Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma.

Amatuximab is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in malignant pleural mesothelioma (MPM). On the basis of its synergy with chemotherapy in preclinical studies, we evaluated the antitumor activity of amatuximab plus pemetrexed and cisplatin in patients with unresectable MPM. In a single-arm phase II study, amatuximab (5 mg/kg) was administered on days 1 and 8 with pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on day 1 of 21-day cycles for up to six cycles. Patients with response or stable disease received amatuximab maintenance until disease progression. Primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were overall survival (OS), response rate, and safety. Eighty-nine patients were enrolled at 26 centers. Median of five cycles (range, 1-6) of combination treatment was administered, and 56 (63%) patients received amatuximab maintenance. Combination therapy resulted in no overlapping toxicities. Eleven patients (12.4%) had amatuximab-related hypersensitivity reactions. Responses included partial responses in 33 (40%) and stable disease in 42 (51%). Six-month PFS rate was 51% [95% confidence interval (CI), 39.1-62.3)], median PFS was 6.1 months (95% CI, 5.8-6.4), and median OS was 14.8 months (95% CI, 12.4-18.5) with 29 patients alive at data cut-off. Amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Although PFS was not significantly different from historical controls, the median OS was 14.8 months with a third of patients alive and 5 continuing to receive amatuximab at the time of analysis.

Hassan R ，Kindler HL ，Jahan T ，Bazhenova L ，Reck M ，Thomas A ，Pastan I ，Parno J ，O'Shannessy DJ ，Fatato P ，Maltzman JD ，Wallin BA ... -  《-》

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

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. Chemotherapy-naive patients with stage III or IV, unresectable, epithelial or biphasic MPM and normal organ functions were eligible. Pemetrexed (500 mg/m(2) on day 1) and cisplatin (75 mg/m(2) 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. 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). 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.

Hassan R ，Sharon E ，Thomas A ，Zhang J ，Ling A ，Miettinen M ，Kreitman RJ ，Steinberg SM ，Hollevoet K ，Pastan I ... -  《-》

Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma.

We conducted a phase I trial of cisplatin/pemetrexed/imatinib mesylate, an oral platelet-derived growth factor receptor (PDGFR) inhibitor, in chemonaive patients with malignant pleural mesothelioma (MPM). A standard 3 + 3 dose-escalating trial was used with the end points of maximum tolerated dose (MTD), response rate, survival, safety/toxicity, and tumor PDGFR levels. Seventeen patients with MPM were enrolled. The most common (any grade) side effects were nausea, fatigue, hypomagnesemia, and anemia. The MTD was established at dose level 3 (imatinib 600 mg) with a dose-limiting toxicity (DLT) of nausea and vomiting. The median progression-free survival (PFS) was 7.9 months and the median overall survival (OS) was 8.8 months. Patients with a sarcomatoid subtype had worse PFS (P = .01) and OS (P = .009), whereas they had a better Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 predicted for improved OS (P = .001) and PFS (P = .013). The 6 patients who completed all 6 treatment cycles had better OS (P = .006); the median PFS was 9.6 months and the OS was 22.4 months. In the translational studies, 14 patients had adequate tumor tissue that could be assessed for immunohistochemical (IHC) analysis and fluorescence in situ hybridization (FISH). Patients with higher than median p-PDGFRα IHC expression had a better OS (P = .013). When assessed as a continuous variable, higher p-PDGFRα in tumor cells correlated with an improved OS (P = .045). None of the other 4 IHC biomarkers were predictive or prognostic for survival. Twelve patients had successful PDGFRB FISH results, but none met the criteria of ≥ 4 copies of the PDGFRB gene; thus a correlation with clinical outcomes could not be done. The cisplatin/pemetrexed/imatinib mesylate combination had clinical benefit in some patients with MPM but was not well tolerated. Further investigation into alternative antiangiogenic agents, including PDGFRα inhibitors, is warranted.

Tsao AS ，Harun N ，Lee JJ ，Heymach J ，Pisters K ，Hong WK ，Fujimoto J ，Wistuba I ... -  《-》

Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma.

CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin. Chemotherapy naïve patients with unresectable MPM were stratified by histology and performance status, and randomized 2:1 to pemetrexed/cisplatin plus CBP501 25mg/m(2) IV (Arm A) or pemetrexed/cisplatin alone (Arm B). The primary endpoint was progression free survival (PFS) at 4 months. 65 patients were randomized, and 63 were treated. Patient characteristics in the two arms were balanced. Based on independent radiology review of the treated population, 25/40 patients (63%) in Arm A and 9/23 (39%) in Arm B had PFS≥4mo; the median PFS was 5.1mo (95% CI, 3.9, 6.5) vs 3.4mo (2.5, 6.7). Median OS was 13.3mo (9.2, 16.3) in Arm A and 12.8 (6.5, 16.1) in Arm B. Adverse events were not different than expected from standard chemotherapy, and comparable in the two arms, aside from infusion reactions which occurred in 70% of patients treated with CBP501. While this randomized phase II trial met its primary endpoint of PFS at 4 months, other parameters such as response rate and overall survival suggest that the addition of CBP501 does not improve the efficacy of standard chemotherapy for MPM.

Krug LM ，Wozniak AJ ，Kindler HL ，Feld R ，Koczywas M ，Morero JL ，Rodriguez CP ，Ross HJ ，Bauman JE ，Orlov SV ，Ruckdeschel JC ，Mita AC ，Fein L ，He X ，Hall R ，Kawabe T ，Sharma S ... -  《-》

A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma.

Malignant mesothelioma (MM) cells express the vascular endothelial growth factor (VEGF) receptor, and VEGF protein expression is detected in a majority of human mesothelioma biopsy specimens. Bevacizumab is a recombinant humanized monoclonal antibody that blocks the binding of VEGF to its receptor. We evaluated the addition of bevacizumab to cisplatin and pemetrexed as first-line treatment in patients with advanced, unresectable MM. Previously untreated MM patients with advanced, unresectable disease received cisplatin (75 mg/m(2)), pemetrexed (500 mg/m(2)), and bevacizumab (15 mg/kg) intravenously every 21 days for a maximum of 6 cycles. Patients with responsive or stable disease received bevacizumab (15 mg/kg) intravenously every 21 days until progression or intolerance. The primary endpoint was progression-free survival rate at 6 months. 53 patients were enrolled at 4 centers; 52 were evaluable for this analysis. The progression-free survival rate at 6 months was 56% and the median progression-free survival was 6.9 months (95% confidence interval [CI], 5.3-7.8 months). The partial response rate was 40% and 35% of patients had stable disease. Median overall survival was 14.8 months (95% CI; 10.0-17.0 months). Grade 3/4 toxicities included neutropenia in 11%, hypertension in 6%, and venous thromboembolism in 13% of patients. This trial evaluating the addition of bevacizumab to cisplatin and pemetrexed in patients with previously untreated, advanced MM failed to meet the primary endpoint of a 33% improvement in the progression-free survival rate at 6 months compared with historical controls treated with cisplatin and pemetrexed alone.

Dowell JE ，Dunphy FR ，Taub RN ，Gerber DE ，Ngov L ，Yan J ，Xie Y ，Kindler HL ... -  《-》