A large first-line, randomized, dose-finding, phase II study on thymosin-alpha 1 (T-alpha 1) plus dacarbazine (DTIC) with or without interferon-alpha (IFN-alpha) compared to DTIC plus IFN-alpha in stage IV melanoma. Tumor response and survival results

Abstract

8535 Background: Thymosin alpha 1 is an immunomodulatory compound that promotes T cell maturation and upregulates T cell response. Ta1 showed clinical potential benefit in a previous pilot study in melanoma patients. Methods: Phase II, randomized, stratified, open-study testing different doses of Ta1 in association with DTIC and IFNa, as first-line therapy in stage IV melanoma patients (AJCC 2001) without brain metastases. The primary endpoint is tumor response and secondary overall survival. Four arms were initially planned: DTIC + IFNa + 1.6 or 3.2 mg Ta1, DTIC + 3.2 mg Ta1, and DTIC + IFNa (control group). A dose-response effect in a preliminary analysis on 142 patients led to the addition of a fifth arm with DTIC + IFNa + 6.4 mg Ta1. Ninety-five patients were allocated to each arm to test the hypothesis that P0 = 0.05 vs the alternative hypothesis that P1 = 0.15 (alpha = 5%, within-group statistical analysis, power = 95%). The five groups were analyzed independently one from the other, nine responses representing the minimal threshold for rejecting the null hypothesis Patients received DTIC (800 mg/m2) iv on day 1, Ta1 (1.6, 3.2 or 6.4 mg) sc on days 8–11 and 15–18, and IFNa (3 MIU) sc on days 11 and 18 during 28d cycles. Tumor response was evaluated every two cycles according to RECIST criteria, utilizing a central review. Results: Data of 483 pts (62% M1c; 25% M1b; 13% M1a) from 64 European sites are given in the table . Thirteen and 10 confirmed responses were observed for the DTIC+ 3.2 mg Ta1 and DTIC+ IFNa + 3.2 mg Ta1 arms (vs 5 in the control group) thus rejecting the null hypothesis that P0 = 0.05. No additional toxicity with the addition of Ta1 was observed. Conclusions: These results suggest a potential survival advantage with the addition of Ta1 to ‘standard‘ treatment of stage IV melanoma patients. The role of Interferon alpha in this therapeutic association is debatable. [Table: see text] [Table: see text]

Thymosin alpha 1: Biological activities, applications and genetic engineering production

“…In a Phase II multicenter, randomized open-label study, different dose levels of T␣1 in combination with Dacarbazine (DTIC) chemotherapy were given to patients with stage IV melanoma. Reported results show that the combination therapy tripled the overall response rate and extended overall survival by nearly 3 months compared with patients treated with DTIC, combined with IFN-␣ [8]. More recently, in patients with unresectable HCC, transarterial chemoembolization (TACE) combined with T␣1 resulted in numerically higher rates of survival and tumor response, including transplant candidacy, with fewer bacterial infections, than TACE alone [29].…”

Systemic therapy for metastatic malignant melanoma – from deeply disappointing to bright future?

“…It appears to have an effect on IL-6 and IL-10, may interact with IL-2, and has an effect on DCs. A phase II study comparing thymosin a-1 plus DTIC with or without IFN-a compared with DTIC + IFN-a in 483 patients suggested a survival benefit with addition of thymosin a-1 to either DTIC or DTIC + IFN, with a median survival of 8.8-10.3 months in the thymosin a-1 arms compared with 6.6 months in the DTIC + IFN arm (119).…”

History of the Discovery of the Thymosins

“…18 Most recently, T␣ 1 has shown significant promise in a phase-II, trial increasing response rates and survival in combination with chemotherapy in a large (500 patients) late stage (stage 4) melanoma trial being conducted in Europe. 19 As shown in FIGURE 9, T␤ 4 is the major actin-sequestering molecule in eukaryotic cells. T␤ 4 is found in almost all cells of the body and is in highest concentrations in the white cell series and in blood platelets.…”

“…Tα 1 is a potent immunomodulatory peptide 18 . Most recently, Tα 1 has shown significant promise in a phase‐II, trial increasing response rates and survival in combination with chemotherapy in a large (500 patients) late stage (stage 4) melanoma trial being conducted in Europe 19 …”

“…A number of the other thymosins, including prothymosin alpha (ProT‐α), thymosin beta 10 (Tβ 10 ), thymosin beta 15 (Tβ 15 ) and others, are the subject of significant research around the world, and are the subject of scientific papers reported in this monograph and elsewhere 19 …”