Effect of Cisplatin and Gemcitabine With or Without Berzosertib in Patients With Advanced Urothelial Carcinoma: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Preclinical studies suggest that inhibition of single-stranded DNA repair by ataxia telangiectasia and Rad3 (ATR) may enhance the cytotoxicity of cisplatin, gemcitabine, and other chemotherapeutic agents. Cisplatin with gemcitabine remains the standard up-front therapy for treatment in patients with metastatic urothelial cancer. OBJECTIVE: To determine whether the use of the selective ATR inhibitor, berzosertib, could augment the activity of cisplatin with gemcitabine. DESIGN, SETTING, AND PARTICIPANTS: In a phase 2 randomized clinical trial, 87 patients across 23 centers in the National Cancer Institute Experimental Therapeutics Clinical Trials Network were randomized to receive either cisplatin with gemcitabine alone (control arm) or cisplatin with gemcitabine plus berzosertib (experimental arm). Key eligibility criteria included confirmed metastatic urothelial cancer, no prior cytotoxic therapy for metastatic disease, 12 months or more since perioperative therapy, and eligibility for cisplatin receipt based on standard criteria. The study was conducted from January 27, 2017, to December 15, 2020. INTERVENTIONS: In the control arm, cisplatin, 70 mg/m2, was given on day 1 and gemcitabine, 1000 mg/m2, was given on days 1 and 8 of a 21-day cycle. In the experimental arm, cisplatin, 60 mg/m2, was given on day 1; gemcitabine, 875 mg/m2, on days 1 and 8; and berzosertib, 90 mg/m2, on days 2 and 9 of a 21-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point of the study was progression-free survival. The analysis was on all patients who started therapy. RESULTS: Of the total of 87 patients randomized, 41 patients received cisplatin with gemcitabine alone and 46 received cisplatin with gemcitabine plus berzosertib. Median age was 67 (range, 32-84) years, and 68 patients (78%) were men. Median progression-free survival was 8.0 months for both arms (Bajorin risk-adjusted hazard ratio, 1.22; 95% CI, 0.72-2.08). Median overall survival was shorter with cisplatin with gemcitabine plus berzosertib compared with cisplatin with gemcitabine alone (14.4 vs 19.8 months; Bajorin risk-adjusted hazard ratio, 1.42; 95% CI, 0.76-2.68). Higher rates of grade 3 vs grade 4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with cisplatin with gemcitabine and berzosertib compared with cisplatin with gemcitabine alone; consequently, more dose reductions were needed in the experimental arm. Patients in the experimental arm received a median cisplatin dose of 250 mg/m2, which was significantly lower than the median dose of 370 mg/m2 in the control arm (P < .001). CONCLUSIONS AND RELEVANCE: The addition of berzosertib to cisplatin with gemcitabine did not prolong progression-free survival relative to cisplatin with gemcitabine alone in patients with metastatic urothelial cancer, and a trend toward inferior survival was observed with this combination. Berzosertib plus cisplatin with gemcitabine was associated with significantly higher hematologic toxicities despite attenuated dosing of cisplatin with gemcitabine. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02567409.

Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients : randomized phase 2 study of ixabepilone or mitoxantrone and prednisone.

BACKGROUND: This randomized, noncomparative, multicenter, clinical trial evaluated ixabepilone or mitoxantrone/prednisone (MP) as second-line chemotherapy for taxane-refractory, hormone-refractory, prostate cancer (HRPC). METHODS: Patients with HRPC that progressed during or within 60 days of cessation of taxane chemotherapy were randomly selected with equal probability to ixabepilone 35 mg/m(2) intravenously every 3 weeks, or mitoxantrone 14 mg/m(2) intravenously every 3 weeks and prednisone 5 mg orally twice daily. Treatment continued until progression or toxicity; crossover was allowed. RESULTS: Forty-one patients were accrued to each arm of the study. The median number of cycles administered for each arm was 3. Median survival from protocol entry was 10.4 months with ixabepilone and 9.8 months with MP. Prostate-specific antigen (PSA) declines of >or=50% were observed in 17% of ixabepilone (95% CI, 7-32) and 20% of second-line MP patients (95% CI, 9-35). Partial responses were observed in 1 of 24 ixabepilone and in 2 of 21 MP patients with evaluable measurable disease. Median duration of second-line ixabepilone and MP treatment was 2.2 months and 2.3 months, respectively. For third-line crossover treatment, PSA declines of >or=50% were observed in 3 of 27 ixabepilone-treated and 4 of 15 MP-treated patients. Prior taxane response was associated with an increased likelihood of second-line ixabepilone or MP response. Low baseline lactate dehydrogenase and absence of visceral metastases independently predicted improved survival. The most common grade 3/4 toxicity associated with second-line treatment was neutropenia (54% of ixabepilone patients and 63% of MP patients). CONCLUSIONS: Ixabepilone and MP had modest activity as second-line chemotherapy for docetaxel-refractory HRPC. The median survival for the entire cohort treated in this study was 9.8 months.

Human kidney injury molecule-1 is a tissue and urinary tumor marker of renal cell carcinoma.

Human kidney injury molecule-1 (hKIM-1) is a type 1 transmembrane protein that is not detectable in normal kidney tissue but is expressed at high levels in human and rodent kidneys with dedifferentiated proximal tubule epithelial cells after ischemic or toxic injury. Therefore, it was hypothesized that renal tumors express hKIM-1 and release this protein into the urine. Forty renal cell carcinoma (RCC) and 484 nonrenal tumors were analyzed by immunohistochemistry for expression of hKIM-1 (group 1). Urine samples before nephrectomy and nephrectomy tissue samples were collected from an additional 42 patients with renal tumors, from 30 normal control subjects, and also from 10 patients with prostate carcinoma (group 2). In five additional patients with RCC, urine was collected before and after nephrectomy (group 3). Tissue was examined for expression of hKIM-1, and cell-free urine supernatants were analyzed for hKIM-1 by ELISA. Urinary hKIM-1 was normalized to the urinary creatinine concentration (U(Cr)). Expression of hKIM-1 was present in 32 tissue sections (91%) of 35 clear cell RCC (group 1). In group 2, the normalized urinary hKIM-1 levels were significantly higher in patients with clear cell RCC (0.39 +/- 0.08 ng/mg U(Cr); n = 21), compared with levels in patients with prostate carcinoma (0.12 +/- 0.03 ng/mg U(Cr); P < 0.02; n = 10), or normal control subjects (0.05 +/- 0.01 ng/mg U(Cr); P < 0.005; n = 30). Tissue sections from 28 (82%) of 34 primary RCC stained positively for the expression of hKIM-1. In all patients with a detectable prenephrectomy urinary hKIM-1 level, there was either complete disappearance or marked reduction after nephrectomy (group 3). In conclusion, the cleaved ectodomain of hKIM-1 can be detected in the urine of patients with RCC and may serve as a new biomarker for early detection of RCC.