Elsevier

Gynecologic Oncology

Volume 146, Issue 3, September 2017, Pages 477-483
Gynecologic Oncology

Randomized phase IIB evaluation of weekly paclitaxel versus weekly paclitaxel with oncolytic reovirus (Reolysin®) in recurrent ovarian, tubal, or peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study

https://doi.org/10.1016/j.ygyno.2017.07.135Get rights and content

Highlights

  • Reovirus when added to paclitaxel is not active in unselected patients with recurrent ovarian cancer.

  • Severe neutropenia and respiratory toxicity is more common with reovirus exposure.

  • The activity of weekly paclitaxel in recurrent ovarian cancer is confirmed.

Abstract

Objective

To assess whether the addition of oncolytic reovirus (Reolysin®) to weekly paclitaxel prolonged progression-free survival (PFS) in the treatment of women with recurrent or persistent ovarian, tubal or primary peritoneal cancer.

Patients and methods

Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to paclitaxel (80 mg/m2 intravenously days 1, 8, and 15 every 4 weeks) or the combination of paclitaxel (80 mg/m2 intravenously days 1, 8, and 15) plus reovirus 3 × 1010 TCID50/day intravenously on days 1–5, both every 4 weeks until disease progression or toxicity. The primary end point was PFS. The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%.

Results

The study accrued 108 patients, 100 of whom were evaluable for toxicity. Median PFS was 4.3 months for paclitaxel and 4.4 months for paclitaxel plus reovirus (hazard ratio, 1.11; 90% two-sided CI, 0.78 to 1.59; one-sided P = 0.687). The proportion responding (overall response rate) to paclitaxel was 20% among 45 patients with measurable disease receiving paclitaxel alone, and 17.4% among the 46 patients treated with the combination. The asymptotic relative probability of responding was 0.87 (90% CI, 0.42 to 1.79). Severe adverse events were more common in the combination regimen than in paclitaxel arm for severe neutropenia (grade  4, 12% versus 0%), and severe respiratory adverse events (grade  3, 25% versus 2%). No deaths were considered treatment related.

Conclusion

The addition of reovirus to weekly paclitaxel in the treatment of women with recurrent or persistent ovarian, tubal or peritoneal cancer did not sufficiently reduce the hazard of progression or death to warrant further investigation.

Introduction

Few FDA approved options exist for the treatment of recurrent ovarian cancer. In patients with recurrent disease, re-treatment with paclitaxel using a weekly schedule has demonstrated activity, possibly through anti-angiogenic as well as direct cytotoxic mechanisms [1]. Gynecologic Oncology Group (GOG)-0126N demonstrated a 21% objective response rate (and a 46% rate of stable disease) in this population [2].

Reovirus serotype 3-dearing strain (Reolysin®) is a naturally occurring, ubiquitous, non-enveloped human reovirus with a genome that consists of 10 segments of double-stranded RNA. While community-acquired reovirus infection in humans is generally mild and limited to the upper respiratory and gastrointestinal tract, reovirus has been shown to replicate specifically in, and be cytopathic to, transformed cells possessing an activated Ras signaling pathway. The specificity of the reovirus for Ras-transformed cells, coupled with its relatively nonpathogenic nature in humans, makes it an attractive anti-cancer therapy candidate. In transformed cells with mutations of the Ras proto-oncogene (approximately 30–40% of all human tumors), reovirus has been shown to possess cytopathic activity [3]. Activated Ras is present in greater than 20% of ovarian cancers, and appears to be dependent on histology [4]. Importantly, activating Ras mutations are not requisite for reovirus efficacy, since activation or over-expression of regulatory elements in Ras signaling pathways can also lead to antitumor effects from reovirus [3]. In ovarian cancer, it has been shown that increased Ras signaling contributes to pathogenesis seen with reovirus [4].

Given the susceptibility of ovarian cancer cells to reovirus and the safety of IV reovirus in patients with advanced malignancies, reovirus has been investigated using IV and intraperitoneal (IP) administration in patients with recurrent ovarian cancer [5], demonstrating viral replication in peritoneal tumors when reovirus is delivered systemically [6].

Recent preclinical data suggests that reovirus has a synergistic effect when administered with taxanes [7]. In an in vitro model, exposure of cells to reovirus in combination with docetaxel or paclitaxel demonstrated enhanced apoptotic cell death when compared to either agent alone. Furthermore, in a murine model, reovirus monotherapy slowed tumor growth and prolonged median overall survival time compared to control treatment, whereas docetaxel alone had no effect. When administered in conjunction with reovirus, the combined therapy significantly suppressed tumor growth and replicating virus was identified within tumors [8]. Thus, we set out to assess whether weekly paclitaxel, when combined with intravenous reovirus, reduces the risk of disease progression when compared with paclitaxel alone.

Section snippets

Methods

This was an open-label prospective randomized phase IIB trial of single-agent weekly paclitaxel compared with weekly paclitaxel plus reovirus (GOG-186-H; ClinicalTrials.gov. Identifier: NCT01166542). Eligible patients included women with measurable (per RECIST 1.1) or detectable persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with documented disease progression. Detectable disease required at least one of the following conditions: cancer antigen

Results

From December 2010 to September 2014, GOG member institutions randomized 108 patients (54 to the reference; 54 to the combination). Two patients were deemed ineligible, and a total of 8 patients were never treated. One patient in Fig. 1 on the experimental arm was ineligible and never treated. Because she was never treated, she was excluded from the toxicity comparison. Thus, 100 treated patients (48 in the paclitaxel arm and 52 patients in the combination arm) were evaluable for toxicity (Fig.

Discussion

Weekly paclitaxel has substantial activity in the treatment of recurrent or persistent ovarian, tubal and peritoneal cancer in both the platinum-sensitive and platinum-resistant settings. However, the addition of intravenous reovirus to weekly paclitaxel did not improve PFS or OS or objective response, regardless of whether the assessment was in the population with measurable or with CA-125 evaluable disease.

Oncolytic reovirus has demonstrated activity against many cancers, including

Conflicts of interest

Dr. Joan Walker received grant funding from NCI and GOG/NRG. She also received support for travel to meetings for the study or other purposes from Mateon.

Dr. David O'Malley was on the Advisory Board for Clovis, Tesaro, Novocure, Janssen, AstraZeneca, Genentech/Roche and Eisai. He served as a consultant for Clovis and Tesaro and was on the Steering Committee for Amgen.

Dr. Debra Richardson received grant funding from NRG. She also served on the Advisory Board for Genentech and AstraZeneca.

Dr.

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This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office (CA 27469), the Gynecologic Oncology Group Statistical Office (CA 37517), NRG Oncology (1 U10 CA180822) and NRG Operations (U10CA180868). The following Gynecologic Oncology institutions participated in this study: Ohio State University Comprehensive Cancer Center, University of Oklahoma Health Sciences Center, University of New Mexico, Case Western Reserve University, Carillion Clinic Gynecological Oncology, Froedtert and the Medical College of Wisconsin, University of New Mexico, University of Texas Southwestern Medical Center, Indiana University Hospital/Melvin and Bren Simon Cancer Center, University of Mississippi Medical Center, Wake Forest University Health Sciences, Women’s Cancer Center of Nevada and Mayo Clinic.

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