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

BACKGROUND: 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. PATIENT AND METHODS: Retrospective analysis of consecutive mHSPC patients treated with ≥3 cycles of D-ADT at Cleveland Clinic and University of Wisconsin-Madison was undertaken. The primary end-points included radiographic progression free survival (rPFS) and OS with first-line treatment for metastatic CRPC (mCRPC). RESULTS: Final analysis included 136 patients, median age 65 (range 35-86), 77% GS ≥ 8, and 79% with high-volume disease who received ≥3 cycles of docetaxel. Undetectable PSA values at 12 and 24 months were observed in 32% and 25% of patients, respectively. Median time to CRPC (biochemical, clinical, or radiographic) was 19.6 months (16.6-22.6). Sixty patients (44%) received ≥1 treatment for CRPC: 48 patients (80%) received a second-generation hormonal therapy (sHT). Among these, 22 received abiraterone acetate, 20 enzalutamide, and six a novel CYP-17 inhibitor on trial (ASN-001). Five patients (8%) received sipuleucel-T; four (7%) radium-223, five (8%) chemotherapy (two carboplatin-based, two single agent cabazitaxel, one single agent docetaxel) and three other. Patients receiving sHT as the first treatment for mCRPC had a median rPFS of 9.0 months (95%CI, 6.9-11.2) compared with 3.0 months (95%CI, 1.5-4.5) for patients who received a non-sHT (P = 0.024). The choice of first therapy for mCRPC was independent of GS (P = 0.909), visceral disease (P = 0.690) and time to CRPC (P = 0.844). Longer OS correlated with time to CRPC (P = 0.010) and first treatment for CRPC with sHT (P = 0.005). CONCLUSIONS: For patients with progressive disease on D-ADT, subsequent treatment with a sHT is associated with a longer rPFS and OS.

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

BACKGROUND: The 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. METHODS: Retrospective 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. RESULTS: Thirty-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%). CONCLUSIONS: VEGFR TKIs have clinical activity in mRCC refractory to IC therapy, possibly impacted by the mechanism of prior combination therapy.

Ketoconazole plus Lenalidomide in patients with Castration-Resistant Prostate Cancer (CRPC): results of an open-label phase II study.

Introduction Ketoconazole is CYP-17 inhibitor with demonstrated activity in men with castration-resistant prostate cancer (CRPC). Lenalidomide is an antiangiogenic and immunomodulatory agent with broad antitumor activity. We hypothesized that the modulation of the cellular immune response to apoptosis caused by ketoconazole may be increased with the addition of lenalidomide. Methods This is an open-label, non-randomized, single-arm phase II study evaluating the efficacy and safety of the combination of ketoconazole and lenalidomide in patients with CRPC. Treatment schema included standard ketoconazole 400 mg orally three times daily plus hydrocortisone orally (20 mg in the morning and 10 mg at night) in combination with lenalidomide 25 mg orally daily for 21 days in a 28-day cycle and aspirin 75 mg daily. The primary endpoint of this study was response (either by ≥ 50% PSA decline or objective disease assessed by RECIST v1.0). Exploratory endpoints included changes in T cell, dendritic cell (DC) marker counts, and their correlation with PSA response to treatment. Results A total of 34 CRPC patients, median age 69 years, 76% ECOG 0 and 76% with metastases participated in the study. Patients received a median of 2 cycles (range 1-35); nine patients (26%) received >10 cycles of treatment. PSA responses were observed in 17 patients (50%) with 11 patients (32%) achieving a PSA decline of >90%. Among the 9 patients with measurable disease, 2 patients (22%) had PR and 2 other (22%) had SD as best response. Median time to failure (TTF) was 2.7 months (range 0.2-32.8); and 8 patients were treated for ≥ 15 months. Most common adverse events included fatigue (76%), skin reactions (62%), lymphopenia (44%) and anemia (44%). One possible treatment-related death was noted. For 16 patients with available serial correlative data, there was a significant increase in the dendritic cells subsets BDCA-1 (+146.7, -20.1 to +501.1%, p = 0.018) and BDCA-3 (39.8%, -100 to 282.6%, p = 0.001) after 8 weeks of treatment. No association between immune cell counts and PSA response at 8 weeks was observed. Conclusion The combination of ketoconazole and lenalidomide was well tolerated but did not meet the primary endpoint of response, despite durable responses were observed in a selected group of patients. Although ketoconazole has now been replaced with more active novel agents, the combination of novel CYP-17 inhibitors with agents capable of modulating the immune system warrants further prospective investigation. NCT00460031.

A phase 2 study of OSI-906 (linsitinib, an insulin-like growth factor receptor-1 inhibitor) in patients with asymptomatic or mildly symptomatic (non-opioid requiring) metastatic castrate resistant prostate cancer (CRPC).

Background The inhibition of insulin-like growth factor receptor-1 (IGF-1R) induces cell cycle arrest and enhancing the effect of castration by delay of progression of human prostate cancer models. Linsitinib is a small molecule and potent dual inhibitor of IGF-1R and insulin receptor tyrosine kinase activity. We report results of a single-arm, phase II study evaluating the safety and efficacy of linsitinib in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC). Methods Patients received at 150 mg orally twice daily on a 28-day cycle. The primary endpoint was prostate specific (PSA) response at 12 weeks and correlative studies included circulating tumor cells (CTCs) and circulating endothelial cells (CECs). Results Seventeen patients, median age 68 (55-78) and pre-treatment PSA of 55.23 (2.46-277.60) were enrolled and completed 12 weeks of therapy. All but two patients discontinued therapy secondary to PSA progression, which met the predefined futility criteria and led to early termination of this study. Overall best response (RECIST v1.1) included a partial response in 1 patient and stable disease in 8 patients. Higher baseline CTCs were associated with higher pre-treatment PSA levels (Spearman r = 0.49, p = 0.04) but no correlation between PSA progression and CTCs/CECs were observed. Most common adverse events included fatigue, nausea/vomiting, AST/ALT changes and prolonged QT interval. Conclusions Single-agent linsitinib was safe and well tolerated but failed to show activity in men with mCRPC. These results highlight the complexity of using IGF-1R as a therapeutic target in this patient population. ClinicalTrials.gov NCT01533246.

Now Is the Time to Strengthen Government-Academic Data Infrastructures to Jump-Start Future Public Health Crisis Response.

During public health crises, the significance of rapid data sharing cannot be overstated. In attempts to accelerate COVID-19 pandemic responses, discussions within society and scholarly research have focused on data sharing among health care providers, across government departments at different levels, and on an international scale. A lesser-addressed yet equally important approach to sharing data during the COVID-19 pandemic and other crises involves cross-sector collaboration between government entities and academic researchers. Specifically, this refers to dedicated projects in which a government entity shares public health data with an academic research team for data analysis to receive data insights to inform policy. In this viewpoint, we identify and outline documented data sharing challenges in the context of COVID-19 and other public health crises, as well as broader crisis scenarios encompassing natural disasters and humanitarian emergencies. We then argue that government-academic data collaborations have the potential to alleviate these challenges, which should place them at the forefront of future research attention. In particular, for researchers, data collaborations with government entities should be considered part of the social infrastructure that bolsters their research efforts toward public health crisis response. Looking ahead, we propose a shift from ad hoc, intermittent collaborations to cultivating robust and enduring partnerships. Thus, we need to move beyond viewing government-academic data interactions as 1-time sharing events. Additionally, given the scarcity of scholarly exploration in this domain, we advocate for further investigation into the real-world practices and experiences related to sharing data from government sources with researchers during public health crises.

Atezolizumab in Metastatic Urothelial Carcinoma Outside Clinical Trials: Focus on Efficacy, Safety, and Response to Subsequent Therapies.

BACKGROUND: Little is known about the outcomes, safety, and response to subsequent therapies of patients with metastatic urothelial carcinoma (mUC) treated with atezolizumab outside clinical trials. OBJECTIVES: The objectives of the study include to report the clinical efficacy and safety of atezolizumab, and the response to future therapies in clinical practice outside clinical trials. PATIENT AND METHODS: This is a retrospective, single-center study including consecutive patients with confirmed mUC who received at least one dose of atezolizumab 1200 mg every 3 weeks between May 2016 and April 2017. RESULTS: Seventy-nine patients, median age 72 years (range 29-93), 71% men and 76% ECOG PS 0-1, were identified. Most patients (79%) had primary cancer in the bladder, 62% had prior surgery, and 75% received at least one prior line of treatment (34 patients had prior cisplatin-based chemotherapy). Best response included 18% partial response, 29% stable disease, and 53% progressive disease. Patients were on atezolizumab for a median of 2.7 months (95%CI, 1.8-3.6) and median PFS was 3.2 months (95%CI, 1.6-4.8). A total of 33 (42%) patients had significant (any cause) AEs, including grade 4 hyperbilirubinemia in two patients; no toxic deaths were reported. At time of data analysis, only 18% of patients received at least one subsequent line of treatment for a median of 1.8 months (95%CI, 0.0-5.0) while 42% were referred to palliative care/hospice or died. CONCLUSIONS: Patients with mUC who progressed on atezolizumab were unlikely to receive subsequent systemic treatments and the benefit of those treatments appeared limited in our cohort. The findings may impact timing and designs of clinical trials in mUC.

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 3ß-hydroxysteroid dehydrogenase 1 (3ßHSD1) 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 3ßHSD1 to multiple steroidal metabolites, including 3-keto-5α-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5α-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-5α-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-5α-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION: Increased generation of 3-keto-5α-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.

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.

Assessment of owner willingness to treat or manage diseases of dogs and cats as a guide to shelter animal adoptability.

OBJECTIVE: To determine community approaches to medical and behavioral diseases in dogs and cats. DESIGN: Cross-sectional descriptive study. SAMPLE: 97 companion animal veterinarians and 424 animal owners. PROCEDURES: Companion animal veterinarians in central Iowa ranked medical or behavioral diseases or conditions by what they thought most clients would consider healthy, treatable, manageable, or unhealthy (unmanageable or untreatable). In a parallel survey, cat- or dog-owning households in central Iowa responded to a telephone survey regarding the relationship of their animal in the household, owner willingness to provide medical or behavioral interventions, and extent of financial commitment to resolving diseases. RESULTS: One hundred twenty common health or behavioral disorders in cats and dogs were ranked by veterinarians as healthy, treatable, manageable, or unhealthy (unmanageable or untreatable) on the basis of their opinion of what most clients would do. Findings were in congruence with animal owners' expressed willingness to provide the type of care required to maintain animals with many acute or chronic medical and behavioral conditions. In general, owners indicated a willingness to use various treatment modalities and spend money on veterinary services when considering current or previously owned animals as well as hypothetical situations with an animal. Past experiences with veterinary care in which an animal did not recover fully did not diminish the willingness of respondents to use veterinary services again in the future. CONCLUSIONS AND CLINICAL RELEVANCE: These results provide a baseline indication of community willingness to address medical or behavioral conditions in dogs and cats. These considerations can be used in conjunction with Asilomar Accords recommendations to assess adoptability of cats and dogs in animal shelters.

Urothelial cancers: ureter, renal pelvis, and bladder.

OBJECTIVES: To review the diagnosis, treatment, and nursing management of patients with urothelial cancers. DATA SOURCES: PubMed, Ovid MEDLINE, Text books, and clinical experience. CONCLUSION: Progress is being made in the surgical and systemic management of urothelial cancers, and the oncology nurse is in a position to make an impact on patient education and overall quality of life. IMPLICATIONS FOR NURSING PRACTICE: Nursing care begins at pre-diagnostic testing and continues through treatment for metastatic disease. Nurses must be knowledgeable about diagnostic tests, treatment options, and the quality-of-life implications of associated surgeries and/or treatments to support and guide patients. Education should be comprehensive, addressing not only treatment side effects but also long-term implications on patients' lives and lifestyles.

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

BACKGROUND: 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. METHODS: Adult patients with mRCC who had received ≤ 1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics. RESULTS: Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report. CONCLUSIONS: In this study of tremelimumab plus sunitinib, rapid-onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses > 6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity.

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.