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Abstract

Sorafenib is an oral multitargeted tyrosine and serine/threonine kinase inhibitor approved for the treatment of advanced renal cell and hepatocellular carcinoma. An understanding of its dose–toxicity relationship has paved the way for trials seeking to enhance its clinical activity through the exploration of alternative dosing strategies. In this article, we review the dose–toxicity relationship of sorafenib observed during its phase I and early phase II testing, explore its toxicity profile at the recommended dose and schedule, discuss the evidence for dose escalation to higher levels, and examine the preliminary evidence for clinical activity of this strategy. Owing to a temporal relationship between toxicity and dose, it may be possible in select patients to escalate sorafenib to doses beyond those currently employed. However, because of the potential for increased toxicity, sorafenib dose escalation should currently be performed only in the context of a clinical trial.

Keywords

dose–response relationship drug maximum tolerated dose toxicity sorafenib

Introduction

The dose and schedule of anticancer agents has traditionally been defined by phase I dose escalation trials during which the compound of interest is administered in successively higher dose levels until dose-limiting toxicity (DLT) is encountered and a maximum tolerated dose (MTD) is determined [Le Tourneau et al. 2009]. Based on this experience, a dose and schedule is recommended for phase II testing and subsequent development. This strategy makes two key assumptions: (1) that toxicity observed in the first cycle of treatment predicts toxicity in subsequent cycles; and (2) that the most effective dose is approximated by the MTD.

Sorafenib is an oral multitargeted inhibitor of tyrosine and serine/threonine kinases which was developed in a series of phase I trials using this strategy [Strumberg et al. 2007]. However, sorafenib-associated toxicities improve with longer treatment [Flaherty and Brose, 2009; Escudier et al. 2007; Ratain et al. 2006; Ahmad and Eisen, 2004] and, consequently, sorafenib therapy violates the first assumption. Based on these observations, exploration of different doses and schedules of sorafenib has been recommended [Rini, 2007]. In this article, we review the development of sorafenib, its dose–toxicity and dose–efficacy relationship, and ongoing trials evaluating dose escalation strategies.

Discovery and preclinical pharmacodynamics

Sorafenib was initially selected for development based on its inhibitory activity against serine/threonine Raf kinases which are pivotal components of the Raf/MEK/ERK signaling pathway, which mediates cellular responses to growth factors through the expression of genes involved in cellular proliferation, survival, and differentiation [Downward, 2003]. In tumor cell lines with activation of the Raf/MEK/ERK pathway by oncogenic Ras or Raf mutations, in vitro studies demonstrate that sorafenib decreases phosphorylated ERK levels and tumor cell proliferation [Wilhelm et al. 2004]. In addition, sorafenib inhibits the receptor tyrosine kinases for vascular endothelial growth factor (VEGF), platelet-derived growth factor β (PDGF-β), FMS-like tyrosine kinase 3 (Flt-3), c-kit, and rearranged during transfection (RET) (Table 1) [Wilhelm et al. 2004].

Table 1.

In vitro activity of sorafenib against selected targets.

Target	IC₅₀ (nmol/l)
C-RAF	6
Wild-type B-RAF	22
B-RAF V600E Mutant	38
RET	47
PDGFR-β	57
Flt-3	58
c-KIT	68
VEGFR-2	90

C-RAF, v-raf-leukemia viral oncogene 1; B-RAF, v-raf murine sarcoma viral oncogene homolog B1; RET, rearranged during transfection; PDGFR-β, platelet derived growth factor receptor β; Flt-3, FMS-like tyrosine kinase 3; c-KIT, stem cell factor receptor; VEGFR-2, vascular endothelial growth factor receptor 2.

In MDA-MB-231 (breast cancer), Mia-PaCa-2 (pancreatic cancer), and both HCT-116 and HT-29 (colon cancer) cell lines, inhibition of the Raf/MEK/ERK pathway by sorafenib, measured by phosphorylation of ERK, was dose dependent [Wilhelm et al. 2004]. Furthermore, a positive dose–response relationship from 7.5 to 60 mg/kg was observed in mice bearing human tumor xenografts given sorafenib daily for 9 days. At doses above 10–30 mg/kg, the area under the curve (AUC) observed in mice (62 µM h and 210 µM h, respectively) is higher than that observed in patients treated with the recommended dose of 400 mg bid continuously (121.7 µM h) [Chang et al. 2007; Clark et al. 2005]. Interestingly, not all cell lines demonstrate evidence of Raf/MEK/ERK pathway inhibition by sorafenib; however, activity against Colo-205 xenografts was observed in the absence of Raf/MEK/ERK pathway inhibition [Wilhelm et al. 2004]. The mechanism of activity of sorafenib was further clarified using both subcutaneous and orthotopic tumors derived from 786-O and Renca renal cell carcinoma (RCC) cell lines [Chang et al. 2007]. In these xenografts, dose-dependent tumor growth inhibition was observed at sorafenib doses from 15 to 90 mg/kg/day. Furthermore, antitumor efficacy appeared to be mediated by a dose-dependent decrease in tumor mean vessel area and resultant apoptosis, suggesting that sorafenib may function as a dose-dependent inhibitor of angiogenesis in tumors derived from these cell lines. Thus, the activity of sorafenib appears to involve inhibition of both tumor proliferative and angiogenic pathways.

Phase I experience

The safety and clinical activity of sorafenib were initially examined in a series of phase I studies conducted in patients with solid tumors, each evaluating different dosing schedules [Awada et al. 2005; Clark et al. 2005; Moore et al. 2005; Strumberg et al. 2005]. Pooled data obtained from these four phase I dose-escalation trials (employing doses ranging from 50 mg every other day to 800 mg twice daily) showed that sorafenib was well tolerated, especially when given at doses of 400 mg twice daily or less [Strumberg et al. 2007]. Adverse effects of any grade occurring in more than 20% of patients included fatigue (40%), anorexia (35%), diarrhea (34%), rash (27%), hand–foot skin reaction (HFSR; 25%), and nausea (22%). In three of the four trials 400 mg twice daily was considered the MTD, while 600 mg twice daily was considered the MTD in the ‘7 days on, 7 days off’ schedule [Clark et al. 2005]. At the 800 mg twice daily continuous dose, two of six patients experienced grade 3 diarrhea. Because the 400 mg twice daily dose was well tolerated, an intermediate dose of 600 mg twice daily was tested. At this dose level, 29% of 14 patients experienced DLTs, primarily skin toxicity, diarrhea, and fatigue. Based on the frequency of DLTs at higher doses, 400 mg twice daily continuously was determined to be the overall recommended dose and schedule for future studies [Strumberg et al. 2005].

Dose–toxicity relationship in phase I and II trials

Significant variability in sorafenib pharmacokinetics was observed between subjects in phase I trials. When the data were pooled, no clear relationship between the C_max and AUC of sorafenib and the severity of drug-related adverse events was noted [Strumberg et al. 2007]. Exposure increased nonlinearly with increased dose. In addition, in a separate phase I trial in patients with organ dysfunction, the concentrations of sorafenib and sorafenib’s major metabolite, N-oxide-sorafenib, did not correlate with degree of renal or hepatic impairment [Miller et al. 2009]. HFSR (8%) and diarrhea (6%) were the most common grade 3 adverse effects in phase I testing [Strumberg et al. 2007, 2006]. At the recommended dose and schedule, 15% of patients experienced grade 2/3 HFSR and 24% experienced grade 2/3 diarrhea. At 600 mg twice daily, HFSR was dose limiting while grade 3 diarrhea became prominent at the 800 mg twice daily dose [Strumberg et al. 2006]. In a pooled retrospective analysis of those patients receiving sorafenib doses at doses from 300–600 mg twice daily, those who experienced grade 2+ skin toxicity/diarrhea had a significantly increased time to progression compared with patients without such toxicity (p < 0.05) [Strumberg et al. 2006].

In a randomized phase II trial of sorafenib versus interferon in the frontline treatment of advanced RCC, sorafenib was escalated to 600 mg twice daily in 66.2% of the patients (n = 44) who progressed on the recommended dose and schedule [Escudier et al. 2009]. The most common toxicities at the higher dose were diarrhea (16.3%), anorexia (16.3%), fatigue (14.0%), HFSR (11.6%), and rash/desquamation (7.0%), but no patient discontinued the escalated dose because of adverse events and new adverse events at the higher dose were infrequent.

Toxicity at the recommended dose and schedule

In the pivotal phase III TARGET study of sorafenib versus placebo in pretreated advanced RCC (n = 903), doses were reduced in 13% of patients in the sorafenib group, as compared with 3% in the placebo group (p < 0.001) [Escudier et al. 2007]. Similarly, doses were interrupted due to adverse events in 21% of patients in the sorafenib group, as compared with 6% in the placebo group (p < 0.001), mainly due to dermatologic and gastrointestinal events. In this trial, investigators were allowed to re-escalate the dose if adverse events resolved to a grade of 1 or less at their discretion, but the frequency of re-escalation was not reported.

A similar distribution of adverse events was seen in the phase III SHARP trial (n = 602) in patients with advanced hepatocellular carcinoma [Llovet et al. 2008]. Hypophosphatemia (11%), diarrhea (8%), and HFSR (8%) were the most common grade 3 adverse effects. In the sorafenib arm, the dose was reduced due to adverse events in 26% of the patients versus 7% of the placebo group and the dose was interrupted due to adverse events in 44% versus 30% of the patients in each group, respectively. Eleven percent of patients in the sorafenib group versus 5% of patients in the placebo group discontinued treatment permanently due to drug-related adverse events.

A cautionary note regarding the toxicity of sorafenib at the recommended dose and schedule comes from published experiences outside of phase III clinical trials. In a prospective cohort of RCC patients treated at the Princess Margaret Hospital (n = 58) on an expanded access protocol, grade 3 adverse events were observed in 64% of patients with 62% requiring interruption of sorafenib dosing for toxicity [Riechelmann et al. 2008]. In a separate retrospective analysis of 24 unselected advanced RCC patients treated with sorafenib at the Medical College of Georgia, 73% experienced grade 3 HFSR and 63% required treatment interruption with a median time to treatment interruption of 2 weeks [La Vine et al. 2010]. Nonetheless, 38% of sorafenib-treated patients were successfully re-escalated to the recommended dose and schedule.

Dose–efficacy relationship

After progression at the recommended dose and schedule in the randomized phase II trial of frontline sorafenib in advanced RCC, tumor shrinkage was observed in 41.9% of 43 patients escalated to 600 mg twice daily [Escudier et al. 2009]. Although no Response Evaluation Criteria in Solid Tumors (RECIST) responses were seen, 39.5% showed stable disease. The median progression-free survival (PFS) in this group was 3.6 months. In a retrospective analysis, George and colleagues identified 14 patients escalated to 600 mg twice daily after progression on the recommended dose and schedule, 71% tolerated the dose escalation without grade 3 toxicities, and 8 patients had stable disease [George et al. 2008]. Four of six patients (67%) subsequently tolerated escalation to 800 mg twice daily. Mancuso and colleagues reported the results of 18 patients with metastatic RCC treated with sorafenib after previous VEGF receptor tyrosine kinase inhibitor (sunitinib or pazopanib) failure [Mancuso et al. 2009]. Of six patients that were escalated to a dose of 600 mg twice daily after RECIST progression at the recommended dose and schedule, three benefited with PFS of >3 months.

In an effort to further explore the dose–efficacy and dose–toxicity relationship in advanced RCC, Amato and colleagues presented the first results of a sorafenib dose-escalation trial in 2007 [Amato et al. 2007]. Forty four evaluable patients who were previously exposed to a maximum of one systemic therapy were treated with 400 mg twice daily of sorafenib on days 1 through 28, followed by 600 mg twice daily (days 29 through 56) and 800 mg twice daily on days 57 and beyond. Outcome measures included response rates, time to disease progression and overall survival. Ninety one percent of patients were escalated to daily doses of 1200 mg or 1600 mg. The median duration of therapy was 6 months. An unprecedented 8 patients had a complete radiographic response, while 14 patients had partial responses and 14 patients had stable disease for 6 months or longer. The results of an additional 22 patients treated on an expanded phase II trial using the same strategy were presented in 2008 [Amato et al. 2008]. Of 14 evaluable patients, all 14 were able to escalate to 800 mg twice daily. The response rate was 32% in this cohort and PFS was greater than 3 months in an additional 50% of patients. In a trial aimed at confirming these results, investigators at Stanford and the University of Nebraska presented the preliminary results of 13 patients treated using a similar protocol [Srinivas et al. 2009]. Although dose escalation was possible in 70% of the patients, early results do not yet show enhanced efficacy for this strategy. Preliminary results of these trials are summarized in Table 2.

Table 2.

Preliminary results of sorafenib dose escalation in clinical trials.

Disease setting	Evaluable (n)	Successful dose escalation (%)	Dose target	RECIST responses (%)	PFS (months)	Reference
Progression on recommended dose	43	100	600 mg bid	0	3.6	Escudier et al. [2009]
Maximum of one prior systemic therapy	44	91	800 mg bid	52	≥3 months	Amato et al. [2007]
Maximum of one prior systemic therapy	14	100	800 mg bid	32	≥3 months	Amato et al. [2008]
Treatment naive	13	70	800 mg bid	15	NR	Srinivas et al. [2009]

bid, twice daily; RECIST, response evaluation criteria in solid tumors; PFS, progression-free survival; NR, not reported.

We have completed accrual to a trial testing the feasibility of primary dose escalation or re-escalation after a dose reduction in a broad range of advanced solid tumors. In this trial, patients received the recommended dose and schedule for the first 4 week cycle, were escalated to 600 mg twice daily for cycle 2 and further escalated to 800 mg twice daily for cycle 3 if no grade 3 toxicities were observed. Patients who required dose reduction during the first cycle were escalated back to 400 mg twice daily if they tolerated a lower dose for the second cycle. Preliminary results are not yet available.

Considerations for future clinical trials

The molecular target of sorafenib (B-Raf, VEGFR-2, VEGFR-3, c-kit, Flt-3, etc) that is primarily responsible for its clinical efficacy is subject to speculation but the possibility that it has greater activity in RCC at higher doses is intriguing. Whether a similar strategy might also have enhanced activity in advanced hepatocellular carcinoma is unknown, although dose escalation may prove to be more difficult in patients with coexistent liver dysfunction.

While there is significant interpatient variability in the C_max and AUC of sorafenib at a given dose, skin toxicity correlates with intrapatient sorafenib concentrations [Hilger et al. 2004]. In the phase I setting, skin toxicity has also been shown to correlate with inhibition of phosphorylated ERK in peripheral blood leukocytes which serves as marker of Raf/MEK/ERK pathway activation. Therefore, it is possible to speculate that higher doses of sorafenib have increased activity due to improved inhibition of Raf/MEK/ERK pathway targets. Alternatively, higher doses may be more effective because elevated concentrations result in greater inhibition of alternative target pathways as observed in RCC xenografts [Chang et al. 2007]. Therefore, correlative analyses of clinical trials assessing the feasibility of sorafenib dose modification may shed light on the mechanisms responsible for its activity in a given tumor.

While the toxicity in large cohorts of patients treated with sorafenib in the community have not been reported, there is preliminary evidence that toxicity exceeds that reported in the literature when the agent is used in standard clinical practice. It is likely that dose escalation will not be possible in all patients, and prospective markers of escalation success will need to be defined. Selection criteria for dose escalation strategies in clinical trials could include low intrapatient sorafenib levels, the absence of toxicity, or polymorphisms in sorafenib kinase targets and metabolizing enzymes. Despite the preliminary reports of success, the results of ongoing trials are needed prior to applying this strategy to patients outside of clinical trials. In addition, should a dose-escalation strategy prove safe and effective in ongoing clinical trials, careful attention must be paid to the applicability of this strategy in the community setting. Several ongoing clinical trials that are evaluating dose-escalation strategies are listed on the ClinicalTrials.gov website (Table 3).

Table 3.

Ongoing trials evaluating sorafenib dose escalation strategies listed at ClinicalTrials.gov as of 15 July 2010.

Lead organization	Tumor type	Identifier
University of California, Davis	Advanced solid tumors	NCT00810394
University of Chicago	Advanced solid tumors	NCT00618982
University of Wisconsin, Madison	Non-small cell lung cancer	NCT00954278
Accelerated Community Oncology Research Network	Renal cell carcinoma	NCT00557830
University of Nebraska	Renal cell carcinoma	NCT00496756
Stanford University	Renal cell carcinoma	NCT00854620
The Methodist Hospital System	Renal cell carcinoma	NCT00445042
Bayer (Europe)	Renal cell carcinoma	NCT00618982

Conclusions

In summary, the recommended dose and schedule of sorafenib is well tolerated by many patients. The recommended dose and schedule was chosen because of skin and gastrointestinal toxicity seen in the first cycle at higher dose levels. Preliminary evidence suggests that certain patients tolerate escalation to dose levels higher than the current recommended dose and schedule in subsequent cycles. Furthermore, emerging studies imply that clinical activity may be enhanced by escalation above standard doses. These data provide the rationale for future trials which are needed to clarify the dose–toxicity and dose–efficacy relationships of sorafenib, to define the pathways affected by higher doses, and to explore the clinical utility of dose escalation and re-escalation.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

Dr Lara has received research funding from Bayer/Onyx Pharmaceuticals. The authors declare that there are no other potential conflicts of interest.

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Enhancing the clinical activity of sorafenib through dose escalation: rationale and current experience

Abstract

Keywords

Introduction

Discovery and preclinical pharmacodynamics

Phase I experience

Dose–toxicity relationship in phase I and II trials

Toxicity at the recommended dose and schedule

Dose–efficacy relationship

Considerations for future clinical trials

Conclusions

Footnotes

Funding

Conflict of interest statement

References