J. Paul Eder

Effects of Sorafenib on Intra-Tumoral Interstitial Fluid Pressure and Circulating Biomarkers in Patients with Refractory Sarcomas (NCI Protocol 6948)

Purpose Sorafenib is a multi-targeted tyrosine kinase inhibitor with therapeutic efficacy in several malignancies. Sorafenib may exert its anti-neoplastic effect in part by altering vascular permeability and reducing intra-tumoral interstitial hypertension. As correlative science with a phase II study in patients with advanced soft-tissue sarcomas (STS), we evaluated the impact of this agent on intra-tumor interstitial fluid pressure (IFP), serum circulating biomarkers, and vascular density. Patients and Methods Patients with advanced STS with measurable disease and at least one superficial lesion amenable to biopsy received sorafenib 400 mg twice daily. Intratumoral IFP and plasma and circulating cell biomarkers were measured before and after 1–2 months of sorafenib administration. Results were analyzed in the context of the primary clinical endpoint of time-to-progression (TTP). Results In 15 patients accrued, the median TTP was 45 days (range 14–228). Intra-tumoral IFP measurements obtained in 6 patients at baseline showed a direct correlation with tumor size. Two patients with stable disease at two months had post-sorafenib IFP evaluations and demonstrated a decline in IFP and vascular density. Sorafenib significantly increased plasma VEGF, PlGF, and SDF1α and decreased sVEGFR-2 levels. Increased plasma SDF1α and decreased sVEGFR-2 levels on day 28 correlated with disease progression. Conclusions Pretreatment intra-tumoral IFP correlated with tumor size and decreased in two evaluable patients with SD on sorafenib. Sorafenib also induced changes in circulating biomarkers consistent with expected VEGF pathway blockade, despite the lack of more striking clinical activity in this small series. Trial Registration ClinicalTrials.gov NCT00330421

Influence of scheduling on two-drug combinations of alkylating agents in vivo

SummaryThe effects of schedule and sequence on the survival of EMT6 tumor cell and bone marrow (CFU-GM) obtained after treatment using combinations of cyclophosphamide (CTX) and thiotEPA or melphalan (l-PAM) were examined and analyzed by isobologram methodology. On a single-injection schedule, when CTX and thiotEPA were given simultaneously or thiotEPA was given prior to CTX, the result was slightly greater than additive tumor-cell kill. However, when CTX preceded thiotEPA by 4 h, there was less than additive cell kill. When the interval between the administration of the two drugs was 8 h, both sequences of the drugs produced greater than additive tumor-cell kill. Simultaneous administration of CTX and thiotEPA on a multiple-injection schedule resulted in sub-additive tumor-cell kill. On the multiple-injection schedule, extending the interval between injections of CTX and thiotEPA to 4 and 8 h resulted in increasing tumor-cell kill. With the 4- and 8-h intervals, no significant sequence-dependent difference in tumor-cell kill was obtained. The results of CTX andl-PAM combinations paralleled those of CTX and thiotEPA. Bone marrow (CFU-GM) survival was used as a representative normal tissue with which to compare tumor-cell survival after each treatment to obtain a measure of therapeutic effect. The trends for the ratios of bone marrow: tumor cell survival were the same for the treatment sequences of CTX with thiotEPA orl-PAM; however, greater magnitudes of differential tumor-cell kill were obtained with CTXl-PAM combinations. Using this measure, the greatest therapeutic effectiveness was seen with single-dosel-PAM or thiotEPA followed 4 h later by CTX and with CTX given as a single or as multiple doses followed 8 h later byl-PAM or thiotEPA. Such data from tumor-model systems may be useful in the development of more effective alkylating agent regimens for use in the clinic.

A Phase I Study of 9-Nitrocamptothecin Given Concurrently with Capecitabine in Patients with Refractory, Metastatic Solid Tumors

9‐Nitrocamptothecin (9‐NC) is an orally available camptothecin analog with antineoplastic activity that results from the inhibition of DNA topoisomerase I. Previous studies have suggested that it has significant clinical efficacy. The primary toxicities of 9‐NC include gastrointestinal upset, cystitis, and myelosuppression at the maximum tolerated dose (MTD) of 1.5 mg/m2 per day. Capecitabine is a prodrug of 5‐fluorouracil that is approved for use in patients with metastatic breast carcinoma and colorectal carcinoma, and it offers the convenience of oral administration. This trial examined the combination of these two oral agents in patients with metastatic solid tumors.

Sequential doxorubicin and topotecan in relapsed/refractory aggressive non-Hodgkin's lymphoma: Results of CALGB 59906

Topoisomerase enzymes are critical components of genomic replication and function to minimize torsional stress on DNA. Sequential administration of a topoisomerase II inhibitor followed by a topoisomerase I inhibitor is potentially synergistic due to increased target enzyme levels. Patients with relapsed or refractory aggressive non-Hodgkins lymphomas (NHL) were eligible for this phase II study of doxorubicin 25 mg/m2 intravenous (IV) on day 1 and topotecan 1.75 mg/m2/day IV on days 3 – 5, every 21 days. The trial objectives included the overall response rate, progression-free survival, and toxicity. Twenty-six patients were enrolled and 25 patients are assessable for toxicity and response. The median age was 58 (range 23 – 74) years. The patients had received a median of two (range one to five) prior regimens, including five patients with a prior stem cell transplant. Five patients (20%, 95% confidence interval 0.07, 0.42) responded with two (8%) complete remissions and three (12%) partial remissions; an additional four (16%) patients had stable disease. Both patients achieving a complete remission had Burkitts lymphoma. There were no treatment-related deaths. In conclusion, the combination of doxorubicin and topotecan is well tolerated and has modest activity in relapsed/refractory NHL, with occasional patients having a prolonged remission. The activity in Burkitts lymphoma should be investigated further.