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1.
Invest New Drugs ; 39(5): 1298-1305, 2021 10.
Article in English | MEDLINE | ID: mdl-33738668

ABSTRACT

Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses >5 mg are often not tolerated when combined with other TKIs2,3. Vorolanib (X-82), an oral anti-VEGFR/platelet derived growth factor receptor (PDGFR)/colony stimulating factor 1 receptor (CSF1R) multitarget TKI, has a short half-life and limited tissue accumulation. We conducted a Phase 1 study of vorolanib with everolimus (10 mg daily) in patients with solid tumors. Methods A 3 + 3 dose escalation design was utilized to determine dose limiting toxicities (DLT) and recommended Phase 2 dose (RP2D) of vorolanib/everolimus. Oral vorolanib at 100, 150, 200, 300, or 400 mg was combined with 10 mg oral everolimus daily. The phase 2 portion was terminated after enrolling two patients due to funding. Results Eighteen patients were evaluable for DLT among 22 treated subjects. Observed DLTs were grade 3 fatigue, hypophosphatemia, and mucositis. The RP2D is vorolanib 300 mg with everolimus 10 mg daily. In 15 patients evaluable for response, three had partial response (PR; 2 RCC, 1 neuroendocrine tumor [NET]) and eight had stable disease (SD; 2 RCC, 6 NET). Conclusions Vorolanib can safely be combined with everolimus. Encouraging activity is seen in RCC and NET. Further studies are warranted. Trial Registration Number: NCT01784861.


Subject(s)
Everolimus/therapeutic use , Indoles/therapeutic use , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrroles/therapeutic use , Pyrrolidines/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dose-Response Relationship, Drug , Female , Humans , Indoles/administration & dosage , Indoles/adverse effects , MTOR Inhibitors/pharmacology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/pathology , Pyrroles/administration & dosage , Pyrroles/adverse effects , Pyrrolidines/administration & dosage , Pyrrolidines/adverse effects , Receptors, Colony-Stimulating Factor/drug effects , Receptors, Platelet-Derived Growth Factor/drug effects , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors
2.
JAMA Oncol ; 6(8): 1231-1240, 2020 08 01.
Article in English | MEDLINE | ID: mdl-32469386

ABSTRACT

Importance: Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). The combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been efficacious as first-line therapy for other gastrointestinal cancers, such as pancreatic and colon cancers. Objective: To evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma. Design, Setting, and Participants: This is an open-label, single-arm phase 2 study of first-line FOLFIRINOX in patients with advanced gastroesophageal adenocarcinoma. Estimated sample size included 41 patients with ERBB2-negative disease with 90% power to detect an ORR of 60% or greater with α of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX. Interventions: Starting doses were fluorouracil, 400 mg/m2 bolus, followed by 2400 mg/m2 over 46 hours; leucovorin, 400 mg/m2; irinotecan, 180 mg/m2; and oxaliplatin, 85 mg/m2. Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease. Main Outcomes and Measures: The primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS), and duration of response. Results: From November 2013 to May 2018, 67 patients were enrolled (median [range] age, 59.0 [34-78] years; including 56 [84%] men), and 26 of 67 (39%) had ERBB2-positive disease. Median follow-up was 17.4 months. The ORR was 61%(95% CI, 44.5%-75.8%) (25 of 41) in the ERBB2-negative group and 85% (95% CI, 65.1%-95.6%) (22 of 26) in the ERBB2-positive group, including 1 patient with complete response. For ERBB2-negative patients, median PFS was 8.4 months and median OS was 15.5 months; for ERBB2-positive patients, median PFS was 13.8 months and median OS was 19.6 months. Fifty-six patients (84%) had dose modifications or treatment delays. The most common toxic effects were neutropenia (91%, n = 61), diarrhea (63%, n = 42), peripheral sensory neuropathy (61%, n = 41), and nausea (48%, n = 32), with no unexpected toxic effects. Conclusions and Relevance: The FOLFIRINOX regimen with or without trastuzumab was associated with improved ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status. Trial Registration: ClinicalTrials.gov Identifier: NCT01928290.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/drug therapy , Stomach Neoplasms/drug therapy , Trastuzumab/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Diarrhea/chemically induced , Female , Fluorouracil/adverse effects , Fluorouracil/therapeutic use , Humans , Irinotecan/adverse effects , Irinotecan/therapeutic use , Leucovorin/adverse effects , Leucovorin/therapeutic use , Male , Middle Aged , Nausea/chemically induced , Neutropenia/chemically induced , Oxaliplatin/adverse effects , Oxaliplatin/therapeutic use , Peripheral Nervous System Diseases/chemically induced , Trastuzumab/adverse effects , Treatment Outcome
3.
J Patient Saf ; 16(3): e179-e181, 2020 09.
Article in English | MEDLINE | ID: mdl-28594650

ABSTRACT

OBJECTIVE: Because internal medicine hospitalist programs were developed to address issues in medicine such as a need to improve quality, improve efficiency, and decrease healthcare cost, obstetrical (OB) hospitalist models were developed to address needs specific to the obstetrics and gynecology field. Our objective was to compare outcomes measured by occurrence of safety events before and after implementation of an OB hospitalist program in a mid-sized OB unit. METHODS: From July 2012 to September 2014, 11 safety events occurred on the labor and delivery floor. A full-time OB hospitalist program was implemented in October 2014. RESULTS: From October 2014 to December 2016, there was 1 safety event associated with labor and delivery. CONCLUSION: It has been speculated that implementation of an OB hospitalist model would be associated with improved maternal and neonatal outcomes; our regional OB referral hospital demonstrated a statistically significant decrease in OB safety events after the OB hospitalist program implementation.


Subject(s)
Hospitalists/standards , Hospitals/standards , Obstetrics/standards , Patient Safety/standards , Female , Humans , Pregnancy
4.
J Natl Compr Canc Netw ; 16(10): 1193-1199, 2018 10.
Article in English | MEDLINE | ID: mdl-30323089

ABSTRACT

Background: Combined hepatocellular-cholangiocarcinoma tumors (cHCC-CCA) are a heterogeneous group of rare malignancies that have no established optimal treatment. Patients and Methods: We identified patients with cHCC-CCA treated at a tertiary center and retrospectively examined their histology, interventions, and outcomes. We calculated disease control rate (DCR), disease progression, overall survival, and progression-free survival (PFS) between treatment subgroups. Results: A total of 123 patients were evaluable. Interventions included resection, locoregional therapy, transplant, chemotherapy, and targeted agents. Ultimately, 68 patients received systemic treatment-57 with gemcitabine plus either 5-fluoropyrimidine (5-FU) or a platinum combination. Disease progression was more common in the gemcitabine/5-FU group versus gemcitabine/platinum (P=.028), whereas DCR favored gemcitabine/platinum (78.4% vs 38.5%; P=.0143). Median PFS from time of initial diagnosis favored the gemcitabine/platinum group, but the difference did not reach statistical significance. Targeted agents had minimal to no effect on survival metrics. Conclusions: Gemcitabine/platinum seems to be a superior regimen for patients with cHCC-CCA who require systemic treatment. Further studies are needed to clarify the regimen's efficacy and applicability in patient subgroups.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bile Duct Neoplasms/therapy , Carcinoma, Hepatocellular/therapy , Cholangiocarcinoma/therapy , Liver Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Bile Duct Neoplasms/complications , Bile Duct Neoplasms/mortality , Bile Duct Neoplasms/pathology , Bile Ducts/pathology , Bile Ducts/surgery , Carcinoma, Hepatocellular/complications , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Chemotherapy, Adjuvant/methods , Cholangiocarcinoma/complications , Cholangiocarcinoma/mortality , Cholangiocarcinoma/pathology , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Disease Progression , Female , Hepatectomy , Humans , Liver/pathology , Liver/surgery , Liver Neoplasms/complications , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Neoadjuvant Therapy/methods , Organoplatinum Compounds/therapeutic use , Progression-Free Survival , Response Evaluation Criteria in Solid Tumors , Retrospective Studies , Young Adult , Gemcitabine
5.
HPB (Oxford) ; 19(2): 133-139, 2017 02.
Article in English | MEDLINE | ID: mdl-27916436

ABSTRACT

BACKGROUND & OBJECTIVES: Multidisciplinary tumor boards (MDTBs) are frequently employed in cancer centers but their value has been debated. We reviewed the decision-making process and resource utilization of our MDTB to assess its utility in the management of pancreatic and upper gastrointestinal tract conditions. METHODS: A prospectively-collected database was reviewed over a 12-month period. The primary outcome was change in management plan as a result of case discussion. Secondary outcomes included resources required to hold MDTB, survival, and adherence to treatment guidelines. RESULTS: Four hundred seventy cases were reviewed. MDTB resulted in a change in the proposed plan of management in 101 of 402 evaluable cases (25.1%). New plans favored obtaining additional diagnostic workup. No recorded variables were associated with a change in plan. For newly-diagnosed cases of pancreatic ductal adenocarcinoma (n = 33), survival time was not impacted by MDTB (p = .154) and adherence to National Comprehensive Cancer Network guidelines was 100%. The estimated cost of physician time per case reviewed was $190. CONCLUSIONS: Our MDTB influences treatment decisions in a sizeable number of cases with excellent adherence to national guidelines. However, this requires significant time expenditure and may not impact outcomes. Regular assessments of the effectiveness of MDTBs should be undertaken.


Subject(s)
Carcinoma, Pancreatic Ductal/therapy , Clinical Decision-Making , Delivery of Health Care, Integrated/statistics & numerical data , Gastrointestinal Neoplasms/therapy , Health Resources/statistics & numerical data , Interdisciplinary Communication , Pancreatic Neoplasms/therapy , Patient Care Team/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/economics , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/pathology , Databases, Factual , Delivery of Health Care, Integrated/economics , Delivery of Health Care, Integrated/standards , Female , Gastrointestinal Neoplasms/economics , Gastrointestinal Neoplasms/mortality , Gastrointestinal Neoplasms/pathology , Guideline Adherence , Health Care Costs , Health Resources/economics , Health Resources/standards , Humans , Male , Middle Aged , Pancreatic Neoplasms/economics , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Patient Care Team/economics , Patient Care Team/standards , Practice Guidelines as Topic , Treatment Outcome , Young Adult
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