Outcome prioritization and preferences among older adults with cancer starting chemotherapy in a randomized clinical trial.

INTRODUCTION: Older adults with cancer facing competing treatments must prioritize between various outcomes. This study assessed health outcome prioritization among older adults with cancer starting chemotherapy. METHODS: Secondary analysis of a randomized trial addressing vulnerabilities in older adults with cancer. Patients completed three validated outcome prioritization tools: 1) Health Outcomes Tool: prioritizes outcomes (survival, independence, symptoms) using a visual analog scale; 2) Now vs. Later Tool: rates the importance of quality of life at three times-today versus 1 or 5 years in the future; and 3) Attitude Scale: rates agreement with outcome-related statements. The authors measured the proportion of patients prioritizing various outcomes and evaluated their characteristics. RESULTS: A total of 219 patients (median [range] age 71 [65-88], 68% with metastatic disease) were included. On the Health Outcomes Tool, 60.7% prioritized survival over other outcomes. Having localized disease was associated with choosing survival as top priority. On the Now vs. Later Tool, 50% gave equal importance to current versus future quality of life. On the Attitude Scale, 53.4% disagreed with the statement "the most important thing to me is living as long as I can, no matter what my quality of life is"; and 82.2% agreed with the statement "it is more important to me to maintain my thinking ability than to live as long as possible". CONCLUSION: Although survival was the top priority for most participants, some older individuals with cancer prioritize other outcomes, such as cognition and function. Clinicians should elicit patient-defined priorities and include them in decision-making.

Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

Regorafenib, Ipilimumab, and Nivolumab for Patients With Microsatellite Stable Colorectal Cancer and Disease Progression With Prior Chemotherapy: A Phase 1 Nonrandomized Clinical Trial.

Importance: Immunotherapy combinations with activity in patients with microsatellite stable (MSS) metastatic colorectal cancer need to be identified. Objective: To determine the recommended phase 2 dose (RP2D) of regorafenib, ipilimumab, and nivolumab (RIN) and evaluate its activity in an expansion cohort of patients with MSS metastatic colorectal cancer. Design, Setting, and Participants: This nonrandomized clinical trial was a single-center 3 + 3 dose de-escalation study with an effectiveness expansion cohort at the RP2D. After the identification of the RP2D, a study amendment was executed to explore a regorafenib dose optimization strategy to mitigate skin-related toxic effects. Study enrollment occurred between May 12, 2020, and January 21, 2022. The trial was conducted at a single academic center. A total of 39 patients with MSS metastatic colorectal cancer whose disease progressed after standard chemotherapy and who had not received prior regorafenib or anti-programmed cell death protein 1 therapy were included. Interventions: Patients received regorafenib daily for 21 days every 4 weeks; fixed-dose ipilimumab, 1 mg/kg, intravenously every 6 weeks; and fixed-dose nivolumab, 240 mg intravenously every 2 weeks. Patients were treated until progression, unacceptable toxic effects, or completion of 2 years of therapy. Main Outcomes and Measures: The primary end point was RP2D selection. Secondary end points were safety and overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours at the RP2D level. Results: A total of 39 patients were enrolled, 23 (59.0%) were female, median age was 54 years (range, 25-75 years), 3 were Black (7.7%), and 26 were White (66.7%). No dose-limiting toxic effects were noted in the first 9 patients at the starting dose of RIN, with regorafenib dosed at 80 mg daily. No dose de-escalation was needed. This dose was declared the RP2D. Twenty more patients were enrolled at this level. The ORR, median progression-free survival (PFS), and overall survival (OS) in the RP2D cohort were 27.6%, 4 months (IQR, 2-9 months), and 20 months (IQR, 7 months to not estimable), respectively. For the 22 patients without liver metastases, the ORR, PFS, and OS were 36.4%, 5 months (IQR, 2-11), and greater than 22 months, respectively. A dose optimization cohort with regorafenib at 40 mg/d on cycle 1 and 80 mg/d on cycle 2 and beyond was associated with lower skin and immune toxic effects but had limited activity with stable disease for 5 of 10 patients as the best response. Conclusions and Relevance: Results of this nonrandomized clinical trial suggest that RIN at the RP2D demonstrated interesting clinical activity in patients with advanced MSS colorectal cancer without liver metastases. These findings should be confirmed in randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04362839.

Patient-Defined Goals and Preferences Among Adults With Advanced Neuroendocrine Tumors.

BACKGROUND: Patient preferences (quantity vs quality of life; present vs future health) have not been investigated in patients with neuroendocrine tumors (NETs). The goal of this cross-sectional study was to evaluate patient values toward treatment goals and competing health outcomes among adults with NETs. PATIENTS AND METHODS: Patients with well-differentiated, grade 1 or 2, advanced NETs starting a new systemic therapy completed 4 tools: (1) Health Outcomes Tool, which ranks the importance of 4 outcomes (survival, function/independence, freedom from pain, freedom from symptoms); (2) Attitude Scale, which identifies the extent to which patients agree with statements related to health outcomes; (3) Now versus Later Tool, which ranks the relative importance of quality of life (QoL) now versus 1 and 5 years from now; and (4) Prognosis and Treatment Perceptions Questionnaire, which identifies the amount of information the patient prefers to receive about their disease and treatment, the patient's treatment goal, the patient's perception of the physician's treatment goal, and self-reported health status. RESULTS: We recruited 60 patients with NETs (50.0% aged ≥65 years; 96.7% with stage IV disease). Primary tumor locations included the gastrointestinal tract (41.7%), pancreas (30.0%), and lung (21.7%). A plurality of patients reported maintaining independence as their most important health outcome (46.7%), followed by survival (30.0%), freedom from pain (11.7%), and freedom from symptoms (11.7%). A total of 67% of patients agreed with the statement, "I would rather live a shorter life than lose my ability to take care of myself"; 85.0% agreed with the statement, "It is more important to me to maintain my thinking ability than to live as long as possible." When asked to choose between current QoL versus QoL 1 year or 5 years in the future as more important, 48.3% and 40.0% of patients valued their QoL 1 year and 5 years in the future, respectively, more than their current QoL. Only 51.7% of patients believed their physician's treatment goals aligned with their own. CONCLUSIONS: Adult patients with NETs strongly value independence over survival. More communication between patients with NETs and their physicians is needed to ensure that patient preferences are incorporated into treatment plans.

Multicenter dose-escalation Phase I trial of mitomycin C pressurized intraperitoneal aerosolized chemotherapy in combination with systemic chemotherapy for appendiceal and colorectal peritoneal metastases: rationale and design.

Objectives: Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC. Methods: This is a multicenter Phase I study of MMC-PIPAC (NCT04329494). Inclusion criteria include treatment with at least 4 months of first- or second-line systemic chemotherapy with ineligibility for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Exclusion criteria are: progression on chemotherapy; extraperitoneal metastases; systemic chemotherapy intolerance; bowel obstruction; or poor performance status (ECOG>2). Escalating MMC-PIPAC doses (7-25 mg/m2) will be administered in combination with standard dose systemic FOLFIRI. Safety evaluation will be performed on 15 patients (dose escalation) and six expansion patients: 21 evaluable patients total. Results: The primary endpoints are recommended MMC dose and safety of MMC-PIPAC with FOLFIRI. Secondary endpoints are assessment of response (by peritoneal regression grade score; Response Evaluation Criteria in Solid Tumors [RECIST 1.1], and peritoneal carcinomatosis index), progression free survival, overall survival, technical failure rate, surgical complications, conversion to curative-intent CRS-HIPEC, patient-reported outcomes, and functional status. Longitudinal blood and tissue specimens will be collected for translational correlatives including pharmacokinetics, circulating biomarkers, immune profiling, and single-cell transcriptomics. Conclusions: This Phase I trial will establish the recommended dose of MMC-PIPAC in combination with FOLFIRI. Additionally, we expect to detect an early efficacy signal for further development of this therapeutic combination.

PIPAC for the Treatment of Gynecologic and Gastrointestinal Peritoneal Metastases: Technical and Logistic Considerations of a Phase 1 Trial.

BACKGROUND: Peritoneal metastases (PM) from ovarian, gastric, appendiceal, or colorectal origin can be treated via cytoreductive surgery with or without the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) for selected patients. Unfortunately, not all patients are candidates for aggressive surgical debulking. For these patients, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) has emerged as an alternative method for intraperitoneal (IP) chemotherapy administration. This report presents the design and implementation of the first phase 1 trial to evaluate the safety and efficacy of PIPAC in the United States. METHODS: This is an ongoing prospective phase 1 clinical trial of PIPAC for patients who have histologically confirmed ovarian, uterine, gastric, appendiceal, or colorectal cancer with PM and have progressed to at least one evidence-based chemotherapeutic regimen. The trial has two clinical arms. The patients in arm 1 have gynecologic and gastric malignancies treated with IP cisplatin and doxorubicin, and the arm 2 patients have colorectal and appendiceal malignancies treated with intravenous fluorouracil and leucovorin followed by IP oxaliplatin. All the patients are monitored for dose-limiting toxicities and adverse events. RESULTS: Practical and technical considerations for the phase 1 PIPAC trial are presented. These considerations include patient selection, operating room setup, and technical details for successful aerosolized chemotherapy delivery. The phase 1 study results will be reported separately at completion of the trial. CONCLUSIONS: The PIPAC treatment is a feasible, minimally invasive approach that permits IP delivery of chemotherapy. Once completed, the ongoing phase 1 trial will help to provide safety and initial efficacy data.

A randomized phase 2 network trial of tivantinib plus cetuximab versus cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma.

BACKGROUND: MET signaling is a well described mechanism of resistance to anti-EGFR therapy, and MET overexpression is common in head and neck squamous cell carcinomas (HNSCCs). In the current trial, the authors compared the oral MET inhibitor tivantinib (ARQ197) in combination with cetuximab (the TC arm) versus a control arm that received cetuximab monotherapy (C) in patients with recurrent/metastatic HNSCC. METHODS: In total, 78 evaluable patients with cetuximab-naive, platinum-refractory HNSCC were enrolled, including 40 on the TC arm and 38 on the C arm (stratified by human papillomavirus [HPV] status). Patients received oral tivantinib 360 mg twice daily and intravenous cetuximab 500 mg/m2 once every 2 weeks. The primary outcome was the response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), and secondary outcomes included progression-free and overall survival. After patients progressed on the C arm, tivantinib monotherapy was optional. RESULTS: The response rate was 7.5% in the TC arm (N = 3; 1 complete response) and 7.9% in the C arm (N = 3; not significantly different [NS]). The median progression-free survival in both arms was 4 months (NS), and the median overall survival was 8 months (NS). Both treatments were well tolerated, with a trend toward increased hematologic toxicities in the TC arm (12.5% had grade 3 leukopenia). The response rate in 31 HPV-positive/p16-positive patients was 0% in both arms, whereas the response rate in HPV-negative patients was 12.7% (12.5% in the TC arm and 13% in the C arm). Fifteen patients received tivantinib monotherapy, and no responses were observed. CONCLUSIONS: Combined tivantinib plus cetuximab does not significantly improve the response rate or survival compared with cetuximab alone but does increase toxicity in an unselected HNSCC population. Cetuximab responses appear to be limited to patients who have HPV-negative HNSCC. MET-aberration-focused trials for HNSCC and the use of higher potency, selective MET inhibitors remain of interest.

Phase I Study of Yttrium-90 Radiolabeled M5A Anti-Carcinoembryonic Antigen Humanized Antibody in Patients with Advanced Carcinoembryonic Antigen Producing Malignancies.

Background: M5A is a humanized monoclonal antibody (mAb) directed against carcinoembryonic antigen (CEA) The purpose of this first in human phase I dose-escalation trial was to characterize the toxicities and determine the maximum tolerated dose (MTD) of yttrium-90 (90Y)-DOTA-M5A as a single agent and in combination with gemcitabine (gem). Methods: Patients with advanced metastatic CEA-producing malignancies who had progressed on standard therapies were first administered indium-111 (111In)-DOTA-M5A. If tumor targeting was observed, the patient then received the therapy dose of 90Y-DOTA-M5A. Serial scans, blood sampling, and 24 h urine collections were then performed to estimate radiation doses to organs and total body. Assays for human antihuman antibody (HAHA) responses were performed out to 6 months. Results: Of the 18 patients who received 111In-DOTA-M5A, 16 received 90Y-DOTA-M5A therapy; 1 patient at 14 mCi/m2 with gem (150 mg/m2 days 1and 3), 3 patients at 12 mCi/m2 with gem, 6 patients at 12 mCi/m2 without gem, and 6 at 10 mCi/m2 without gem. Prolonged cytopenias resulted in discontinuation of dose escalation with gemcitabine. A single agent MTD of 10 mCi/m2 was established based on dose-limiting hematopoietic toxicities. HAHA immune response was identified in 2 of 16 patients (12.5%). Stable disease at 3 months was seen in 10 patients and 2 patients demonstrated an 88% and 64% decrease in CEA back to normal levels. In 2 patients 111In-DOTA-M5A imaging revealed previously unknown brain metastases. Conclusion: This study demonstrates the potential utility of the 90Y-DOTA-M5A anti-CEA mAb as a therapeutic antibody. There is decreased immunogenicity compared with murine and chimeric mAbs, allowing for the potential of multiple administrations. Combined modality therapy approaches incorporating this agent should continue to be evaluated.

A Pilot Feasibility Study of Yttrium-90 Liver Radioembolization Followed by Durvalumab and Tremelimumab in Patients with Microsatellite Stable Colorectal Cancer Liver Metastases.

LESSONS LEARNED: Radioembolization with yttrium-90 resin microspheres can be combined safely with full doses of durvalumab and tremelimumab in patients with metastatic colorectal cancer. Regional radioembolization with yttrium-90 resin microspheres did not result in any hepatic or extrahepatic responses to a combination of durvalumab and tremelimumab. The lack of immunomodulatory responses to yttrium-90 on biopsies before and after treatment rules out a potential role for this strategy in converting a "cold tumor" into an "inflamed," immune responsive tumor. BACKGROUND: PD-1 inhibitors have been ineffective in microsatellite stable (MSS) metastatic colorectal cancer (CRC). Preclinical models suggest that radiation therapy may sensitize MSS CRC to PD-1 blockade. METHODS: Patients with MSS metastatic CRC with liver-predominant disease who progressed following at least one prior line of treatment were treated with yttrium-90 (Y90) radioembolization to the liver (SIR-Spheres; Sirtex, Woburn, MA) followed 2-3 weeks later by the combination of durvalumab and tremelimumab. A Simon two-stage design was implemented, with a planned expansion to 18 patients if at least one response was noted in the first nine patients. RESULTS: Nine patients enrolled in the first stage of the study, all with progressive disease (PD) during or after their first two cycles of treatment. Per preplanned design, the study was closed because of futility. No treatment-related grade 3 or greater toxicities were recorded. Correlative studies with tumor biopsies showed low levels of tumor-infiltrating lymphocyte (TIL) infiltration in tumor cancer islands before and after Y90 radioembolization. CONCLUSION: Y90 radioembolization can be added safely to durvalumab and tremelimumab but did not promote tumor-directed immune responses against liver-metastasized MSS CRC.

Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial.

PURPOSE: The reported maximum tolerated dose (MTD) of single-agent belinostat is 1000 mg/m2 given days 1-5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50-100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors. METHODS: Belinostat was administered days 1-5 and 13-cRA days 1-14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to belinostat. RESULTS: Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m2/day belinostat with 100 mg/m2/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m2/day belinostat with 100 mg/m2/day 13-cRA. The MTD was not reached. Pharmacokinetics of belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer. CONCLUSIONS: The combination of belinostat 2000 mg/m2 days 1-5 and 13-cRA 100 mg/m2 days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of belinostat.

Randomized trial of oral cyclophosphamide versus oral cyclophosphamide with celecoxib for recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer.

BACKGROUND: Oral metronomic chemotherapy, which has low toxicity, has demonstrated promising anti-tumor and anti-angiogenic properties that may lead to prolonged progression-free survival and improved response rates in patients with recurrent epithelial ovarian cancer (EOC). These effects may be enhanced by the co-administration of anti-angiogenic agents. METHODS: We conducted a randomized phase II clinical trial to evaluate the therapeutic benefit of oral metronomic cyclophosphamide (CTX) alone and with the anti-angiogenic drug celecoxib in patients with gynecological malignancies. 52 patients were randomly assigned to two treatments arms: 50 mg oral CTX daily alone (Arm A) or with 400 mg celecoxib twice daily (Arm B). The primary endpoint was response rate. Secondary endpoints included toxicity, time to treatment failure, and overall survival. RESULTS: In Arm A (n = 26), 3 patients (12%) had stable disease >6 months and 1 (4%) had a partial response. In Arm B, 5 (19%) had stable disease >6 months and 1 patient (4%) had a partial response. There were no significant between-group differences in overall survival (9.69 months [95% CI 3.84-13.18] vs. 12.55 months [6.67-17.61]) or in median time to treatment failure (1.84 months [1.68-2.76] vs. 1.92 months [1.64-5.22]). The most common adverse events were nausea, vomiting, and abdominal pain. CONCLUSIONS: Oral metronomic CTX has activity with no major toxicities in heavily pretreated recurrent gynecological cancers and may be considered in patients with indolent disease. We did not observe any additional benefit of celecoxib treatment, though this may be due to small sample sizes.

Understanding Caregiver Quality of Life in Caregivers of Hospitalized Older Adults With Cancer.

BACKGROUND/OBJECTIVES: Caregivers of older adults with cancer assist both with cancer care and other health issues, which may make them vulnerable to consequences of caregiving. Hospitalization may represent a time when a caregiver's ability to provide care at home is exceeded. We sought to characterize caregivers of hospitalized older adults with cancer, determine their quality of life (QOL), and identify factors associated with caregiver QOL. METHODS: Patients (n = 100), aged 65 years and older, with an unplanned hospitalization and their caregivers were included. Caregivers completed a questionnaire about their health, social support, caregiving relationship, QOL (Caregiver Quality of Life Index-Cancer [CQOLC] tool), and patient function. Patient medical history was obtained via chart review. The association between patient, caregiving, and caregiver factors and CQOLC was determined using multivariate linear regression. RESULTS: Most patients (73%) had metastatic/advanced disease, and 71% received treatment for their cancer within 30 days of hospitalization. Median Karnofsky Performance Status (KPS) was 60%, and 89% required help with instrumental activities of daily living, as reported by caregivers. Median caregiver age was 65 years (range = 29-84 years). The majority (60%) had no major comorbidities and rated their health as excellent/good (79%), though 22% reported worsening health due to caregiving. Caregivers had a median Mental Health Inventory-18 score of 70 (range = 0-97), a median Medical Outcomes Study (MOS)-social activity score of 56 (range = 0-87.5), and a median MOS-Social Support Survey score of 68 (range = 0-100). Caregivers provided a median of 35 hours of care per week (range = 0-168 hours of care per week). Mean CQOLC was 84.6 ± 23.5. Lower caregiver QOL was associated with poorer caregiver mental health, less social support, and poorer patient KPS (P < .05). CONCLUSION: Caregivers of hospitalized older adults with cancer are older but generally in good health. Those with poorer mental health, less social support, and caring for patients with poorer performance status are more likely to experience lower QOL. J Am Geriatr Soc 67:978-986, 2019.

A Pilot Study of Vinorelbine Safety and Pharmacokinetics in Patients with Varying Degrees of Liver Dysfunction.

BACKGROUND: Vinorelbine has demonstrated anticancer activity and is primarily metabolized in the liver. This single-institution, phase I pilot study describes the safety and pharmacokinetics of vinorelbine in patients with varying degrees of hepatic impairment. MATERIALS AND METHODS: Patients with treatment-refractory solid tumors were enrolled into treatment arms based on vinorelbine dose (weekly infusions of 7.5-30 mg/m2) and liver function (normal liver function, mild, moderate, or severe liver dysfunction). Vinorelbine pharmacokinetics were evaluated to describe its relationship with liver function. Indocyanine green (ICG) clearance was assessed for correlation with pharmacokinetics. RESULTS: Forty-seven patients were enrolled, and a total of 108 grade 3-4 treatment-related adverse events (AEs) occurred. Of these, grade 3-4 myelosuppression was the most common (34.3%). Thirty-three (30.6%), 22 (20.4%), and 9 (8.3%) grade 3-4 AEs were observed in the vinorelbine 20 mg/m2/severe, 15 mg/m2/moderate, and 7.5 mg/m2/severe liver dysfunction groups, respectively, with the majority being nonhematologic toxicities. ICG clearance decreased as liver function worsened. Vinorelbine pharmacokinetics were not correlated with ICG elimination or the degree of liver dysfunction. CONCLUSION: For patients with severe liver dysfunction (bilirubin >3.0 mg/dL), vinorelbine doses ≥7.5 mg/m2 are poorly tolerated. The high incidence of grade 3-4 AEs with 15 mg/m2 vinorelbine in moderate liver dysfunction (bilirubin 1.5-3.0 mg/dL) raises concerns for its safety in this population. Vinorelbine pharmacokinetics are not affected by liver dysfunction; however, levels of the active metabolite 4-O-deacetylvinorelbine were not measured and may be higher in patients with liver dysfunction if its elimination is impacted by liver impairment to a greater degree than the parent drug. IMPLICATIONS FOR PRACTICE: Vinorelbine remains widely prescribed in advanced malignancies and is under development in immunotherapy combinations. Given vinorelbine is primarily hepatically metabolized, understanding its safety and pharmacokinetics in liver dysfunction remains paramount. In this phase I pilot study, weekly vinorelbine at doses ≥7.5 mg/m2 is poorly tolerated in those with severe liver dysfunction. Furthermore, a high incidence of grade 3-4 toxicities was observed with vinorelbine at 15 mg/m2 in those with moderate liver dysfunction. Vinorelbine pharmacokinetics do not appear affected by degree of liver dysfunction. Further evaluation of levels of the free drug and active metabolites in relationship to liver function are warranted.

A phase I trial of intraperitoneal nab-paclitaxel in the treatment of advanced malignancies primarily confined to the peritoneal cavity.

PURPOSE: To evaluate intraperitoneal (IP) nab-paclitaxel in patients with advanced malignancies that are primarily confined to the peritoneal cavity in a phase I trial. METHODS: Using a 3 + 3 dose escalation of IP nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle, we evaluated six dose levels (35-175 mg/m2/dose). Maximum tolerated dose (MTD) and pharmacokinetics (PK) of IP nab-paclitaxel were determined. RESULTS: There were no dose-limiting toxicities (DLTs) in cohorts 1-3. There was a DLT in one of six patients in cohort 4 (112.5 mg/m2) (grade 3 neutropenia causing treatment delay > 15 days) and a DLT in one of three patients in cohort 6 (175 mg/m2) (grade 4 neutropenia and grade 3 abdominal pain). A second patient in cohort 6 experienced a serious adverse event (cycle 1, grade 4 ANC ≤ 7 days, cycle 4, grade 2 left ventricular dysfunction). This dose level was determined to be above the MTD. No DLTs were seen in seven patients treated in cohort 5 (140 mg/m2). The MTD of IP nab-paclitaxel was established at 140 mg/m2 on days 1, 8, and 15 of a 28-day cycle. There was a PK advantage for IP nab-paclitaxel, with an IP plasma area under the concentration-time curve (AUC) ratio of 147-fold (range 50-403) and therapeutic range systemic drug levels. Eight of 27 enrolled patients had progression-free survival ≥ 6 months. One patient experienced complete response, and one patient experienced partial response. Six patients had stable disease. CONCLUSIONS: Weekly IP nab-paclitaxel has a favorable toxicity profile, a significant pharmacologic advantage, and promising clinical activity. CLINICAL TRIAL REGISTRATION: NCT00825201.

Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742).

Purpose This multinational study evaluated the antitumor activity of nivolumab in nasopharyngeal carcinoma (NPC). Tumor and plasma-based biomarkers were investigated in an exploratory analysis. Patients and Methods Patients with multiply pretreated recurrent or metastatic NPC were treated with nivolumab until disease progression. The primary end point was objective response rate (ORR) and secondary end points included survival and toxicity. The expression of programmed death-ligand 1 (PD-L1) and human leukocyte antigens A and B in archived tumors and plasma clearance of Epstein-Barr virus DNA were correlated with ORR and survival. Results A total of 44 patients were evaluated and the overall ORR was 20.5% (complete response, n = 1; partial response, n = 8). Nine patients received nivolumab for > 12 months (20%). The 1-year overall survival rate was 59% (95% CI, 44.3% to 78.5%) and 1-year progression-free survival (PFS) rate was 19.3% (95% CI, 10.1% to 37.2%). There was no statistical correlation between ORR and the biomarkers; however, a descriptive analysis showed that the proportion of patients who responded was higher among those with PD-L1 positive tumors (> 1% expression) than those with PD-L1-negative tumors. The loss of expression of one or both human leukocyte antigen class 1 proteins was associated with better PFS than when both proteins were expressed (1-year PFS, 30.9% v 5.6%; log-rank P = .01). There was no association between survival and PD-L1 expression or plasma Epstein-Barr virus DNA clearance. There was no unexpected toxicity to nivolumab. Conclusion Nivolumab has promising activity in NPC and the 1-year overall survival rate compares favorably with historic data in similar populations. Additional evaluation in a randomized setting is warranted. The biomarker results were hypothesis generating and validation in larger cohorts is needed.

A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy.

BACKGROUND: This was a first in-human, open-label, dose-escalation phase I study conducted to evaluate the maximum tolerated dose (MTD), safety, and efficacy of the combination of oral binimetinib and FOLFOX. MATERIALS AND METHODS: Patients with metastatic colorectal cancer (mCRC) who progressed on prior standard therapies received twice daily binimetinib continuously or intermittently with FOLFOX. Dose-limiting toxicities (DLTs) were assessed in the first 2 cycles of study treatment. Pharmacokinetic (PK) analysis of 5-FU and oxaliplatin was performed at the MTD in an expanded 6 patient cohort. RESULTS: Twenty-six patients were enrolled and assessed for safety. In the dose-escalation phase, no DLTs were noted in all binimetinib dosing schedules and the MTD of binimetinib in with FOLFOX was 45 mg orally twice daily. There were no significant differences in the PKs of 5-FU or oxaliplatin with or without binimetinib. Continuous dosing of binimetinib produced SD at 2 months in 9 of 13 evaluable patients and a median PFS of 3.5 months. Nine of 10 patients had PD at 2 months on the intermittent arm. CONCLUSIONS: Oral binimetinib and FOLFOX has a manageable toxicity profile and showed some evidence of antitumor activity in heavily pretreated mCRC patients.

NCCN Guidelines Insights: Antiemesis, Version 2.2017.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis address all aspects of management for chemotherapy-induced nausea and vomiting. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Antiemesis, specifically those regarding carboplatin, granisetron, and olanzapine.

Complete response of skull base inverted papilloma to chemotherapy: Case report.

BACKGROUND: Inverted papilloma (IP) is the most common benign sinonasal neoplasm. Endoscopic techniques, improved understanding of pathophysiology, and novel surgical approaches have allowed rhinologists to treat IPs more effectively, with surgery being the mainstay of therapy. Frontal sinus IP poses a challenge for surgical therapy due to complex anatomy and potentially difficult surgical access. OBJECTIVES: We reported a unique case of a massive frontal sinus IP that presented with intracranial and orbital extension, with near resolution after chemotherapy. METHODS: A retrospective case review of a patient with a frontal sinus IP treated at a tertiary academic medical center. RESULTS: A 75-year-old male patient presented with nasal obstruction, purulent nasal discharge, and a growing left supraorbital mass. Endoscopy demonstrated a mass that filled both frontal and ethmoid sinuses, with orbital invasion. There also was substantial erosion of the posterior table, which measured 1.73 × 1.40 cm. A biopsy specimen demonstrated IP with carcinoma in situ. The patient was deemed unresectable on initial evaluation and, subsequently, underwent chemotherapy (carboplatin and paclitaxel). The tumor had a dramatic response to chemotherapy, and the patient elected for definitive surgery to remove any residual disease. During surgery, only a small focus of IP was found along the superior wall of the frontal sinus. No tumor was found elsewhere, including at the site of skull base erosion. The final pathology was IP without carcinoma in situ or dysplasia. CONCLUSION: This was the first reported case of chemotherapeutic "debulking" of IP, which facilitated surgical resection, despite substantial intracranial and orbital involvement. Although nearly all IPs can be treated surgically, rare cases, such as unresectable tumors, may benefit from systemic chemotherapy.

Pilot trial of CRLX101 in patients with advanced, chemotherapy-refractory gastroesophageal cancer.

BACKGROUND: CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload. Preclinical evidence indicated preferential uptake in tumors, and tumor xenograft models demonstrate superiority of CRLX101 over irinotecan. A pilot trial was conducted at recommended phase 2 dosing (RP2D) using the bimonthly schedule to assess preferential uptake of CRLX101 in tumor vs. adjacent normal tissue in endoscopically accessible tumors in chemotherapy-refractory gastroesophageal cancer. Results from the biopsies were previously reported and herein we present the clinical outcomes. METHODS: Patients initiated CRLX101 dosed at RP2D (15 mg/m2) on days 1 and 15 of a 28-day cycle. Detection of preferential CRLX101 tumor uptake was the primary endpoint and objective response rate (ORR) was a secondary endpoint. With a sample size of ten patients, the study had 90% power to detect ≥1 responder if the true response rate is ≥21%. RESULTS: Between Dec. 2012 and Dec. 2014, ten patients with chemotherapy-refractory (median 2 prior lines of therapy, range 1-4) gastric adenocarcinoma were enrolled. The median time-to-progression was 1.7 months. Best response was seen in one patient with stable disease (SD) for 8 cycles. Only ≥ grade 3 drug-related toxicity occurred in one patient with grade 3 cardiac chest pain who was able to resume therapy after CRLX101 was reduced to 12 mg/m2. CONCLUSIONS: Bimonthly CRLX101 demonstrated minimal activity with SD as best response in this heavily pretreated population. Future efforts with CRLX101 in gastric cancer should focus on combination and more dose-intensive strategies given its favorable toxicity profile and evidence of preferential tumor uptake.