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

Abstract

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/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.

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.

Keywords: SS1P; immunotoxin; mesothelin; pleural mesothelioma.

Figure 1.

(A) This waterfall plot illustrates representative radiologic responses and the greatest relative change in the sum of greatest dimensions of target lesions for all evaluable patients (n520). Yellow, gray, and blue bars indicate patients who attained a partial response, stable disease, and progressive disease, respectively. The dashed line at 230% indicates a partial response; asterisks indicate patients who received the maximum tolerated dose. (B) These are axial computed tomographic images of patient 009 before treatment and after 6 treatment cycles and of patient of 018 before treatment and after 2 treatment cycles. Both patients had partial responses to treatment. Arrow indicate areas of tumor involvement.

Figure 2.

Grade 2 or higher toxicities related to (A) 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) and (B) and chemotherapy are illustrated. The highest grade for each patient is depicted.

Figure 3.

Representative immunohistochemical staining of tumor samples reveals various intensities of mesothelin staining: (A) strong, (B) moderate, and (C) weak. Areas of brown indicate mesothelin staining of tumor cells.

Figure 4.

Waterfall plots depict the relative biomarker changes and the best radiologic response in each of the 20 evaluable patients. For (A) mesothelin and (C) cancer antigen 125 (CA 125), the relative biomarker changes are based on the maximal change during therapy compared with baseline. (B) For megakaryocyte potentiating factor (MPF), the displayed biomarker changes indicate the relative difference between pretherapy and post-therapy samples. Dotted lines at –15% and 15% represent the thresholds for a significant change; asterisks indicate patients who received the maximum tolerated dose. PD indicates progressive disease; SD, stable disease; PR, partial response.

Figure 5.

The pharmacokinetics of 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) are illustrated. Scatter plots illustrate (A) individual patient values for the mean peak concentration (Cmax) (in ng/mL); (B) the area under the receiver operating characteristic curve (AUC) from zero to time t (AUC0-t) (in μg/mL per minute); and (C) the half-life (t1/2) (in minutes) of SS1P at the dose levels 25 μg/kg, 35 μg/kg, and 45 μg/kg. Serum SS1P, AUC0-t, and t1/2 values did not differ statistically between the different dose levels. Horizontal bars indicate mean SS1P Cmax, AUC0-t, and t1/2 values.