Abstract
CLO19-037: Reducing the Duration, Incidence and Severity of Mucosal Injury Due to Cancer Radiation therapy (RT); Positive Randomized Phase 2b Trial Results With GC4419 (Avasopasem Manganese), a Small Molecule Superoxide (SO) Dismutase (SOD) Mimetic
Journal of the National Comprehensive Cancer Network, Vol.17(3.5), p.CLO19-037
03/08/2019
DOI: 10.6004/jnccn.2018.7136
Abstract
Introduction:
RT-induced SO contributes to initiation of mucosal injury; eg, oral mucositis (OM) and esophagitis. GC4419 specifically mimics SOD’s dismutation of SO to hydrogen peroxide (H
2
O
2
), interdicting OM initiation. GC4419 reduced RT-severe OM (SOM) in a hamster cheek pouch model, and protected mucosa and other normal tissues from radiation-induced injury in other animal models. In a published phase 1b/2a open-label trial (Anderson et al, IJROBP, 1 Feb 2018), GC4419 attenuated SOM in patients (Pts) receiving intensity-modulated RT (IMRT) plus concurrent cisplatin (CDDP) for locally advanced head & neck cancer (HNC).
Objectives
: Determine whether GC4419 reduces duration, incidence, & severity of SOM.
Methods:
Pts with locally advanced oral cavity or oropharyngeal cancer; definitive or postoperative intensity-modulated (IM)RT (approximately 70 Gy [
>
50 Gy to
>
2 oral sites]) plus CDDP (weekly or q3wk) were randomized (stratification: tumor HPV status, CDDP schedule) to 30 or 90 mg of GC4419, or placebo (PBO), 60-minute IV infusion, M–F, ending
<
60 minutes before IMRT delivered in 35 fractions over 7 weeks. WHO grade OM was assessed by trained evaluators biw during IMRT & qwk for up to 8 wks after IMRT. Primary endpoint: duration of SOM. Efficacy was tested for each active dose vs PBO (ITT population) by a sequential, conditional approach (2-sided alpha, 0.05).
Results:
223 pts (44 sites): 90 mg (n=76), 30 mg (n=73), or PBO (n=74). Baseline patient and tumor characteristics and treatment delivery were balanced. Efficacy: At 90 mg GC4419 vs PBO, duration of SOM was significantly reduced (median, 1.5 vs 19 d;
P
=.024). SOM incidence (43% vs 65%;
P
=.009), and grade 4 incidence (16% vs 30%;
P
=.045) also improved. There were intermediate improvements with 30 mg. Safety was comparable across arms; no significant GC4419-specific toxicity; other known toxicities of IMRT/CDDP were not increased.
Conclusions:
GC4419 demonstrated a significant, clinically meaningful reduction of SOM duration, and dose-dependent improvements in other SOM parameters, with acceptable safety. A confirmatory phase 3 trial (NCT03689712) is in progress. Clinical trials to reduce RT-related esophagitis are also planned.
Details
- Title: Subtitle
- CLO19-037: Reducing the Duration, Incidence and Severity of Mucosal Injury Due to Cancer Radiation therapy (RT); Positive Randomized Phase 2b Trial Results With GC4419 (Avasopasem Manganese), a Small Molecule Superoxide (SO) Dismutase (SOD) Mimetic
- Creators
- Jon T. Holmlund - aGalera Therapeutics, Inc., Malvern, PACarryn M. Anderson - University of IowaStephen T. Sonis - cBioModels, Boston, MARobert Beardsley - aGalera Therapeutics, Inc., Malvern, PADennis Riley - aGalera Therapeutics, Inc., Malvern, PAJeffrey Mark Brill - aGalera Therapeutics, Inc., Malvern, PAMelissa Brookes - aGalera Therapeutics, Inc., Malvern, PAKara Terry - aGalera Therapeutics, Inc., Malvern, PAJ. Mel Sorensen - aGalera Therapeutics, Inc., Malvern, PA
- Resource Type
- Abstract
- Publication Details
- Journal of the National Comprehensive Cancer Network, Vol.17(3.5), p.CLO19-037
- DOI
- 10.6004/jnccn.2018.7136
- ISSN
- 1540-1405
- eISSN
- 1540-1413
- Language
- English
- Date published
- 03/08/2019
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984315659102771
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