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

Abstract

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 2.5 × 1011, 5.0 × 1011, 1.0 × 1012 viral particles (vps). No dose-limiting toxicities or treatment-related serious adverse events (SAEs) were seen. In Part 2, a dose-expansion phase, 19 patients received AdAPT-001 at 1.0 × 1012 vps until disease progression according to Response Evaluation Criteria in Solid Tumors or RECIST 1.1. The overall responses to treatment included confirmed partial responses (3), durable stable disease ≥ 6 months (5), and progressive disease (13). AdAPT-001 is well tolerated. Evidence of an anti-tumor effect was seen in both injected and uninjected lesions. The recommended Phase 2 dose was 1.0 × 1012 vp administered by intratumoral injection once every 2 weeks. Combination of AdAPT-001 with a checkpoint inhibition is enrolling.

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

“…In treatment-refractory patients that have received multiple doses of locally injected AdAPT-001 on the Phase 1/2 BETA PRIME trial (NCT04673942), 7 we estimate that 45% (20/44) have experienced PsP or reactive tumor inflammation 8 9 —that is, a temporary or prolonged enlargement of lesions with or without improved clinical symptoms (but more often with symptomatic improvement) and whether or not the Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 criteria for the progressive disease was strictly met followed by delayed shrinkage sometimes months later.…”

“…In treatment-refractory patients that have received multiple doses of locally injected AdAPT-001 on the Phase 1/2 BETA PRIME trial (NCT04673942), 7 we estimate that 45% (20/44) have experienced PsP or reactive tumor inflammation 8 9 -that is, a temporary or prolonged enlargement of lesions with or without improved clinical symptoms (but more often with symptomatic improvement) and whether or not the Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 criteria for the progressive disease was strictly met followed by delayed shrinkage sometimes months later. Also, of six patients with eccrine carcinoma, chordoma, breast angiosarcoma, arm/breast melanoma, dedifferentiated liposarcoma, and alveolar soft part sarcoma who were treated beyond RECIST progressive disease only the eccrine adenocarcinoma, chordoma, and breast angiosarcoma, that is, 3/6 or 50% of them, went on to show clinical benefit; as of this date, May 01, 2024, the treatment of all three patients is ongoing with durations ranging from 4 to 14 months post RECIST-progression.…”

Translation of oncolytic viruses in sarcoma

“…reported the results of a first-in-human phase I trial using AdAPT-001 demonstrating the safety and tolerability of intratumoral AdAPT-001 therapy at doses up to 1e12 viral particles (vp). 53 …”

“… 44 ≥18 IT 2 AdApt-001 NCT04673942 I Conley et al. 53 ≥18 IT 13 Herpes simplex virus type 1 HSV1716 32 , 33 NCT00931931 I Streby et al. 33 ≥7 to ≤30 IT 8 Streby et al.…”