Citations

TPS8584 Background: The first-line standard of care for the majority of patients (pts) with extensive-stage small-cell lung cancer (ES-SCLC) is platinum-based chemotherapy with etoposide, but survival outcomes remain poor (median OS, < 1 year) despite initial response rates ranging from 50-70%. Atezolizumab (atezo), an anti–PD-L1 mAb, prevents the binding of PD-L1 with its receptors PD-1 and B7.1 and restores anticancer T-cell activity. Tolerable safety with promising durability of response has been shown with atezo in pts with ES-SCLC: confirmed ORR was 6% (n = 1/17 [partial response]; DOR of 7 mo) by RECIST v1.1 and 24% by immune-related response criteria (irRC; n = 4/17, with 2 pts on atezo for ≥ 12 mo). Preliminary data also indicate the potential synergy between atezo and platinum-based chemotherapy in NSCLC, whereby durable responses may translate into improved survival over atezo alone. IMpower133 (NCT02763579), a global, Phase I/III, randomized, multicenter, double-blinded, placebo-controlled trial will evaluate the efficacy and safety of 1L atezo + carboplatin + etoposide compared with placebo + carboplatin + etoposide in treatment-naive pts with ES-SCLC. Methods: Pts with measurable (RECIST v1.1) ES-SCLC, who have ECOG PS 0-1 and no prior systemic anticancer treatment, are eligible for the study. Exclusion criteria include untreated CNS metastases and history of autoimmune disease. The study requires submission of tumor tissue, but pts will be enrolled regardless of biomarker status. Pts will be stratified by sex, ECOG PS and presence of treated brain metastases. Eligible pts will be randomized 1:1 to receive four 21-day cycles of atezo (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min IV, d 1) and etoposide (100 mg/m2 IV, d 1-3), followed by maintenance therapy with atezo or placebo until PD per RECIST v1.1. Pts can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints are investigator-assessed PFS per RECIST v1.1 and OS. Secondary efficacy endpoints include investigator-assessed ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 pts will be enrolled. Clinical trial information: NCT02763579.

7003 Background: Gilteritinib, a highly selective FLT3/AXL inhibitor, has displayed antileukemic activity in FLT3 mutation-positive (FLT3mut+) relapsed/refractory (R/R) AML in the CHRYSALIS Phase I/II study (NCT02014558), specifically at doses ≥80 mg/d. This exploratory analysis assessed molecular response to gilteritinib in a CHRYSALIS subpopulation. Methods: Molecular response was assessed from bone marrow aspirates obtained at baseline and at ≥1 additional time point from FLT3mut+ patients (≥18 y) treated with 120 or 200 mg/d gilteritinib. These doses were identified due to their ability to induce consistent, potent FLT3 inhibition and high clinical response rates. FLT3-ITD and total FLT3 were quantified by NGS to assess molecular response. A Cox regression model of overall survival (OS) by Kaplan-Meier estimation established a FLT3-ITD:total FLT3 ratio (ITD signal ratio) of 10−2as the threshold for improved survival. Results: Of 147 FLT3-ITDmut+ patients who received gilteritinib 120 or 200 mg/d, 80 were included in this analysis. Composite response rate for these 80 patients was 55%. During response, 20 patients (25%) had an ITD signal ratio of ≤10−2. Of these 20 patients, 18 had a ratio of ≤10−3 (major molecular response [MMR]) and 13 had a ratio of ≤10−4 (minimal residual disease [MRD] negative). Median time to achieve minimum signal ratio was 54 days. Elimination of morphologic leukemia was observed in 80% of patients with ITD signal ratios <10−2. Patients who had a signal ratio ≤10−2, MMR, or were MRD negative had significantly longer median OS than those who did not (Table). Conclusions: Molecular responses to gilteritinib in FLT3-ITDmut+ R/R AML correlated with clinical response and improved OS. This is the first demonstration of molecular response to a FLT3 inhibitor in AML. These data suggest ITD signal ratio may predict durable clinical benefit of gilteritinib. Clinical trial information: NCT02014558. [Table: see text]

4106 Background: Cancer stem cells are fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapy and targeted agents. Methods: A phase Ib/II multi-center study in mPDAC pts was performed to confirm the RP2D, PK profile and evidence of anticancer activity of napabucasin in combination with nabPTX and Gem. Pts received napabucasin 240 mg BID with weekly nabPTX 125 mg/m2 and gem 1000 mg/m2for 3 out of every 4 weeks until disease progression (PD) or other discontinuation criterion. Results: Of 71 intent to treat (ITT) pts enrolled, 49 (69%) were treatment-naïve and 22 (31%) received neoadjuvant treatment. There were no significant PK interactions, dose-limiting or unexpected toxicities. Most common adverse events (AEs) included grade 1 diarrhea/cramping, nausea and fatigue with grade 3 AEs noted in 12 pts: fatigue (8), electrolyte imbalance (2), diarrhea (1), dehydration (1), nausea (1) and weight loss (1). Among pts who received RECIST evaluation (60), disease control (DCR; CR+PR+SD) was observed in 55 (92%), with 1 CR (2%) and 26 PR (43%) (31 - 78% regression). Of 11 pts with non-evaluable disease, treatment stopped due to compliance (4), consent withdrawal (3), clinical PD (1), toxicity (1), insurance (1) and death (1). Among 71 ITT pts, DCR was observed in 55 (77%), with 1 CR (1.4%) and 26 PR (37%). Maturing median progression free survival and overall survival (OS) in ITT pts is >7.1 and >10.4 m, respectively. Conclusions: This study showed that napabucasin can be combined with nabPTX and gem, with encouraging signs of efficacy in mPDAC now being confirmed in a phase 3 study. Clinical trial information: NCT02231723. [Table: see text]

TPS3102 Background: Multiple myeloma (MM) is largely incurable despite available therapies, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs). As most MM patients (pts) eventually have relapsed/refractory (RR) disease, there is an unmet need. Myeloma cells upregulate PD-L1 [Liu et al, 2007]. Nivolumab (nivo), an immuno-oncology mAb, binds PD-1 on T cells and natural killer cells and inhibits signaling by PD-L1–expressing tumor cells, thus augmenting antitumor immunity. Nivo monotherapy has shown acceptable safety and modest clinical activity in RRMM [Lesokhin et al 2016]. Daratumumab (dara) is a cytolytic mAb that targets CD38+ myeloma cells, inducing antibody‐dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis, and may have an immunomodulatory role via depletion of CD38+ immune-suppressor cells [Dimopoulos et al 2016]. Dara is approved as monotherapy (US: after ≥3 prior lines of therapy; EU: after a prior PI and IMiD and progression on last therapy), and with lenalidomide/dexamethasone (dex) or bortezomib/dex (US: after ≥1 prior line of therapy for both combinations). Combining PD-1 and CD38 mAbs, immunotherapies with different mechanisms of action, may overcome resistance and improve outcomes. This phase 1 safety study (NCT01592370) includes multiple cohorts of nivo as monotherapy or in combination regimens across RR hematologic malignancies; 2 MM cohorts will evaluate nivo plus dara, with or without pomalidomide and dex. Methods: Eligible pts are aged ≥18 y, with RRMM after ≥2 prior therapies. Pts are RR to their last regimen, RR to prior IMiD and PI therapy, and agreed to bone marrow aspiration. Primary outcome of safety/tolerability will be measured by incidence of drug-related adverse events (AEs), serious AEs, and laboratory test abnormalities. Secondary endpoints include minimal residual disease, overall response rates and duration of response, and progression-free survival. Study funding: BMS. Writing support: C Tomas, Caudex, funded by BMS. Clinical trial information: NCT01592370.

3529 Background: Cancer stem cells are considered to be fundamentally important for resistance, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinically, napabucasin sensitizes cancer cells to chemotherapy and targeted agents. Methods: A phase Ib/II multi-center study in mCRC pts was done to confirm the RP2D and signs of anti-cancer activity of napabucasin in combination with FOLFIRI +/- Bev. Pts received napabucasin 240 mg PO BID with bi-weekly FOLFIRI IV +/- Bev 5 mg/kg until disease progression or other discontinuation criterion. Results: 82 pretreated mCRC pts were enrolled (ITT); including 32 (39%) previously treated with FOLFIRI +/- bev. Of the 82 pts, 48 received FOLFIRI and 34 FOLFIRI plus bev in combination with napabucasin. There was no dose-limiting or unexpected toxicity or significant PK interactions. Most common adverse events (AEs) included grade 1/2 diarrhea, cramping, nausea, vomiting, fatigue and anorexia with grade 4 diarrhea in 1 pt and 27 pts with grade 3 AEs including: diarrhea (15), fatigue (5), dehydration (1), electrolyte imbalance (4), abdominal pain (1), vomiting (1) and weight loss (1), which resolved with dose reduction and supportive care. Disease control (CR+PR+SD) was observed in 55 of 66 pts who received RECIST evaluation (83%), with 1 CR (1.5%), 13 PR (20%) (33-100% regression) and 27 SD with tumor regression (41%). Conclusions: This phase Ib/II study confirmed that napabucasin can be safely combined with FOLFIRI +/- bev, and shows encouraging signs of efficacy in pretreated mCRC pts, including pts previously treated with FOLFIRI +/- bev. Clinical trial information: NCT02024607. [Table: see text]

TPS2079 Background: Patient with glioblastoma (GBM) with unmethylated MGMT promoters derive limited benefit from temozolomide (TMZ) and have dismal outcome. Prioritizing the numerous available therapies and biomarkers for late stage testing requires an efficient clinical testing platform. INSIGhT (NCT02977780) is a biomarker-based, Bayesian adaptively randomized, multi-arm phase II platform screening trial for patients with newly diagnosed GBM and unmethylated MGMT promoters. Methods: INSIGhT compares experimental arms to a common control of standard concurrent TMZ and radiation therapy (RT) followed by adjuvant TMZ. The primary endpoint is overall survival (OS). Patients with newly diagnosed, unmethylated GBM that are IDH R132H mutation negative, and with genomic data available or who consent to whole exome sequencing through the ALLELE companion study for biomarker grouping are eligible. Two experimental arms consist of concurrent RT/TMZ followed by adjuvant neratinib (EGFR, HER2, and HER4 inhibitor) or abemaciclib CDK 4/6 inhibitor), respectively, in place of TMZ. The other experimental arm is CC-115 (TORC1/2 and DNA PK inhibitor), which replaces TMZ in both the concurrent and adjuvant phases. Biomarker groups include: EGFR + patients with EGFR amplification/mutation; PI3K + patients with PIK3CA mutation/amplification, PIK3R1 mutation, AKT3amplification, PIK3C2B > 1 copy gain, or PTEN dual loss; CDK: + patients with wild-type RB1 and CDK4 amplification, CDK6 amplification, or CDKN2A > 1 copy loss. Given the lack of pretrial biomarker data and the anticipated overlap of the groups, randomization will initially be equal. As the trial progresses, randomization probabilities will be adapted based on the Bayesian estimation of the probability of treatment impact on progression-free survival (PFS). These randomization probabilities can vary among the biomarker groups so predictive biomarkers will be identified and utilized if present. Treatment arms may drop due to low probability of treatment impact on OS, and new arms may be added. Experimental arms are compared only with control and should be thought of as discrete experimental questions, with INSIGhT being open to new investigators with proposed therapeutic hypotheses. Clinical trial information: NCT02977780.

TPS5602 Background: Primary cytoreductive surgery (PDS) followed by chemotherapy has been considered as standard management for advanced ovarian cancer patients (pts) over decades. An alternative approach of interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT) was subsequently reported by two randomized phase III trials (EORTC‐GCG, CHORUS). Owing to important limitations of these studies, especially regarding surgical quality, optimal timing of surgical therapy in advanced ovarian cancer is still unclear. Methods: TRUST is an international open, randomized, controlled multicenter trial investigating overall survival (OS; primary endpoint) after PDS vs NACT and subsequent IDS in pts with FIGO stage IIIB‐IVB ovarian, tubal, and peritoneal carcinoma. Secondary objectives are safety of complete tumor resection, progression‐free survival and quality of life (QoL) as well as surgical morbidity. In order to guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (e.g. ≥50% complete resection rate in upfront surgery for FIGO IIIB-IV pts, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST Quality committee delegates. A 1:1 randomization to PDS or NACT followed by IDS stratified by center and age‐ECOG combination (ECOG 0 and age ≤65 years vs ECOG > 0 or age > 65 years) is performed. Pts in the PDS arm will undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas pts in the IDS arm will be treated with 3 cycles of NACT after histologic confirmation of the disease, followed by IDS and subsequently 3 cycles of platinum-based chemotherapy. Intention of surgery for both groups will be complete tumor resection as per guideline recommendations. Health related QoL will be assessed using the EORTC QLQ‐C30, QLQ‐OV28, and EQ‐5D‐3L questionnaires. For sample size planning, we considered a prolongation of median OS from 45 months in the IDS arm to 60 months in the PDS arm (HR 0.75) as clinically relevant. 380 events are needed to obtain a power of 80% in two‐sided log-rank test with significance level of 0.05. The primary analysis will be done in the ITT‐population of 686 randomized pts. By Feb 3 2017, 46 pts were randomized. Clinical trial information: NCT02828618.