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.

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.