patients were previously treated with radiation and temozolomide; the median number of prior lines of systemic therapy was 1 (range 1-4). For patients with NSCLC, all patients were previously treated with an EGFR inhibitor (prior osimertinib 88%); the median number of prior lines of systemic therapy was 1.5 (range 1-6). The median duration of exposure to WSD0922-Fu among all patients was 54 days (range 2-258 days). The most common (≥25%) treatment-related adverse events included fatigue (68%), acneiform rash (68%), diarrhea (52%), nausea (48%) and pruritis (28%). The frequency of severe AEs was dose dependent. The most common Grade 3+ AEs (≥10%) included lymphopenia (16%), acneiform rash (12%), headache (12%) and diarrhea (12%). The MTD was defined as 160 mg twice daily. At Cycle 1 Day 15 for patients treated at this dose level, the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h; range 6.2-78.7 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Oral clearance at steady state was inversely related with dose, suggesting either inhibition or saturation of clearance processes. Among patients treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients with NSCLC demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses (intracranial and extracranial). Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Conclusions: The MTD for WSD0922-Fu monotherapy is 160 mg BID. Preliminary efficacy was observed in patients with osimertinib-resistant NSCLC and EGFRvIII mutant HGA. Enrollment to expansion cohorts is ongoing. Clinical trial information: NCT04197934 .

Inhibition of FASN as a potential treatment of advanced endocrine therapy-resistant breast cancer.

e13077 Background: The past decade has seen significant advancement in increasing survival estrogen receptor alpha (ERα) positive breast cancer. The use of selective estrogen receptor down-regulators and modulators (SERMs) and cyclin-dependent kinase inhibitors aided to extend overall survival of breast cancer patients. However, resistance to endocrine therapy is a common occurrence and patients will eventually succumb to their disease. Fatty acid synthase (FASN), a key enzyme in lipid biosynthesis, is overexpressed in more aggressive and therapy-resistant tumors, including breast cancers. FASN inhibitor, TVB-2640, has been evaluated in multiple tumor cell lines and in a phase 1 clinical study, and showed partial responses in 5 patients and multiple patients with prolonged stable disease (≥16 weeks). Methods: We generated therapy-resistant cells by long term exposure to tamoxifen (MCF7/TamR cells), and fulvestrant (MCF7/FR cells). Palbociclib-resistant (MCF7/RB1Crispr and ZR75/RB1Crispr) cells were generated through CRISPR/Cas9 knockout of the retinoblastoma (RB) gene. We assessed the impact of TVB-3166 inhibitor in these cells on proliferation, viability, cell cycle, apoptosis, ERα expression in patient derived explants, and tumor growth in xenografts. RNA sequencing of tamoxifen- and fulvestrant-resistant cells was performed to investigate gene expression. Subcellular localization of ERα was assessed using subcellular fractionations. Palmitoylation and ubiquitination of ERα were assessed by immunoprecipitation. ERα and p-eIF2α protein levels were analyzed by western blot after treatment with TVB with or without the addition of palmitate or BAPTA. Results: TVB treatment leads to a marked inhibition of proliferation in tamoxifen-, fulvestrant- and palbociclib-resistant cells compared to the parental cells. RNA sequencing of explants of patients with ERα positive disease showed down regulation of ESR1 related genes and genes involved in invasiveness. RNA sequencing of fulvestrant-resistant cells showed that treatment with TVB results in down regulation of EMT and E2F target genes, cholesterol homeostasis genes and mTORC1 signaling. Additionally, TVB significantly inhibited tumor growth in mice and decreased proliferation of primary tumor explants compared to untreated controls. FASN inhibition significantly reduced ERα levels most prominently in endocrine resistant cells and altered its subcellular localization. Furthermore, we showed that the reduction of ERα expression upon TVB treatment is mediated through the induction of endoplasmic reticulum stress. Conclusions: Our preclinical data provide evidence that FASN inhibition presents a promising therapeutic strategy for treatment of endocrine-resistant breast cancer. Further clinical development of FASN inhibitors for endocrine resistant breast cancer should be considered.

Phase 1/2 dose escalation and dose expansion study of TransCon IL-2 β/γ alone or in combination with pembrolizumab: Initial results from dose escalation.

e14597 Background: TransCon IL-2 β/γ is a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 analog (IL-2 β/γ) designed to optimally address the drawbacks of interleukin-2 (IL-2) therapy. IL-2 β/γ was created by permanently attaching a 5 kDa mPEG in the IL-2Rα binding site. To improve the pharmacokinetic (PK) properties, IL-2 β/γ was transiently attached to a 40 kDa mPEG carrier via a TransCon linker creating a prodrug, TransCon IL-2 β/γ. Under physiological conditions, TransCon IL-2 β/γ releases active IL-2 β/γ from the carrier via autocleavage in a controlled manner. The associated long effective half-life and sustained IL-2 β/γ exposure results in robust activation of IL-Rβ/γ+ cytotoxic immune cells, at a lower Cmax compared to IL-2 therapy. The primary objectives of the IL-Believe trial are to evaluate safety and tolerability, and to define the maximum tolerated dose and recommended Phase 2 dose of TransCon IL-2 β/γ alone or in combination with pembrolizumab. Methods: In dose escalation (3+3 design), patients aged ≥18 with advanced solid tumors receive TransCon IL-2 β/γ as monotherapy or in combination with pembrolizumab with IV dosing every 3 weeks. Disease is assessed every 9 weeks using RECIST 1.1. Safety, PK, and pharmacodynamics (PD) are evaluated. Results: As of 25 Jan 2023, 27 patients were treated in dose escalation: 18 in monotherapy (Dose Levels (DL) 1-4) and 9 in combination therapy (DL1, DL2). The most common tumor types in monotherapy and in combination therapy were head &amp; neck (19%), colorectal (11%) and endometrial (11%). Patients received a median of 3 prior lines of therapy in monotherapy. The most common Treatment Related Adverse Events (TRAEs) in monotherapy and in combination therapy were pyrexia (30%), Cytokine Release Syndrome (CRS) (26%) and fatigue (22%). Grade 3 (G3) TRAEs in monotherapy were anemia (17%), CRS (6%), thrombocytopenia (6%), hypoxia (6%), all reported at DL4. 1 Dose Limiting Toxicity of G3 CRS was reported at DL4. Preliminary PK results showed systemic drug exposure of TransCon IL-2 β/γ with a half-life of ~ 35 hours and no PK interaction with pembrolizumab was observed. PD data were consistent with sustained activation and dose dependent expansion of cytotoxic effector cells, in comparison, Tregs were only expanded minimally. Absolute lymphocyte counts increased in a dose dependent manner while eosinophils remained low. Prolonged stable disease ( &gt; 32 weeks) was observed in one pancreatic cancer patient on monotherapy. Conclusions: TransCon IL-2 β/γ is generally well-tolerated as monotherapy and in combination with pembrolizumab. The pharmacodynamics data confirm a durable activation and expansion of IL-2Rβ/γ+ cytotoxic immune cells over IL-2Rα+ eosinophils and Tregs. Clinical trial information: NCT05081609 .

Results from a first-in-human phase 1B study of a complement factor H inhibitor (GT103) in patients with non-small cell lung cancer (NSCLC).

9128 Background: GT103 is a first-in-class IgG3 monoclonal antibody that was derived from a single human B cell and inhibits complement factor H (CFH). CFH is implicated in cancer immune evasion and overexpression portends a poor prognosis in multiple malignancies. CFH regulates C3 convertase in the alternative pathway of the complement cascade, limiting downstream opsonization and membrane attack complex formation. Monoclonal antibody inhibition of CFH facilitates complement-dependent tumor cell lysis, modulates the adaptive immune response, and inhibits tumor growth. Methods: GT103 is being evaluated in a multi-institutional, first-in-human, phase Ib study in patients with advanced stage, refractory NSCLC. A standard ‘3+3’ dose escalation schema was used across four dose levels, with treatment given until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) observation period included cycle 1 and radiographic disease assessment was performed every 6 weeks. We have previously reported that no DLT was seen at the highest two dose levels of 3 mg /kg or 10 mg/kg administered IV every 3 weeks. Two expansion cohorts have now been opened at 10 mg/kg IV every 2 week and 15 mg/kg every 3 weeks dose levels allowing up to 6 patients at each dose level. We herein present updated clinical outcomes and analysis of correlative biomarkers. Results: As of February 3, 2023, twenty-five patients have been treated, with a median follow up of 230 days. Five of the 21 patients in the dose escalation cohort demonstrated stable disease by RECIST criteria. In the 10 mg/kg dose level, one patient has experienced prolonged disease stabilization and has received 12 cycles to date with tumor reduction on CT. The DLT period is ongoing for two patients enrolled in the 10 mg/kg IV every 2 weeks and two patients in the 15 mg/kg every 3 weeks expansion cohorts. Soluble C5b-9 (s C5b-9) is a candidate pharmacodynamic biomarker for GT103 and was measured at baseline and at day 15 from patients in all four dose escalation levels (0.3, 1, 3, 10 mg/kg). An increase in sC5b-9 was found in 13 of 21 patients at day 15. A marked doubling of the baseline sC5b-9 level was demonstrated in a subset of patients by day 15 indicative of biologic activity. Conclusions: GT103 is well tolerated in heavily pretreated advanced NSCLC population. Early clinical activity has been demonstrated to date with stable disease seen in 24% of patients. Updated clinical results and correlative data will be presented. A separate phase 2 study of combination GT103 with pembrolizumab is planned for patients with refractory NSCLC. Trial Registration: The study was approved by Duke University IRB with approval number Pro00104564. Clinical trial information: NCT04314089 .

ETCTN/NCI 10330: A phase 2 study of belinostat with SGI-110 (guadecitabine) or ASTX727 (decitabine/cedazuridine) for the treatment of unresectable and metastatic conventional chondrosarcoma.

11531 Background: Conventional chondrosarcoma (cCS) is the 2nd most common primary bone tumor and is resistant to chemotherapy and radiation. IDH1/2 mutations (m) occur in 50% of cCS. Both IDHm and wild-type (wt) cCS harbor epigenetic dysregulation. In preclinical models of IDHm and wt cCS, combination treatment with HDAC and DNMT inhibitors (i) suppressed growth in vitro and in vivo by reversing the hypermethylated state and inducing tumor suppressors, interferon response genes and apoptosis (Sheikh T, Schwartz G. Mol Cancer Ther 2021;20). Methods: NCI 10330 is a single-arm, multicenter, phase 2 study evaluating the HDACi belinostat (B) with the DNMTi SGI-110 (S) or ASTX727 (A). A replaced S due to drug availability (pts were replaced). Pts had advanced cCS, ECOG PS ≤ 2 and could be treatment naïve. Progression was required for grade 1 cCS. Pts received B 1000mg/m2 IV + S 45mg/m2 SC both days 1-5 or B (same dosing) + A (cedazuridine 100mg/decitabine 35mg) PO both days 1-5, in 28-day cycles. 1° endpoint was objective response. A Simon 2-stage design was used. If ≥ 2/13 responses occurred in stage 1, the study would proceed to full accrual. Design had 85% power with α = 0.05 to test ORR 8% vs 28%. 2° endpoints included safety, PFS and OS. A safety lead-in was performed. Paired biopsies were collected. Results: Stage 1 is complete. 19 pts were treated: 6 on B+S and 13 on B+A. Median age was 50 and 67 years, respectively. All pts had prior surgery. 17% (B+S) and 38% (B+A) had prior radiation. 33% (B+S) and 55% (B+A) were IDHm. 67% (B+S) and 75% (B+A) were histologic grade ≥ 2. There were no objective responses. Best response (at 8 weeks) was stable disease (SD) in 4/6 pts (67%) on B+S and 6/10 pts (60%) on B+A. mPFS was 4.2 mos (95% CI 1.97-NR) for B+S and 3.8 mos (95% CI 2.17-NR) for B+A. mOS has not been reached. For B+A, mPFS for IDHm vs wt pts was 4.7 and 3.1 mos, respectively (p=0.21). One pt with IDHm grade 2 cCS who progressed on FT-2102 (IDH1i) remains on B+A &gt; 1 year. There were no DLTs during either safety lead-in. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 17% (B+S) and 69% (B+A). For B+A, the most common grade 3/4 TRAE was neutropenia (54%) and the most common all-grade TRAEs were nausea (69%), leukopenia (61%), neutropenia (54%), anemia (46%) and fatigue (46%). Paired tumor biopsies are being evaluated with whole exome sequencing, RNAseq, methylation array and multiplex IHC with results forthcoming. Conclusions: Combination HDACi + DNMTi was well-tolerated in advanced cCS. There were no objective responses; however, a subset of pts experienced prolonged SD with a trend towards improved mPFS in IDHm pts. Correlative work is ongoing with a focus on differential effects on IDHm tumors and whether modulation of the immune microenvironment might support combinations with immunotherapy. Support: UM1CA186689. Clinical trial information: NCT04340843 .