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AbGn-107 is an antibody-drug conjugate directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in a variety of gastrointestinal (GI) malignancies. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a GI cancer-specific Phase I trial. Standard 3 + 3 dose escalation was used evaluating intravenous doses ranging from 0.1 mg/kg every 4 weeks to 1.0 mg/kg every 2 weeks. Key eligibility included chemo-refractory locally advanced, recurrent, or metastatic gastric, colorectal, pancreatic, or biliary cancer, with ECOG PS 0-1; positive AG-7 expression was not required during dose escalation phase. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments every 8 weeks. Primary objectives included safety and determination of maximum tolerated dose; secondary objectives included efficacy defined by objective response rate. Thirty-nine patients were enrolled across seven dose levels during dose escalation phase. Based on safety profile and pharmacokinetic data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase, in which an additional seven patients were enrolled. Median number of lines of prior therapy was 3 (range 1-7). AbGn-107 was generally well-tolerated, with infections, cytopenias, hyponatremia, fatigue, abdominal pain, and diarrhea representing the most common grade 3 or higher treatment-emergent adverse events. One subject achieved a partial response, while 18 (46.2%) achieved a best response of stable disease. Disease control lasting > 6 months was observed in 6 subjects (13.0%), including 4 of 15 (26.7%) treated at the highest dose level. AbGn-107 showed a reasonable safety profile and modest clinical activity in this highly pretreated patient population. Further evaluation is required to assess the clinical validity of AG-7 as a suitable antigen for therapeutic targeting. Clinical Trial information: NCT02908451., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations. Methods This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results Twelve patients were enrolled prior to early termination of the trial. Partial responses were observed in 1 from 12 patients. Median PFS was 2.4 months and median OS was 15.7 months. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed. Conclusions Ponatinib as a single agent in FGFR altered BTC is tolerable with limited clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Mixed adeno-neuroendocrine carcinoma (MANEC) is a rare pathologic diagnosis recently defined by the World Health Organization in 2010. Due to poor understanding of MANEC as a clinical entity, there is significant variation in the management of these patients. The purpose of our study was to characterize MANEC to develop evidence-based treatment strategies., Methods: The Ohio State University patient database was queried for the diagnosis of MANEC and 46 patients were identified. For comparison, the database also was queried for goblet cell carcinoid (GCC) of the appendix, signet ring cell carcinoma, and carcinoid/neuroendocrine tumor of the appendix. Charts were then retrospectively reviewed for clinicopathologic characteristics, patient treatment, and survival data., Results: The mean age of diagnosis of MANEC was 54 years. Eighty-seven percent of MANEC arose from the appendix, with 28 % of patients undergoing appendectomy and 35 % undergoing right hemicolectomy as their index operation. Immunohistochemical staining was positive for chromogranin (82 %), synaptophysin (97 %), and CD56 (67 %). Sixty-seven percent of patients presented with stage IV disease and 41 % had nodal metastases. Overall survival was 4.1 years, which was statistically significantly different (p ≤ 0.05) compared with carcinoid tumors (13.4 years), GCC (15.4 years), and signet ring carcinoma (2.2 years)., Conclusions: MANEC is a more aggressive clinical entity than both GCC of the appendix and carcinoid/neuroendocrine tumors of the appendix. Based on these findings, we recommend patients with MANEC tumors undergo aggressive multidisciplinary cancer management and close surveillance.

Multiple chemotherapy regimens are available for the treatment of metastatic pancreas cancer (mPCA). Choice of regimen is based on the patient's performance status and toxicity profile of the regimen. The objective of this study was to analyze the costs of first-line regimens to further aid in decision-making and develop a platform upon which to assess value. We calculated the monthly cost for individual standard regimens (gemcitabine, gemcitabine/nab-paclitaxel, gemcitabine/erlotinib and FOLFIRINOX) and the overall treatment cost for a course of therapy based on the median progression-free survival achieved in published studies. In addition to cost of drugs, we included administration costs and costs of toxicities (including growth factor support, blood product transfusion and hospitalization for toxicities). Costs for administration and management of adverse events were based on Medicare reimbursement rates for hospital and physician services. Drug costs were based on Medicare average sale prices (all 2014 US$). The monthly costs for gemcitabine, FOLFIRINOX, gemcitabine/erlotinib and gemcitabine/nab-paclitaxel were $1363, $7234, $8007 and $12,221, respectively. The overall treatment costs for a course of the same regimens based on median PFS were $5043, $46,298, $51,004 and $67,216, respectively. The choice of chemotherapy regimen for mPCA should be based on tolerability and efficacy of the regimen individualized to patient's performance status. Healthcare systems have finite resources; thus, there is increasing emphasis on metrics to define value in health care when outcomes of therapy are similar or produce marked differences in value. These data provide useful financial information to incorporate into the decision-making process.

Pancreatic adenocarcinoma is the fourth leading cause of cancer death. Recently, MM-398 (nanoliposomal irinotecan) was shown to be associated with significant improvement in outcome measures with acceptable toxicities when combined with 5-fluorouracil (5-FU)/leucovorin (LV) compared to 5-FU/LV alone in patients failing one line of gemcitabine-based therapy. There is a paucity of data evaluating the role of irinotecan in combination with 5FU in advanced pancreas cancer (APC). We performed a retrospective analysis of all patients who received mFOLFIRI (minus bolus 5FU and LV). All patients with metastatic disease who had failed at least one line of gemcitabine-based therapy prior to receiving mFOLFIRI were included in this study. Descriptive statistics were used to assess the continuous variables and adverse events (AEs), and Kaplan-Meier methods were used to calculate the median progression-free survival (PFS) and overall survival (OS). Forty patients were included in this analysis. Patients received 1-5 lines of prior therapy (25 % with more than 3 lines of prior therapy). The mean age at diagnosis was 60, and 98 % had ECOG of 1. The mean CA 19-9 at the start of therapy was 33,169 U/ml. The median PFS was 2.59 months [95 % confidence interval (CI) (1.90, 3.54)], and OS was 4.75 months [95 % CI (3.14, 8.98)]. The most common AEs included fatigue (98 %), neuropathy (83 %), anorexia (68 %), nausea (60 %) and constipation (55 %). Grade 3 toxicities included fatigue (13 %) and rash (3 %). There were no observed grade 4 toxicities. In this single-institution retrospective analysis, mFOLFIRI was found to be both tolerable and relatively effective in a heavily pretreated patient population with APC. Future prospective studies should consider evaluating the role of mFOLFIRI in refractory APC.

Gemcitabine in combination with low-dose cisplatin has shown promising activity in pancreatic cancer with manageable toxicities. The purpose of this study is to assess the activity of a combination of gemcitabine and low-dose cisplatin in the first-line treatment of metastatic and locally advanced pancreatic cancer patients. We conducted a retrospective analysis of all patients diagnosed with metastatic and locally advanced pancreatic cancer who received a combination of gemcitabine and cisplatin in the first-line setting. Patients with baseline cytopenias and elevated liver function tests were included. Patients received cisplatin at 20 mg per square meter followed by gemcitabine at a dose of 1000 mg per square meter at fixed dose rate every 2 weeks. Patients were treated until disease progression or unacceptable toxicities. A total of 58 patients were included in the analysis. The median progression-free survival was 4.4 months [95 % confidence interval (CI) 3.6-6.4], and median overall survival was 6.7 months (95 % CI 4.4-10.9). Thirty-eight patients (66 %) experienced at least one grade 3 or 4 toxicity. The most common grade 3 or 4 toxicity was hematologic toxicity (25 patients, 43 %). Biweekly fixed dose rate gemcitabine combined with low-dose cisplatin shows interesting activity in advanced pancreatic cancer. This regimen is an acceptable alternative for patients ineligible for gemcitabine plus nab-paclitaxel (i.e., those with elevated bilirubin at baseline) or clinical trials. Additionally, this regimen should be considered as a first-line option for those patients with breast cancer susceptibility gene mutations (BRCA1 and/or BRCA2).

Background: For patients with metastatic pancreatic cancer, FOLFIRINOX (fluorouracil [5-FU], leucovorin [LV], irinotecan [IRI], and oxaliplatin) has shown improved survival rates compared with gemcitabine but with significant toxicity, particularly in patients with a high tumor burden. Because of reported response rates exceeding 30 %, the authors began to use a modified (m) FOLFIRINOX regimen for patients with advanced nonmetastatic disease aimed at downstaging for resection. This report describes their experience with mFOLFIRINOX and aggressive surgical resection., Methods: Between January 2011 and August of 2013, 43 patients with borderline resectable pancreatic cancer (BRPC, n = 18) or locally advanced pancreatic cancer (LAPC, n = 25) were treated with mFOLFIRINOX (no bolus 5-FU, no LV, and decreased IRI). Radiation was used based on response and intended surgery. Charts were retrospectively reviewed to assess response, toxicities, and extent of resection when possible., Results: The most common grade 3/4 toxicity was diarrhea in six patients (14 %) with no grade 3/4 neutropenia or thrombocytopenia. Resection was attempted in 31 cases (72 %) and accomplished in 22 cases (51.1 %) including 11 of 25 LAPC cases (44 %). Vascular resection was required in 4 cases (18 %), with R0 resection in 86.4 % of the resections. Complications occurred in 6 cases (27 %), with no perioperative deaths. The median progression-free survival period was 18 months if the resection was achieved compared with 8 months if no resection was performed (p < 0.001)., Conclusion: Neoadjuvant mFOLFIRINOX is an effective, well-tolerated regimen for patients with advanced nonmetastatic pancreatic cancer. When mFOLFIRINOX is coupled with aggressive surgery, high resection rates are possible even when the initial imaging shows locally advanced disease. Although data are still maturing, resection appears to offer at least a progression-free survival advantage.

Background: Pancreas cancer is highly lethal even at early stages. Adjuvant therapy with chemotherapy (CT) or chemoradiation (CRT) is standard following surgery to delay recurrence and improve survival. There is no consensus on the added value of radiotherapy (RT). We conducted a retrospective analysis of clinical outcomes in pancreas cancer patients treated with CT or CRT following surgery., Methods: Patients with resected pancreas adenocarcinoma were identified in our institutional database. Relevant clinicopathologic and demographic data were collected. Patients were grouped according to adjuvant treatment: group A: no treatment; group B: CT; group C: CRT. The primary endpoint of overall survival was compared between groups B vs. C. Univariate and multivariate analyses of potential prognostic factors were conducted including all patients., Results: A total of 146 evaluable patients were included (group A: n = 33; group B: n = 45; group C: n = 68). Demographics and pathologic characteristics were comparable. There was no significant survival benefit for CRT compared with CT (mOS 16.8 months vs. 21.5 months, respectively, p = 0.76). Local recurrence rates were similar in all three groups. Univariate analyses identified absence of lymph node involvement (hazards ratio [HR] 1.43, p = 0.0082) and administration of adjuvant therapy (HR 0.496, p = 0.0008) as significant predictors for improved survival. Multivariate analyses suggested that patients without nodal involvement derived the most benefit from adjuvant treatment., Conclusions: The addition of RT to CT did not improve survival over CT. Lymph node involvement predicts inferior clinical outcome.

Purpose: Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance., Patients and Methods: This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3 + 3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity., Results: Six of the thirteen patients (46 %) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (n = 6), mucositis or stomatitis (n = 5), and diarrhea (n = 2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54 %) were evaluable for response. The objective response rate was 14 %: one patient had a partial response lasting 6 months. Two patients had stable disease (29 %), and four had progressive disease (57 %). Median progression free survival was 2.1 months (95 % CI, 1.5-4.9) and median overall survival was 3.7 months (95 % CI, 1.6-7.9)., Conclusion: Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.

Purpose: Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G., Experimental Design: Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m(2) over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured., Results: Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m(2) (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome., Conclusions: This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.

Background: Hereditary diffuse gastric cancer (HDGC) represents a minority of gastric cancer (GC) cases. The goal of this study is to use a RAND/University of California Los Angeles (UCLA) appropriateness methodology to examine indications for genetic referral, CDH1 testing, and consideration of prophylactic total gastrectomy (PTG)., Methods: A multidisciplinary expert panel of 16 physicians from six countries scored 47 scenarios. Appropriateness of scenarios was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores (AS) of 1-3 were considered inappropriate, 4-6 uncertain, and 7-9 appropriate. Agreement was reached when 12 of 16 panelists scored the statement similarly. Appropriate scenarios agreed upon were subsequently scored for necessity., Results: The panel felt that patients with family history of diffuse gastric cancer (DGC), lobular breast cancer, or multiple family members with GC should be referred for genetic assessment and multidisciplinary decision-making. The panel felt that it is appropriate for patients with DGC to have CDH1 mutation testing in a family with (1) ≥2 cases of GC, with at least one case of DGC diagnosed before age of 50 years; (2) ≥3 cases of GC diagnosed at any age, one or more of which is DGC; (3) a patient diagnosed with DGC and lobular breast carcinoma; or (4) patients diagnosed with DGC under age of 35 years. The panel felt that PTG should be offered to CDH1 mutation carriers 20 years or older., Conclusions: Identification of genetic mutations in patients at risk for hereditary GC is important, and criteria for testing are suggested.

CA19-9 is the most specific biomarker for pancreas cancer. We investigated the prognostic significance of normal (≤ 37 U/mL) versus elevated (>37 U/mL) CA19-9 levels in patients with resected and advanced pancreas cancer. Relevant data were obtained from patients treated for early-stage or advanced pancreatic adenocarcinoma at our institution. Log-rank tests were used to evaluate relationship between CA19-9 and clinical outcomes of interest for both early- and advanced-stage patients. A total of 123 patients were included (Group A: N = 30 stage I/II; Group B: N = 93 stage III/IV). In group A, elevated preoperative CA19-9 was significantly associated with lymph node involvement (p = 0.031), tumor ≥ 3 cm (p = 0.011), and lack of tumor differentiation (p = 0.048). Failure of postoperative CA19-9 to normalize predicted significantly worse DFS (p = 0.021). For group B, elevated baseline CA19-9 was associated with shorter OS on chemotherapy (p = 0.0008) and decline in CA19-9 >25 % with treatment was a significant predictor of improved OS (p = 0.0099). Higher than normal CA19-9 level is an adverse prognostic factor in both early and advanced settings and may prove to be useful in the selection of patients for more aggressive therapy in future trials. CA19-9 level decrease of >25 % predicts improved survival in advanced disease on chemotherapy.

Purpose: Based on the promising activity and tolerability of flavopiridol administered with a pharmacokinetically-derived dosing schedule in chronic lymphocytic leukemia (CLL), we conducted a phase I study using this schedule in patients with advanced solid tumors., Experimental Design: Flavopiridol was given IV as a 30-min loading dose followed by a 4-hr infusion weekly for 4 weeks repeated every 6 weeks. Dose-escalation was in cohorts of three patients using the standard 3+3 phase I study design. Blood samples were obtained for pharmacokinetic and pharmacodynamic studies., Results: Thirty-four eligible patients with advanced solid tumors received a total of 208 doses (median 7, range 1-24). Total doses ranged from 40 to 105 mg/m(2). The primary dose limiting toxicity was cytokine release syndrome (CKRS). No antitumor responses were observed. The mean peak plasma concentration across all doses was 1.65 ± 0.86 μM. Area under the concentration-versus-time curve ([Formula: see text]) ranged from 4.31 to 32.2 μM[Symbol: see text]hr with an overall mean of 13.6 ± 7.0 μM[Symbol: see text]hr. Plasma flavopiridol concentrations and AUC increased proportionally with dose. There was no correlation between cytokine levels and clinical outcomes., Conclusions: The maximum-tolerated dose of flavopiridol is 20 mg/m(2) bolus followed by 20 mg/m(2) infusion over 4 h given weekly for 4 weeks on a 6-week cycle in patients with advanced solid tumors. Flavopiridol PK was notably different, and there was a higher frequency of CKRS, despite prophylactic steroids, seen in this patient group compared to previous studies with CLL using a similar dosing schedule.

Purpose: Gemcitabine and topotecan are commonly used anti-tumor agents with a wide spectrum of activity in vitro and in vivo. A phase I trial of a combination of these two agents was initiated based on the premise that both gemcitabine and topotecan cause DNA damage and interfere with DNA repair by different mechanisms. Synergism has been demonstrated in vitro when gemcitabine and other topoisomerase I inhibitors have been combined., Patients and Methods: Seventeen patients with advanced solid tumors signed consent and were treated on this study with at least one cycle. Treatment consisted of gemcitabine at doses of 400 to 625 mg/m(2) days 1 and 5 in combination with topotecan at doses of 0.8 to 1 mg/m(2) given on days 2 through 5 every 21 days., Results: The dose limiting toxicities of granulocytopenia and thrombocytopenia were reached at the highest dose level of gemcitabine 625 mg/m(2) and topotecan 1 mg/m(2). A diffuse skin rash was also seen in four treated patients and responded well to treatment with steroids. One partial response and seven stable disease were seen as best response in 16 evaluable patients., Conclusion: The combination of gemcitabine and topotecan was found to be tolerable with interesting preliminary activity. The recommended phase II dose for this combination is gemcitabine at 500 mg/m(2) on days 1 and 5 with topotecan at 0.8 mg/m(2) on days 2 to 5.

Purpose: Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases 1 and 2. We conducted a phase II clinical study to determine the efficacy and toxicities of PZA in patients with metastatic breast cancer (MBC)., Experimental Design: In this phase II multicenter study, patients who were treated with no more than one prior chemotherapy for MBC were treated with 750 mg/m² of PZA given as a 3-hour intravenous infusion every 3 weeks. Treatment cycles were continued until disease progression or unacceptable toxicities. The study was designed to distinguish between a response rate of < 15% vs > 30% (alpha = 0.10, beta = 0.10) using Simons optimal 2-stage design. At least 2 responses were required in the first 12 patients in the 1st stage and 6 of 35 in the 2nd stage to recommend the agent for further study., Results: Two patients in the first stage had a response allowing accrual to second stage. A total of 15 patients (out of 35 planned) were treated on the study prior to premature closure. Three patients had a partial response (20%) lasting 4.5-6 months. Two patients had stable disease for 3 and 5 months. The dose limiting toxicity was granulocytopenia with ten patients requiring dose reduction or dose delay for grade 4 neutropenia. Other grade 3 and 4 toxicities include vomiting (n = 2), nausea (n = 2), neurotoxicity (n = 1), fatigue (n = 1), anemia (n = 1), dyspnea 9n = 1) and renal (n = 1)., Conclusions: Pyrazoloacridine demonstrated modest activity in patients with metastatic breast cancer.