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Purpose:Atezolizumab [anti–programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC.Patients and Methods:This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments.Results:All 35 evaluable patients [median age, 68 years (range, 45–83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9–not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34–70); 2-year OS was 35.9% (95% CI: 13–59). Median follow-up was 13.0 months (range, 1.2–28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy.Conclusions:Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.

Background Docetaxel has immunostimulatory effects that may promote an immunoresponsive prostate tumour microenvironment, providing a rationale for combination with nivolumab (programmed death-1 inhibitor) for metastatic castration-resistant prostate cancer (mCRPC). Methods In the non-randomised, multicohort, global phase II CheckMate 9KD trial, 84 patients with chemotherapy-naive mCRPC, ongoing androgen deprivation therapy and ≤2 prior novel hormonal therapies (NHTs) received nivolumab 360 mg and docetaxel 75 mg/m2 every 3 weeks with prednisone 5 mg twice daily (≤10 cycles) and then nivolumab 480 mg every 4 weeks (≤2 years). The co-primary end-points were objective response rate (ORR) and prostate-specific antigen response rate (PSA50-RR; ≥50% decrease from baseline). Results The confirmed ORR (95% confidence interval [CI]) was 40.0% (25.7–55.7), and the confirmed PSA50-RR (95% CI) was 46.9% (35.7–58.3). The median (95% CI) radiographic progression-free survival (rPFS) and overall survival (OS) were 9.0 (8.0–11.6) and 18.2 (14.6–20.7) months, respectively. In subpopulations with versus without prior NHT, the ORR was 38.7% versus 42.9%, the PSA50-RR was 39.6% versus 60.7%, the median rPFS was 8.5 versus 12.0 months and the median OS was 16.2 months versus not reached. Homologous recombination deficiency status or tumour mutational burden did not appear to impact efficacy. The most common any-grade and grade III–IV treatment-related adverse events were fatigue (39.3%) and neutropenia (16.7%), respectively. Three treatment-related deaths occurred (1 pneumonitis related to nivolumab; 2 pneumonias related to docetaxel). Conclusions Nivolumab plus docetaxel has clinical activity in patients with chemotherapy-naive mCRPC. Safety was consistent with the individual components. These results support further investigation in the ongoing phase III CheckMate 7DX trial. ClinicalTrials.gov registration NCT03338790.

Summary Background Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. Methods We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0–1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov ( NCT02501096 ) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. Findings Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3–28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8–89·3) of 22 treatment-naive patients, seven (41·2%, 18·4–67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7–65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). Interpretation Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. Funding Eisai and Merck Sharp & Dohme.

Purpose: Atezolizumab [anti–programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC. Patients and Methods: This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments. Results: All 35 evaluable patients [median age, 68 years (range, 45–83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9–not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34–70); 2-year OS was 35.9% (95% CI: 13–59). Median follow-up was 13.0 months (range, 1.2–28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy. Conclusions: Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.

BackgroundCheckMate 9KD (NCT03338790) is a non-randomized, multicohort, phase 2 trial of nivolumab plus other anticancer treatments for metastatic castration-resistant prostate cancer (mCRPC). We report results from cohorts A1 and A2 of CheckMate 9KD, specifically evaluating nivolumab plus rucaparib.MethodsCheckMate 9KD enrolled adult patients with histologically confirmed mCRPC, ongoing androgen deprivation therapy, and an Eastern Cooperative Oncology Group performance status of 0–1. Cohort A1 included patients with postchemotherapy mCRPC (1–2 prior taxane-based regimens) and ≤2 prior novel hormonal therapies (eg, abiraterone, enzalutamide, apalutamide); cohort A2 included patients with chemotherapy-naïve mCRPC and prior novel hormonal therapy. Patients received nivolumab 480 mg every 4 weeks plus rucaparib 600 mg two times per day (nivolumab dosing ≤2 years). Coprimary endpoints were objective response rate (ORR) per Prostate Cancer Clinical Trials Working Group 3 and prostate-specific antigen response rate (PSA50-RR; ≥50% PSA reduction) in all-treated patients and patients with homologous recombination deficiency (HRD)-positive tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety.ResultsOutcomes (95% CI) among all-treated, HRD-positive, and BRCA1/2-positive populations for cohort A1 were confirmed ORR: 10.3% (3.9–21.2) (n=58), 17.2% (5.8–35.8) (n=29), and 33.3% (7.5–70.1) (n=9); confirmed PSA50-RR: 11.9% (5.9–20.8) (n=84), 18.2% (8.2–32.7) (n=44), and 41.7% (15.2–72.3) (n=12); median rPFS: 4.9 (3.7–5.7) (n=88), 5.8 (3.7–8.4) (n=45), and 5.6 (2.8–15.7) (n=12) months; and median OS: 13.9 (10.4–15.8) (n=88), 15.4 (11.4–18.2) (n=45), and 15.2 (3.0–not estimable) (n=12) months. For cohort A2 they were confirmed ORR: 15.4% (5.9–30.5) (n=39), 25.0% (8.7–49.1) (n=20), and 33.3% (7.5–70.1) (n=9); confirmed PSA50-RR: 27.3% (17.0–39.6) (n=66), 41.9 (24.5–60.9) (n=31), and 84.6% (54.6–98.1) (n=13); median rPFS: 8.1 (5.6–10.9) (n=71), 10.9 (6.7–12.0) (n=34), and 10.9 (5.6–12.0) (n=15) months; and median OS: 20.2 (14.1–22.8) (n=71), 22.7 (14.1–not estimable) (n=34), and 20.2 (11.1–not estimable) (n=15) months. In cohorts A1 and A2, respectively, the most common any-grade and grade 3–4 treatment-related adverse events (TRAEs) were nausea (40.9% and 40.8%) and anemia (20.5% and 14.1%). Discontinuation rates due to TRAEs were 27.3% and 23.9%, respectively.ConclusionsNivolumab plus rucaparib is active in patients with HRD-positive postchemotherapy or chemotherapy-naïve mCRPC, particularly those harboring BRCA1/2 mutations. Safety was as expected, with no new signals identified. Whether the addition of nivolumab incrementally improves outcomes versus rucaparib alone cannot be determined from this trial.Trial registration numberNCT03338790.

291 Background: Combination systemic therapy with tyrosine kinase inhibitors (TKIs) and an immune checkpoint inhibitor (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We performed a phase I/II study to investigate the safety and efficacy combining the TKI axitinib (axi) with the IO agent nivolumab (nivo). Methods: This phase I/II study investigated the combination of axi and nivo in an initial dose finding phase I portion with a 3+3 design to determine the recommended phase 2 dose (RP2D) of axi. The phase II portion included 2 parallel arms: treatment naïve mRCC patients and mRCC patients previously treated with TKIs alone or IO/IO combination (NCT03172754). We are presenting results from the treatment naïve arm only. Included patients had to have histology with any clear cell component, ECOG performance status of 0-1, no known or symptomatic brain metastases, and no history of autoimmune disease. The RP2D of axi was 5 mg BID from the phase I portion and patients could be treated for up to 2 years. The primary endpoint of the phase II portion was objective response rate (ORR) per investigator assessment. Results: Forty-four patients were accrued to the treatment naïve arm. One withdrew consent and was replaced but is included in the safety analysis, while 42 patients are evaluable for efficacy. The median age was 65 yrs (range: 42-84 yrs) and the group was predominantly male (83.7%) and white (95.3%). Using the IMDC risk group grading, 18 patients (41.9%) were favorable risk, 22 patients (51.2%) were intermediate risk and 3 patients (7 %) were poor risk. Median follow-up was 11.5 months. Best response data is shown in the table and is notable for an ORR of 69.0%, with only 1 patient (2.4%) experiencing primary progressive disease, for a disease control rate of 97.6%. Median progression free survival was 16.4 months (95% CI: 10.6 - 21.9 mo), and median overall survival (OS) was not reached. OS at 12 months was 86.7%. Adverse event (AE) data was similar to published data for IO/TKI combinations, with no grade 4-5 AEs. Twenty-nine patients experienced a grade 3 AE (70.7%), the most common of which was hypertension, and 14.0% discontinued the study due to treatment-related toxicity. Conclusions: The combination of axi/nivo for treatment naïve patients with mRCC demonstrated efficacy comparable to available IO/TKI combinations with a similar safety profile. Clinical trial information: NCT03172754. [Table: see text]

A 30-year-old man with severe antenatal Bartter syndrome, diagnosed and treated in infancy, developed testicular carcinoma. Despite the known renal complications of cisplatin, this drug was used for his chemotherapy because of its superior antineoplastic effect. Nonsteroidal anti-inflammatory drug administration was continued during cisplatin therapy. Despite an increase in his oral potassium requirement, renal function was maintained following completion of chemotherapy. In spite of its significant associated nephrotoxicity, cisplatin can be used in patients with severe antenatal Bartter syndrome if required for therapy of malignancy.

BACKGROUND In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC). METHODS In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate. RESULTS Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group. CONCLUSIONS Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.

Purpose Clinical trials are critical to informing cancer care but often are hampered by slow accrual and lack of generalizability because of poor geographic accessibility. We tested the feasibility of replacing onsite study visits with telemedicine visits in a prospective clinical trial. Methods Castration-naïve patients with prostate cancer and a rising serum prostate-specific antigen after definitive local therapy were eligible. Patients were required to have a single onsite visit for enrollment. Study treatment consisted of oral metformin 850 mg daily for 1 month followed by 850 mg twice daily for 5 months. Telehealth video visits (televisits) were conducted monthly by using a Health Insurance Portability and Accountability Act–compliant smartphone application. The primary objective was to determine the feasibility of telemedicine-enabled study visits. Secondary objectives were defining safety, anticancer activity, quality of life, and patient satisfaction. Results Fifteen patients with a median age of 68 years (range, 57 to 83 years) and median one-way driving time to the study center of 71 minutes (range, 12 to 147 minutes) were enrolled. The patients completed 84 eligible televisits (completion rate, 100%; 95% CI, 0.80 to 1). Diarrhea was the most common adverse event but was limited to grade 1 in severity; a single patient experienced grade ≥ 3 adverse events. Seven patients (46.7%; 95% CI, 24.8% to 69.9%) had a ≤ 20% increase in prostate-specific antigen relative to baseline. Patients agreed or strongly agreed that they would participate in a telemedicine-enabled clinical trial in the future. Conclusion To our knowledge, this interventional oncology clinical trial is the first to be conducted through telemedicine. Telemedicine-enabled trials are feasible and may overcome geographic barriers to trial participation. Metformin was generally well tolerated but associated with modest anticancer activity.

e16542 Background: Immune checkpoint inhibitors (ICIs) are commonly used as first-line treatment for pts with advanced RCC. In the recent phase 3 CLEAR trial, LEN + PEMBRO showed improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) vs sunitinib in first-line treatment of advanced RCC (Motzer R et al. NEJM. 2021). Additional treatment options are needed for pts with disease progression on ICIs. A phase 1b trial of LEN + PEMBRO was performed in multiple tumor types and included an expansion part into a phase 2 cohort of ICI-pretreated, treatment-naïve, or previously treated ICI-naïve pts with metastatic RCC (NCT02501096). We report the final results of the RCC cohort with an extended follow-up. Methods: Eligible pts were ≥18 years old and had measurable disease. Efficacy analyses were conducted by prior therapy grouping. The primary endpoint was ORR at week 24 (ORRwk24) per immune-related (ir) RECIST by investigator assessment. Secondary endpoints included ORR, duration of response (DOR), PFS, OS, and safety. Exploratory endpoints included tumor response assessed per RECIST v1.1 by independent review committee (IRC). Subgroup analyses of the ICI-pretreated group will be included in the poster. Results: The recommended doses determined in phase 1b were LEN 20 mg daily + PEMBRO 200 mg once every 3 weeks (Taylor M et al. JCO. 2020). The study enrolled 145 pts (efficacy analysis, n=143; safety analysis, n=145). At data cutoff (August 18, 2020), the median follow-up time was 19.8 months. The ORRwk24 was 55.8% (95% CI 45.7–65.5) for ICI-pretreated pts (n=104), 72.7% (95% CI 49.8–89.3) for treatment-naïve pts (n=22), and 41.2% (95% CI 18.4–67.1) for previously treated ICI-naïve pts (n=17). The median OS for the previously treated ICI-naïve pts was 30.3 months and was not reached in the other groups. Additional efficacy analyses are shown in the table. Treatment-related adverse events occurred in 99.3% of pts; the most common were fatigue (58.6%), diarrhea (55.2%), and hypertension (40.0%). Most pts (69%) maintained the LEN starting dose or were reduced to LEN 14 mg daily (dose level −1). Conclusions: LEN + PEMBRO demonstrated promising antitumor activity with a manageable safety profile in pts with metastatic RCC, including pts who were ICI-pretreated. Clinical trial information: NCT02501096. [Table: see text]

5044 Background: CheckMate 9KD is a phase 2 trial of NIVO (anti-PD-1) combined with either rucaparib, docetaxel, or enzalutamide for mCRPC. PARP inhibitors, like rucaparib, increase cellular DNA damage, particularly in tumors with DNA repair defects, leading to genomic instability and cell death. This DNA damage promotes immune priming and adaptive PD-L1 upregulation. Consequently, dual PD-(L)1 and PARP inhibition is a plausible therapeutic strategy for mCRPC. We report final results for cohort A1 (NIVO + rucaparib for post-CT mCRPC) of CheckMate 9KD. Methods: Cohort A1 enrolled patients (pts) with post-CT mCRPC (1–2 prior taxane regimens), ongoing ADT, ≤ 2 prior novel hormonal therapies (abiraterone, enzalutamide, etc) for mCRPC, and no prior PARP inhibitor treatment. Pts received NIVO 480 mg Q4W + rucaparib 600 mg BID until disease progression/unacceptable toxicity (NIVO dosing limited to 2 yrs). Coprimary endpoints: objective response rate (ORR) per PCWG3 criteria and prostate-specific antigen response rate (PSA-RR; ≥ 50% PSA reduction) in all treated pts and pts with homologous recombination deficiency positive (HRD+) tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. Results: Of 88 treated pts, median age 66 yrs (range, 46–85), 34.1% had visceral metastases and 65.9% had measurable disease. Median follow-up was 11.9 mo. Pts had a median of 4.5 NIVO doses and 3.8 mo of rucaparib. The table summarizes primary and key secondary efficacy results, and shows better outcomes for HRD+ vs HRD–/not evaluable (NE) tumors. In pts with BRCA2 mutations, confirmed ORR was 37.5% (3/8 pts) and confirmed PSA-RR was 45.5% (5/11 pts). Any-grade treatment-related AEs (TRAEs) occurred in 93.2% of pts, most commonly nausea (40.9%) and fatigue (33.0%). Grade ≥ 3 TRAEs occurred in 54.5% of pts, most commonly anemia (20.5%) and neutropenia (10.2%). TRAEs led to discontinuation in 27.3% of pts. One pt had a stroke, considered related to rucaparib by the investigator, after 28 days on rucaparib and 2 NIVO doses and died 2 months later due to post-thrombolysis hematoma. Conclusions: NIVO + rucaparib is active in pts with HRD+ post-CT mCRPC, although the trial design and short follow-up limit assessment of benefits of the combination vs individual components. Pts with HRD– tumors did not appear to benefit from either drug. No new safety signals were observed with NIVO + rucaparib. Additional biomarker analyses are ongoing. Clinical trial information: NCT03338790. [Table: see text]

12 Background: CheckMate 9KD (NCT03338790) is a phase 2 trial of nivolumab (NIVO; anti-PD-1) in combination with rucaparib, docetaxel (DOCE), or enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC). DOCE is a standard-of-care chemotherapy for mCRPC that may potentiate antitumor immune responses, thus supporting its use in combination with NIVO, which has shown limited antitumor activity in mCRPC as monotherapy. We report final analysis results for Arm B (NIVO + DOCE) of CheckMate 9KD. Methods: Arm B enrolled patients with chemotherapy-naive mCRPC with ongoing androgen deprivation therapy and ≤ 2 prior novel antiandrogen therapies (NATs; i.e., abiraterone, enzalutamide, etc.). Patients received NIVO 360 mg + DOCE 75 mg/m2 Q3W + prednisone 5 mg BID for ≤ 10 cycles, followed by NIVO 480 mg Q4W until disease progression/unacceptable toxicity (up to 2 years). Coprimary endpoints were objective response rate (ORR) and prostate-specific antigen response rate (PSA-RR; defined as a ≥ 50% PSA reduction). Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. Results: Of 84 treated patients with a median age of 71 years (range: 53-88), 27% had visceral disease and 54% had measurable disease. The median number of docetaxel cycles was 8; the median number of nivolumab doses was 11. Median follow up was 15.2 months. The table displays the efficacy outcomes, which appear to show comparable ORR in patients receiving versus not receiving prior NAT. There was 1 (2.2%) complete objective response and 17 (37.8%) partial responses in 45 patients with measurable disease. Any-grade treatment-related AEs (TRAEs) occurred in 95.2% of patients, most commonly fatigue (39.3%), diarrhea (35.7%), and alopecia (34.5%). Grade 3-4 TRAEs occurred in 47.6% of patients, most commonly neutropenia (16.7%). TRAEs led to discontinuation in 29.8% of patients. The most common immune-related AEs were GI (35.7%) or skin-related (26.2%). There were 3 treatment-related deaths (1 pneumonitis related to NIVO; 2 pneumonias related to DOCE). Conclusions: NIVO + DOCE has encouraging clinical activity in patients with chemotherapy-naïve mCRPC, regardless of prior NAT, with a safety profile consistent with those of the individual agents. These outcomes support the ongoing phase 3 CheckMate 7DX trial of NIVO + DOCE vs placebo + DOCE for mCRPC (NCT04100018). Clinical trial information: NCT03338790. [Table: see text]

Purpose This trial assessed the efficacy and safety of docetaxel monotherapy or docetaxel in combination with ramucirumab (vascular endothelial growth factor receptor 2 antibody) or icrucumab (vascular endothelial growth factor receptor 1 antibody) after progression during or within 12 months of platinum-based regimens for patients with locally advanced or metastatic urothelial carcinoma. Patients and Methods Patients were randomly assigned (1:1:1) to receive docetaxel 75 mg/m2 intravenously (IV) on day 1 of a 3-week cycle (arm A), docetaxel 75 mg/m2 IV plus ramucirumab 10 mg/kg IV on day 1 of a 3-week cycle (arm B), or docetaxel 75 mg/m2 IV on day 1 plus icrucumab 12 mg/kg IV on days 1 and 8 of a 3-week cycle (arm C). Treatment continued until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression-free survival (PFS). Results A total of 140 patients were randomly assigned and treated in arms A (n = 45), B (n = 46), or C (n = 49). PFS was significantly longer in arm B compared with arm A (median, 5.4 months; 95% CI, 3.1 to 6.9 months v 2.8 months; 95% CI, 1.9 to 3.6 months; stratified hazard ratio, 0.389; 95% CI, 0.235 to 0.643; P = .0002). Arm C did not experience improved PFS compared with arm A (1.6 months; 95% CI, 1.4 to 2.9; stratified hazard ratio, 0.863; 95% CI, 0.550 to 1.357; P = .5053). The most common grade 3 or worse adverse events (arms A, B, and C) were neutropenia (36%, 33%, and 39%), fatigue (13%, 30%, and 20%), febrile neutropenia (13%, 17%, and 6.1%), and anemia (6.7%, 13%, and 14%, respectively). Conclusion The addition of ramucirumab to docetaxel met the prespecified efficacy end point for prolonging PFS in patients with locally advanced or metastatic urothelial carcinoma receiving second-line treatment and warrants further investigation in the phase III setting.

5008 Background: LEN, a multikinase VEGFR inhibitor, plus everolimus is approved for advanced RCC after prior VEGF-targeted therapy. PEMBRO, an anti-PD-1 antibody, plus axitinib is approved as first-line therapy of advanced RCC. We report phase 2 results of the RCC cohort of a phase 1b/2 trial (Study 111/KEYNOTE-146) of LEN + PEMBRO in patients (pts) who progressed after ICI therapy. Methods: We performed a multicenter, open-label study of pts with mccRCC, who previously had disease progression by RECIST (confirmed ≥ 4 weeks later) during or following ICI therapy. Pts had measurable disease by immune-related RECIST, and ≥ 1 prior therapy. Pts received LEN 20 mg orally once daily plus PEMBRO 200 mg IV every 3 weeks until disease progression or toxicity. Tumor assessments were performed every 6 weeks (until week 24), then every 9 weeks. The primary endpoint was objective response rate (ORR) at Week 24 by irRECIST. Results: 104 pts were enrolled. At data cutoff (January 12, 2020), 71 (69%) pts were still on study treatment. Most pts had ≥2 prior anticancer regimens (58%). 91 of 104 pts were evaluable for response at Week 12 (13 pts NE at Week 12); 46 of 91 pts achieved a confirmed partial response for an ORR of 51% (Table). Median progression-free survival (PFS) was 11.7 months and median duration of response (DOR) was 9.9 months. The most common treatment-related adverse events (TRAEs) were fatigue (49%), diarrhea (44%), proteinuria (37%), hypertension (31%), nausea (31%), dysphonia (29%), stomatitis (29%), and arthralgia (27%). There was 1 grade 5 TRAE (upper gastrointestinal hemorrhage). 43% of pts required dose reduction and 12% of pts discontinued treatment due to TRAEs. Response and safety data will be updated to include all pts evaluable at an April 9, 2020 cut-off. Conclusions: LEN + PEMBRO demonstrated promising antitumor activity in pts with mccRCC with disease progression following ICI therapy. No new safety signals were detected. Efficacy outcomes by investigator review per irRECIST. Clinical trial information: NCT02501096 . [Table: see text]

Background Lenvatinib (LEN) is a multikinase VEGFR inhibitor approved for use in combination with everolimus to treat advanced RCC after prior VEGF-targeted therapy. Pembrolizumab (PEMBRO) is an anti-PD-1 antibody. Here, we report results of an interim analysis of the RCC cohort of a phase II trial of LEN + PEMBRO, specifically in patients (pts) who progressed with prior immune checkpoint inhibitor (ICI) therapy. Methods This is a per-protocol interim analysis of a multicenter, open-label study for pts with mccRCC, ≥1 prior therapy, RECIST disease progression on or following an ICI regimen (confirmed ≥ 4 weeks later), measurable disease, and Eastern Cooperative Oncology Group performance status ≤ 1. Pts received LEN 20 mg/d PO plus PEMBRO 200 mg intravenously Q3W until disease progression or toxicity occurred. Tumor assessments were performed every 6 weeks (until week 24), then every 9 weeks. Results At data cutoff (March 29, 2019), the first 33 pts enrolled were followed for ≥12 weeks for response evaluation, and 24 (73%) pts were still on study treatment. The objective response rate was 52%, the disease control rate was 94%, and most pts had tumor shrinkage. Median follow-up time for progression-free survival was 4.2 months. Pt characteristics and efficacy outcomes are summarized in the table. The most common treatment-related adverse events were fatigue (49%), dysphonia (36%), diarrhea (33%), stomatitis (30%), hypertension (24%), dry mouth, nausea, proteinuria, and hand-foot syndrome (21% each). Three (9%) pts discontinued treatment due to adverse events. Conclusions For the subset of mccRCC pts with disease progression during or following ICI therapy, LEN + PEMBRO demonstrated promising antitumor activity. No new safety signals were detected. The study will continue to full cohort expansion. Table . 1187PD Summary of patient characteristics and efficacy outcomes Patient Characteristics, n (%) LEN + PEMBRO (n = 33) ECOG performance status 0 18 (54.5) 1 15 (45.5) Prior anticancer regimens 1 prior regimen 14 (42%) >1 prior regimen 19 (58%) Prior VEGF-targeted therapy 26 (78.8%) Prior ICI therapy 33 (100%) PD-1/PD-L1 monotherapy 14 (42.4%) with VEGF agents 9 (27.7%) nivolumab + ipilimumab 7 (21.2%) with other agents 2 (6.1%) PD-L1 positive 12 (36.4) * Investigator assessment of efficacy outcomes by irRECIST LEN + PEMBRO (n = 33) ORR, n (%) 95% CI 17 (51.5) 33.5–69.2 Median PFS (95% CI), months PFS rate, % (95% CI) at: 3 months 6 months 9 months NR (5.6–NR) 93.4 (76.1–98.3) 73.8 (45.7–88.9) 64.6 (34.5–83.5) Median DOR, (95% CI) months NR (4.2–NR) Median follow-up time for DOR, months 6.0 (1.4–7.0) Response duration > = 6 months, n (%) ** 80.8 (42.3–94.9) * 30.3% were negative and 33.3% were not available ** Response duration is based on Kaplan-Meier estimation with 95% CI based on the Greenwood formula using log-log transformation DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; irRECIST, immune-related Response Evaluation Criteria In Solid Tumors; NR, not reached; ORR, objective response rate; PD-L1, programmed death-ligand-1; PFS, progression-free survival; VEGF, vascular endothelial growth factor. Clinical trial identification NCT02501096; Release date: July 17, 2015. Editorial acknowledgement Tarah M. Connolly, PhD of Oxford PharmaGenesis, Newtown, PA, funded by Eisai Inc. Legal entity responsible for the study Eisai Inc. Funding Eisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure C. Lee: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Calithera; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Amgen. A.Y. Shah: Honoraria (self), Non-remunerated activity/ies, research: Eisai Inc.; Honoraria (self): Oncology Information Group; Non-remunerated activity/ies, research: EMD Serono; Non-remunerated activity/ies, research: Bristol-Myers Squibb. V. Makker: Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Eisai; Honoraria (self), Non-remunerated activity/ies: Merck; Non-remunerated activity/ies: Lilly; Honoraria (self), Non-remunerated activity/ies: Karyopharm; Non-remunerated activity/ies: Takeda; Non-remunerated activity/ies: Genentech. M.H. Taylor: Research grant / Funding (institution): BioAlta; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Array Biopharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: LOXO; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Blueprint; Honoraria (self), Advisory / Consultancy: Arquele; Honoraria (self), Advisory / Consultancy: Novartis. J.J. Hsieh: Honoraria (self): Eisai Inc. A. Pinto Marin: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: EUSA Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Clovis; Honoraria (self): Aveo. D.W. Rasco: Research grant / Funding (self): Eisai Inc.; Research grant / Funding (self): Merck. D.E. Stepan: Full / Part-time employment: Formerly of Eisai Inc. C.E. Dutcus: Leadership role, Full / Part-time employment: Eisai Inc. J. Wu: Full / Part-time employment: Eisai Inc. E.V. Schmidt: Full / Part-time employment: Merck & Co Inc. R.F. Perini: Full / Part-time employment: Merck & Co Inc. R.J. Motzer: Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Exelixis; Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self): Novartis; Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Merck; Advisory / Consultancy: Incyte. All other authors have declared no conflicts of interest.

Background The antitumor activity of programmed death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibition alone is limited in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Combining immunotherapy with standard-of-care chemotherapy could improve outcomes in mCRPC. We report interim analysis results for the nivolumab + docetaxel (NIVO+DOCE) treatment arm from CheckMate 9KD. Methods CheckMate 9KD is a phase II study of NIVO in combination with DOCE, rucaparib, or enzalutamide. Eligible pts had confirmed metastatic adenocarcinoma of the prostate, ongoing androgen deprivation therapy, and evaluable tumor biopsy. Pts assigned to NIVO+DOCE (chemotherapy-naive and received ≤2 prior second-generation hormonal therapies) received NIVO 360mg every 3 weeks + DOCE 75mg/m2 every 3 weeks + prednisone 5mg twice daily for ≤10 cycles followed by NIVO 480mg every 4 weeks alone until disease progression or unacceptable toxicity (up to 2 years). Coprimary endpoints were objective response rate (ORR) and prostate-specific antigen response rate (PSA-RR; defined as≥50% PSA reduction from baseline). Secondary endpoints included radiographic progression-free survival (rPFS), and safety/tolerability in all treated pts. Association of biomarkers with efficacy was an exploratory endpoint. Results This interim analysis included 41 pts in the NIVO+DOCE arm with a minimum follow-up of 28 weeks, of whom 19 (46.3%) had measurable disease. At the time of the analysis, 24 (58.5%) had discontinued study treatment. ORR in pts with measurable disease was 36.8% (95% confidence interval [CI], 16.3–61.6) with 1 complete response and 6 partial responses. Confirmed PSA-RR was 46.3% (95% CI, 30.7–62.6). Median rPFS was 8.2 months (95% CI, 6.6–not estimable). The 6-month rPFS rate was 71.5%. Any-grade and grade 3/4 treatment-related adverse events occurred in 92.7% and 48.8% of pts, respectively. Associations of biomarkers are also evaluated. Conclusions The combination of NIVO+DOCE showed encouraging clinical activity in pts with mCRPC, with a safety profile consistent with those of the individual agents. A phase III trial is warranted to further evaluate NIVO+DOCE in mCRPC. Clinical trial identification NCT03338790. Editorial acknowledgement Professional medical writing assistance was provided by Nicolette Belletier, PhD, of Parexel, and funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb and Ono Pharmaceutical Company Limited. Disclosure K. Fizazi: Advisory / Consultancy: Janssen; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: Orion. A. Rezazadeh Kalebasty: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Exelexis; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AZ; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Macrogenics; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Beyond Spring; Research grant / Funding (institution): Bioclin/Rainier Therapeutics; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Bavarian; Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Seattle Genetics; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Shareholder / Stockholder / Stock options: ECOM; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Speaker Bureau / Expert testimony: Amgen; Travel / Accommodation / Expenses: Prometheus Labs. J.C. Vazquez Limon: Non-remunerated activity/ies, Personal Fees and non-financial support: AstraZeneca; Non-remunerated activity/ies, Non-financial support: Merck; Non-remunerated activity/ies, Personal fees: Roche; Non-remunerated activity/ies, Personal fees: Bristol-Myers Squibb. A.J. Armstrong: Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Pfizer/Astellas; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Dendreon; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Byer; Research grant / Funding (institution): Constellation; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Clovis. B. Sharkey: Full / Part-time employment: Bristol-Myers Squibb. A. Saci: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. J. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. X. Wang: Full / Part-time employment: Bristol-Myers Squibb. M. Ciprotti: Full / Part-time employment: Bristol-Myers Squibb. P. Sathyanarayana: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. F. Saad: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer. D.P. Petrylak: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Bellicum; Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Endocyte ; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ferring; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Innocrin; Advisory / Consultancy, Research grant / Funding (institution): Johnson and Johnson; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Millineum; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Progenics; Research grant / Funding (institution): Roche Labatories; Advisory / Consultancy, Research grant / Funding (institution): Sanofi Aventis; Research grant / Funding (institution): Sotio; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Tyme Pharmaceuticals. R.K. Pachynski: Advisory / Consultancy, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony: Dendreon; Advisory / Consultancy: EMD Serono/Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genomic Health; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy: Jounce Therapeutics. C. Drake: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Compugen; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): Janssen Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Astellas Medivation; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tizona Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: F-Star; Advisory / Consultancy, Shareholder / Stockholder / Stock options: KLEO; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Harpoon; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Shattuck Labs; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Werewolf; Advisory / Consultancy: Genocea; Advisory / Consultancy: Sanofi Aventis; Advisory / Consultancy, Licensing / Royalties: Amplimmune; Advisory / Consultancy, Licensing / Royalties: BMS; Advisory / Consultancy: EMD. All other authors have declared no conflicts of interest.

The effects of mammalian target of rapamycin (mTOR) inhibition are limited by feedback reactivation of receptor tyrosine kinase signaling in phosphatase and tensin homolog-null tumors. Thus, this study tested the combination of mTOR inhibition (everolimus) and epidermal growth factor receptor inhibition (gefitinib) in castration-resistant prostate cancer (CRPC).

Background Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle–drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. Patients and methods Patients with mRCC and 2–3 prior lines of therapy were randomized 1:1 to CRLX101 + bevacizumab versus SOC, defined as investigator’s choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. Results In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0–4.3) and 3.9 months (95% confidence interval 2.2–5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel–Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. Conclusions Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. Clinical trial identification NCT02187302 (NIH).

TPS498 Background: Combination therapy with agents targeting molecular and cellular mechanisms of CIT resistance is a rational approach to restoring CIT efficacy in patients (pts) with immunotherapy-resistant UC. Sitravatinib is a tyrosine kinase inhibitor (TKI) that targets multiple closely-related receptor tyrosine kinase (RTK) pathways, including the split RTKs VEGFR-2 and KIT, as well as the TAM (TYRO3, AXL, and MER) RTKs. Inhibition of the split RTKs enhances antitumor activity by reduction of immunosuppressive regulatory T cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME). Inhibition of TAM RTKs further restores a more immune-supportive TME by depletion of MDSCs and repolarization of tumor-associated macrophages to the M1 phenotype associated with secretion of pro-inflammatory cytokines. Given these pleiotropic immune-activating effects, the combination of sitravatinib with nivolumab is a rational approach to restoring or enhancing CIT clinical activity in pts with immunotherapy-resistant UC. This combination has been shown to be safe and tolerable in an ongoing Phase 2 study in pts with metastatic non-small cell lung cancer. Methods: This open-label Phase 2 study evaluates tolerability and clinical activity of sitravatinib in combination with nivolumab in pts with advanced or metastatic UC who experienced disease progression on or after CIT as the most recent systemic therapy. Enrollment is stratified by prior receipt of platinum-based chemotherapy. If the initial 2 cohorts are of high interest for efficacy, the protocol allows for addition of new cohorts to include pts previously treated with selected immunotherapies (anti-CTLA-4, anti-OX40 or anti–CD137 therapy) or who are CIT-naïve. The primary objective is Objective Response Rate. A Predictive Probability Design will be applied allowing for expansion to 40 pts per cohort. Sitravatinib is administered orally daily in continuous 28-day cycles at 120 mg; nivolumab intravenously at 240 mg every 2 weeks or 480 mg every 4 weeks. Status: The study is open for enrollment and recruitment is ongoing. Clinical trial information: NCT03606174.

The burden of providing informal care to a family member can lead to caregiver depression and potentially harmful caregiving behavior. Given the interpersonal nature of caregiving, the relationship between caregivers and care recipients may impact caregiver responses. We applied attachment theory to understanding caregiver depression, and both potentially harmful and exemplary caregiving responses. We present data from 430 caregivers in the Family Relationships in Late Life (FRILL 2) Project, a multi-site, longitudinal study of caregiving. Age, gender, and model of self were related to caregiving responses, suggesting that model of self may help identify caregivers at risk for poor responses.

TPS3126Background: Although multiple new agents have been approved for mCRPC over the last decade, median survival remains unsatisfactory at ~12-35 months. Immunotherapy targeted solely at programm...

187 Background: In the past decade, several therapies have been approved for mCRPC. However, most pts develop resistance and experience disease progression. Thus, there remains a high unmet need. Atezo (anti–PD-L1) blocks the interaction between PD-L1 and its receptors, PD-1 and B7.1, thereby restoring anti-tumor immunity. Atezo has demonstrated clinical efficacy in many tumor types. Here we report the clinical safety and activity of atezo in pts with mCRPC from a Phase Ia study (PCD4989g; NCT01375842). Methods: Eligible pts previously received enzalutamide and/or sipuleucel-T for mCRPC. Pts also had PSA or radiographic progression prior to enrollment. Atezo 1200mg was administered IV q3w. CT and bone scans were performed q6w for 24w and q12w thereafter (q6w if treatment beyond disease progression). Primary objectives were safety and tolerability; OS was an exploratory objective. mCRPC cohort–specific objectives included PSA response, radiographic progression per PCWG2 criteria, soft tissue response per RECIST v1.1 and immune-related response criteria (irRC). Survival follow-up data was collected ≈ every 3 mo until death or loss to follow-up. Results: The 15 pts in the initial mCRPC cohort were evaluated (clinical cutoff: December 31, 2016). 13 pts (87%) had received ≥ 2 prior lines of therapy for mCRPC. Median survival follow-up was 15.8 mo (range, 2.3-23.0). 9 pts (60%) had a treatment-related AE (TRAE); only 1 pt (7%) experienced a Gr 3 TRAE (hyponatremia). No Gr 4-5 TRAEs were reported. The landmark 12-mo OS rate was 55.6% (95% CI: 27.4, 83.7); median OS was not reached (range, 2.3-23.0 mo). Median PFS was 3.4 mo (95% CI: 2.3, 5.7); the 6-mo PFS rate was 26.7% (95% CI: 4.3, 49.1). 1 pt (9%) had a PR per irRC (irPR); 5 pts (45%) had SD per RECIST v1.1 and irRC. 2 pts (13%) had a ≥ 50% decrease in PSA from baseline. The pt who experienced an irPR had increased CD8 expression and expansion of T-cell clones on study treatment. Conclusions: Atezo was well tolerated and demonstrated long-term disease control in pts with heavily pretreated mCRPC, with a 12-mo OS rate of 55.6%. Preliminary biomarker analyses from the pt who experienced an irPR were suggestive of an activated immune response. Clinical trial information: NCT01375842.

Twenty-two patients with recurrent glioblastoma (GBM) were prospectively treated with everolimus and gefitinib, designed to test the combined inhibition of mammalian target of rapamycin (mTOR) and epidermal growth factor receptor (EGFR) as part of a larger clinical trial. The primary endpoint was radiographic response rate. Secondary endpoints included progression-free survival and correlation of molecular profiles with treatment response. 36% of patients had stable disease and 14% a partial response; however, responses were not durable and only one patient was progression-free at six months. Radiographic changes were not well characterized by conventional response criteria, and implied differential effects of therapy within the tumor and/or antiangiogenic effects. EGFR and PTEN status did not clearly predict response to treatment.

Purpose: To evaluate a new measure assessing excellent, or exemplary, informal care—an aspect of caregiving that has received little attention. The Exemplary Care Scale (ECS) was developed on the basis of insights from previous research with items generated by the authors in consultation with a multidisciplinary research team. Design: 310 informal caregivers and 283 of their elderly care recipients completed the ECS and other measures pertaining to quality of care and its presumed correlates. Results: Factor analyses indicated that the ECS consists of 2 factors reflecting provision of exceptional care (Provide) and respect for care recipient autonomy, wishes, and the like (Respect). The ECS factor structure was equivalent among caregivers and care recipients. Both factors were empirically distinct from existing measures of poor quality and adequate care. Each ECS factor was associated with other care-related constructs in predictable ways, implying construct validity. Conclusions: The ECS, in conjunction with existing measures, provides a more comprehensive assessment of the quality-of-care continuum and should prove useful to researchers and practitioners interested in quality of informal care provided to chronically ill or disabled people.

Purpose: To better direct targeted therapies to the patients with tumors that express the target, there is an urgent need for blood-based assays that provide expression information on a consistent basis in real time with minimal patient discomfort. We aimed to use immunomagnetic-capture technology to isolate and analyze circulating tumor cells (CTC) from small volumes of peripheral blood of patients with advanced prostate cancer. Experimental Design: Blood was collected from 63 patients with metastatic prostate cancer. CTCs were isolated by the Cell Search system, which uses antibodies to epithelial cell adhesion marker and immunomagnetic capture. CTCs were defined as nucleated cells positive for cytokeratins and negative for CD45. Captured cells were analyzed by immunofluorescence, Papanicolau staining, and fluorescence in situ hybridization. Results: Most patients (65%) had 5 or more CTCs per 7.5 mL blood sample. Cell counts were consistent between laboratories (c = 0.99) and did not change significantly over 72 or 96 h of storage before processing (c = 0.99). Their identity as prostate cancer cells was confirmed by conventional cytologic analysis. Molecular profiling, including analysis of epidermal growth factor receptor (EGFR) expression, chromosome ploidy, and androgen receptor (AR) gene amplification, was possible for all prostate cancer patients with ≥5 CTCs. Conclusions: The analysis of cancer-related alterations at the DNA and protein level from CTCs is feasible in a hospital-based clinical laboratory. The alterations observed in EGFR and AR suggest that the methodology may have a role in clinical decision making.

The effects of mammalian target of rapamycin (mTOR) inhibition are limited by feedback reactivation of receptor tyrosine kinase signaling in phosphatase and tensin homolog-null tumors. Thus, this study tested the combination of mTOR inhibition (everolimus) and epidermal growth factor receptor inhibition (gefitinib) in castration-resistant prostate cancer (CRPC).In phase 1, 12 patients (10 with CRPC and 2 with glioblastoma) received daily gefitinib (250 mg) with weekly everolimus (30, 50, or 70 mg). In phase 2, 27 CRPC patients received gefitinib with everolimus (70 mg).Phase 1 revealed no pharmacokinetic interactions and no dose-limiting toxicities. In phase 2, 18 of 27 patients (67%) discontinued treatment before the 12-week evaluation because of progression as evidenced by prostate-specific antigen (PSA) levels (n = 6) or imaging (n = 5) or because of a grade 2 or higher toxicity (n = 7). Thirteen of the 37 CRPC patients (35%) exhibited a rapidly rising PSA level after they had begun treatment, and this declined upon discontinuation. Fluorodeoxyglucose positron emission tomography 24 to 72 hours after the initiation of treatment showed a decrease in the standardized uptake value consistent with mTOR inhibition in 27 of the 33 evaluable patients (82%); there was a corresponding rise in PSA in 20 of these 27 patients (74%).The combination of gefitinib and everolimus did not result in significant antitumor activity. The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data showing that phosphoinositide 3-kinase (PI3K) pathway signaling feedback inhibits the androgen receptor (AR). This clinical evidence of relief of feedback inhibition promoting enhanced AR activity supports future studies combining PI3K pathway inhibitors and second-generation AR inhibitors in CRPC.

This study tested a model that specifies that the psychosocial impact of women’s precollege sports participation depends on the quality of their sports experience, that is, on participants’ enjoyment of sports and the benefits derived from athletic pursuits. A sample of 245 college women (mean age = 19.9 years) provided retrospective reports of their precollege sports involvement as well as assessments of their enjoyment of sports, perceived physical competence, body image, gender role orientation, and self-esteem. Consistent with past research, women students’ precollege sport participation was a modest predictor of their self-esteem in bivariate analyses. Follow-up analyses revealed that enjoyment of sports mediated the sports participation/self-esteem relationship and implied that female participants who find sports less enjoyable may be at risk of experiencing declining self-esteem. However, enjoyment of sports explained little unique variance in global self-esteem after we controlled for the influence of other sports-related benefits (e.g., improved physical competence). Implications for those who hope to help more girls reap psychosocial benefits from sporting activities are discussed.

The interaction between stromal cells and tumor cells is emerging as a critical aspect of tumor progression. Yet there is a paucity of molecular markers for cells participating in such interactions, and only few genes are known to play a critical role in this process. Here, we describe the identification of ADAM12 (a disintegrin and metalloprotease 12) as a novel marker for a subpopulation of stromal cells that are adjacent to epithelial tumor cells in three mouse carcinoma models (models for prostate, breast and colon cancer). Moreover, we show that ADAM12 is essential for tumor development and progression in the W10 mouse model for prostate cancer. These results suggest that ADAM12 might be a useful marker for stromal cells in mouse tumors that are likely to participate in stromal/tumor cell crosstalk, and that ADAM12 is a potential target for design of drugs that prevent carcinoma growth.

ADAM9 is a membrane-anchored metalloprotease that is markedly up-regulated in several human carcinomas. Here, we show that ADAM9 is similarly up-regulated in mouse models for prostate, breast, and intestinal carcinoma. To assess whether ADAM9 is critical for the pathogenesis of prostate carcinoma, one of the most common cancers in men, we evaluated how loss of ADAM9 affects tumorigenesis in W10 mice, a mouse model for this disease. In the absence of ADAM9, most tumors in 50-week-old W10 mice were well differentiated, whereas littermate controls expressing wild-type ADAM9 had predominantly poorly differentiated, and in some cases significantly larger, tumors. Moreover, gain-of-function experiments in which ADAM9 was overexpressed in mouse prostate epithelium resulted in significant abnormalities, including epithelial hyperplasia at 4 to 6 months of age, and prostatic intraepithelial neoplasia after 1 year. A potential underlying mechanism for the role of ADAM9 in prostate cancer emerged from cell-based assays: ADAM9 can cleave and release epidermal growth factor and FGFR2iiib from cells, both of which have pivotal functions in the pathogenesis of this disease. Taken together, these results suggest that ADAM9 contributes to the pathogenesis of prostate cancer and potentially also other carcinomas, raising the possibility that ADAM9 might be a good target for antitumor drugs.

The mean-Gini framework has been suggested as a robust alternative to the portfolio approach to futures hedging given its optimality under general distributional conditions. However, calculation of the Gini hedge ratio requires estimation of the underlying price distribution. We estimate minimum-Gini hedge ratios using two widely-used estimation procedures, the empirical distribution function method and the kernel method, for three emerging market and three developed market currencies. We find that these methods yield different Gini hedge ratios. These differences increase with risk aversion and are statistically significant for all developed market currencies but only one emerging market currency. In-sample analyses show that the empirical distribution function method is more effective at risk reduction than the kernel method for developed market currencies, whereas the kernel method is superior for emerging market currencies. Post-sample analyses strengthen the superiority of the empirical distribution function method for developed market and, in several cases, for emerging market currencies.

This study assessed the merits of an amended Interpersonal Exchange Model of Sexual Satisfaction (IEMSS; Lawrance & Byers, 1992, 1995) that includes a measure of relationship communality, a construct not adequately captured by existing exchange models of sexual/relationship satisfaction. A total of 189 undergraduates (102 female) in sexually active dating relationships completed measures of sexual satisfaction, relationship satisfaction, favorability of sexual exchanges, and the extent to which their romantic relationships were characterized by mutually communal behaviors (i.e., relationship communality). Analyses revealed that relationship communality made a small but unique contribution to sexual satisfaction and a large contribution to relationship satisfaction, even after controlling for sexual satisfaction and favorability of sexual exchanges. Implications for understanding the dynamics of sexually active dating relationships are discussed.

This study examines the performance of short and long hedgers using four stock index futures contracts traded at the Taiwan Futures Exchange. We compare the optimal hedge ratios and resulting hedge performances based on three risk measures: variance, extended Gini, and lower partial moment. We find that long hedgers achieve greater hedging performance than short hedgers for both the minimum-extended Gini and minimum-lower partial moment hedge ratios. These results are observed in both in-sample and post-sample analyses. We also find that the minimum-extended Gini hedge ratio dominates the lower partial hedge ratio in terms of post-sample hedging performance.

Reduced p27 levels correlate with poor prognosis in a wide spectrum of human tumors and can accelerate tumorigenesis in mouse tissues. To determine whether p27 deficiency can accelerate tumorigenesis in tissues with inactive Rb and p53 pathways, we examined the effect of p27 status on prostate tumorigenesis in mice expressing simian virus 40 large T antigen (LT). In p27-deficient mice expressing LT, tumors progressed from high-grade prostatic intraepithelial neoplasia to poorly differentiated carcinoma at a greatly accelerated rate. p27 deficiency could not collaborate with a mutant of LT that fails to inactivate the Rb pathway alone. Furthermore, p27 deficiency does not increase the proliferation index, reduce the apoptotic index, or affect the expression of E2F-dependent genes in cells expressing LT at any stage of the disease. Expression of LT alone leads to maximal proliferation, but p27 deficiency still increases the amount of cyclin A and cyclin-dependent kinase 2-associated kinase activity in tissues. Interestingly, this model recapitulates an important feature of the human disease, specifically a high frequency of allelic loss of chromosome 16q, which is syntenic to mouse chromosome 8. Loss of heterozygosity may accelerate the inactivation of other tumor suppressors, such as E-cadherin, which are located in this interval. These experiments provide direct physiological and causal evidence that p27 has tumor suppressive functions independent of its role regulating cell proliferation.

This paper compares the hedging performance of the minimum‐extended Gini hedge ratio (MEGHR) and the minimum‐variance hedge ratio (MVHR) using three emerging market currencies. The MEGHR is consistent with the expected utility hypothesis under very general conditions, unlike the MVHR which requires special distributional assumptions. Our sample violates these conditions, and thus provides a context for contrasting the performance of the MEGHR and MVHR. Our results show that the MVHR and MEGHR are indeed different and in some cases the differences are substantial, both statistically and in order of magnitude. This indicates that the MEGHR should provide superior hedging performance given its theoretical robustness. Our hedging performance results support this conclusion for all currencies.

Past research suggests that US stock market volatility was greater during the 1930s than in any other 10-year time period and the post-WWII era is a period of relative stability, despite slightly higher volatility levels during the 1970s and 1980s. More recent evidence suggests that volatility levels from 1998 to 2001 have more in common with 1930s levels than with any other time period. We extend this body of research to include the volatility experiences of seven equity markets in the US, Europe, and Asia. For each market, we compare the average monthly volatility of each five-year period, beginning with January 1923, with that for the most recent period in the study, January 1998 to August 2001. We find that when there are statistical differences between current and past levels of volatility, recent volatility is usually significantly greater than past volatility. In only a small number of cases do we find current volatility to be less than past volatility. This suggests that the 1998–2001 period was unusually volatile for most markets examined. We also find that volatility behavior tends to be country-specific and cannot be generalized on an aggregate basis.

In a test of the assumed dissimilarity/revulsion (AD/R) model of homophobia, 58 heterosexual males who differed in homophobia participated in an acquaintanceship exercise with a male partner who self-disclosed, midway through the exercise, that his sexual orientation was homosexual or heterosexual. As predicted by the AD/R model, (1) participants high in homophobia became less emotionally invested in their self-disclosures after learning of a homosexual partner's sexual orientation, whereas those low in homophobia disclosed with more emotion over time; (2) participants high in homophobia interacting with a homosexual partner reported more negative affect stemming from the acquaintanceship exercise, evaluated their partner less favorably and indicated greater desired and actual social distancing from their partner than did participants in the remaining three conditions; and (3) the relatively negative behavioral/evaluative responses of participants high in homophobia to homosexual (but not heteros...

Despite high response rates and palliative clinical benefits, androgen ablation does not cure advanced prostate cancer because of the inevitable emergence of resistant cells. Many new therapies under development for prostate cancer target pathways and molecules that contribute to the growth and survival of these cells. The rational and effective use of targeted therapies to eradicate resistant populations of tumour cells should be grounded on the premise that prostate cancer is a dynamic disease that evolves as it progresses, and that specific molecular determinants mediating sensitivity and resistance may be relevant only during specific states of the disease. Directed approaches must account for this changing dynamic so that clinical outcomes may be improved.

This study compares minimum‐extended Gini hedge ratios estimated by the rank‐based method of Lerman and Yitzhaki and a nonparametric kernel method. The rankbased method is more prevalent in the Gini hedging literature, however, the kernel estimator provides a more powerful approach to estimation. The empirical results show that the hedge ratios calculated using these two methods are different for all levels of risk aversion, and that rank‐based hedge ratios are typically larger than those estimated using the kernel method. Moreover, the differences tend to be larger at moderate and high levels of risk aversion and smaller at lower levels. Statistical evidence shows that the hedge ratios are highly statistically different for three of the five commodities tested. However, despite these differences, we find no differences in hedging performance.

In an initial experiment, men and women with varied gender-role orientations evaluated gender-stereotyped and nonstereotyped advertisements for “gendered” products that are actually used by both sexes. Consistent with a gender-role congruence model of advertising effectiveness, traditional participants (masculine men; feminine women) responded more favorably to traditional (i.e., gender-stereotyped) than to nontraditional advertisements, whereas nontraditional participants (androgynous individuals; feminine men; masculine women) reacted somewhat more favorably to the nontraditional advertisements. Experiment 2 revealed that when encouraged to self reference, traditional participants became much more responsive to nontraditional advertisements, even more so than were the nontraditional participants. Practical implications of these results are discussed.

In a sample of 59 chronically ill pediatric patients and their maternal caregivers, both child-reported pain and caregiver-reported depression predicted child-reported depression. Results further suggested that the association between pain and depression in children is ameliorated by caregiver coping strategies and that how caregivers cope is a function of their attachment-related representations of the self and others. Caregivers with a negative model of the self were more depressed, and those with a negative model of others were more prone to use avoidant coping strategies, and, in turn, to be more depressed. However. the extent to which caregivers with negative models of self used more avoidant and less approach coping appeared to depend on whether they perceived that others were likely to respond to their needs.

This paper empirically compares two multiperiod hedging strategies—a strip hedge and a stack-and-roll hedge—to hedge a forward commitment. The multiperiod strip hedge is found to outperform the stack-and-roll hedge when forward prices are subject to multiple sources of price uncertainty and to perform no better when only one source of uncertainty is present. Moreover, the relative superiority of the strip hedge increases with the presence of multiple sources of uncertainty. Last, the strip hedge is found to be more costly to trade than the stack-and-roll hedge; however, its cost varies directly with its superiority at reducing risk.

243 Background: Clinical trials are critical to informing cancer care but are hampered by slow accrual and suboptimal generalizability, both contributed to by poor geographic accessibility. We previously reported that > 50% of the US population resides > 1 hour from the nearest PCa clinical trial site (Galsky, JAMA Int Med, 2015). We sought to test the feasibility of replacing on-site study visits with telemedicine visits in a prospective clinical trial. Methods: Castration-naïve non-metastatic pts with PCa and a rising PSA after local therapy were eligible. Pts required a single on-site visit for enrollment. Treatment consisted of metformin 850 mg QD x 1 month followed by 850 mg BID x 5 months. Telemedicine visits were conducted monthly using a HIPAA-compliant smartphone application. The primary objective was to determine feasibility defined as completion of all eligible telemedicine visits by > 2/3 enrolled pts; pts were ineligible for future telemedicine visits if treatment discontinued early for toxicity or disease progression. Secondary objectives included safety, % patients with ≤ 20% PSA rise at 6 months, quality of life, and patient satisfaction. Results: 15 pts were enrolled, median age 68 (range, 57, 83), one-way driving time 1.3 hours (range, 0.2-2.8), Gleason score 7 (range, 6, 9), and pre-study PSA 4.1 (range, 0.52, 31.7). The 6 month course of metformin was completed by 11/15 (73%) pts; 2 discontinued early due to rising PSA, 1 due to adverse event (AE), and 1 remains on study. Excluding 1 pt still on study, 14/14 (100%; 95% CI 76, 100) pts completed all 78 eligible telemedicine visits. The most common AEs were diarrhea (grade 1 = 60%) and fatigue (grade 1 = 20%); 1 pt experienced grade ≥ 3 AE (dehydration). The 6-month PSA was ≤ 20% baseline in 1 pt; median % PSA change at last televisit was +52.8% (range, -3.0, +318.8). Quality of life and pt satisfaction will be reported at the meeting. Conclusions: To our knowledge, this is the first ever interventional oncology clinical trial conducted via telemedicine. Telemedicine-enabled trials are feasible and may overcome barriers to trial participation. Metformin was generally well tolerated but associated with minimal anti-PCa activity as measured by PSA. Clinical trial information: NCT02376166.

Structured interview data from 142 caregivers (98 wives, 44 husbands) indicate that more depressed caregivers are more likely to treat their spouses in potentially harmful ways. However, consistent with hypotheses derived from communal relationships theory, when the preillness relationship between caregiver and care recipient was characterized by mutual responsiveness to each other's needs (i.e., was more communal), caregivers were less depressed and less frequently engaged in potentially harmful behaviors. These effects were not attributable to demographic factors, amount of care provided, care recipient dementia status, or length of time in the caregiving role. Rather, multivariate analyses suggest that the extent to which premorbid relationships were communal in nature determines whether caregivers perceive their current relationships as rewarding, which, in turn, predicts caregiver depression and potentially harmful behaviors.

One hundred twenty participants functioned as mock-jurors and as members of deliberating juries in an experiment designed to assess the impact of dispositional instruction on verdicts rendered in an insanity trial. Consistent with prior research (K. E. WhittemoreJ. R. Ogloff, 1995), dispositional instruction had no effect on the verdict preferences of individual jurors prior to deliberating. Yet, as expected, the instruction manipulation had a major impact on postdeliberative decisions (i.e., group verdicts; individual juror verdict preferences). Content analyses of jury deliberations revealed that postdeliberative shifts toward harsh verdicts in uninstructed juries and toward lenient verdicts in instructed juries were mediated by the impact of the Instruction manipulation on the content of jury deliberations: uninstructed juries feared that an acquitted-insane defendant would be freed to act again, whereas instructed juries recognized that finding for an insane defendant implied his retention and treatment. Implications of these results for both legal policy and the conduct of mock-trial research are discussed.