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.

Interleukin-2 treatment in lymphomas : a phase II multicenter study

A phase II study was undertaker to assess whether continous infusion of high-dose recombinant interleukin-2 (rIL-2) alone was active against different histologic subtypes of heavily pretreated lymphoma. Sixty one lymphomas were included in the study rIL-2 (Roussel UCLAF, Romainville, France) was administered by continous infusion at 20 x 10 6 IU/m2 for threee cycles of 5 days, 4 days, and 3 days, during the first week, third week, and fith week, respectively. Twenty-four low-grade non-Hodgkin's lymphomas (NHL) were resistant to an anthracycline-containing regimen. Twenty-three intermediate and high-grade NHL were refractory to initial treatment or to salvage therapy. Seven Hodgkin's diseases were refractory to at least three regimens or relapsed after autologous bone marrow transplantation. Seven mycoses fungoides were refractory to chemotherapy. In low-grade NHL, one complete response (CR) was observed. In aggressive NHL, there were threee CRs and two partial reponses (PRs). No response was noted in Hodgkin's disease. One CR and four PRs were observed in mycosis fungoides. Complete response durations were 23, 20, 17, 12, and 4 months. Grade 4 toxicity was observed in 29 patients leading to arrest to therapy in 12 patients. The response to rIL-2 therapy in lymphoma differs according to histologic subtypes. Five responses were observed in 23 aggressive lymphomas. Five of seven mycosis fungoides responded; these preliminary results warrant testing of a larger number of patients

A pilot study of autologous bone marrow transplantation followed by recombinant interleukin-2 malignant lymphomas

In this study, we investigated the impact of recombinant interleukin-2 (rIL-2) after high dose chemotherapy and autologous bone marrow transplantation (ABMT) in 25 patients with refractory or relapsed Hodgkin's disease (HD) (11 patients) and non Hodgkin's lymphoma (NHL) (14 patients). 48 percent of patients had resistant disease, 84 percent achieved complete remission after ABMT. rIL-2 was started at a median of 54 days post-transplant and consisted of a first cycle of 5 days followed by 4 cycles of 2 days every other week. Patients received a mean of 160 x 10 6 IU/m2 rIL-2 and hematological toxicity was moderate and transient. None of the 5 evaluable patients with measurable disease responded to rIL-2. After a 5 year median follow-up, the probability of survival and DFS is 72 percent (HD: 73 percent and NHL: 70 percent, p=NS) and 45 percent (HD:36 percent and NHL: 48 percent, p=NS) respectively. These somewhat encouraging results warrant further evaluation of rIL-2 after ABMT in controlled studies, especially in NHL patients stratified for previous chemosensitivity

The use of a sequential high dose recombinant interleukin 2 regimen after autologous bone marrow transplantation does not improve the disease free survival of patients with acute leukemia transplanted in first complete remission

We report the outcome of 50 consecutive patients with CR1 acute leukemia (AML=22; ALL=28) treated with autologous BMT, after cyclophosphamide and TBI, followed with a sequential high dose rIL2 regimen. rIL2 (RU 49637 from Roussed-Uclaf, Roainville, France) was started after hematological reconstitution an average of 72+-22 days post transplant. The schedule consisted of a continous infusion over 5 cycles (Cycle1:5 days starting on day 1; cycle 2-5: 2 days starting on day 15,29,43 and 57). Patients were treated at 4 different dosages (12 (N=40),16 (N=3), 20 (N=2), 24 (N=5) x 10 6 IU/m2/day). Toxicities were maily related to capillary leak syndrome and thrombocytopenia. Patients received an average of 122 +-49 106 IU/m2. Two patients with AML died from toxicity. rIL-2 infusion was associated with very a high level of immune stimulation of both T-cells (P<0.05) and natural killer (NK) cells (P<0.05) and associated cytolytic functions (P<0.05). With a minimal and median follow-up of 21 and 46 months, 3 year leukemia free survival is 41 +-6 per cent overall, 39+- 10 per cent and 43 +- 8 per cent for AML and ALL respectively. Relapse probabilities at 3 years are 59 +- 11 per cent for AML and 57 +- 8 per cent for ALL. We conclude that this short infusion of rIL-2 over 2 months, resulting in an increased immune stimulation, is not associated with a better leukemic control for patients with acute leukemia transplanted early reaching first complete remission