Nab-paclitaxel Research Articles

Telotristat ethyl, a tryptophan hydroxylase inhibitor, enhances antitumor efficacy of standard chemotherapy in preclinical cholangiocarcinoma models.

Cholangiocarcinoma (CCA), an aggressive biliary tract cancer, carries a grim prognosis with a 5-year survival rate of 5%-15%. Standard chemotherapy regimens for CCA, gemcitabine plus cisplatin (GemCis) or its recently approved combination with durvalumab demonstrate dismal clinical activity, yielding a median survival of 12-14 months. Increased serotonin accumulation and secretion have been implicated in the oncogenic activity of CCA. This study investigated the therapeutic efficacy of telotristat ethyl (TE), a tryptophan hydroxylase inhibitor blocking serotonin biosynthesis, in combination with standard chemotherapies in preclinical CCA models. Nab-paclitaxel (NPT) significantly enhanced animal survival (60%), surpassing the marginal effects of TE (11%) or GemCis (9%) in peritoneal dissemination xenografts. Combining TE with GemCis (26%) or NPT (68%) further increased survival rates. In intrahepatic (iCCA), distal (dCCA) and perihilar (pCCA) subcutaneous xenografts, TE exhibited substantial tumour growth inhibition (41%-53%) compared to NPT (56%-69%) or GemCis (37%-58%). The combination of TE with chemotherapy demonstrated enhanced tumour growth inhibition in all three cell-derived xenografts (67%-90%). PDX studies revealed TE's marked inhibition of tumour growth (40%-73%) compared to GemCis (80%-86%) or NPT (57%-76%). Again, combining TE with chemotherapy exhibited an additive effect. Tumour cell proliferation reduction aligned with tumour growth inhibition in all CDX and PDX tumours. Furthermore, TE treatment consistently decreased serotonin levels in all tumours under all therapeutic conditions. This investigation decisively demonstrated the antitumor efficacy of TE across a spectrum of CCA preclinical models, suggesting that combination therapies involving TE, particularly for patients exhibiting serotonin overexpression, hold the promise of improving clinical CCA therapy.

First-line Chemotherapy in Combination With Oral Recombinant Methioninase and a Low-methionine Diet for a Stage IV Inoperable Pancreatic-Cancer Patient Resulted in 40% Tumor Reduction and an 86% CA19-9 Biomarker Decrease.

Pancreatic cancer has a very poor prognosis with a 5-year survival rate of less than 5% among patients with distant metastasis, a figure that has not improved over many decades. Only 10 to 20% patients are candidates for curative surgery at presentation due to the aggressive nature and asymptomatic progression of pancreatic cancer. Although first-line chemotherapy, such as FOLFIRINOX and gemcitabine + nab paclitaxel, improved the median survival from 8.5 to 11.1 months, more effective treatments are immediately needed. The aim of the present study was to evaluate the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet combined with first-line chemotherapy on a patient with stage IV metastatic pancreatic cancer. A 63-year-old female was diagnosed with metastatic pancreatic cancer in October 2023. The patient started FOLFIRINOX as first-line chemotherapy in combination with methionine restriction, which comprised o-rMETase 250 units twice a day and a low-methionine diet. The patient was monitored using computed tomography and CA19-9 blood tests. After five months from the start of combination therapy, the size of the primary tumor decreased by 40% along with liver-metastasis regression. The CA19-9 blood marker decreased by 86%. The patient sustains a high performance status and continues the combination therapy without severe side effects. Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with first-line chemotherapy, was highly effective in a patient with inoperable stage IV pancreatic cancer.

Hyaluronidase improves the efficacy of nab-paclitaxel after prolonged angiogenesis inhibition in preclinical models for esophagogastric cancer

BackgroundLong-term anti-angiogenesis leads to pruned vasculature, densely deposited extracellular matrix (ECM), and consequently reduced chemotherapy delivery in esophagogastric cancer (EGC). To address this issue, we evaluated the efficacy of adding a hyaluronidase or a NO-donor to the regimen of chemotherapy and anti-angiogenic drugs. MethodsA patient-derived EGC xenograft model was developed. Grafted mice were randomly assigned to four experimental groups and one control group. The experimental groups received DC101, a murine angiogenesis inhibitor, and nab-paclitaxel (NPTX), with the addition of hyaluronidase (PEGPH20), or NO-donor (nitroglycerine, NTG), or their combination, respectively. We compared tumor growth during 17 days of treatment. We performed immunohistochemistry for ECM components hyaluronan (HA) and collagen, CD31 for endothelial cells, and γH2AX for DNA damage. The positively stained areas were quantified, and vessel diameters were measured using QuPath software. ResultsProlonged DC101 treatment induced deposition of HA (p<0.01) and collagen (p<0.01). HA was effectively degraded by PEGPH20 (p<0.001), but not by NTG as expected. Both PEGPH20 (p<0.05) and NTG (p<0.01) dilated vessels collapsed in response to long-term DC101 treatment. However, only PEGPH20 (rather than NTG) was found to significantly inhibit tumor growth (p<0.05) in combination with NPTX and DC101. ConclusionsThese findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC.

Nanoliposomal irinotecan with fluorouracil and folinic acid, FOLFIRINOX, and S-1 as second-line treatment for unresectable pancreatic cancer after gemcitabine/nab-paclitaxel

This study aimed to compare second-line treatment outcomes for patients with unresectable pancreatic cancer previously treated with gemcitabine plus nab–paclitaxel (GnP) therapy. We conducted an integrated analysis of two retrospective studies included 318 patients receiving nanoliposomal irinotecan + 5-fluorouracil/folinic acid (NFF) (n = 102), S-1 (n = 57), or FOLFIRINOX (n = 14) as second-line treatment. Median overall survival (OS) in the NFF group was 9.08 months, significantly better than S-1 (4.90 months, P = 0.002). FOLFIRINOX had a median OS of 4.77 months, not statistically different from NFF. Subgroup analyses of OS indicated NFF was generally superior, however, a statistical interaction was observed between the treatment regimen in serum Alb < 3.5 g/dL (P = 0.042) and serum CRP ≥ 0.3 mg/dL (P = 0.006). Median progression-free survival (PFS) was 2.93 months for NFF, significantly better than S-1 (2.53 months, P = 0.024), while FOLFIRINOX had a comparable PFS (3.04 months, P = 0.948). Multivariate analysis identified the serum CRP, serum CA19-9, duration of first-line GnP therapy, and use (yes/no) of S-1 for second-line treatment as independent predictors for OS. This study concludes that second-line NFF therapy demonstrated a more favorable OS compared to S-1 therapy, however, it is still important to consider the patient background characteristics while selecting the most appropriate treatment.

Phase II trial of biologically optimized schedule of gemcitabine and nab-paclitaxel in metastatic pancreatic cancer.

e16325 Background: Metastatic pancreatic adenocarcinoma (PDAC) has a poor prognosis and limited therapeutic options. In addition to efforts to develop novel agents, there is a need to optimize and maximize the benefit of currently approved drugs such as gemcitabine (G) + nab-paclitaxel (NP). NP is albumin–bound, hence albumin uptake is critical for its effect. Caveolae are small membrane invaginations essential for transendothelial albumin uptake. Cav-1 is the principal structural component of caveolae. We have shown that tumor cell-specific Cav-1 expression directly correlates with albumin and albumin-bound chemotherapy uptake and subsequent apoptotic response in tumor cells. In vitro studies showed that exposure of PDAC cells to G resulted in up-regulation of Cav-1 peaking 48 hours after G exposure. This Cav-1 up-regulation correlated with increased temporal albumin cellular uptake. In addition, we noted that exposure of PDAC cells to G resulted in a time–specific re-entry of cells into the G2/M phase (NP cytotoxicity phase) between 48-60 hours after G treatment. Collectively this data suggest that infusing NP 48 hours after G infusion would be optimal for both increased uptake as well as increased susceptibility to apoptosis of tumor cells. We have shown this effect on multiple cell lines and mouse models. Methods: This is a phase II trial (NCT04115163) where patients (pts) receive G + NP every 2 weeks with modification of the schedule to deliver NP 48 hours (2 days) after G infusions. The primary endpoint is ORR, with a null hypothesis of 20% vs a target of 35%. Employing a 2-stage minimax design minimax and assuming 80% power and a 0.05 significance level, a total of 53 pts are required. In the first stage, if at least 7/31 pts respond to therapy, an additional 22 pts will be added for a total of 53 pts. The study will be terminated early if ≤ 6 pts respond in the first stage. Observation of response in at least 16/53 pts would be required to warrant further investigation of this infusion schedule. Secondary endpoints include safety of the regimen schedule, relative dose intensity, disease control rate, PFS, and OS. The trial opened to enrolment in June 2020. Results: Interim analysis was conducted after 43 pts had been enrolled. 29 pts were found to be evaluable for the primary endpoint of response. Objective response was seen in 11 out of 29 (37.9%) evaluable pts thus meeting statistical criteria to continue enrolment on stage 2 of the study. The regimen was well tolerated with no new safety signals. Toxicities are summarized in table. Conclusions: Biologically optimized G + NP was well tolerated with interim analysis revealing response rate of 37.9%. Enrolment is ongoing with plans for correlative analysis related to Cav-1. Clinical trial information: NCT04115163 . [Table: see text]

Efficacy and safety of surufatinib, toripalimab, nab-paclitaxel in combination with radiotherapy or surgery in the first-line treatment of esophageal squamous cell cancer: A single-centered prospective clinical trial.

e16047 Background: Chemotherapy(CT) plus immune checkpoint inhibitors (ICIs) has become the current standard of care in the first-line treatment of metastatic esophageal squamous cell cancer(ESCC). In locally advanced setting, radiochemotherapy with or without resection remains the standard of care. Surufatinib, a novel small-molecule kinase inhibitor targeting VEGFR1-3, FGFR and CSF-1R, in combination with PD-1 inhibitors have demonstrated synergistic anti-tumor activities in previous studies. This single-centered prospective clinical trial aims to evaluate the efficacy and safety of surufatinib(SUR), toripalimab(TOR), nab-paclitaxel(NAB) in combination with radiotherapy or surgery in the first-line treatment of locally advanced(LA) or metastatic(R/M) ESCC. Methods: Eligible patients(pts) with confirmed LA or R/M, ECOG PS 0-2 and no prior systematic treatment were enrolled in the trial. Pts would receive 260mg/m2 NAB and TOR 240mg on day 1 and SUR 250mg once daily in each 21-day cycle as induction therapy for two cycles, followed by surgery or another two cycles of concurrent chemoradiotherapy(CCRT) with NAB, SUR and radiotherapy, in which involved-field irradiation were conducted at the dose of 50-63 Gy/25-30F, 1.8-2 Gy per fraction, 5 fractions per week. As maintenance therapy, daily SUR and TOR every three week were administered until disease progression or unacceptable toxicities. Progression-free survival (PFS) was the primary endpoint. Results: As of Jan 7, 2024, 16 pts were enrolled, of whom 15 were evaluable. 14(87.5%) pts were male. The median age was 69.5 (range: 45-79). Tumor located in upper(18.8%), middle(25%) and lower(56.2%) thoracic. 1(6.2%) is Stage II disease, 12(75%) Stage III and 3(18.8%) Stage IV. 8 (50%) pts were with PD-L1 CPS greater than 1, 5 (31.25%) pts greater than 5, and 3 (18.75%) pts greater than 10. PD-L1 CPS of 6(37.50%) pts was unknown. With a median follow-up time of 5 (range: 1-12) months, despite the immatureness of PFS, the 12-month PFS rate was 77.14% (95% CI: 48.89%-100%). The objective response rate was 93.3% (14/15), and disease control rate was 100% (15/15). Five of the included pts met the resection criteria during treatment and underwent subsequent R0 resection. The most common adverse events (≥20%) of all grades were hypoesthesia (62.5%), nausea and vomiting (50%), and white blood cell decrease (43.75%). Conclusions: The combination ofsurufatinib, toripalimab, nab-paclitaxel with radiotherapy or surgery has demonstrated promising efficacy and a well-tolerated safety profile as a potential first-line treatment for LA or R/M ESCC. This ongoing trial merits further investigation and holds significant implications for clinical practice.

Abstract 5957: Development of a selective, oral ATP-competitive CDK9 inhibitor, BLX-3030, for treatment of pancreatic cancer

Abstract Introduction Transcription regulators, such as cyclin-dependent kinase 9 (CDK9), have been implicated in the super-enhancer driven transcriptional control of oncogenes in multiple cancers including pancreatic cancer. CDK9 has been shown to be employed by cancer cells for the constant production of short-lived oncoproteins such as c-Myc to maintain their survival. Due to its critical role in regulating transcription in cancer cells, CDK9 has emerged as a potential therapeutic target. Here, we report the antitumor activity of a selective, oral ATP-competitive CDK9 inhibitor, BLX-3030, in preclinical models for pancreatic cancer. Experimental Procedures Fragment-based MolecuLern driven AI workflow methods were used to design a series of ATP-competitive CDK9 specific kinase inhibitors. BLX-3030 was selected as one of the most potent leads with an IC50 of 1.1 nM in a cell-free CDK9 kinase assay. A Sulforhodamine B (SRB) assay was used to evaluate the cell growth inhibitory activity of BLX-3030 in a panel of 10 pancreatic ductal adenocarcinoma (PDAC) and 2 pancreatic neuroendocrine tumor (pNET) cell lines. Western blotting was used to determine the effects of BLX-3030 treatment on c-Myc expression in cancer cells. The combination effects between BLX-3030 and standard of care regimen, gemcitabine (GEM) and nab-paclitaxel (NP), was assessed using the SRB assay. Finally, the in vivo antitumor activity of BLX-3030 alone or in combination with GEM and NP was evaluated in a mouse cell line xenograft model for pancreatic cancer. Results BLX-3030 exhibited potent cell growth inhibitory activity in the panel of pancreatic cancer cell lines with IC50 values ranging from 133.5 nM to 508.1 nM. The potency of BLX-3030 in the cell lines appears to correlate with the expression level of c-Myc in the cell lines. BLX-3030 showed similar activities in PDAC and pNET cell lines with mean IC50 values of 244.5 nM and 194.6 nM, respectively. However, treatment with BLX-3030 for 48 hours did not seem to significantly reduce c-Myc expression in PSN-1 PDAC cells. When combined with GEM and NP, BLX-3030 demonstrated mostly additive effects in PSN-1 cells. Preliminary data from the in vivo study show that BLX-3030 improves the antitumor activity of GEM and NP. Conclusion In summary, BLX-3030 potently inhibited the growth of both PDAC and pNET cells in vitro. The growth inhibitory activity of BLX-3030 in PDAC cell lines correlates with their c-Myc expression levels. BLX-3030 showed an additive effect when combined with standard of care drugs (GEM and NP) in PDAC cell lines. Overall, the novel CDK9 inhibitor, BLX-3030, demonstrated potent activity in pancreatic cancer cell line models and presents a promising preclinical lead for pancreatic cancer. (This work was supported in part by Biolexis Therapeutics and the Seena Magowitz Foundation). Citation Format: Yesenia Barrera-Millan, Zhaoliang Li, Hariprasad Vankayalapati, David J. Bearss, Daniel D. Von Hoff, Haiyong Han. Development of a selective, oral ATP-competitive CDK9 inhibitor, BLX-3030, for treatment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5957.

Abstract B111: Developing prognostic signatures (ep-Sigs) through epigenetic predictive markers in pancreatic ductal adenocarcinoma (PDA) – A pilot study based on The Cancer Genome Atlas (TCGA) data

Abstract Current genomic testing (mutation profiling) has not proven beneficial for optimal treatment selection or for monitoring drug resistance, which is critical for neoadjuvant therapy (NAT) in borderline resectable/resectable PDA and first-line therapy for advanced PDA. Failure to administer an effective chemotherapy combination results in early progression of the disease, life-threatening complications, and a decline in the patient’s performance status, rendering them ineligible for further anti-cancer treatment. We hypothesized that our panel of epigenetic markers (DNA-methylation changes) is a surrogate for protein/gene expression and will develop an ep-Sigs that also has predictive value. The genes in this panel have been curated from extant literature and belong to one of two broad categories: one with known prognostic value (PvG) and the other with preclinical or clinical evidence of influencing one of the drugs (DrG) used in PDA management (gemcitabine (gem), 5-fluorouracil (5FU), oxaliplatin (Ox), irinotecan (Iri), nab-paclitaxel (NP), paclitaxel (Tax), and cisplatin (Cis)). Some genes/proteins were critical for more than one drug. To accomplish this, we tested the panel in the TCGA pancreatic adenocarcinoma (PAAD) data with 182 patients. For univariate survival analysis (UVA), we used Cox regression models for each marker. For multivariate survival analysis (MVA), we used penalized Cox regression models (i.e., LASSO, Elastic-Net) for identifying marker signatures. The area under the ROC Curve (AUC) was calculated to assess each signature’s predictive performance. We identified 301 cytosines followed by guanine residue (CpG) sites among the 67 genes (gem=35, 5FU=13, 5FU+gem=10, NP=6, Cis=6, and PvG=23) in the panel with significant (p&amp;lt;0.05) association with overall survival (OS) through UVA. We identified five ep-Sigs through MVA that could predict poor OS (p&amp;lt;0.05), which are a combination of markers from PvG and DrG. The number of markers and relevant DrG in them are as follows, 15 &amp; Gem/Cis; 30 &amp; Gem/5FU/Cis/Tax/Iri; 28 &amp; Gem/5FU/NP/Cis/Tax/Iri; 23 &amp; Gem/5FU; 29 &amp; Gem/5FU/NP. We did a similar analysis for RNA-sequencing data from TCGA. We identified 17 markers and 9 signatures on UVA and MVA, respectively. Interestingly, the expression of 100/105 markers in the panel was significantly (p=4.19e-66) high in PDA compared to normal tissues, indicating this panel has diagnostic value too. We believe this project is the first step for this approach, and this concept needs to be evolved with prospective studies and larger samples. The ep-Sigs with a panel of epigenetic markers with a proven influence on resistance to frequently used drugs could help in developing meaningful models that change the approach to managing PDA, especially for NAT. Citation Format: Ashish Manne, Wancai Yang, Davendra Sohal, Ashwini Esnakula, Lianbo Yu. Developing prognostic signatures (ep-Sigs) through epigenetic predictive markers in pancreatic ductal adenocarcinoma (PDA) – A pilot study based on The Cancer Genome Atlas (TCGA) data [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B111.

A First in Human Phase I Trial (LS1681) of Abraxane/Rituximab 160 Nm Nanoparticle (AR160) in Relapsed Refractory B-Cell Lymphomas Including Transformed Follicular Lymphoma: A Final Report

Introduction: Nanotechnology for cancer therapy aims to increase drug delivery to tumor sites while lowering toxicity. AR160 is a novel 160 nm nano-immunoconjugate consisting of commercial grade nab-paclitaxel (NP) nanoparticles non-covalently coated with rituximab (R) for targeted delivery into tissues expressing CD20. The drug delivery system and clinical grade product was developed in the laboratory of Svetomir N. Markovic, M.D.,Ph.D. Single agent rituximab at a dose of 375 mg/m 2 in relapsed patients with aggressive lymphomas is not utilized and has limited activity in patients with multiple relapses. Taxanes (Younes 1995, Wilson 1995) have modest clinical activity as a single agent with overall response rates of 23% and 17%, respectively, when administered at doses of 200 mg/m 2 and 140 mg/m 2 in previously treated patients with non-Hodgkin lymphoma (NHL). We hypothesized that utilizing the targeted ability of rituximab that the AR160 taxane nanoparticle would have activity in relapsed B-cell NHL and offer a new class of agents for relapsed B-cell NHL. Methods: A 3+3 phase I clinical trial was conducted in patients with relapsed refractory non-Hodgkin lymphoma to determine the maximum tolerated dose of AR160 administered intravenously on days 1, 8, and 15 of a 28-day cycle. Patients were required to have had prior systemic treatment with no other therapy with clinical benefit. Patients with aggressive lymphoma were required to have a stem cell transplant if transplant eligible. AR160 was prepared on-site in the Mayo Clinic Cancer Center Research Pharmacy, and the product was reconstituted by mixing the two agents delivering as one combined infusion at a specific concentration. The starting dose level (DL1) was NP at 100mg/m 2 with R at 40 mg/m 2. These doses were significantly lower than standard doses. Disease evaluations were conducted after every 2 treatment cycles using CT based criteria from the revised 2014 Lugano Classification or PET scans. Patients were treated until disease progression or intolerability. Samples were collected for pharmacokinetic (PK) studies. Results: Nine (7 males and 2 females) patients with a median age of 61 (range 55-84 years) were enrolled (2 follicular lymphoma (FL), 1 previously transformed from FL to diffuse large B-cell lymphoma (DLBCL) followed by FL relapse, 1 high-grade B-cell lymphoma with MYC and BCL2 rearrangements transformed from FL, 1 transformed FL to DLBCL, 2 high-grade B-cell lymphoma with MYC and BCL2 rearrangements, 1 high-grade B-cell lymphoma NOS and 1 mantle cell lymphoma. The median number of prior treatments was 4 (range 3-16). At dose level 1, all 3 of the first 3 patients experienced grade 3 or 4 neutropenia (C1D15, C4D1, and C1D15) with the C4D1 a grade 4 and unlikely related. After the first three patients, de-escalation to dose level -1 was implemented per protocol with NP at 75 mg/m 2 and rituximab at 30 mg/m 2. There was one patient with a grade 3 non-hematological adverse event all possibly related to treatment (anorexia, diarrhea, and enterocolitis). There were 6 partial responses (71%), 1 complete response (14%) with high-grade B-cell lymphoma with MYC and BCL2 rearrangement, 1 stable disease with mantle cell lymphoma and 1 patient had progressive disease. Six of the 9 patients were alive with subsequent therapies. PK evaluation is pending. Conclusion: AR160 therapy is a novel drug delivery system incorporating significantly lower doses of paclitaxel and rituximab that is safe and demonstrates promising clinical activity in patients with low-grade and high-grade previously treated B-cell lymphomas. This principle of treatment is applicable to other disorders. Further clinical testing is warranted in these patient populations.

Trends of cancer drug cost increases and impact of generic and biosimilar drug launches.

19 Background: Drug cost increases are key contributors to cancer care spending in the US. These increases often outpace consumer price index (CPI) inflation, and impact patient access, outcomes, and cost sharing. We analyzed pricing trends and impacts of lower cost generic or biosimilar alternative (LCA) drug launches for key cancer drugs. Methods: Using Medicare Part B drug (Part B) administration &amp; Part D drug (Part D) dispense data for 15 practices in The US Oncology Network, we obtained the unit cost to Medicare for top 30 drugs by total spend over a 6-year period (July 2016 – June 2022). Evaluating cost change patterns in Part B and Part D, we compared trends before and after LCA launches. Results: Over a 6-year period, mean drug costs increased by 12.3% (range: -41.8% to 39%) for Part B and 46.2% (range: -67.5% to 278.2%) for Part D. The largest increases were for Protein-bound Paclitaxel (Part B) (39%) and Ibrutinib (Part D) (278.2%). Many increases exceeded CPI inflation (23.2%) over the same period. Part B/Part D drugs with LCA launches had decreases of -11%/-39%. Non-LCA Part B/Part D drugs increased 21%/ 67%. Prior to LCA launches, Part B/Part D LCA drugs had a mean increase of 22%. After LCA launches, a mean decrease of 36% was observed. Conclusions: Part D drugs have 3.75 times higher increases versus Part B and often outpace CPI inflation. LCAs for branded drugs bend cost increase trends. The impacts of evergreening drug patents and potential shifting of drug coverage from Part B to Part D on costs are ripe for evaluation. The inflation-based rebate and Part D coverage changes in the Inflation Reduction Act (IRA) need to be monitored for its impact on cancer drug cost trends, access, affordability, and financial toxicity for patients. [Table: see text]

Synthesis and characterization of multi-targeted polymeric antibody-microparticle conjugates with controlled drug release

The presented experiments aimed to synthesize multi-targeted polymeric antibody-microparticles for the treatment of CD19+/CD20+ cancers. It is hypothesized that (1) targeting multiple tumor specific antigen (TSA) improves drug delivery by increasing binding in patients with low TSA expression and (2) polymeric drug encapsulation enables controlled drug release. Protein-bound paclitaxel was successfully entrapped in biotin-avidin-antibody coated poly(lactic-co-glycolic acid) (PLGA). Targeting layers and antibody attachment did not negatively impacted drug release in vitro. Cell viability was reduced after administration in target cell lines. The presented technology forms a foundation for further investigation of multi-targeted polymeric antibody-microparticle conjugates capable of optimizing cancer treatment.

Treatment Outcomes and Toxicity Profile of MRI-Guided Gated-Real Time Online Adaptive Stereotactic Body Radiotherapy to Patients with Pancreatic Tumors

Stereotactic body radiation therapy (SBRT) to patients with inoperable pancreas cancer has shown promising outcomes. Dose escalation is challenging given the associated risks to nearby organs at risk and requires treatment plan adaptation and motion management. This study reports the treatment related adverse events and treatment outcomes of MRI-guided SBRT utilizing gated-real time online adaptive radiotherapy to patients with pancreatic tumors. This is a single institution retrospective IRB approved study and included patients with pancreatic tumors who were treated with MRI-guided SBRT utilizing gated-real time online adaptive radiotherapy, consecutively between 2019 and 2022. All patients were treated with 0.35T MRI linear accelerator. All patients' charts and radiation plans were reviewed for this study. The study included 25 patients treated consecutively to 125 radiation fractions with MRI-guided SBRT. The study included 15 females and 10 males, 19 white, 2 Asians, 1 Latin American and 2 African Americans. The median age was 74, and all patients had pancreatic adenocarcinoma (92%) except two patients who had biopsy proven renal cell carcinoma metastatic to the pancreas without evidence of disease elsewhere. Most patients (68%) received chemotherapy (FOLFIRINOX or Gemcitabine / Protein-bound paclitaxel) prior to SBRT. The median dose to gross target volume (GTV) was 50 Gy, and to planning target volume (PTV) was 35 Gy. All patients were treated in 5 radiation fractions. Thirteen patients (52%) received elective nodal irradiation (ENI). All patients had at least a single real-time online adaptive replanning (median 3 fractions, range 1-5 fractions). All treatment fractions were gated (100%) with MRI guidance. The 1-, 2-, & 3- year local-regional control (LRC) were 81%, 57%, & 57% respectively (Median 16 months). The 1-, 2-, & 3- year Distant Control (DC) were 81%, 74%, & 56% respectively (Median 14 months). The 1-, 2-, 3-year overall survival (OS) were 77%, 35%, & 24% (Median 21 months). Planning Target Volume (PTV) dose ≥40Gy was significantly associated with improved local-regional control (p = 0.02). Gross Target Volume (GTV) dose <50Gy was significantly associated with lower DC (p = 0.03). ENI showed a trend towards improved local-regional control but was not statistically significant (p = 0.1). None of the patients experienced ≥ grade 3 toxicities. Most common adverse event were grades 1 or 2 fatigue (24%), nausea (16%), and abdominal discomfort (12%). In this cohort, MRI-guided SBRT utilizing gated-real time online adaptive radiotherapy was a safe and effective approach for patients with pancreatic tumors who are not surgical candidates. In this study, dose escalation was significantly associated with improved local-regional (PTV ≥40 Gy) and distant control (GTV ≥50Gy). None of the patients experienced grade ≥3 radiation induced adverse events.

Pilot clinical trial and phenotypic analysis in chemotherapy-pretreated, metastatic triple-negative breast cancer patients treated with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency followed by cisplatin and nab paclitaxel

BackgroundA subset of triple-negative breast cancers (TNBCs) have homologous recombination deficiency with upregulation of compensatory DNA repair pathways. PIKTOR, a combination of TAK-228 (TORC1/2 inhibitor) and TAK-117 (PI3Kα inhibitor), is hypothesized to increase genomic instability and increase DNA damage repair (DDR) deficiency, leading to increased sensitivity to DNA-damaging chemotherapy and to immune checkpoint blockade inhibitors.Methods10 metastatic TNBC patients received 4 mg TAK-228 and 200 mg TAK-117 (PIKTOR) orally each day for 3 days followed by 4 days off, weekly, until disease progression (PD), followed by intravenous cisplatin 75 mg/m2 plus nab paclitaxel 220 mg/m2 every 3 weeks for up to 6 cycles. Patients received subsequent treatment with pembrolizumab and/or chemotherapy. Primary endpoints were objective response rate with cisplatin/nab paclitaxel and safety. Biopsies of a metastatic lesion were collected prior to and at PD on PIKTOR. Whole exome and RNA-sequencing and reverse phase protein arrays (RPPA) were used to phenotype tumors pre- and post-PIKTOR for alterations in DDR, proliferation, and immune response.ResultsWith cisplatin/nab paclitaxel (cis/nab pac) therapy post PIKTOR, 3 patients had clinical benefit (1 partial response (PR) and 2 stable disease (SD) ≥ 6 months) and continued to have durable benefit in progression-free survival with pembrolizumab post-cis/nab pac for 1.2, 2, and 3.6 years. Their post-PIKTOR metastatic tissue displayed decreased mismatch repair (MMR), increased tumor mutation burden, and significantly lower levels of 53BP1, DAG Lipase β, GCN2, AKT Ser473, and PKCzeta Thr410/403 compared to pre-PIKTOR tumor tissue.ConclusionsPriming patients’ chemotherapy-pretreated metastatic TNBC with PIKTOR led to very prolonged response/disease control with subsequent cis/nab pac, followed by pembrolizumab, in 3 of 10 treated patients. Our multi-omics approach revealed a higher number of genomic alterations, reductions in MMR, and alterations in immune and stress response pathways post-PIKTOR in patients who had durable responses.Trial RegistrationThis clinical trial was registered on June 21, 2017, at ClinicalTrials.gov using identifier NCT03193853.

PhD Project: Predictive and Functional Evaluation of Patients Derived Tumor Spheroids and Organoids-Investigating the Relationship between Size and Testing Performance

PhD Project: Predictive and Functional Evaluation of Patients Derived Tumor Spheroids and Organoids-Investigating the Relationship between Size and Testing Performance

Phase 1b study of batiraxcept (AVB-S6-500, BT) plus gemcitabine (G) and nab-paclitaxel (NP) as first-line treatment (1L) for advanced pancreatic adenocarcinoma (PDAC).

e16258 Background: PDAC is a deadly aggressive cancer characterized by up to 80% tumor stroma enriched by macrophages, fibroblasts, and collagen deposition that influences resistance to therapy. Tyrosine kinase receptor AXL and ligand expression of growth arrest specific protein 6 (GAS6) produce tumor associated macrophages and fibroblasts and correlate with poor prognosis. GAS6 blockade partially reverses epithelial-to-mesenchymal transition of tumor and supports NK cell activation, inhibiting metastasis. As a novel decoy FC fusion protein, batiraxcept (BT) binds to GAS6 and demonstrates highly potent and specific AXL inhibition. Preclinical studies showed a relationship between AXL signaling and response to DNA damage in PDAC models. Methods: This dose escalation study tested BT 15 mg/kg on day 1 and 15 in combination with G 1000 mg/m2 and NP 125 mg/m2 days 1, 8, 15 of a 28-day cycle. Primary endpoints are safety and objective response rate (ORR) using RECIST v1.1; key secondary endpoints are progression free survival (PFS) and overall survival (OS); pharmacokinetic data were collected to determine exposure-PFS response (E-R) relationship. Results: As of January 17, 2023, 21 patients (pts) received BT/G/NP of which 10 (48%) were male and 3 (14%) received prior neoadjuvant/adjuvant therapy. BT-related AEs &gt; 10% pts included fatigue (n=7, 33%), diarrhea (n=4, 19%), infusion related reaction and neutropenia (n=3, 14% each). Grade ≥ 3 BT-related AE occurred in 6 pts (29%). BT administration reduced GAS6 to non-quantifiable levels until treatment ended. 18 pts (86%) discontinued treatment, primarily due to toxicity (n=2) and progressive disease (n=13). Median (m) BT/G/NP treatment duration was 13.1 weeks (range 0.1─74.7). ORR is 29%; mPFS and mOS were 5.4 mo (2.1, 5.6) and 12.3 mo (4.11─NE) respectively. BT efficacy results are described by a minimally efficacious concentration (MEC) of 14.5 mg/L identified by E-R modeling. Conclusions: BT/G/NP combination was well tolerated, and the BT safety profile is consistent with prior trials. Patients with BT trough &gt; MEC had longer PFS and OS. In addition, in these patients OS appears longer than historical data of 8.5 months. Due to increased stroma seen in PDAC, a higher BT MEC may be required to maximize efficacy. Higher BT dose levels in combination with G/NP are under study. Clinical trial information: NCT04983407 . [Table: see text]

Abstract 3434: Selective glucocorticoid receptor modulation reveals a new role for CLEC10A in patients with solid tumors

Abstract Selective glucocorticoid receptor (GR) modulators (SGRMs) represent a clinically validated mechanism of enhancing chemosensitivity and ameliorating the sequelae of hypercortisolism. While GRs reportedly control the expression of up to 20% of the human genome, specific targets of systemic GR antagonism in humans have yet to be identified. To address this question, we established a robust NanoString assay to measure candidate GR target genes in human blood and assessed them before and after therapy with the oral SGRM relacorilant, which selectively antagonizes the GR. In a randomized, controlled phase 2 study in patients with recurrent, platinum-resistant ovarian cancer (NCT03776812), gene changes were assessed in 139 patients after treatment with relacorilant + nab-paclitaxel (NP) or NP alone. Using cross-validated random forest methods, a gene panel that accurately identified patients who had received relacorilant was established (ROC AUC 0.945 +/- 0.038). In 13 patients who crossed over from NP alone to relacorilant + NP, the genes in the panel were modified only after crossover (paired t-test P=0.0003), validating the gene panel’s ability to detect GR activity. The 4 most induced (LILRB4, FPR3, CLEC10A, CCR2) and 4 most suppressed (CDKN1C, TNFRSF17, BRIP1, PDK1) genes by relacorilant + NP vs. NP alone were selected and shown to be reliable indicators of GR activity across clinical studies in patients with pancreatic, prostate, and other solid tumors (NCT04329949, NCT03674814, NCT02762981), independent of concomitant medications or other confounders. CLEC10A (C-type lectin domain containing 10A) was identified as a particularly sensitive marker of GR activity as its expression was strongly suppressed by the GR agonist prednisone in healthy volunteers (paired t-test P&amp;lt;0.00010, NCT03335956) and strongly induced by relacorilant in patients with solid tumors (paired t-test P&amp;lt;0.00010). CLEC10A induction in blood by relacorilant was associated with longer overall survival in patients with ovarian cancer treated with relacorilant + NP (HR=0.39, Cox PH P=0.0135). High baseline tumor CLEC10A expression was also associated with longer overall survival in a large tumor ‘omics’ database (N=1656 ovarian tumors; HR 0.8, log-rank P=0.0008). CLEC10A and the genes correlated with its expression were found to be primarily expressed by a specific subset of dendritic cells, supporting previous reports that GR agonism can suppress dendritic cells. This analysis of CLEC10A and other identified GR target genes confirmed that systemic GR activity in patients with a range of solid tumors can be modulated pharmacologically, indicates that GR modulation may be associated with survival in patients with ovarian cancer, and provides new insights into the systemic functions of the GR in humans. Citation Format: Nicoletta Colombo, Toon Van Gorp, Ursula A. Matulonis, Ana Oaknin, Rachel N. Grisham, Diane Provencher, Gini F. Fleming, Alexander B. Olawaiye, Erkut H. Borazanci, Russell Z. Szmulewitz, Subhagya A. Wadekar, Grace Mann, Hazel J. Hunt, Andrew E. Greenstein, Domenica Lorusso. Selective glucocorticoid receptor modulation reveals a new role for CLEC10A in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3434.

Clinical benefit of granulocyte-colony stimulating factor (GCSF) use during chemoimmunotherapy treatment for metastatic pancreatic adenocarcinoma (mPDAC).

757 Background: GCSF is used for primary/secondary prophylaxis of chemotherapy(chemo)-associated neutropenia in patients (pts) with mPDAC. GCSF may also increase the populations of healthy, naïve immune cells in an otherwise immunologically dysregulated and cold environment, potentially augmenting therapy outcome with immunomodulatory (IO) agents. Here, we describe the impact of GCSF administration on OS, PFS, and time on treatment (TOT) in the setting of mPDAC for (1) a trial in which pts were administered chemo-IO combinations and (2) a synthetic control arm using retrospective real-world data from pts who received standard-of-care (SOC) chemo (PASCAL). Methods: PRINCE is a ph1b/2 study evaluating gemcitabine (gem) and nab-paclitaxel (NP) ± sotigalimab (sotiga; CD40 agonist) ± nivolumab (nivo; anti-PD1) for pts with mPDAC (NCT0324250), where prophylactic GCSF use was prohibited. PASCAL pts received SOC gem/NP and primary/secondary GCSF use was allowed. In this retrospective analysis, GCSF use was defined as receiving at least 1 dose of GCSF anytime during treatment. OS, PFS, and TOT and associated HRs and CIs were calculated using Kaplan-Meier and Cox methods. PFS data not available for PASCAL. Results: 32/123 (26%) and 16/68 (24%) pts received GCSF in PRINCE and PASCAL, with 84% and 88% of pts receiving at least 1 dose within the first 3 cycles, respectively. In PRINCE, GCSF use was associated with significant improvements in OS (HR [95% CI]: 0.62 [0.40-0.97]), PFS (0.71 [0.47-1.08]), and TOT (0.67 [0.45-1.01]). These improvements were most notable in the sotiga-containing arms (table). In the absence of IO treatment, however, no statistical significance was observed in PASCAL (HR [95% CI]: OS = 0.81 [0.44-1.51]; TOT = 0.90 [0.51-1.58]). Additional work is ongoing to understand the association of GCSF usage with known prognostic factors. Conclusions: These analyses suggest that GCSF use may enhance the clinical benefits of chemo-IO in mPDAC. These potential benefits of GCSF usage warrant further evaluation in other chemo-IO trials as well as prospective evaluation in pre-clinical and clinical settings. Clinical trial information: NCT03214250 . [Table: see text]

Assessment of an emergency 14-day (d) integrative supportive care program (14-EISCP) followed by early chemotherapy (CTx) in symptomatic patients (pts) with advanced pancreatic ductal adenocarcinoma (aPDAC): A prospective ARCAD cohort study.

700 Background: Pts with aPDAC often have general health impairment due to high symptom burden at diagnosis. We investigated prospectively the clinical benefit (CB) of an EISCP followed by CTx as early as suspicion of aPDAC in pts with ECOG performance status (PS)≥2. Methods: In this multicenter study, PS≥2 pts with pathologically confirmed or suspected aPDAC on imaging were included at first oncology visit (V1) in a personalized 14-d EISCP including pain, nutritional, diagnostic/stenting procedures. Post-EISCP PS≤1 pts received mFOLFIRINOX or gemcitabine(Gem)/Nab-paclitaxel(NP), PS≥2 received mFOLFOX7 or investigator choice CTx or best supportive care (BSC). The primary endpoint was the 14-EISCP success on both feasibility of procedures within 14-d±2 and CB defined by post-EISCP PS≤1, ≥5 points improvement of either fatigue/pain/global health EORTC QLQ-C15-PAL quality of life (QOL) scores, or CTx start ≤30d, aiming 59% success for clinical relevance. Secondary endpoint included uni/multivariate median overall survival (mOS) analyses. Results: As of 07/2022, 106 pts were included; 93 pts were evaluable for primary endpoint: male 46%, mean age 74 yrs, PS2/3 79%/21%, metastases (M1) 62%, pathological diagnosis needed 53%, biliary stenting 16%. V1 mean QOL global health score was 48±23. mOS was 4.1 months (IC95 2.8-5.7). The 14-d feasibility was achieved in 71%. Post-EISCP CB was observed in 82% of pts: 13%, PS improvement to 0/1, 23% QOL improvement and/or 73% CTx start ≤30-d. Eight pts (9%) died during the EISCP. The primary endpoint was achieved in 59% of pts (n=55). Overall, 17 pts (16%) received mFOLFIRINOX/GemNP, 32 (30%) FOLFOX, 29 (27%) Gem or 5FU alone, and 28 (27%) BSC. OS analyses are shown. At d30, pts receiving CTx had a mean change of QOL global health score from 51±23 to 60±23. Conclusions: In PS≥2 pts with aPDAC, a personalized 14-EISCP is feasible and lead to a meaningful CB allowing the administration of doublet/triplet CTx in nearly half of the pts. Pts starting CTx within 30d had improved OS. Clinical trial information: NCT02979483 . [Table: see text]

536P Relacorilant + nab-paclitaxel in patients with recurrent, platinum-resistant ovarian cancer: Phase II subgroup analysis mirroring the patient population of an upcoming phase III study

Therapy options for patients with recurrent, platinum-resistant ovarian cancer are limited. Cortisol contributes to chemotherapy resistance, one driver of poor outcomes, by suppressing apoptotic pathways used by cytotoxic agents. A phase 2 study of relacorilant (RELA) + nab-paclitaxel (NP) in patients with ovarian cancer has shown that glucocorticoid receptor modulation with RELA can improve the efficacy of NP. In all patients, intermittent RELA + NP significantly improved progression-free survival (PFS) and improved overall survival (OS) without additional side-effect burden.

524MO Glucocorticoid receptor expression and activity in a phase II ovarian cancer trial of the glucocorticoid receptor modulator relacorilant in combination with nab-paclitaxel

Cortisol activity at the glucocorticoid receptor (GR) contributes to chemotherapy resistance by suppressing apoptotic pathways that taxanes utilize, and high tumor GR expression is associated with poor chemotherapy response in ovarian cancer. A phase 2 ovarian cancer study (NCT03776812) demonstrated the clinical benefit of adding relacorilant (RELA), a selective GR modulator, to nab-paclitaxel (NP) compared to NP alone. We present biomarker analyses from this study.