describes the characteristics of the eight patients, six males and two females, with malignant mesothelioma treated at NCI. All patients had serum CA-125 measurement before and at different time-points after therapy. Out of these eight patients four had pleural and four had peritoneal mesothelioma of the epithelial subtype; this tumor type has high cell surface mesothelin expression. These patients had all failed prior chemotherapy before going on this study. The patients were treated at various dose levels of MORAb-009 as per the phase I dose escalation design. One patient each was treated at 12.5, 25, 50 and 100 mg/m2, and two patients each were treated at 200 and 400 mg/m2.1 Out of the six patients who were evaluable for tumor response four had stable disease and two had progressive disease, using the Response Evaluation Criteria in Solid Tumors. Patients 1007 and 1008 were not evaluable for tumor response. Patient 1007 received only one dose of MORAb-009 and was taken off-study because of transient grade 4 elevation of liver transaminases, which was judged to be unrelated to MORAb-009 since the patient had a prior history of transient grade 2–3 liver transaminase elevations. Patient 1008 was taken off-study since she developed serum sickness after the second dose of MORAb-009 and was not evaluable for tumor response. Details regarding the clinical trial including dose escalation, adverse events, tumor response and MORAb-009 pharmacokinetics in the 24 patients treated on-study will be presented separately.
Although measurement of serum CA-125 levels was not part of the protocol, we routinely follow CA-125 levels in patients treated in our Mesothelioma Clinic at NCI, because several studies have previously shown that it may be a useful tumor marker to follow response to therapy in patients with mesothelioma [22
]. In all patients we noted a very interesting effect of MORAb-009 on serum CA-125 levels, which are summarized in .
Effect of MORAb-009 Treatment on Serum CA-125 Levels
Elevated serum CA-125 levels prior to treatment with MORAb-009 were present in 6/8 patients, but not patients 1002 and 1007. There was a wide variation in serum levels among patients, which is most likely a reflection of tumor burden. Following treatment with MORAb-009 all patients had an increase in their serum CA-125 levels. For example, the baseline CA-125 level in patient 1001 was 1,887 U/ml and by day 35 had increased to 2,917 U/ml. In patient 1002, the baseline CA-125 levels were within the normal range prior to treatment and increased to 47 U/ml on day 35. This increase in CA-125 levels following treatment with MORAb-009 was seen in patients with both peritoneal and pleural mesothelioma.
As illustrated by patients 1002 and 1007, even patients with CA-125 levels within the normal range prior to treatment had an increase in CA-125 levels following treatment with MORAb-009. Furthermore, our results demonstrate that the marked increase in CA-125 levels can occur even with a single-dose of MORAb-009. In patient 1006 with pleural mesothelioma, the CA-125 levels increased from 128 U/ml to 262 U/ml after one infusion of MORAb-009 and to 644 after four infusions. Similarly, in patient 1007 the pre-treatment CA-125 level was 8 U/ml and increased more than 13-fold to 110 U/ml after just one infusion of MORAb-009.
illustrates the kinetics of CA-125 rise and fall following treatment with MORAb-009. In patient 1003 with peritoneal mesothelioma (), the serum CA-125 levels increased more than 15-fold on day 22 to 752 U/ml (i.e. after patient had received 3 weekly infusions of MORAb-009) and gradually fell to five times the baseline levels on day 49 to 495 U/ml and were close to the pre-treatment values on day 176. This patient has continued to have stable disease on imaging studies on day 176. Similarly in patient 1005 (), who had pleural mesothelioma with an elevated baseline CA-125 value of 399 U/ml and received two cycles of MORAb-009, the CA-125 levels continued to increase while the patient was receiving therapy but decreased to pre-treatment levels once treatment was completed. The peak CA-125 level of 882 U/ml occurred on day 83, about 2 weeks after the last MORAb-009 dose on day 70 and by day 120 the CA-125 levels had decreased by about half to 466 U/ml. These results illustrate that the increase in serum CA-125 levels was not due to disease progression but rather a consequence of MORAb-009 therapy.
Fig. 1 Effect of MORAb-009 on serum CA-125 levels. The serum CA-125 levels before, during and following completion of MORAb-009 therapy are shown for a patient with peritoneal mesothelioma (1003) and pleural mesothelioma (1005). Arrowheads indicate day of MORAb-009 (more ...)
To rule out the possibility that the rise in serum CA-125 was due to MORAb-009 interfering with the clinical assay, we did the CA-125 assay in the presence of MORAb-009. Serum samples from patients with ovarian cancer with serum CA-125 levels within normal limits (sample A, ) or with elevated serum CA1–25 level (sample B, ) were spiked with 100 μg/ml of MORAb-009, and then CA-125 levels measured. As a control, these serum samples were also spiked with the isotype matched antibody rituximab using the same concentration. The concentration of antibody added to the serum samples was similar to the peak MORAb-009 levels observed in patients treated at the highest dose level of MORAb-009 (unpublished data). As shown in , the addition of MORAb-009 (or rituximab) did not interfere with the measurement of serum CA-125 levels demonstrating that the elevation in serum CA-125 levels observed in our patients was not a consequence of MORAb-009 present in the serum interfering with the clinical assay used to measure CA-125.
Fig. 2 Effect of MORAb-009 on serum CA-125 assay. Serum samples obtained from patients with ovarian cancer with CA-125 levels within normal range (sample A) or with elevated CA-125 concentration (sample B) were mixed with MORAb-009 (100 μg/ml), rituximab (more ...)