![]() ![]() Biochemical profiling comprised sodium, potassium, urea, creatinine, chloride, bicarbonate, bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST) or alanine aminotransferase (ALT), lactate dehydrogenase (LDH), albumin, total protein, calcium, phosphate, magnesium, and urinalysis (pH, protein, blood, ketones, glucose). Hematologic profiling comprised assessment of the hematocrit, hemoglobin, red cell count (RCC), white cell count with differential, and platelets. The maximum planned sample size for the carboplatin cohort was 18 patients.Ĭollection of archival formalin-fixed paraffin-embedded (FFPE) diagnostic tissue was mandatory and undertaken at each patient's screening visit prior to registration. An accelerated escalation design toward 200 mg/m 2 ganetespib struck a balance between quickly moving toward a likely safe dose, while still allowing for reintroduction of a 3 + 3 procedure if any DLTs were observed. An accelerated titration design was used here as the carboplatin cohort was introduced following a protocol amendment after 9 patients had been treated with cisplatin, none of whom experienced any DLTs. If ganetespib reached the estimate of the MTD, the cohort was expanded to 9 patients overall. If no DLT was observed, the next patient would receive the next highest dose otherwise, a 3 + 3 design would begin (i.e., the same as for the cisplatin-treated cohort). At dose levels below 200 mg/m 2, one patient would receive treatment. Patients and Methodsįor patients receiving carboplatin with ganetespib and pemetrexed (i.e., the carboplatin cohort), dose escalation of ganetespib was conducted using an accelerated titration design with a starting dose of 100 mg/m 2. We hypothesized that the addition of ganetespib to pemetrexed and either cisplatin or carboplatin, can be safely delivered, that there might be a synergistic interaction clinically, and that patients harboring genomic instability (reflected in somatic copy number alterations, loss of heterozygosity, and homozygous deletions) might exhibit resistance to ganetespib. Furthermore, inhibition of Hsp90 with ganetespib has been shown to enhance T-cell–mediated antitumor immune response ( 20). Single-agent ganetespib demonstrates significant activity for downregulating Hsp90 client protein levels with acceptable toxicity at a recommended dose of 200 mg/m 2 from phase II studies ( 18, 19). Ganetespib (ADX-1612), an Hsp90 inhibitor, is a synthetic quadricyclic triazolone with a small molecular weight that binds to the adenosine triphosphate pocket in the N-terminus of Hsp90 ( 17, 18). Furthermore, preclinical studies show that inhibition of Hsp90 mediates synergistic toxicity due to cisplatin ( 17). ![]() Thymidylate synthase (TS) is a Hsp90 client, implicated in antifolate resistance, which is downregulated following inhibition of Hsp90 ( 16). This study supports further investigation of ganetespib combination therapy to treat MPM in a large randomized controlled trial. Response rates of ganetespib are comparable or better than those observed in other novel-agent MPM trials. We observed promising antitumor activity including partial responses, particularly in patients with epithelioid histology, and loss of heterozygosity was associated with shorter time to progression. This novel combination was well tolerated. We present the MESO-02 trial of ganetespib plus pemetrexed and cisplatin/carboplatin in patients with chemotherapy-naïve MPM. Furthermore, Hsp90 inhibition with ganetespib can enhance T-cell–mediated antitumor immune response. Ganetespib, a potent small-molecule Hsp90 inhibitor, demonstrates significant activity for downregulating Hsp90 client protein levels with acceptable toxicity in single-agent phase II solid tumor studies. Hsp90 inhibition reportedly induces apoptosis in MPM and mediates synergistic cisplatin-related toxicity in preclinical studies. There remains an unmet need for effective therapies for first-line treatment of malignant pleural mesothelioma (MPM). ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |