Lack of Availability and Efficacy of Phase I and Basket Trials for Patients With Gastrointestinal Cancers.

In the modern era of targeted and immune-based therapies, investigator and patient expectations of availability and efficacy in phase I trials have increased. We assessed availability of, and benefit from, early drug development trials, specifically in patients with gastrointestinal cancers. We reviewed computerized referral records of the Early Drug Development Service at our institution to identify patients internally referred from our Gastrointestinal Oncology Service in calendar year 2018. End points were treatment on a trial, 3- and 6-month progression-free survival (PFS), and any tumor shrinkage. Of 394 gastrointestinal cancer patients referred in 2018, 54 enrolled on a trial and 53 (13.5%) were treated (1 withdrew before treatment): 34 on immune-based and 19 on targeted (3 to phase II basket) studies. None of the 52 patients who had exhausted standard therapy achieved 6-month PFS, two (3.8%) met 3-month PFS with tumor growth below Response Evaluation Criteria in Solid Tumors progression at 3 months, and both came off study for progression at 4 months. One patient who was to receive an irinotecan-based regimen as standard therapy instead received irinotecan plus an investigational targeted agent and remained stable for 8 months. No patients achieved any degree of tumor shrinkage. The most common reasons for nonaccrual were lack of available protocol treatment openings and failure to meet eligibility criteria for specific trials. Thus, availability and benefit from investigational treatment in this treatment-refractory gastrointestinal cancer patient population was extremely modest. Expectations regarding both availability and efficacy of phase I investigational therapy in gastrointestinal cancer patients likely exceed what our experience suggests.

First-in-Human Phase I Study of the Activin A Inhibitor, STM 434, in Patients with Granulosa Cell Ovarian Cancer and Other Advanced Solid Tumors.

PURPOSE: STM 434 is a soluble receptor ligand trap targeting activin A, a protein in the TGFß family that plays important roles in growth, differentiation, and cancer cachexia. This study evaluated the safety, antitumor activity, and metabolic effects of STM 434 in a first-in-human, multicenter, phase I clinical trial (NCT02262455). PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled in 8 dose cohorts ranging from 0.25 mg/kg every 4 weeks to 8 mg/kg every 2 weeks via a 3 + 3 dose-escalation design. The primary endpoint was maximum tolerated dose (MTD). Secondary endpoints included safety, pharmacokinetics, and response. As activin A is implicated in metabolism and muscle function, changes in key metabolic parameters, including lean body mass and 6-minute walk test, were serially measured. RESULTS: Thirty-two patients were treated on study. The most common treatment-related adverse events were fatigue (41%) and mucocutaneous bleeding complications including epistaxis (34%) and gingival bleeding (22%), likely related to off-target inhibition of bone morphogenetic protein 9 (BMP9). STM 434 treatment resulted in the expected follicle-stimulating hormone level decreases in most patients and in metabolic parameter changes, including an increase in total lean body mass and 6-minute walk test distance. No responses were observed in the 30 evaluable patients, but the stable disease rate in patients with granulosa cell ovarian cancer was 10 of 12 (80%). CONCLUSIONS: Although no direct antitumor efficacy was documented, potentially clinically meaningful dose-related metabolic effects, including treatment of cancer cachexia, were observed that support further exploration of activin A inhibitors that limit BMP9 blockade.See related commentary by Bonilla and Oza, p. 5432.

Real-World Outcomes of an Automated Physician Support System for Genome-Driven Oncology.

PURPOSE: Matching patients to investigational therapies requires new tools to support physician decision making. We designed and implemented Precision Insight Support Engine (PRECISE), an automated, just-in-time, clinical-grade informatics platform to identify and dynamically track patients on the basis of molecular and clinical criteria. Real-world use of this tool was analyzed to determine whether PRECISE facilitated enrollment to early-phase, genome-driven trials. MATERIALS AND METHODS: We analyzed patients who were enrolled in genome-driven, early-phase trials using PRECISE at Memorial Sloan Kettering Cancer Center between April 2014 and January 2018. Primary end point was the proportion of enrolled patients who were successfully identified using PRECISE before enrollment. Secondary end points included time from sequencing and PRECISE identification to enrollment. Reasons for a failure to identify genomically matched patients were also explored. RESULTS: Data were analyzed from 41 therapeutic trials led by 19 principal investigators. In total, 755 patients were accrued to these studies during the period that PRECISE was used. PRECISE successfully identified 327 patients (43%) before enrollment. Patients were diagnosed with 29 tumor types and harbored alterations in 43 oncogenes, most commonly ERBB2 (21.3%), PIK3CA (14.1%), and BRAF (8.7%). Median time from sequencing to enrollment was 163 days (interquartile range, 66 to 357 days), and from PRECISE identification to enrollment 87 days (interquartile range, 37 to 180 days). Common reasons for failing to identify patients before enrollment included accrual on the basis of molecular alterations that did not match pre-established PRECISE genomic eligibility (140 [33%] of 428) and external sequencing not available for parsing (127 [30%] of 428). CONCLUSION: PRECISE identified 43% of all patients accrued to a diverse cohort of early-phase, genome-matched studies. Purpose-built informatics platforms represent a novel and potentially effective method for matching patients to molecularly selected studies.

A Randomized Trial of Prophylactic Extended Carboplatin Infusion to Reduce Hypersensitivity Reactions in Recurrent Ovarian Cancer.

OBJECTIVE: Hypersensitivity with repeated exposure to platinum agents is common and can preclude continued treatment, even in patients with disease that remains platinum sensitive. We sought to compare the effects of prophylactic, extended carboplatin infusion versus standard infusion on the rate of carboplatin hypersensitivity reactions (HSRs) in women with recurrent ovarian cancer. METHODS: This was a single-institution, randomized, nonblinded trial comparing a graded, 3-hour extended infusion of carboplatin with a standard 30-minute infusion in patients with recurrent ovarian cancer who were enrolled from January 2011 to April 2015. The study was designed to detect a decrease in the HSR rate from 20% (standard infusion) to 5% (extended infusion) assuming a type 1 error of 10% and power of 80% using a 1-sided test. RESULTS: Of 146 enrolled patients, 114 were evaluable. Fifteen (13%) had an HSR-11% (6/56) in the extended-infusion and 16% (9/58) in the standard-infusion groups (P = 0.582). Planned treatment completion was achieved in 50 (89%) of 56 patients and 49 (84%) of 58 patients, respectively. Of 25 patients who received single-agent carboplatin, 8 (32%) had an HSR (53% of all patients who had an HSR [8/15]). Of 23 patients who received carboplatin with gemcitabine, 4 (17%) had an HSR (27% of all patients who had an HSR [4/15]). Of 8 patients who received carboplatin with paclitaxel, 3 (38%) had an HSR (20% of all patients who had an HSR [3/15]). There were no HSRs with pegylated liposomal doxorubicin, the most commonly given concurrent chemotherapy (46% of all patients). CONCLUSIONS: A prophylactic, extended carboplatin infusion was not associated with a decreased HSR rate. The overall low HSR rate suggests that premedication may help reduce HSRs.

Nonbacterial thrombotic endocarditis with embolic cerebral vascular accidents in a patient with advanced, recurrent clear cell carcinoma of the ovary: A case report.

•Nonbacterial thrombotic endocarditis can occur in ovarian clear cell carcinoma.•We report on NBTE-associated embolic cerebrovascular infarcts in advanced OCCC.•Further NBTE-associated embolic events can be prevented with anticoagulant therapy.

An Assessment of Prognostic Factors, Adjuvant Treatment, and Outcomes of Stage IA Polyp-Limited Versus Endometrium-Limited Type II Endometrial Carcinoma.

OBJECTIVE: To determine clinical outcomes in patients with stage IA polyp-limited versus endometrium-limited high-grade (type II) endometrial carcinoma (EC). METHODS: We identified all cases of stage IA polyp-limited or endometrium-limited high-grade EC (FIGO grade 3 endometrioid, serous, clear cell, or mixed) who underwent simple hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, omental biopsy, and pelvic and para-aortic lymph node dissection and received adjuvant treatment at our institution from October 1995 to November 2012. Progression-free survival (PFS) and overall survival (OS) by histology, adjuvant therapy, and polyp-limited versus endometrium-limited disease status were determined using log-rank test. We analyzed 3 treatment groups: patients who received chemotherapy with or without radiation therapy (RT) (intravaginal or pelvic); patients who received RT (intravaginal RT or pelvic RT) alone; and patients who received no adjuvant treatment. RESULTS: In all, 85 women underwent hysterectomy/salpingo-oophorectomy; all were surgically staged with lymph node assessment and had stage IA EC with no lymphovascular or myometrial invasion. Median follow-up for survivors was 46.5 months (range, 1.98-188.8 months). Forty-nine patients (57.6%) had polyp-limited disease, and 36 (42.4%) had endometrium-limited disease. There were no significant differences in clinicopathologic characteristics between patients within the 3 treatment groups with regard to age at diagnosis, mean body mass index, ECOG (Eastern Cooperative Oncology Group) performance status, polyp-limited or endometrium-limited disease, diabetes, or race. The 3-year PFS rate was 94.9% and the 3-year OS rate was 98.8%. Univariate PFS and OS analysis revealed that age was a relevant prognostic factor (PFS hazard ratio [95% confidence interval], 1.13 [1.02-1.25]; P = 0.022; OS hazard ratio [95% confidence interval], 1.19 [1.02-1.38]; P = 0.03). Adjuvant treatment did not impact outcomes. CONCLUSIONS: Clinical outcomes of surgical stage IA type II polyp- or endometrium-limited high-grade epithelial EC are equally favorable regardless of histologic subtype or adjuvant therapy received. The benefit of adjuvant therapy in this select group remains to be determined.