In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 2576-2576
Kurzfassung:
2576 Background: Everolimus (E), an mTOR inhibitor, and Lenalidomide (L) are both potent anti cancer agents with immunomodulatory effects. Preclinical evidence of enhanced cytotoxicity of the combination of an mTOR inhibitor and lenalidomide provided the rationale for this phase I study. Methods: Patients with advanced solid malignancies, ECOG performance status (PS) 0-2 and adequate organ function were eligible. Using standard 3+3 dose escalation schema, patients were treated in cohorts of three with increasing doses of E (5mg, 10mg) and L (10, 15, 20, 25mg) on day 1-28 of a 28-day cycle. Treatment cycles were repeated until disease progression by RECIST criteria or intolerable toxicity. Pharmacodynamic (PD) effects of treatment on circulating B and T lymphocytes subsets were assessed by multiparameter flow cytometry at baseline and after 2 cycles. Results: We enrolled 21 patients (thyroid-5, salivary gland-5, colon-4, sarcoma-2, and others-5); median age-58 (29-74); male-13; ECOG PS of 0, 1, 2 (3/17/1). Salient grade 3/4 toxicities included rash (67%), anemia (19%) and vomiting (5%) without dose limiting toxicities. The median number of completed cycles was 3 (1 - ≥15) and best response in 14 of 18 evaluable patients was stable disease (range 2- ≥14 months); median PFS was 116 days (14- ≥498). The RP2D of E and L was defined as 10mg and 25mg once daily, respectively. PD endpoint analysis after 2 cycles of treatment showed a significant increase in activated cytotoxic T cell subset (CD8+ICOS1+) in patients with salivary or thyroid cancers compared to other tumor types (+2051.0 vs. +394 vs. -1687.4 respectively; p=0.0303) and a trend for an increase in patients with non-progressing tumors (+661.7 vs. -384.1; p=0.0988). Other significant correlations were: Changes in total B-cells (CD3-CD19+) with PFS; NK cells with age (p=0.0211) and activated T cells (CD3+CD69+; CD3+CD62L-; p=0.01) with gender. Conclusions: The combination of E and L is well tolerated at the recommended single agent doses and showed promising efficacy in neuroendocrine and salivary adenoidcystic carcinoma. Modulation of activated T cell subsets (CD8+ICOS1+) correlates with efficacy of these agents.
Materialart:
Online-Ressource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.2576
Sprache:
Englisch
Verlag:
American Society of Clinical Oncology (ASCO)
Publikationsdatum:
2012
ZDB Id:
2005181-5
