Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas.

BACKGROUND: SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. METHODS: SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. RESULTS: A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. CONCLUSIONS: SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. TRIAL REGISTRATION NUMBER: NCT02376699.

Outpatient administration of paclitaxel, ifosfamide, and cisplatin (TIP) for germ cell tumor.

PURPOSE: The combination of paclitaxel, ifosfamide, and cisplatin (TIP) is frequently used for the treatment of metastatic germ cell tumors. Due to complex supportive care and infusion requirements, TIP is typically given in the inpatient setting. This analysis describes the development and implementation of a protocol for complete outpatient administration of TIP chemotherapy. METHODS: From July 2020 to June 2021, adults receiving TIP for germ cell tumor at University of Michigan Rogel Cancer Center were evaluated for outpatient administration. The primary outcome was number of inpatient bed days saved by giving outpatient TIP chemotherapy, with the goal of giving 75% of TIP cycles outpatient. Patients receiving outpatient TIP were also assessed for chemotherapy dose reduction or delays and acute toxicities of kidney injury, encephalopathy, and hemorrhagic cystitis. RESULTS: From July 2020 to July 2021, three patients received 13 cycles of TIP. Ten cycles (77%) were administered in the outpatient setting, resulting in a savings of 50 inpatient bed days in one year. No patients required a dose reduction or delay in chemotherapy or experienced acute kidney injury, encephalopathy, or hemorrhagic cystitis during outpatient TIP treatment. CONCLUSION: Despite logistic and supportive care challenges, TIP can be administered completely in the outpatient setting.

First-in-Human Study of INCB062079, a Fibroblast Growth Factor Receptor 4 Inhibitor, in Patients with Advanced Solid Tumors.

INTRODUCTION: Fibroblast growth factor receptor (FGFR)-4/FGF19 pathway dysregulation is implicated in hepatobiliary and other solid tumors. INCB062079, an oral, selective, FGFR4 inhibitor, inhibits growth in FGF19/FGFR4-driven liver cancer models. METHODS: This was a two-part, phase I study (NCT03144661) in previously treated patients with advanced solid tumors. The primary objective was to determine safety, tolerability, and maximum tolerated dose (MTD), while secondary objectives included pharmacokinetics, pharmacodynamics (plasma FGF19; bile acid salts/7α-hydroxy-4-cholesten-3-one [C4] levels), and preliminary efficacy. In Part 1, patients received INCB062079 starting at 10 mg once daily, with 3 + 3 dose escalation. Part 2 (dose expansion) was not conducted because of study termination. RESULTS: Twenty-three patients were treated (hepatobiliary, n = 11; ovarian, n = 9; other, n = 3). Among six patients receiving 15 mg twice daily, two patients had dose-limiting toxicities (DLTs; grade 3 diarrhea, grade 3 transaminitis). Both had high pretreatment C4 concentrations, prompting a protocol amendment requiring pretreatment C4 concentrations < 40.9 ng/mL and concomitant prophylactic bile acid sequestrant treatment. No additional DLTs were reported at 10 and 15 mg twice daily; higher doses were not assessed. The most common toxicity was diarrhea (60.9%). INCB062079 exposure was dose-proportional; FGF19 and bile acid/C4 concentrations increased with exposure. One partial response was achieved (15 mg twice daily; ovarian cancer; FGF/FGFR status unknown; duration of response, 7.5 months); two patients had stable disease. CONCLUSIONS: With C4 cut-off and prophylactic bile acid sequestrant implementation, INCB062079 demonstrated a manageable safety profile and evidence of target inhibition. In view of the rarity of FGF19/FGFR4 alterations and slow patient accrual, the study was terminated before establishing an MTD.

Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab.

PURPOSE: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. PATIENTS AND METHODS: Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. RESULTS: Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. CONCLUSION: Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

A Phase 2 Trial of Nab-paclitaxel in Combination With Anti-PD1 Therapy in Advanced Urothelial Cancer.

PURPOSE: Immune checkpoint inhibitor therapy and nab-paclitaxel have each shown efficacy in platinum-refractory advanced urothelial cancer. We conducted a single-arm phase 2 trial of the combination of nab-paclitaxel and pembrolizumab in platinum-refractory or cisplatin-ineligible advanced urothelial cancer (NCT03240016). MATERIALS AND METHODS: Eligible patients had RECIST 1.1 measurable and cisplatin-ineligible or platinum-refractory advanced urothelial cancer. Patients received nab-paclitaxel at starting dose of 125 mg/m2 intravenously on days 1 and 8 and pembrolizumab 200 mg intravenously on day 1 in 21-day cycles until progression, intolerable toxicity, or death. Nab-paclitaxel was permitted to be discontinued after 6 cycles. The nab-paclitaxel starting dose was reduced to 100 mg/m2 after planned interim analysis. Primary end point was overall response rate by RECIST 1.1. Secondary end points included safety/toxicity, duration of response, progression-free survival), and overall survival. RESULTS: Between February 2018 and April 2021, 36 response-evaluable patients were enrolled. There was an equal split of platinum-refractory and cisplatin-ineligible patients. Confirmed overall response rate was 50.0% (18/36) including 3 complete and 15 partial responses; 31/36 patients experienced some tumor shrinkage. At a median follow-up of 19.7 months, median duration of response was 4.4 months (95% CI: 4.0-8.6), median progression-free survival 6.8 months (95% CI: 4.4-not reached), and median overall survival 18.2 months (95% CI: 10.6-not reached). Grade ≥3 adverse events occurred in 21/36 patients including fatigue (n=6) and anemia (n=4). Ten patients had immune-mediated adverse events. CONCLUSIONS: The combination of nab-paclitaxel and pembrolizumab exhibited promising activity in advanced urothelial cancer and warrants further study in this population. After reduction in nab-paclitaxel starting dose, no unanticipated or unexpected toxicities emerged.

Prostate Cancer With Peritoneal Carcinomatosis: A Robotic-assisted Radical Prostatectomy-based Case Series.

OBJECTIVE: To aid in the diagnosis and treatment of patients with metastatic tumor seeding, an exceedingly rare phenomenon following minimally invasive urological surgery, additional case reports are needed. MATERIALS AND METHODS: We report our experience with patients determined to have peritoneal carcinomatosis following robotic-assisted radical prostatectomy (RARP) and provide a descriptive summary of these unique cases. RESULTS: Five cases of peritoneal carcinomatosis were identified, all of which occurred relatively late-between 8 and 13 years-following RARP. Four of the 5 cases had T3 disease at the time of prostatectomy. 68Ga-PSMA PET identified peritoneal carcinomatosis in 3 of 5 cases. CONCLUSION: Certain clinical factors, such as advanced pathologic stage at the time of prostatectomy, may predict risk for carcinomatosis following RARP. Additionally, next-generation imaging modalities, such as PSMA PET, may aid in identifying these metastases and are likely to identify increasing numbers of these patients as next-generation imaging becomes more widely available. Continued documentation and classification of this atypical presentation are needed to improve our understanding and management of this phenomenon.

Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours.

BACKGROUND: This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours. METHODS: Patients (n = 94) received oral WNT974 at doses of 5-30 mg once-daily, plus additional dosing schedules. RESULTS: The maximum tolerated dose was not established; the recommended dose for expansion was 10 mg once-daily. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n = 52) and 74% of paired tumour biopsies (n = 35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumour samples (n = 8). CONCLUSIONS: Single-agent WNT974 treatment was generally well tolerated. Biomarker analyses suggest that WNT974 may influence immune cell recruitment to tumours, and may enhance checkpoint inhibitor activity. CLINICAL TRIAL REGISTRATION: NCT01351103.

Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors.

IMPORTANCE: Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain. OBJECTIVE: To determine which patients derived the greatest degree of clinical benefit from NGS profiling. DESIGN, SETTING, AND PARTICIPANTS: Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020. MAIN OUTCOMES AND MEASURES: Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer. RESULTS: During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses. CONCLUSIONS AND RELEVANCE: The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.

TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer.

PURPOSE: Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC). METHODS: The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101). The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL). RESULTS: The PFS was 5.7 months for both arms (hazard ratio [HR], 1.14; 95% CI, 0.83 to 1.55; P = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT. The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; P = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; P = .80). OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; P = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT. CONCLUSION: This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.

Multigene Profiling of Circulating Tumor Cells (CTCs) for Prognostic Assessment in Treatment-Naïve Metastatic Hormone-Sensitive Prostate Cancer (mHSPC).

The substantial biological heterogeneity of metastatic prostate cancer has hindered the development of personalized therapeutic approaches. Therefore, it is difficult to predict the course of metastatic hormone-sensitive prostate cancer (mHSPC), with some men remaining on first-line androgen deprivation therapy (ADT) for several years while others progress more rapidly. Improving our ability to risk-stratify patients would allow for the optimization of systemic therapies and support the development of stratified prospective clinical trials focused on patients likely to have the greatest potential benefit. Here, we applied a liquid biopsy approach to identify clinically relevant, blood-based prognostic biomarkers in patients with mHSPC. Gene expression indicating the presence of CTCs was greater in CHAARTED high-volume (HV) patients (52% CTChigh) than in low-volume (LV) patients (23% CTChigh; * p = 0.03). HV disease (p = 0.005, q = 0.033) and CTC presence at baseline prior to treatment initiation (p = 0.008, q = 0.033) were found to be independently associated with the risk of nonresponse at 7 months. The pooled gene expression from CTCs of pre-ADT samples found AR, DSG2, KLK3, MDK, and PCA3 as genes predictive of nonresponse. These observations support the utility of liquid biomarker approaches to identify patients with poor initial response. This approach could facilitate more precise treatment intensification in the highest risk patients.

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer.

BACKGROUND: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. METHODS: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). RESULTS: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. CONCLUSIONS: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01058707.

Efficacy and Effect of Cabozantinib on Bone Metastases in Treatment-naive Castration-resistant Prostate Cancer.

BACKGROUND: Cabozantinib is active in advanced prostate cancer with improvement on bone scans in men on phase II trials. This trial evaluated the efficacy and changes in bone lesions in men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabozantinib. PATIENTS AND METHODS: Eligible patients with mCRPC involving bone underwent biopsy of a bone lesion followed by cabozantinib starting at 60 mg daily and continuing until progression or intolerable toxicity. The primary study endpoint was progression-free survival at 12 weeks. The bone lesion was rebiopsied at 6 weeks. Expression of CMET, phospho-CMET, and VEGFR2 was assayed by immunohistochemistry. Serum was obtained at baseline, and at 3, 6, and 12 weeks and assayed for bone remodeling markers. RESULTS: A total of 25 patients were enrolled: 22 were evaluable, and 3 were excluded before receiving cabozantinib. At 12 weeks, 17 (77%) of 22 patients had stable disease or better. The median time on treatment was 24 weeks (range, 3-112 weeks). The overall median progression-free survival was 43.7 weeks (95% confidence interval, 23.7-97.0 weeks). Eight (36%) of 22 patients had markedly reduced uptake on bone scan. Patients with significant response on bone scan had higher bone morphogenic protein-2 levels at baseline, stable N-telopeptides levels, increased vascular endothelial growth factor receptor 2 expression, and a trend towards increased phospho-CMET while on cabozantinib compared with patients with stable disease. CONCLUSIONS: Cabozantinib is active in men with mCRPC, inducing significant changes on bone scan in one-third of patients with changes in markers of bone formation and the tumor microenvironment.

A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma.

Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with very limited treatment options. Nevanimibe HCl (formerly ATR-101), a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, has been shown in nonclinical studies to decrease adrenal steroidogenesis at lower doses and to cause apoptosis of adrenocortical cells at higher doses. Methods This phase 1, multicenter, open-label study assessed the safety and pharmacokinetics (PK) of nevanimibe in adults with metastatic ACC (NCT01898715). A "3 + 3" dose-escalation design was used. Adverse events (AEs), PK, and tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were evaluated every 2 months. Results 63 patients with metastatic ACC, all of whom had previously failed systemic chemotherapy and only 2 of whom were mitotane-naïve, were dosed with oral nevanimibe at doses ranging from 1.6 mg/kg/day to 158.5 mg/kg/day. Subjects who did not experience tumor progression or a dose-limiting toxicity (DLT) could continue to receive additional cycles. No patients experienced a complete or partial response; however, 13 of the 48 (27%) patients who underwent imaging at 2 months had stable disease (SD), and 4 of these had SD > 4 months. In addition, drug-related adrenal insufficiency, considered a pharmacologic effect of nevanimibe, was observed in two patients. The most common treatment-emergent AEs were gastrointestinal disorders (76%), including diarrhea (44%) and vomiting (35%). A maximum tolerated dose (MTD) could not be defined, as very few dose-limiting toxicities (DLTs) occurred. Because the large number of tablets required at the highest dose (i.e., ~24 tablets/day) resulted in low-grade gastrointestinal adverse effects, a maximum feasible dose of 128.2 mg/kg/day was established as a dose that could be taken on a long-term basis. Conclusions This study demonstrated the safety of nevanimibe at doses of up to ~6000 mg BID. As the total number of tablets required to achieve an MTD exceeded practical administration limits, a maximum feasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of nevanimibe had limited efficacy in patients with advanced ACC.

Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies.

PURPOSE: Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137). PATIENTS AND METHODS: Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability. RESULTS: Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses. CONCLUSIONS: INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.

PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open-label single-arm phase 2 study.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. METHODS: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. RESULTS: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. CONCLUSIONS: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.

Testicular Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Testicular cancer is relatively uncommon and accounts for <1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nerve-sparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with >50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.

First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy.

PURPOSE: This first-in-human Phase I study investigated the safety, pharmacokinetics (PK), pharmacodynamic profile, and preliminary efficacy of CC-115, a dual inhibitor of mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase. PATIENTS AND METHODS: Patients with advanced solid or hematologic malignancies were enrolled in dose-finding and cohort expansion phases. In dose-finding, once-daily or twice-daily (BID) ascending oral doses of CC-115 (range: 0.5-40 mg/day) in 28-day continuous cycles identified the maximum-tolerated dose for cohort expansion in 5 specified tumor types. Twelve additional patients with mixed solid tumors participated in a bioavailability substudy. RESULTS: Forty-four patients were enrolled in the dose-finding cohort. Dose-limiting toxicity included thrombocytopenia, stomatitis, hyperglycemia, asthenia/fatigue, and increased transaminases. CC-115 10 mg BID was selected for cohort expansion (n=74) in which fatigue, nausea, and decreased appetite were the most frequent toxicities. Dose-proportional PK was found. CC-115 distributed to glioblastoma tissue (mean tumor/plasma concentration ratio: 0.713). Total exposure of CC-115 was similar under fasting and fed conditions. A patient with endometrial carcinoma remained in complete remission >4 years. Partial response (PR; n=2) and stable disease (SD; n=4) were reported in the bioavailability substudy; SD was reached in 53%, 22%, 21%, and 64% of patients with head and neck squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme, and castration-resistant prostate cancer, respectively. Chronic lymphocytic leukemia/small lymphocytic lymphoma showed 38% PR and 25% SD. CONCLUSION: CC-115 was well-tolerated, with toxicities consistent with mTOR inhibitors. Together with biomarker inhibition and preliminary efficacy, oral CC-115 10 mg BID is a promising novel anticancer treatment. CLINICAL TRIAL REGISTRATION: NCT01353625.

Five-Year Survival and Correlates Among Patients With Advanced Melanoma, Renal Cell Carcinoma, or Non-Small Cell Lung Cancer Treated With Nivolumab.

IMPORTANCE: Nivolumab, a monoclonal antibody that inhibits programmed cell death 1, is approved by the US Food and Drug Administration for treating advanced melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and other malignancies. Data on long-term survival among patients receiving nivolumab are limited. OBJECTIVES: To analyze long-term overall survival (OS) among patients receiving nivolumab and identify clinical and laboratory measures associated with tumor regression and OS. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of the phase 1 CA209-003 trial (with expansion cohorts), which was conducted at 13 US medical centers and included 270 patients with advanced melanoma, RCC, or NSCLC who received nivolumab and were enrolled between October 30, 2008, and December 28, 2011. The analyses were either specified in the original protocol or included in subsequent protocol amendments that were implemented between 2008 and 2012. Statistical analysis was performed from October 30, 2008, to November 11, 2016. INTERVENTION: In the CA209-003 trial, patients received nivolumab (0.1-10.0 mg/kg) every 2 weeks in 8-week cycles for up to 96 weeks, unless they developed progressive disease, achieved a complete response, experienced unacceptable toxic effects, or withdrew consent. MAIN OUTCOMES AND MEASURES: Safety and activity of nivolumab; OS was a post hoc end point with a minimum follow-up of 58.3 months. RESULTS: Of 270 patients included in this analysis, 107 (39.6%) had melanoma (72 [67.3%] male; median age, 61 [range, 29-85] years), 34 (12.6%) had RCC (26 [76.5%] male; median age, 58 [range, 35-74] years), and 129 (47.8%) had NSCLC (79 [61.2%] male; median age, 65 [range, 38-85] years). Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC. In a multivariable analysis, the presence of liver (odds ratio [OR], 0.31; 95% CI, 0.12-0.83; P = .02) or bone metastases (OR, 0.31; 95% CI, 0.10-0.93; P = .04) was independently associated with reduced likelihood of survival at 5 years, whereas an Eastern Cooperative Oncology Group performance status of 0 (OR, 2.74; 95% CI, 1.43-5.27; P = .003) was independently associated with an increased likelihood of 5-year survival. Overall survival was significantly longer among patients with treatment-related AEs of any grade (median, 19.8 months; 95% CI, 13.8-26.9 months) or grade 3 or more (median, 20.3 months; 95% CI, 12.5-44.9 months) compared with those without treatment-related AEs (median, 5.8 months; 95% CI, 4.6-7.8 months) (P < .001 for both comparisons based on hazard ratios). CONCLUSIONS AND RELEVANCE: Nivolumab treatment was associated with long-term survival in a subset of heavily pretreated patients with advanced melanoma, RCC, or NSCLC. Characterizing factors associated with long-term survival may inform treatment approaches and strategies for future clinical trial development. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00730639.

Cardiovascular and Metabolic Toxicity of Abiraterone in Castration-resistant Prostate Cancer: Post-marketing Experience.

INTRODUCTION: Abiraterone improves survival in metastatic castration-resistant prostate cancer (mCRPC) but may result in the development or worsening of comorbid conditions. We assessed the course of these conditions in patients receiving abiraterone in clinical practice and compared outcomes with those in clinical trials. MATERIALS AND METHODS: Medical records of patients with mCRPC who started abiraterone at an academic institution between 2012 and 2015 were reviewed for emergency department (ED) visits, hospitalizations, and the development and/or worsening of key comorbid conditions while on abiraterone. Patient characteristics and adverse events were compared with those from clinical trials. RESULTS: In a cohort of 174 patients, 28% experienced either the development or worsening of a comorbid disease; 8% required an ED visit or hospitalization owing to known adverse effects of abiraterone. Increasing age (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.17), higher prostate-specific antigen at initiation of treatment (OR, 1.68; 95% CI, 1.18-2.47), preexisting uncontrolled hypertension (OR, 7.61; 95% CI, 1.22-38.70), congestive heart failure (OR, 7.61; 95% CI, 1.22-38.70), and cardiac arrhythmias (OR, 4.73; 95% CI, 1.39-15.12) were associated with increased odds of an ED visit or hospitalization owing to known adverse effects of abiraterone. The rate of discontinuation (6%) was similar to 1 phase III trial that demonstrated the drug's efficacy in chemotherapy-naive patients. CONCLUSION: Few patients discontinued abiraterone owing to toxicity; however, the fact that over one-quarter of patients experienced the development or worsening of cardiovascular and metabolic diseases warrants development of team-based approaches to the management of these comorbid conditions.

Detection of CTC Clusters and a Dedifferentiated RNA-Expression Survival Signature in Prostate Cancer.

Rates of progression and treatment response in advanced prostate cancer are highly variable, necessitating non-invasive methods to assess the molecular characteristics of these tumors in real time. The unique potential of circulating tumor cells (CTCs) to serve as a clinically useful liquid biomarker is due to their ability to inform via both enumeration and RNA expression. A microfluidic graphene oxide-based device (GO Chip) is used to isolate CTCs and CTC clusters from the whole blood of 41 men with metastatic castration-resistant prostate cancer. Additionally, the expression of 96 genes of interest is determined by RT-qPCR. Multivariate analyses are conducted to determine the genes most closely associated with overall survival, PSA progression, and radioclinical progression. A preliminary signature, comprising high expression of stemness genes and low expression of epithelial and mesenchymal genes, potentially implicates an undifferentiated CTC phenotype as a marker of poor prognosis in this setting.