Clinical Trial Reports: September 2007

%u25BA PHASE IV Obesity a Major Risk Factor for Multiple Myeloma

Investigators following the continuing natural histories of the more than 135,000 people enrolled in the Nurses Health Study and the Health Professionals Follow-up Study have confirmed a suspected link: obesity and multiple myeloma. They found that increasing body mass index (BMI) correlates with increasing incidence of multiple myeloma.

Cancer Epidemiology, Biomarkers & Prevention

The authors of an article appearing in the July 2007 issue of indicated that 215 cases of multiple myeloma had been confirmed among the two studies’ 136,623 participants. The incidence of multiple myeloma was twice as high in men with a BMI of 30 kg/m² compared with patients whose BMIs were below 22 kg/m². The incidence of multiple myeloma but the effect was not as strong.

Risk of Multiple Myeloma in Relation to Body Mass Index

Reference Group

Relative Risk

Men with BMI < 22.0 kg/m²

1.0

Men with BMI ≥ 30 kg/m²

2.4

Women with BMI 25—29.9 kg/m²

1.6

Women with BMI ≥ 30 kg/m²

1.2

The researchers believe that this research indicates that people can help reduce their risk of multiple myeloma, although it is not known why the relative risk is more low in lean individuals compared with those of normal body weight (BMI, 25 kg/m²).

Birmann BM, Giovannucci E, Rosner B, et al: Body mass index, physical activity, and risk of multiple myeloma.

2007;16:1474-1478

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Cancer Epidemiol Biomarkers Prev

%u25BA PHASE III

Long-Term Safety of Adjuvant Trastuzumab (Herceptin)

Adjuvant trastuzumab (T) for the treatment of early-stage breast cancer with human epidermal growth-factor receptor-2 (HER-2) overexpression has been shown to reduce recurrence and increase survival. Long-term safety issues are still in question, however, especially regarding long-term cardiotoxicity and specific patterns of relapse such as brain metastases. Italian researchers recently assessed the magnitude of those two risks by performing a literature-based meta-analysis.

Five randomized clinical trials were included in the evaluation, totaling 11,187 patients. The follow-up in these trials averaged two years. Three of the trials reported results for brain metastases (6,738 patients). A significant increased risk of grade III or IV congestive heart failure was found in the trastuzumab arm (absolute difference, 1.61 percentage points; P < .00001). The authors note that this can be interpreted to mean that 62 patients must be treated to reveal harm to one.

They also observed a higher risk of asymptomatic leftventricular ejection fraction reduction in the patients taking trastuzumab (absolute difference, 7.20 percentage points; P < .00001). These researchers from the Regina Elena National Cancer Institute in Rome found that the incidence of brain metastases was significantly greater in the trastuzumab arm of the trials (absolute difference, 0.62 percentage points; P = .033). This small absolute difference translates into 161 patients having to be treated for one to have brain metastases.

Rates for disease-free survival and overall survival were significantly better in the trastuzumab arms of each of these trials. The authors conclude that although trastuzumab has been shown to be an important oncological discovery, “the biological activity of the drug needs to be investigated more extensively for long-term safety and specific relapse patterns.”

Bria E, Cuppone F, Fornier M, et al: Cardiotoxicity and incidence of brain metastases after adjuvant trastuzumab for early breast cancer: The dark side of the moon? A meta-analysis of the randomized trials

July 19, 2007 (E-pub, ahead of print).

. Breast Cancer Res Treat

%u25BA PHASE III Bevacizumb (Avastin) Helps Slow Tumor Growth in Patients with Advanced Non-Small-Cell Lung Cancer

Christian Manegold, MD, Professor of Medicine, University of Heidelberg, Germany, provided the results of a multicenter, randomized, double-blind, Phase III study of bevacizumab (Avastin) in combination with cisplatin and gemcitabine in chemotherapynaive patients with advanced or recurrent non-squamous non—small-cell lung cancer (NSCLC) were presented. In the study, patients were randomized to receive either chemotherapy alone or chemotherapy plus either a standard dose of bevacizumab or a lower dose.

Thirty-four percent of patients in the lowdose bevacizumab group and 30% of those in the high-dose bevacizumab group saw their tumors shrink, compared with only 20% in the chemotherapy-alone group. The duration of response was 6.1 months in both bevacizumab groups versus 4.7 months in the control group. These data confirm earlier results showing a benefit for bevacizumab.

Dr. Manegold stated, “There have been some advances, but we have reached a treatment plateau and we need more agents which may help us to offer better treatment to patients. We were able to confirm that Avastin (bevacizumab) adds efficacy to standard chemotherapy and provides hope for patients suffering from a deadly disease.”

Approximately 9% of patients taking the higher dose of bevacizumab experienced hypertension, compared with 6% in the lowerdose group and 2 % in the chemotherapy-only group. Up to 1.5% of patients in the low-dose bevacizumab group suffered from lung bleeding, compared with <1% in the high-dose bevacizumab and chemotherapy-only groups.

“It’s a step-wise improvement that we are making,” said Roy S. Herbst, MD, PhD, Professor of Medicine at the University of Texas M.D. Anderson Cancer Center and moderator of a panel on treatments for difficult-to-treat cancers.

Although both doses of bevacizumab appeared to be similarly effective in stemming tumor growth, the trial was not designed to compare the doses, so definitive conclusions about dosing cannot be made without further investigation.

Bevacizumab is a humanized anti—vascular endothelial growth factor (VEGF) monoclonal antibody for the treatment of solid tumors. It was the first commercially available angiogenesis inhibitor. It is approved by the U.S. Food and Drug Administration for use in combination with intravenous 5-fluorouracil-based chemotherapy for the first- or secondline treatment of metastatic carcinoma of the colon or rectum, and in combination with carboplatin and paclitaxel for the first-line treatment of unresectable, locally advanced, recurrent or metastatic NSCLC.

Presented at the American Society of Clinical Oncology 43rd Annual Meeting: Abstract LBA7514. Presented June 2, 2007.

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PHASE III Addition of Bevacizumab to Interferon Alfa 2a Nearly Doubles Median Progression-Free Survival in Patients with Previously Untreated Advanced Kidney Cancer

Results of the pivotal, Phase III AVOREN trial were presented by Bernard Escudier, MD, Institut de cancerologie Gustave Roussy, Villejuif, France in a plenary session. The AVOREN trial was conducted to evaluate the efficacy and safety of bevacizumab in combination with interferon alfa 2a as a first-line treatment in metastatic renal-cell carcinoma (RCC). Dr. Escudier was the principal investigator of the study.

In the trial, nephrectomized patients with metastatic RCC, no central nervous system metastases, and adequate organ function were randomized to receive interferon alfa 2a (9 MIU thrice weekly) plus either bevacizumab (10 mg/kg every two weeks) or placebo until disease progression. Tumor assessments were performed every 8 weeks until Week 32 and every 12 weeks thereafter. A total of 649 patients at 101 centers in 18 countries were randomized.

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P

The addition of bevacizumab to interferon alfa 2a significantly increased progression-free survival (10.2 vs. 5.4 months; < 0.0001) and objective tumor response rate (30.6% vs. 12.4%; < 0.0001). In addition, a trend toward improved overall survival was observed with the addition of bevacizumab to interferon alfa 2a.

The most common adverse events that occurred more often in the combination-therapy arm included bleeding, hypertension, and proteinuria. Grade 3/4 fatigue occurred in 23% of patients in the combination-therapy arm, compared with 15% in the interferon alfa 2a arm.

The study was originally designed to measure an improvement in overall survival. However, in prior consultation with the U.S. Food and Drug Administration and European regulatory authorities, the primary analysis endpoint was revised to assess improvement in progression-free survival. The study protocol specified an interim overall survival analysis be performed at approximately 50% of events. That interim analysis showed a trend toward an increase in overall survival. However, the final survival data are still pending.

The benefits of bevacizumab observed during the trial were so positive that based on earlier interim results in December 2006, the Drug Safety Monitoring Board recommended that the trial was unblinded, and all patients were offered treatment with bevacizumab.

“Patients with metastatic RCC often express elevated levels of vascular endothelial growth factor, or VEGF,” said Dr. Escudier. “These data suggest that specifically blocking VEGF with Avastin may provide important clinical benefit for patients with this difficult-to-treat disease.”

Escudier B, et al. A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/ interferon-2a vs. placebo/interferon-2a as first-line therapy in metastatic renal cell carcinoma

2007;25 (No 18S).

. Journal of Clinical Oncology

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PHASE III New Hope for the Treatment of Advanced Melanoma

Final results of the largest randomized, Phase III trial of adjuvant pegylated interferon alfa-2b ever conducted in patients with resected, Stage III melanoma were revealed at the 43rd American Society of Clinical Oncology annual meeting, Chicago, Illinois in an oral presentation given by Alexander M. Eggermont, MD, PhD, lead investigator of the study and head of the Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.

The investigators enrolled a total of 1,256 patients with stage III melanoma. Participants were either observed or given pegylated interferon alfa-2b at a dose of 6 μg/kg per week for 8 weeks (induction phase) followed by 3 μg/kg per week (maintenance phase), for a total treatment duration of 5 years.

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Median relapse-free survival was 34.8 months in the pegylated interferon alfa-2b arm vs. 25.5 months in the observation arm ( = 0.01). Median distant metastasis—free survival was 45.6 months and 36.1 months, respectively ( = 0.11). Response was most pronounced among patients with only microscopic nodal involvement, a group that represented 43% of the total study population.

During the induction and maintenance phases, respectively, study enrollees attained a median 88% and 83% of planned dose intensity. Grade 3/4 toxicities were reported in 45% of patients in the pegylated interferon alfa-2 group and 12% of the observation group. The majority of these events were Grade 3 fatigue, hepatotoxicity, and depression. An Eastern Cooperative Oncology Group (ECOG) 0-1 Performance Status was maintained in 83 % of patients during the maintenance phase. Forty percent of patients in the pegylated interferon alfa-2 group discontinued treatment because of toxicity, and 23% of patients in this group continued to Year 4 or Year 5 of treatment.

Although these data represent the planned final analysis (with a median follow-up period of 3.8 years), study participants will be followed for survival for a total of 10 years.

Dr. Eggermont stated, “Advanced stage melanoma remains difficult to treat and a need still exists to find treatment options. These findings demonstrate the benefit of an increased relapse-free survival despite no difference in overall survival.”

This is an important study because it establishes the efficacy of a new agent for Stage III melanoma. Currently, effective treatment options for patients with Stage III melanoma are extremely limited. In addition, the subanalysis in patients with only microscopic nodal involvement provides important information. Owing to the increased use of sentinel node staging, this patient population is made up largely of persons with Stage III disease. Safety in the pegylated interferon alfa-2 group was acceptable. The occurrence of Grade 3/4 (mostly Grade 3) toxicities in 45% of patients was offset by the maintenance of good performance status.

Currently, pegylated interferon alfa-2b is approved in the US for use alone or with ribavirin for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and who are at least 18 years of age.

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PHASE II Leukemia Treatment With Fludarabine Plus Cyclophosphamide

The standard treatment for chronic lymphocytic leukemia (CLL) should be fludarabine plus cyclophosphamide, according to a study by British researchers that found significantly better progression-free survival than monotherapy with fludarabine or chlorambucil. They did caution, however, that patients who have the 17p gene deletion did not respond well to the treatment.

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The 777 study participants with CLL were randomized to receive one of three therapies: (1) fludarabine given for six courses, (2) chlorambucil given for 12 courses, or (3) a combination of the two agents. At five years, progression-free survival was significantly better with the combination of the two agents (36% vs. 10% with each of the monotherapies; < .00005). The two-drug combination also had a higher treatment response rate. The three treatment regimens had an overall survival that was comparable.

Fludarabine, alone or in combination with cyclophosphamide, was more likely to cause neutropenia and longer hospital stays than chlorambucil. There was less hemolytic anemia noted with the drug combination treatment than with either monotherapy.

Responders had a better quality of lifethan nonresponders, the authors acknowledged, although the drug treatment had no effect on quality of life per se.

Catovsky D, Richards S, Matutes E, et al: Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): A randomised controlled trial

2007;370:230-239.

. Lancet

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PHASE II Study Supports Activity of Gemcitabine HC1 for Injection (Gemzar) in the Treatment of Early-Stage Breast Cancer

Gemcitabine HC1 for injection (Gemzar), approved in combination with paclitaxel (Taxol) in the first-line, postsurgical treatment of metastatic breast cancer, showed encouraging results in the presurgical treatment of breast cancer.

Results showed that adding gemcitabine HC1 for injection to the current standard-ofcare treatment was a promising regimen for patients with stage II—III breast cancer. Eli Lilly and Company, the manufacturer and marketer of Gemzar, also cited five completed or ongoing Phase III trials which will further study Gemzar as a chemotherapeutic foundation for the treatment of early-stage breast cancer.

The Phase II study evaluated the addition of gemcitabine HC1 for injection to the current standard of care of epirubicin and cyclophosphamide followed by paclitaxel in patients with stage II—III breast cancer. The treatment schedule was a dose-dense sequential neoadjuvant (presurgical) chemotherapy combination, meaning that the combination was administered at shorter intervals between treatments. Results showed a promising regimen in terms of pathologic complete response (pCR-the absence of invasive tumor in the breast). In addition, patients who tested positive for the HER-2 gene also were given trastuzumab (Herceptin) and demonstrated additional response.

“The data released today reflect our ongoing, aggressive research plan involving Gemzar as a key therapeutic foundation for the treatment of breast cancer,” said Allen Melemed, MD, Medical Director, Global Oncology at Lilly. “We are encouraged with the activity Gemzar has shown in this breast cancer study.”

Enrollment has been completed in one trial, and is ongoing in an additional four, Phase III early-stage breast cancer studies evaluating the addition of gemcitabine HC1 for injection to commonly used treatment regimens. Two adjuvant (postsurgical) therapy trials, NSABP B-38 (4,400 patients) and TANGO (3,000 patients), will compare the addition of Gemzar with the paclitaxel arm of each study. A third adjuvant trial, SUCCESS (3,600 patients), will compare the addition of Gemzar with a docetaxel-based regimen. Two additional trials, which are neoadjuvant specific, NSABP B-40 (1,200 patients) and Neo-TANGO (800 patients), will evaluate the addition of Gemzar to the paclitaxel or docetaxel arm of the treatment regimen.

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PHASE II Refractory SoftTissue Sarcoma Treatment

There is no standard treatment for patients with advanced soft tissue sarcoma (STS) after previous chemotherapy with ifosfamide and anthracyclines. A multicenter Phase II study of the German sarcoma group (AIO-001) has evaluated the efficacy of bendamustine hydrochloride, a bifunctional alkylating drug, in previously treated individuals.

A total of 101 cycles (median, 2 cycles; range, 1—8 cycles), 21 as second-line treatment and 15 as third-line treatment were given to 36 screened patients (mean age, 55 yr) who participated in the study. The intravenous infusion of bendamustine 100 mg/m2 was administered over 30 minutes on two consecutive days and repeated every 28 days.

According to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, the best overall response was one partial remission (3%), whereas 31% experienced disease stabilization. Of the 15 patients with leiomyosarcoma histology, six (40%) attained stable disease. For all histologic subtypes, three-month and six-month survival rates were estimated to be 35.3% and 23.5%, respectively.

Bendamustine was well tolerated in patients with refractory STS, the researchers commented, with a mild toxicity profile. The drug seems to be moderately effective, they added, especially in patients with leiomyosarcoma histology.

Hartmann JT, Mayer F, Schleicher J, et al: Bendamustine hydrochloride in patients with refractory softtissue sarcoma: A noncomparative multicenter phase 2 trial of the German Sarcoma Group (AIO-001)

June 28, 2007.

. Cancer

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PHASE II Gefitinib Monotherapy Trials

Patients with non—small-cell lung cancer who respond well to gefitinib typically are found to have epidermal growth factor receptor (EGFR) mutations. In order to better understand the efficacy and safety of selecting patients to be given gefitinib based on their genotype, researchers from Boston, Massachusetts, compiled available data from Phase II and prospective trials of gefitinib.

Gefitinib is a EGFR tyrosine-kinase inhibitor (TKI). These investigators from the Harvard Medical School identified five studies, totaling 101 patients with non—small-cell lung cancer who were EGFR-mutation positive and received gefitinib 250 mg/day.

Gefitinib was given to 59 individuals as their first line of therapy and 42 patients after they underwent chemotherapy. In the 99 evaluable patients, the combined rate of complete and partial response (CR PR) was 80.8%, with only 7.1% had progressive disease instead of stable disease or at least partial response. This figure did not change significantly when patients were stratified by mutation type.

The median progression-free survival time ranged between 7.7 and 12.9 months. Most patients patients with EGFR mutations had objective responses with gefitinib monotherapy, the researchers stated. They added that the clinical benefits were similar regardless of whether the patients had the L858R and deletion 19 mutations.

Costa DB, Kobayashi S, Tenen DG, et al: Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non—small cell lung cancers

2007;July 2, 2007 (E-pub, ahead of print).

. Lung Cancer

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PHASE II Decreasing PSA, Decreasing Prostate Tumor Size

Despite the use of treatments to interfere with production of androgens in patients with prostate tumors, recent studies have indicated androgens are still produced inside the tumors, even in castrated patients. Since abiraterone is a selective inhibitor of CYP450c17, the key enzyme in androgen synthesis, it was hypothesized that this oral agent might better prevent the body from producing testosterone. According to new research, it has been shown to decrease blood levels of prostate-specific antigen (PSA), a prostate cancer marker, by 50%, according to British and American researchers. They reported early results of two ongoing Phase II trials of abiraterone in men with advanced prostate cancer and also demonstrated that the drug reduced the size of tumors in men with continued prostate cancer growth even while receiving treatment.

The study participants had been medically or surgically castrated to prevent testosterone production. They received a daily dose of abiraterone 1 g.

In the first study of 34 men who had not previously undergone chemotherapy treatment, 22 patients experienced a drop of at least 50% in their PSA levels after two months. The researchers noted that in some individuals the tumors shrank.

The 28 men in the second study had continued tumor growth despite being treated with docetaxel, a standard chemotherapy drug. Declines of more than 50% in PSA levels lasting at least three months were seen in 10 (36%) of these subjects.

To date, no major irreversible side effects have been reported in either study.

Attard G, Reid A, MolifeR, et al: Abiraterone, an oral, irreversible, CYP450c17 enzyme inhibitor appears to have activitiy in postdocetaxel castration refractory prostate cancer patients. Presented at the annual meeting of the European Society for Medical Oncology, July 5—8, 2007, Lugano, Switzerland.

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PHASE II Cetuximab Treatment for Patients With Advanced Hepatocellular Carcinoma

Patients with hepatocellular carcinoma (HCC) frequently experience increased ligand expression and activity of epidermal growth factor receptor (EGFR). A Phase II study was recently conducted by Boston researchers who used cetuximab, a chimeric monoclonal antibody that binds specifically to EGFR, for the treatment of patients with advanced HCC.

The study group comprised 30 patients. Criteria for inclusion was metastatic or unresectable measurable HCC, a score of no more than 3 based on the Cancer of the Liver Italian Program criteria, sufficient organ functions, and a rating of no greater than 2 on the Eastern Cooperative Oncology Group performance score.

After an initial intravenous dose of cetuximab 400 mg/m², infusions of 250 mg/m² were given weekly. Each cycle consisted of six consecutive weekly treatments. In general, all treatment was well tolerated.

Although tumor responses were not seen in any of the subjects, stable disease was noted in five patients (median time, 4.2 mo; range, 2.8—4.2 mo). The median survival was 9.6 months, and the median progression-free survival of 1.4 months.

Cetuximab displayed no antitumor activity in HCC, the researchers acknowledged, but it could be safely administered with tolerable toxicity profiles.

Zhu AX, Stuart K, Blaszkowsky LS: Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma

2007;June 21 (E-pub, ahead of print).

. Cancer

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PHASE I Radiation-Induced Vision Loss Curtailed by Cancer Drug

Archives of Ophthalmology

Vision loss as a result of radiation therapy for eye cancer may be controlled by injecting a widely used cancer drug into the eye. A study by New York researchers of six patients who were given plaque radiation retinopathy and were treated with intravitreal injections of bevacizumab every six to eight weeks was recently reported in the medical journal .

All of the patients reported improved vision after three months. Improved visual acuity or sharpness occurred in two patients, while four noticed less haze and distorted vision. After the treatment ended, there was no sign of reduced visual acuity. Bevacizumab stabilized or improved vision by decreasing abnormal blood vessel growth, swelling, and leakage in the eye, which the researchers noted are the major causes of irreversible vision loss for subjects with radiation retinopathy. No clinical side effects were seen within eight months of completing therapy.

According to the researchers, this finding is especially promising because, until the use of bevacizumab, there was no effective treatment for macular radiation retinopathy. They advise that larger trials are necessary before widespread use can be recommended.

Finger PT, Chin K: Antivascular endothelial growth factor bevacizumab (Avastin) for radiation retinopathy

2007; 125:751-756.

. Arch Ophthalmol