Paul Hamberg

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.

Clinical Activity and Tolerability of Enzalutamide ( MDV3100) in Patients With Metastatic, Castration- Resistant Prostate Cancer Who Progress After Docetaxel and Abiraterone Treatment

Enzalutamide (Enz) and abiraterone acetate (AA) are hormone treatments that have a proven survival advantage in patients with metastatic, castration‐resistant prostate cancer who previously received docetaxel (Doc). Recently, limited activity of AA after Enz and of Enz after AA was demonstrated in small cohort studies. Here, the authors present the activity and tolerability of Enz in patients who previously received AA and Doc in the largest cohort to date.

(Pre-)Clinical Pharmacology and Activity of Pazopanib, a Novel Multikinase Angiogenesis Inhibitor

Pazopanib is a recently approved, novel tyrosine kinase inhibitor specifically designed to impair angiogenesis by abrogating vascular endothelial growth factor receptor 2 (VEGFR-2) to exert its function. Pazopanib inhibits VEGF-induced endothelial cell proliferation in vitro and angiogenesis in vivo and demonstrates antitumor activity in mouse models. Furthermore, the pazopanib concentration resulting in maximal inhibition of VEGFR-2 phosphorylation in vivo was in line with the steady-state concentration required to inhibit growth of tumor xenografts, suggesting that pazopanibs mechanism of action is indeed through VEGFR-2 inhibition. In a phase I trial, a generally well-tolerated dose was identified at which the majority of patients achieved pazopanib plasma concentrations above the concentration required for maximal in vivo inhibition of VEGFR-2 phosphorylation in preclinical models. Administered as monotherapy, evidence of antitumor activity was observed in phase II studies in several tumor types, including soft tissue sarcoma, renal cell cancer (RCC), ovarian cancer, and non-small cell lung cancer. Recently, the U.S. Food and Drug Administration granted approval for treatment with pazopanib in patients with RCC based on the longer progression-free survival time observed with this agent in a placebo-controlled, randomized trial. This review summarizes the preclinical and clinical pharmacokinetics and pharmacodynamics of pazopanib, as well as data on clinical activity, that ultimately resulted in its recent approval.

Phase I Safety, Pharmacokinetics, and Inhibition of Src Activity Study of Saracatinib in Patients with Solid Tumors

Purpose: This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors. Experimental Design: Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing. Results: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and Cmax of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours. Conclusions: Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d. Clin Cancer Res; 16(19); 4876–83. ©2010 AACR.

Randomized phase II study comparing efficacy and safety of combination-therapy trastuzumab and docetaxel vs. sequential therapy of trastuzumab followed by docetaxel alone at progression as first-line chemotherapy in patients with HER2+ metastatic breast cancer: HERTAX trial.

BACKGROUND Because chemotherapy for metastatic breast cancer (MBC) is associated with relevant toxicity, sequential monotherapy trastuzumab followed by cytotoxic therapy at disease progression might be an attractive approach. METHODS In a multicenter phase II trial, 101 patients with overexpression of human epidermal growth factor receptor 2 (HER2(+)) MBC were randomized between combination-therapy trastuzumab (Herceptin) plus docetaxel (H+D) and sequential therapy of single-agent trastuzumab followed at disease progression by docetaxel alone (H→D) as first-line chemotherapy for metastatic disease. The primary endpoint was progression-free survival (PFS) after completed sequential or combination therapy. RESULTS For the H+D group the median PFS was 9.4 vs. 9.9 months for the H→D group and 1-year PFS rates were 44% vs. 35%, respectively. However the overall response rates (ORRs) were 79% vs. 53%, respectively (P = .016), and overall survival was 30.5 vs. 19.7 months, respectively (P = .11). In the H→D group, response rates to monotherapy trastuzumab and subsequent docetaxel were 34% and 39%, respectively, with a median PFS during single-agent trastuzumab of 3.9 months. The incidence and severity of neuropathy were significantly higher in the H+D group. Retrospective analysis of trastuzumab treatment beyond progression (applied in 46% of patients in the H+D group and 37% in the H→D group) showed a correlation with longer overall survival in both treatment arms (36.0 vs. 18.0 months and 30.3 vs. 18.6 months, respectively). CONCLUSION First-line treatment in patients with MBC with H→D resulted in a similar PFS compared with H+D, but the response rate was lower and the overall survival nonsignificantly shorter.

Dose-escalation models for combination phase I trials in oncology

Designing combination drug phase I trials has become increasingly complex, due to the increasing diversity in classes of agents, mechanisms of action, safety profiles and drug-administration schedules. With approximately 850 agents currently in development for cancer treatment, it is evident that combination development must be prioritised, as based on a specific hypothesis, as well as a projected development path for the involved combination. In this manuscript the most relevant issues and pitfalls for combination drug phase I trial design are discussed. Several phase I study designs that incorporate controls to circumvent bias due to imbalances in observed background toxicity are discussed.

The influence of prior novel androgen receptor targeted therapy on the efficacy of cabazitaxel in men with metastatic castration-resistant prostate cancer

INTRODUCTION The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has expanded with the introduction of several new therapies. In this treatment continuum, it is unclear whether the efficacy of cabazitaxel is affected by prior novel androgen receptor targeted therapies (ART) such as abiraterone and enzalutamide. In this study, we investigated the influence of prior ART on the efficacy of cabazitaxel in men with mCRPC. PATIENTS AND METHODS Data from an ongoing multicentre, phase II trial were used comprising 114 men with mCRPC treated with cabazitaxel in the post-docetaxel setting. The primary endpoints of the current analysis were prostate-specific antigen (PSA) response (⩾ 50%), and overall survival (OS). Univariate and multivariable analyses were conducted to investigate the influence of prior ART on the efficacy of cabazitaxel. RESULTS From the 114 patients included in this analysis, 44 men received prior ART and 70 men did not receive prior ART before treatment with cabazitaxel. PSA response rates while on cabazitaxel treatment were similar in patients with and without prior ART (34% versus 40%, respectively, P = 0.53). Likewise, median OS was not significantly different between men with and without prior ART (13.0 versus 14.0 months, respectively, logrank P = 0.65). In multivariable analysis, the only variables significantly associated with OS were performance status, serum albumin and alkaline phosphatase. CONCLUSION Our study showed that prior treatment with ART may not influence the efficacy of cabazitaxel in men with mCRPC. With emerging evidence of cross-resistance in the treatment of mCRPC, cabazitaxel provides a good treatment option irrespective of prior ART.

When to start cytotoxic therapy in asymptomatic patients with hormone refractory prostate cancer

Until the publication of two pivotal trials, there were no treatment options available that did prolong the overall survival in men with hormone refractory prostate cancer (HRPC). Currently, docetaxel-based cytotoxic treatment is considered as a standard of care in all the patients with progressive metastatic HRPC. The use of this treatment regimen renders an equal survival benefit in all the subgroups of patients; however, there is a substantial difference in the overall survival between the subgroups. This review addresses the optimal timing of the cytotoxic treatment in asymptomatic patients with HRPC.

CAST: A retrospective analysis of cabazitaxel and abiraterone acetate sequential treatment in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel

Cabazitaxel and abiraterone have both received approval for treating metastatic castrate‐resistant prostate cancer (mCRPC) patients after first‐line docetaxel therapy. In the cabazitaxel and abiraterone sequential treatment (CAST) study, the clinical outcome of docetaxel‐treated mCRPC patients treated sequentially with both cabazitaxel and abiraterone was studied. Data were collected retrospectively from mCRPC patients at 12 hospitals across the Netherlands who initiated cabazitaxel and/or abiraterone before December 2012. Primary outcome measure was overall survival (OS); secondary measures were progression‐free survival (PFS), biochemical PFS, and best clinical and PSA response. Hospital admission data during treatment were collected, as well as toxicities resulting in treatment discontinuation or patient death. Sixty‐three and 69 patients received Cab→Abi (cabazitaxel prior to abiraterone) and Abi→Cab before July 10th, 2013, respectively. Median OS was 19.1 months and 17.0 months in Cab→Abi and Abi→Cab treated patients, respectively (p = 0.369). Median PFS and biochemical PFS were significantly longer in Cab→Abi treated patients: 8.1 versus 6.5 (p = 0.050) and 9.5 versus 7.7 months (p = 0.024), respectively. Although partial responses to cabazitaxel occurred in both groups, Abi→Cab treated patients had a significantly decreased antitumor response from cabazitaxel than Cab→Abi treated patients (median PFS 5.0 versus 2.6 months, p < 0.001). Minor differences in toxicities were observed based on therapy sequence; generally, toxicity from cabazitaxel could be severe, while abiraterone toxicity was milder. This retrospective analysis indicates that primary progression on cabazitaxel or abiraterone did not preclude a response to the other agent in mCRPC patients. However, tumor response of both agents, particularly cabazitaxel, was lower when administered as higher‐line therapy in the selected study population.

Phase I Drug Combination Trial Design: Walking the Tightrope

Drug combination strategies are used in the palliative and curative settings for patients with cancer. Before a specific drug is incorporated into such a combination treatment strategy, it has to be explored using the clinical drug development route. The first critical step is the design of a combination phase I trial. As for all phase I trials, the design of a phase I drug combination trial is of utmost importance because it will dictate the course of the trial and, by its nature, it already incorporates, implicitly or explicitly, a short list of the potential answers to the primary end point question. While many consider phase I trials of drug combinations uninteresting and while there has not been much debate on their design, in reality, the complexity of the design of a phase I trial increases exponentially with the number of different drugs and treatment modalities included in the treatment strategy. If the treatment strategy to which the new drug is added already has curative intent, this adds a complicating dimension to the design of the trial. It means that the researchers will have to balance determining the feasible dose of the added experimental agent without compromising cure. In this issue of Journal of Clinical Oncology, Haddad et al report a phase I study of cetuximab/docetaxel/cisplatin/fluorouracil given as induction treatment to patients with locally advanced squamous cell carcinoma of the head and neck. Taking all the aforementioned factors into account, they should be applauded for performing a dose-finding study in the curative setting. Yet, the study raises some phase I methodology questions. In a series of theoretical phase I trials of drug A and drug B, considering only one dosing regimen per drug and disregarding all available drug data except for the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) for each drug given as a single agent, as a result of the dose escalation track used, different theoretical MTDs and RP2Ds can be defined. For instance, a fixed dose of drug A (at its MTD) can be used while escalating drug B until the MTD of this combination has been determined. One should bear in mind that the MTD of drug B in the combination is not necessarily determined by its single-agent MTD; it could be higher than the single-agent MTD, perhaps because of drug-drug interactions with drug A. A similar trial could be designed for a fixed dose of drug B and dose escalation of drug A, potentially rendering a different MTD of the combination. A different approach would be a dose escalation in which both drugs are started at a relatively low dose and increased alternately. Depending on the escalation steps, different MTDs can be determined. Because the escalation steps can go back and forth between the two drugs whenever an MTD is determined, at least two MTDs can be determined. For example, the MTD is exceeded at dose level 4 for both drugs. If the previous dose level (drug A at dose level 4 and drug B at dose level 3) was safe, that can be called the MTD. However, one could also argue that the combination of drug A at dose level 3 and drug B at dose level 4 should be evaluated for feasibility and, if it is considered safe, that can also be called the MTD. As illustrated in this theoretical example in a simple combination phase I trial with only two drugs, the number of dose-escalating options to approach the MTD easily reaches four, potentially rendering four different MTDs. By adding drug C, this theoretical number rapidly increases to at least 18, and one does not want to think about the potential number of MTDs that are definable with four drugs, as used in the study by Haddad et al. Thus, one of the basic dilemmas facing investigators who design combination phase I trials is choosing the dose escalation approach that will determine the most biologically optimal and useful MTD. From a purely phase I methodology point of view, there is no right or wrong dose escalation approach, because at the end of the study, there will be an answer: one of the many possible MTDs. However, from a treatment practice point of view (even more so when there is curative intent), one should try to identify the dose escalation approach that is best supported by conceptual and actual data and will lead to dose recommendations that, after subsequent phase II and III studies, stand the best chance of changing practice by improved outcome. Guidance can be found in data on toxicity patterns, trials on comparable agents, and (if more than two drugs are used) in previously defined MTDs of the specific combinations to which a new drug is added. Guidance should not be sought in maximizing potential sales of the investigated drug or in beliefs not supported by evidence. As noted, the choice of the dose escalation approach should be determined by the best possible scientific and clinical practice rationale. Haddad et al elected to determine the MTD with a fixed dose of cetuximab (C), cisplatin (P), and docetaxel (D) while escalating the dose of fluorouracil (F). This approach is somewhat remarkable, because the same group of investigators reported that the current standard of induction chemotherapy in patients with squamous cell carcinoma of the head and neck consists of P F with or without D. The authors’ rationale for choosing their dose escalation approach is the potential overlap in the GI toxicity of C and F, but it is unclear why they compromised on the dose of the standard drug (F) and not on the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 27 SEPTEMBER 2