A phase I clinical trial of Ad5/3-Δ24, a novel serotype-chimeric, infectivity-enhanced, conditionally-replicative adenovirus (CRAd), in patients with recurrent ovarian cancer

Abstract

Objective The conditionally replicative adenovirus Ad5/3-Δ24 has a type-3 knob incorporated into the type-5 fiber that facilitates enhanced ovarian cancer infectivity. Preclinical studies have shown that Ad5/3-Δ24 achieves significant oncolysis and antitumor activity in ovarian cancer models. The purpose of this study was to evaluate in a Phase I trial the feasibility and safety of intraperitoneal (IP) Ad5/3-Δ24 in recurrent ovarian cancer patients. Methods Eligible patients were treated with IP Ad5/3-Δ24 for 3 consecutive days in one of three dose cohorts ranging 1 × 1010–1 × 1012 vp. Toxicity was assessed utilizing CTC grading and efficacy with RECIST. Ascites, serum, and other samples were obtained to evaluate gene transfer, generation of wildtype virus, viral shedding, and antibody response. Results Nine of 10 patients completed treatment per protocol. A total of 15 vector-related adverse events were experienced in 5 patients. These events included fever or chills, nausea, fatigue, and myalgia. All were grade 1–2 in nature, transient, and medically managed. Of the 8 treated patients evaluable for response, six patients had stable disease and 2 patients had progressive disease. Three patients had decreased CA-125 from pretreatment levels one month after treatment. Ancillary biologic studies indicated Ad5/3-Δ24 replication in patients in the higher dose cohorts. All patients experienced an anti-adenoviral neutralizing antibody effect. Conclusions This study suggests the feasibility and safety of a serotype chimeric infectivity-enhanced CRAd, Ad5/3-Δ24, as a potential therapeutic option for recurrent ovarian cancer patients.

Talimogene Laherparepvec (T-VEC) for the Treatment of Advanced Melanoma

“…In many studies across several cancer types, these agents were administered systemically, often in combination with other antineoplastic therapies [22]. Although some activity has been observed in these early phase trials, the presence of concurrent therapies and low objective response rates highlights the need for randomized clinical trials [23–27]. Systemic delivery of oncolytic viruses is limited by antibody and complement coating causing sequestration and clearance in the liver and spleen [21].…”

Oncolytic viruses: From bench to bedside with a focus on safety

“…ONYX-015, H101 (Oncorine) and other first-generation oncolytic crHAdVs have gone through several phase I/II trials without relevant signs of high grade toxicity but also without significant therapeutic effects, resulting in discontinuation of further trails. 48 More recent clinical trials employing new generations of crHAdVs like RGD retargeted oncolytic crHAdVs, 20,49,50 crHAdV-5/3 chimeric vectors, 32,[51][52][53][54] ColoAd1, 55 hTERT-promoter driven crHAdV-5 vector Telomelysin, 56 E2F-1-promoter driven CG0070 33 , Rbtargeted crHAdV expressing hyaluronidase (VCN-01) 57 and crHAdV vectors expressing immunomodulating genes have shown safety (low toxicity) with some promising preliminary results.…”

Trial Watch:

“…Nine patients completed the therapeutic protocol and only manageable Grade I/II side effects were recorded. In spite of the development of neutralizing immunity in all individuals, 6 out of 8 patients that could be evaluated for response experienced disease stabilization 204 . Kanerva and coworkers tested multiple immunological and clinicopathological parameters in 115 cancer patients treated with CGTG-102, either as a single injection, either in a serial manner (3 injections over 10 wks), or in the context of a switch protocol involving the administration of viruses with modified capsid proteins to avoid neutralizing immunity.…”