Citations

11564 Background: Epithelioid sarcoma (ES) is a rare, aggressive soft tissue sarcoma characterized by loss of inhibitor of integrase 1 (INI1), allowing enhancer of zeste homologue 2 (EZH2) to repress cell differentiation and promote tumorigenesis. Tazemetostat (TAZ) is a selective inhibitor of EZH2 approved by the FDA for treatment of patients (pts) aged ≥16 years with metastatic or locally advanced ES ineligible for complete resection. Methods: This open-label, multicenter, multi-cohort phase 2 study (NCT02601950) evaluated safety and efficacy of TAZ in pts with INI1-negative tumors. ES pts were enrolled in Cohorts 5 and 6; pts in Cohort 6 underwent mandatory pre-dose (at screening) and post-dose biopsies (at Day 1 of cycle 2). Herein, we report the interim efficacy and safety data from Cohort 6. Results: As of July 31 2019, 44 pts were enrolled into Cohort 6 and treated with TAZ 800 mg BID. The objective response rate (ORR) was 11.4%; 4 pts (9.1%) had a partial response and 1 pt (2.3%) had a complete response (Table). Another 17 pts (38.6%) had stable disease (SD). 18 pts had progressive disease; 13 of these pts remained on study beyond progression. Progression-free survival (PFS) and overall survival (OS) at 56 weeks were 19.4% and 59.4%, respectively. In a pooled posthoc analysis of 106 ES pts from Cohorts 5 (n = 62), and 6, ORR was 13.2%. Grade 3–4 adverse events (AEs) were reported in 16 pts (36.4%), most commonly anemia (6.8%; n = 3) and tumor pain (6.8%; n = 3). 3 pts (6.8%) experienced grade 3–4 treatment-related AEs. One pt discontinued study drug and there were no treatment-emergent dose reductions or treatment-related deaths. These safety data from Cohort 6 are consistent with previously reported data from Cohort 5. 19 paired biopsies were included for translational endpoint analyses. Preliminary RNA seq and pathway analyses are currently ongoing and updated data, including additional biomarker data will be presented. Conclusions: Consistent with previously reported data from the completed Cohort 5, TAZ demonstrated clinically meaningful, durable, single agent activity in ES pts. Efficacy data from Cohort 6 continue to mature with 8 patients still on treatment. TAZ was well tolerated with a low incidence of treatment related AEs. Clinical trial information: NCT02601950 . [Table: see text]

11539 Background: Ripretinib is a novel switch-control TKI that broadly inhibits KIT and PDGFRA kinase signaling. In INVICTUS (NCT03353753), a randomized, double-blind, placebo (PBO)-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs PBO with a favorable overall safety profile. Common ( > 20%) adverse events (AEs) included, but were not limited to, alopecia and PPES. Exploratory analyses evaluated the impact of alopecia and PPES on quality of life (QoL). Methods: Patients (pts) with advanced GIST previously treated with at least imatinib, sunitinib, and regorafenib were randomized (2:1) to ripretinib 150 mg QD or PBO. AEs were graded using CTCAE v4 and PROs collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). Repeated measures (RM) models assessed the impact of alopecia and PPES on 5 PROs (EQ5D visual analogue scale; and C30 physical functioning, role functioning, and the overall health and overall QoL questions) within the ripretinib arm. Fixed effects were sex, alopecia/PPES, and ECOG scores at baseline. Results: 128/129 randomized pts received treatment (85 ripretinib 150 mg QD; 43 PBO). Alopecia, regardless of causality, occurred in 44 (51.8%) on ripretinib (34 [40.0%] grade 1; 10 [11.8%] grade 2) and 2 (4.7%) on PBO (both grade 1). PPES occurred in 18 (21.2%) on ripretinib (11 [12.9%] grade 1; 7 [8.2%] grade 2); none on PBO. The median times in days to first occurrence and worst severity grade with ripretinib were 57.0 and 62.5 for alopecia; 56.5 and 57.0 for PPES. The RM models showed a slight trend towards improvement in PRO score over time for pts with alopecia; the only association reaching a P-value of < 0.05 was between alopecia and increased overall QoL. None of the associations between PPES and PRO scores reach P < 0.05. All PRO p-values are nominal, and no statistical significance is being claimed. Conclusions: Ripretinib had a favorable overall safety and tolerability profile. When stratified by alopecia and PPES, patient-reported assessments of function, overall health, and overall QoL were maintained over time. For both alopecia and PPES, onset and maximum severity occurred almost simultaneously, indicating that these events generally did not progressively worsen. These results suggest that alopecia and PPES are manageable and do not have a negative effect on function, overall health, and QoL. Clinical trial information: NCT03353753 .

11535 Background: Ripretinib is a novel switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits KIT and PDGFRA kinase signaling through a dual mechanism of action. In INVICTUS (NCT03353753), a randomized, double-blind, placebo-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs placebo and had a favorable overall safety profile in patients previously treated with ≥3 prior TKIs. Methods: As part of the INVICTUS trial, patient reported outcome (PRO) measures were collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). In prespecified and additional analyses, ANCOVA models were built to compare changes from baseline to cycle 2 day 1 (C2D1) for PRO measures within the ripretinib and placebo arms and determine the difference between treatment arms. PRO measures included the EQ5D visual analogue scale (VAS) and the C30 physical functioning (PF) and role functioning (RF) scales (all scores range from 0–100; higher scores are better). The C30 overall health and overall QoL questions were also assessed (scores range from 1–7; higher scores are better). Fixed effects included treatment arm, number of previous anticancer treatments (3 vs ≥4), and ECOG score at baseline (0 vs 1/2). Results: Overall, 129 patients were randomized and 128 received treatment (85 to ripretinib 150 mg QD; 43 to placebo). All PRO p-values are nominal, and no statistical significance is being claimed. VAS scores improved an average 3.7 points from baseline to C2D1 with ripretinib vs an average decline of 8.9 with placebo (P = 0.004; improvement or no change, 67% vs 41% of patients, respectively). Similarly, the average PF score improved 1.6 points with ripretinib and decreased 8.9 with placebo (P = 0.004; improvement or no change, 68% vs 44%). RF scores also improved an average of 3.5 points with ripretinib vs a decrease of 17.1 with placebo (P = 0.001; improvement or no change, 77% vs 50%). For the overall health and overall QoL questions, scores increased with ripretinib an average of 0.20 and 0.28, respectively, and decreased 0.78 and 0.76 with placebo (both P = 0.001; improvement or no change, 74% vs 47% and 79% vs 59%, respectively). Conclusions: Based on the 5 PRO measures assessed, when compared with placebo and best supportive care, ripretinib provided patient-benefit in advanced GIST with PRO measures of role and physical function, VAS, overall health, and overall QoL remaining stable. Clinical trial information: NCT03353753 .

e16686 Background: Genetic alterations in the FGFR pathway are emerging as promising therapeutic targets in CCA. The clinical and molecular features of patients (pts) with CCA harboring FGFR genetic alterations are reported here. Methods: A retrospective chart review was performed in pts with CCA who were found to have an FGFR alteration on tumor molecular profiling as part of routine care between 9/2007 and 12/2019. Data on demographics, risk factors, pathology, molecular characteristics, systemic therapies, radiographical response, time on treatment, and overall survival (OS) were collected in a multi-center collaborative effort across seven academic centers. Results: Among 135 pts with FGFR-altered CCA, the median age at diagnosis was 57 years old (range = 25-92 years), and 80 (59.3%) pts were female, 129 (95.6%) had intrahepatic CCA, and 6 (5.6%) had chronic HBV. At presentation, 28.2% of pts had resectable disease, including 65.0% with Stage I-II, 22.5% with Stage III, and 5.0% with Stage IV. At the time of initial diagnosis, CA19-9 was < 35U/mL in 42.6% of pts. Bone metastases were observed in 41 (30.6%) pts with advanced disease. FGFR2 fusions were the most common FGFR alteration (68.2%), followed by FGFR2 mutations (21.5%), FGFR3 mutations (3.7%), FGFR2 rearrangements (1.5%), FGFR1 amplification (1.5%), and FGFR2 amplification (1.5%). The most common FGFR2 fusion partners were BICC1 (28.3%), SORBS1 (4.4%), POC1B (3.3%), and TACC2 (3.3%). The median lines of palliative systemic therapies received was 3 (range = 0-8), and 40/135 (29.6%) pts received a liver-directed therapy. For the 55 (59.8%) pts with FGFR2 fusions who received gemcitabine/cisplatin as first-line palliative systemic therapy, the median time on treatment was 6.2 months (95% CI: 4.1-9.3). The median OS from time of initial diagnosis was 36.1 months (95% CI: 28.3-51.6) in the FGFR2 fusion positive cohort. Among the 92 pts with FGFR2 fusions, 70 (76.1%) pts received an FGFR inhibitor on a clinical trial; 12 (17.1%) were subsequently treated with a second FGFR inhibitor, and 58.3% stayed on the second FGFR inhibitor for ≥4 months. Pts with a BICC1 fusion partner (n = 16) had an overall response rate of 42.9% on FGFR-selective inhibitors compared to 30.8% in non-BICC1 fusion partners (n = 54). Conclusions: Pts with CCA harboring FGFR alterations were found to have a high rate of normal CA19-9, high rate of bone metastases, and short median time on treatment on first-line palliative gemcitabine/cisplatin. Additional comparative studies are necessary to evaluate these findings.

4508 Background: The combination of dual immune checkpoint inhibitors (ICI) T (anti–CTLA-4) and D (anti–PD-L1) showed tolerability with a promising objective response rate (ORR) in the initial cohort of this study (NCT02519348). Subsequent evaluation of pts with solid tumors treated with increasing doses of T suggested priming with a higher dose of T may induce a stronger immune response and enhance anti-tumor activity. Thus, the randomized expansion cohorts comprised 4 arms evaluating T and D as monotherapies and 2 T+D regimens, including a novel T+D regimen featuring a single, priming dose of T. Methods: ICI-naïve pts with aHCC who progressed on, were intolerant to, or refused sorafenib were randomized to one of two T+D combinations: T300+D (T 300 mg + D 1500 mg 1 dose followed by D Q4 weekly [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses] followed by D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W). Safety was the primary endpoint. ORR by blinded, independent central review using RECIST v1.1, duration of response (DoR), circulating lymphocytes, and overall survival (OS) were assessed. Results: At data cut-off (09/02/2019), 332 pts were enrolled. Median follow-ups were 11.7 months (mo) for T300+D, 14.6 (T75+D), 8.9 (D), and 15.8 (T). Treatment-related adverse event (trAE) incidences are shown (Table); no deaths were attributed to trAEs for T300+D or T. The T300+D arm had the highest confirmed ORR (DoR not reached [NR]) and longest OS (Table). A unique proliferative T cell profile was identified for pts in the T300+D arm, suggesting additive biologic activity for the combination, and showed pts with an OR exhibited high cytotoxic (CD8) counts. Conclusions: The encouraging clinical activity and tolerable safety profile suggest T300+D provides the best benefit-risk profile as opposed to T75+D or monotherapies. The unique pharmacodynamic activity of the T300+D regimen further supports its use in aHCC. T300+D and D are being evaluated in the ongoing phase III HIMALAYA study (NCT03298451) in first-line HCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348 . [Table: see text]

Purpose. Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. Patients and Methods. Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles. Results. Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (p=0.47). Median OS was not reached in either arm. Conclusions. Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.

Abstract Background Rapid blood culture diagnostics are of unclear benefit for patients with gram-negative bacilli (GNB) bloodstream infections (BSIs). We conducted a multicenter, randomized, controlled trial comparing outcomes of patients with GNB BSIs who had blood culture testing with standard-of-care (SOC) culture and antimicrobial susceptibility testing (AST) vs rapid organism identification (ID) and phenotypic AST using the Accelerate Pheno System (RAPID). Methods Patients with positive blood cultures with Gram stains showing GNB were randomized to SOC testing with antimicrobial stewardship (AS) review or RAPID with AS. The primary outcome was time to first antibiotic modification within 72 hours of randomization. Results Of 500 randomized patients, 448 were included (226 SOC, 222 RAPID). Mean (standard deviation) time to results was faster for RAPID than SOC for organism ID (2.7 [1.2] vs 11.7 [10.5] hours; P &lt; .001) and AST (13.5 [56] vs 44.9 [12.1] hours; P &lt; .001). Median (interquartile range [IQR]) time to first antibiotic modification was faster in the RAPID arm vs the SOC arm for overall antibiotics (8.6 [2.6–27.6] vs 14.9 [3.3–41.1] hours; P = .02) and gram-negative antibiotics (17.3 [4.9–72] vs 42.1 [10.1–72] hours; P &lt; .001). Median (IQR) time to antibiotic escalation was faster in the RAPID arm vs the SOC arm for antimicrobial-resistant BSIs (18.4 [5.8–72] vs 61.7 [30.4–72] hours; P = .01). There were no differences between the arms in patient outcomes. Conclusions Rapid organism ID and phenotypic AST led to faster changes in antibiotic therapy for gram-negative BSIs. Clinical Trials Registration NCT03218397.

Abstract Background: Responses to the novel HDAC inhibitor romidepsin were observed in patients (pts) with T-cell lymphoma in a phase 1 NCI trial. Aims: To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced cutaneous T-cell lymphoma (CTCL). As an exploratory endpoint, to examine the molecular effects of romidepsin in both CTCL and peripheral T-cell lymphoma (PTCL). Methods: This Phase 2, open-label, multi-arm, multicenter study enrolled 71 CTCL pts from the NCI and 9 extramural sites. PTCL pts were also enrolled. Clinical results for pts with CTCL and biomarker analyses for both PTCL and CTCL are presented here; clinical results for the PTCL pts are presented elsewhere. This study is now closed to accrual. Pts with recurrent CTCL (Stages IA-IVB) received romidepsin at 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 q 28 days. Responses were assessed using a composite endpoint that evaluated overall changes in skin (modified Physicians Global Assessment), lymph nodes, extranodal visceral lesions and abnormal circulating T-cells. Molecular endpoints evaluated in NCI pts were: histone acetylation in peripheral blood mononuclear cells (PBMCs); MDR-1 gene expression in PBMCs and in biopsy samples; and blood fetal hemoglobin levels. Results: 71 pts (48 men and 23 women) with a mean age of 56 yrs (range 28–84) were enrolled and received romidepsin; 63 pts received ≥2 cycles of therapy. Mean number of prior therapies was 3.4 (range 1–10). Objective disease response rates (ORR) are presented in the table. Overall disease control (CR+PR+SD90) was 62% in all pts and 70% in pts who received ≥2 cycles. Target skin lesions were followed and changes were generally similar to overall skin changes. Median duration of response (DOR) was 11 months (mo) and the maximum DOR as of data cut-off was 5.5+ yrs. The most frequent drug-related AEs (all grades, all cycles) were generally mild, including nausea (82%; 4% ≥grade 3), fatigue (73%; 14% ≥ grade 3), electrocardiogram T-wave amplitude decreased (69%, 0% ≥grade 3); hemoglobin decreased (59%, 9% ≥grade 3), and platelet count decreased (59%; 13% ≥grade 3). Six pts died within 30 days of study drug administration: 2 after salvage chemotherapy, 1 with ARDS due to PD, 2 with infection, and 1 of unknown cause; 2 of these deaths were considered possibly related to treatment. An increase in all biomarkers measured was observed, although not in all pts. Correlation between global histone H3 acetylation (AcH3) at the 24-hr time point and Cmax, AUC, and clearance was observed (r = 0.37, 0.36, and −0.44, respectively, p = 0.03). Pts with major responses were more likely to have higher levels of AcH3 at 24 hr. Conclusions: This study demonstrates tolerability and durable clinical benefit (ORR of 35% and median DOR of 11 mo in all pts) of romidepsin in pts with recurrent CTCL. Significant responses were observed at all stages of disease, including an ORR of 32% in all pts with stage ≥IIB and 20% in all pts with stage IV. Time to response was rapid, within 2 mo in most pts, and responses were durable, &gt;6 mo in most pts. Molecular analyses confirmed that romidepsin inhibits its target deacetylases in pts. Increases were not observed in all pts, perhaps reflecting, in part, variable drug exposure or variable response to HDAC inhibition. Correlation of global acetylation with PK parameters suggests that increased drug exposure results in increased global acetylation. All Pts N=71 Pts ≥ 2 cycles N=63 ORR (CR+PR), n (%) 25 (35%) 25 (40%) PR, n (%) 21 (30%) 21 (33%) CR, n (%) 4 (6%) 4 (6%) SD90, n(%) 19 (27%) 19 (30%) Overall disease control (CR+PR+ SD90) 44 (62%) 44 (70%) DOR 11 (1+ mo, 5.5+ yrs) 11 (1+ mo, 5.5+ yrs) OR for pts with stage ≥ IIB, n (%) 20/62 (32%) 20/55 (36%) SD90= stable disease for ≥90 days

Abstract Background: The histone deacetylase (HDAC) inhibitors are a class of epigenetic agents undergoing clinical testing. HDAC inhibitors modulate expression of genes involved in cell cycle regulation, leading to induction of differentiation or apoptosis. Romidepsin, a novel, HDAC inhibitor, has previously demonstrated activity as a single agent in patients (pts) with T-cell lymphoma in a phase 1 NCI study. Aims: To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced PTCL and as an exploratory endpoint, to examine the molecular effects of romidepsin in both PTCL and cutaneous T-cell lymphoma (CTCL). Methods: This Phase 2, open-label, multi-arm, multicenter study enrolled 43 PTCL pts from the NCI and 9 extramural sites. CTCL pts were also enrolled in this study. The clinical results for pts with PTCL are presented here; the clinical results for the pts with CTCL and the biomarker analyses for both PTCL and CTCL are presented elsewhere. This study is now closed to accrual. Pts with relapsed or refractory PTCL or primary cutaneous anaplastic large cell lymphoma were eligible. Pts received romidepsin 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 every 28 days. Responses were assessed using elements of the IWG criteria and RECIST, as appropriate, for pts with lymph node involvement and extranodal disease. Results: 43 pts (23[53%] men and 20 [47%] women) with a mean age of 58.1 (range: 27 to 84) years were treated with romidepsin. 31 pts received ≥ 2 cycles of therapy. Mean number of prior therapies was 3.9 (range 1 to 12). Objective disease response rates (ORR) are summarized in the table. The mean number of cycles of treatment was 6.8 (range 1–37) and the overall median duration of response was 8.3 months (range 1.6 months to 4.8+ yrs) for all pts. The median duration of response for the 7 pts who achieved CR was 8.5 months (range 4.6 months to 4.8+yrs). The most frequent drug-related AEs (all grades, all cycles) were generally mild and included: nausea (86%; 0% ≥grade 3), fatigue (79%; 0% ≥grade 3), decreased platelets (70%; 7% ≥grade 3), and decreased AGC (63%; 5% ≥grade 3). One death, in a pt with significant cardiovascular disease who had achieved a CR, was considered possibly related to treatment. Conclusions: This study demonstrates tolerability and durable clinical benefit (ORR of 39% and median duration of response of 8.3 months) of romidepsin in pts with recurrent or refractory PTCL. Based on these promising results, a Phase 2B protocol investigating romidepsin in pts with progressive or relapsed PTCL is ongoing at multiple international centers. All Pts N=43 Pts ≥ 2 cycles N=31 ORR (CR+PR), n (%) 17 (39%) 17 (55%) PR, n (%) 10 (23%) 10 (32%) CR, n (%) 7 (16%) 7 (23%)