A Phase IB open-label, dose-escalation study of NUC 1031 in combination with carboplatin for recurrent ovarian cancer

Funding: The study was funded and the investigational drug NUC-1031 was supplied by NuCana plc.Purpose: NUC-1031 is a first-in-class ProTide modification of gemcitabine. In PRO-002, NUC‑1031 was combined with carboplatin in recurrent ovarian cancer (OC). Experimental Design: NUC-1031 was administered on days 1 & 8 with carboplatin on day 1 every 3 weeks for up to 6 cycles. Four dose cohorts of NUC-1031 (500, 625 and 750 mg/m2) with carboplatin (AUC4 or 5) were investigated. Primary endpoint was RP2CD. Secondary endpoints included safety, investigator-assessed objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS) and pharmacokinetics (PK). Results: 25 women with recurrent OC, a mean of 3.8 prior lines of chemotherapy and a median platinum-free interval (PFI) of 5 months (range: 7 - 451 days) were enrolled, 15/25 (60%) platinum-resistant; 9 (36%) partially platinum-sensitive and 1 (4%) platinum-sensitive. Of the 23 response-evaluable: there was 1 confirmed complete response (CR, 4%), 5 partial responses (PR, 17%) and 8 (35%) stable disease (SD). The ORR was 26% and CBR was 74% across all doses and 100% in the RP2CD cohort. Median PFS was 27.1 weeks. NUC-1031 was stable in the plasma and rapidly generated high intracellular dFdCTP levels that were unaffected by carboplatin. Conclusions: NUC-1031 combined with carboplatin is well tolerated in recurrent OC. Highest efficacy was observed at the RP2CD of 500 mg/m2 NUC-1031 on days 1 & 8 with AUC5 carboplatin day 1, every 3 weeks for 6 cycles. The ability to deliver carboplatin at AUC5 and the efficacy of this schedule even in patients with platinum-resistant disease makes this an attractive therapeutic combination.PostprintPeer reviewe

The RNA-binding protein LARP1 is a cancer therapeutic target

Ovarian cancer is the most lethal of gynecological cancers killing 60% of women diagnosed with the disease within 5 years. The major contributor to this high mortality is the emergence of chemotherapy resistance; the tumor is initially sensitive to chemotherapy (especially cisplatin, the mainstay of treatment) but recurs with increasingly resistant disease. Effective methods of overcoming treatment resistance are a major unmet medical need and would prolong survival and improve quality of life for women with this disease. We have shown previously that the RNA binding protein La-related protein 1 (LARP1) binds and post-transcriptionally regulates the stability of mRNAs encoding cell survival and stress response proteins including mTOR, BCL2 and BIK. In ovarian cancer tissue, elevated levels of LARP1 protein correlate with adverse survival outcome and chemotherapy resistance. In vivo inhibition of LARP1 using therapeutic RNA interference (packaged in DOPC nanoliposomes) restores cisplatin sensitivity in resistant ovarian cancer xenograft models. In concurrent studies, using a novel ultra-high performance liquid chromatography tandem mass spectrometry method, we have quantified LARP1 in the circulation of ovarian cancer patients and found that high levels correspond with poor prognosis. Circulating LARP1 has prognostic significance and may act as a companion biomarker to a LARP1 inhibitor. We conclude that LARP1, through its regulation of multiple mRNAs within critical pathophysiological pathways, is an important cancer therapeutic target and that RNA-based drugs designed to target LARP1 restore chemotherapy sensitivity in xenograft models

A phase Ib study of NUC-1031 in combination with cisplatin for the first-line treatment of patients with advanced biliary tract cancer (ABC-08)

Background: Cisplatin/gemcitabine is standard first‐line treatment for patients with advanced biliary tract cancer (ABC). NUC‐1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites. Methods: Patients with untreated ABC, Eastern Cooperative Oncology Group performance status 0–1 received NUC‐1031 (625 or 725 mg/m2) and cisplatin (25 mg/m2) on days 1 and 8, every 21 days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression‐free survival (PFS), and overall survival (OS). Results: Twenty‐one patients (median age 61 years, n = 13 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC‐1031 625 mg/m2 (n = 8 and expansion n = 7; median six cycles) or 725 mg/m2 (n = 6; median 7.5 cycles). Treatment was well tolerated; most common treatment‐emergent grade 3–4 adverse events occurring in more than one patient with 625 mg/m2 NUC‐1031 were increased gamma‐glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg/m2, increased GGT, 67%, and fatigue, 33%. NUC‐1031 725 mg/m2 was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3–10.1), and median OS was 9.6 months (95% CI, 6.7–13.1). The median estimates of area under the plasma concentration–time curve from time 0 to last measurable time and maximum concentration were highest for NUC‐1031 (218–324 μg•h/mL and 309–889 μg/mL, respectively) and lowest for di‐fluoro‐deoxycytidine (0.47–1.56 μg•h/mL and 0.284–0.522 μg/mL, respectively). Conclusion: This is the first study reporting on the combination of NUC‐1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg/m2 NUC‐1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: NCT02351765; EudraCT ID: 2015‐000100‐26). Implications for Practice: The prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin/gemcitabine combination is standard first‐line treatment for patients with ABC. NUC‐1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC‐08) demonstrated a favorable safety profile of NUC‐1031 in combination with cisplatin for the first‐line treatment of patients with ABC, and 725 mg/m2 NUC‐1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling