A phase 1 dose-escalation study of the poly(ADP-ribose) polymerase inhibitor senaparib in Australian patients with advanced solid tumors.

BACKGROUND: Senaparib is a novel, selective poly(ADP-ribose) polymerase-1/2 inhibitor with strong antitumor activity in preclinical studies. This first-in-human, phase 1, dose-escalation study examined the safety and preliminary efficacy of senaparib in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors were enrolled from three centers in Australia, using a conventional 3 + 3 design. Dose-escalation cohorts continued until the maximum tolerated dose or a recommended phase 2 dose was determined. Patients received one dose of oral senaparib and, if no dose-limiting toxicity occurred within 7 days, they received senaparib once daily in 3-week cycles. The primary end points were safety and tolerability. RESULTS: Thirty-nine patients were enrolled at 10 dose levels ranging from 2 to 150 mg. No dose-limiting toxicities were observed in any cohort. Most treatment-emergent adverse events were grade 1-2 (91%). Seven patients (17.9%) reported hematologic treatment-emergent adverse events. Treatment-related adverse events occurred in eight patients (20.5%), and the most frequent was nausea (7.7%). Two deaths were reported after the end of study treatment, one of which was considered a complication from senaparib-related bone marrow failure. Pharmacokinetic analysis indicated that senaparib the accumulation index was 1.06-1.67, and absorption saturation was 80-150 mg daily. In 22 patients with evaluable disease, the overall response rate was 13.6%, and the disease control rate was 81.8%. The overall response rate was 33.3% for the BRCA mutation-positive subgroup and 6.3% for the nonmutated subgroup. CONCLUSIONS: Senaparib was well tolerated in Australian patients with advanced solid tumors, with encouraging signals of antitumor activity. The recommended phase 2 dose for senaparib was determined to be 100 mg daily. GOV ID: NCT03507543.

Safety, Tolerability, and Pharmacokinetics of Senaparib, a Novel PARP1/2 Inhibitor, in Chinese Patients With Advanced Solid Tumors: A Phase I Trial.

BACKGROUND: Senaparib, a novel poly(ADP-ribose) polymerase 1/2 inhibitor, demonstrated antitumor activity in preclinical studies. This phase I, first-in-human, dose-escalation/-expansion study explored the pharmacokinetics, safety and tolerability, and preliminary antitumor activity of senaparib in Chinese patients with advanced solid tumors. PATIENTS AND METHODS: Adults with advanced solid tumors who had failed ³1 line of prior systemic treatment were enrolled. Senaparib (once daily [QD]) dose was escalated from 2 mg until the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) using a modified 3 + 3 design. Dose expansion included: dose groups with ≥1 objective response and one dose higher, as well as those at the MTD/RP2D. Primary objectives were to evaluate the safety and tolerability, and determine the MTD and/or RP2D of senaparib. RESULTS: Fifty-seven patients were enrolled across 10 dose groups (2-120 mg QD, and 50 mg twice daily). No dose-limiting toxicities were observed. The most common senaparib-related adverse events were anemia (80.9%), white blood cell count decreased (43.9%), platelet count decreased (28.1%), and asthenia (26.3%). Senaparib exposure increased dose proportionately at 2-80 mg; absorption saturated at 80-120 mg. Senaparib accumulation was minimal after repeated QD administration (accumulation ratio=1.1-1.5). The objective response rate was 22.7% (n=10/44) overall (all partial responses) and 26.9% (n=7/26) for patients harboring BRCA1/BRCA2 mutations. Disease control rates were 63.6% and 73.1%, respectively. CONCLUSIONS: Senaparib was well tolerated and demonstrated promising antitumor activity in Chinese patients with advanced solid tumors. The RP2D for this clinical study in China was identified as 100 mg QD. CLINICALTRIALS.GOV IDENTIFIER: NCT03508011.

Effect of a strong CYP3A4 inhibitor and inducer on the pharmacokinetics of senaparib (IMP4297) in healthy volunteers: A drug-drug interaction study.

AIMS: A phase I open-label study assessed the effect of multiple oral doses of a potent CYP3A4 inhibitor (itraconazole) and inducer (rifampicin) on the pharmacokinetic profile of a single oral dose of senaparib, a novel, highly potent poly-(ADP-ribose) polymerase 1/2 inhibitor and CYP3A4 substrate, in Chinese healthy male volunteers (HMV). METHODS: Adult HMV were enrolled to the itraconazole or rifampicin group (n = 16 each). In Period 1, all participants received a single oral dose of senaparib 40 mg (itraconazole group) or 100 mg (rifampicin group). In Period 2, the same dose was coadministered with itraconazole (200 mg) and rifampicin (600 mg), respectively. The primary endpoints were senaparib exposure parameters. RESULTS: Coadministration with itraconazole significantly increased exposure of senaparib and decreased that of its major metabolites M9 and M14. Maximum plasma senaparib concentration (Cmax ) was increased by ~79% and area under the concentration-time curve (AUC) increased by ~2.8-fold. Coadministration with rifampicin significantly reduced the Cmax and AUC of senaparib by ~59 and 83%, respectively. The Cmax for both M9 and M14 was slightly increased, although AUC was decreased. All treatment-emergent adverse events were grade ≤2, regardless of the treatment administered. CONCLUSION: In Chinese HMV, the exposure of senaparib was significantly increased when coadministered with itraconazole and significantly decreased when coadministered with rifampicin. It is recommended to avoid concomitant use of senaparib and strong inhibitors or inducers of CYP3A4.

Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .

Differences in sensitivity to new therapies between primary and metastatic breast cancer: A need to stratify the tumor response?

OBJECTIVE: We compared therapeutic response of Varlitinib + Capecitabine (VC) versus Lapatinib + Capecitabine (LC) in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer after trastuzumab therapy by assessing changes in target lesion (TL) diameter and volume per location. METHODS: We retrospectively analyzed the CT data of the ASLAN001-003 study (NCT02338245). We analyzed TL size and number at each location focusing on therapeutic response from baseline to Week 12. We used TL diameter and volume to conduct an inter-arm comparison of the response according to: RECIST 1.1; stratified per TL location and considering TLs independently. Multiple pairwise intra-arm comparisons of therapeutic responses were performed. Considering TL independently, weighted models were designed by adding weighted mean TL responses grouped by location. RESULTS: We evaluated 42 patients (88 TL) and 35 patients (74 TL), respectively, at baseline and Week 12. We found reductions in breast TL burden in the VC arm compared to the LC arm (p = 0.002 (diameter), p < 0.001 (volume)). Responses and TL sizes at baseline were not correlated. Explained variabilities of volume change per TL location, patient and patient:TL interaction were 36%, 10% and 4% (VC), and 13%, 1% and 23%, (LC). A test of inter-arm difference of responses yielded p = 0.07 (diameter), and p < 0.001 (volume). CONCLUSIONS: The therapeutic responses differed across tumors' locations; the magnitude of the differences of responses across the tumors' locations were drug-dependent. Stratified analysis of the response by tumor location improved drug comparisons and is a powerful tool to understand TL heterogeneity.

Safety and efficacy of nilotinib in routine clinical practice in patients with chronic myeloid leukemia in chronic or accelerated phase with resistance or intolerance to imatinib: results from the NOVEL study.

BACKGROUND: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), is approved for the treatment of patients with chronic myeloid leukemia (CML) in many countries, including Taiwan. Though a number of controlled clinical trials have demonstrated the safety and efficacy of nilotinib, studies assessing the safety and efficacy of nilotinib in routine clinical practice are limited. METHODS: The current study was an open-label, single-arm study conducted across 12 centers in Taiwan in adult patients with CML in chronic or accelerated phase with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to one or more previous TKIs. The primary objective was to collect the long-term safety data in patients treated with nilotinib 400 mg, twice daily for up to 2 years. RESULTS: The study enrolled 85 patients with CML, including 76 in the chronic phase (CML-CP) and 9 in the accelerated phase (CML-AP). Overall, 1166 adverse events (AEs) were reported in 80 patients (94.1%), of which 70 AEs (6%) in 28 patients (32.9%) were serious and 336 AEs (28.8%) reported in 60 patients (70.6%) were drug-related. Common drug-related AEs were thrombocytopenia (21.2%), increased alanine aminotransferase (21.2%) and pruritus (17.7%). Of the 85 patients, 19 switched from imatinib due to intolerance - AEs were resolved in 16 of these 19 patients (84.2%). By 24 months, the cumulative rates of complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0 (BCR-ABL1IS ⩽0.01%) and MR4.5 (BCR-ABL1IS ⩽0.0032%) were 75.3, 56.8, 16.2 and 7.4%, respectively. Patients with CML-CP at baseline had higher overall survival (OS) and progression-free survival (PFS) than those with CML-AP. CONCLUSION: This is the first study that demonstrated that nilotinib is effective and well-tolerated in patients resistant or intolerant to imatinib in the real-world setting in Taiwan, reflecting effective management of CML by physicians under routine clinical practice in Taiwan.

Characterization of patterned poly(methyl methacrylate) brushes under various structures upon solvent immersion.

In this paper we describe a graft polymerization/solvent immersion method for generating various patterns of polymer brushes. We used a very-large-scale integration (VLSI) process and oxygen plasma system to generate well-defined patterns of polymerized methyl methacrylate (MMA) on patterned Si(100) surfaces through atom transfer radical polymerization (ATRP). After immersion of wafers presenting lines of these PMMA brushes in water and tetrahydrofuran, we observed mushroom- and brush-like regimes through grafting densities and surface coverages, respectively, for the PMMA brushes with various pattern resolutions. In the mushroom-like regime, the distance between lines of PMMA brushes was smaller than that of the lines patterned lithographically on the wafer; in the brush-like regime, this distance was approximately the same. This new strategy allows polymer brushes to be prepared through graft polymerization and then have their patterns varied through solvent immersion.