Adjei, Alex A.

TPS3161 Background: VV1 is an oncolytic vesicular stomatitis virus engineered to express human IFNβ to enhance cellular anti-tumor immune responses and tumor selectivity, and the human sodium iodide symporter (NIS) for virus tracking by SPECT imaging. Cancer cells are often hyporesponsive to IFNβ, enabling the efficient spread of VV1 and resulting in increased oncolysis. Differently from other oncolytic viruses, VV1 is suitable for both intra-tumoral (IT) and/or intra-venous (IV) administration. Despite considerable anti-tumor activity with checkpoint inhibitors (CPI) among some malignancies, long term survival and overall cures remain elusive. Prior Ph 1 studies have shown significant anti-tumor activity among several malignancies when VV1 was administered either as monotherapy or in combination with a CPI, despite progression on prior CPI monotherapy. Furthermore, pre- and post-treatment biopsy evaluations after VV1 treatment have demonstrated T cell infiltration and inflammation in both IT injected and non-injected lesions. Among IV treated patients (pts), IFNβ was detectable in the serum correlating with viral replication, making it an effective biomarker. C is a high-affinity potent human IgG4 anti-PD-1 monoclonal antibody. Though approved for use in cutaneous squamous cell carcinoma, C has shown anti-tumor activity, similar to other CPI, in several other indications. Therefore, VV1 and C could be an attractive combination for the immunotherapy for several solid tumors. This study represents the first clinical evaluation of VV1 in combination with C in pts with advanced solid tumors. Methods: The Ph 2 Simon 2 stage five-arm study of IV administration VV1 in combination with IV C will enroll pts with advanced NSCLC, HCC, melanoma & endometrial cancer. Enrolled pts with NSCLC & melanoma will be recent CPI-progressors, whereas enrolled HCC & endometrial cancer will be CPI-naïve. The study’s objectives include assessment of preliminary anti-tumor activity, safety, & immuno-regulatory activity of the combination. Pts will receive IV VV1 once on D1 and IV C once every 3 weeks until confirmed disease progression or intolerable toxicity. Pts enrolled in one melanoma cohort will also receive IT VV1 administered to palpable lesions. Response will be assessed every 9 weeks per RECIST v1.1. The null hypothesis of each cohort’s ORR will be tested versus a one-sided alternative yielding a Type I error rate of 5% and power of 80%. Cohorts will be expanded based on signal of activity. Clinical trial information: NCT .

8580 Background: This pooled analysis examined the relationship between single-item and multiple-item quality of life (QOL) measures and assessed the agreement between changes in QOL and patient-reported adverse events (AE). Methods: Data from six lung cancer clinical trials involving 358 patients were pooled. All trials incorporated the UNISCALE and one of three multiple-item assessments: the Functional Assessment for Cancer Therapy-Lung, the Lung Cancer Symptom Scale, or the Symptom Distress Scale. A clinically significant decline (CSD) in QOL was defined as a 10-point drop from baseline. A CSD in AE was defined as a change from ≤ grade 2 at baseline to ≥ grade 3 post-baseline. Spearman rank correlations and Bland-Altman approach were used to assess agreement. The Kaplan-Meier method was used to evaluate the time to the first occurrence of a severe (grade 3+) AE and first CSD in QOL. Results: Correlations between the UNISCALE and multi-item assessments were modest (rho=0.49–0.66). At least one 10-point decline in the UNISCALE and multi-item assessments were reported by 58% and 40% respectively. At least one severe AE was reported in 44% of patients post-baseline. The percent agreement between experiencing a severe AE and a CSD in QOL was 49% and 59% for UNISCALE and the multi-item tools. For individual AE, the percent agreement between a CSD in AE and a CSD in QOL ranged from 37% to 50% for UNISCALE and 44% to 69% for the multi-item tools. The median time to the first CSD in QOL for UNISCALE and multi-item tools was 67 and 142 days respectively. The median time to the first occurrence of a severe AE was 304 days. Conclusions: QOL and AE provide quantifiably different information. A 10-point decline in QOL occurs earlier than CTC AE reporting. Patient reported outcomes may be more sensitive in identifying clinically relevant problems than physician rated symptom assessments. No significant financial relationships to disclose.

Abstract Background: Bimiralisib is a balanced dual panPI3K/mTOR inhibitor, which demonstrated anti-cancer activity in a number of preclinical models. Pharmacokinetic (PK) data suggested that intermittent targeting of the PI3K/mTOR pathway could be preferable to continuous daily dosing. Preclinical models in squamous cell head and neck cancer (SCCHN) demonstrated that NOTCH1 Loss of Function (LoF) mutations were associated with efficacy of bimiralisib and other PI3K inhibitors. Methods: We conducted a first-in-human dose-escalation study (3+3 design) to identify the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), dose-limiting toxicities (DLT) and overall safety (CTCAE v4) of bimiralisib administered either as a continuous (80 mg – 120 mg daily) or one of two intermittent schedules (schedule A: twice weekly 80 mg – 200 mg on Day 1 and 2, or schedule B: twice weekly 80mg – 200 mg on Day 1 and 4) until disease progression or unacceptable adverse events (AEs). Eligible patients had histologically confirmed solid cancers refractory to standard therapies, ECOG <1, life expectancy >12 weeks, adequate bone marrow, liver, and renal functions, HgbA1c <7%, and fasting plasma glucose < 7.0mmol/L. Tumor responses were evaluated according to RECIST v1.1 every 6 weeks. PK and blood biomarkers were analyzed. Results: 70 patients (female, 70%; white, 93%; median age 57 years [range, 49-65]) with heavily pretreated advanced solid cancers were enrolled (continuous schedule, 21; intermittent schedule A, 25; intermittent schedule B, 24). The MTD for the continuous schedule was established as 80 mg daily. For all treatment groups, DLTs included grade 2 and 3 fatigue. Clinically significant treatment-related AEs included fatigue in the continuous schedule, none in the intermittent schedule A and diarrhea, hyperglycemia in the intermittent schedule B. Intermittent schedules A and B did not reach the MTD, and after review of PK data, 140 mg administered in schedule A was selected as the RP2D for further exploration. Day 1 peak plasma concentration proportionally increased with increasing doses of bimiralisib only up to 140mg. Weekly AUC on intermittent dosing at all dose levels studied were considerably lower than continuous daily dosing at 80mg. There was one partial response (PR, -85% per RECIST) in a heavily pretreated patient with SCCHN and NOTCH1 LoF mutation, which was maintained for 8.2 months until death from pulmonary artery rupture in the setting of known fistula (assessed as unrelated to bimiralisib). In addition, 30 (42.9%) pts achieved stable disease (SD) including one with anal SCC carrying a NOTCH1 LoF mutation. SD > 6 months was observed in five pts (23.8%) in continuous schedule, 12 (48%) in intermittent schedule A, and 13 (54.2%) in intermittent schedule B. Results on patients, who consented to the serial circulating tumor DNA collection will be presented. Conclusions: Bimiralisib was well tolerated and RP2D of 140 mg given orally twice weekly on Days 1 and 2 was selected for further studies. In agreement with our preclinical models, there was an encouraging activity in a SCCHN patient with NOTCH1 LoF mutation and this observation is now being validated in a proof-of-concept phase 2 study (NCT03740100). Citation Format: Filip Janku, Faye M. Johnson, Mateusz Opyrchal, Afshin Dowlati, Cinta Hierro, Martin Forester, Sarah P. Blagden, Andreas Wicki, Debora Schmitz, Alex A. Adjei. Oral dual PI3K/mTOR inhibitor bimiralisib demonstrates tolerability and a signal of activity in head and neck squamous cell cancer with NOTCH1 loss-of-function mutation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B109. doi:10.1158/1535-7163.TARG-19-B109

e20077 Background: Small cell lung cancer (SCLC) accounts for about 10% to 15% of lung cancers among women and men. Though heavily associated with smoking, its incidence in women is rapidly increasing despite a decline in cigarette exposure. Given the changing demographics of SCLC and hormonal factors associated with other forms of lung cancer, we studied differences between sexes in SCLC. Methods: Utilizing the National Cancer Database, we identified all incident SCLC cases from 2004 to 2014. Patients were classified as limited stage (LS) or extensive stage (ES). Women were stratified by menopausal status (≥55 years = postmenopausal). Kaplan-Meier method and Cox regression were used for overall survival (OS) and multivariable analysis. Results: 161,978 patients were identified. No significant sociodemographic differences were observed between sexes. The majority of patients were non-Hispanic whites (89.1%), followed by non-Hispanic blacks (7.5%). Men were more likely to be diagnosed with ES disease than women (63% vs. 56%). Both sexes initiated treatment within a similar time frame from diagnosis (chemotherapy, median: 18 days, IQR 8-32). Women had better median OS compared to men in both LS (15.2 vs. 12.7 months, HR: 0.85, 95% CI 0.83-0.86, p < 0.0001) and ES (6.4 vs. 5.7 months, HR: 0.88, 95% CI 0.87-0.90, p < 0.0001). No racial or ethnic disparities in OS were observed, overall and when examined within sex and disease stage groups. Differences between sexes in OS were also observed when comparing patients within the same racial/ethnic group (women having better OS). When divided by menopausal status, postmenopausal women with LS and ES had worse OS than premenopausal women (14.7 vs. 22 months, HR: 1.50, 95% CI 1.44-1.56; 6.1 vs. 9.8 months, HR: 1.41, 95% CI: 1.37-1.46, respectively). We also observed worse OS in older men when divided by age ( < 55 years and ≥55 years). In multivariable analysis, older age, postmenopausal status, and Medicaid as primary insurance were associated with worse OS for both LS and ES. Conclusions: In this large cohort, women with SCLC had better OS compared to men. Post-menopausal women had worse OS compared to pre-menopausal women. Since older men had a similar trend of worse survival compared to younger men, age might exert a more significant influence on survival than hormonal status in SCLC. Further studies with data on sexual hormone levels are necessary to better understand their role in women with SCLC.

TPS7570 Background: The DIAL study is testing the efficacy of dual immunomodulation in patients with advanced B cell non-Hodgkin lymphoma (B-NHL). Developed by the Cancer Therapy Evaluation Program (CTEP), the trial combines the use of a programmed cell death protein 1 (PD-1) inhibitor (nivolumab) with an agonist of the CD27 receptor (varlilumab) in a randomized phase 2 design. CD27, a co-stimulatory receptor, regulates T cell activation through interaction with CD70. T cell exhaustion plays a major role in immune evasion in B-NHL. Varlilumab is an agonistic IgG1 monoclonal antibody that recognizes CD27 leading to prevention or reversal of exhaustion. Varlilumab also demonstrates direct anti-tumoral activity in xenograft models of human lymphoma cell lines via antibody-dependent cell-mediated cytotoxicity. Phase 1 data supports the safety and tolerability of single-agent varlilumab in advanced hematologic malignancies. We hypothesize that CD27 activation synergizes with PD-1 inhibition resulting in a superior anti-lymphoma effect compared to PD-1 blockade alone. The study will also evaluate the effect of these agents on tumor and immune cells using IHC, mass cytometry (CyTOF), multiplex ELISA, imaging mass cytometry, and whole exome sequencing. Methods: The trial is enrolling patients with advanced aggressive B-NHL. Standard inclusion criteria and prior treatment with at least 2 lines of standard therapy are required. Prior autologous stem cell transplant and/or chimeric antigen receptor (CAR) T cell therapy is allowed. Patients with active CNS disease are excluded. Eligible patients will be randomized to treatment with single-agent nivolumab (group 1) or dual immunotherapy with nivolumab and varlilumab. Group 1 is allowed to cross-over at the time of progression. Nivolumab will be administered intravenously (IV) every 2 weeks (240 mg) for 4 months followed by monthly dosing thereafter (480 mg). Varlilumab will be given IV every 4 weeks (3 mg/kg). Response assessment will be done by PET-CT scan every 12 weeks. Primary outcome is overall response rate (ORR) according to the LYRIC criteria. The trial will enroll 48 patients per arm, allowing 80% power to detect at least 20% increase in ORR in the experimental arm (group 2) assuming a 25% ORR in the control arm (group 1). The trial is registered and open to participation to members of ETCTN and EDDOP. Clinical trial information: NCT03038672.

7509 Background: NTX-010 is a naturally occurring replication-competent picornavirus with potent and selective tropism for SCLC tumor cells expressing neuroendocrine markers. A phase I study of NTX-010 showed evidence of antitumor activity in patients with SCLC. Methods: ES-SCLC patients (pts) with SD, PR or CR after at least 4 cycles of platinum-based chemotherapy were pre-registered to confirm diagnosis of SCLC with > 1 neuroendocrine marker by a central pathology review. Eligible pts were.randomized 1:1 to placebo (B) or NTX-010 (A). NTX-010 or placebo was administered intravenously as a 1-hour infusion in 100 mL normal saline as a single dose of 1 x1011vp/kg. Viral studies to determine distribution, clearance of the virus and the presence of neutralizing antibodies were done. The primary goal of this trial was to compare the progression-free survival (PFS) of arm A to B based on a sample size of 45 patients per arm to detect an improvement in median PFS from 3 to 5 months (m). A pre-planned interim futility analysis was done after 40 PFS events, and reported here. Results: The trial is permanently closed to accrual. One-hundred and twenty pts were pre-registered, of whom 58 were randomized. Baseline age, gender, ECOG performance status, and histology were balanced between arms. Median age was 63 (range: 44 - 82). 31% of pts had a PS of 0 and 69% of 1. Grade 4 adverse events were seen in 3 (12.5%) patients in arm A and none in arm B. Based on the interim futility analysis, PFS was 1.7 m (95% CI: 1.3-3.1) for arm A and 1.7 m (95% CI: 1.4-4.3) for arm B. Pts with viral RNA at 7 (7 pts) and 14 (6 pts) days had worse PFS compared to those with no detectable levels within arm A (1.0 vs 1.6 m, p=0.02; 0.9 vs. 1.2 m, p=0.06). Median follow-up in pts is 6.1 m. The 3-month OS estimates are 83% (95% CI: 69%-100%) and 85% (70%-100%) for arms A and B respectively. Conclusions: This phase II study showed no benefit in PFS for ES-SCLC patients receiving NTX-010. Pts with detectable virus at 7 and 14 days had worse PFS. Clinical trial information: NCT01017601.

2551 Background: Protein kinase C iota (PKCi) is overexpressed in non-small cell lung (NSCLC), ovarian and pancreatic cancers and promotes tumorigenesis. The gold compound aurothiomalate (ATM) inhibits downstream activation of Rac1 by PKCi. We sought to determine the maximum tolerated dose (MTD) of ATM. Methods: We conducted a phase I dose escalation trial of ATM in patients with NSCLC, ovarian or pancreatic cancer. In the dose escalation cohort patients received ATM IM weekly for three cycles (cycle duration 4 weeks) at 25 mg, 50 mg or 75 mg in a 3+3 design. The dose was not escalated for individual patients. Up to 9 subjects were allowed to enroll in the expansion cohort at the MTD. Blood samples were analyzed for elemental gold levels. Patients were evaluated for response every eight weeks with computed tomography using modified response evaluation criteria in solid tumors. Results: Fifteen patients, all pretreated, enrolled in this study. There were ten patients with NSCLC, four with ovarian cancer and one with pancreatic cancer. Six patients were treated at the 25 mg dose, 6 patients at 50 mg, and 2 at 75 mg. There was 1 dose limiting toxicity (DLT) at 25 mg (hypokalemia), 1 DLT at 50 mg (urinary tract infection), and none at 75 mg. There were 3 grade 3 hematologic toxicities in the dose escalation cohort. The recommended MTD of ATM is 50 mg, and 1 subject was treated in the expansion cohort at 50 mg. Patients received treatment for a median of 2 cycles (range 1-3). The best response observed was stable disease in 2 subjects. There appeared to be a dose-related accumulation of steady-state plasma concentrations of gold with concentrations exceeding 20 µM after one month of therapy with 75 mg of ATM and after 2 months of therapy with 50 mg of ATM, consistent with linear pharmacokinetics. Conclusions: In summary, this phase I study was successful in identifying ATM 50 mg IM weekly as the MTD. In this heavily pre-treated group of patients in who we observed at best stable disease, it remains unclear whether future investigations that target PKCi should focus on single agent ATM, combination therapy with ATM, or other PKCi inhibitors that are currently in development. Clinical trial information: NCT00575393.

7605 Background: Overall survival (OS) can be partitioned into progression-free survival (PFS) and PPS. PPS helps to understand trial results, especially when PFS and OS data on trial treatment effects are discordant. At ASCO 2011, we reported that the magnitude of difference in the PFS estimates using different DP date methods was large enough to alter trial conclusions. Here, we investigate the impact of the DP date method on 1) PPS estimates, and 2) predictive utility of DP metrics on subsequent OS (SOS). Methods: Individual patient (pt) data from 14 trials were pooled. DP date was determined using: reported progression date (RPD) (method 1, M1), one day after last progression-free (PF) scan (M2), and midpoint between last PF scan and RPD (M3). PPS was estimated using the method of Kaplan-Meier for the 3 DP date methods. A flexible landmark analysis at 2, 4, and 6 months (mos) using Cox proportional hazards model was used to assess the impact of DP status (progression versus no-progression) on SOS (using M1, M2, or M3). Results: Among NSCLC (SCLC), 87% (91%) of pts reported DP. As expected, the PPS estimates were the lowest for RPD, highest for M2, and in-between for M3 (a direct consequence of the DP date method); with no difference by arm for the randomized trials. Regardless of the DP date method, patients who were progression-free had improved SOS (NSCLC: Hazard ratio, HR<=0.33; p < 0.0001; SCLC: HR<=0.48; p < 0.002) at each landmark time point, with comparable concordance index (SCLC: 0.57-0.65; NSCLC: 0.63-0.67), i.e., ability to discriminate patients with different SOS outcomes. Conclusions: While the DP date methods do not impact the predictive utility of the DP metrics, they significantly impact PPS estimates. The translation of a significant treatment effect on PFS to an effect on OS is influenced by PPS (longer PPS dilutes effect on OS). Standards for declaring DP date are thus critical to trial design and for trial go/no-go decisions. [Table: see text]

7510 Background: We previously demonstrated that PFS may be a candidate surrogate endpoint for OS in ES-SCLC using data from 3 randomized trials (Foster, Cancer 2011). Here, we sought to formally assess the patient- and trial-level surrogacy of PFS using data from 9 additional randomized phase II and III trials conducted by the NCI-funded cancer cooperative groups since 1986. Methods: Individual patient data from all 12 trials (3178 patients: 9 phase III and 3 phase II) were pooled. OS was the primary endpoint in all phase III trials; 3 phase III and 1 phase II trial were positive per protocol. Patient-level surrogacy (Kendall’s tau) was assessed using the Clayton copula bivariate survival model. Trial-level surrogacy was assessed via association of the log hazard ratios on OS and PFS across trials, including: weighted (by trial size) least squares regression of Cox model effects (R² WLS) and weighted (by trial size) correlation of the copula effects (R² Copula). One trial had 4 treatment arms thus 14 total two-arm comparisons were made. Results: With a median follow-up of 41.8 months in the 106 patients still alive, the median OS and PFS across trials were 9.7 months (95% CI: 9.5, 9.9) and 5.7 months (95% CI: 5.5, 5.8), respectively. There were 3120 PFS events in total (2564 disease progressions and 556 deaths without progression). The median time from progression to death was 4.1 months (95% CI: 3.9, 4.3). PFS showed modest association with OS at the patient-level (tau= 0.56) and at the trial-level (R² WLS = 0.58; R² Copula (standard error) = 0.55 (0.29)). The 95% CIs for the predicted HR for OS given observed HR on PFS under a weighted leave-one-out prediction always included the observed HR for OS; however such intervals were wide, suggesting uncertainty on the practical use of PFS as a surrogate for OS in this setting. Conclusions: PFS failed to demonstrate surrogacy for OS in ES-SCLC based on this large pooled analysis. Given that the difference in the median PFS and OS is less than 6 months, we recommend using OS as the primary endpoint in phase III trials of previously untreated ES-SCLC.

7555 Background: In a retrospective exploratory analysis of E4599, patients (pts) > 70 yo had a higher frequency of and more severe toxicities without apparent survival benefit from the addition of B to C+paclitaxel. We hypothesized that in this pt population, B will have better safety and efficacy profile when used in combination with C+P. Methods: Pts >/= 70 yo with previously untreated stage IIIB/IV (TNM 6th ed) nonsquamous NSCLC, ECOG PS 0-1, measurable disease and adequate organ function were eligible. C at AUC 6, P at 500 mg/m2 and B at 15 mg/kg were administered on day 1 of each 21-day cycle for up to 6 cycles followed by maintenance P+B in patients with CR, PR or SD. The primary endpoint was 6-month progression-free survival (PFS) rate. The treatment would be considered promising based on a single arm one-stage binomial design if 34 or more successes out of 55 patients were observed. This design had an exact significance level of 0.05 at 93% power to detect a true success rate of at least 70%. Polymorphisms in VEGFA, FPGS, GGH, SLC19A1 and TYMS in germline DNA were correlated with treatment outcome. Results: 58 eligible pts were enrolled; 29 males/29 females. Median age was 75. Median treatment cycles received was 6. Grade 3 or higher adverse events (AE) were reported in 49 (85%) pts. There were no treatment-related deaths. The most common grade 3/4 AEs(regardless of attribution) were hypertension (10%), fatigue (28%), dehydration (9%), neutropenia (43%) and thrombocytopenia (21%). There were 3 (5%) grade 3/4 hemorrhagic events. 8 (14%) had grade 4 neutropenia and 3 (5%) had grade 4 thrombocytopenia. Grade 3/4 ischemic/thromboembolic events occurred in 6 pts (10%). Thirty-four out of the first 54 (63%, 95% CI: 48.7-75.7%) evaluable pts met the primary endpoint (4 pts were lost to follow-up prior to 6 months). The confirmed ORR was 37.9% (95% CI: 25.5-51.6%). Median time to treatment failure was 4.8 months (95% CI: 3.9-6.4). Median PFS was 7.1 months (95% CI: 5.9-11.7), median OS was 13.7 months (95% CI: 9.4-15.7). Results of SNP analysis will be presented. Conclusions: C+P+B followed by maintenance P+B is an active and tolerable first-line regimen for elderly patients with good PS.