Allison Janine Tyler

Phase 1 dose‐escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma

On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP‐675206; an antibody against cytotoxic T‐lymphocyte–associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated.

A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors

Purpose: Bevacizumab is an antibody against vascular endothelial growth factor; sunitinib is an inhibitor of vascular endothelial growth factor and related receptors. The safety and maximum tolerated dose of sunitinib plus bevacizumab was assessed in this phase I trial. Experimental Design: Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level, 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level, 5 mg/kg) on days 1, 15, and 29 of a 42-day cycle. Dose-limiting toxicities during the first 6-week cycle were used to determine the maximum tolerated dose. Results: Thirty-eight patients were enrolled. Patients received a median of 3 cycles of treatment (range, 1-17+). There was one dose-limiting toxicity (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed Response Evaluation Criteria in Solid Tumors–defined partial response (18%; 95% confidence interval, 8-34%). Nineteen of the 32 patients with a postbaseline scan (59%) had at least some reduction in overall tumor burden (median, 32%; range, 3-73%). Conclusions: The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Antitumor activity was observed across multiple solid tumors. (Clin Cancer Res 2009;15(19):6277–83)

Toxicity of Sunitinib Plus Bevacizumab in Renal Cell Carcinoma

TO THE EDITOR: Inhibition of vascular endothelial growth factor (VEGF), either via antibody-mediated binding of the ligand or small molecule inhibition of the VEGF receptor, has demonstrated clinically relevant benefits in metastatic renal cell carcinoma (RCC) and other solid tumors. Recently, combinations of VEGFinhibiting approaches have been studied in an attempt to maximize VEGF blockade and extend the clinical benefit of these approaches. Sunitinib (Sutent; Pfizer Inc, New York, NY), a small-molecule tyrosine kinase inhibitor of a family of receptors including VEGF receptor and bevacizumab (Avastin; Genentech, South San Francisco, CA), a recombinant humanized monoclonal antibody that binds and neutralizes circulating VEGF, have been previously combined in two separate phase I trials. A phase I trial conducted exclusively in metastatic renal cell carcinoma (RCC) and with fixed bevacizumab dosing at 10 mg/kg intravenously every 2 weeks reported unacceptable toxicity, including thrombotic microangiopathy (TMA). We previously reported a similar phase I trial of this combination in 38 patients with advanced solid tumors, notable for the diverse tumor type as well as lower initial doses of bevacizumab. This trial failed to demonstrate laboratory or clinical evidence of TMA in any patent, including the six RCC patients (median, 8 cycles of therapy; range, 2 to 13), all of whom had undergone nephrectomy, and including all patients treated at the highest dose levels up to 20 months of treatment. Due to increased toxicity seen with chronic dosing at higher dose levels in our study and the TMA seen in the other trial, an expanded cohort of patients with RCC was planned to collect more safety experience at dosing of 37.5 mg sunitinib 4 weeks on followed by 2 weeks off and bevacizumab 5 mg/kg intravenously on days 1, 15, and 29 of a 42-day cycle. Five patients were enrolled in this expanded cohort. Three of five patients demonstrated laboratory evidence of TMA. This included low haptoglobin, thrombocytopenia, and schistocytes on peripheral blood smear at the end of cycles 2 and 4 for two patients, and an isolated single low haptoglobin value for the third patient. None of the patients had any clinical signs or symptoms associated with the laboratory abnormalities. Table 1 depicts the patient characteristics and relevant data for the three cases of TMA and the remainder of the patients with RCC enrolled on the initial study and expanded cohort. The first two TMA patients continued to have haptoglobin levels lower than 20 mg/dL for 2 and 20 weeks after discontinuation of bevacizumab (both patients continued on sunitinib monotherapy). The third patient developed the isolated low haptoglobin while receiving sunitinib monotherapy after bevacizumab had been discontinued 8 weeks prior. The haptoglobin normalized 2 weeks later and remained in normal range with continued sunitinib monotherapy for this patient. All five patients on the expanded cohort discontinued bevacizumab when TMA was observed in the initial two patients. Further accrual of patients with RCC was suspended due to this safety signal.

Sargramostim (GM-CSF) and lenalidomide in castration-resistant prostate cancer (CRPC): Results from a phase I-II clinical trial

BACKGROUND Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that stimulates dendritic cells (DCs) and promotes uptake of tumor antigens by DCs leading to T-cell cross-priming. Lenalidomide (Revlimid) is an immunomodulatory analog of thalidomide with significant T-cell stimulatory and antiangiogenic properties. GM-CSF in combination with thalidomide induces prostate-specific antigen (PSA) responses in 20% to 25% of patients with castration-resistant prostate cancer (CRPC). In an effort to further evaluate the clinical and immune activity of GM-CSF and lenalidomide, we conducted a phase I-II trial in patients with CRPC. METHODS Asymptomatic patients with CRPC were enrolled. Prior immunotherapy or chemotherapy was not allowed. All the patients received 250 μg of GM-CSF administered subcutaneously 3 times weekly along with 25mg/d of lenalidomide administered orally on days 1 to 21 of a 28-day cycle. The primary end points were objective, PSA response, and safety. Exploratory end points included activation of circulating DCs, regulatory T cells, and Th1 cytokine production. RESULTS Thirty-two patients were enrolled in the study. No dose-limiting toxicities occurred in the phase I portion of the study. Although 81% of the patients achieved a decline in the levels of PSA while on therapy, only 4 achieved a PSA level decline of ≥ 50%. The overall response rate among 11 patients with response evaluation criteria in solid tumors-defined measurable disease was 18%. Overall toxicity was G1 and G2 in nature and included fatigue observed in 69% of the patients, nausea/vomiting in 34%, and diarrhea in 28% of the patients. Grade 3 or 4 toxicities occurred in 22% of the patients and were primarily thrombocytopenia (9%) or neutropenia (19%) or both. CONCLUSIONS Administration of GM-CSF and lenalidomide in patients with CRPC is safe with modest evidence of antitumor activity and no immune changes observed.

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer

BACKGROUND. A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3&bgr;-hydroxysteroid dehydrogenase 1 (3&bgr;HSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3&bgr;HSD1 to multiple steroidal metabolites, including 3-keto-5&agr;-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5&agr;-abiraterone synthesis in patients. METHODS. First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5&agr;-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics. RESULTS. Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5&agr;-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION. Increased generation of 3-keto-5&agr;-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition. FUNDING. Prostate Cancer Foundation Challenge Award, National Cancer Institute.

A phase II study of linsitinib (OSI-906) in patients with asymptomatic or mildly symptomatic (non-opioid requiring) metastatic castrate resistant prostate cancer (CRPC).

197 Background: Novel agents capable of blocking AR ligand independent pathways responsible for the development of CRPC are needed. IGF-1R and its ligands (IGF-1/IGF-2) play a key role in regulating growth, resistance to apoptosis, and invasion in PCa. IGF-1R is overexpressed in PCa and mediates resistance to ADT. OSI-906 is a small molecule potent dual inhibitor of IGF-1R and insulin receptor TK activity. To determine the activity of OSI-906 in men with CRPC a Simon two-staged phase II study was conducted. METHODS Men with asymptomatic or mildly symptomatic Met CRPC were eligible. ECOG 0-1, adequate organ function, and no prior chemotherapy for CRPC were required. Pts received OSI-906 at 150mg orally twice daily on a 28-day cycle. Endpoints included PSA response at 12 wks, safety, RECIST-defined response, time to PSA progression, and OS. Correlative studies explored the impact of OSI-906 on AR signaling (androstenedione, DHEA, DHEA-sulfate, p-IGF-1R, p-IR), markers of PD (TGF-b1, IL-6, TNF-a, MCP-1), and CTC and CECs. RESULTS To date 18 pts have enrolled and completed 12 wks of therapy. Median age 68 (55-78); Median pre-treatment PSA was 55.23 (range 2.46-277.60); 41% of pts had bone-only disease, 29% soft-tissue only and 29% had both. Although transient PSA declines were noted, 17/18 pts discontinued therapy sec PSA progression. RECIST-defined SD was observed in 8 pts. Pts received a median of 3 cycles of therapy (range 2-6+). Most common G1/2 AEs included AST/ALT changes observed in 41 and 18% of patients respectively, fatigue (59%); prolong QT interval (35%) and nausea/vomiting (35%). No significant change in the number of CTC and CEC counts was observed. An association between pre-treatment PSA and pre-treatment CTC was observed (Spearman r=0.49, p=.04). No correlation between CTC changes and PSA progression was observed .Evaluation of other molecular markers of PD is underway. CONCLUSIONS Treatment with OSI-906 is safe. No PSA responses or changes in CTC/CECs were noted. Markers of PD might help elucidate potential mechanisms of escape to this alternative pathway in CRPC. OSI-906 plus an AA might provide synergistic activity in this setting. CLINICAL TRIAL INFORMATION NCT01533246.

Treatment selection for men with metastatic prostate cancer who progress on upfront chemo-hormonal therapy

Androgen deprivation therapy plus docetaxel (D‐ADT) increases overall survival (OS) in men with high‐volume, metastatic hormone‐sensitive prostate cancer (mHSPC). Although the vast majority of men initially respond to D‐ADT, most will progress and develop castration‐resistant prostate cancer (CRPC). Little is known about the optimal treatment sequence for men with progressive disease on D‐ADT.

The efficacy of VEGFR TKI therapy after progression on immune combination therapy in metastatic renal cell carcinoma

BACKGROUNDThe outcome of patients who progress on front-line immune-based combination regimens (IC) including immune checkpoint inhibitors (CPI) and receive subsequent systemic therapy is unknown.MethodsRetrospective analysis of consecutive patients with clear-cell mRCC who progressed on one of seven clinical trials investigating an IC and received ≥1 line of subsequent VEGFR TKI therapy.ResultsThirty-three patients [median age 57 (37–77), 85% male, 73% ECOG 0] were included. For evaluable patients (N = 28), the best response to first subsequent therapy was 29% partial response, 54% stable disease, and 18% progressive disease. The median PFS (mPFS) for first subsequent therapy was 6.4 months (95% CI, 4.4–8.4); no difference in mPFS by prior type of IC (VEGFR TKI-CPI vs. CPI-CPI) was noted (p = 0.310). Significant AEs were observed in 30% of patients, more frequently transaminitis (9%).ConclusionsVEGFR TKIs have clinical activity in mRCC refractory to IC therapy, possibly impacted by the mechanism of prior combination therapy.

Correlation of myeloid derived suppressor cell (MDSC) populations with clinicopathologic features in urothelial carcinoma (UC).

434 Background: MDSC are a heterogeneous population of potent immunosuppressive cells with potential predictive/prognostic significance in solid tumors. The association between MDSC and clinicopathologic features in patients (pts) with UC was investigated. Methods: Peripheral blood from 26 non-metastatic UC pts scheduled to undergo cystectomy or nephroureterectomy at Cleveland Clinic was collected. MDSC were enumerated in fresh unfractionated blood (WB) and in peripheral blood mononuclear cells (PBMC). (T)otal MDSC were defined as CD33+/HLADR-; out of T-MDSC, (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+) and (I)mmature (CD15-CD14-) MDSC were identified. CD11b MDSC (Linlo/HLADR-/CD33+/CD11b+) were identified in WB. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Wilcoxon rank sum test was used to assess associations between MDSC populations and clinicopathologic features. Due to the exploratory nature of the study, p < .10 was considered significa...