ESMO-poster 2020
A Phase 1 b, international, dose-escalation study to evaluate the safety, Pharmacokinetics (PK), Pharmacodynamics (PD) and efficacy of ST-617, for the attenuation of Oral Mucositis (OM) in patients receiving Chemoradiation (CRT) for Head & Neck (H&N) cancer.
3692A 1846P
D. Osei-Fofie1, G. Landers2, J. A. Wetter3, P. Kraus4, S. Sukumaran5, H. Mun6, B. Stein7, V. Bray8, C. Connell9, B. Framroze10, J. Gelfand11, A. Lategan12, P. Song13, M. Dimitriu12, S. Sonis14
Authors Information
1 — Medical Oncology, Kimberley Hospital, Kimberley, South Africa; 2 — Medical Oncology, The Oncology Centre Drs Callaghan, Marais, Narsai and Associates, Durban, South Africa; 3 — Medical Oncology, University Hospital Cape Town, Cape Town, South Africa; 4 — Medical Oncology, Outeniqua Oncology Centre – Cancercare, George, South Africa; 5 — Medical Oncology, Flinders Centre for Innovation in Cancer, Bedford Park, SA, Australia; 6 — Oncology, Chris O‘Brien Life House, Camperdown, ACT, Australia; 7 — Oncology, Adelaide Cancer Centre, Adelaide, Australia; 8 — Medical Oncology, Concord Repatriation General Hospital, Concord, NSW, Australia; 9 — Radiation, Adelaide Radiotherapy Centre-St Andrew‘s Hospital, Adelaide, Australia; 10 — Pharmacology, GPH Biotech LLC, Menlo Park, CA, United States of America; 11 — Harvard Medical School and Division of Infectious Diseases Dept. of Medecine Massachusetts General Hospital, Boston, MA, United States of America; 12 — Development, Supportive Therapeutics, Cambridge, United States of America; 13 — Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America; 14 — Primary Endpoint Solutions, Waltham, MA and the Dana-Farber Cancer Institute, Boston, MA
Introduction
ST–617 to mitigate Oral Mucositis.
Oral Mucositis (OM) is a common, devastating side effect of concomitant Chemoradiation Therapy (CRT) employed for the treatment of cancers of the mouth and oropharynx.(1,3) Despite a profound impact on tolerance to treatment and a high burden of disease, OM is a condition that remains without any approved therapeutic intervention.(2)
ST-617 is a novel formulation of a dithiolethine, a molecule that has been clinically used for over three decades. ST-617 targets two facets of OM pathogenesis, namely oxidative stress and pro-inflammatory cytokine production by impacting Nrf-2 and NF-kB.(2,4)
Xenograft studies have confirmed the lack of interference with CRT efficacy. ST-617 is being developed for the prevention and mitigation of OM.
Study Design
A multi-national, multi-dose, open-label design for the treatment of OM.
A multi-national, multi-dose, open-label design for the treatment of OM.
A multi-national, multi-dose, open-label design for the treatment of OM in patients undergoing CRT for oral, oropharynx and/or nasopharynx cancer
Orally ST-617 is a palatable swish & swallow formulation administered daily 3 days prior to CRT and daily thereafter until end of treatment
Dose-dependent results on OM severity and duration, PK, PD (Mode of Action) and systemic/topical responses are reported
Results
Confirmation of Mechanism of Action.
Reduction in oxidative damage and increase in anti-oxidative enzyme levels. ROS/RNS decreased from baseline and glutathione increased from baseline in a dose-dependent manner.
In patients (n=7) receiving 50 mg, plasma ROS levels reduced by 23.0% and 18.2%, respectively
Greater reduction in plasma and buccal ROS levels in patients treated with 100 mg: 25.9% (n=3) and 32.1% (n=5), respectively
Doses of 150 mg (n=2) produced similar reductions in ROS levels as seen with 100 mg: 26.8% in plasma and 33.4% in buccal cells
Dose-dependent Pharmacokinetics.
Plasma concentrations following oral administration of ST-617 at 50, 100 or 150 mg daily.
Plasma samples collected for 24 hours after administration of ST-617 on day -3, day 1 and day 21 in respect to start of CRT (day 0) (50 mg: N=7, 100 mg N=3 or 4 and 150 mg N=2)
Figure 2. Pharmacokinetics of ST-617 in plasma following oral administration
Pharmacodynamics confirms redox signal.
ST-617 increases plasma and buccal cell reduced glutathione (GSH) over 5 weeks of CRT in a dose-dependent manner with a platea between 100mg and 150mg dose
Pre-treatment with ST-617 three days (W1D-3) before CRT helps prepare cells for CRT by increasing GSH on day 1 of treatment (W1D1)
ST-617 leads to increased GSH in buccal cells, reflected by lower OM occurrence and lower OM severity in the oral cavity
Figure 3. PD ROS/RNS in Plasma and Buccal Cells
ST-617 reduces plasma and buccal ROS/RNS over 5 weeks of CRT in a dose-dependent manner with a plateauing between 100 mg and 150 mg
Pre-treatment with ST-617 three days (W1D-3) before CRT helps prepare the cells for CRT with reduced ROS/RNS on day 1 of treatment (W1D1)
ST-617 leads to a decrease in ROS/RNS in buccal cells, reflected by lower OM occurrence and lower OM in the oral cavity
Figure 4. PD GSH Plasma and Buccal Cells
The WHO OM scores – Phase 1 b data show the significant advantage of ST-617.
The WHO OM scores – Phase 1 b data show the significant advantage of ST-617.
Overall severity of OM is blunted in patients who receive 50 mg or 100 mg or 150 mg doses of ST-617
Trajectory of SOM in ST-617-treated patients is consistent with the ability of ST-617 to attenuate CRT-induced damage evidenced by delayed onset, reduction in peak scores, and faster resolution
Figure 5. The average WHO OM weekly scores
Safety.
No early Dose Limiting Toxicity (DLT) or Serious Adverse Events (SAE) related to ST-617 have been observed
All doses of ST-617 well-tolerated including 150 mg per day
No interruption of CRT due to OM in ST-617 treated patients
Oral Mucositis severity and incidence markedly reduced when compared with historical controls
Conclusion
References
Authors
Corresponding authors:
mdimitriu@stpharma.com,
danoseifofie@hotmail.com
The authors thank the patients, investigators and study teams at each of the participating centers. The trial was sponsored by Supportive Therapeutics LLC. Copies of this e-poster are for personal use only and may not be reproduced without written permission of the authors.
Conflict of Interests:
No disclosures to make