Phase I clinical trial of BromoHydrin PyroPhosphate, BrHPP (Phosphostim), a Vγ9Vδ2 T lymphocytes agonist in combination with low dose Interleukin-2 in patients with solid tumors

Abstract

2536 Background: Vγ9Vδ2 (γδ) T lymphocytes, a critical peripheral blood lymphocyte (PBL) subset, are directly cytotoxic against several tumor types, including renal carcinoma cells (RCC). (γδ) lymphocytes can be selectively expanded in vivo with BrHPP (Phosphostim) and IL-2. We conducted a phase I trial, to define the dose limiting toxicities (DLT), characterize PK and PD, and recommend a dose for phase II studies. Methods: Patients (pts), with advanced solid tumors and no organ dysfunction and PS of 0–1 were included. A single, one hour intravenous infusion of BrHPP was administered alone at cycle 1, combined with low dose of SC IL-2 (1 MIU/M2 d1 to d7) in the subsequent cycles (day 1 every 3 weeks). BrHPP dosage was escalated in cohorts of 3 pts extended to 6 if 1/3 patients on a dose level had a DLT. Results: 18 pts (10 mRCC, 1 colon, 2 breast, 1 ovarian, 1 gastric, 3 oesophageal cancer) have been enrolled to date at 4 dose levels: 4 pts 200 mg/m2, 3 pts 600 mg/m2, 6 pts 1200 mg/m2, 5 pts 1800 mg/m2. At 1800 mg/m2 (first cycle): 2 out of 5 pts presented a completely reversible serious adverse event fulfilling a DLT criteria: one Gr3 hypotension (1 pt) and one Gr3 (1 pt) hyperthermia suggesting cytokine release syndrome immediately following first infusion. At lower doses the treatment was well tolerated, the most frequent adverse events being mild fever, chills, abdominal pain, without exacerbation in the IL-2 combined cycles. BrHPP alone did not induce significant γδ lymphocytes expansion whereas the addition of SC- IL-2 demonstrated an increase of γδ in all tested doses (from 5 to 50 fold expansion rate). Complete results of pharmacokinetics, pharmacodynamics, tolerance and tumour response evaluation at all dose levels will be presented at the meeting. Conclusion: BrHPP in combination with SC low dose IL 2 is safe, well tolerated, and allows to induce a potent γδ T lymphocytes expansion in pts. Clinical activity will be evaluated in phase II clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Innate Innate Innate