El-Rayes, Bassel F

Abstract Background This phase 1 study aimed to determine the maximum tolerated dose (MTD) and evaluate the safety and preliminary efficacy of rucaparib (RUB), a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor, combined with liposomal irinotecan (nal‐IRI) and 5‐fluorouracil (5‐FU) in metastatic gastrointestinal (GI) cancers. RUB targets DNA repair pathways, showing efficacy in tumors with homologous recombination deficiency, such as BRCA mutations. Preclinical data suggest synergy with irinotecan, but overlapping toxicities pose challenges. Methods Eighteen patients with metastatic GI cancers, who previously progressed on at least one systemic therapy, were enrolled. A novel sequential dosing regimen, informed by nal‐IRI pharmacokinetic analysis, was used. Twelve patients were evaluable for dose‐limiting toxicity (DLT) and 12 for response per Response Evaluation Criteria in Solid Tumors v1.1 criteria. Results The MTD was established as RUB 600 mg twice daily, nal‐IRI 50 mg/m 2 , and 5‐FU 2400 mg/m 2 over 46 hours. The objective response rate (ORR) was 33% (4 of 12), and the disease control rate (DCR) was 75% (9 of 12). Common grade 3 adverse events included diarrhea (33%) and neutropenia (25%), with no grade 4/5 events. Responses were notable in patients with somatic ATM and BRCA mutations, especially those with prior platinum exposure. No DLTs occurred at the recommended phase 2 dose. Conclusions This optimized dosing schedule successfully established the MTD for RUB with nal‐IRI and 5‐FU, overcoming prior challenges with PARP inhibitor and irinotecan combinations. The promising ORR and DCR support further evaluation of this regimen in advanced GI malignancies.

Abstract Background: Pancreatic adenocarcinoma (PDAC) is an aggressive malignancy with dismal prognosis. Most patients present with advanced stages. Heightened levels of serum interleukin-6 (IL-6) are associated with carcinogenesis, immune suppression, and poor prognosis in PDAC. Preclinical data of dual inhibition of IL-6 and programmed death ligand-1 (PD-L1) facilitates CD8+ T-cell migration into pancreatic tumors and was effective in controlling tumor growth in syngeneic and genetically engineered PDAC mouse models. Siltuximab (Sil) is a chimeric monoclonal antibody which targets the IL-6 molecule specifically. Spartalizumab (Sparta) is a high-affinity ligand-blocking humanized IgG4 antibody against the PD-1 receptor. We developed a phase Ib/II trial to evaluate the safety, immunogenicity and preliminary antitumor activity of Sil and Sparta in metastatic PDAC (mPDAC). Methods: Patients (pts) with mPDAC who have progressed on at least one line of systemic chemotherapy were eligible for the trial. Other selected inclusion criteria were ≥18 years of age, ECOG PS 0-1 and measurable disease per RECIST v1.1. The phase Ib trial design is standard 3+3, with a primary endpoint of recommended phase II dose (RP2D). An additional 24 patients were planned for an expansion cohort. Sil was administered at escalating dose levels of 6 mg/kg (DL1) and 11 mg/kg (DL2), in combination with Sparta at 300 mg IV on day 1 of each 21-day cycle. Key secondary endpoints included overall response rate (ORR = CR + PR), progression-free survival (PFS) and overall survival (OS). Results: We enrolled 4 patients on DL1 and escalated to DL2/RP2D in the absence of a dose limiting toxicity (DLT). A total of 31 patients were subsequently treated at the RP2D (escalation + expansion). The median age was 68 years, 42% were male. Majority were White (63%) and 20% were Black. About 43% had head of pancreas primary tumors and 86% had liver involvement. The median number of lines of prior therapy was 3 (range 1-4). There was no objective response among the 4 patients on DL1; 1 had stable disease (SD) for 11 weeks as best response. 17 of 31 patients on RP2D had only a baseline assessment and came off study for progression of disease, prior to follow-up imaging assessment for response evaluation. Of the 14 RP2D patients with a follow-up assessment, ORR was 0% (3 were SD and 11 had progression of disease (PD) as best response), mPFS - 2.2 mos (95% CI: 1.9, 2.6), mOS - 5.5mos (95% CI: 2.8, 6.5). Treatment related adverse events (TRAEs) of any grade included fatigue (23%), anemia (18%), and increased liver enzymes (9.5%). There were no grade 4-5 TRAEs. Conclusions: The combination Sil/Sparta had an acceptable safety profile but did not elicit responses in advanced PDAC pts. Correlative studies using paired biopsies and blood are ongoing to determine how dual IL-6/PD-1 blockade impacts stromal and immune biomarkers in relationship to the clinical outcome measures. Funding and medications for the study were provided by Novartis and Recordati Rare Diseases Inc (NCT04191421) and NIH/NCI (R21CA266088). Citation Format: Olatunji B. Alese, Olumide Gbolahan, Kathleen M. Coleman, Yichun Cao, Sujata Kane, Sarah Craven, Emily Greene, Natalie Horvat, Andrew McDonald, Walid L. Shaib, Christina S. Wu, Mehmet Akce, Maria Diab, Jeffrey M. Switchenko, Gregory B. Lesinski, Bassel F. El-Rayes. Phase Ib study of siltuximab and spartalizumab in advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT136.

TPS578 Background: Liver transplantation is a curative treatment option in hepatocellular carcinoma (HCC) however; up to 20% of patients develop recurrent disease. HCC recurrence post-transplant is usually extrahepatic (up to 67%) hence requires effective systemic therapy options. Available data are limited and restricted to small non-randomized studies and case series. Lack of prospective clinical trial data and limited data indicates an area of unmet need in treatment of recurrent HCC after liver transplantation. This phase II study aims evaluate the safety and efficacy of lenvatinib in patients with recurrent HCC after liver transplantation. Methods: This is a multi-institutional phase II trial with lenvatinib in patients with recurrent HCC after transplantation. Lenvatinib is administered 12 mg daily orally in patients ≥60 kg, and 8 mg daily orally in patients <60 kg. Each cycle is 28 days. Restaging scans will be performed every 8 weeks. Eligible patients must have histologically proven HCC that has recurred after liver transplantation and not amenable for surgical resection, age ≥18 years, ECOG PS 0-1, Child Pugh Class A, measurable disease per RECIST version 1.1, adequate organ function, no prior systemic therapy with lenvatinib or another systemic therapy in the post-transplant setting. Prior liver directed therapy is allowed, should be at least >28 days prior to the study enrollment, and should have at least one measurable untreated lesion by RECIST 1.1 Primary endpoint is overall response rate (ORR). Secondary endpoints are safety/tolerability, progression free survival, and overall survival. Pre-treatment and on-treatment peripheral blood samples will be collected for correlative research. A Simon`s two stage Minimax design is employed (H0: ORR = 5%; H1: ORR = 24%; Type I error = 0.05; power = 80%). In the first stage, 11 patients will be accrued, and if there is no objective response among them, the study will be stopped for futility. Otherwise, additional 6 patients will be accrued for a total of 17 patients. This study is currently enrolling patients. Clinical trial information: NCT05103904 .

Background Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study. Methods Nivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0–1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry. Results A total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50–67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475). Conclusions Nivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients.

3580 Background: TAS-102 (FTD/TPI) is a combination of a nucleoside analogue and a thymidine phosphorylase inhibitor, and has showed activity in 5FU-resistant CRC. Nal-IRI achieves higher intra-tumor concentrations than irinotecan (Iri; 142-fold) and its major metabolite, SN-38 (9-fold). This resulted in superior anti-tumor activity compared to free Iri in multiple tumor xenografts. Furthermore, multiple clinical trials have established the activity of nal-IRI in combination with 5FU in pancreaticobiliary cancers. The combination of nal-IRI with the more potent nucleoside analogue TAS-102 may thus result in a more effective systemic therapy. We conducted this study to define the safety and efficacy of the combination of TAS-102 and nal-IRI in advanced CRC. Methods: Eligible patients (pts) on this investigator-initiated phase II study had advanced CRC and must have had disease progression on at least one prior therapy. Additional inclusion criteria - measurable disease, ECOG PS 0-1 & adequate organ function. Based on previously published dose escalation phase I data, the pts were treated at the recommended phase II dose of TAS-102 (given orally at 35mg/m2 bid on days 1-5) and nal-IRI (60mg/m2 IV on day 1) in 14-day cycles. The primary endpoint was objective response rate (ORR) = complete (CR) + partial (PR) response per RECIST v1.1. Multiple secondary endpoints included safety/tolerability, progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and duration of response (DoR). Results: Twenty-two pts were enrolled, of whom 20 were evaluable for response. Male - 50%; ECOG PS 1 – 75%; African Americans – 38%; median age - 58yrs (interquartile range [IQR] 49-67). Median line of prior therapy was 1 (IQR 1-2) and 13.6% (3 pts enrolled during the dose escalation phase) had received prior Iri. 47.6% received concurrent Bevacizumab. ORR was 15% (3 PR, 0 CR). 60% had stable disease (SD) as best response; DCR of 75%. mPFS - 9.7 mos (95% CI: 5.6, 14.2); mOS - 10.1 mos (95% CI: 7.3, 15.9). 12-month PFS and OS rates were 34.6% and 39.5% respectively. At a median follow up of 11.9 mos, DoR was yet to be determined and 50% of the pts had maintained response for 12 mos. Median duration of progression free among pts with SD was 7.6 mos (95% CI: 4.6, 13.2), with a 12-month survival rate of 47.7% (95% CI: 15.5%, 74.5%). Median time to response (TTR) was 4.8mos. Most common treatment related toxicities included fatigue and neutropenia (G3; 27.3% each); anemia and leucopenia (G3; 18.2% each). Other G3 AEs included febrile neutropenia, diarrhea, hypokalemia, lymphopenia and nausea (4.5% each). Conclusions: We demonstrated that the combination of TAS-102 and nal-IRI had an acceptable safety profile, and showed antitumor activity in patients with advanced CRC. Additional biomarker analyses such as survival correlation with UGT1A1 phenotype and RAS mutational status are ongoing. (NCT03368963). Clinical trial information: NCT03368963 .

3579 Background: Panitumumab (Pmab) is a recombinant monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR) and it is indicated for the treatment of metastatic colorectal carcinoma (mCRC). However, the objective response rates (ORR) for the single agent are historically about 8-11%. EGFR inhibition induces synthetic lethality with poly ADP ribose polymerase inhibitors (PARPi) such as Niraparib, by attenuating DNA repair pathways. Combining PARP and EGFR inhibition has the potential to confer synergistic benefit, while also ameliorating resistance mechanism to EGFRi. We conducted this study to define the safety and efficacy of the combination of Niraparib and Pmab in RAS wildtype (WT) mCRC. Methods: Patients (pts) with RAS WT mCRC who have progressed on at least one line of systemic chemotherapy were eligible for the trial. Other selected inclusion criteria were ≥18 years of age, ECOG PS 0-1 and measurable disease per RECIST 1.1. Pmab was administered at 6 mg/kg IV on days 1 & 15 of each 28-day cycle, while Niraparib was taken orally at 200mg or 300mg (based on body weight and platelet count) daily throughout the cycle. The primary endpoint was clinical benefit rate (CBR) defined as complete (CR) + partial (PR) response + stable disease (SD) per RECIST v1.1. Multiple secondary endpoints included safety/tolerability, ORR, progression-free survival (PFS), overall survival (OS), and duration of response (DoR). Results: A safety run-in cohort of 6 pts was initially enrolled. Following a preplanned safety analysis showing an acceptable toxicity profile, an additional 19 pts were enrolled. Of the total 25 enrolled pts, 24 were evaluable for response. Male - 50%; Whites/African Americans/Asians – 65.2%/21.7%/13%; median age – 58.5yrs. The majority had left sided tumor (92%) and the median line of prior therapy was 2 (range 1-4). CBR was 83.3% (0 CR, 6 PR, 14 SD) and ORR was 25%. mPFS – 5.6mos (95% CI: 3.7, 6.9); mOS – 20.9mos (95% CI: 9.2, NR). Six-month PFS and OS rates were 48.4% and 100% respectively. At a median follow up time of 7.5mos (95% CI: 4.2, 10.4), 3 patients remained on treatment and DoR was yet to be determined. Muco-cutaneous adverse events (AEs) of any grade included rash (58.4%), oral mucositis (20.8%), dry skin (16.7%) and paronychia (4.2%). Most common (grade > 2) treatment related AEs (TRAEs) were anemia (G3; 12.5%), dermatitis, oral mucositis, hypertension and neutropenia (G3; 4.2% each). There were no grade 4-5 TRAEs. Conclusions: The combination of Pmab and Niraparib had an acceptable safety profile, and showed considerable antitumor activity in pts with advanced RAS WT mCRC compared to historical rates. Additional biomarker analyses such as survival correlation with immune cell infiltration in paired skin biopsies and HER2/BRAF mutational status are ongoing. Funding and product (Niraparib) for the study were provided by GSK (NCT03983993). Clinical trial information: NCT03983993 .

Hepatocellular carcinoma (HCC) is the fastest increasing cause of cancer-related mortality in the United States and is projected to be the third leading cause of cancer-related mortality in the United States by 2030. Main risk factors include alcoholic cirrhosis, chronic hepatitis B, hepatitis C, and nonalcoholic steatohepatitis (NASH). More than half of the patients have advanced-stage disease at presentation. Currently approved frontline systemic therapy options include sorafenib, lenvatinib, and atezolizumab/bevacizumab. Over the past decade, there has been a significant improvement in survival with a median overall survival of 19.2 months reported with first-line treatment with atezolizumab/bevacizumab. Based on positive results of randomized phase III HIMALAYA trial, durvalumab and tremelimumab combination could become another frontline option. Multiple frontline clinical trials with immune checkpoint inhibitor (ICI) or ICI combined with other novel agents are underway. In the frontline setting, identifying predictive biomarkers for ICI-based or tyrosine kinase (TKI)-based therapy is an unmet need. Subsequent treatment is poorly defined in patients with prior ICI-based therapy since all the available second-line and beyond therapy was studied after first-line sorafenib. Frontline systemic therapy is poorly defined in certain subgroups of HCC such as Child–Pugh B and post-transplant recurrent HCC. The landscape of frontline HCC treatment is rapidly changing, and this article reviews the most recent treatment approaches to frontline therapy for advanced HCC.

563 Background: RUB is an oral PARP1,2,3 inhibitor that demonstrated efficacy in patients (pts) with ovarian and prostate cancers harboring deleterious BRCA mutations. RUB exerts synergistic anti-tumor effect with IRI preclinically though the combination has overlapping toxicities. We previously published on the population PK of nal-IRI (Adiwijaya, Ma et al, Clin Pharm Ther 2017). We conducted a phase I study to evaluate a novel sequential dosing of RUB with nal-IRI/5FU in mGI cancer pts. Methods: Eligible pts had incurable mGI cancer previously received > 1 line of therapy (rx), ECOG PS 0-1, had RECIST measurable disease, adequate organ reserves and not received IRI for metastatic disease. Previous PARPi rx was excluded. The endpoints included dose limiting toxicity (DLT), maximum tolerated dose (MTD) and toxicity profile. The dose escalation utilized the 3+3 design. RUB was given oral bid on Day 4 to 13 and 18 to 27 with nal-IRI i.v. and 5FU i.v. 2400 mg/m2 over 46 hr on Day 1 and 15, every 28 day. Planned dose levels were RUB 400 mg/nal-IRI 50 mg/m2 (DL1), 400 mg/70 mg/m2 (DL2) and 600 mg/70 mg/m2 (DL3). Adverse events (AEs) were scored per CTCAE v4.03. Molecular profile was evaluated by CLIA-certified NGS testing. Results: Eighteen pts including 11 colorectal (CRC), 6 PANC, 1 gastroesophageal (GE) were enrolled and 12 were evaluable for DLTs. DL2 was not tolerable (DLT: G3 diarrhea, nausea and vomiting) and DL2A was added (RUB 600 mg/nal-IRI 50 mg/m2). DL2A enrolled 6 pts with no DLT and was determined as the MTD. Of DLT-evaluable pts, G3 and worse treatment-related AEs from all cycles were diarrhea (33%), fatigue (25%), leukopenia (25%), neutropenia (25%), anemia (8%) and nausea (8%). Four of 12 response evaluable pts had partial response: 2 CRC (1 had ATM mut), 1 PANC ( ATM mut), 1 GE ( BRCA2 mut) whilst 3 responders previously had platinum (PLA). Five pts had stable disease beyond 16 weeks (range 18.9 to 100.7 weeks), and all had prior PLA. Conclusions: The study successfully determined the MTD of RUB in combination with nal-IRI and 5FU. Encouraging efficacy was observed in PLA-treated mGI cancers including responses in those harboring ATM and BRCA alterations. The study is proceeding to evaluate the efficacy of the combination in metastatic pancreas cancer pts with and without BRCA1/2 or PALB2 alterations. Clinical trial information: NCT03337087.

Abstract Background Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. Materials and Methods Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. Results A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p &lt; .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p &lt; .001). Patients aged &gt;65 had significantly worse PFS rates as compared with patients aged ≤65 (p &lt; .001). Conclusion BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age &gt;65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. Implications for Practice The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

413 Background: Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR)-mediated signaling and angiogenesis contribute to the pathogenesis and progression of pancreatic adenocarcinoma (PCA).VEGF is expressed in all PCA tumors. VEGF-A/VEGFR-2 signaling plays an important role in inducing invasion and migration of PCA cells. The pVEGFR-2 is significantly associated with invasion of the anterior capsule of pancreas and arteries. In preclinical studies, the anti-tumor activity of fluoropyrimidines, but not that of gemcitabine, caused the release of bone marrow derived circulating endothelial progenitor cells (CEPs) and Tie-2 expressing monocytes (TEMs) as well as the induction of pro-angiogenic growth factors. Methods: This phase II randomized, multi-center, and double-blinded trial was designed to compare the efficacy and safety of mFOLFIRINOX/ramucirumab (Arm A) versus mFOLFIRINOX/ placebo (Arm B) as front-line therapy in recurrent or metastatic PCA patients. The primary endpoint was progression free survival (PFS) at 9 months, and the secondary endpoints included overall survival (OS) and response rate. Results: A total of 86 subjects were enrolled, 82 were eligible (42 in Arm A v. 40 in Arm B). The mean age of the subjects in the two arms were comparable (61.7 v. 63.0, respectively); 43 male, 69 Caucasian. On the univariate analysis, there was no difference in distribution between the 2 arms for age, gender, race and ethnicity. The median PFS was 5.6 in Arm A compared to 6.7 months in Arm B (one-sided log-rank, p = 0.322). At 9 months, the progression free rates were 25.1% v. 35% for Arms A and B, respectively. The mFOLFIRINOX/ramucirumab combination was well tolerated. Patients in Arm A reported a slightly higher number of adverse events (AEs) encounters, most commonly diarrhea (29 vs 28), fatigue (25 v. 25), vomiting (24 v. 14), weight loss (23 v. 17), and abdominal pain (20 v. 15). Arm A had more SAEs than Arm B (43 v. 25), with sepsis most commonly reported in both arms (3 in each), vomiting (3 v. 2), diarrhea (3 v.1) and duodenal obstruction (3 v. 0). Arm B had a slightly higher response rate (22.58%) compared to Arm A (17.65%) that was not statistically significant. The median OS in Arm A was 10.3 compared to 9.7 months for Arm B (one-sided log-rank, p = 0.094). Conclusions: In this randomized phase 2 study, the addition of ramucirumab to mFOLFIRINOX did not improve PFS, response rate, or OS as initial therapy for metastatic pancreatic cancer. FOLFIRINOX/Ramucirumab combination was well tolerated in the treatment of PCA. Clinical trial information: NCT02581215.