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A phase 1 trial of 4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid (PENAO) in patients with advanced solid tumours

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Abstract

Purpose

This phase I study was conducted to evaluate the safety and Maximum Tolerated Dose of PENAO (4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid), a second-generation organic arsenical with anti-mitochondrial activity, when given as a continuous intravenous infusion (CIVI), in patients with advanced solid tumours.

Methods

Eligibility criteria for this trial included age ≥ 18 years, advanced solid tumour, ECOG Performance Status ≤ 1 and adequate organ function. PENAO was administered by CIVI, with dose levels initially increased by infusion duration in a 21-day cycle at a fixed daily dose and then increased daily dose. Standard dose-limiting toxicity (DLT) definitions were used in a “3 + 3” design. Patients had regular monitoring of toxicity and efficacy. Pharmacokinetic assays of serum and urine As were performed.

Results

Twenty-six patients were treated across 8 dose levels. The only dose-limiting toxicity (DLT) observed was fatigue, that occurred in one patient treated at the highest dose level of 9 mg/m2/day. No significant organ toxicity or objective responses were observed, although there were two patients with stable disease lasting up to 7 months. Pharmacokinetic analysis unexpectedly indicated a half-life of 9–19 days, invalidating the CIVI dosing resulting in discontinuation of the study before the RP2D was defined.

Conclusions

PENAO was administered by CIVI at dose levels up to 9 mg/m2/day with only one DLT noted. Pharmacokinetic studies invalidated the rationale for continuous dosing and led to discontinuation of the trial without defining a RP2D. Future clinical development of PENAO will use intermittent dosing schedule, alone and in combination with rapamycin.

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Authors and Affiliations

  1. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

    Sunit Sarkar, Peter Savas, James R. Whittle, James C. Kuo, Danny Rischin & Anne Hamilton

  2. Department of Medical Oncology, Royal Melbourne Hospital, Melbourne, Australia

    Ben Tran, Michael Lam & Jayesh Desai

  3. Chris O’Brien Lifehouse, Sydney, Australia

    Lisa Horvath & Peter Grimison

  4. Royal Prince Alfred Hospital, Sydney, Australia

    Lisa Horvath & Peter Grimison

  5. University of Sydney, Sydney, Australia

    Lisa Horvath & Peter Grimison

  6. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia

    Peter Savas, Danny Rischin, Jayesh Desai & Anne Hamilton

  7. University of New South Wales, Sydney, Australia

    James C. Kuo

  8. Auckland, New Zealand

    Nicole Signal

  9. CMC Regulatory, Sydney, Australia

    David Edmonds

  10. The Centenary Institute, Sydney, Australia

    Philip Hogg

  11. NHMRC Clinical Trials Centre, Sydney, Australia

    Philip Hogg

  12. Sydney Medical School, University of Sydney, Sydney, Australia

    Philip Hogg

Authors
  1. Sunit Sarkar
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  2. Ben Tran
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  4. Michael Lam
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  11. Philip Hogg
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  12. Danny Rischin
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Corresponding author

Correspondence to Philip Hogg.

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Conflict of interest

Ben Tran has received financial support from Amgen and Astellas Pharma. Ben Tran has received honoraria from Astellas Pharma, Janssen-Cilag, Sanofi, Tolmar and Amgen. Ben Tran has received institutional research funding from Astellas Pharma, Janssen-Cilag, Amgen, Pfizer, Genentech, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharp and Dohme and Ispen. Danny Rischin received grants from Merck, Bristol-Myers Squibb, Roche and Regeneron. Danny Rischin has also received grants and personal fees from GlaxoSmithKline and Merck Sharp and Dohme. Ben Tran has acted in an advisory or consultant role for Amgen, Astellas Pharma, Bayer, Sanofi, Tolmar, Janssen-Cilag, Bristol-Myers Squibb, Ipsen, Merck Sharp and Dohme and AstraZeneca. Peter Savvas has acted as an uncompensated Consultant for Roche-Genentech. Danny Rischin has had uncompensated role on Trial Steering Committees and/or advisory boards for Merck Sharp and Dohme, Bristol-Myers Squibb, GlaxoSmithKline, Regeneron and Sanofi.

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Sarkar, S., Tran, B., Horvath, L. et al. A phase 1 trial of 4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid (PENAO) in patients with advanced solid tumours. Cancer Chemother Pharmacol 87, 613–620 (2021). https://doi.org/10.1007/s00280-020-04225-7

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  • DOI: https://doi.org/10.1007/s00280-020-04225-7

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