Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting: Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249).

BackgroundS0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity.MethodsPatients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status.ResultsA total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were < 9.0, 9.0-12.9, 12.9-22.8, and > 22.8 ng/mL, respectively. EVE trough levels increased with increasing age (p < 0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p = 0.01). Risk of grade 2 + triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.08; p = 0.02 and OR = 2.63; p = 0.002). Risk of grade 2 + rash was increased in Q2 and Q4 vs Q1 (OR = 2.99; p = 0.01 and OR = 2.90; p = 0.02). There was also an increased risk of any grade 3 + tox in Q2 vs Q1 (OR = 1.71; p = 0.05).ConclusionsWe identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity

Circulating microRNAs and treatment response in the Phase II SWOG S0925 study for patients with new metastatic hormone‐sensitive prostate cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141181/1/pros23452.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141181/2/pros23452_am.pd

A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors.

PurposeImmune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).Patients and methodsWe performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity.ResultsThirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13-64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%-52%); median OS was 11 months (95% CI, 6-∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events.ConclusionsIpilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease

Abiraterone Acetate for Metastatic Prostate Cancer in Patients With Suboptimal Biochemical Response to Hormone Induction.

IMPORTANCE: Men with metastatic prostate cancer who have a poor response to initial androgen-deprivation therapy (ADT), as reflected by a prostate-specific antigen (PSA) level higher than 4.0 ng/mL after 7 months of ADT, have a poor prognosis, based on historical controls. OBJECTIVE: To determine the efficacy of abiraterone acetate with prednisone in these high-risk patients with a suboptimal response to hormonal induction. DESIGN, SETTING, AND PARTICIPANTS: A phase 2 single-arm study was conducted through the National Clinical Trials Network-Southwest Oncology Group. Eligible patients had metastatic prostate cancer and a PSA level higher than 4.0 ng/mL between 6 and 12 months after starting ADT. The PSA level could be rising or falling at the time of enrollment, but had to be higher than 4.0 ng/mL. No previous chemotherapy or secondary hormonal therapies were allowed, except in patients receiving a standard, first-generation antiandrogen agent with a falling PSA level at the time of enrollment; this therapy was continued in this cohort. Abiraterone acetate, 1000 mg, once daily with prednisone, 5 mg, twice daily was administered to all participants. A total of 41 men were enrolled between the trials activation on August 9, 2011, and closure on August 1, 2013. Data analysis was conducted from March 21 to November 29, 2016. INTERVENTIONS: Abiraterone acetate, 1000 mg, once daily by mouth with prednisone, 5 mg, by mouth twice daily. MAIN OUTCOMES AND MEASURES: The primary end point was a PSA level of 0.2 ng/mL or lower within 12 months of starting abiraterone acetate plus prednisone. A partial response (PR) was a secondary end point, defined as a PSA level reduction to lower than 4.0 ng/mL but higher than 0.2 ng/mL. RESULTS: Of the 41 men enrolled, 1 did not receive any protocol treatment and was excluded from analysis. The median (range) age of the 40 participants was 66 (39-85) years. Five (13%) patients achieved a PSA level of 0.2 ng/mL or lower (95% CI, 4%-27%). Thirteen (33%) additional patients achieved a partial response, with a reduction in the PSA level to lower than 4.0 ng/mL but higher than 0.2 ng/mL. Sixteen (40%) patients had no PSA response and 6 (15%) were not assessable and assumed to be nonresponders. The median progression-free survival was 17.5 months (95% CI, 8.6-25.0 months) and the median overall survival was 25.8 months (95% CI, 15.7-25.8 months). There was 1 incident each of grade 4 adverse events of alanine aminotransferase level elevation and rectal hemorrhage. Eleven patients reported grade 3 adverse events. CONCLUSIONS AND RELEVANCE: This study did not reach its prescribed level of 6 PSA responses of 0.2 ng/mL or lower, although 5 responses were observed. The overall survival and progression-free survival rates observed in this trial are encouraging compared with historical controls. The therapy was generally well tolerated, without any clear signal of any unexpected adverse effects

Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting: Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249).

BackgroundS0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity.MethodsPatients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status.ResultsA total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were < 9.0, 9.0-12.9, 12.9-22.8, and > 22.8 ng/mL, respectively. EVE trough levels increased with increasing age (p < 0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p = 0.01). Risk of grade 2 + triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.08; p = 0.02 and OR = 2.63; p = 0.002). Risk of grade 2 + rash was increased in Q2 and Q4 vs Q1 (OR = 2.99; p = 0.01 and OR = 2.90; p = 0.02). There was also an increased risk of any grade 3 + tox in Q2 vs Q1 (OR = 1.71; p = 0.05).ConclusionsWe identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity

A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors.

Background: The potential therapeutic benefits of checkpoint inhibitors and their application to many different tumor types has been a key factor in the advancement of medical oncology since their first approval for metastatic melanoma in 2011. However, their efficacy in rare tumor types remains to be seen. This paper presents the results of combination therapy with both anti-CTLA and anti-PD-1 in the small bowel cohort of SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART).Methods: This study is designed as a prospective, open-label, multicenter phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks) in rare tumors. Here we report the outcomes from patients diagnosed with small bowel cancer (SBC). The primary endpoints included overall response rate (ORR) (RECIST v1.1) (complete response (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease \u3e6 months, and toxicity were the secondary endpoints.Results: Twenty five patients were registered to the cohort and twenty three received therapy. The duodenum was the primary site of origin in 52% (N=11), 14% (N=3) arose in the ileum and 14% (N=3) arose in the jejunum. The primary site of origin was unknown in 19% (N=4). The overall response rate was 8% (CR, 4%, N= 1; PR, 4%, N= 1). The median PFS was 2 months; 6-month OS was 48% and median OS 6 months. The most common toxicities were diarrhea and fatigue (both 17%) followed by dyspnea (13%) with diarrhea, increased bilirubin, colitis and elevated lipase (all 4.3%) as the most common grade 3-5 immune-related adverse events.Conclusions: Combination therapy with ipilimumab plus nivolumab in small bowel tumors resulted in an overall response rate of 8% with one partial and one complete response in twenty three treated patients

Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART)

PURPOSE: Angiosarcoma is a rare aggressive endothelial cell cancer with high mortality. Isolated reports suggest immune checkpoint inhibition efficacy in angiosarcoma, but no prospective studies have been published. We report results for angiosarcoma treated with ipilimumab and nivolumab as a cohort of an ongoing rare cancer study. METHODS: This is a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) for metastatic or unresectable angiosarcoma. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free (PFS) and overall survival, and toxicity. A two-stage design was used. RESULTS: Overall, there were 16 evaluable patients. Median age was 68 years (range, 25-81); median number of prior lines of therapy, 2. Nine patients had cutaneous and seven non-cutaneous primary tumors. ORR was 25% (4/16). Sixty per cent of patients (3/5) with primary cutaneous scalp or face tumors attained a confirmed response. Six-month PFS was 38%. Altogether, 75% of patients experienced an adverse event (AE) (at least possibly related to drug) (25% grade 3-4 AE); 68.8%, an immune-related AE (irAE) (2 (12.5%), grade 3 or 4 irAEs (alanine aminotransferase/aspartate aminotransferase increase and diarrhea)). There were no grade 5 toxicities. One of seven patients in whom tumor mutation burden (TMB) was assessed showed a high TMB (24 mutations/mb); that patient achieved a partial response (PR). Two of three patients with PDL1 immunohistochemistry assessed had high PDL1 expression; one achieved a PR. CONCLUSION: The combination of ipilimumab and nivolumab demonstrated an ORR of 25% in angiosarcoma, with three of five patients with cutaneous tumors of the scalp or face responding. Ipilimumab and nivolumab warrant further investigation in angiosarcoma. TRIAL REGISTRATION NUMBER: NCT02834013

Orteronel for Metastatic Hormone-Sensitive Prostate Cancer: A Multicenter, Randomized, Open-Label Phase III Trial (SWOG-1216).

PURPOSE: Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. METHODS: In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 1:1 to ADT with orteronel (300 mg oral twice daily; experimental arm) or ADT with bicalutamide (50 mg oral once daily; control arm). The primary objective was the comparison of overall survival (OS), targeting a 33% improvement in median survival. A stratified log-rank test with a one-sided RESULTS: Among 1,279 patients included in the analysis, 638 were randomly assigned to the ADT plus orteronel arm and 641 to the control arm. The median age was 68 years; 49% had extensive disease. After a median follow-up of 4.9 years, there was a significant improvement in PFS (median 47.6 CONCLUSION: The study did not meet the primary end point of improved OS with orteronel. The lack of correlation of PFS and PSA response with OS raises concerns over assumption of their consistent surrogacy for OS in the context of extensive postprotocol therapy in this setting