Phase Ib/II trial of tipapkinogene sovacivec, a therapeutic human papillomavirus16-vaccine, in combination with avelumab in patients with advanced human papillomavirus16-positive cancers.

PURPOSE: To evaluate tipapkinogene sovacivec (TG4001), a viral immunotherapeutic vaccine expressing human papillomavirus (HPV)16 E6/E7 non-oncogenic proteins and IL-2, in combination with avelumab in HPV16+ cancer patients. PATIENTS AND METHODS: In this open-label, phase Ib/II, multicenter study, HPV16+ advanced cancer patients received subcutaneous TG4001 at two dose levels (DL) in phase Ib and at the recommended phase II dose (RP2D) in phase II weekly for 6 weeks, then every 2 weeks (q2Wk) until 6 months, thereafter every 12 weeks, in combination with avelumab q2Wk starting from day 8. Exploratory end-points included immunomonitoring from sequential tumour and blood samples. RESULTS: Forty-three patients, mainly heavily pretreated (88% ≥ 1 previous line), were included in the safety analysis, with a majority of anal cancer (44%). No dose-limiting toxicities were reported, and DL2 (5 × 107 Plaque forming units (PFU)) was selected as the RP2D. Treatment-related adverse events to TG4001 occurred in 93% of patients, mostly grade 1/2, with grade 3 anaemia in one patient and no grade 4/5. Overall response rate (ORR) was 22% (8/36) and 32% (8/25) in all and patients without liver metastases, respectively. Median progression-free survival (PFS) and Overall Survival (OS) were 2.8 months (95% CI: 1.4-5.6) and 11.0 months (95% CI:7.5-16.7) in the total population and 5.6 months (95% CI:1.6-9.6) and 13.3 months (95% CI:8.7-32.7) in patients without liver metastases. Antigen-specific T-cell response was identified in 7/11 patients by IFNγ ELISpot. CONCLUSIONS: TG4001 in combination with avelumab is safe, demonstrated antitumour activity in heavily pre-treated HPV16+ cancer patients, and is currently being evaluated in a randomised phase II trial in patients with incurable anogenital cancer and limited hepatic involvement. GOV IDENTIFIER: NCT03260023.

Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial.

Treatment of chronic hepatitis B (CHB) typically requires life-long administration of drugs. Cohort and pre-clinical studies have established the link between a functional T-cell-mounted immunity and resolution of infection. TG1050 is an adenovirus 5-based vaccine that expresses HBV polymerase and domains of core and surface antigen and has shown immunogenicity and antiviral effects in mice. We performed a phase 1 clinical trial to assess safety and explore immunogenicity and early efficacy of TG1050 in CHB patients. This randomized, double blind, placebo-controlled study included two sequential phases: one single dose cohort (SD, n = 12) and one multiple (3) doses cohort (MD, n = 36). Patients, virally suppressed under nucleoside(d)tide analog NUC therapy, were randomized 1:1:1 across 3 dose levels (DL) and assigned to receive 109, 1010, 1011 virus particles (vp) of TG1050 and then randomized within each DL to placebo (3:1 and 9:3 vaccines/placebo in each DL, respectively, for the SD and MD cohorts). Cellular (ELISPOT) and antibody responses (anti-Adenovirus), as well as evolution of circulating HBsAg and HBcrAg, were monitored. All doses were well tolerated in both cohorts, without severe adverse event. TG1050 was capable to induce IFN-γ producing T-cells targeting 1 to 3 encoded antigens, in particular at the 1010vp dose. Overall, minor decreases of HBsAg were observed while a number of vaccinees reached unquantifiable HBcrAg by end of the study. In CHB patients under NUC, TG1050 exhibited a good safety profile and was capable to induce HBV-specific cellular immune response. These data support further clinical evaluation, especially in combination studies.

Mild to moderate liver dysfunction does not require dose reduction of oral or intravenous vinorelbine: results of a pharmacokinetic study.

We studied the pharmacokinetic profile of weekly oral and intravenous vinorelbine in cancer patients with various degrees of hepatic function, and assessed an intra-patient comparison of the pharmacokinetics of i.v. versus oral vinorelbine. In this open-label study, patients were randomised to receive an initial dose of vinorelbine at day 1 by either i.v. or the oral route followed by a second dose on day 8 via the alternative route. A total of 16 patients were included, 12 patients received the planned two administrations. Toxicities were similar for all cohorts and were mainly of haematological and gastrointestinal origin. Pharmacokinetic analysis of both routes did not reveal any differences between cohort I and II. Based on these findings in patients with mild to moderate liver dysfunction no dose modifications of vinorelbine have to be taken into consideration.

Phase II study of vinorelbine (alternating intravenous and oral) in combination with docetaxel as first-line chemotherapy in metastatic breast cancer.

PURPOSE: Combination of intravenous (i.v.) vinorelbine and docetaxel was shown to be feasible and effective in metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated in first-line treatment a regimen alternating i.v. and oral vinorelbine in combination with docetaxel. PATIENTS AND METHODS: Forty-nine patients (median age, 53 years) with MBC received a maximum of 6 cycles consisting of i.v. vinorelbine 20 mg/m(2) plus docetaxel 60 mg/m(2) given on day 1, and oral vinorelbine 60 mg/m(2) on day 15 every 3 weeks in an open-label, multicentre phase II study (recommended dose established in phase I study [1]). RESULTS: Sixty-three percent of the patient had received prior adjuvant chemotherapy and 78% presented visceral involvement. Twenty-four responses were documented and validated by an independent panel review, yielding response rates of 49% (95% CI: 34-64) in the 49 enrolled patients and 55.8% (95% CI: 40-71) in the 43 evaluable patients. Median duration of response was 9.4 months. Median progression-free survival and median overall survival were 5.5 and 33.2 months, respectively. Neutropenia was the main dose-limiting toxicity but complications were uncommon, four patients having experienced febrile neutropenia and one having developed neutropenic infection. Other frequently reported adverse events included alopecia, fatigue, stomatitis, constipation, diarrhoea and nausea, which were rarely severe. CONCLUSIONS: This regimen alternating oral and i.v. vinorelbine in combination with docetaxel is effective and manageable. Vinorelbine i.v. per oral day 1 per day 15-docetaxel day 1 every 3 weeks represents a convenient option to combine docetaxel and vinorelbine for the palliative treatment of MBC.