Bone Marrow Function Research Articles

Abstract CT116: First-in-human study of AZD8853, an anti-growth and differentiation factor 15 (GDF15) antibody, in patients (pts) with advanced/metastatic solid tumors

Abstract Background: The cytokine GDF15 is overexpressed in solid malignant tumors such as colorectal, lung and urothelial cancer, where it modulates T cells, dendritic cells (DCs) and myeloid-derived cells, driving the tumor microenvironment toward an immunosuppressive, tumor-promoting state. AZD8853 is a humanized immunoglobulin G1 monoclonal antibody that binds to, and neutralizes, GDF15. Anti-GDF15 treatment increased T cell proliferation and DC activation, leading to an antitumor immune response in preclinical studies of anti-PD-L1 resistant models. In vitro and in vivo preclinical data support the potential antitumor activity of AZD8853 in pts with selected advanced/metastatic cancers. Methods: This Phase I/IIa, first-in-human, open-label study (NCT05397171) assesses the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD8853 in pts with histologically or cytologically confirmed locally advanced, unresectable or metastatic mismatch repair-proficient colorectal cancer (pMMR-CRC), non-small-cell lung cancer (NSCLC) and urothelial carcinoma (UC). Up to 165 pts will be enrolled in 3 parts: Part A, dose escalation; Part B, pharmacodynamics expansion; and Part C, efficacy expansion. All pts receive AZD8853 IV. Eligible pts are ≥18 years old with ≥1 measurable target lesion per RECIST v1.1, ECOG PS of 0/1, life expectancy ≥12 weeks and adequate organ and bone marrow function. Pts with NSCLC must have had ≥1 prior line of systemic treatment in the advanced/metastatic setting, and no sensitizing EGFR or ALK aberrations. Pts with pMMR-CRC must have had ≥2 prior treatments in the advanced/metastatic setting. Pts with UC must have had ≥1 prior treatment in the advanced/metastatic setting including platinum-containing therapy and/or a PD-(L)1-inhibitor. Pts with Grade ≥2 unresolved toxicities from prior therapy, symptomatic CNS metastases or leptomeningeal disease, or prespecified active/ongoing infections are excluded. The primary objective is safety, including dose-limiting toxicities, adverse events (AEs), serious AEs and AEs leading to AZD8853 discontinuation. The secondary objectives include assessment of efficacy (objective response rate, disease control rate, duration of response, percentage change from baseline in target lesion size, change from baseline in circulating tumor DNA, and progression-free and overall survival), PK and immunogenicity. Changes in GDF15 serum levels are measured in Parts A and B. Tumoral CD8+ T cell infiltration is measured in a subset of pts from Part B using PET/CT imaging and IHC of paired biopsies. The study is currently recruiting at centers in the USA and Canada with additional sites planned in the UK, France and Spain. Citation Format: Benedito A. Carneiro, Maria Diab, Brian A. Van Tine, Anthony F. Shields, Albiruni Abdul Razak, John F. Hilton, Rafael Santana-Davila, Elhan Sanai, Jorge Zeron-Medina, Veronique Bragulat, Kath Lowery, Arthur Lambert, John Hood, Rakesh Kumar, Duncan Jodrell, Patricia LoRusso. First-in-human study of AZD8853, an anti-growth and differentiation factor 15 (GDF15) antibody, in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT116.

Abstract CT135: A pilot clinical study of orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors

Abstract Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also used off-label to treat a range of adult and pediatric tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days in combination with other agents such as temozolomide has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. Methods: Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day will be studied in combination with fixed-dose temozolomide using a standard 3 + 3 phase I design. In the event the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed. This trial is ongoing (CT.gov: NCT04337177), with no DLT observed to date. Citation Format: Jeffrey Bacha, Dennis Brown, Sarath Kanekal, Neil Sankar, Lorena Lopez, Noymi Yam, Lars Wagner, James Geller, Markos Leggas, Patrick Thompson, Javier Osterheld. A pilot clinical study of orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT135.

Abstract CT058: TROPION-PanTumor03: Phase 2, multicenter study of datopotamab deruxtecan (Dato-DXd) as monotherapy and in combination with anticancer agents in patients (pts) with advanced/metastatic solid tumors

Abstract Background: Pts with metastatic epithelial tumors who progress after initial therapy have a poor prognosis; new therapeutic agents could potentially improve outcomes. Trophoblast cell surface protein 2 (TROP2) is a transmembrane glycoprotein that is over-expressed on the cell surface of many epithelial cancers representing a promising target for surface-directed therapeutic modalities. Dato-DXd is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd monotherapy demonstrated encouraging efficacy and safety in pts with lung and breast cancer (TROPION-PanTumor01 study; NCT03401385). Methods: The phase 2, multicenter, open-label TROPION-Pantumor03 study (NCT05489211) is exploring safety and efficacy of Dato-DXd as monotherapy and in combination with various anticancer agents (e.g. durvalumab, AZD5305, nivolumab, bevacizumab, chemotherapies) that may be active in the tumor types being evaluated. TROPION-Pantumor03 is a master trial comprising independent substudies to enable simultaneous evaluation of the recommended phase 2 dose (RP2D), safety, and preliminary efficacy of Dato-DXd across several tumor types and treatment combinations. Pts with endometrial, gastric, metastatic castration-resistant prostate (mCRPC), ovarian, and colorectal (CRC) cancer are being enrolled. Eligible pts: age ≥18 years, histologically/cytologically documented advanced or metastatic disease, ≥1 measurable target lesion (RECIST 1.1) not previously irradiated (mCRPC substudy: non-measurable bone metastatic disease permitted), and adequate bone marrow and organ function. An FFPE tumor sample must be available for all pts. Prospective selection for TROP2 expression is required in pts with CRC; in all other cohorts, TROP2 expression will be analyzed retrospectively. In all monotherapy cohorts, pts will receive Dato-DXd 6 mg/kg IV infusion Q3W; in the combination cohorts, Dato-DXd 4 or 6 mg/kg Q3W, as appropriate for each combination. Pts will receive treatment until disease progression, unacceptable toxicity, or withdrawal. Primary Endpoints: Objective response rate, PSA50 response (mCRPC substudy only), and safety/tolerability. Secondary Endpoints: Progression-free survival, duration of response, disease control rate, best % change in tumor size, pharmacokinetics, and immunogenicity (anti-drug antibodies). Exploratory endpoints incl. overall survival, pt-reported outcomes, and biomarker analysis (incl. TROP2 and PD-L1 expression, tumor mutational profiling, proteomics and ctDNA profiling). Recruitment is ongoing as of Jan 2023. Citation Format: Funda Meric-Bernstam, Yelena Janjigian, Joshua Lang, Kristen K. Ciombor, Isabelle Ray-Coquard, Amit Oza, Kan Yonemori, Ruihua Xu, Jimmy L. Zhao, Srikanth Gajavelli, Justyna Filant, Tina Hovey, Ana Oaknin. TROPION-PanTumor03: Phase 2, multicenter study of datopotamab deruxtecan (Dato-DXd) as monotherapy and in combination with anticancer agents in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT058.

Abstract CT069: Randomized phase 3 study (STARBOARD) evaluating encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of unresectable locally advanced or metastatic BRAF V600-mutant melanoma

Abstract Background BRAF V600 mutations are frequently found in metastatic melanoma. This mutation constitutively activates the MAPK pathway, which leads to melanoma progression. Patients with BRAF V600-mutant metastatic melanoma typically receive BRAF inhibitors (BRAFi) + MEK inhibitors (MEKi), such as enco + bini, or immune checkpoint inhibitors (CPIs; eg, pembro). However, these have limitations. BRAFi and MEKi may increase BRAF V600-mutant tumor sensitivity to CPIs. Previous studies reported improved progression-free survival (PFS) in patients with advanced BRAF V600-mutant melanoma receiving BRAFi + MEKi + CPI compared with targeted therapy alone. This phase 3 trial will evaluate the efficacy and safety of enco + bini + pembro vs placebo + pembro for unresectable locally advanced or metastatic BRAF V600-mutant melanoma. A safety lead-in (SLI) was built in to determine the recommended phase 3 dose (RP3D) prior to starting phase 3. Trial design STARBOARD (NCT04657991) is a randomized, double-blind, placebo-controlled, phase 3 study evaluating approximately 600 patients with BRAF V600 advanced melanoma. Patients will be stratified by prior systemic adjuvant treatment (CPI, BRAFi/MEKi, or none) and by disease stage (per AJCC 8th edition; IIIB, IIIC, IIID, IV M1a[0], and IV M1b[0] vs IV M1a[1], IV M1b[1], IV M1c[0], IV M1c[1], IV M1d[0], and IV M1d[1]). Patients must have measurable disease (per RECIST 1.1); ECOG performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients must not have received prior systemic therapy for unresectable or metastatic melanoma; adjuvant treatment with BRAFi/MEKi, anti-PD-1, or anti-CTLA-4 is permitted. Patients cannot have symptomatic brain metastases. Study treatments and end points are shown in Table 1. RP3D was established in May 2022; phase 3 enrollment began in June 2022. Table 1. Study treatments and end points Phase 3 Treatment (21-day cycle) RP3D from SLI: enco + bini + pembro Control: placebo + pembro Primary PFS (RP3D vs control; by BICR) Secondary Key: OS (RP3D vs control) Other: PFS by investigator assessment, objective response rate, duration of response, disease control rate, and time to response, all by BICR and investigator assessment, PFS2, quality of life, safety, pharmacokinetics BICR, blinded independent central review; OS, overall survival. Citation Format: Dirk Schadendorf, Reinhard Dummer, Caroline Robert, Antoni Ribas, Ryan J. Sullivan, Timothy Panella, Meredith McKean, Edgardo S. Santos, Jill Clancy, Anna Polli, Alessandra di Pietro, Paolo A. Ascierto. Randomized phase 3 study (STARBOARD) evaluating encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of unresectable locally advanced or metastatic BRAF V600-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT069.

Abstract 6655: A real world analysis: Impact of clinical trial eligibility criteria on clinical outcomes among patients with advanced non-small cell lung cancer (aNSCLC) receiving second line (2L) immune checkpoint inhibitor (ICI) therapy

Abstract Background. Clinical trials (CT) include patients (pts) satisfying eligibility criteria including normal organ function and low comorbidity. Real-world outcomes for pts with aNSCLC receiving ICIs in 2L were compared based on whether pts met CT eligibility criteria. Methods. 2L- associated outcomes were compared between pts with aNSCLC diagnosed between 04/01/2015 - 12/31/2020 in US community health systems that fulfilled or failed to fulfill CT eligibility criteria. CT-eligible (CTE) pts had at 2L: performance status of 0-1; normal renal, hepatic, and bone marrow function; no evidence of Hepatitis B or C, HIV, rheumatic diseases, or interstitial lung disease. Pts were CT-ineligible (CTI) if they failed to meet one or more of these criteria. Follow-up spanned 2L start to the first of: outcome of interest, death, or study end on 06/30/2021. Outcomes were evaluated in pts receiving ICI monotherapy (monotherapy) or ICI + chemotherapy (combination). Results. Of the 505 pts in this analysis, 81% and 19% received monotherapy and combination, respectively; 19% of pts were CTE (76% monotherapy, 24% combination, Table). Overall, in ICI subgroups among monotherapy pts, pembrolizumab-treated pts had longer OS and TTNT; time to treatment discontinuation (TTD) was less variable across subgroups. CTE pts in the monotherapy group had longer OS, shorter TTNT, and similar TTD compared to CTI. Among combination pts, CTE had similar OS and TTD, but shorter TTNT compared to CTI. Conclusions. CTE pts appear to have longer survival than CTI pts with aNSCLC receiving ICI monotherapy, but not among pts receiving combination. TTNT was longer for CTI pts in both groups. In addition to CTE pts, some CTI pts appear to benefit from 2L ICI therapy. Time-to-event outcomes (months), median (95% CI) in the study cohort Monotherapy (N = 412) Monotherapy (N = 412) Monotherapy (N = 412) Monotherapy (N = 412) Combination (N = 93) Combination (N = 93) Combination (N = 93) Combination (N = 93) N (%) OS TTNT TTD N (%) OS TTNT TTD Atezolizumab 37 (9%) 7 (3-16) 9 (7-NA) 2 (1-3) 9 (10%) 6 (5-NA) NA (5-NA) 2 (1-NA) Nivolumab 234 (57%) 14 (9-18) 20 (15-NA) 2 (2-3) 9 (10%) 36 (6-NA) 23 (6-NA) 5 (3-NA) Pembrolizumab 138 (34%) 20 (16-28) NA (31-NA) 2 (1-3) 75 (80%) 12 (8-NA) 20 (15-NA) 1 (1-3) Overall - 15 (13-18) 23 (18-NA) 2 (2-2) - 11 (7-NA) 20 (10-NA) 2 (1-3) Trial-Eligible (all regimens) 72 (18%) 20 (12-NA) 19 (10-NA) 2 (2-3) 23 (25%) 11 (5-NA) 10 (7-NA) 3 (1-6) Trial-Ineligible(all regimens) 292 (70%) 13 (8-16) 26 (18-NA) 2 (2-2) 64 (69%) 11 (7-NA) 20 (9-NA) 2 (1-3) Unknown Trial Eligibility 47 (12%) - - - 6 (6%) - - - Citation Format: Hina Mohammed, Miso Kim, Mahder Teka, Monika Izano, Frank Wolf, Thomas Brown. A real world analysis: Impact of clinical trial eligibility criteria on clinical outcomes among patients with advanced non-small cell lung cancer (aNSCLC) receiving second line (2L) immune checkpoint inhibitor (ICI) therapy [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 6655.

381 Repeated Opening of the Blood-Brain Barrier With the Skull-implantable SonoCloud-9 (SC9) Device: Phase 1 Trial of Nab-Paclitaxel and SC9 in Recurrent Glioblastoma

INTRODUCTION: The blood-brain barrier (BBB) is a major impediment to pharmacological treatment of gliomas, as these infiltrate the brain. Low-intensity pulsed ultrasound with concomitant intravenous microbubbles (LIPU/MB), opens the BBB. METHODS: To perform LIPU/MB-based BBB opening prior to ABX infusions, we used a novel 6 x 6 cm device with 9 ultrasound emitters (SC9) that is implanted in a skull window after tumor resection. A Phase 1 dose-escalation trial using Bayesian adaptive design was initiated at our institution (NCT04528680). Patients with recurrent operable glioblastoma, a WHO PS ≤ 2 and normal bone marrow and organ function were eligible. After tumor resection and implantation of SC9, repeated cycles of BBB opening by LIPU/MB immediately followed by ABX, were performed Q3W. Intraoperative LIPU/MB and low dose ABX was given prior to tumor resection for pharmacokinetic studies. RESULTS: Seventeen patients were enrolled, and dose levels 40-260 mg/m2 were investigated. At dose of 260 mgm2, a grade 3 reversible taxane-associated encephalopathy was observed in one patient, considered a dose-limiting toxicity. The patient continued treatment at a lower dose in subsequent cycles. A second patient exhibited encephalopathy on cycle 2. Pharmacokinetic studies showed that ABX tissue concentrations in non-enhancing peri-tumoral brain were increased 3.7-fold after LIPU/MB. sc-RNA-sequencing showed transcriptional dysregulation of membrane transporters, pathways related to trans-cytosis as well as cell-cell and cell-matrix adhesion. Ultrastructural analysis of brain capillaries revealed that LIPU/MB led to time-dependent emergence of vesicles in endothelial cells CONCLUSIONS: The LIPU/MB using skull-implantable ultrasound enhances the penetration of ABX in large regions of the brain, a procedure that can be performed repeatedly and safely. LIPU-based BBB opening leads to ultrastructural transcriptional alterations in brain endothelium. Funding: NIH/NCI 1R01CA245969-01A1, CarThera (SC9 devices), BMS/Celgene (Abraxane®).

Changes in retinal circulation and choroidal thickness in patients with acute myeloid leukemia detected by optical coherence tomography angiography.

To investigate changes in retinal circulation and the choroid in patients with acute myeloid leukemia (AML) in the acute and remission stages, to analyze the correlation between retinal circulation and laboratory parameters, and to assess risk factors associated with leukemic retinopathy. Forty-eight patients (93 eyes) with AML were enrolled and divided into two groups according to fundus examination findings: the retinopathy and no retinopathy groups. Patients underwent eye measurements before treatment and after remission. Macular vessel density (VD), perfusion density (PD), foveal avascular zone (FAZ), and choroidal thickness (ChT) were measured using optical coherence tomography angiography. Patients with healthy eyes were recruited as control participants. Patients with leukemic retinopathy had higher measurements of white blood cells (WBCs), circulating blasts, fibrin degradation products, and cross-linked fibrin degradation products (D-dimer) and a lower hemoglobin (HB) count (p < 0.05). In the acute phase of the disease, the VD and PD were lower and the ChT was thicker in patients with AML than in controls (p < 0.05), irrespective of the presence of leukemic retinopathy; however, the patients were partially recovered in the remission stage. The VD was lower in patients with higher WBC (r = -0.217, p = 0.036), D-dimer (r = -0.279, p = 0.001), fasting blood glucose (FBG) (r = -0.298, p = 0.004) and triglyceride (r = -0.336, p = 0.001) levels. The FAZ area was negatively correlated with HB (r = -0.258, p = 0.012). Patients with AML appear to have subclinical retinal perfusion loss and choroidal thickening in the acute phase of the disease, but this is reversible. Injury to bone marrow function may cause a decrease in retinal perfusion. Leukemic retinopathy is associated with abnormal hematologic parameters and coagulopathy.

Electrical Sympathetic Neuromodulation Protects Bone Marrow Niche and Drives Hematopoietic Regeneration during Chemotherapy.

The sympathetic nervous system (SNS) of the bone marrow regulates the regeneration and mobilization of hematopoietic stem cells. Chemotherapy can damage bone marrow SNS, which impairs hematopoietic regeneration and aggravates hematologic toxicities. This leads to long-term bone marrow niche damage and increases mortality in patients undergoing chemotherapy. Electrical neuromodulation has been used to improve functional recovery after peripheral nerve injury. This study demonstrates that electrical sympathetic neuromodulation (ESN) of bone marrow can protect the bone marrow niche from chemotherapy-induced injury. Using carboplatin-treated rats, the SNS via the sciatic nerve innervating the femoral marrow with the effective protocol for bone marrow sympathetic activation is electrically stimulated. ESN can mediate several hematopoietic stem cells maintenance factors and promote hematopoietic regeneration after chemotherapy. It also activates adrenergic signals and reduces the release of pro-inflammatory cytokines, particularly interleukin-1 β, which contribute to chemotherapy-related nerve injury. Consequently, the severity of chemotherapy-related leukopenia, thrombocytopenia, and mortality can be reduced by ESN. As a result, in contrast to current drug-based treatment, such as granulocyte colony-stimulating factor, ESN can be a disruptive adjuvant treatment by protecting and modulating bone marrow function to reduce hematologic toxicity during chemotherapy.

A prospective phase II trial of pembrolizumab plus lenvatinib in advanced adrenal cortical carcinoma after failure of platinum- and mitotane-based chemotherapy (ACCOMPLISH).

TPS3 Background: Adrenal cortical carcinoma (ACC) is a very rare cancer with poor prognosis. For advanced ACC, systemic treatment options are limited. There has been only one randomized phase III clinical trial in which etoposide, doxorubicin, cisplatin, and mitotane (EDP-M) achieved statistically significant improvement in terms of objective response rate (ORR) and progression-free survival (PFS). However, after failure of EDP-M regimen, no universally accepted treatment option exists. In human ACC sample, vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) expression were higher than adrenal adenoma, and 10-20% of tumor cells and 70% of tumor infiltrating monocyte are PD-L1 positive. In retrospective review of cabozantinib in advanced ACC, cabozantinib demonstrated 19% of ORR and 16.2 weeks of median PFS. Also, in phase II clinical trial of pembrolizumab in advanced ACC, ORR of 14-23% were shown. Considering synergism of VEGFR tyrosine kinase inhibitors (TKIs) and immune check point inhibitors (ICIs) in other cancers, combination of VEGFR TKI and ICI is an attractive approach in advanced ACC. Methods: This is an open-label,single-arm,multi-center,investigator-initiated phase II trial of lenvatinib plus pembrolizumab in patients with advanced ACC who failed previous platinum and mitotane therapy (NCT 05036434). Using Simon’s optimal two-stage design, 10 patients will be enrolled initially in the first stage. If at least 2 or more patients achieve complete response or partial response, the trial will continue until enrollment of a total of 30 patients. Patients will receive 200 mg of pembrolizumab every 3 weeks intravenously and 20 mg of daily lenvatinib orally until disease progression, intolerable toxicity, or patients’ withdrawal of consent. Key eligibility criteria are age ≥ 19 years, ECOG PS 0-1, biopsy-proven ACC, disease progression despite cisplatin- and mitotane-based chemotherapy, measurable disease according to RECIST v1.1, no uncontrolled hypertension, adequate kidney, liver, and bone marrow function. Primary endpoint is ORR, and secondary endpoints include PFS, safety profile, overall survival, duration of response. Exploratory evaluation of tumor genomics and immune microenvironment by whole exome sequencing, single-cell RNA sequencing, and T cell receptor sequencing in correlation with response will be performed. Enrollment began in June 2022 and projected enrollment goal is 3 years. Clinical trial information: NCT05036434 .

VIOLET: A phase I/II trial evaluation of radioligand treatment in men with metastatic castration-resistant prostate cancer with [161Tb]Tb-PSMA-I&amp;T.

TPS281 Background: [177Lu]Lu-PSMA is an effective class of therapy for men with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response is partially explained by the presence of micrometastatic deposits. Single tumor cells and micrometastases are energy-sheltered deposits receiving low absorbed radiation, due to the ~0.7mm mean path-length of Lutetium-177 (177Lu). Terbium-161 (161Tb) has abundant emission of Auger electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. 161Tb has shown superior in-vitro and in-vivo results in comparison with 177Lu. We hypothesize that [161Tb]Tb-PSMA-I&amp;T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 to 36 men with progressive mCRPC. The phase I dose-escalation is designed with a 3+3 model to establish the safest dose of [161Tb]Tb-PSMA-I&amp;T (dose levels: 4.4, 5.5 and 7.4 GBq). The maximum tolerated dose (MTD) will be defined as the highest dose level at which a dose-limiting toxicity occurs in less than 1/3 or 2/6 participants. The phase II dose-expansion will include 24 participants at the MTD. Up to six cycles of [161Tb]Tb-PSMA-I&amp;T will be administered intravenously every six weeks, with each subsequent dose for each patient reduced by 0.4GBq. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy and a second-generation anti-androgen, PSMA-positive disease on PSMA PET/CT (SUVmax ≥20), no sites of discordance on FDG PET/CT, adequate bone marrow, hepatic and renal function, ECOG performance status ≤2, and no prior treatment with another radioisotope. The co-primary objectives are to establish the MTD of [161Tb]Tb-PSMA-I&amp;T, and safety profile [CTCAE v5.0]. Secondary objectives include measuring absorbed radiation dose [Gray], evaluating anti-tumour activity [PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective response rate], and evaluation of pain [BPI-SF] and health-related quality of life [FACT-P and FACT-RNT] over the first 12 months after treatment commences. Exploratory objectives include ctDNA analysis at baseline, during treatment and at progression, and optional tissue biopsies, to determine biomarkers of treatment response and resistance. Patient enrolment began in October 2022, with recruitment expected to continue for 24 months. Clinical trial information: NCT05521412 .

LuCAB: A phase I/II trial evaluating cabazitaxel in combination with [177Lu]Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

TPS278 Background: [177Lu]Lu-PSMA-617 was recently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Despite conferring a survival benefit, for many the treatment response is short, and progression is inevitable. One of the likely mechanisms limiting the durability of responses to [177Lu]Lu-PSMA-617 is heterogeneity in tumor PSMA expression. This can be screened for visually using PSMA and FDG PET/CT scans and inspecting for discordant disease, however, micrometastatic disease is unable to be evaluated in this way. In addition, [177Lu]Lu-PSMA-617 may not effectively target micrometastatic disease due to the longer path length of beta emitters. Cabazitaxel has radiosensitizing properties that may enhance the cytotoxic effect of [177Lu]Lu-PSMA-617, whilst also treating any PSMA-negative disease. We hypothesize that the combination of [177Lu]Lu-PSMA-617 and cabazitaxel will be well tolerated and lead to more durable responses. Methods: This single-centre, single-arm phase I/II trial will enrol 32-38 pts with mCRPC to evaluate the safety and preliminary efficacy of cabazitaxel and [177Lu]Lu-PSMA-617 in combination. Up to 6 doses of [177Lu]Lu-PSMA-617 (7.4 GBq) will be administered intravenously every 6 weeks. Cabazitaxel will be given concurrently (dose range 12.5mg/m2 - 20mg/m2), on Day 2 and Day 23 of each 6-week cycle. The dose of cabazitaxel will be escalated using a traditional 3+3 design. Key eligibility criteria include a diagnosis of mCRPC with PSMA-positive disease on PSMA PET/CT (SUVmax ≥15), with no evidence of diffuse marrow disease or sites of discordance on FDG PET/CT. Pts must have progressed after prior docetaxel and a second-generation antiandrogen, have adequate bone marrow and organ function and an ECOG performance status of 0-1. The primary objective is to establish the maximum tolerated dose of cabazitaxel and [177Lu]Lu-PSMA-617. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life over the first 12 months. Bloods will be taken at baseline, during treatment and at progression for ctDNA analysis, the results of which will be correlated with baseline pt and disease characteristics, and response outcomes, to determine biomarkers of treatment response and resistance. Pt recruitment commenced in August 2022 and will continue for 18 months. Clinical trial information: NCT05340374 .

AlphaBet: A phase I/II trial evaluating the combination of radium-223 and [177Lu]Lu-PSMA-I&amp;T in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

TPS280 Background: [177Lu]Lu-PSMA-I&amp;T (LuPSMA) is a small molecule radioligand that delivers radiation via beta-particulate emission to cells expressing prostate-specific membrane antigen (PSMA). Despite a survival benefit in mCRPC, responses for many are not durable, with the majority of pts developing progressive osseous disease. Due to the lack of crossfire radiation in micrometastatic disease, small cancer cell clusters in the bone marrow may not receive an adequate dose of radiation from 177Lu to induce cytotoxic double-stranded DNA breaks. Alpha-emitters have a shorter path length (≤100 µm) and higher linear energy transfer, making them better suited for treating micrometastatic disease. As a calcium-mimetic, radium-223 (223Ra) is a bone-specific alpha-emitter which targets osteoblastic bone metastases. We hypothesise that the combination of LuPSMA with 223Ra will be well tolerated and lead to improved response durability. Methods: This phase I/II, single-arm, single-centre study will enrol 36 patients with mCRPC who have progressed on a prior second-generation antiandrogen. Up to 6 cycles of LuPSMA (7.4 GBq) and 223Ra (28 kBq/kg - 55 kBq/kg) will be given intravenously every 6 weeks, along with background androgen deprivation and bone protective therapy. Key eligibility criteria include a diagnosis of mCRPC with at least two untreated bone metastases visible on bone scintigraphy and PSMA-positive disease on PSMA PET/CT (SUVmax ≥20). Sites of FDG-positive disease must be either PSMA-positive or have increased uptake on bone scan. Other eligibility criteria include an ECOG status of 0-2, and adequate bone marrow and organ function. Patients treated with more than one line of chemotherapy for metastatic prostate cancer are not eligible. Blood samples and biopsies will be taken at baseline, on treatment, and at progression to develop tumor- and immune-based biomarkers that predict treatment response and associated survival benefit. A traditional 3+3 dose-escalation model will be utilized initially, escalating the dose of 223Ra. The dose of LuPSMA will remain fixed. The co-primary objectives of this study are to determine the maximum tolerated dose of 223Ra when combined with LuPSMA, and the 50% PSA response rate. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through overall, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life. Enrolment commenced in September 2022 and will continue for 24 months. Clinical trial information: NCT05383079 .

Trials in progress: TAM kinase inhibitor PF-07265807 and sasanlimab plus axitinib in patients with advanced or metastatic renal cell carcinoma—A phase 1, open-label, pharmacokinetic, safety and tolerability study.

TPS743 Background: Tumor-associated macrophage kinases (TAMK) are expressed on tumor cells during malignant transformation. Inhibition of AXL and MERTK, members of the TAMK family, may lower the immune activation threshold and promote antitumor immunity. PF-07265807 (ARRY-067) is a small-molecule inhibitor of MERTK and AXL showing antitumor activity in preclinical models as monotherapy or combined with anti-programmed cell death protein 1 (anti-PD-1) antibodies (ab). Sasanlimab is an anti-PD-1 ab with acceptable safety profile being tested (300 mg SC Q4W, Phase 3) in non-muscle invasive bladder cancer. Axitinib is a VEGF inhibitor approved (single agent and combined with anti-PD-1 inhibitors) for advanced renal cell carcinoma (RCC). This first-in-human Phase 1, open-label, multi-center study (NCT04458259) will evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of PF-07265807 in patients (pts) with advanced or metastatic solid tumors as a single agent and in combination with sasanlimab with or without axitinib. We describe here the dose escalation (Part 3) and dose expansion (Part 4) for the triplet combination of PF-07265807 + sasanlimab + axitinib. Methods: Eligible participants for the triplet cohorts are adult pts with confirmed unresectable advanced or metastatic clear cell RCC, with estimated creatinine clearance ≥30 mL/min and urinary protein &lt;2+ or ≥2+ but 24-h urine protein:creatinine ratio &lt;2 g/24 h. Pts for Part 4 need to have intermediate and poor risk RCC and no prior systemic therapy for metastatic disease. Other key eligibility criteria: measurable disease by RECIST 1.1 or non-measurable disease, ECOG PS 0–2, adequate bone marrow and liver function, and resolved acute effects of prior therapy. Each cycle is 21 days. Part 3 will determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of PF-07265807 in triplet therapy using a Bayesian logistic regression model and the escalation with overdose control principle. After the MTD/RP2D is identified, Part 4 will further evaluate the safety and preliminary efficacy of PF-07265807 combined with sasanlimab and axitinib. Treatment with study drug will continue until disease progression, consent withdrawal, or unacceptable toxicity, whichever occurs first. Primary endpoints of Part 3 are incidence of dose-limiting toxicities, adverse events (AE), and laboratory (lab) abnormalities. For Part 4, the primary endpoints are objective response rate and complete response rate; secondary endpoints include disease control rate; time-to-event endpoints; AEs; lab abnormalities; concentrations of PF-07265807 and its metabolite, sasanlimab, and axitinib; and incidence and titer of anti-sasanlimab anti-drug antibodies response. The study started in late 2020 and is recruiting. Clinical trial information: NCT04458259 .

EFFECTS OF TRAUMA PLASMA-DERIVED EXOSOMES ON HEMATOPOIETIC PROGENITOR CELLS.

Background: Severe trauma disrupts bone marrow function resulting in persistent anemia and immunosuppression. Exosomes are extracellular vesicles implicated in disease, cellular functions, and immunomodulation. The effects of trauma plasma-derived exosomes on bone marrow hematopoiesis are unstudied; we hypothesized that trauma plasma-derived exosomes suppress bone marrow hematopoietic progenitor cell (HPC) growth and contribute to increased inflammatory cytokines and HPC mobilization. Methods: Plasma was collected from a prospective, cohort study of trauma patients (n = 15) with hip and/or femur fractures and an ISS > 15 and elective total hip arthroplasty (THA) patients (n = 15). Exosomes were isolated from both groups using the Invitrogen Total Exosome Isolation Kit. Healthy bone marrow was cultured with 2% plasma, 50 μg, 100 μg, or 200 μg of exosomal protein and HPC (granulocyte, erythrocyte, monocyte, megakaryocyte colony-forming units [CFU-GEMM], erythroid burst-forming units [BFU-E], and macrophage colony-forming units [CFU-GM]) growth assessed. After culturing healthy bone marrow stroma with 100 μg of exosomal protein, expression of cytokines and factors influencing HPC mobilization were assessed by qPCR. Differences were compared using the ANOVA, with significance defined as P < 0.05. Results: The only demographic difference was age; trauma patients were significantly younger than THA (mean 44 vs. 63 years). In vitro exposure to trauma plasma significantly decreased growth of all HPCs. In vitro exposure to 100 μg or 200 μg of trauma exosomal protein significantly decreased growth of BFU-E and CFU-GM, whereas 50 μg had no effect. Culture of trauma exosomal protein with bone marrow stromal cells resulted in increased expression of IFN-γ, IL-1α, TNF-α, G-CSF, CXCR4, SDF-1, and VCAM-1 in bone marrow stroma. Conclusions: Both plasma and plasma-derived exosomes from trauma patients adversely affect bone marrow function. Plasma-derived exosomes may contribute to altered hematopoiesis after severe trauma; analysis of exosomal content may improve our understanding of altered bone marrow function.

Evaluation of systemic impact of tricuspid regurgitation: an appleal for the notion of tricuspid regurgitation.

Evaluation of systemic impact of tricuspid regurgitation: an appleal for the notion of tricuspid regurgitation.

Phase I study of trifluridine/tipiracil in combination with gemcitabine (gem) and nab-paclitaxel (nab-P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC).

731 Background: The incidence of PDAC is on the rise and it is predicted to be the 2nd leading cause of cancer related mortality in the next decade. Most patients present with advanced disease at diagnoses with limited systemic treatment options. Fluoropyrimidines are active in PDAC. Lonsurf (L) is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Preclinical data demonstrate Lonsurf may have activity in 5-FU resistant malignancies. This phase I study combines Gem, nab-P, and L. Methods: Gem and nab-P are dosed on days 1 and 15 IV on a 28 day cycle. L (20-30mg/m2) is dosed twice daily on days 2-6 and 16-20 (table 1). Dose escalation is by 3+3 design. Key eligibility include pts with untreated locally advanced or metastatic PDAC, ECOG 0-1, and adequate hepatic and bone marrow function. Results: 14 pts (median age 62 yrs [range 43-74]) have been enrolled. Dose was initiated at DL1. The first 3 pts were treated without DLT. DL2 exceeded the MTD with 1 patient experiencing grade 3 infection (cholangitis). Dose expansion to 7 patients was completed at DL 1 with no further DLTs. The RP2D is Gem 800mg/m2, Nab-P 100mg/m2, and L 25mg/m2. Of the 10 patients with evaluable disease, 2 (20%) had PR and 7 (70%) had SD. Pts were on study a median of 14 months (range 4 -31+). Most common grade 3/4 AEs include fatigue (46%,) neutropenia (38%), anemia (31%) anorexia (15%), nausea (15%), vomiting (15%), abdominal pain (15%), hyperglycemia (15%). No grade 5 events occurred. Conclusions: The RP2D is Gem 800mg/m2, Nab-P 100mg/m2, and L 25mg/m2. This combination was well tolerated with expected toxicities of myelosuppression with prolonged responses seen. Clinical trial information: NCT04046887 . [Table: see text]

Phase Ib study testing neoadjuvant transforming growth factor (TGF)-β antibody, NIS793, plus 5-fluorouracil, irinotecan, and oxaliplatin chemotherapy (FOLFIRINOX) in patients (pts) with borderline resectable (BR)/locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC).

TPS762 Background: Overcoming resistance to chemotherapy and immune checkpoint inhibitors remains an unmet need for PDAC. In this context, TGF-β plays a key role in PDAC by promoting the activation of fibroblasts and extracellular matrix deposition, facilitating epithelial-to-mesenchymal transition, immune evasion, and resistance to chemotherapy. Combination of FOLFIRINOX with losartan, an indirect TGF-β inhibitor with antifibrotic properties, has shown an increased R0 resection rate in pts with BR/LA PDAC, providing the rationale to explore the combination of other TGF-β targeting agents with FOLFIRINOX in the neoadjuvant setting (PMID: 34884782; PMID: 31145418). NIS793 is a first-in-class monoclonal antibody that directly binds TGF-β and reduces intratumoral fibrosis in preclinical models (PMID: 33298926). NIS793 also has an acceptable safety profile and preliminary clinical activity. This study investigates whether NIS793 modulation of the tumor fibrotic network improves clinical outcomes of FOLFIRINOX neoadjuvant therapy in BR/LA PDAC. Our aim is to demonstrate how TGF-β inhibition and stroma remodeling contribute to clinical outcomes. Methods: This is a single institution, open label, 2-part, 2-arm, non-comparator, Phase Ib study (NCT05417386) of FOLFIRINOX + NIS793 as neoadjuvant therapy for pts with untreated BR/LA PDAC. Eligible pts are adults with measurable disease, adequate organ and bone marrow function, and ECOG PS ≤1. In Part 1 (safety run-in), 6-18 pts with histologically confirmed untreated metastatic PDAC receive FOLFIRINOX + NIS793 at different dose levels. Dose escalation is primarily guided by the number of dose-limiting toxicities. Primary objectives are assessing safety, defining the recommended Phase II dose (RP2D), and providing initial evidence of clinical benefit of the combination. In Part 2, pts with untreated BR/LA PDAC are randomized 4:1 and stratified by BR vs LA. Pts in Arm 1 (n=5) receive 8 cycles of FOLFIRINOX followed by chemoradiation therapy (CRT) and surgery. Pts in Arm 2 (n=23) receive 8 cycles of FOLFIRINOX + NIS793 at RP2D followed by CRT + NIS793, surgery, and 12 cycles of adjuvant NIS793. The primary endpoint is R0 resection rate. Secondary endpoints are disease-free survival, progression-free survival, overall survival, and pathologic complete response. The effect of neoadjuvant therapy will be assessed by ferumoxytol-MRI, circulating cell-free DNA dynamics analysis, single-cell RNA sequencing, immunohistochemistry, and digital spatial analysis. Together, these correlative analyses may enable development of a mechanistic model for TGF-β inhibition in PDAC. This study is ongoing. The first pt was treated on Aug 2, 2022. Clinical trial information: NCT05417386 .

SEAMARK: Randomized phase 2 study of pembrolizumab + encorafenib + cetuximab vs pembrolizumab alone for first-line treatment of BRAF V600E–mutant microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC).

TPS268 Background: Among patients with MSI-H/dMMR CRC, BRAF mutations occur in approximately 30%. MSI-H/dMMR and BRAF mutations are both associated with poor prognosis; in patients who have both biomarkers, poor prognosis is thought to be driven by the BRAF mutation. Pembrolizumab is indicated for the treatment of patients with MSI-H/dMMR unresectable or metastatic CRC (mCRC). The BRAF inhibitor encorafenib, in combination with cetuximab, an anti-EGFR antibody, is indicated for previously treated patients with BRAF V600E-mutant mCRC. Currently, there are no first-line treatment options indicated specifically for patients with both MSI-H/dMMR and BRAF V600E-mutant mCRC. To assess the safety and efficacy of combining pembrolizumab with encorafenib + cetuximab, the SEAMARK study will evaluate this combination vs pembrolizumab alone in patients with previously untreated BRAF V600E-mutant MSI-H/dMMR mCRC. Methods: SEAMARK (NCT05217446) is an open-label, multicenter, randomized, phase 2 study. Approximately 104 patients (randomized 1:1; stratified by Eastern Cooperative Oncology Group Performance Status [ECOG PS] 0 vs 1) will receive either pembrolizumab + encorafenib + cetuximab or pembrolizumab. Enrolled patients must be aged ≥16 or ≥18 years (per country-specific regulations) and have previously untreated BRAF V600E-mutant MSI-H/dMMR mCRC; measurable disease (Response Evaluation Criteria in Solid Tumors 1.1); ECOG PS 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients who received prior treatment with BRAF/EGFR inhibitors or immune checkpoint inhibitors, or who have brain metastases (unless radiologically stable) or RAS mutation (or unknown RAS status), will be excluded. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include safety and tolerability, overall survival, objective response rate, duration of response, and quality of life. Enrollment started in July 2022. Clinical trial information: NCT05217446 .

Trials in progress: A phase 1, open-label, pharmacokinetic, safety and tolerability study of PF-07265807 (selective TAM kinase inhibitor) alone or with sasanlimab in patients with advanced or metastatic solid tumors.

TPS270 Background: Inhibition of Mer Proto-oncogene tyrosine kinase (MERTK) and AXL may lower the threshold for immune activation thereby promoting anti-tumor activity. PF-07265807 (ARRY-067) is a selective small-molecule inhibitor of the tumor-associated macrophage kinases MERTK and AXL. In preclinical models, PF-07265807 plus anti-programmed cell death protein 1 (anti-PD-1) antibodies show antitumor activity that results in long-term cures and resistance to tumor re-challenge. Sasanlimab is a monoclonal antibody to PD-1 administered subcutaneously (300 mg every 4 wk or equivalent); it has an acceptable safety profile and is being tested in a Phase 3 trial in non-muscle invasive bladder cancer. This first-in-human study will evaluate safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of PF-07265807 alone and with sasanlimab in patients (pts) with selected advanced or metastatic solid tumors. Study design of PF-07265807 monotherapy dose escalation (Part 1) was presented at ASCO 2021 (TPS2671). Here, we describe dose escalation (Part 2) and dose expansion (Part 4) cohorts for the doublet combination of PF-07265807 + sasanlimab. Methods: This is a Phase 1, open-label, multi-center study (NCT04458259) of PF-07265807. Adult pts with selected advanced or metastatic solid tumors who are intolerant or resistant to standard therapy will enroll into doublet therapy dose escalation (Part 2). Pts who are anti-PD-1/PD-L1 treatment naïve with intermediate tumor mutational burden (defined as ≥6 and &lt; 16 microsatellite stable) colorectal cancer (CRC) or PD-L1+ (defined as combined positive score ≥1) gastric cancer will enroll into doublet therapy dose expansion cohorts (Part 4). Other key eligibility criteria: measurable or non-measurable disease by RECIST 1.1; ECOG PS 0–2; adequate bone marrow, renal and liver function; and resolved acute effects of any prior therapy. Each cycle will be 21 days. Treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. The doublet maximum tolerated dose (MTD) will be guided by a Bayesian analysis of dose limiting toxicity (DLT) data for doublet therapy (Part 2). The recommended phase 2 dose (RP2D) will then be determined via holistic data review with/without the MTD identification. Primary endpoints in Part 2 include the incidence of DLTs, adverse events and laboratory abnormalities. After doublet MTD/RP2D is identified in Part 2, the preliminary anti-tumor activity of PF-07265807 + sasanlimab will be explored in Part 4. Primary endpoints in Part 4 include objective response and complete response rates; secondary endpoints include disease control rate and response duration, adverse events and laboratory abnormalities. The study began in Q4 2020 and is recruiting pts. Clinical trial information: NCT04458259 .

An adaptive approach to neoadjuvant therapy to maximize resection rates for pancreatic adenocarcinoma: A phase II trial.

TPS771 Background: Curative treatment for potentially resectable (resectable or borderline resectable) pancreatic adenocarcinoma, despite recent advances, leads to only suboptimal outcomes. Recent US national cooperative group trials have demonstrated the safety and feasibility of neoadjuvant chemotherapy (PMID 33475684, PMID 35834226), and also show that the two frontline regimens, FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin) and gemcitabine/nab-paclitaxel (GnP), are comparable in this setting. Finally, ability to undergo resection remains the key driver of cure. Therefore, an approach that selects chemotherapy based on early response assessment, to maximize the probability of resection, is likely to improve curative outcomes. Methods: This is a phase II study intended to maximize the probability of surgical resection for pancreatic cancer. Key eligibility requirements include adult patients with a confirmed histopathologic diagnosis of pancreatic carcinoma or adenocarcinoma, an ECOG PS ≤ 1, resectable or borderline resectable disease by central radiology review, no prior therapy for index pancreatic cancer, and adequate bone marrow, liver and kidney function. Treatment includes 4 doses (~ 2 months total treatment time) of FOLFIRINOX (“Chemo1”). After a re-evaluation, using radiologic response, CA19.9 response, and chemotherapy toxicity, patients will either continue with “Chemo1” for another 4 cycles (8 doses) or switch to GnP (“Chemo2”) which will be administered for 4 cycles (12 doses, for ~4 month total treatment time), followed by surgical resection. Primary outcome will measure the proportion of patients undergoing surgical resection using historical dated compared to 32 patients in a current study with a time frame of 16 months. Using historical data, the expected proportion of patients undergoing resection is ~60%. The goal of this study is to increase this to 80% or higher. With a one-sided of 0.05 and power of 80%, 32 patients will be needed to demonstrate this difference. Key translational correlatives will include serial circulating tumor DNA assessment and extensive tumor molecular profiling. Clinical trial information: NCT04594772 .