Hypothesis: AdAPT-001 and pseudoprogression - when seeing is not necessarily believing.

The purpose of this commentary is to highlight the high occurrence of clinical pseudoprogression and delayed responses that have been observed to date with the locally injected oncolytic adenovirus, AdAPT-001, currently in a Phase 1/2 clinical trial (NCT04673942) for the treatment of treatment-refractory tumors. Not surprisingly, these have led to confusion about response assessment and whether to continue patients on treatment. AdAPT-001 carries a transforming growth factor (TGF)-beta trap (TGF-β), which sequesters TGF-β, a cytokine that potently regulates inflammation, fibrosis, and immunosuppression in cancer.

BETA prime: a first-in-man phase 1 study of AdAPT-001, an armed oncolytic adenovirus for solid tumors.

AdAPT-001 is an oncolytic adenovirus (OAV) with a transforming growth factor beta (TGF-ß) trap, which neutralizes the immunosuppressive and profibrotic cytokine, TGF-ß. The aim or purpose of this phase 1 study was to assess the safety and tolerability and, secondarily, the efficacy of AdAPT-001 after single intratumoral injection (IT) (Part 1) and multidose IT injection (Part 2) in patients with superficially accessible, advanced refractory solid tumors. Part 1 enrolled 9 patients with a 3 + 3 single dose-escalation safety run-in involving 2.

Data Management 101 for drug developers: A peek behind the curtain.

In drug development a frequently used phrase is "data-driven". Just as high-test gas fuels a car, so drug development "runs on" high-quality data; hence, good data management practices, which involve case report form design, data entry, data capture, data validation, medical coding, database closure, and database locking, are critically important. This review covers the essentials of clinical data management (CDM) for the United States.

Case Report of AdAPT-001-Mediated Sensitization to a Previously Failed Checkpoint Inhibitor in a Metastatic Chordoma Patient.

Chordoma is a rare, but aggressive bone tumor with a high recurrence rate that primarily arises at the cranial and caudal ends of the axial skeleton. Systemic chemotherapies are not effective against the tumor, and outside of surgical resection and radiation, no approved options are available. Prognosis depends on the extent of surgical resection, with the more the better, and adjuvant radiotherapy.

Patent and Marketing Exclusivities 101 for Drug Developers.

Despite an ever-increasing need for newer, safer, more effective, and more affordable therapies to treat a multitude of diseases and conditions, drug development takes too long, costs too much, and is too uncertain to be undertaken without the conferment of exclusionary rights or entry barriers to motivate and sustain investment in it. These entry barriers take the form of patents that protect intellectual property and marketing exclusivity provisions that are provided by statute. This review focuses on the basic ins and outs of regulatory and patent exclusivities for which new chemical entities (NCEs), referring to never-before approved drugs with an entirely new active ingredient, are eligible and uses RRx-001, a small molecule aerospace-derived NCE in development for the treatment of cancer, radiation toxicity, and diseases of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, as a "real world" example.

ROCKET: Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer.

Introduction: RRx-001 is a novel cysteine-targeted alkylating agent that releases nitric oxide (NO). The primary biological activities of this hybrid molecule include macrophage repolarizing and vascular normalization. The purpose of this clinical trial (ROCKET) (NCT02096354) was to compare the safety and efficacy of the combination therapy RRx-001 + irinotecan vs.

Subset analysis of safety and efficacy in asian patients treated with RRx-001 across three clinical trials.

RRx-001, a CD47 antagonist via its inhibition of MYC and the γ-subtype of the peroxisome proliferator-activated receptor (PPAR) has been associated to date with minimal toxicity. The aim of this analysis was to evaluate the toxicity and efficacy of RRx-001 in Asian patients since RRx-001, in the context of multiple Phase 3 studies, will be administered in China and Chinese territories as well as potentially throughout the rest of Asia. Patients received 4 mg of RRx-001 in three different antitumor clinical trials with chemotherapy and/or radiation and a retrospective subset efficacy and toxicity analysis was conducted for patients with Asian ancestry in comparison to patients with other ethnic backgrounds.

BETA PRIME: Phase I study of AdAPT-001 as monotherapy and combined with a checkpoint inhibitor in superficially accessible, treatment-refractory solid tumors.

AdAPT-001 is an investigational therapy consisting of a replicative type 5 adenovirus armed with a TGF-β receptor-immunoglobulin Fc fusion trap, designed to neutralize isoforms 1 and 3 of the profibrotic and immunosuppressive cytokine, TGF-β. In preclinical studies with an immunocompetent mouse model, AdAPT-001 eradicated directly treated 'cold' tumors as well as distant untreated tumors, and, from its induction of systemic CD8 T cell-mediated antitumor immunity, protected the mice from rechallenge with tumor cells. AdAPT-001 also sensitized resistant tumors to checkpoint blockade.

Confirmatory Trials in the Evaluation of Anticancer Medicinal Products in Man--PFS2: A Measure of Therapeutic Action-At-A-Distance.

Overall survival (OS) has emerged as the definitive regulatory "be-all, end-all" for the demonstration of benefit in cancer clinical trials. The reason and the rationale for why this is so are easily appreciated: literally a "test of time," OS is a seemingly unambiguous, agenda-free end point, independent of bias-prone variables such as the frequency and methods of assessment, clinical evaluation, and the definition of progression. However, by general consensus, OS is an imperfect end point for several reasons: First, it may often be impractical because of the length, cost, and the size of clinical trials.

Safety and activity of RRx-001 in patients with advanced cancer: a first-in-human, open-label, dose-escalation phase 1 study.

Background: Epigenetic alterations have been strongly associated with tumour formation and resistance to chemotherapeutic drugs, and epigenetic modifications are an attractive target in cancer research. RRx-001 is activated by hypoxia and induces the generation of reactive oxygen and nitrogen species that can epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation. The aim of this phase 1 study was to assess the safety, tolerability, and pharmacokinetics of RRx-001.

Going viral: a review of replication-selective oncolytic adenoviruses.

Oncolytic viruses have had a tumultuous course, from the initial anecdotal reports of patients having antineoplastic effects after natural viral infections a century ago to the development of current cutting-edge therapies in clinical trials. Adenoviruses have long been the workhorse of virotherapy, and we review both the scientific and the not-so-scientific forces that have shaped the development of these therapeutics from wild-type viral pathogens, turning an old foe into a new friend. After a brief review of the mechanics of viral replication and how it has been modified to engineer tumor selectivity, we give particular attention to ONYX-015, the forerunner of virotherapy with extensive clinical testing that pioneered the field.