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e20594 Background: RRx-001 is a small molecule immunotherapeutic in Phase 3 for the treatment of SCLC that is associated with M2-M1 tumor associated macrophage (TAM) repolarization with CD47 downregulation, vascular normalization and reversal of chemoresistance. In a controlled, multicenter clinical trial called REPLATINUM that was prematurely halted due to COVID-19, data from 17 patients with third line or beyond SCLC was analyzed. Moving forward, REPLATINUM(restarted) has added SARS-CoV-2 exclusion criteria. Our aim was to explore the efficacy of RRx-001 in REPLATINUM and to assess the statistical assumptions of the REPLATINUM(restarted) trial in order to inform future clinical development in SCLC. Methods: Patients in REPLATINUM were randomized to receive 1 of 2 arms: 1) carboplatin AUC 5 IV on day 1 or cisplatin 60 mg/m2 IV on day 1 plus etoposide 100 mg/m2 IV on days 1 through 3 every 21 days for up to 4 cycles or 2) 4 mg of RRx-001 administered sequentially with 4 cycles of a platinum doublet (cisplatin or carboplatin plus etoposide as outlined above). Progression Free Survival (PFS) was the primary efficacy endpoint based on a blinded independent central review (BICR). Results: The trial was suspended prematurely after 17 patients had been enrolled due to widespread COVID-19 exposure with the plan to restart the trial. The decision to restart the trial has provided an opportunity to examine the data for preliminary evidence of treatment efficacy. At the time that the REPLATINUM trial was halted, there were 11 patients enrolled on the control arm and 6 on the investigational arm. The BICR assessed median PFS was approximately 7.1 months for RRx-001 + platinum doublet and 3.5 months for the platinum doublet alone based on the truncated database. The BICR assessed PFS hazard ratio was approximately 0.5. OS medians were approximately 8.2 and 6.3 months for RRx-001 + platinum doublet and platinum doublet alone, respectively. Additionally, patients on the RRx-001 + platinum doublet-treated experimental arm experienced less toxicity than patients on the platinum doublet-treated control arm. Conclusions: Despite the small sample size, preliminary results from REPLATINUM suggest a trend toward a favorable primary outcome and improved safety in RRx-001-treated patients and support the validity of the statistical assumptions that underlie the REPLATINUM(restarted) trial. Pivotal evidence will emerge from REPLATINUM(restarted), which is imminently recommencing. Clinical trial information: NCT03699956.

e15119 Background: RRx-001 is a minimally toxic small molecule that downregulates CD47 via Myc inhibition and repolarizes tumor-associated macrophages (TAMs). A phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced traditionally non-immunogenic cancers and no standard options. Methods: This single arm, open-label pilot study (NCT02518958) was designed to evaluate the safety profile of RRx-001 + nivolumab in patients with advanced malignancies. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, 12 patients received treatment for 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events occurring within 16 weeks of the first dose of RRx-001 + nivolumab were characterized according to CTCAE v4.03. Results: 12 patients received > 1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no dose-limiting toxicities. The main adverse event related to RRx-001 was pain on infusion (33.3%). The main adverse event related to the combination was pseudoprogression (larger tumors in symptomatically improved patients) (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). Objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of > SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination. Conclusions: RRx-001 + nivolumab was well-tolerated with preliminary evidence of anti-cancer activity in non-immunogenic cancers. Further analyses with a larger sample size are required to confirm activity. Clinical trial information: NCT02518958 .

e16031 Background: RRx-001 is a downregulator of CD-47 and SIRP-alpha, which demonstrated a clinically meaningful improvement in OS and PFS vs. regorafenib when dosed sequentially with irinotecan in a 3rd/4th line colorectal cancer randomized trial called ROCKET (NCT02096354). Recently, RRx-001 has been shown to downregulate PD-L1 on circulating tumor cells. This phase 1 trial named PAYLOAD (NCT02801097) was performed to assess the safety and tolerability of the combination of RRx-001 and irinotecan and to determine a recommended phase II dose (RP2D). Methods: Eligible patients (pts) had adequate organ and bone marrow functions and an ECOG of 0-2 and evaluable refractory advanced solid tumors. RRx-001 was administered once per week for 3 weeks and thereafter once every two weeks. RRx-001 was administered as a 10-15 min IV infusion with irinotecan, which began on Week 4 and which was also given every other week, staggered with RRx-001 . Dose escalation followed a standard 3 + 3 design with co-escalation of RRx-001 and irinotecan as follows: 1: Irinotecan 120 mg/m2 + RRx-001, 0.5 mg 2: Irinotecan 120 mg/m2 + RRx-001, 2 mg 3: Irinotecan 120 mg/m2 + RRx-001, 4 mg 4: Irinotecan 150 mg/m2 + RRx-001, 4 mg Radiological imaging was performed every 8 weeks. Results: 12 pts; 1 gallbladder, 1 ampullary carcinoma, 1 cholangiocarcinoma, 5 colon, 1 GE junction, 2 pancreatic and 2 rectal cancers were enrolled from January 2018 to November 2018. 1 and 18 doses (median: 6 doses) of the combination of RRx-001 and irinotecan were received. The median number of prior treatments was 4 (range 1-5). There were 2 Grade 3 events, leukopenia and anemia, judged not related to RRx-001 but related to irinotecan, 1 Grade 4 event, leukopenia, judged not related to RRx-001 but related to irinotecan and 1 Grade 5 event, neutropenic enterocolitis, also judged not related to RRx-001 but related to irinotecan. No dose-limiting toxicities were identified. The median overall survival was ~ 6.5 months. Conclusions: Alternating weekly infusions of 150 mg/m2 of irinotecan and 4 mg of RRx-001 were well tolerated. No Grade 2 or above diarrhea was observed with irinotecan treatment, which suggests that RRx-001 may protect against gastrointestinal (GI) toxicities, since RRx-001 has also demonstrated anti- oral mucositis and anti-diarrheal properties in other studies.This dose level is the recommended phase 2 dose for future trials. Clinical trial information: NCT02801097 .

9062 Background: In a Phase 2 trial called QUADRUPLE THREAT (QT) (NCT02489903), where 2nd line+ small cell lung cancer (SCLC) patients were treated with RRx-001 and a platinum doublet, the programmed death-ligand 1 (PD-L1) status of circulating tumor cells (CTCs) in 14 patient samples was evaluated. Methods: 26 consented patients received weekly RRx-001 4 mg followed by a reintroduced platinum doublet; epithelial cell adhesion molecule (EPCAM+) CTCs from 10 ml of blood on two consecutive timepoints cycle 1 day 1 and cycle 3 day 8 (cycle duration = 1 week) were detected by EpCAM-based immunomagnetic capture and flow cytometric analysis. CTCs were further characterized for protein expression of PD-L1. Tumor response was classified as partial or complete response based on the response evaluation criteria in solid tumors (RECISTv1.1) measured every 6 weeks. Results: The analyzed clinical data set comprised 14 RECIST-evaluable patients. 50% were females (7/14) and the median age (years) at baseline was 64.5 (Min = 48.5, Max = 84.2, SD = 10.3). The logistic model McFadden goodness of fit score (0 to 100) is 0.477, which is a strong correlation value. The logistic model analyzing the association of CTC PD-L1 expression at two timepoints and response had an approximate 92.8% accuracy in its prediction of clinical benefit (SD/PR/CR). Accuracy is defined in the standard way as 1- (False positive rate + False negative rate). The estimated ROC displayed in Figure 1 suggests a ROC AUC of 0.93 (95% CI: 0.78, 0.99), an excellent measure of performance. Conclusions: Reduction of PD-L1 expression was correlated with good clinical outcome after RRx-001 + platinum doublet treatment. PD-L1 expression reduction in favor of RRx-001 RECIST clinical benefit was clinically significant as compared to non-responders with progressive disease (PD). In the ongoing SCLC Phase 3 study called REPLATINUM (NCT03699956), analyses are planned to correlate response and survival with expression of CD47 and PD-L1 on CTCs. Clinical trial information: NCT02489903.

2516Background: Differential response to tamoxifen observed in patients (pts) with hormone receptor-positive cancer may be due to variations in tamoxifen metabolism from CYP2D6 genetic polymorphism...

2587Background: Wee1 tyrosine kinase promotes G2 cell cycle arrest following DNA damage via inactivating phosphorylation of cyclin-dependent kinase 1. We are conducting a phase I study of the oral ...

TPS3128Background: Interleukin-15 is a stimulatory cytokine. Recombinant human IL-15 (rhIL-15), a nonglycosylated single-chain peptide, increased circulating CD8+T-cells, NK cells and inflammatory ...

2549Background: Ataxia-telangiectasia-related (ATR) protein kinase is central to the repair of damaged DNA through the homologous recombination (HR) pathway, activating phosphorylation cascades tha...

TPS2609 Background: The DNA damage response (DDR) pathway is a key element of cellular integrity. Platinum compounds form covalent bonds with purine bases causing DNA cross-links that stall replication forks halting transcription. Poly (ADP-ribose)polymerase-1 (PARP-1) plays a pivotal role in DDR and base-excision repair. Ataxia-telangiectasia-related (ATR) protein kinase is also central to DDR and homologous recombination, activating a series of phosphorylation cascades culminating in cell cycle arrest to allow time for DNA repair. Veliparib (ABT-888) is a PARP 1/2 inhibitor (PARPi) with clinical evidence of antitumor activity in combination with cisplatin in BRCA mutation carriers (Rodler et al, Cancer Res. 2011). VX-970 is a potent ATR inhibitor, with antitumor activity across a range of cell lines in combination with DNA damaging agents, including cisplatin (Huntoon et al, Cancer Res. 2013). In this trial, we will evaluate whether the combination of veliparib + VX-970 impairs DNA repair, inducing a “BRCA null”-like phenotype leading to potentiation of the antitumor activity of cisplatin. Methods: Open label phase I trial of the veliparib+VX-970+cisplatin combination, following a 3+3 design, with dose limiting toxicities defined during cycle 1. Estimated enrollment: 24 patients (pts); Dana Farber and MD Anderson planned as additional sites. Drug administration over a 21-day cycle: VX- intravenously (IV) on Days 2 and 9; Veliparib orally twice daily (q12 hours ± 1 hour) Days 1-3 and 8-10; cisplatin 40 mg/m2 IV Day 1 (with Day 8 added from DL3 onwards). Pts must be ≥ 18 years of age; have histologically confirmed solid tumors that have progressed on standard of care therapy known to prolong survival or without known standard, ECOG PS ≤2, and life expectancy ≥3 months. Pts with treated brain metastasis with stable disease ≥4 weeks without requiring steroids or anti-seizure medication are eligible. Exclusion criteria include a prolonged QTc interval, and sensory/motor neuropathy ≥grade 2 by CTCAE v.4. At this time, cohort 3 has enrolled 1 of 3 planned pts. Assessment of DDR and apoptosis biomarkers at the maximally tolerated dose using a validated and quantitative immunofluorescence assay is planned. Clinical trial information: NCT02723864.

2558 Background: Indenoisoquinolines (ID) are non-camptothecin inhibitors of topoisomerase (TOP1) identified following a COMPARE analysis of the National Cancer Institute’s (NCI) in vitro anticancer drug discovery screen. IDs have improved characteristics over camptothecin top1 inhibitors, with better chemical stability (lacking the labile hydroxylactone E-ring) producing stable DNA breaks that are resistant to reversal of the trapped DNA-TOP1 cleavage complex and at different DNA sequence sites to camptothecins (Kohlhagen et al. Mol Pharmacol. 2005). IDs have shown more activity against camptothecin-resistant cell lines and mouse models, as well as in cells overexpressing the ATP-binding cassette (ABC) transporters, and multidrug resistance (MDR-1/ABCB1) genes. A parallel first-in-human Phase I study conducted at the NCI of LMP400 in patients with refractory solid tumors and lymphomas showed this molecule to be well tolerated (Kummar et al, Cancer Chemother Pharmacol. 2016). A trial of LMP776 (NSC725776), has completed accrual. Primary Objectives: define the maximum tolerated dose (MTD) of LMP776 and the dose-limiting toxicities (DLTs). Methods: Phase I trial using Design 4 of the Simon accelerated titration designs (Simon et al. JNCI, 1997), with doses escalated based on toxicity during cycle 1. LMP776 was administered via central line QD over 1 hour on days 1–5 q 28-days. Response is defined by RECIST 1.1 on CT. Results: 32 of 34 patients (pts) were evaluable for toxicity and response. Enrollment was expanded at dose level (DL) 2 to 6 pts due to a hypocalcemia DLT, with subsequent enrollment on a 3+3 design. MTD was established at DL7 (12mg/m2, DLT myelosuppression). Common Grade 3/4 adverse events by CTCAE v.4 included anemia (5 pts, 15%), thrombocytopenia (5), lymphopenia (5) and neutropenia (3 pts, 9%). 12 (37%) pts experienced stable disease (SD), with a median of 4 cycles of treatment (range 2-9). 10 (30%) pts with SD remained on study for ≥4 months, with 4 pts on study ≥6 months. Conclusions: LMP776 is overall well tolerated. Explorative correlatives and additional trials are being considered. Clinical trial information: NCT01051635.

PURPOSE: We conducted a phase I and pharmacologic study of a weekly 96-hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites. PATIENTS AND METHODS: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed. RESULTS: In 11 patients who were treated with irinotecan at 12.5 mg/m2/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3 diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two patients. The recommended phase II dose is 10 mg/m2/d for 4 days given weekly for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of total SN-38 (the active metabolite of irinotecan) was 6.42 ± 1.10 nmol/L, and the Css of total irinotecan was 28.60 ± 17.78 nmol/L. No patient experienced grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to moderate. The systemic exposure to SN-38 relative to irinotecan was greater than anticipated, with a molar ratio of the area under the concentration curve (AUC) of SN-38 to irinotecan of 0.24 ± 0.08. One objective response lasting 12 months in duration was observed in a patient with metastatic colon cancer. CONCLUSION: The recommended phase II dose of irinotecan of 10 mg/m2/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.