Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front‐line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125

• Autor: Hassan, Raffit ; Sharon, Elad ; Thomas, Anish ; Zhang, Jingli ; Ling, Alexander ; Miettinen, Markku ; Kreitman, Robert J. ; Steinberg, Seth M. ; Hollevoet, Kevin ; Pastan, Ira
• Assuntos: ADP Ribose Transferases ; Aged ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - blood ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; Bacterial Toxins ; Biological and medical sciences ; CA-125 Antigen - blood ; Cisplatin - administration & dosage ; Exotoxins ; Female ; Glutamates - administration & dosage ; GPI-Linked Proteins - administration & dosage ; GPI-Linked Proteins - blood ; Guanine - administration & dosage ; Guanine - analogs & derivatives ; Humans ; immunotoxin ; Lung Neoplasms - blood ; Lung Neoplasms - drug therapy ; Lung Neoplasms - pathology ; Male ; Maximum Tolerated Dose ; Medical sciences ; Mesothelin ; Mesothelioma - blood ; Mesothelioma - drug therapy ; Mesothelioma - pathology ; Mesothelioma, Malignant ; Middle Aged ; Neoplasm Staging ; Pemetrexed ; pleural mesothelioma ; Pleural Neoplasms - blood ; Pleural Neoplasms - drug therapy ; Pleural Neoplasms - pathology ; Pneumology ; Pseudomonas ; Pseudomonas aeruginosa Exotoxin A ; SS1P ; Tumors ; Tumors of the respiratory system and mediastinum ; Virulence Factors
• É parte de: Cancer, 2014-11, Vol.120 (21), p.3311-3319
• Notas: this issue.
  3268–71
  See editorial on pages
  Presented in part at the Annual Meeting of the American Society of Clinical Oncology; June 3‐7, 2011; Chicago, Illinois.
  ObjectType-Article-1
  SourceType-Scholarly Journals-1
  ObjectType-Feature-2
  content type line 23
  
• Descrição: BACKGROUND The primary objective of this study was to determine the safety and maximum tolerated dose (MTD) of the antimesothelin immunotoxin SS1(dsFv)PE38 (SS1P) (a recombinant antimesothelin immunotoxin consisting of a murine antimesothelin variable antibody fragment [Fv] linked to PE38, a truncated portion of Pseudomonas exotoxin A) in combination with pemetrexed and cisplatin in chemotherapy‐naive patients with advanced malignant pleural mesothelioma (MPM). Secondary objectives included tumor response, SS1P pharmacokinetics, and serum biomarkers of response. METHODS Chemotherapy‐naive patients with stage III or IV, unresectable, epithelial or biphasic MPM and normal organ functions were eligible. Pemetrexed (500 mg/m2 on day 1) and cisplatin (75 mg/m2 on day 1) were administered every 3 weeks for up to 6 cycles with escalating doses of SS1P administered intravenously on days 1, 3, and 5 during cycles 1 and 2. Tumor response was evaluated every 6 weeks. RESULTS Twenty‐four patients received SS1P at 4 dose levels from 25 to 55 mcg/kg. Grade 3 fatigue was dose‐limiting in 1 patient at 55 mcg/kg. The MTD of SS1P was established as 45 mcg/kg. Other grade 3 toxicities associated with SS1P included hypoalbuminemia (21%), back pain (13%), and hypotension (8%). Of 20 evaluable patients, 12 (60%) had a partial response, 3 had stable disease, and 5 had progressive disease. Of 13 patients who received the MTD, 10 (77%) had a partial response, 1 had stable disease, and 2 had progressive disease. Objective radiologic responses were associated with significant decreases in serum mesothelin (P=.0030), megakaryocyte potentiating factor (P=.0005), and cancer antigen 125 (P < .0001). CONCLUSIONS SS1P given with pemetrexed and cisplatin is safe and well tolerated and exhibits significant antitumor activity in patients with unresectable, advanced pleural mesothelioma. Serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125 levels correlated with objective tumor responses. Cancer 2014;120:3311–3319. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. In this first clinical evaluation of the combination of an immunotoxin with chemotherapy, SS1P, an antimesothelin immunotoxin, was combined with pemetrexed and cisplatin in chemotherapy‐naive patients who had advanced malignant pleural mesothelioma. The results from this phase 1 trial demonstrate that SS1P and chemotherapy can be safely combined with no overlapping toxicity. In addition, the objective tumor response rate for the combination is higher than expected with chemotherapy alone and provides a strong rationale for a randomized trial to confirm this finding.
  
• Editor: Hoboken, NJ: Wiley-Blackwell
  
• Idioma: Inglês