Citations

The TP53 tumor-suppressor gene is mutated in >50% of human tumors and Li-Fraumeni patients with germ line inactivation are predisposed to developing cancer. Here, we generated tp53 deleted zebrafish that spontaneously develop malignant peripheral nerve-sheath tumors, angiosarcomas, germ cell tumors, and an aggressive Natural Killer cell-like leukemia for which no animal model has been developed. Because the tp53 deletion was generated in syngeneic zebrafish, engraftment of fluorescent-labeled tumors could be dynamically visualized over time. Importantly, engrafted tumors shared gene expression signatures with predicted cells of origin in human tissue. Finally, we showed that tp53del/del enhanced invasion and metastasis in kRASG12D-induced embryonal rhabdomyosarcoma (ERMS), but did not alter the overall frequency of cancer stem cells, suggesting novel pro-metastatic roles for TP53 loss-of-function in human muscle tumors. In summary, we have developed a Li-Fraumeni zebrafish model that is amenable to large-scale transplantation and direct visualization of tumor growth in live animals.

2534 Background: The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were derived from an international collaborative effort supported by data from clinical trials (16 studies, 9147 patients) on cytotoxic chemotherapy (CT), providing a standard tool for response assessment. RECIST’s role has been questioned for TCA. Using a pooled individual patient database (IPD) from clinical trials performed by industry and cooperative groups, we assessed whether modifications to RECIST are required to evaluate antitumor activity of TCA. Methods: Data were collected from phase 2 and 3 clinical trials testing TCA in solid tumors. To study the occurrence of mixed responses, the variability of response of lesions within patients was studied. Furthermore, response was correlated with survival through landmark analyses and time dependent Cox models. Results: Clinical data were obtained from 23,259 patients, mainly with lung (36%), colorectal (28%) or breast cancer (11%). 15,620 patients (67%) received a TCA, mainly transduction or angiogenesis inhibitors, either as single agent (37%) or combined with other TCAs (7%) or CT (56%); 28% received CT only and 5% best supportive care or placebo. Within-patient variability reduced as the number of lesions used for response assessment increased, and did so similarly for TCAs (+/- CT) and CT. Mixed responses seemed to occur similarly across these treatment categories as well. Landmark analyses showed improving overall survival by % tumor shrinkage and a clear distinction between the effect of tumor shrinkage and progressive disease (PD) according to RECIST 1.1. This was confirmed by time dependent analysis. In addition target lesion growth showed no marked improvement in overall survival prediction over and above the other components of RECIST 1.1 PD (new lesions, non-target PD), regardless of treatment (TCA, CT or both) received. Similar results were seen focusing on major tumor types and classes of TCA. Conclusions: Using a large IPD dataset we demonstrated that RECIST 1.1 performs equally well for response assessment of TCA as for CT. No modifications are required.

11058 Background: Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS) typically seen in young adults accounting for < 1% of all STS. While local disease may be indolent, ES can rapidly spread and patients (pts) with distant metastasis are often resistant to systemic treatment with 1 year survival of < 50%. The defining molecular feature of ES is the absence of tumor expression of INI1, a SWI/SNF subunit member involved in chromatin remodeling. Tazemetostat, a potent and selective EZH2 inhibitor, has demonstrated tumor regressions in INI1 negative preclinical malignant rhabdoid tumors (MRT) models and phase 1 clinical activity in MRT and ES pts. The proposed mechanism of tazemetostat sensitivity is INI1 loss inducing compromised SWI/SNF activity and tumor dependence on PRC2 activity (of which EZH2 is the catalytic subunit). Preliminary phase 2 safety and efficacy of tazemetostat in ES pts is reported here. Methods: This is a phase 2 multicenter open-label single arm study of tazemetostat (800 mg po BID) in adult pts with ES whose tumors harbor evidence of INI1 loss. Pts enroll into 1 of 5 cohorts of different tumor types with INI1 loss/reduction, up to 30 pts each, using a 2-stage Green-Dahlberg design. For the ES cohort, primary endpoint is disease control rate (DCR) defined as objective response of any duration or stable disease (SD) lasting ≥32 wks. Success at stage 2 required DCR in ≥5/30 treated pts. Key secondary endpoints include safety/tolerability, ORR, PFS, OS, PK and response biomarkers e.g. H3K27me3. Results: In 31 ES pts with a median of 1 prior systemic therapy, stage 2 DCR criteria was surpassed with a RECIST confirmed PR (4 pts) and SD ≥32 wks (2 pts) observed to date. 13 pts are still on treatment therefore DCR and ORR will be updated. Tazemetostat was well tolerated with grade 1/2 fatigue (39%), nausea (26%) and vomiting (19%) as the most frequently reported AEs regardless of attribution. Conclusions: In the largest prospective clinical trial of ES to date, tazemetostat monotherapy shows promising antitumor activity, including confirmed responses and long-term SD, with favorable safety/tolerability in ES. Enrollment has been expanded to 60 ES pts given the clinical activity described here. Clinical trial information: NCT02601950.

11006 Background: CMB305 is an active immunotherapy regimen designed to generate and expand anti-NY-ESO-1 T cells. It consists of LV305, a dendritic cell targeting lentiviral vector encoding NY-ESO-1, and a boost with G305, an NY-ESO-1 recombinant protein plus GLA-SE, a TLR-4 agonist. An LV305 phase 1 study demonstrated a 1-yr survival of 81% and induction of anti-NY-ESO-1 T cells in sarcoma patients (pts). This first-in-human study of CMB305 examined safety, immunogenicity, and efficacy in pts with NY-ESO-1 positive (+) solid tumors. Methods: Adults with previously treated NY-ESO-1+ sarcomas, NSCLC, ovarian cancer were enrolled in a 3+3 dose-escalation with an expansion phase 1 study. The CMB305 regimen included 4 intradermal injections of LV305 at 109 or 1010 vector genomes, alternating with 3 intramuscular G305 injections at 250 µg for 3 months, then bimonthly G305 injections up to 1 yr. Results: As of 31Dec2016, 25 pts with STS (15 synovial (SS), 8 myxoid/round cell liposarcoma (MRCL), 2 other) were evaluable for safety; 23 SS/MRCL pts were evaluable for immune response (IR) and efficacy. All SS and MRCL pts received prior therapy for locally advanced/metastatic disease, 67% > = 2 prior chemo regimens. No DLTs were observed; treatment related AEs were grade 1 and 2, except 1 pt with grade 3 SAE (prostatic pain). Of 11 SS/MRCL pts tested, 64% pts developed NY-ESO-1 specific T cells and 72% pts anti-NY-ESO-1 antibodies. T cell receptor sequencing indicated increased clonality, and antigen spreading after CMB305. Best response by immune related response criteria was stable disease in 8/15 (53%) SS pts and 6/8 (75%) MRCL pts. The 3 month PFS rate was 74% and 75% for SS and MRCL pts. Median survival has not been reached with 1-yr survival rate of 86% and 100% for SS and MRCL pts. Conclusions: CMB305 is safe, well tolerated, and demonstrates a survival rate that is favorable when compared with approved agents for recurrent STS. CMB305 resulted in a stronger and broader integrated IR than LV305, including antigen spreading. These data warrant further investigation of CMB305 as a monotherapy in a randomized clinical study in STS. A randomized study of CMB305 in combination with atezolizumab in SS/MRCL pts is ongoing. Clinical trial information: NCT02387125.

7516 Background: PCNSL is a diffuse large B cell lymphoma confined to the CNS. Pomalidomide (POM) is a novel immunomodulatory agent with excellent CNS penetration (~40%) based on CNS PK analysis in rats and pre-clinical therapeutic activity against CNS lymphoma. Methods: A Phase I clinical trial was undertaken to determine the maximal tolerated dose (MTD) of POM, safety profile and overall response rate (ORR). Treatment consists of POM daily for 21 days every 28 days in combination with dexamethasone 40 mg PO weekly for two cycles followed by POM alone in subsequent cycles until progression or intolerance. 4 dose escalation levels of POM (3mg, 5mg, 7mg, and 10 mg) were planned. Thromboprophylaxis with oral anticoagulant or aspirin was required. MTD determination has been completed and expansion of the MTD cohort is ongoing. Therapeutic responses were evaluated per the international PCNSL collaborative group (IPCG) criteria after 2 cycles of treatment. The trial is registered with ClinicalTrials.gov (#NCT01722305). Results: 21 of 25 patients accrued were eligible for assessment. The MTD was determined to be 5 mg qd for 21 days every 28 days. Two DLTs were seen at dose level 3 (Grade 3 dyspnea and grade 4 thrombocytopenia). One DLT was seen in the expanded MTD cohort (Grade 4 neutropenia and lymphocytopenia). ORR for the study (9/21) was 43% (95% CI- 22%, 66%) with 4 CR, 1 CRu and 4 PR. 3 responders completed 2, 4, and 6 cycles before progression. 6 responders have completed 4, 5, 6, 10, 12, and 32 cycles and remain on treatment. ORR for the MTD dose level was (5/12) 42% (95% CI- 15%, 72%) with 3 CR and 2 PR. 2 patients had stable disease (SD). Pseudo-progression was seen in 1 patient. Overall, grade 3/4 toxicity was hematologic (neutropenia, anemia, and thrombocytopenia) in 38.1% and non-hematologic in 33.3% (fatigue, pneumonia, sepsis, syncope, dyspnea, hypoxia, respiratory failure and maculo-papular rash). Percent CSF/blood ratio of POM was determined to be 19% in 1 patient. Conclusions: Pomalidomide treatment is feasible with therapeutic activity against relapsed/refractory PCNSL and should be further developed. Clinical trial information: NCT01722305.