Motexafin Gadolinium for the Treatment of Metastatic Renal Cell Carcinoma: Phase II Study Results

Abstract and Introduction
Abstract

Background: Thioredoxin reductase (Trx) has been implicated in activation of hypoxia-inducible factor-1α, which is overexpressed in > 85% of renal cell carcinomas (RCCs). We evaluated the safety and efficacy of motexafin gadolinium (MGd), a Trx inhibitor, as a single-agent therapy for metastatic RCC.
Patients and Methods: Patients with metastatic RCC were infused daily with MGd 5 mg/kg on days 1-5 and days 15-19 of each 28-day cycle. Patients were evaluated for response on days 21-28 of every third cycle. Those with tumor response or stable disease (SD) continued treatment for ≤ 12 cycles. Twenty-five patients with confirmed metastatic RCC were enrolled. All were evaluable for toxicity, and 20 were evaluable for response.
Results: While no clinical responses were observed, 8 patients had SD after 3 treatment cycles, as did 4 after 6 cycles. Median overall survival was 10.1 months, and median progression- free survival was 2.7 months. The most common treatment-related toxicities were grade 1/2 pain, nausea, skin discoloration, fatigue, blisters, and headache. The most common grade 3 toxicity was hypophosphatemia, observed in 5 patients. MGd was reasonably tolerated, and disease stabilization was observed in several patients with metastatic RCC.
Conclusion: These results show promise for the use of MGd in combination with other molecularly targeted therapies in previously treated patients with metastatic RCC. However, further investigation of MGd alone for metastatic RCC is not recommended.
Introduction

Renal cell carcinoma (RCC) remains one of the more problematic human cancers. In 2008, an estimated 54,390 people were expected to be diagnosed with the disease and 13,010 to die from it.[1] Renal cell carcinoma arises in the tubal epithelium, often as the result of von Hippel-Lindau (VHL) tumor suppressor gene inactivation.[2,3] By some estimates, up to half of all patients with RCC present with metastatic disease at diagnosis, and metastasis occurs in 20%-30% of patients with early-stage disease treated with radical or nephronsparing nephrectomy.[4,5] Treatment is further complicated by RCC's resistance to cytotoxic therapy and radiation therapy (RT).[2,6] Consequently, the median overall survival (OS) for all patients with metastatic RCC is 10 months.[7]

In an effort to identify more effective metastatic RCC treatments, researchers have explored specific disease pathways and molecular targets associated with cancer in general and metastatic RCC in particular. Up to 60% of all RCC cases arise from mutations in the VHL tumor suppressor gene, which deregulates and induces hypoxia-responsive genes involved in the regulation of vascular endothelial growth factor (VEGF) and angiogenesis.[8-10] In December 2005/January 2006, the oral tyrosine kinase (TK) inhibitors sunitinib and sorafenib were approved for first- and second-line treatment, respectively, of patients with metastatic RCC.[11,12] Both agents selectively target receptor TKs that regulate VEGF, platelet-derived growth factor, and c-Kit.

Overexpression of the transcription factor hypoxia-inducible factor (HIF)-1α has been associated with a variety of human cancers and VHL disease,[13-16] which has in turn spawned interest in targets associated with the HIF transcription cascade. Temsirolimus (formerly known as CCI-779) is a cell-cycle and mammalian target of rapamycin (mTOR) inhibitor that acts on the HIF transcription cascade and other tumor-promoting pathways. It recently joined sunitinib as the only other molecularly targeted agent recommended for first-line therapy against advanced RCC.[17] Each of these new agents has produced significantly better response rates and have prolonged progression-free survival (PFS) compared with traditional cytokine therapy.[11,12,17]

Another target associated with the HIF transcription cascade is thioredoxin (Trx). Increases in Trx expression in cancer cells have recently been linked to increases in HIF-1α in these same cells,[18] and Trx inhibitors, by extension, have been shown to inhibit HIF-1α.[19] One promising Trx inhibitor is motexafin gadolinium (MGd), a rationally engineered aromatic macrocycle (texaphyrin) developed to interact with and weaken cellular processes by generating reactive oxygen species (ROS). MGd has been found to inhibit Trx directly by transferring electrons from enzyme cofactors to form ROS and indirectly by increasing intracellular levels of free zinc, a known Trx inhibitor.[20-22] Preclinical studies have demonstrated that MGd enhances tumor cell cytotoxicity in combination with radiation and chemotherapy in a variety of in vitro and in vivo tumor models. Mice treated with MGd in conjunction with radiation had delayed tumor regrowth and improved survival compared with mice treated with radiation alone.[23] Additionally, the cytotoxicities of bleomycin, doxorubicin, carboplatin, docetaxel, and temozolomide were all enhanced in MGd combination regimens.[24-30]

Clinically, MGd has been studied most extensively in patients with cancers that metastasized to the brain.[31,32] The first trial studied patients with brain metastasis from a variety of primary cancers who received whole-brain RT (WBRT) with or without MGd. While no significant differences in survival or time to neurologic progression were noted for the entire population of trial patients, the study did note improved PFS (P = .048) in patients with non- small cell lung cancer (NSCLC).[33] A subsequent international randomized trial of the same therapeutic regimen specifically targeted patients with NSCLC with brain metastases. That trial also noted improved neurologic progression times with MGd (15.4 months with MGd vs. 10 months for WBRT alone; P = .12).[34]

Because of the near-simultaneous approval of new metastatic RCC therapies that act on VEGF and the HIF transcription cascade, Trx inhibitors such as MGd should be explored as potential candidates in the treatment of metastatic RCC. The current study assessed the efficacy of MGd as a single-agent therapy for metastatic RCC.Patients

Patients in this study were adults (aged ≥ 18 years) with histologically confirmed metastatic RCC who were deemed ineligible for interleukin-2 therapy or had received ≤ 2 previous treatments. All had previously undergone nephrectomies. Measurable disease was confirmed using Response Evaluation Criteria in Solid Tumors (RECIST).[35] Eligibility also required adequate hematologic function (white blood cell count ≥ 3000 cells/mm3, absolute neutrophil count ≥ 1500 cells/mm3, hemoglobin ≥ 9 g/dL, and platelets ≥ 100,000 cells/mm3); serum creatinine ≤ 2 mg/dL, total bilirubin and aspartate aminotransferase or alanine aminotransferase ≤ 2 times upper limit of normal (ULN), alkaline phosphatase ≤ 5 times ULN, and an Eastern Cooperative Oncology Group (ECOG) score of 0-2.[36]

Patients provided written informed consent and agreed to use contraception if procreative potential existed. Exclusion criteria included evidence of brain metastasis within the year before the study, surgical resection, or other RCC therapies within 4 weeks before enrollment or a known history of uncontrolled hypertension, diabetes mellitus, or HIV infection. Patients who were pregnant (as confirmed by β-human chorionic gonadotropin [β-HCG)]) or lactating were excluded from the study.
Pretreatment Evaluation

Baseline evaluation was conducted within 14 days of starting treatment and consisted of a medical history; physical examination with ECOG PS; vital signs; hematology, coagulation, and chemistry profile; and computed tomography scan of the chest, abdomen, and pelvis. A β-HCG pregnancy test was administered to all female patients of childbearing potential within 14 days before initiating treatment.
Treatment Regimen

The study was designed to administer ≤ 6 28-day cycles of therapy. The investigator and trial sponsor could elect to continue treatment for ≤ 12 cycles in patients who were tolerating and benefiting from therapy. Eligible patients were infused daily with MGd 5 mg/kg on days 1-5 and days 15-19 of each 28-day cycle. Preclinical trials in the treatment of other cancers have established that MGd at this dose level is tolerable. Days 6-14 and 21-28 were considered rest days in every cycle. Patients were evaluated for response on days 21-28 of cycles 3 and 6. If patients were stable or responding to therapy at cycle 6, they continued on study and were evaluated for response at the end of cycles 9 and 12.
Evaluation and Response Criteria

Laboratory assessments were performed within 72 hours before each treatment cycle. Before starting therapy on day 1 of each cycle, patients received physical examinations with ECOG PS and vital signs and had complete hematology and chemistry profiles. Before day 15 of each cycle, vital signs and complete hematology and chemistry profiles were measured. Blood pressure was monitored at each MGd infusion. Toxicity assessments were performed before and concurrent with therapy and were scored according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).[37] RECIST definitions were applied to assessments of complete response (CR), partial response (PR), progressive disease, and stable disease (SD).[35]
Statistical Considerations

The trial was based on a Simon 2-stage clinical trial design.[38] The study's design called for enrolling approximately 43 patients but discontinuing enrollment if ≤ 2 responses were observed after cycle 3 in the first 22 patients evaluated. However, patients with tumor response or SD after cycle 3 continued through cycle 6, and patients tolerating and benefiting from treatment could continue ≤ 12 cycles. Because the response criteria for continuation were not met, the study of MGd alone was closed early. The study's primary objective was to assess the clinical response rate (CR and PR) to MGd in patients with metastatic RCC. Secondary endpoints were the combined clinical benefit rate (including SD along with CR and PR), PFS, and OS. Progression-free survival was defined as the time from first dose to disease progression, and OS was defined as time from first dose to death. Progression-free survival and OS were plotted using Kaplan-Meier curves (Figures 1 and 2).