Phase Ib Study of Ulixertinib Plus Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Adenocarcinoma.

BACKGROUND: Ulixertinib is a novel oral ERK inhibitor that has shown promising single-agent activity in a phase I clinical trial that included patients with RAS-mutant cancers. METHODS: We conducted a phase Ib trial combining ulixertinib with gemcitabine and nab-paclitaxel (GnP) for untreated metastatic pancreatic adenocarcinoma. The trial comprised a dose de-escalation part and a cohort expansion part at the recommended phase II dose (RP2D). Primary endpoint was to determine the RP2D of ulixertinib plus GnP and secondary endpoints were to assess toxicity and safety profile, biochemical and radiographic response, progression-free survival (PFS) and overall survival (OS). RESULTS: Eighteen patients were enrolled. Ulixertinib 600 mg PO twice daily (BID) with GnP was initially administered but was de-escalated to 450 mg BID as RP2D early during dose expansion due to poor tolerability, which ultimately led to premature termination of the study. Common treatment-related adverse events (TRAEs) were anemia, thrombocytopenia, rash and diarrhea. For 5 response evaluable patients, one patient achieved a partial response and 2 patients achieved stable disease. For 15 patients who received the triplet, median PFS and OS were 5.46 and 12.23 months, respectively. CONCLUSION: Ulixertinib plus GnP had similar frequency of grade ≥3 TRAEs and potentially efficacy as GnP, however was complicated by a high rate of all-grade TRAEs (ClinicalTrials.gov Identifier: NCT02608229).

First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors.

BACKGROUND: CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal antibody, alone or with durvalumab in patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC). METHODS: Patients received oleclumab 5-40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W. RESULTS: 192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy and combination therapy escalation cohorts, treatment-related adverse events (TRAEs) occurred in 55 and 54%, respectively, the most common being fatigue (17 and 25%). In the CRC, PDAC, and NSCLC expansion cohorts, 60, 57, and 45% of patients had TRAEs, respectively; the most common were fatigue (15%), diarrhea (9%), and rash (7%). Free soluble CD73 and CD73 expression on peripheral T cells and tumor cells showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumor cells. Objective response rate during escalation was 0%. Response rates in the CRC, PDAC, and NSCLC expansion cohorts were 2.4% (1 complete response [CR]), 4.8% (1 CR, 1 partial response [PR]), and 9.5% (4 PRs), respectively; 6-month progression-free survival rates were 5.4, 13.2, and 16.0%. CONCLUSIONS: Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab's mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT02503774; date of registration, July 17, 2015.

The relationship between response style and symptom reporting in cancer patients.

PURPOSE: Patient-reported outcomes are considered the gold standard for documenting treatment-related toxicities and cancer-related symptoms in the management of oncology patients. Poor concordance between patients and health care professionals (HCPs) on patients' symptoms has been documented. The purpose of this study is to examine the association between social desirability, a response style, and symptom reporting in a colorectal cancer clinic. METHODS: Patients being treated for colorectal cancer completed a social desirability measure and a symptom measure before their appointment in the oncology clinic. The HCP who saw the patient completed a symptom measure for the patient after the clinic visit. RESULTS: One hundred sixty-nine patients consented to participate in the study. The majority of the patients had stage 4 disease. There was a statistically significant positive correlation between social desirability and overall reported symptom burden. There was a statistically significant negative correlation between social desirability and concordance between the patient and the HCP on the patient's symptoms. Social desirability scores were stable over the course of 1 year. CONCLUSION: Sensitivity to social desirability effects seems to play an important role in patient self-report of symptoms. As social desirability is a stable quality, patients sensitive to it may be persistently at risk for undertreatment of symptoms due to limited symptom reporting.

Myocardial uptake of 68Ga-DOTATATE: correlation with cardiac disease and risk factors.

BACKGROUND: Myocardial uptake on 68Ga-DOTATATE PET/CT is often observed and its clinical relevance is poorly understood. PURPOSE: To detect any correlation between myocardial uptake of 68Ga-DOTATATE and presence of cardiac disease or risk factors. MATERIAL AND METHODS: In this institutional review board-approved retrospective study, we reviewed 68Ga-DOTATATE PET/CT scans in our institution between 1 May 2018 and 30 September 2018. A semi-quantitative score (MUS) for myocardial uptake of 68Ga-DOTATATE was developed by measuring mean standardized uptake value (SUV) in five myocardial regions, corrected by blood pool activity, and MUS was validated between two readers. We investigated the relationship between MUS and presence of cardiac disease or risk factors, including Framingham score and coronary calcification. RESULTS: A total of 145 scans were included (79 women; mean age = 56.9 ± 13.7 years). Inter-reader agreement was excellent with intraclass correlation coefficient (r) = 0.964 (95% confidence interval [CI] = 0.903-0.987; P < 0.001). There was a weak but significant positive correlation between MUS and presence of coronary calcifications (Spearman rho = 0.20; P = 0.016). MUS was higher in patients with heart disease or risk factors (n = 83, mean MUS 2.03, 95% CI = 1.85-2.21) compared to those without (n = 23, mean MUS 1.40, 95% CI = 1.17-1.62; P < 0.001), although the cardiac disease group was older with a higher percentage of men (62.0 years, 57.8% men compared to 47.6 years, 13.0% men; P value <0.0001 for both comparisons). CONCLUSION: For patients undergoing 68Ga-DOTATATE PET/CT scan, an elevated MUS might indicate an underlying heart disease.

Effect of metastatic site on survival in patients with neuroendocrine neoplasms (NENs). An analysis of SEER data from 2010 to 2014.

BACKGROUND: Neuroendocrine neoplasms (NENs) display variable behaviors based on origin and grade. We assumed that both tumor origin and the location of metastasis may play a role in survival. METHODS: We queried the SEER database (2010-2014) for patients with an established diagnosis of NENs and documented site of metastasis and identified 2005 patients. Overall survival (OS) at the time points were estimated by the Kaplan-Meier method Cox proportional-hazards models were used to evaluate the relationship of the interested variables and OS. RESULTS: Lung, liver, bone and brain metastases were observed in 9, 77, 7 and 6% of metastatic patients respectively. In the multivariate model, metastasis locations were significantly associated with worse survival (liver HR: 1.677 (1.226-2.294); (bone metastasis HR: 1.412 (0.965-2.065); brain HR: 1.666 (1.177-2.357)). We produced a scoring system based on site of origin, metastasis location, age, gender, histology and tumor size that can stratify metastatic NEN patients in low, intermediate and high-risk categories to help physicians with decision making. CONCLUSION: Site of metastasis plays an important role in survival of metastatic NEN patients independent of commonly described prognostic factors and should be considered in survival estimates.

Systemic Therapy for Combined Hepatocellular-Cholangiocarcinoma: A Single-Institution Experience.

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.

Phase 2 study of combination SPI-1620 with docetaxel as second-line advanced biliary tract cancer treatment.

BACKGROUND: This multicentre, open-label study evaluated the efficacy and safety of SPI-1620, an analogue of endothelin-1, administered in combination with docetaxel as second-line treatment for patients with advanced biliary tract cancer (ABTC). METHODS: Eligible patients received continuous cycles of combination therapy with SPI-1620 (11 µg m-2) and docetaxel (75 mg m-2) intravenously every 3 weeks until disease progression (PD) or intolerable toxicity. Tumour response was evaluated using computed tomography or magnetic resonance imaging every 2 cycles (6 weeks). The primary efficacy end point was progression-free survival (PFS); secondary end points included overall response rate (ORR), duration of response, and overall survival (OS) that were estimated using the Kaplan-Meier method. RESULTS: Of the 30 enrolled patients, 25 patients had qualifying events (PD or death), 1 patient was nonevaluable, and 4 patients were censored at the time of their last tumour assessment. Our primary end point of PFS ⩾5 months was not reached. Median PFS was 2.6 months (95% confidence interval (CI): 1.4-2.8), ranging from 0.7 to 8.4 months. The ORR was 10.3% (95% CI: 0.02-0.27). Eleven additional patients achieved stable disease. The OS was 4.87 months. The most common grade 3-4 toxicities were febrile neutropenia and neutropenia. CONCLUSIONS: The addition of docetaxel to SPI-1620 in second-line ABTC did not meet the pre-specified primary end point of PFS ⩾5 months in unselected patient population.

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors.

BACKGROUND: MK-5108 is a potent/highly selective Aurora A kinase inhibitor. METHODS: A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m(2), determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. RESULTS: 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). CONCLUSIONS: MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 µM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.

Biphenotypic Primary Liver Carcinomas: Assessing Outcomes of Hepatic Directed Therapy.

BACKGROUND: Primary liver carcinomas with hepatocellular and cholangiocellular differentiation (b[HB]-PLC) are rare. Surgery offers the best prognosis, but there is a paucity of literature to guide therapy for patients with advanced or unresectable disease. This study aimed to evaluate outcomes of hepatic-directed therapy compared with those of systemic chemotherapy and surgery. METHODS: A retrospective evaluation of patients with b(HB)-PLC from 1 January 2008 to 1 September 2014 was conducted. The patients were divided into the following four groups: transplantation (TX) group, surgical resection (SX) group, hepatic directed (HD) group, and systemic chemotherapy alone (SC) group. Overall and progression-free survival, treatment response, and clinicopathologic data were analyzed. RESULTS: The study included 79 patients (37 females) with an average age of 62 years. The number of patients in each group were as follows: TX group (n = 6), SX group (n = 27), HD group (n = 18), and SC group (n = 28). The mean follow-up periods were 33 months for the TX group, 17 months for the SX group, 14 months for the HD group, and 7 months for the SX group. Overall, 28 % of the patients had cirrhosis and 35 % had viral hepatitis. The candidates for surgery comprised 42 % of the patients. The HD group (n = 18) had a significantly greater objective response than the SC group (n = 28) (47 vs. 6 %; p = 0.02). Two patients who underwent hepatic arterial infusion pump treatment were downstaged to resection. A trend toward improved OS/PFS was observed in the HD group versus the SC group, although statistically significant. The SX group had significantly improved survival (p < 0.001) as did the transplanted patients. CONCLUSIONS: Although surgery offers the best survival for b(HB)-PLC patients, only a minority are candidates for surgery. Because HD therapy showed a superior objective response over SC therapy, it may offer a survival advantage and may downstage patients for surgical resection or transplantation.

Complete Response to Erlotinib and Bevacizumab in a Patient With Biphenotypic (Hepatobiliary) Primary Liver Carcinoma.

Biphenotypic (hepatobiliary) primary liver carcinomas [B(H-B)PLCs] are rare tumors with features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). These tumors are associated with a poor overall prognosis and treatment is not well defined. Research over the past 20 years has identified aberrations in several molecular pathways, including epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) in hepatocellular and biliary tract cancers. These discoveries led to the evaluation of targeted therapies, such as tyrosine kinase inhibitors, for the treatment of HCC and ICC. We report a case of a patient with metastatic B(H-B)PLC found to have a single nucleotide variant in the EGFR gene locus R521K who achieved a complete response on imaging after treatment with the combination of an EGFR inhibitor and a VEGF inhibitor. This case prompts consideration of further genomic analysis of these rare tumors and the potential use of targeted therapies in the treatment of patients with B(H-B)PLCs.

Surveillance With Serial Imaging and CA 19-9 Tumor Marker Testing After Resection of Pancreatic Cancer: A Single-Center Retrospective Study.

OBJECTIVES: Most patients receiving curative-intent surgery for pancreatic cancer will experience cancer recurrence. However, evidence that postoperative surveillance testing improves survival or quality of life is lacking. We evaluated the use and characteristics of surveillance with serial imaging and CA 19-9 tumor marker testing at an NCI-designated comprehensive cancer center. METHODS: We conducted a retrospective cohort study of patients who entered surveillance after curative-intent resection of pancreatic adenocarcinoma. We abstracted information from the electronic medical record about oncology office visits, surveillance testing (cross-sectional imaging and CA 19-9 tumor marker testing), and pancreatic cancer recurrence, with follow-up through 2 years after pancreatectomy. We conducted analyses to describe the use of surveillance testing and to characterize the sensitivity and specificity of CA 19-9 tumor marker testing for the identification of cancer recurrence. RESULTS: We identified 90 patients entering surveillance after pancreatectomy. CA 19-9 was the most frequently used surveillance test, followed by CT imaging. Forty-seven patients (52.2%) experienced recurrence within two years of pancreatectomy. Recurrence risk was 58.8% versus 31.8% in patients with elevated versus normal CA 19-9 at diagnosis ( P =0.03). Elevated CA 19-9 at any point during surveillance was significantly associated with 2-year recurrence risk ( P <0.001). Elevated CA 19-9 had a sensitivity of 83% (95% CI 0.72-0.95) and specificity of 87% (0.76-0.98) for identification of recurrence within 2 years of pancreatectomy. CONCLUSIONS: CA 19-9 demonstrates clinical validity for identifying recurrence of pancreatic cancer during surveillance. Surveillance approaches with reduced reliance on imaging should be prospectively evaluated.

Immunotherapy in Anal Cancer.

The incidence and mortality of squamous cell carcinoma of the anus has been gradually increasing globally over the last few decades. The evolution of different modalities, including immunotherapies, has changed the treatment paradigm of metastatic anal cancers. Chemotherapy, radiation therapy, and immune-modulating therapies form the backbone of treatment of anal cancer in various stages. Most anal cancers are linked to high-risk human papilloma virus (HPV) infections. HPV oncoproteins E6 and E7 are responsible for an anti-tumor immune response triggering the recruitment of tumor-infiltrating lymphocytes. This has led to the development and utilization of immunotherapy in anal cancers. Current research in anal cancer is moving forward to discover ways to incorporate immunotherapy in the treatment sequencing in various stages of anal cancers. Immune checkpoint inhibitors alone or in combination, adoptive cell therapy, and vaccines are the areas of active investigations in anal cancer in both locally advanced and metastatic settings. Immunomodulating properties of non-immunotherapies are incorporated to enhance immune checkpoint inhibitors' effectiveness in some of the clinical trials. The aim of this review is to summarize the potential role of immunotherapy in anal squamous cell cancers and future directions.

Genomic profile of Pancoast syndrome due to hepatocellular carcinoma: A case report.

Hepatocellular carcinoma (HCC) is a common cancer and is frequently diagnosed at a late and unresectable stage with limited effective treatment options. Here, we present the fifth reported case of a 77 year-old male with metastatic HCC presenting as a symptomatic superior sulcus lung tumor and discuss the genomic profile of this rare presentation of HCC for the first time, which included multiple classic mutations in HCC such as TERT, TP53, and WNT/ß-catenin signaling as well as in the DNA repair gene ATM. The patient was treated with palliative radiotherapy to the Pancoast tumor followed by atezolizumab plus bevacizumab and passed away 6 months after diagnosis. This rare case highlights the need for effective treatment in aggressive and unresectable HCC and the utility of early genomic studies to allow for targeted therapy such as poly (ADP-ribose) polymerase (PARP)-inhibitors.

A Pilot Study of Paricalcitol plus Nanoliposomal Irinotecan and 5-FU/LV in Advanced Pancreatic Cancer Patients after Progression on Gemcitabine-Based Therapy.

PURPOSE: Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models. PATIENTS AND METHODS: We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2). The primary endpoint was safety, and secondary endpoints included overall response rate, progression-free survival (PFS), and overall survival (OS). Correlative objectives aimed to identify molecular predictors of response and alterations in the tumor stroma. RESULTS: Twenty patients (10 each in DL1 and DL2) enrolled between March 2019 and May 2021. No grade 3/4 adverse events related to paricalcitol were observed. The most common toxicities were nausea, diarrhea and fatigue, which were similar in both cohorts. Three patients discontinued study after one cycle and were not radiographically evaluable. Of the remaining 17 evaluable patients, 2 had partial response and 12 had stable disease. The median PFS for response-evaluable patients in DL1 was 4.14 months, for DL2 was 4.83 months. Intent-to-treat median OS was 6.15 and 6.66 months for DL1 and DL2, respectively. Correlative studies showed increased tumor vascularity in posttreatment samples in patients receiving the higher dose of paricalcitol (DL2). CONCLUSIONS: Paricalcitol at 7 mcg/kg/week in combination with Nal-iri/ 5-FU/LV is safely tolerated, may increase tumor vascularity and warrants further investigation.

Temozolomide duration and secondary hematological neoplasms: A literature review and implications for patients with neuroendocrine neoplasms.

Evidence-based recommendations for the optimal duration and sequencing of temozolomide-based treatments in advanced neuroendocrine neoplasms are lacking. Here, we conducted a systematic review of the literature for a descriptive analysis of temozolomide-associated myelodysplasias and leukemias to guide treatment planning. A database search of PubMed and Embase was conducted to identify case reports and/or case series reporting secondary myelodysplasias or leukemias in the setting of temozolomide therapy. Key data items extracted from the studies were the temozolomide dose and duration, latency to hematological disorder, type of secondary malignancy and cytogenetics. Reported cases were summarized graphically. A total of 16 studies with 27 patient cases of therapy-related hematologic neoplasms were identified, all of which were case reports or case series. The median treatment duration and cumulative dose were 19 months and 18,000 mg/m2 , respectively. Most patients (21/27) were diagnosed on, or after, 12 months, while only one patient was diagnosed before 6 months of treatment. Most of the patients were diagnosed, while still on treatment with temozolomide. Graphically, cases clustered around a cumulative dose of 10,000 to 30,000 mg/m2 and a latency period of 10 to 40 months which translates to an approximate treatment duration of 12.5 to 37.5 months. Taken together, most reported treatment-related hematological neoplasms appear to develop on or beyond the 12-month mark, while patients are still on treatment with temozolomide. For patients with neuroendocrine neoplasms, where sequencing of multiple therapies is important, we suggest an approach to optimizing treatment duration by establishing disease response at 6 months before continuing further treatment and restricting treatment to or establishing closer vigilance beyond 12 months.

Preliminary experience with a new institutional tumor board dedicated to patients with neuroendocrine neoplasms.

PURPOSE: To determine the decision patterns of a neuroendocrine neoplasm (NEN) tumor board (TB) and the factors behind those. METHODS: We retrospectively reviewed all NEN-TB recommendations from 07/2018 to 12/2021 and recorded patient characteristics, TB outcomes and associations between them. RESULTS: A total of 652 patient entries were identified. Median age of participants was 61 years and an equal number of men and women were presented. Most patients (33.4%) had tumors originating in the small bowel with 16.8% of high grade and 25.9% of pancreatic origin. Imaging was reviewed 97.2% of the time, with most frequently reviewed modalities being PET (55.3%) and CT (44.3%). Imaging review determined that there was no disease progression 20.8% of the time and significant treatment changes were recommended in 36.1% of patients. Major pathology amendments occurred in 3.7% of cases and a clinical trial was identified in 2.6%. There was no association between patient or disease presentation with the tumor board outcomes. There was a slight decrease in number of patients discussed per session, from 10.0 to 8.2 (p < 0.001) when the TB transitioned to a virtual format during the COVID-19 pandemic but all other factors remained unchanged. CONCLUSION: NEN-TB relies heavily on image review, can impact significant treatment changes in patients with rare tumors like NENs, and was not affected by the switch to a virtual format. Finally, none of the examined factors were predictive of the tumor board recommendations.

Phase 1b trial of anti-VEGF/PDGFR vorolanib combined with immune checkpoint inhibitors in patients with advanced solid tumors.

PURPOSE: Vorolanib is a multi-target tyrosine kinase inhibitor with anti-angiogenic properties. This study aimed to evaluate the tolerability, safety and efficacy of vorolanib when added to checkpoint inhibitors (CPIs) in patients with advanced solid tumors. METHODS: We conducted a phase 1b study of vorolanib (300 or 400 mg orally once daily) plus pembrolizumab or nivolumab using a standard 3 + 3 design to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). The endpoints included safety, toxicity and objective response rate, according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). RESULTS: Sixteen patients (9 in pembrolizumab arm, 7 in nivolumab arm) with gastrointestinal or lung cancers were enrolled. All patients had at least 1 treatment-related adverse event (TRAE). The most common TRAEs across all cohorts were lymphopenia (n = 7), leukopenia (n = 5), fatigue (n = 5), and alanine aminotransferase elevation (n = 5); most toxicities were grade (G) 1-2. DLTs were reported in 3 patients at vorolanib 400 mg dose level, with G3 aspartate aminotransferase elevation, G3 rectal hemorrhage, and G3 rash. Of 13 total response-evaluable patients, 2 patients had confirmed partial responses (1 rectal squamous cell cancer and 1 small cell lung cancer). Two patients achieved prolonged stable disease. Vorolanib 300 mg daily was determined to be the RP2D for either pembrolizumab or nivolumab. CONCLUSION: Combination vorolanib 300 mg orally once daily plus CPI appears to be a feasible regimen with manageable toxicity and promising efficacy in select tumor types. NCT03511222. Date of Registration: April 18, 2018.

Single institutional experience on primary neuroendocrine neoplasms of the kidney: a rare distinct entity.

Primary pure renal neuroendocrine neoplasms (R-NENs) are a distinct and rare entity. Not much is known about the histopathology and biologic behavior of these tumors. We attempted to review the clinicopathologic aspects of these neoplasms encountered at our institution. We performed a retrospective chart review to identify primary pure (not admixed with any other tumor component) R-NENs from institutional Cancer Registry database. Pathologic review of the diagnostic archival slides was done for detailed assessment of the histologic features. R-NENs were classified according to the current WHO system for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Eight pure R-NEN cases were identified, all unifocal, and most (6/8) involved the right kidney. Three patients had poorly differentiated neuroendocrine carcinoma (NEC), and five had well-differentiated neuroendocrine tumor (NET). All tumors were located near the renal hilum, stained diffusely with synaptophysin, variably with chromogranin, and were negative for renal site-specific marker PAX8 or for markers of renal cell carcinoma. We identified two distinct patterns of growth: one of sheets with interspersed rosettes and the other of large nests with low proliferative crowded centers and peripheral cells with higher proliferation and prominent palisading. Based on Ki-67 proliferative index, the tumors were classifiable into WHO grade 1 or grade 2 (based on GEP-NEN). All three NECs characteristically showed cytologic features intermediate between classic large and small cell type. This is the first comprehensive clinicopathologic study involving the rare group of R-NEN. Classifying and grading them according to the GEP-NEN system is of prognostic significance.

Phase I Study of Docetaxel and Temsirolimus in Refractory Solid Tumors.

INTRODUCTION: The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, and plays a central role in cell proliferation, growth, differentiation, migration, and survival. Temsirolimus (CCI-779), a selective inhibitor of the mTOR, is an ester analog of rapamycin (sirolimus) with improved aqueous solubility and pharmacokinetic (PK) properties. Preclinical studies have confirmed additive and synergistic antitumor activity in cancer cell lines (breast, prostate cancer) with combinations of taxanes and mTOR inhibitors. We conducted a phase I open-label, dose-escalation study to determine the maximal tolerated dose (MTD) of docetaxel in combination with temsirolimus in patients with refractory solid tumors. PATIENTS AND METHODS: Eligible patients had a diagnosis of a refractory solid malignancy, measurable disease, and adequate organ function. Patients were sequentially enrolled in 4 dose level intravenous combinations of docetaxel and temsirolimus. Temsirolimus was administered weekly with docetaxel administered every 3 weeks. Laboratory data for tumor markers and radiologic imaging were conducted prestudy and then after every 2 cycles of the treatment. Radiologic response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Blood samples for PK and pharmacodynamic analysis were planned to be drawn at MTD. Apart from the traditional 3+3 design, we also implemented Bayesian Optimal Interval design which uses isotonic regression method to select MTD. We proceeded with isotonic regression analysis by using 20% dose-limiting toxicity (DLT) rate as target. RESULTS: Twenty-six patients were treated in this study in 4 cohorts and dose levels. Fourteen males and 12 females were enrolled with a median age of 50 years (range of 27 to 72 y) and median Eastern Cooperative Oncology Group performance score of 1. Tumor histologies included pancreas (6), colon (5), rectum (3), gallbladder (2), non-small cell lung (2), endometrium (1), neuroendocrine (1), esophagus (1), stomach (1), pharynx (1), small intestine (1), and duodenum (1). Stable disease was observed in 2/4 (50%), 3/7 (43%), 4/10 (40%), and 3/5 (60%) patients in cohorts 1, 2, 3, and 4, respectively. Dose escalation in cohorts 2, 3, and 4 was complicated by DLTs such as grade 4 neutropenia and grade 3 diarrhea and an inability for patients to tolerate treatments during and beyond cycle 1 without dose reductions. Therefore, we could not determine an MTD or recommended phase II dose using the traditional 3+3 study analysis. Blood samples for PK and pharmacodynamic analysis were not collected since MTD was not determined. By using 20% DLT rate closest to the target, isotonic regression analysis showed identical estimated DLT rates in dose -1 (docetaxel 50 mg/m2 and temsirolimus 15 mg/m2) and dose level 1 (docetaxel 60mg/m2 and temsirolimus 15 mg/m2). CONCLUSIONS: Dose escalation of docetaxel and temsirolimus was limited by severe myelosuppressive toxicity in this phase I study. Most of the DLTs occurred after cycle 1 of therapy hence, we were unable to determine MTD or collect blood samples for PK and pharmacodynamic analysis. Our trial did not meet its objectives due to significant DLTs with this chemotherapy combination. Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.

Nonoperative Rectal Cancer Management With Short-Course Radiation Followed by Chemotherapy: A Nonrandomized Control Trial.

PURPOSE: Short-course radiation therapy (SCRT) and nonoperative management are emerging paradigms for rectal cancer treatment. This clinical trial is the first to evaluate SCRT followed by chemotherapy as a nonoperative treatment modality. METHODS: Patients with nonmetastatic rectal adenocarcinoma were treated on the single-arm, Nonoperative Radiation Management of Adenocarcinoma of the Lower Rectum study of SCRT followed by chemotherapy. Patients received 25 Gy in 5 fractions to the pelvis followed by FOLFOX ×8 or CAPOX ×5 cycles. Patients with clinical complete response (cCR) underwent nonoperative surveillance. The primary end point was cCR at 1 year. Secondary end points included safety profile and anorectal function. RESULTS: From June 2016 to March 2019, 19 patients were treated (21% stage I, 32% stage II, and 47% stage III disease). At a median follow-up of 27.7 months for living patients, the 1-year cCR rate was 68%. Eighteen of 19 patients are alive without evidence of disease. Patients with cCR versus without had improved 2-year disease-free survival (93% vs 67%; P = .006), distant metastasis-free survival (100% vs 67%; P = .03), and overall survival (100% vs 67%; P = .03). Involved versus uninvolved circumferential resection margin on magnetic resonance imaging was associated with less initial cCR (40% vs 93%; P = .04). Anorectal function by Functional Assessment of Cancer Therapy-Colorectal cancer score at 1 year was not different than baseline. There were no severe late effects. CONCLUSIONS: Treatment with SCRT and chemotherapy resulted in high cCR rate, intact anorectal function, and no severe late effects. NCT02641691.