Phase I study of bromohydrin pyrophosphate (BrHPP, IPH 1101), a Vgamma9Vdelta2 T lymphocyte agonist in patients with solid tumors.

Abstract

PURPOSE:

Vgamma9Vdelta2 (gammadelta) T lymphocytes, a critical peripheral blood lymphocyte subset, are directly cytotoxic against many solid and hematologic tumor types. Vgamma9Vdelta2 T lymphocytes can be selectively expanded in vivo with BrHPP (IPH1101) and IL-2. The present phase I trial was conducted with the aim of determining the maximum-tolerated dose (MTD) and safety of IPH1101 combined with a low dose of IL-2 in patients with solid tumors.

EXPERIMENTAL DESIGN:

A 1-h intravenous infusion of IPH11 was administered alone at cycle 1, combined with a low dose of SC IL-2 (1 MIU/M(2) d1 to d7) in the subsequent cycles (day 1 every 3 weeks). The dose of IPH1101 was escalated from 200 to 1,800 mg/m(2).

RESULTS:

As much as 28 patients with solid tumors underwent a total of 109 treatment cycles. Pharmacodynamics data demonstrate that gammadelta T lymphocyte amplification in humans requires the co-administration of IL-2 and is dependent on IPH 1101 dose. Dose-limiting toxicity occurred in two patients at a dose of 1,800 mg/m(2): one grade 3 fever (1 patient) and one grade 3 hypotension (1 patient) suggesting cytokine release syndrome immediately following the first infusion. At lower doses the treatment was well tolerated; the most frequent adverse events were mild fever, chills and abdominal pain, without exacerbation in the IL-2 combined cycles.

CONCLUSION:

IPH1101 in combination with SC low-dose IL-2 is safe, well tolerated and induces a potent gammadelta T lymphocyte expansion in patients. Its clinical activity will be evaluated in phase II clinical trials.

• Authors: Jaafar Bennouna, Vincent Levy, Hélène Sicard, Hélène Senellart, Marie Audrain, Sandrine Hiret, Frédéric Rolland, Heriberto Bruzzoni-Giovanelli, Marie Rimbert, Céline Galéa, Jérome Tiollier, Fabien Calvo
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 59 Issue 10 Pg. 1521-30 (Oct 2010) ISSN: 1432-0851 [Electronic] Germany
• PMID: 20563721 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Antineoplastic Agents
• Diphosphates
• Interleukin-2
• bromohydrin pyrophosphate

Topics

• Adult
• Aged
• Antineoplastic Agents (pharmacokinetics, pharmacology, therapeutic use)
• Diphosphates (pharmacokinetics, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Humans
• Interleukin-2 (pharmacokinetics, pharmacology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (immunology)
• T-Lymphocyte Subsets (classification, drug effects)
• T-Lymphocytes (classification, drug effects)