Chugh, Rashmi

Purpose. There are no known effective medical treatments for refractory MPNST. Inactivation of the NF1 tumor suppressor in MPNST results in upregulation of mTOR (mammalian target of rapamycin) signaling and angiogenesis, which contributes to disease progression. We conducted a phase II study for patients (pts) with refractory MPNST combining everolimus (10 mg PO once daily) with bevacizumab (10 mg/kg IV every 2 weeks) to determine the clinical benefit rate (CBR) (complete response, partial response (PR), or stable disease (SD) ≥ 4 months). Patients and Methods. Patients ≥18 years old with chemotherapy refractory sporadic or NF1 MPNST were eligible. Tumor response was assessed after every 2 cycles (the WHO criteria). A two-stage design targeting a 25% CBR was used: if ≥ 1/15 pts in stage 1 responded, enrollment would be expanded by 10 pts, and if ≥ 4/25 patients had clinical benefit, the combination would be considered active. Results. Twenty-five pts, 17 with NF1 and 8 with sporadic MPNST, enrolled. One of 15 pts in stage 1 had clinical benefit. Of 10 additional pts enrolled, 2 had clinical benefit. The median number of completed cycles was 3 (range 1–16). Adverse events were similar to those known for this combination. Conclusion. With a CBR of 12% (3/25), the combination of everolimus and bevacizumab did not reach the study’s target response rate and is not considered active in refractory MPNST.

Background Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM‐1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma. Methods Part 1 was an open‐label, dose‐finding, safety lead‐in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m 2 gemcitabine on days 1 and 8 and 75 mg/m 2 docetaxel on day 8). In part 2, patients were randomized in a double‐blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts. Results In part 2 with 209 patients, no significant difference in progression‐free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7‐6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6‐8.3 months) was observed ( P = .67; hazard ratio [HR], 1.07; 95% CI, 0.77‐1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2‐21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P = .32; HR, 1.23; 95% CI, 0.82‐1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated. Conclusions Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft‐tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone.

Introduction . Primary cardiac sarcoma (PCS) has a poor prognosis compared to other sarcomas due to late presentation, challenging resection, incidence of metastases, and limited efficacy of systemic therapies. Methods . A medical record search engine was queried to identify patients diagnosed with PCS from 1992 to 2017 at the University of Michigan. Results . Thirty-nine patients with PCS had a median age of 41 years (range 2–77). Common histologies were angiosarcoma (AS, 14), high-grade undifferentiated pleomorphic sarcoma (UPS, 10), and leiomyosarcoma (LMS, 5). Sites of origin were left atrium (18), right atrium (16), and pericardium (5). AS was the most common right-sided tumor; UPS was more common on the left. Eighteen patients presented with metastases involving lung (10), bone (7), liver (5), and brain (4). Twenty-five patients underwent resection, achieving 3 R 0 resections. Patients received a median of 2 (1–6) systemic therapies. Median overall survival (OS) was 12.1 months (range 0–79). Median OS was 14.0 months and 8.2 months in patients who did or did not undergo resection, respectively ( p = 0.018 ). Brain metastases occurred in 12 (31%) patients, 9 (75%) of whom had left heart tumors, at a median of 8.5 months (range 0–75) from diagnosis. Median OS was 5.6 months (range 0–30) after the diagnosis of brain metastases. Conclusions . PCS portends a poor prognosis, because of difficulty in obtaining complete resection of sarcoma, advanced stage at diagnosis, and high risk of brain metastases. Providers should be aware of the increased risk of brain metastases and consider brain imaging at diagnosis and follow-up.

Histone deacetylase inhibitors (HDACi) can reverse chemoresistance, enhance chemotherapy-induced cytotoxicity, and reduce sarcoma proliferation in cell lines and animal models. We sought to determine the safety and toxicity of mocetinostat and its ability to reverse chemoresistance when administered with gemcitabine in patients with metastatic leiomyosarcoma resistant to prior gemcitabine-containing therapy. Participants with metastatic leiomyosarcoma received mocetinostat orally, 70 mg per day, three days per week, increasing to 90 mg after three weeks if well tolerated. Gemcitabine was administered at 1,000 mg/m2 intravenously at 10 mg/m2/minute on days five and 12 of every 21-day cycle. Disease response was evaluated with CT or MRI. Twenty participants with leiomyosarcoma were evaluated for toxicity. Median time to disease progression was 2.0 months (95% CI 1.54–3.12). Eighteen participants were evaluated for radiologic response by RECIST 1.1. Best responses included one PR and 12 SD. Tumor size reduced in 3 patients. Most common toxicities were fatigue, thrombocytopenia, anemia, nausea, and anorexia. One patient experienced a significant pericardial adverse event. No study-related deaths were observed. Rechallenging with gemcitabine by adding mocetinostat was feasible and demonstrated modest activity in patients with leiomyosarcoma. Further studies are needed to better define the role of HDAC inhibitors in patients with metastatic leiomyosarcoma.

Abstract Background: Activation of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor receptor (MET) pathway promotes tumor growth, invasion and dissemination. Emibetuzumab is a humanized IgG4 monoclonal antibody that binds to and inhibits ligand-dependent and ligand-independent activation of MET. In the first-in-human dose escalation study NCT0128756, emibetuzumab demonstrated favorable tolerability when administered up to 2000mg Q2W IV in unselected patients. The study was expanded to evaluate emibetuzumab in expansion cohorts for patients with tumors positive for MET expression. Methods: Patients with locally advanced or metastatic castration-resistant prostate cancer (CRPC) with bone metastasis, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and hepatocellular carcinoma (HCC) received 2000 mg emibetuzumab Q2W IV on a 28-day cycle. RCC, NSCLC, and HCC patients were required to have measurable disease as defined by RECIST v1.1 and have MET positive tumors (≥50% of cells to be ≥2+ for MET expression) as determined by a MET IHC assay (Ventana). The objectives were to evaluate the safety and activity of emibetuzumab in patients with MET positive tumors. Additional objectives included pharmacokinetics (PK) and pharmacodynamics (PD). Results: A total of 62 patients received emibetuzumab across the 4 cohorts: CRPC n = 15, RCC n = 19, NSCLC n = 19,and HCC n = 9, with a median of prior systemic oncology therapies of 6, 3, 5, and 3, respectively. Common possibly related treatment-emergent adverse events included fatigue (29% all grades, 3% Gr3/4), nausea (13% all grades, no Gr3/4), edema of limbs (8% all grades, 2% Gr3/4), and anorexia (8%, no Gr3/4) and were similar among cohorts. No evidence of clinical activity was observed in CRPC patients. For RCC, NSCLC, and HCC patients with MET positive tumors, an overall disease control rate (DCR = partial response [PR] + stable disease [SD]) of 32% (15/47) was observed. In the individual cohorts, DCR was 26% (5/19) in RCC, 26% (5/19) in NSCLC, and 56% (5/9) in HCC. The median duration of disease stabilization in the 3 cohorts was: 4.2 months (range 1.6-24.6) in RCC, 3.9 months (range 2.5-6.4) in NSCLC, and 3.7 months (range 1.2-6.6) in HCC. One PR was observed in an HCC patient with MET amplification. After a single dose of 2000 mg emibetuzumab, PK parameters were similar among these cohorts and also comparable to patients treated at this dose during dose escalation. Conclusions: In cohorts enriched for tumor MET expression, limited single-agent activity of emibetuzumab was observed indicating that MET positivity by IHC (Ventana assay) at the cut-point employed here might not be a sufficient predictive biomarker to select patients receiving benefit from emibetuzumab monotherapy for the tumor types studied. Further evaluation of biomarkers/assays to identify patients who may benefit from treatment with emibetuzumab may be warranted. Citation Format: Michaela S. Banck, Rashmi Chugh, Ronald B. Natale, Alain Algazi, Bradley C. Carthon, Lee S. Rosen, Michael E. Menefee, Andrew Xiuxuan Zhu, Takami Sato, Brian Moser, P. Kellie Turner, Jay Tuttle, Xuejing Aimee Wang, Volker Wacheck, Frederick E. Millard. Phase 1 results of emibetuzumab (LY2875358), a bivalent MET antibody, in patients with advanced castration-resistant prostate cancer, and MET positive renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A55.