Ofranergene obadenovec (VB-111) in platinum resistant ovarian cancer: with an immunotherapeutic effect.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5542-5542
Author(s):  
Yael Chava Cohen ◽  
Suzanne T. Berlin ◽  
Michael J. Birrer ◽  
Susana M. Campos ◽  
Tamar Rachmilewitz Minei ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
T Cells ◽  
Phase I ◽  
Therapeutic Dose ◽  
Weekly Paclitaxel ◽  
Ca 125 ◽  
Open Label ◽  
Platinum Resistant ◽  
Platinum Refractory

5542 Background: VB-111 is a targeted anti-cancer gene therapy with a dual mechanism: anti angiogenic/vascular disruption and induction of an anti-tumor directed immune response. We report final results of a phase I/II study of VB-111 in combination with paclitaxel in patients with platinum-resistant ovarian cancer. Methods: Study NCT01711970 was a prospective, open label, dose escalating study assessing combination treatment of VB-111 Q8W and weekly Paclitaxel. In the phase I part of the study patients were treated with escalating doses of intravenous VB-111 and Paclitaxel. In phase 2 patients were treated with therapeutic doses of VB-111 1x1013 Viral Particles and paclitaxel 80mg/m2. Assessments included safety, overall survival (OS), PFS, tumor response (CA-125 and RECIST) and histopathology. Results: 21 patients with recurrent platinum-resistant ovarian cancer were enrolled and treated in 2 US sites. Patients received a mean of 2.3 ±1.8 repeat doses of VB-111. 17/21 received the therapeutic dose. Median age was 65 (41-79) with a median of 3 (1-4) prior lines of therapy. Half of the subjects were Platinum refractory, and half were previously treated with antiangiogenics. No DLTs were observed. VB-111 was well tolerated and was associated with generally mild flu-like symptoms. In the therapeutic dose cohort, a 58% CA-125 GCIG response rate was seen in evaluable patients including durable responses, and responses in patients with platinum refractory disease and post anti-angiogenic failure . The median OS was 498 days in patients treated with Therapeutic Dose compared to 173 days in Sub-therapueutic dose (p = 0.028). Tumor Specimens taken after treatment demonstrated tumor infiltrated with cytotoxic CD8 T-cells and regions of apoptotic cancer cells. Conclusions: Treatment with VB-111 in combination with weekly Paclitaxel was safe and well tolerated. Favorable tumor responses and overall survival outcomes were associated with induction of an immunotherapeutic effect manifested as tumor infiltration with CD-8 T cells. Encouraging results are the basis for further exploration in the ongoing, placebo controlled, pivotal OVAL study. Clinical trial information: NCT01711970.

Clinical trial in progress: Pivotal study of VB-111 combined with paclitaxel versus paclitaxel for treatment of platinum-resistant ovarian cancer (OVAL, VB-111-701/GOG-3018).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5599-TPS5599
Author(s):  
Rebecca Christian Arend ◽  
Bradley J. Monk ◽  
Thomas J. Herzog ◽  
Jonathan A. Ledermann ◽  
Kathleen N. Moore ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Antiangiogenic Therapy ◽  
Objective Response ◽  
Phase Iii ◽  
Weekly Paclitaxel ◽  
Ca 125 ◽  
Recist 1.1 ◽  
Platinum Resistant ◽  
Phase Iii Study

TPS5599 Background: Ofranergene obadenovec (VB-111) is a targeted anti-cancer gene therapy with a dual mechanism of action that includes a broad antiangiogenic effect and induction of a tumor directed immune response. A phase II trial in patients with platinum resistant ovarian cancer showed that VB-111 in combination with weekly paclitaxel was well tolerated and associated with a CA-125 Objective Response Rate (ORR) of 58% with a trend for improved survival. The favorable outcomes were associated with induction of an immunotherapeutic effect of tumor infiltration with CD-8 T cells. Based on these observations, a phase III study was initiated in collaboration with the GOG Foundation, Inc. Methods: Study NCT03398655 is an international, randomized, double-blind, placebo-controlled, phase III study. Eligible patients have recurrent platinum-resistant epithelial ovarian cancer with measurable disease (RECIST 1.1), and may have been previously treated with up to 5 prior lines of therapy. Patient are randomized 1:1 to receive VB-111 (1x1013 VPs) with weekly paclitaxel (80mg/m2), or weekly paclitaxel with placebo. Randomization is stratified by number of prior treatment lines, prior antiangiogenic therapy and platinum refractory disease status. The efficacy endpoints are OS, PFS and ORR by RECIST 1.1 and by CA-125 (GCIG criteria). A pre-planned interim analysis was performed by the DSMC in the first 60 patients evaluable for CA-125 response. The analysis met the pre-defined criteria of a CA-125 ORR (GCIG) in the treatment arm at least 10% higher than in the control arm. Study enrolment is ongoing and over 220 patients were enrolled in the US, EU, and Israel. Enrolment of the full sample size of 400 patients is expected to complete by the end of 2021. Clinical trial information: NCT03398655.

INNOVATE: A phase II study of TTFields (200 kHz) concomitant with weekly paclitaxel for recurrent ovarian cancer—Updated safety and efficacy results.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5580-5580 ◽  
Author(s):  
Ignace Vergote ◽  
Roger von Moos ◽  
Luis Manso ◽  
Cristiana Sessa
Keyword(s):  
Ovarian Cancer ◽  
Adverse Events ◽  
Cancer Patients ◽  
Electric Fields ◽  
Skin Irritation ◽  
Intermediate Frequency ◽  
Weekly Paclitaxel ◽  
Ca 125 ◽  
Serious Adverse Events ◽  
Platinum Resistant

5580 Background: TTFields are a non-invasive, regional antimitotic treatment modality, which have been approved for the treatment of recurrent and newly diagnosed glioblastoma by the FDA. TTFields act by delivering intermediate frequency alternating electric fields to the tumor, predominantly by disrupting the formation of the mitotic spindle during metaphase. INNOVATE was the first trial testing TTFields (200kHz) in ovarian cancer patients. Methods: Thirty-one recurrent, platinum-resistant, unresectable ovarian cancer patients were enrolled in the INNOVATE trial and treated with TTFields in combination with weekly paclitaxel. The primary endpoint was treatment emergent adverse events. Secondary endpoints included progression free-survival, overall survival and radiological response rate. Results: The median age was 60 (range – 45-77), most patients (77%) had serous histology. 52% had an ECOG score of 0. The median number of prior chemotherapy regimens was 4.1 (range 1-11). All patients were platinum-resistant, and 97% of patients received prior taxane-containing regimens. Ten (32%) patients suffered from serious adverse events (SAEs) during the study, none were related to TTFields. Of all reported SAEs, 31% were related to gastrointestinal disorders (ileus, jaundice and ascites) and 31% were respiratory events (dyspnea, pleural effusion and pulmonary embolism). Only one SAE which, related to the tumor, led to permanent discontinuation of the device. Most patients were reported to have mild-moderate, TTFields-related skin irritation, out of whom only two patients (6.4%) had severe-grade events. The median PFS was 8.9 months (95% CI 4.7, NA). Of the evaluable tumors, 25% had partial response and another 46.4% stable disease – a clinical benefit of 71.4%. Six patients (19.4%) had a CA 125 response, translating into a decrease of 50% or more in serum levels. The median OS was not reached. Conclusions: TTFields concomitant to weekly paclitaxel are tolerable and safe in heavily pre-treated platinum-resistant ovarian cancer ovarian cancer patients. These data support further clinical testing of TTFields with chemotherapy in ovarian cancer. Clinical trial information: NCT02244502.

Open label phase I trial using SPL-108 in combination with weekly paclitaxel final report with molecular correlates.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18040-e18040
Author(s):  
Eugenia Girda ◽  
June YiJuan Hou ◽  
Alexandre Buckley De Meritens ◽  
Ruth Stephenson ◽  
Aliza L. Leiser ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Single Agent ◽  
Unmet Need ◽  
Chemotherapeutic Agents ◽  
Ovarian Tumors ◽  
Final Report ◽  
Refractory Disease ◽  
Open Label ◽  
Platinum Refractory

e18040 Background: Therapeutic options for patients with recurrent platinum resistant ovarian cancer are scarce and represent an unmet need in ovarian cancer. Chemotherapy resistance has been linked to many CD44 pathways including P-glycoprotein mediated efflux of chemotherapeutic agents. Our working hypothesis was that chemotherapy resistant ovarian tumors that expressed CD44 would revert drug resistance by using a CD44 inhibitor SPL-108, that had proven safe as a single agent. Methods: Patients with platinum refractory or resistant CD44+ ovarian tumors were eligible. We used a standard 3+3 phase I design, open-label, 2-arm trial of the combination of SPL-108 and IV paclitaxel (PTX): Arm 1 (2 cohorts) Safety Phase: Cohort 1: SPL-108 150 mg SQ Daily +80 mg PTX weekly Cohort 2: SPL-108 300mg daily +80 mg PTX weekly Arm 2 (1 cohort) Exploratory Phase: Cohort 3: SPL-108 daily dose 300 mg +80 mg PTX weekly Days 1-15 in 28 day cycles Primary end points were safety and tolerability. Secondary endpoints included determining molecular signatures of response using NGS. Tumors were sequenced at the time of recurrence or initial diagnosis. Results: Fourteen patients were enrolled in the study. Prior number of treatments ranged from 2-6, except for one patient with platinum refractory disease that progressed during first line of therapy. There was no DLT and all cohorts were completed as designed. The treatment was well tolerated. There was one instance of a bowel micro-perforation that was treated medically. This patient had platinum refractory disease and eventually underwent an interval cytoreduction. There was one patient with grade 3 neurotoxicity. Sixty-two% of the patients had clinical benefit with 36% having a PR. Forty-three % of patient had a PFS of more than 6 months. Two patients enjoyed a PR of 12 months. Molecular profiling of the tumors revealed that all tumors had TP53 alterations and the 4 patients that did not have a response had tumors with TP53 truncations or a lack of function alteration. Conclusions: Daily SPL-108 300mg SQ in combination with weekly PTX is safe and feasible. The promising clinical activity on drug resistant ovarian tumors warrants further investigation. Resistance to SPL-108 are characterized by lack of function of TP53, mostly early truncations. It is possible that SPL-108 may be reactivating TP53 by promoting its active conformation. Once TP53 is active CD44 expression is abrogated at the promoter. Therefore SPL-108 is effectively acting on CD44 through 2 different mechanisms to promote chemotherapy sensitivity. Clinical trial information: NCT03078400.

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