Prior Gemcitabine Research Articles

A phase 2a safety run-in and preliminary efficacy study of liposomal gemcitabine (FF-10832) in combination with pembrolizumab in patients with advanced solid tumors.

2615 Background: FF-10832 (FF832) [liposomal gemcitabine (GEM)] has demonstrated superior activity preclinically compared to GEM via preferential tumor accumulation & induction of antitumor immune responses. Further enhanced activity has been shown in combination with immune checkpoint inhibitors. We evaluated the tolerability & preliminary efficacy of FF832 in combination with the PD-1 antibody pembrolizumab (PEM) in a Phase 2a safety run-in study in patients (pts) with advanced solid tumors. Methods: Pts received 200 mg PEM followed by 40 mg/m2 FF832 on Day 1 of a 21-day cycle to validate the recommended Phase 2 dose (RP2D) for combination therapy; treatment was continued until disease progression or unacceptable toxicity. Response was assessed by RECIST 1.1 every 2 cycles. Tumor PD-L1 expression, mutational burden, and modulation of circulating immune cells were assessed, & population PK modeling performed. Results: Twelve pts [NSCLC (6), urothelial cancer, UC (4), renal cell carcinoma (2); 6M/6F; median age, 69 (42-82) & median # prior therapies, 5 (1-7); prior GEM (5), prior PEM (9)] received a median of 2 (1-8) cycles FF832+PEM. Median time on study was 6.1 (1.1–23.7) weeks. FF832+PEM was well-tolerated. Common AEs related to FF832 were Gr≤2 fatigue (50%) with 1 Gr 3, anemia (33%) with 2 Gr 3, & Gr ≤2 decreased appetite, diarrhea, ↑AST, ↑AlkPhos, muscular weakness, nausea, and pyrexia (25% each). Common AEs related to FF832+PEM were Gr≤2 fatigue (33%) & nausea (25%). Three pts had Gr≤2 infusion reactions with the first FF832 infusion; all resolved & were successfully rechallenged. FF832 dose was reduced to 30 mg/m2 after Cycle 1 in 3 pts due to Gr 3 rash (1), Gr 2 fatigue (1), & one DLT of Gr 3 malaise, pain, and arthralgia. Of 9 pts evaluable for response, one achieved an unconfirmed PR after one cycle (UC, prior GEM/PEM, 42%↓ in target lesions). Five pts had a best response of SD with 2 maintained for 6-8 cycles. Median PFS was 6 weeks (95%CI: 3.1–NR); median OS was 23.3 weeks (95%CI: 4–NR). An extended plasma t1/2 (~30 hours) & exposures consistent with FF832 monotherapy at the RP2D were observed. As with FF832 monotherapy, multi-log decreases were observed in circulating Ki67+ Tregs relative to total CD4+ cells while CD8+ cells increased, suggesting FF832+PEM could enhance shifts to a more immunocompetent tumor microenvironment. Conclusions: The safety and preliminary efficacy of FF832+PEM was demonstrated in heavily pre-treated pts with solid tumors whose disease progressed on prior GEM and/or PEM. Continuous GEM exposure from FF832 along with immune checkpoint blockade may improve antitumor activity. Evaluation of FF832 at the RP2D/schedule of 40 m/gm2 Q 21 days alone and in combination with PEM is ongoing in a randomized expansion study in pts with metastatic NSCLC and UC with prior disease progression on PD-1/L1 therapy. Clinical trial information: NCT05318573 .

Sintilimab plus nab-paclitaxel as second-line treatment for advanced biliary tract cancer: study protocol for an investigator-initiated phase 2 trial (NapaSinti trial)

BackgroundBiliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin–bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients.MethodsThe NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon’s two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China.DiscussionThe NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research.Trial registrationChinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.

Nail toxicity with nail bed ulceration associated with pembrolizumab

A 70-year-old Japanese man was diagnosed with bladder cancer and started pembrolizumab. After six courses of pembrolizumab, all fingernails and toenails had fallen off and the nail beds were ulcerated. Pembrolizumab was discontinued, and he was treated with topical steroids and topical prostaglandin E1 ointment. Pembrolizumab is an immune checkpoint inhibitor (ICI) that exerts its anti-tumor effect by inhibiting the binding of PD-1 on T cells to PD-L1 on tumor cells. While its efficacy has been extensively evaluated, immune-related adverse events (irAEs) have become problematic. A 70-year-old Japanese man was diagnosed with bladder cancer at his previous urologist's department 2 years prior to his first visit. He had undergone resection, but the disease recurred 1 year later. Despite treatment with gemcitabine and cisplatin, he experienced progressive disease, and started pembrolizumab 9 months before the first visit to our department. After six courses of pembrolizumab, subungual hemorrhage appeared in his fingers and toes, and the nails subsequently detached and fell off. The nail lesions were thought to be caused by pembrolizumab, so the drug was discontinued, and he was scheduled for additional surgery. No irAEs other than nail symptoms were observed. He was referred to the Department of Urology at our hospital for surgery and to our department for management of nail symptoms. At the time of the first visit, all the nails on his fingers and toes had fallen off, and the nail beds were ulcerated (Figure 1A, B). The nails of the thumbs and index fingers of both hands had partially regrown. Since the patient was scheduled for surgery, he was not treated with oral prednisolone but rather with topical steroids. Epithelialization of the nail beds did not progress; therefore, the patient was switched to topical prostaglandin E1 ointment. Two months after the first visit, the nail beds were almost epithelialized, but the nails did not regrow, except for those of the both thumbs and index fingers (Figure 1C-E). Four reports of cases of nail toxicity caused by pembrolizumab have been published,1-3 all of which occurred in patients older than 70 years; the number of cycles administered until nail toxicity were observed ranged from 7 to 29. Although their symptoms were confined to the toes, two of these cases had ulcerated nail beds and most of the nails did not regrow,1 similar to the present patient. It is important to note that in these four previous cases, prior gemcitabine and platinum treatment might have affected nail symptoms; furthermore, nail symptoms were only treated with topical steroids. No other cases of ulceration of all the nail beds of the fingers and toes as in the present case have been reported; therefore, the present case appears to reflect the most severe case of nail side effects caused by pembrolizumab reported thus far. Histological findings were not available because the patients did not consent to skin biopsy. The histological findings of cases 1 and 2 showed a lichenoid reaction,1 the similar mechanism is thought to be present in this case. However, the mechanism underlying severe inflammation confined to the nail matrix and nail bed in patients treated with ICIs remains unclear. Although this is a rare side effect, the number of reports of similar irAEs is expected to increase as the indications of ICIs expand. None. The authors declare no conflict of interest. Approval of the research protocol: Not applicable. Informed consent: Informed consent was obtained from the patient. Registry and the registration no.: N/A. Animal studies: N/A.

Nab-paclitaxel plus anti–PD-1 antibody as second-line treatment for advanced biliary tract cancer: An investigator-initiated phase 2 study (NapaSinti trial).

564 Background: Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. Gemcitabine + cisplatin ±durvalumab is the standard first-line treatment for advanced BTC. But in second-line setting, there is no satisfactory regimen for most patients without specific genetic mutations. This prospective, single-arm, phase 2 study is conducted to investigate the efficacy and safety of second-line nab-paclitaxel combined with sintilimab in advanced BTC patients. Methods: Eligible patients are histologically confirmed local advanced or metastatic adenocarcinoma or cholangiocellular carcinoma in biliary tract; aged from 18 to 75 years; with a performance status and adequate organ function; with documented disease progression after prior gemcitabine or fluorouracil-based systemic chemotherapy; not received taxol drugs or immune checkpoint inhibitors treatment. Enrolled patients will receive nab-paclitaxel 125mg/m2 on day 1, 8 plus sintilimab 200mg on day 1, administered intravenously every three weeks. The primary end point is objective response rate (ORR). The secondary end points are progression free survival (PFS), overall survival (OS) and adverse reactions. Next-generation sequencing (NGS) is voluntary before treatment. Results: Up to September 2022, 24 BTC patients have been enrolled, including 22 patients available for efficacy evaluation. The ORR is 27.3% (6/22), including 1 complete response (CR) and 5 partial response (PR). Disease control rate is 63.6% (14/22). And median PFS is 5.63 months (95% CI: 1.92-9.35 months). Median OS from enrollment to death of any cause is 12.60 months (95%CI: 7.84-17.36 months). The frequent grade 3 drug-related adverse events are leukopenia (16.7%), anemia (12.5%), neutropenia (8.3%), peripheral neuropathy (8.3%). There is no grade 4 drug-related adverse event occurred. One patient has experienced grade 3 immunological colitis. 11 participants have received NGS testing, with 9 ones are available for efficacy evaluation. Among the 9 participants, 5 patients harbor TP53 mutation [2 evaluated as PR, 2 SD (stable disease) and 1 PD (progressive disease)]; 3 patients harbor genetic mutations associated with DNA damage response pathway (2 evaluated as PR and 1 PD); and 1 patient is in status of microsatellite instability-high (MSI-H) evaluated as PR. Conclusions: The preliminary results of NapaSinti trial propose a brand new and effective regimen as second-line treatment for advanced biliary tract cancer. NGS may become a hopeful tool for efficacy prediction. Clinical trial information: ChiCTR2100052118 .

A phase 1, first-in-human, dose-escalation and biomarker trial of liposomal gemcitabine (FF-10832) in patients with advanced solid tumors.

3097 Background: FF-10832 is a stable liposomal formulation of gemcitabine (GEM) shown to overcome resistance through increased plasma stability and enhanced tumor drug delivery. Macrophage uptake and immune activation in the tumor microenvironment (TME) play a role in the superior efficacy of FF-10832 compared to GEM, with selective, marrow-sparing biodistribution contributing to an improved safety profile. Methods: A 3+3 design determined the safety, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended Phase 2 dose (RP2D). FF-10832 was administered IV once or twice per cycle on a 28 or 21-day schedule until disease progression or unacceptable toxicity. Circulating immune cell populations were measured over time by flow cytometry. Results: Patients (pts) [n = 73, 26M/47F; median age, 64 (range, 26–84); # prior therapies, 3 (1–11); prior GEM, 60%] received FF-10832 on Day 1 and 15 Q28 days (1.2–30 mg/m2), Day 1 and 8 Q21 days (12–23 mg/m2), or Day 1 only Q28 or 21 days (30–55 mg/m2); median # cycles = 2 (1–14) & time on study = 8.3 (4–60) weeks. Common drug-related adverse events were Grade (Gr) ≤2 rash (22%), nausea (22%, 1 Gr 3), and pyrexia (21%, 2 Gr 3). Dose-limiting Gr ≥3 cellulitis/skin ulcers were observed at ≥23 mg/m2 with twice per cycle dosing and those regimens discontinued. Dose frequency was reduced to Day 1 only, which was well-tolerated without significant skin toxicity. Gr ≥3 thrombocytopenia and pneumonitis were observed at 55 mg/m2 Q21 days and the MTD confirmed at 40 (Q21) and 48 mg/m2 (Q28). Median OS = 25.3 (95%CI: 16–27.1) weeks and PFS = 9.6 (95%CI: 7.9–17.6) weeks. Three of 35 evaluable pts achieved a partial response (PR): one pt with gallbladder cancer who previously progressed on GEM achieved a 50%↓ by Cycle 13 at 40 mg/m2 Q28 days & maintains response on study at 60 weeks; two pts with pancreatic cancer had ≥30%↓: one adenocarcinoma after 2 cycles at 4.8 mg/m2 Days 1 & 15 Q28 days, and one acinar cell after 7 cycles at 40 mg/m2 Q28 days who remains on study. Stable disease (SD) was observed in 16 pts; 9 for ≥20 weeks. AUC increased in proportion to dose without accumulation. An extended plasma t1/2 (hrs) for released (39) & total GEM (26) with a free fraction < 1% of total GEM concentrations suggests continuous release in the TME. Pts with PR or SD had dose and time-related log decreases in Ki67+ regulatory T cells relative to total CD4+ cells with increases in anti-tumor CD8+ cells, suggesting a shift to a more immunocompetent environment. Conclusions: FF-10832 was well-tolerated in heavily pre-treated pts with solid tumors, with evidence of anti-tumor activity in pts who progressed on prior GEM. Prolonged, continuous exposure and enhancement of anti-tumor immunity may contribute to improved efficacy. Expansion is ongoing in biliary tract cancer pts treated at the RP2D/schedule of 40 mg/m2 Day 1 of a 21-day cycle. Clinical trial information: NCT03440450.

A study of relacorilant in combination with nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma.

4140 Background: Pancreatic cancer remains the third-leading cause of cancer-related death in the US. Average overall survival is only one year, and no standard therapies exist beyond second line. Chemotherapy resistance is one reason for the poor outcomes in pancreatic cancer, which can be caused by, among other factors, excess tumor expression of the glucocorticoid receptor (GR). Nonclinical and clinical data indicate that GR antagonism may enhance or restore chemotherapy sensitivity. Here, we report the interim analysis of RELIANT, a trial evaluating the efficacy and safety of relacorilant, a selective GR modulator, with nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: RELIANT (NCT04329949) was a single-arm, open-label, multicenter study of relacorilant (100 mg QD) + nab-paclitaxel (80 mg/m2 on days 1, 8, and 15 of each 28-day cycle) in patients with histologically confirmed mPDAC. Based on tolerability, relacorilant doses were escalated up to 150 mg. Patients with 2+ prior lines of therapy, including prior gemcitabine- and fluoropyrimidine-based therapy, were enrolled. Planned enrollment was 80 patients. The study included a planned interim analysis after approximately 40 patients had completed 12 weeks of treatment or discontinued study treatment due to disease progression or toxicity. Objective response rate (ORR) by blinded independent central review was the primary endpoint. At the interim analysis, ORR was assessed by the investigator. Results: At the interim analysis, 43 heavily pretreated patients with a median age of 64 years (range: 43–78; 56% male) had been enrolled. 27/43 (63%) patients had received ≥2 prior lines of therapy (range: 2–5), and all but 3 patients had received prior treatment with nab-paclitaxel. Twelve patients (28%) did not have a post-baseline radiographic tumor assessment and were hence not efficacy evaluable. Most common reasons for discontinuation from relacorilant were disease progression (n = 16), adverse event (AE, n = 8), and patient decision (n = 9). Relacorilant + nab-paclitaxel demonstrated antitumor activity with 15/43 (35%) patients showing decreases in target lesion size, 10/43 (23%) achieving disease control for at least 12 weeks, and 17/43 (40%) having decreases in CA 19-9. Of note, one patient has been on study treatment for > 15 months. No confirmed responses by RECIST (CR or PR) were observed, and enrollment was thus stopped after the interim analysis. No new safety signals were identified. The most common AEs were fatigue, nausea, and decreased appetite. Suppression of GR target genes was also observed. Conclusions: Modest antitumor activity of relacorilant + nab-paclitaxel was observed in this heavily pretreated patient population, with a safety profile similar to that observed for relacorilant in other oncology studies. Clinical trial information: NCT04329949.

Expression of PD-L1 as a predictive marker of sensitivity to immune checkpoint inhibitors in patients with advanced biliary tract cancer.

Background:Expression of programmed death-ligand 1 (PD-L1) has been reported to correlate with response to immune checkpoint inhibitors (ICIs) in various tumor types. However, there are few data on the role of PD-L1 expression as a predictive and prognostic biomarker of sensitivity to ICIs in patients with advanced biliary tract cancer (BTC).Objectives:We evaluated the role of PD-L1 expression as a predictive and prognostic biomarker of response to ICIs in patients with advanced BTC.Design:We retrospectively analyzed data from 83 advanced BTC patients who received ICIs as second- or third-line treatment between February 2018 and April 2021.Methods:All patient data analysis included evaluation of PD-L1 expression by the combined positive score (CPS).Results:Among 83 patients, 56 (67.5%) had PD-L1 positivity (CPS ⩾ 1). The objective response rate (ORR) to ICIs was significantly higher in advanced BTC patients with PD-L1 expression compared to those without PD-L1 expression (17.8% versus 0%, p = 0.026). However, there were no significant differences in median progression-free survival (PFS; 2.9 versus 2.6 months, p = 0.330) and median overall survival (OS; 8.1 versus 6.3 months, p = 0.289) as a response to ICIs between patients with and without PD-L1 expression. Also, there were no significant differences in ORR, PFS, and OS as a response to ICIs in conjunction with a response to a prior gemcitabine plus cisplatin regimen (p = 0.654, p = 0.278, and p = 0.302, respectively).Conclusions:The present study suggests that the expression of PD-L1 alone was not sufficient as a novel marker to select advanced BTC patients who might benefit from ICIs. Additional comprehensive studies of biomarkers that can assist in predicting BTC patient responses to pembrolizumab and/or nivolumab therapy are required.

A phase II study of infigratinib in previously treated advanced/metastatic cholangiocarcinoma with FGFR gene fusions/alterations.

TPS356 Background: The FGFR family plays an important role in cholangiocarcinoma, with FGFR2 gene fusions detected in about 15% of patients with cholangiocarcinoma. Infigratinib is an FGFR1–3-selective oral tyrosine kinase inhibitor under evaluation in multiple indications including front-line and pre-treated cholangiocarcinoma. CBGJ398X2204 is an ongoing phase II study evaluating the efficacy of single-agent infigratinib in patients with advanced or metastatic cholangiocarcinoma with FGFR genetic alterations who have received prior gemcitabine. Methods: Study CBGJ398X2204 consists of 3 cohorts and patients in all cohorts receive oral infigratinib once daily for 21 days of a 28-day treatment cycle. Treatment will continue until progressive disease, intolerance, withdrawal of consent, or death. Cohort 1 includes patients with FGFR2 gene fusions or translocations. Cohort 2 includes patients with FGFR genetic alterations other than FGFR2 gene fusions (patients in both Cohorts 1 and 2 must not have received any prior FGFR inhibitors). Cohort 3 includes patients with FGFR2 gene fusions who have received prior treatment with a selective FGFR inhibitor other than infigratinib. The primary endpoint is objective response rate (ORR, RECIST v1.1 per central review). Secondary endpoints include overall survival and overall response rate (per investigator). Safety, pharmacokinetics, and exploratory genetic alterations/biomarkers will also be measured. The study was initiated in 2014 and has a planned enrollment of up to 160 patients across all 3 cohorts (120 in Cohort 1, 20 in Cohort 2, and 20 in Cohort 3). Cohort 1 has completed enrollment and findings from this Cohort are the focus of a separate abstract submitted to the meeting. Results are not currently available from Cohorts 2 and 3 (trial in progress). Clinical trial information: NCT02150967.

Phase Ib study of decitabine in combination with gemcitabine in treatment of advanced soft tissue and bone sarcomas.

11550 Background: Sarcomas are a heterogeneous group of tumors and are associated with high rates of metastases leading to poor prognosis. Numerous epigenetic changes including hypermethylation have been identified in several sarcoma subtypes. Restoration of normal methylation patterns using DNA hypomethylating agent when combined with chemotherapy has shown to slow tumor growth in preclinical studies. Low continuous dosing of hypomethylating agent has epigenetic modulating effect with less toxicity. We conducted a Phase 1b study evaluating safety & tolerability and identifying the recommended phase 2 dose (RP2D) of subcutaneous (SQ) decitabine (DEC) given with fixed dose infusion gemcitabine (GEM) in patients with advanced soft tissue sarcomas (STS) and bone sarcomas. Methods: Eligible patients at least age 18 yrs with metastatic histologically confirmed STS or bone sarcoma after progression on one line or if refused adriamycin for STS were included. Prior GEM use was permitted. A modified 3+3 dose escalation design was used exploring two dose cohorts of DEC, 0.1 and 0.2 mg/kg SQ administered on a twice weekly schedule for three weeks and GEM given as 900 mg/m2, IV over 90 min on days 1, 8 & 15 of a 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) was defined as any drug related non-hematological grade 3 or 4 toxicity per CTCAE v4.0. Disease assessment was performed every 8 weeks using RECIST v1.1. Results: 31 patients (25 STS & 6 bone sarcomas) were enrolled of which 7 were non-evaluable. There were 12 evaluable patients in each dosing cohort. Of the total 744 adverse events (AE) 17.2% were grade 3/4 and most were neutropenia without neutropenic fever. 45.7% AEs were possibly (44.6%) or probably (1.1%) attributed to DEC use. The toxicities were not significantly different between DEC doses. No DLTs were observed. One patient died due to progressive disease. Conclusions: Combination of fixed dose infusion GEM with low dose subcutaneous DEC is moderately toxic. Most toxicities were hematological. While there were few responses, the RP2D of DEC selected was 0.1 mg/kg as it showed prolonged disease stabilization. Clinical trial information: NCT02959164 . [Table: see text]

Clinical outcomes of first-line FOLFIRINOX versus gemcitabine plus nab-paclitaxel in metastatic pancreatic cancer at the Yale Smilow Healthcare System.

769 Background: FOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GN) are established first line (1L) therapies for metastatic pancreatic cancer (MPC) but real-world data on their comparative effectiveness is limited. Methods: All cases of MPC treated with 1L FFX or GN at Yale Smilow Cancer Hospital and the affiliated community care centers (CCC) from January 2011 – April 2019 were reviewed. Patient (pt) demographics, prior therapy, initial and subsequent dose reductions (DR), time to treatment discontinuation (TTD), overall survival (OS), and second line (2L) treatment data were manually abstracted from the electronic medical record. Categorical and continuous variables were compared between 1L FFX and GN cohorts via the Chi-squared and Wilcoxon rank-sum tests. Median OS was calculated by the Kaplan-Meier method. Results: We identified 363 MPC pts treated with 1L FFX or GN; 269 (74%) pts were treated with FFX and 94 (26%) with GN as 1L therapy. 204 (56%) pts were treated at the main campus and 159 (44%) at a CCC. Demographics and baseline characteristics (FFX/GN) were as follows: gender (male) 55% / 41%; race (white) 82% / 77%; age < 76 90% / 71% ( P < 0.001). 332 (91%) of pts received no prior therapy; 21 (6%) had prior surgery plus adjuvant gemcitabine and 10 (3%) had surgery alone. 98% of FFX-treated pts were treated with upfront DR, compared to 78% of GN-treated pts ( P= 0.003). 78% and 53% of FFX-treated and GN-treated pts, respectively, had subsequent DR ( P< 0.001). Median TTD was 4.8 months with FFX and 3.4 months with GN ( P= 0.0029) and the median OS was 11.3 months with FFX versus 7.2 months with GN ( P < 0.0001). After 1L, 33% and 61% of FFX- and GN-treated pts, respectively, received no further chemotherapy ( P< 0.001). Conclusions: In the largest manually abstracted retrospective analysis to date, MPC pts treated with 1L FFX were younger, more likely to receive 2L therapy, and had increased survival compared to pts treated with GN. The OS of pts treated with FFX was similar to the OS reported by Conroy et al despite upfront dose attenuations in 98% of pts. A randomized trial is needed to confirm optimal sequencing of chemotherapy in MPC.

Abstract NT-101: QUADRA: A PHASE 2, OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE SINGLE-AGENT NIRAPARIB TREATMENT IN PATIENTS WITH RELAPSED OVARIAN CANCER (ROC) WHO HAVE RECEIVED ≥3 PRIOR CHEMOTHERAPY REGIMENS

Abstract BACKGROUND: Patients with ROC have limited treatment options in later lines of therapy, as many become platinum-resistant or -ineligible. Poly(ADP-ribose) polymerase inhibitor (PARPi) treatment is one option, however these agents are currently not approved for BRCAwt patients in the treatment setting. Niraparib, a PARPi, has demonstrated increased progression-free survival vs placebo as maintenance therapy for platinum-responsive ROC. Niraparib was effective regardless of BRCAmut or homologous recombination deficiency (HRD) status, although an increased treatment effect was observed in the HRDpos population. QUADRA (NCT02354586) evaluated niraparib treatment in heavily pretreated ROC patients, regardless of BRCAmut or HRD status, platinum sensitivity, or prior PARPi use. METHODS: Eligible patients had grade 2-3 serous ROC, ≥3 prior chemotherapy lines, and measurable disease. Patients were evaluated for BRCAmut and HRD status (MyChoice HRD Test). Patients received niraparib 300 mg once daily until progression; dose could be lowered to 200 mg or 100 mg due to treatment-emergent adverse events (TEAEs). The primary endpoint was objective response rate (ORR) per RECIST v1.1 in patients treated in 4th or 5th line who were HRDpos, platinum sensitive, and PARPi naïve. RESULTS: 463 patients were treated. Of these, 161 were platinum refractory, 151 platinum resistant, and 120 platinum sensitive to their last line of platinum therapy. Of note, 83 patients were primary platinum resistant or refractory (42 and 41, respectively). Median number of prior lines of therapy was 4 (range 2-16), and 27% of patients were treated in 6th or later line. 100% of patients received prior platinum, 99.6% received prior taxane, 81% received prior doxorubicin, 63% received prior bevacizumab, and 59% received prior gemcitabine. In the primary efficacy population (N=45), ORR was 29% (95% CI: 16-44, P=0.0003), disease control rate (DCR) was 71% (95% CI: 56-84), and duration of response (DOR) was 9.2 months (95% CI: 5.9-NE); overall survival (OS) was not reached (95% CI: 18.5-NE). The efficacy outcomes in all 456 patients with measurable disease at baseline treated in 4th or later line demonstrated a DCR of 49% with 2 complete responses (CR), 36 partial responses (PR), and 187 patients with stable disease (SD). The responses were durable with a median DOR of 9.4 months, a clinical benefit rate (CR+PR+SD) at 16 weeks of 29%, and median OS of 17.2 months (95% CI: 14.9-19.8) among all patients treated in 4th or later line. 266 (57.5%) patients had grade ≥3 treatment-related TEAEs. Grade ≥3 thrombocytopenia event (thrombocytopenia or decreased platelet count) by dose at onset of the event was 27.5% at 300 mg, 4.7% at 200 mg, and 2.7% at 100 mg. The other most common grade ≥3 TEAEs were anemia (26.3%) and neutropenia (8.2%). Hematologic TEAEs were most frequent in the first month and decreased in frequency and severity after dose reduction during months 2-3. CONCLUSIONS: Niraparib demonstrated durable anticancer activity in this heavily treated (≥3 lines) ROC population, including platinum-resistant or BRCAwt patients. Toxicities were consistent with previous niraparib studies. DISCLOSURE Funded by TESARO, Inc. Citation Format: Kathleen Moore, Angeles Secord, Melissa Geller, David Miller, Noelle Cloven, Gini Fleming, Andrea E. Wahner Hendrickson, Masoud Azodi, Paul Disilvestro, Amit Oza, Mihaela Cristea, Jonathan S. Berek, John Chan, Yong Li, Kaiming Sun, Katarina Luptakova, Ursula A. Matulonis, Bradley J. Monk. QUADRA: A PHASE 2, OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE SINGLE-AGENT NIRAPARIB TREATMENT IN PATIENTS WITH RELAPSED OVARIAN CANCER (ROC) WHO HAVE RECEIVED ≥3 PRIOR CHEMOTHERAPY REGIMENS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-101.

708P - A phase I/Ib, multi-center trial of ARQ-761 (Beta-Lapachone) with gemcitabine/nab-paclitaxel in patients with advanced pancreatic cancer

BackgroundARQ761 (β-lapachone) is a hydroquinone analog that exploits the unique elevation of NQO1 found in 90% of pancreatic cancer cells and causes tumor-specific cell death by eliciting a futile redox cycle generating high levels of reactive oxygen species and ultimately PARP1 hyperactivation-dependent cell death. ARQ761 induces cell death which is: (i) not dependent on p53 status; (ii) not dependent on cell cycle status; (iii) not affected by known oncogenic driver or carrier mutations; and (iv) not affected by loss of caspases. We demonstrated that ARQ761 has synergistic antitumor activity with chemotherapy in pancreatic cancer preclinical models. MethodsThis was a single arm phase-1b clinical trial of ARQ-761 plus gemcitabine and nab-paclitaxel for patients with pancreatic cancer. The primary objective was to determine the maximum tolerated dose of ARQ 761 in combination with chemotherapy. Secondary objectives were to assess clinical activity, safety, tolerability and pharmacodynamic effects. Patients with metastatic pancreatic adenocarcinoma not treated with prior gemcitabine with adequate hematologic, renal and liver function and good performance status were enrolled. Dose levels are described in the table. Immunohistochemistry was used to assess for NQO1 expression. ResultsFifteen patients were evaluable for safety, 67% were male, 53% had received prior chemotherapy and 96% tested positive for NQO1 expression. The most common treatment related toxicities were anemia and fatigue. The following dose limiting toxicities were observed (dose level 1: neutropenia, anemia, dose level -1 fatigue). The maximum tolerated dose of ARQ761/gemcitabine/nab-paclitaxel is 156/800/100mg/m2. Tumour response was stable disease in 53% Pharmacodynamic analysis was performed on post treatment biopsies. ConclusionsWe report results of a phase 1b clinical trial of the novel NQO1 bioactivatable compound, ARQ761, in combination with gemcitabine/nab-paclitaxel. Treatment related toxicities were observed which were noted in preclinical models and managed with routine dose adjustment. Clinical trial identificationNCT02514031. Legal entity responsible for the studyUT Southwestern Medical Center. FundingPancreatic Cancer Action Network, Rising Tide, Gateway, Arqule Pharmaceuticals. DisclosureM.S. Beg: Research grant / Funding (institution): Arqule; Advisory / Consultancy: Array; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy: Guardant; Advisory / Consultancy: Genentech. D. Boothman: Research grant / Funding (institution): Arqule; Advisory / Consultancy: Toray global; Speaker Bureau / Expert testimony: systems oncology. Y. Arriaga: Full / Part-time employment: IBM. A. Sanjeeviaiah: Advisory / Consultancy, 1500$: Guardant health. B. Schwartz: Full / Part-time employment: Arqule. All other authors have declared no conflicts of interest.

Phase 1/2 trial of FF-10502-01, a pyrimidine antimetabolite, in patients with advanced cholangiocarcinoma and solid tumors.

3008 Background: FF10502 is a synthetic pyrimidine nucleoside similar to gemcitabine (gem) with a sulfur in the pentose ring. FF10502 is a more potent inhibitor of DNA polymerase Beta than gem with activity in gem resistant patient (pt) derived xenograft models. FF10502 is avidly taken up into DNA and has greater activity against quiescent cells than gem. Methods: Pts > 18 years old with advanced disease who had progressed on standard of care were enrolled into 9 dose levels to determine maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) and subsequently into two expansion cohorts: biliary or solid tumors (ST). FF10502 at doses of 8 to 135 mg/m2 was administered iv on days 1, 8, 15 of a 28-day cycle until progressive disease or toxicity. PK/PD evaluations were performed on all pts. Response was assessed by RECIST 1.1. Results: 76 pts were treated; 35 pts in dose escalation, including 7 cholangiocarcinoma pts. MTD was 90 mg/m2. DLTs included 2 pts with hypotension at 135mg/m2 (G3 and G4) and 1 pt each with G3 fatigue and G2 rash at 100mg/m2. In expansion, 19 cholangiocarcinoma, 3 gallbladder and 19 other pts (13 pancreatic, 2 urothelial, and 1 each ovarian, prostate, NSCLC, SCCHN each) were treated. 1 pt with prior rituximab for ITP developed PML. G3 treatment-related low platelets occurred in 3 pts at 90mg/m2 after cycle 1. There were 5 partial responses (PRs), including 4 pts who had progressed on prior gemcitabine: 3 of 26 pts with cholangiocarcinoma, 1 urothelial carcinoma and 1 chondroblastic osteosarcoma. 7 cholangiocarcinoma pts stayed on therapy for ≥6 months. FF10502 incorporation intoperipheral blood cellular DNA was seen, andbiomarkeranalysisdata to identify pts with higher potential for clinical response will be presented. Conclusions: FF10502 is well tolerated in pts with advanced cancers refractory to standard therapies. Early signals of efficacy warranting further exploration were seen in heavily pretreated cholangiocarcinoma pts (median: 4 prior therapies). Patient selection based on differential effects of FF10502 on DNA polymerases will be explored. Clinical trial information: NCT02661542.

Meta-analysis of OS for pancreatic cancer patients receiving 5FU and oxaliplatin-based therapy after failing first-line gemcitabine-containing therapy.

202 Background: Pancreatic cancer is the 3rd most common cause of cancer-related death in US. After progression on first-line gemcitabine-based therapy, guidelines suggest that 5FU with nanoliposomal irinotecan/irinotecan is the preferred regimen. Oxaliplatin (OXA) is not endorsed as prominently, as conflicting results have emerged on the efficacy of 5FU/OXA. This large variability in efficacy outcomes may be due to the heterogeneity of patient performance status (PS) or other confounding factors. We performed a meta analysis in an attempt to estimate the median (m) OS of patients receiving 5FU/OXA-containing regiments after failing first-line treatment with gemcitabine-containing therapy. Methods: A systematic review of literature and existing meta analyses for second-line treatment of pancreatic cancer was performed. Selection inclusion criteria included: prior gemcitabine treatment, second-line treatment of locally advanced or metastatic pancreatic cancer, 5FU and OXA; exclusion criteria included: oral 5FU (S1), irinotecan, capecitabine/cisplatin, no ECOG disclosure. A Bayesian fixed effect meta analysis was performed for the mOS with PS as predictor. A non-informative prior was used to establish the relationship between mOS and PS. The posterior median of OS and 95% predictive interval (PI) were summarized. Results: Eleven studies (454 patients) met the selection criteria for analysis. Median OS for patients receiving second-line 5FU and OXA-based therapy with ECOG PS 0-1 was 6.2 months (95% PI 5.4, 7.1). Restricting to FOLFOX (6 studies, 258 patients), mOS was 6.3 months (95% PI, 5.4, 7.4). Median OS were comparable to those observed with nanoliposomal irinotecan (NAPOLI-1) where 90% patients had ECOG 0-1. Some of the most frequent ( > 10%) grade 3-4 AEs for 5FU and OXA included neutropenia, thrombocytopenia, anemia, and fatigue, comparable to that reported with irinotecan-based therapy. Conclusions: This meta analysis suggests that after progression on a first-line gemcitabine containing regimen, 5FU and OXA-based therapy (eg. FOLFOX) may be a viable and acceptable treatment for patients with pancreatic cancer with good PS.

Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study

BackgroundGemcitabine is used to treat a wide range of tumours, but its efficacy is limited by cancer cell resistance mechanisms. NUC-1031, a phosphoramidate modification of gemcitabine, is the first anti-cancer ProTide to enter the clinic and is designed to overcome these key resistance mechanisms.MethodsSixty-eight patients with advanced solid tumours who had relapsed after treatment with standard therapy were recruited to a dose escalation study to determine the recommended Phase II dose (RP2D) and assess the safety of NUC-1031. Pharmacokinetics and anti-tumour activity was also assessed.ResultsSixty-eight patients received treatment, 50% of whom had prior exposure to gemcitabine. NUC-1031 was well tolerated with the most common Grade 3/4 adverse events of neutropaenia, lymphopaenia and fatigue occurring in 13 patients each (19%). In 49 response-evaluable patients, 5 (10%) achieved a partial response and 33 (67%) had stable disease, resulting in a 78% disease control rate. Cmax levels of the active intracellular metabolite, dFdCTP, were 217-times greater than those reported for equimolar doses of gemcitabine, with minimal toxic metabolite accumulation. The RP2D was determined as 825 mg/m2 on days 1, 8 and 15 of a 28-day cycle.ConclusionsNUC-1031 was well tolerated and demonstrated clinically significant anti-tumour activity, even in patients with prior gemcitabine exposure and in cancers not traditionally perceived as gemcitabine-responsive.

Abstract CT136: Phase Ib study of Decitabine in combination with Gemcitabine in treatment of refractory pancreatic adenocarcinoma and advanced soft tissue or bone sarcomas

Abstract Background and Objectives: Metastatic pancreatic adenocarcinoma is the second leading cause of cancer related death in the US with limited therapeutic options. Preclinical data have shown that methylation alongside other epigenetic modifications play a role in carcinogenesis and development of chemotherapy resistance in that disease. Sarcomas are a heterogeneous group of tumors originating from mesenchyme and are associated with high rates of metastases leading to poor prognosis. Numerous epigenetic changes including hypermethylation have been identified in several sarcoma subtypes as well. Preclinical work suggested that Methylation plays a role in cellular reprogramming to a less differentiated, more invasive cell that is resistant to chemotherapy. Based on that, restoration of normal methylation patterns is a potential therapeutic target for these tumors. Experience from other disease settings showed that protracted intermittent low dosing of hypomethylating agents do have epigenetic modulating effect with less toxicity. The concept of this trial is to assess the feasibility of combining a standard of care chemotherapy with a protracted course of intermittent low dose DNMT inhibitor. Gemcitabine is a universally accepted therapy option for both pancreatic adenocarcinoma as well as Sarcomas while Decitabine is a potent DNMT inhibitor. Our primary objectives are to assess the safety and tolerability of protracted course of intermittent low dose Decitabine in combination with Gemcitabine in previously treated patients with advanced PADC and sarcomas, to identify the recommended phase 2 dosing (RP2D) and to describe the dose limiting toxicities (DLT). Methods: Patients with metastatic histologically or cytologically confirmed PADC or sarcoma (soft tissue or bone) after who meet inclusion criteria will be enrolled. Prior Gemcitabine exposure is allowed. A total of 18 patients (9 from each diagnostic group) will be enrolled. A modified 3+3 dose escalation design is employed for each diagnostic group. Two dose levels of Decitabine, 0.1 and 0.2 mg/kg subcutaneously administered on twice weekly schedule for three weeks of a 28-day cycle are being tested. Gemcitabine is given as 900 mg/m2, IV over 90 min on Days 1, 8 and 15 of a 28-day cycle. Treatment is continued until disease progression or unacceptable toxicity. DLT is defined as any drug related non-hematological grade 3 or 4 toxicities per CTCAE v 4.0. Disease assessment is performed every 8 weeks using RECIST v1.1. Patients will be monitored for tolerance and safety with routine clinical exams, laboratory studies, and periodic CT scans to assess response to therapy. The study is currently open to accrual with 5 PDAC patients and 9 Sarcoma patients already enrolled. Preliminary data has shown excellent tolerance for the regimen in the completed Sarcoma cohort and an expansion phase had been designed and is currently underway. Clinical trial identifier: NCT02959164. Citation Format: Laith Abushahin, Varum Monga, Daniel Berg, Chandrikha Chandrasekharan, Munir Tanas, Michael Henry, Mariel Mckay, Sarah Mott, Mohammed Milhem. Phase Ib study of Decitabine in combination with Gemcitabine in treatment of refractory pancreatic adenocarcinoma and advanced soft tissue or bone sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT136.

A Phase I/II Study Targeting Angiogenesis Using Bevacizumab Combined with Chemotherapy and a Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas.

Epigenetic events and genetic alterations under the control of the tumor microenvironment potentially mediate tumor induced angiogenesis involved in soft tissue sarcoma (STS) metastasis. Addition of antiangiogenic agent, such as bevacizumab, to standard chemotherapy in treatment of sarcoma has been studied in clinical trials, but most of the findings have not supported its use. We hypothesized the existence of an epigenetically mediated “angiogenic switch”, and the tumor microenvironment, prevents bevacizumab from truly blocking angiogenesis. The addition of valproic acid (VPA), a weak histone deacetylase inhibitor, and bevacizumab, a monoclonal antibody against vascular endothelial growth factor, together with the cytotoxic effects of gemcitabine and docetaxel, may enhance responses and alter chemoresistance. This was designed as a phase I/II trial with primary endpoints including safety of the treatment combination and tumor response. Unresectable or metastatic sarcoma patients >18 years of age, irrespective of number of prior treatments, received VPA 40 mg/kg orally for 5 days prior to day 1, bevacizumab at 15 mg/kg IV on day 1, gemcitabine 900 mg/m2 (day 1, day 8), and docetaxel 75 mg/m2 (day 8). Cycles were of 28 day duration. Bevacizumab and VPA were continued as maintenance after 6 cycles, until disease progression. A standard 3 + 3 phase I dose de-escalation design was utilized to evaluate safety. Gain of function p53 gene mutation testing was performed on available archival tissue specimens. A total of 46 patients (30 female, 16 male) with median age of 60 (range 24–81) years were enrolled; 34 (73.9%) patients received prior chemotherapy, 14 (30%) of which received prior gemcitabine and docetaxel. Patients received a median of 5.5 cycles (range 0–24 of treatment (min 0, one patient died prior to completing the first cycle; max: 24, one patient received 6 cycles and 18 maintenance cycles before progressing). Seventeen patients underwent dose reduction, of which VPA was reduced in 6 patients. Forty-one patients were evaluable for response. There was a confirmed complete response in 1 (epithelioid sarcoma), and a partial response (PR) in 6 (1 carcinosarcoma, 2 extrauterine leiomyosarcoma (LMS), 2 undifferentiated pleomorphic sarcoma, and 1 uterine LMS) patients. Stable disease (SD) was seen in 21 patients for at least 2 months. One subject with prior gemcitabine and docetaxel had PR, and 7 had SD. Median progression-free survival (PFS) was 5.7 months (95% CI: 2.1–8.0), and overall survival (OS) was 12.9 months (95% CI: 8.3–14.5). Three patients died due to tumor progression while on the study. The combination of VPA, bevacizumab, gemcitabine, and docetaxel appears to be moderately safe and well tolerated. Given that there are very limited options for patients with relapsed refractory STS, this drug combination may be an important therapy to consider. This combination treatment deserves further investigation in epithelioid and carcinosarcoma subtypes.

The nab-paclitaxel/gemcitabine regimen for patients with refractory advanced pancreatic adenocarcinoma.

The phase III MPACT trial for metastatic pancreatic cancer (PC) showed improved overall survival (OS), progression free survival (PFS) and response rates (RRs) for first-line nab-paclitaxel (Abraxane) and gemcitabine (the AG combination) compared to gemcitabine monotherapy. The safety and efficacy of the AG combination has not been systematically studied as second-line therapy or beyond for metastatic PC. We conducted an IRB-approved retrospective analysis of all patients diagnosed between September 2010 and August 2014 with advanced refractory PC that received combination treatment with AG at our institution. Demographic and survival data were extracted from the registry. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 and on days 1, 8 and 15 of a 28-day cycle with subsequent dose modifications based on tolerance. Data on 59 patients was available; the median age was 61; 55% were male; 56% received AG as second line therapy and 44% received it as third-line or beyond. Five (10%) patients had a confirmed partial response (PR), 23 (47%) had stable disease (SD) and 21 (43%) had disease progression as their best response. Among the 31 (52%) patients who received prior gemcitabine, 18 (58%) had clinical benefit; 3 had a PR and 15 had SD. The median OS was 3.9 months and the median progression-free survival was 3 months. Toxicity was similar to what was reported in the MPACT trial. This retrospective analysis suggests that AG is active in PC patients previously treated with either fluoropyrimidine-based therapy or gemcitabine-based therapy with manageable toxicities.

Abstract B23: A pilot study targeting angiogenesis using bevacizumab combined with gemcitabine/docetaxel and valproic acid (VPA), a histone deacetylase inhibitor (HDACi), in advanced soft tissue sarcomas (STS)

Abstract Introduction: Many of the signaling pathways involved in angiogenesis also drive STS tumor cell growth. Autocrine and paracrine vascular endothelial growth factor (VEGF) and platelet-derived growth factor mediated growth plays a role in the pathogenesis of several STS subtypes. Relatively few clinical trials have evaluated the role of combining angiogenesis inhibitors, like bevacizumab, with chemotherapy in sarcoma with mostly negative results. We hypothesized that the microenvironment may prevent bevacizumab from truly blocking angiogenesis and that there may exist an “angiogenic switch” that is epigenetically mediated. Epigenetically modifying the tumor microenvironment prior to chemotherapy has been shown to improve cytotoxic cell kill and response rates. Gain-of-function p53 mutant tumors are poor chemotherapy responders and cause genome-wide increase in histone methylation and acetylation. VPA is a known HDACi with antitumor effects and suppresses neovascularization. Herein we combined pulse dose of VPA with bevacizumab and standard chemotherapy (gemcitabine/docetaxel) to better modulate the cytotoxic effects against STS. Materials and Methods: Subjects with locally advanced, unresectable, or metastatic STS of any site and all subtypes with measurable disease were enrolled. GIST, bone, and Kaposi's sarcomas were excluded. VPA at 40-mg/kg dosage was given for 5 days prior to each cycle and was repeated before each cycle. Gemcitabine 900 mg/m2 on days 1 and 8 and docetaxel 75 mg/m2 on day 8 were administered on a 28-day schedule. Bevacizumab 15 mg/kg every 4 weeks was administered on day 1 throughout chemotherapy and after chemotherapy was completed. Subjects were treated for a total of 6 cycles and assessed every 2 cycles for progression. Treatment was terminated on disease progression or with unacceptable toxicity. All pathologic diagnoses were confirmed by a pathologist with subspecialty training in bone and soft-tissue pathology. Results: 46 subjects (30 female, 16 male) with median age of 60 (range 24-81) years and a median of 1 (range 0-6) prior line of chemotherapy were enrolled. Sarcoma subtypes included extrauterine leiomyosarcoma (LMS) (9), uterine LMS (8), undifferentiated pleomorphic (7), angiosarcoma, carcinosarcoma, liposarcoma (4 each), and other types (10). 34 (73.9%) subjects received prior chemotherapy, 14 (30%) of whom received prior gemcitabine and docetaxel. 16 (34.8%) received prior radiation and 44 (95.7%) had prior surgery. 5 (12%) of 41 subjects had gain-of-function p53 mutation. Subjects received a median of 5.5 cycles (0-15) of treatment. 17 subjects underwent dose reduction of which VPA was reduced in 6 subjects. 42 subjects were evaluable for response. There was a complete response in 1 (epithelioid) and a partial response (PR) in 6 (1 carcinosarcoma, 2 extrauterine LMS, 2 undifferentiated pleomorphic, and 1 uterine LMS) subjects. Stable disease (SD) was seen in 21 subjects. One subject with prior gemcitabine and docetaxel had PR and 7 had SD. Median progression-free survival (PFS) was 5.7 months (95% CI: 2.1-8) and overall survival (OS) was 12.9 months (95% CI: 8.3-14.5). In LMS subgroup median PFS was 8.4 months (95% CI: 2-8.6) and median OS was 16.3 months (95% CI: 8.1-26.5). Grade 3/4 bevacizumab and VPA-related hematologic toxicities were observed in 2% and 13% and nonhematological toxicities in 9% and 13% of subjects, respectively. Conclusions: Addition of VPA and bevacizumab to gemcitabine and docetaxel showed a clinical benefit rate of 61.54 % in subjects with prior gemcitabine and docetaxel. This regimen is safe and toxicities are manageable. The overall response rate in the study was 16.67%. The combination deserves further investigation in epithelioid and carcinosarcoma subgroups. Citation Format: Umang Swami, Varun Monga, Munir Tanas, Aaron Bossler, Sarah Mott, Brian Smith, Mohammed Milhem. A pilot study targeting angiogenesis using bevacizumab combined with gemcitabine/docetaxel and valproic acid (VPA), a histone deacetylase inhibitor (HDACi), in advanced soft tissue sarcomas (STS) [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B23.

Abstract CT100: First-in-human phase 1 trial of pyrimidine anti-metabolite FF-10502-01 in patients with advanced cancer

Abstract Background: FF10502-01 is a synthetic pyrimidine nucleoside analogue that is structurally similar to gemcitabine with a substitution of sulfur for oxygen in the pentose ring. FF-10502-01 showed potent anti-tumor activity in preclinical studies. In Capan-1 and SUIT-2 pancreatic ca xenograft models, FF-502-01 achieved superior tumor growth suppression and survival, respectively, compared to gemcitabine (gem), with less toxicity at clinically relevant doses. In gem-resistant pancreatic PDX models, FF-10502-01, alone and in combination with nab-paclitaxel (nab-pac), had higher efficacy and tolerability than gem/gem+nab-pac. Methods: We conducted a standard 3+3, dose-escalation phase 1 trial with FF-10502-01 to determine safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) i.e. FF-10502 incorporation into peripheral blood cellular DNA, and preliminary antitumor activity. Eligibility criteria included age >18 years, solid tumors refractory to standard treatment and adequate organ function. FF-10502-01 was administered IV over 60 minutes on days 1, 8, and 15 every 4 weeks. Planned dosing cohorts included 8, 12, 18, 27, 40, 60, 90, 135 and 200 mg/m2. Supportive medications such as anti-nausea prophylaxis were allowed. Results: 22 patients (pts) have been treated in 6 dose cohorts of 8-60 mg/m2. The median number of cycles received was 2 (range 1 to >12). Pts with the following cancers were enrolled: pancreatic (5 pts); ovarian and cholangiocarcinoma (3 each); parotid gland, prostate, and sarcoma (2 each); and endometrial, squamous cell carcinoma of the head and neck, anal, colon-neuroendocrine, and unknown primary (1 pt each). 11 pts were male and 11 female, median age 63 years (range 21-80), average number of prior cytotoxic therapies 3 (range 1-7) and 9 pts with prior gemcitabine therapy. Common related adverse events were Gr 1/2 nausea (43%), rash (38%), fever (29%), fatigue (19%), and vomiting despite prophylactic ondansetron and dexamethasone (14%). One pt had Gr 3 nausea (a DLT). Cytopenias have been minimal: 2 pts with Gr 1 and 2 anemia; with no neutropenia or thrombocytopenia. No pts have required dose reduction for toxicity. To date, an MTD has not been identified and enrollment continues. A pt with chondroblastic osteogenic sarcoma (18 mg/m2) achieved an unconfirmed partial response (73% decrease) in a maxillary mass but developed progressive disease at another site. 3 currently active patients (1 each of acinar pancreatic, prostate, parotid gland), demonstrated durable stable disease for > 48, 40 and 28 weeks, respectively, at doses ranging from 8 to 27 mg/m2. FF-10502 plasma concentrations increased with dose. Additional PK and PD data will be presented. Conclusions: The pyrimidine nucleoside antimetabolite FF-10502-01 is well tolerated with prophylactic anti-emetics and demonstrated preliminary antitumor activity in heavily pretreated patients. Citation Format: Gerald Steven Falchook, Lindsay Bramwell, Lori Hannan, Deeksha Vishwamitra, Takayuki Yamada, Michele Rosner, David Wages, Thomas Myers, Linda Paradiso, Filip Janku. First-in-human phase 1 trial of pyrimidine anti-metabolite FF-10502-01 in patients with advanced cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT100. doi:10.1158/1538-7445.AM2017-CT100