Martijn P. Lolkema

Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR-V7 in Circulating Tumor Cells.

BACKGROUND Androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) was recently demonstrated to be associated with resistance to abiraterone and enzalutamide. Cabazitaxel might, however, remain effective in AR-V7-positive patients. OBJECTIVE To investigate the association between AR-V7 expression in CTCs and resistance to cabazitaxel. DESIGN, SETTING, AND PARTICIPANTS We selected patients with mCRPC from the multicenter, randomized, phase 2, randomized, open-label, multicenter study in mCRPC on the pharmacodynamic effects of budesonide on cabazitaxel (Jevtana) (CABARESC). Before the start of the first and third cabazitaxel cycle, CTCs were enumerated using the CellSearch System. In patients with ≥10 CTCs in 7.5 ml blood at baseline, the expression of AR-V7 was assessed by quantitative polymerase chain reaction. OUTCOME MEASURES AND STATISTICAL ANALYSIS The primary end point was the association between the AR-V7 status and the CTC response rate (decrease to fewer than five CTCs in 7.5 ml blood during treatment). Secondary end points were the prostate-specific antigen (PSA) response rate (RR) and overall survival (OS). Analyses were performed using chi-square and log-rank tests. RESULTS AND LIMITATIONS AR-V7 was detected in 16 of 29 patients (55%) with ≥10 CTCs and was more frequently found in abiraterone pretreated patients (5 of 5 [100%] treated vs 7 of 20 [35%] untreated; p=0.009). We found no differences in CTC and PSA RRs. The presence of AR-V7 in CTCs was not associated with progression-free survival (hazard ratio [HR]: 0.8; 95% confidence interval [CI], 0.4-1.8) or overall survival (HR 1.6; 95% CI, 0.6-4.4). CONCLUSIONS The response to cabazitaxel seems to be independent of the AR-V7 status of CTCs from mCRPC patients. Consequently, cabazitaxel might be a valid treatment option for patients with AR-V7-positive CTCs. PATIENT SUMMARY Tools are needed to select specific treatments for specific patients at specific times. The presence of the gene AR-V7 in CTCs has been associated with resistance to anti-androgen receptor treatments. We investigated whether this holds true for cabazitaxel, but we found cabazitaxel to be effective independent of the presence of AR-V7.

A phase I study of the combination of intravenous reovirus type 3 Dearing and gemcitabine in patients with advanced cancer.

Purpose: This study combined systemic administration of the oncolytic reovirus type 3 Dearing (reovirus) with chemotherapy in human subjects. We aimed to determine the safety and feasibility of combining reovirus administration with gemcitabine and to describe the effects of gemcitabine on the antireoviral immune response. Experimental Design: Patients received reovirus in various doses, initially we dosed for five consecutive days but this was poorly tolerated. We amended the protocol to administer a single dose and administered up to 3 × 1010 TCID50. Toxicity was assessed by monitoring of clinical and laboratory measurements. We assessed antibody response by cytotoxicity neutralization assay. Results: Sixteen patients received 47 cycles of reovirus. The two initial patients and one patient in the final cohort experienced dose limiting toxicity (DLT). The DLTs consisted of two asymptomatic grade 3 liver enzyme rises and one asymptomatic grade 3 troponin I rise. Common toxicities consisted of known reovirus and gemcitabine associated side effects. Further analysis showed a potential interaction between reovirus and gemcitabine in causing liver enzyme rises. Grade 3 rises in liver enzymes were associated with concomitant aminocetophen use. Importantly, the duration of the liver enzyme rise was short and reversible. Neutralizing antibody responses to reovirus were attenuated both in time-to-occurrence and peak height of the response. Conclusions: Reovirus at the dose of 1 × 1010 TCID50 can be safely combined with full dose gemcitabine. Combination of reovirus with gemcitabine affects the neutralizing antibody response and this could impact both safety and efficacy of this treatment schedule. Clin Cancer Res; 17(3); 581–8. ©2010 AACR.

Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors

BACKGROUND To determine, for each of two dosing schedules, the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of AZD1152, an Aurora B kinase inhibitor, and to evaluate its safety, biologic activity and pharmacokinetics (PK). PATIENTS AND METHODS Patients with advanced solid malignancies were treated with escalating doses (100-650 mg) of AZD1152, administered as a 2-h infusion every 7 days (A) or 14 days (B). Adverse events (AEs), PK variables and tumor response were assessed. RESULTS Fifty-nine patients were treated; 19 in schedule A and 40 in schedule B. The MTDs were 200 and 450 mg, respectively. Neutropenia (with/without fever) was the most frequent AE and DLT in each schedule. Common Terminology Criteria of Adverse Events version 3.0 grade ≥3 neutropenia and leukopenia occurred in 58% and 11% of patients, respectively, in schedule A and 43% and 20%, respectively, in schedule B. No objective tumor responses were observed at any dose or schedule, although stable disease, as defined by RECIST, was achieved in 15 patients (25%) overall. Systemic exposure to AZD1152-hQPA (active drug) was observed by 1 h into the infusion and exhibited linear PK. CONCLUSIONS AZD1152 was generally well tolerated with neutropenia being the most frequently reported AE and DLT. Exposure to AZD1152-hQPA, the active drug of AZD1152, was linear.

Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours

Background:Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.Methods:Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml−1 and the patient did not show any grade ⩾3 toxicity, the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from grade ⩾3 toxicity, the sunitinib dose was lowered by 12.5 mg.Results:Twenty-nine out of 43 patients were evaluable for PK assessments. Grade ⩾3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity.Conclusions:In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice.

Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors

Purpose: This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor of class I PI3K, and mTOR kinases. Experimental Design: Once-daily oral apitolisib was administered to patients with solid tumors for days 1 to 21 or 1 to 28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed. Results: Overall, 120 patients were treated at doses between 2 and 70 mg. The commonest ≥G3 toxicities related to apitolisib at the recommended phase 2 dose (RP2D) at 40 mg once daily included hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). Dose-limiting toxicities (1 patient each) were G4 fasting hyperglycemia at 40 mg (21/28 schedule) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg (21/28 schedule). The pharmacokinetic profile was dose-proportional. Phosphorylated serine-473 AKT levels were suppressed by ≥90% in platelet-rich plasma within 4 hours at the MTD (50 mg). Pharmacodynamic decreases in fluorodeoxyglucose positron emission tomography uptake of >25% occurred in 66% (21/32) of patients dosed at 40 mg once daily. Evidence of single-agent activity included 10 RECIST partial responses (PR; confirmed for peritoneal mesothelioma, PIK3CA mutant head-and-neck cancer, and three pleural mesotheliomas). Conclusions: Apitolisib exhibited dose-proportional pharmacokinetics with target modulation at doses ≥16 mg. The RP2D was 40 mg once-daily 28/28 schedule; severe on-target toxicities were apparent at ≥40 mg, particularly pneumonitis. Apitolisib was reasonably tolerated at 30 mg, the selected dose for pleural mesothelioma patients given limited respiratory reserve. Modest but durable antitumor activity was demonstrated. Clin Cancer Res; 22(12); 2874–84. ©2016 AACR.

The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation

Purpose: The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor. Experimental Design: We performed a phase I dose-escalation study according to the standard 3+3 design. Results: Even at subtherapeutic doses, mild though recurrent renal toxicity was observed in virtually all patients. Renal toxicity had not been observed in preclinical studies in rats and dogs. Additional preclinical studies pointed toward the rabbit as a suitable toxicology model, as the formation of the M10 metabolite of JNJ-38877605 specifically occurred in rabbits and humans. Additional toxicology studies in rabbits clearly demonstrated that JNJ-38877605 induced species-specific renal toxicity. Histopathological evaluation in rabbits revealed renal crystal formation with degenerative and inflammatory changes. Identification of the components of these renal crystals revealed M1/3 and M5/6 metabolites. Accordingly, it was found that humans and rabbits showed significantly increased systemic exposure to these metabolites relative to other species. These main culprit insoluble metabolites were generated by aldehyde oxidase activity. Alternative dosing schedules of JNJ-3877605 and concomitant probenecid administration in rabbits failed to prevent renal toxicity at dose levels that could be pharmacologically active. Conclusions: Combined clinical and correlative preclinical studies suggest that renal toxicity of JNJ-38877605 is caused by the formation of species-specific insoluble metabolites. These observations preclude further clinical development of JNJ-38877605. Clin Cancer Res; 21(10); 2297–304. ©2015 AACR.

Systematic Review of Immune Checkpoint Inhibition in Urological Cancers

CONTEXT In patients with advanced and metastatic urological cancers, clinical outcome may be improved by immune checkpoint inhibitors (ICIs). OBJECTIVE To systematically review relevant literature on efficacy and safety of ICIs in patients with advanced and metastatic urothelial cell cancer (UCC), renal cell cancer (RCC), and prostate cancer. EVIDENCE ACQUISITION Relevant databases, including Medline, Embase, and the Cochrane Library, were searched up to March 16, 2017. A narrative review of randomized clinical trials (RCTs) was performed. EVIDENCE SYNTHESIS Six RCTs were included for the systematic review. In platinum-pretreated UCC, efficacy of pembrolizumab was superior to chemotherapy, with longer median overall survival (OS; 10.3 vs 7.4 mo), a higher objective response rate (ORR; 21.1% vs 11.4%, p=0.001), and a lower adverse event rate (60.9% vs 90.2%). Three RCTs assessed the safety and efficacy of nivolumab in advanced RCC. The median OS (25.0 vs 19.6 mo) and the ORR (25% vs 5%) were higher in patients treated with nivolumab compared with second-line everolimus. In all three studies, the safety profile of nivolumab was favorable. In patients with metastatic castration-resistant prostate cancer, two RCTs were identified, which did not show significant benefits for ipilimumab over placebo. In UCC and RCC, there was no conclusive association between programmed cell death receptor ligand 1 (PD-L1) expression in tumor tissue and clinical outcome during pembrolizumab and nivolumab treatment, respectively. CONCLUSION In metastatic UCC and RCC, pembrolizumab and nivolumab have superior efficacy and safety to second-line chemotherapy and everolimus, respectively. No beneficial effect of ipilimumab was observed in prostate cancer patients. PD-L1 expression status is currently not suitable as a predictive marker for treatment outcome. PATIENT SUMMARY Immune checkpoint inhibitors are able to reactivate the immune system against tumor cells. In second-line setting, pembrolizumab and nivolumab are safe and confer survival benefit in advanced urothelial cell and renal cell cancer, respectively.

Unsolicited findings of next-generation sequencing for tumor analysis within a Dutch consortium: clinical daily practice reconsidered

Cancer patients participating in studies involving experimental or diagnostic next-generation sequencing (NGS) procedures are confronted with the possibility of unsolicited findings. The Center for Personalized Cancer Treatment (CPCT), a Dutch consortium of cancer centers, is offering centralized large-scale NGS for the discovery of somatic tumor mutations with their germline DNA as reference. The CPCT aims to give all cancer patients with advanced disease stages access to tumor DNA analysis in order to improve selection for experimental therapy. In this article, our experiences at the CPCT will serve as an example to discuss the ethical and practical aspects regarding the management of unsolicited findings in personalized cancer research and treatment. Generic issues, relevant for all researchers in this field are discussed and illustrated by description of three patients faced with an unsolicited DNA finding, while they intended to be candidate for future anticancer treatment by participating in a trial that included NGS of both somatic and germline DNA. As options for DNA analysis expand and costs decrease rapidly, more and more patients are offered large-scale NGS testing. After reviewing current recommendations in literature, we conclude that classical informed consent procedures need to be adapted to become more explicit in asking patients if they want to be informed about unsolicited findings and if so, what level of detail of genetic risk information exactly they want to be returned after the analysis.

Phase I and pharmacological study of pazopanib in combination with oral topotecan in patients with advanced solid tumours.

Background:This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD) and pharmacokinetics of two dosing schedules of oral topotecan in combination with pazopanib in patients with advanced solid tumours.Methods:Stage I of this study was to determine whether there was an impact of pazopanib on topotecan exposure. In stage II, the MTD and safety profile of oral topotecan given weekly on days 1, 8 and 15 in a 28-day cycle; or daily-times-five on days 1–5 in a 21-day cycle, both in combination with daily pazopanib, were explored.Results:In total, 67 patients were enroled. Pazopanib co-administration caused a substantial increase in exposure to total topotecan (1.7-fold) compared with topotecan alone, which is considered clinically relevant. Topotecan had no effect on pazopanib concentrations. Safety findings were consistent with the known profile of both agents. There were three drug-related deaths, liver failure, tumour haemorrhage and myelosuppression. Two patients experienced dose-limiting toxicities (DLTs; hand–foot syndrome, myelosuppression and diarrhoea) on the weekly topotecan schedule and four patients experienced DLTs (myelosuppression) on the daily-times-five topotecan schedule. When combined with pazopanib, 800 mg daily, the recommended doses for oral topotecan are: 8 mg weekly and 2.5 mg daily-times-five. Seven of eight patients with partial response had platinum-resistant ovarian cancer. In addition, 54% of patients had stable disease with 22% stable for 6 months.Conclusions:Total topotecan exposure is 1.7-fold higher when co-administered with pazopanib. Both schedules of administration were tolerated and would permit further evaluation, especially the weekly schedule.

The time to progression ratio: a new individualized volumetric parameter for the early detection of clinical benefit of targeted therapies

BACKGROUND Early signs of efficacy are critical in drug development. Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to determine the efficacy of anti-cancer therapy in clinical trials. RECIST, however, emphasizes the value of tumor shrinkage, while many targeted agents induce prolonged tumor growth arrest. This limits its use for the detection of treatment efficacy for these more cytostatic regimens. Therefore, we designed an individualized variant of a time to progression (TTP) end point based on prospective volumetric measurements and an intra-patient control, the TTP ratio. PATIENTS AND METHODS Patients with any metastatic malignancy, without regular treatment options, were treated with the mTOR inhibitor everolimus. Treatment response was determined using both RECIST and the TTP ratio. The TTP ratio was defined as the volumetric pretreatment TTP divided by the volumetric on-treatment TTP. A patient was classified as a responder if the TTP ratio was <0.7. Consistency and reproducibility of volumetric measurements were determined. RESULTS Seventy-three patients were included of whom 59 started treatment. A TTP ratio could be established in 73% (n = 43) of the treated patients. The inter-observer agreement for volumetric progression was 0.78 (95% confidence interval 0.70-0.87) (Krippendorffs α-coefficient). According to RECIST, 35 patients (59%) had stable disease (SD) and 1 patient demonstrated a partial response (PR), whereas only 21 patients (36%) met the prespecified criteria for treatment efficacy according to the TTP ratio. Treatment response according to both the TTP ratio and RECIST (SD + PR) correlated with overall survival (OS) [P(log-rank) < 0.001]. The TTP ratio, however, was also able to differentiate which patients had a better OS within the RECIST SD group [P(log-rank) = 0.0496]. CONCLUSION The TTP ratio had a high inter-observer agreement, correlated with OS and identified which patients within the RECIST SD group had a longer OS. CLINICALTRIALSGOV IDENTIFIER NCT01566279.