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Ephrin receptors and their membrane-localized ligands induce bidirectional signaling and facilitate tumor-stroma interactions. Blocking the EphB4-EphrinB2 pathway, which can be accomplished by soluble EphB4 conjugated to human serum albumin (sEphB4-HSA), promotes cell death in preclinical models of aggressive prostate cancer. We hypothesized that targeting the EphB4-EphrinB2 pathway may serve as a therapeutic target in the treatment of metastatic castration resistant prostate cancer (mCRPC).We conducted a single arm, phase II trial in patients with progressive mCRPC who had received no more than 3 prior therapies for mCRPC. sEphB4-HSA 1000 mg IV was administered every 2 weeks, extending to 3 weeks starting from cycle 7. The primary endpoint was confirmed prostate specific antigen (PSA) response rate. We employed a Simon 2-stage Minimax design with 15 patients in the first stage and 10 additional patients in the second stage.Fourteen eligible patients enrolled in the study with median age of 73.5 years (range: 52-83) and median baseline PSA of 65.11 ng/mL (range: 7.77-2850 ng/mL). Most patients received 3 prior therapies for mCRPC. The median treatment duration with sEphB4-HSA was 6.5 weeks (range: 2-35 weeks). Three patients experienced a serious adverse event potentially related to therapy, including 1 patient with a grade 5 event (cerebral vascular accident) possibly related to the study drug. No patient had a confirmed PSA response, and the study was stopped for futility. Thirteen patients had PSA progression. The median time to PSA progression was 28 days (90% CI: 28-42 days), and median time to radiologic progression was 55 days (90% CI: 54-72 days). Of 3 patients with measurable disease, 2 had stable disease and one had progressive disease.In patients with mCRPC who progressed on prior second generation AR-targeted therapy, sEphB4-HSA monotherapy had no discernable anti-tumor activity.

Background: Temozolomide is efficacious as an oral alternative for patients with metastatic melanoma (MM). Calcitriol has anti-proliferative properties and vitamin D receptor (VDR) polymorphisms are associated with alterations in melanoma susceptibility and progression. Methods: Tem 150 mg/m2 was administered on days 2–8 and 16–22 every 28 days. Calcitriol was given on days 1 and 15 every 28 days. VDR gene analysis was completed using PCR-RFLP based assays. Tolerability was the primary objective with secondary objectives of time to progression (TTP) and overall survival (OS). Results: Twenty pts with MM were registered. Cytopenias and thrombosis were the most common grade 3 or 4 toxicities. Median TTP was 1.8 mo. Pts with high-risk VDR genotype tt+/−ff (n = 6) had an OS of 3.8 mo from time of enrollment, compared to 7.4 mo for those with non-tt/ff genotypes (n = 11), although not statistically significant (HR = 1.20, 95% CI 0.41–3.53, p = 0.74). Conclusions: The extended dosing of Tem with calcitriol is a well-tolerated regimen. The trend toward improved OS in non-tt/ff VDR genotypes is consistent with prior studies associating the tt/ff genotype with biologic aggressiveness.

Purpose: Angiostatin4.5 (AS4.5), the endogenous human angiostatin, is derived from plasminogen in a two-step process. A plasminogen activator converts plasminogen to plasmin, then plasmin undergoes autoproteolysis to AS4.5. A free sulfhydryl donor can mediate plasmin autoproteolysis. To translate this process to human cancer therapy, we conducted a phase I trial of administration of a tissue plasminogen activator (tPA) with a free sulfhydryl donor (mesna). Patients and Methods: Fifteen patients with advanced solid tumors were treated. The dose of tPA was escalated (cohorts; 1, 2, 3, 5, and 7.5 mg/h for 6 hours). Mesna was administered as a 240 mg/m2 bolus followed by an infusion of 50 mg/h, concurrent with tPA. Both tPA and mesna were administered 3 consecutive days every 14 days. Results: No dose-limiting toxicity was observed. Two AS4.5 isoforms were generated, Lys-AS4.5 and Glu-AS4.5. Mean baseline Lys-AS4.5 level was 20.4 nmol/L (SE, 2.9). In the 5 mg/h tPA cohort, Lys-AS4.5 levels increased by an average of 143% or 24 nmol/L (SE, 4.9) above baseline. Glu-AS4.5 (Mr ∼ 62,000) was also generated (additional 77 amino acids at amino terminus compared with Lys-AS4.5). Glu-AS4.5 level at baseline was undetectable in four of five patients in the 5 mg/h tPA cohort, but at end of infusion, was ∼67 nmol/L (SE, 20). Two patients in the 5 mg/h tPA cohort experienced decreases in tumor markers with treatment, although no clinical objective responses were observed. Conclusion: This study shows that in vivo generation of AS4.5 is safe in humans and may provide a practical approach to achieve antiangiogenic therapy.

High-dose (HD) IL-2 is approved to treat renal cell carcinoma (RCC) with modest response rates and significant toxicity. Enhancement of cytotoxic T-cell activity by IL-2 is 1 mechanism of action. IL-2 also stimulates regulatory T lymphocytes (Tregs), which are associated with poor prognosis. Favorable outcomes are associated with greater rebound absolute lymphocyte count (Fumagalli 2003). DD depletes IL-2 receptor (CD25 component) expressing cells. We hypothesized that sequential therapy could complement each other; DD would deplete Tregs so IL-2 could more effectively stimulate proliferation and activity of cytotoxic T lymphocytes. Patients (n=18) received standard HD IL-2 and 1 dose of DD daily for 3 days; periodic flow cytometry and complete blood counts were performed. Group A included 3 patients to assess safety only with DD 6 μg/kg between the IL-2 courses. Group B included 9 patients at 9 μg/kg DD before the IL-2 courses. Group C included 6 patients at 9 μg/kg DD between the IL-2 courses. Efficacy using the RECIST criteria was assessed after the treatment. Fifteen patients from a study of IL-2 without DD served as controls for toxicity comparison and 13 of these for flow cytometry comparisons. No unusual toxicity was noted. For group B/C patients receiving DD, the median decline in Tregs was 56.3% from pre-DD to post-DD (P=0.013). Peak absolute lymphocyte count change from baseline was +9980/μL for group B, +4470/μL for group C, and +4720/μL for the controls (P=0.005 B vs. C). The overall response rate was 5 of 15 (33%); 3 of 9 (33%) and 2 of 6 (33%) for groups B and C, respectively, including 2 patients with sarcomatoid RCC and 1 with earlier sunitinib therapy.

Patients with myelodysplastic syndromes (MDS) show a decrease in the number and function of natural killer (NK) cells, including lymphokine activated killer (LAK) cell activity. Interleukin-2 (IL-2) stimulates the proliferation and activity of these lymphocytes. Anecdotal clinical experience has shown haematological and cytogenetic improvement in myelodysplasia by low-dose IL-2 treatment. A total of 10 patients with MDS were treated with 1 million units of IL-2 subcutaneously daily for 12 weeks. Even though improvement in CD16+/CD56+ cell numbers was seen in a majority of the patients, the haematological status and transfusion requirements remained unchanged. There was minimal toxicity from this therapy.

e15554 Background: Many pts receiving tyrosine kinase inhibitors for RCC manifest stable disease as their best response by RECIST criteria. We hypothesized that tumor necrosis by DCE and DW-MRI after brief treatment with neoS may correlate with pathologic findings. We investigated in a pilot study whether these MRI changes may serve as an imaging biomarker predictive of clinical outcome. Methods: Pts with locally advanced or metastatic clear cell RCC undergoing nephrectomy or metastastectomy were treated with neoS 400mg PO bid for 28 days prior to surgery. The feasibility and safety of neoS was determined. Tumor necrosis detected by DCE and DW MRI’s pre- and post-neoS were compared and correlated with survival and pathologic findings at surgery. RECIST/WHO criteria were also compared. Results: 9 pts were enrolled, and all underwent surgery after neoS, 4 weeks (n=7) or less for toxicity (n=2). Clear cell/sarcomatoid histology was noted in 8 pts, and papillary in 1. All pts had T3 or T4 disease. 7 had M1 disease. No surgical complications occurred. 7 pts (78%) experienced Grade 3 toxicities, including hypertension (n=1), pancreatitis (n=1), hand-foot syndrome (n=1), hyponatremia (n=2), and rash (n=2). No grade 4 or 5 toxicities were observed. 4 of 8 clear cell/sarcomatoid pts (50%) have died, 3 due to progressive disease and 1 of unrelated causes. DCE and DW MRI’s with direct surgical pathological correlation were available in 7 of these pts. The mean ADC DW MRI changes in the renal lesion of 4 longer term survivors (median survival = 43 months) was +.22 vs. –0.07 in the 3 short term survivors (median survival = 13 months). RECIST/WHO criteria did not correlate with response. Evaluation of lack of enhancement on DCE MRI and increase in ADC on DW MRI were seen and correlated with necrosis on pathologic specimens. Conclusions: Four weeks of neoS is associated with significant necrosis that correlates with DCE-MRI and DW-MRI. There may be a trend in survival with greater necrosis, suggesting a role for these imaging biomarkers to assess early benefits of therapy. Clinical trial information: NCT00727532.

Background: CD4+CD25+hi T cells (Treg) play a suppressive role in immune regulation. DD is an IL-2 receptor specific cytotoxin. We postulated depletion of Treg with DD may enhance immune effector cell populations after HDIL-2 treatment, including rebound lymphocytosis and also eosinophilia which has been reported to be involved in immune response to neoplasm (Mattes J Exp Med 197: 387, 2003). Methods: In this pilot study, 12 pts (8 male, median age 58 yrs) with MRCC were tx with HDIL-2 and DD in different schedules to determine safety and effect on immune response as manifested by changes in Treg, peak lymphocyte, and eosinophil counts. Pts were treated with IL-2 600,000 IU/kg Q8H on days (d) 1–5 and 15–19. Three (group A) and 4 (group B) pts were given 6 and 9ug/kg daily on d8–10 respectively, while 5 (group C) pts received 9ug/kg of DD on d −4 to −2. Nine (group D) pts with metastatic melanoma who received HDIL-2 as above but without DD were included as controls. Flow cytometry was done on days −4, 1,8,10,15,22 for group C and on days 1,8,10,15,22 for groups B, and D. CBC was obtained concurrent or within 24 hours of flow cytometry. Group A pts were evaluated for safety only and were excluded from analysis. Results: Prior to enrollment, all pts had undergone nephrectomy and four patients received interferon-alpha. One pt from group B withdrew from study and was not included in analysis. Administration of DD resulted in a median decline of 25% in Treg number (not significant). DD given before HDIL-2 was associated with a greater increase in Treg post HDIL-2. In Group C there was an increase of rebound median Treg count of 0.88k/ul compared with 0.060k/ul in group B (p=0.025). Absolute lymphocytosis was higher in the combined group getting DD compared to control (median maximal increase of 7.6 vs 4.7 k/ul, respectively) although the difference did not reach statistical significance. However, group C pts had a greater increase in absolute lymphocytosis than did group B pts in which absolute lymphocytosis actually decreased (median increase 10.6 vs. median decrease 0.4 k/ul, p=0.025). A higher peak level of eosinophilia was noted in groups B and C compared with group D (mean increase of 10.5 vs. 4.0 k/ul p=0.2). Group C had a greater peak eosinophilia than group B (11.2 vs 2.2 k/ul p=0.053) Toxicity was manageable and consistent with those seen with HDIL-2. Median HDIL-2 dose given was 21 (range, 14–28). No clinical responses were observed. Of 11 pts included in the analysis 1 pt from group A expired 68 weeks after enrollment. All remaining patients are alive. Survival from enrollment ranges from 11 to 93 weeks. Conclusion: Overall, the combination of DD and HDIL-2 results in a stimulatory effect as manifested by increased rebound lymphocytosis and eosinophilia compared to HDIL-2 alone. Administration of DD in conjunction with HDIL-2 was associated with a rebound in Treg that may be schedule and dose dependent. The results suggest an enhanced immune stimulatory effect as manifested by lymphocytosis and peak eosinophilia in group C. However, this stimulatory effect also extends to Treg that may prove detrimental clinically. Further exploration of these effects in immunotherapy naïve patients would be beneficial.

Treatment of advanced mycosis fungoides (MF)/Sézary syndrome (SS) remains difficult as virtually all pts become refractory to most standard therapies. The CD52 monoclonal antibody alemtuzumab is a new therapeutic option. We report from a clinical trial as well as clinical use in E-CTCL. Alemtuzumab was IV administered at a dose of 30 mg three times per week (t.i.w.) for 4 weeks (Dose 1 and 2: 3 mg and 10 mg, respectively) followed by SQ administration of 30 mg for an additional 8 weeks t.i.w. All pts received prophylactic treatment with TMP-SMZ, acyclovir, and fluconazole until immune reconstitution. 19 pts with E-CTCL have been treated to date. 15 pts have been enrolled into the study; while 4 pts who did not meet the pre-study criteria were treated off study (including second malignancy without recurrence diagnosed within 5 years prior study entry in 2 pts and living too remote from study center in 2 pts). Median age was 63 yrs, (39 to 88 years). Clinical stages were: 8 (42%) stage III; 10 (53%) stage IVA; 1 (5%) stage IVB. All pts were heavily pretreated with a median of 5 prior treatments. The ORR was 79% (15 pts.) with CR in 47% (9 pts) and PR in 32 % (6 pts) with effective clearing of circulating Sézary cells in 100%. Four pts (21%) developed PD with the development of cutaneous tumors in one patient despite complete clearing of circulating Sézary cells. Median response duration was 7 months (1–39 months). We have analyzed minimal residual disease (MRD) by PCR of γ/δ TCR after treatment in skin and/or blood samples in 11 pts who achieved CR and PR. MRD was detected in 8 pts with subsequent relapse in 5 pts after a median time of 6 months. Only 3 pts had negative blood samples tested with histologic evidence of cutaneous residual disease in 2 pts (PR). Patients remained in remission for 17, 4, and 5 months, respectively. Another patient with CR had negative skin, but a positive blood sample tested and relapsed after 3 months. The median overall survival of all pts. was 18 months (1–50 months). Ten pts (53%) have died, 7 (37%) attributable to MF. One patient developed a second B-cell lymphoma approximately 6 months after completing alemtuzumab. One patient died of aplastic anemia. None of the pts died of infectious complications. In general, treatment was well tolerated, with the majority of toxicities being Grade 2 in severity and transient. The major hematologic side effect was T-cell depletion (lymphopenia Grade 4) with infectious complications in 4 pts (including PICC line infection in 2 pts, and Herpes zoster infection and neck abscess formation in one pt each) and neutropenic fever in one patient without documented infection. 6 pts developed grade 3 or 4 leukopenia with prolonged cytopenias in 2 pts requiring withholding and/or discontinuation from treatment. No patient manifested reactivation of CMV infection. One patient developed a fungal otitis externa remote from study during the terminal phase of CTCL. In conclusion, alemtuzumab has shown impressive responses in patients with refractory E-CTCL and could be considered for first-line therapy. The persistence of MRD suggests that a longer duration of therapy or sequential use of other biologic agents may enhance responses or improve durability.