A phase I study of the vascular-disrupting agent BNC105P in combination with gemcitabine-carboplatin in platinum-sensitive ovarian cancer patients in first or second relapse.

3569 Background: EPC2407 is a 4-aryl-chromene single isomer microtubulin inhibitor with vascular disrupting and apoptotic activity at nanomolar concentrations. In an earlier phase I study dosing by 1 hr infusions daily x3 on a 21 day cycle, DLT at 21 mg/m2 was pain at tumor sites and vasoconstriction with increases of BP and QTc. MTD was 13 mg/m2 over 1 hr (ASCO 2008, Abst 2531). All drug-related toxicities resolved within an hour of stopping the infusion. Prolonged infusion of EPC2407 to extend exposure of tumor vasculature was designed with administration of EPC2407 over 4 hrs for 3 consecutive days of a 21 day cycle. Eleven patients have received this schedule and their cancers included leiomyosarcoma, colo-rectal, ovary, hepatocellular (2), NSCLC, pancreas, carcinoid, hemangiopericytoma, larynx and small bowel. Results: Doses escalated from 13 to 30 mg/m2 over 4 hours, with MTD determined to be 24 mg/m2. DLTs at 30 mg/m2 were similar to those seen in the 1 hr infusion, with pain at tumor sites in 1 participant and asymptomatic ST depression in a second. Other toxicities were also similar and included transient hypertension. QTc increases were not significant and no new toxicities were encountered. T1/2 with 4 hr infusion was ∼2hr, also seen with 1 hr infusion. AUC and Cmax values were similar to that predicted from the 1 hr data except AUC at 13 mg/m2 was lower than expected. DCE-MRI was done at baseline and after infusion on day 3, cycle 1. Analysis to date of DCE-MRI data of 4 patients showed a median decrease of 40% in both tumor permeability (Ktrans) and tumor perfusion volume (Vp). The two patients with hepatocellular carcinoma had notable stable disease and clear clinical benefit. Both patients received 18 mg/m2 dose, with one receiving 7 cycles over 5 months, and the other still on study (cycle 6) with stable disease for at least 4 cycles. Conclusions: EPC2407 shows clinical promise, with infusion-associated toxicities characteristic of the VDA drug class but without sustained or cumulative toxicity. Studies combining EPC2407 with conventional cytotoxic/cytostatic regimens are being designed. [Table: see text]

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A phase I study of bevacizumab in combination with niraparib in patients with platinum-sensitive epithelial ovarian cancer: The ENGOT-OV24/AVANOVA1 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.5555 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. 5555-5555 ◽

Cited By ~ 6

Author(s):

Mansoor Raza Mirza ◽

Christiane Ehlers Mortensen ◽

Rene dePont Christensen ◽

Louise Christoffersen ◽

Mia Westergaard ◽

...

Keyword(s):

Ovarian Cancer ◽

Phase I ◽

Epithelial Ovarian Cancer ◽

Phase I Study ◽

Platinum Sensitive

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Phase I study to assess the safety, tolerability, pharmacokinetics/pharmacodynamics and preliminary efficacy of SC10914 in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6047 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6047-6047

Author(s):

Jifang Gong ◽

Jinhai Tang ◽

Yongmei Yin ◽

Dingwei Ye ◽

Jian Zhang ◽

...

Keyword(s):

Ovarian Cancer ◽

Phase I ◽

Cancer Patients ◽

Solid Tumors ◽

Phase I Study ◽

Advanced Solid Tumors ◽

Dose Escalation Study ◽

Adequate Organ Function ◽

Grade 3 ◽

Wbc Count

6047 Background: SC10914 is a highly selective inhibitor of PARP enzymes, including PARP1 and PARP2. SC10914 has a similar structure with olaparib. We conducted a phase I study to assess the safety, tolerability, PK/PD and preliminary efficacy of SC10914 in patients with advanced solid tumors. Methods: This is a phase I dose-escalation study with 3+3 design, we enrolled patients at 4 sites in China. Eligible patients were diagnosed with advanced solid malignancies who are refractory to standard therapies or for which no standard therapy exists; had measurable disease; had adequate organ function. Patients received SC10914 daily at ten escalating doses from 30 mg QD to 500 mg TID in a 28-day cycle. We obtained blood for PK and CA125 assessments. Toxic effects were assessed by CTCAE 4.03 criteria and tumour responses ascribed by RECIST 1.1 and CA125 was assessed by GCIG criteria. Results: As of January 2020, 52 patients were enrolled, of which 14 were males and 38 were females. Ten doses were escalated to 500mg TID, and no DLT was observed, and MTD was not obtained. The incidence of grade 3/4 AEs and SAEs that were related to SC10914 were 34.6% (18/52) and 13.5% (7/52). Grade 3/4 adverse reaction happened in at least two patients were anaemia/reduced hemoglobin (10/52, 19.2%), decreased WBC count (5/52, 9.6%), neutropenia (3/52, 5.8%), thrombocytopenia (2/52, 3.8%), and decreased lymphocyte count (2/52, 3.8%). A total of 17 gBRCAm evaluable ovarian cancer patients were enrolled, 6 of them had PR, the ORR was 35.3% (6/17). 10 gBRCAm ovarian cancer patients were enrolled in TID groups (including 2 patients who received BID doses at the beginning and changed to 300 mg TID dose after several cycles of treatment), 5 of them had PR, the ORR was 50% (5/10). The ORR of 400 mg TID group was 66.7%(4/6). PK data showed that the exposure of SC10914 was increased with dose increasing at the dose of 30 mg to 250 mg. The half-life of SC10914 was about 2-5 hours. Conclusions: SC10914 was safe in patients with advanced solid tumors. The main toxicity was blood-related adverse reactions. SC10914 was effective in gBRCAm ovarian cancer patients. 400 mg TID might be RP2D. Clinical trial information: NCT02940132.

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