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Clinical Trial Reports

OBTN, July 2008, Volume 2, Issue 7

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Clinical Trial Reports

Phase III

Does Finasteride Prevent Prostate Cancer?

Finasteride has been used for many years in the treatment of benign prostatic hyperplasia (BPH) to improve the symptoms associated with enlarged prostate. However, it was not known if finasteride simply improved symptoms or actually helped prevent prostate cancer. Researchers from the Prostate Cancer Prevention Trial (PCPT) sought to determine the answer to this question, and found some encouraging results.

In this phase III trial, clinicians from the University of Texas Health Science Center, San Antonio, utilized a logistic regression model to evaluate men in the PCPT placebo group. In order to predict prostate cancer during the study’s subsequent seven years, prostate cancer risk at entry was assessed. No one was included if their prostate-specific antigen (PSA) level exceeded 3.0 ng/mL. The extent that finasteride may affect prostate cancer prevention was evaluated across risk and PSA strata.

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P

Participants in each risk quintile experienced a significant reduction of prostate cancer risk with finasteride treatment. The risk of prostate cancer was cut by at least 28% (Figure) ( ≤ .05). Although the benefit of finasteride use did not appear to trend with increasing or decreasing overall risk, there did seem to be some association with baseline PSA level. For example, the odds ratio increased (smaller treatment effect of finasteride) from 0.60 for those with PSA levels below 0.7 ng/mL to 0.69 for men with PSA concentrations from 1.8 to 3.0 ng/mL. However, the treatment effect still continued to be statistically significant, even at the highest PSA concentration ( < .001).

Likelihood of Cancer Decreased With Finasteride Use,Regardless of Prostate Cancer Risk

Risk Quintile*

Odds Ratio

1

0.72

2

0.52

3

0.64

4

0.66

5

0.71

* Highest risk is 5.

The risk of prostate cancer was significantly reduced by finasteride treatment, the researchers concluded, regardless of the level of this risk. That suggests, they added, that finasteride has both treatment and preventive effects, and all men should be made aware of the agent’s potential to reduce prostate cancer risk when they have PSA screenings.

Thompson IM, Tangen CM, Parnes HL, et al: Does the level of prostate cancer risk affect cancer prevention with finasteride?

2008;71:854-857.

Urology

Phase IIILapatinib Plus Trastuzumab for Patients With Progressing Metastatic HER-2—Positive Breast Cancer

Approximately 25% to 30% of patients with breast cancer are HER-2 positive, and this is a particularly aggressive form. Results from a first-ever randomized, multicenter, open-label phase III trial demonstrated that the combination of two targeted agents, lapatinib plus trastuzumab produced positive outcomes for women with HER-2 breast cancer.

The study group comprised 296 subjects with HER-2 positive breast cancer whose disease had progressed with the use of prior trastuzumab treatment. They were randomized to receive either treatment with lapatinib 1,000 mg/day plus trastuzumab 2 mg/kg weekly after a 4 mg/kg loading dose, or lapatinib 1,500 mg/day alone. All of the participants had previously received anthracycline and taxane therapy, and a median of six prior chemotherapy regimens.

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The Figure shows that progression-free survival and clinical benefit rate at 24 weeks were significantly improved with the combination therapy, although the absolute difference in terms of time was limited. The researchers pointed out that response rate and overall survival were not different between groups. Generally, both treatment regimens were well tolerated although grades 1 and 2 diarrhea occurred more frequently in the combination therapy group (53% vs. 41%, = .03). Symptomatic decreases in left ventricular ejection fraction were noted in the two patients in the combination group and in one in the monotherapy group. One patient receiving combination therapy died as a result of cardiac toxicity.

Progression-Free Survival Improved With Lapatnib + TrastuzumabTreatment In HER2 + Metastatic Breast Cancer

Lapatinib + Trastuzumab

Lapatinib Alone

PFS (median, wk)

12.0

8.4*

OS (median, wk)

51.6

39.0

* P = .03. Not statistically significant.PFS = Progression-free survival; OS = overall survival.

The investigators concluded that the combination of lapatinib and trastuzumab showed encouraging results in patients with metastatic breast cancer whose HER2-positive disease had progressed with the use of trastuzumab alone. They noted that the addition of lapatinib did not significantly change patients’ exposure to adverse events related to therapy.

O’Shaughnessy J, Blackwell KL, Burstein H, et al: A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. Presented at the 2008 annual meeting of the American Society of Clinical Oncology, Chicago, May 31, 2008.

Phase IIIBreast Cancer Risk Reduced With Raloxifene, but for Which Subgroups of Women?

The Raloxifene Use for The Heart (RUTH) trial originally enrolled more than 10,000 postmenopausal women with coronary heart disease (CHD) or multiple CHD risk factors. In the original trial, the RUTH investigators found that although raloxifene reduced the risk of invasive breast cancer and vertebral fractures it did not reduce the risk of cardiovascular events over a median follow-up of 5.6 years. In this subgroup analysis, the RUTH researchers reported on the extent of breast cancer protection using raloxifene 60 mg.

Data from the original study revealed that raloxifene reduced the risk of invasive breast cancer by 44% (hazard ratio [HR] = 0.56) compared with women who did not take the drug. In the drill-down analysis, the RUTH researchers found that of the 5,044 women given raloxifene, 55% had a reduction in the risk of developing invasive estrogen receptor—positive breast cancer (HR = 0.45), compared with 5,057 women receiving a placebo. The clinicians pointed out that that corresponds to an absolute reduction in risk of 1.2 cases per 1,000 women treated for one year.

Raloxifene therapy did not appear to affect the risk of either invasive or noninvasive ER-negative breast cancer, according to the investigators. After adjusting for age, body mass index, prior hormone use, or baseline risk of breast cancer, the results were unaffected. In view of the side effects associated with raloxifene, they concluded that their findings of benefit being restricted to patients with ER-positive breast cancer can be an important consideration in the patient and clinician discussion of risk versus benefit of using raloxifene.

Grady D, Cauley JA, Geiger MJ, et al: Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk.

2008;100: 854-861.May 31, 2008.

J Natl Cancer Inst

Phase IIIErlotinib Treatment for the Elderly With Advanced Non—Small-Cell Lung Cancer

Survival after initial therapy fails for non—small-cell lung cancer (NSCLC) can be particularly grim. Previous research has determined that erlotinib can have positive effects in patients with NSCLC who failed first- or second-line treatment. A research group from the Department of Medical Oncology, Princess Margaret Hospital, Toronto, Canada, sought to determine whether age at time of treatment affects patients’ response to erlotinib.

A total of 731 patients enrolled in this double-blind study (National Cancer Institute of Canada Clinical Trials Group Study BR.21) and were randomly assigned to receive either erlotinib 150 mg daily or placebo. The clinicians analyzed endpoints including progression-free survival and overall survival, quality of life (QOL), drug exposure, response, and toxicity. Patients were stratified into two age groups of the elderly (≥ 70 yr [163 patients] or < 70 yr [568 patients]). The researchers assigned roughly two patients to receive erlotinib for every one patient in the placebo group.

They reported significant differences between the treatment and control groups within each age cohort, but significant differences were not observed between the two age groups with regard to progression-free and overall survival (Table). The age groups experienced similar response rates.

Survival Outcomes in Erlotinib and Control Groups, by Patient Age

Age Group (yr)

Progression-Free Survival* (mo)

Overall Survival* (mo)

Erlotinib

Placebo

Erlotinib

Placebo

<70

2.1

1.8

6.4

4.7

>70

3.0

2.1

7.6

5.0

*P = .77 and P = .31 for the interaction between age groups, respectively.

Statistically significant (at least P < .009).

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P

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As one might suspect, the older patients more frequently exhibited toxic effects of treatment and had more frequent episodes of severe (grade 3 and 4) toxicity compared with young patients (35% vs. 18%; < .001). They were also more likely to stop their therapy because of treatment-related toxicity (12% vs. 3%; < .0001) and had lower relative dose intensity (64% vs. 82% received > 90% planned dose; < .001).

Although the elderly individuals with NSCLC who received erlotinib treatment had similar survival benefits compared with younger patients, the researchers pointed out that they did experience greater toxicity.

Wheatley-Price P, Ding K, Seymour L, et al: Erlotinib for advanced non—small-cell lung cancer in the elderly: An analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21.

2008;26:2350-2357.

J Clin Oncol

Phase II

Biomarker Influence for Untreated, Diffuse, Large B-Cell Lymphoma

The race to predict which patients may have optimal benefit from specific therapies is well underway, and scientists are evaluating many potential molecular or genetic markers that may guide them to the finish line. Researchers from Bethesda, Maryland; Boston, Massachusetts; and Hartford, Connecticut recently reported the results of a study to determine the influence of biomarkers on the outcome of patients using a specific chemotherapy regimen for the treatment of diffuse, large B-cell lymphoma.

The researchers evaluated biomarkers for tumor proliferation, apoptosis inhibition, and cellular differentiation in 72 adult patients (mean age, 50 yr) receiving etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) plus rituximab infusion therapy. They utilized immunohistochemistry to assess germinal center and post—germinal center B-cell subtypes. Patients were eligible for study if their disease was classified as stage II or higher.

The investigators revealed a 5-year progression- free survival (PFS) of 79% and an overall survival (OS) of 80%. The median follow-up was 54 months. When they stratified patients by the number of International Prognostic Index (IPI) factors, the PFS ranged from 91% for those with no more than one IPI factor to 47% for those with four or five factors (OS, 100% and 37%, respectively).

The investigators did not uncover any outcome association with the Bcl-2 biomarker for apoptosis inhibition or MIB-1 biomarker for tumor proliferation. However, Bcl-2—positive tumors responded to rituximab, compared with a group of historical controls receiving EPOCH alone. Patients with translocation of Bcl-6, which regulates germinal center B-cell differentiation and inflammation, seemed to have higher PFS than the controls. The researchers also found that patients with germinal center subtypes had slightly better PFS compared with patients with post–germinal center biomarkers.

The status of the MIB-1 marker for tumor proliferation did not affect the outcome of patients receiving this chemotherapy regimen, stated the researchers. They believed that the addition of rituximab to EPOCH therapy helped overcome EPOCH’s adverse effect of apoptosis inhibition. They concluded also that the Bcl-6 marker may be a promising indicator of better outcome with EPOCH and rituximab therapy.

Wilson WH, Dunleavy K, Pittaluga S, et al: Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post—germinal center biomarkers.

2008;26:2717-2724.

J Clin Oncol

Phase IIMonotherapy Effective for Multiple Myeloma

Lenalidomide plus high-dose dexamethasone has been an approved treatment for individuals who were previously treated for multiple myeloma (MM). However, according to study results from researchers at The Moffitt Cancer Center, Tampa, Florida, who presented their findings at the 2008 ASCO Annual Meeting, lenalidomide also appears to be an effective and well-tolerated monotherapy for those patients.

In this single-arm, open-label, multicenter trial, lenalidomide (30 mg/day) was administered to the 222 enrolled patients with relapsed/refractory MM daily on days 1 through 21 for each 28-day cycle. The participants had been given at least two previous MM therapies, with 80% receiving thalidomide in the past. Forty-six percent had undergone at least four treatments.

By the time the data collection was complete, 64 subjects (29%) had been treated for more than nine months. Complete or partial remission was achieved in 26% of the patients, with another 66% achieving stable disease. The overall response for the 184 efficacy-evaluable subjects was 32%. Sixty-eight percent attained stable disease, according to the investigators.

At the end of the study, progression was noted in 151 patients (69%) who had a median time to progression of 5.4 months.

After three years of follow-up, 41% of the patients were still alive. The researchers reported a median overall survival of 1.9 years, with a median progression-free survival of 4.7 months. Grade 3 or 4 side effects included neutropenia (60%), thrombocytopenia (39%), and anemia (20%).

In patients with relapsed/ refractory MM who were heavily pretreated, lenalidomide. monotherapy is effective and durable, the clinicians stated, in addition to being well-tolerated. Double-blind, randomized studies should be performed to validate the results of this nonrandomized, uncontrolled study.

Hussein MA, Richardson PG, Jagannath S, et al: Final analysis of MM-014: Single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Presented at the 2008 annual meeting of the American Society of Clinical Oncology, Chicago, May 31, 2008.

Phase IINew Chemotherapy Combination for Late-Stage Melanoma

Malignant melanoma, the deadliest form of skin cancer, has a high cure rate when caught early and completely excised. However, metastatic melanoma continues to daunt clinicians, and no therapy has been found to significantly improve survival in late-stage disease. Meanwhile, the percentage of U.S. residents developing melanoma has more than doubled over the past 30 years. In patients with stage IV disease, a new chemotherapy combination seems to offer some promise in extending their progression- free and overall survival.

A phase II study had been conducted among 21 centers testing the utility of elesclomol and paclitaxel in patients overall with late-stage melanoma. In the retrospective subgroup analysis reported at the American Society of Clinical Oncology meeting, investigators from Emory University School of Medicine, Atlanta, evaluated their study results with regard to whether patients had been exposed to previous chemotherapy regimens. A total of 81 patients received either elesclomol 213 mg/m2 infused with paclitaxel 80 mg/m2 or paclitaxel alone in 4-week cycles (once weekly for 3 wk plus 1 wk of rest) until the disease progressed.

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The investigators revealed that patients without previous chemotherapy exposure who had received the combination treatment (24 patients) experienced a 69% reduction in the risk of disease progression or death compared with the paclitaxel monotherapy group (8 patients). They lived nearly six months longer and had a significantly greater median progression-free survival (7.1 mo vs. 1.8 mo; = .02) (Figure). In patients who received one prior chemotherapy regimen, the trends were similar but not statistically significant.

Elesclomol and Paclitaxel Versus Paclitaxel Alone inPatients Naive to Chemotherapy

Elesclomol + Paclitaxel

Paclitaxel Only

Median PFS*

7.1 months

1.8 months (1.6 - 3.4 mo)

Median OS*

15.1 months

10 months

*From randomization.

The researchers pointed out that the most common grade 3 or 4 adverse events in the group receiving combination therapy, regardless of previous chemotherapy, included back pain, fatigue, and neuropathy, although milder side effects were frequently reported.

Based on these apparent gains in overall survival and progression-free survival in patients with late-stage melanoma who did not receive previous chemotherapy, further study seems warranted in much larger study groups, concluded the investigators.

Gonzalez R, Lawson DH, Weber RW, et al: Phase 2 trial of elesclomol (formerly STA-4783) and paclitaxel in stage IV metastatic melanoma (MM): Subgroup analysis by prior chemotherapy. Presented at the 2008 annual meeting of the American Society of Clinical Oncology, Chicago, May 31, 2008.

Advances in Solid Tumors: mTOR Pathway in Cancer Therapy

At the National Comprehensive Cancer Network (NCCN) 13th Annual Conference earlier this year, Robert A. Figlin, MD, City of Hope National Medical Center, Duarte, California, presented a task force report on the emerging role of the mTOR pathway in recent solid tumor research. According to Dr. Figlin, mTOR, a kinase in the PI3-K/Akt signaling pathway, controls cell growth and angiogenesis. The mTOR kinase integrates multiple signals, including growth factor receptor activity, cellular energy, nutrients, and oxygen levels, signals from other cellular signaling pathways, and estrogen receptor signaling. In addition, mTOR, in response to the aforementioned signals, controls the production of proteins regulating cell growth, angiogenesis, and nutrient uptake in the cell.

Although mTOR inhibition offers promise as a treatment modality for a number of cancers, the case for its use in some cancers is less than it is in others. “I’m not a big believer in throwing (an mTOR inhibition) agent at all cancers,” reported Dr. Figlin. “Most diseases will not benefit from mTOR monotherapy,” he said, adding that mTOR inhibitors “often must be combined with other therapies” for optimal treatment. “One of the problems,” explained Dr. Figlin, “with mTOR (or any single pathway) inhibition is that tumors have built in redundancies. Inhibiting a single pathway tends to activate a feedback loop” that adapts to and circumvents mTOR inhibition, bypassing it downstream and finding another pathway.

Citing a successful proof of concept study and several evolving clinical trials, Dr. Figlin asserted that mTOR inhibitor prospects are “best in kidney cancer.”

J Urol

Illustrating how mTOR inhibitors target renal cell carcinoma (RCC) cancer cells, Dr. Figlin explained the rationale for mTOR inhibition in RCC: mTOR is a positive regulator of HIF-1 and HIF-2 response to hypoxic stress. HIF-1a and HIF-2a are targeted for degradation by Von Hippel-Lindau tumor suppressor gene (VHL). Loss of VHL sensitizes RCC to growth inhibition by mTOR inhibitors. VHL mutations (57%) and loss of heterozygosity (98%) occur in clear-cell RCC (Horiguchi. 2003;169:710). HIF’s turn on genes responsible for tumor cell growth and angiogenesis. Thus, according to Dr. Figlin, “blocking mTOR inhibits RCC growth and tumor-induced angiogenesis.”

Although other data were cited, Dr. Figlin focused on one study in particular to demonstrate the evolving body of evidence supporting the safety and efficacy of the mTOR inhibitor class in RCC.

N Engl J Med

The study, a global phase III trial of temsirolimus (Torisel) and IFN-a (Interferon alpha) for the first line treatment of metastatic renal cell carcinoma (mRCC), randomized 626 patients into three cohorts (Hudes, et al. 2007;356:2271-2281). The first group (N = 207) received IFN-a monotherapy, escalating to 18 MU SC three times per week. Group two (N = 209) was treated with temsirolimus 25 mg IV once weekly. The third group (N = 210) was given a combination of temsirolimus 15 mg IV once weekly plus IFN-a 6 MU SC 3 times a week.

The temsirolimus monotherapy cohort demonstrated improved overall survival (the primary endpoint), progression- free survival, and objective response rates, when compared with the two groups treated with IFN-a monotherapy and temsirolimus plus IFN-a combination therapy, respectively (Figure). According to Dr. Figlin, this trial is the first in which an mTOR inhibitor was shown to have a survival benefit.

Phase III Study of Temsirolimus and IFN-a for First-Line Treatment of mRCC:Key Findings

(Overall Survival [OS], Progression-Free Survival [PFS], andOverall Response Rate [ORR])

Median OS (in months)

Median PFS (in months)

ORR (%)

IFN

7.3

1.9

4.8

Temsirolimus

10.9

3.8

8.6

Temsirolimus plus IFN

8.4

3.7

8.1

OS = Overall Survival; PFS = Progression-Free Survival;ORR = Overall Response Rate; IFN = Interferon.

While concluding the portion of his talk dealing with mTOR inhibitor use in RCC, Dr. Figlin stated, “mTOR is an important therapeutic target. mTOR inhibitors pro- vide a platform for the treatment of angiogenesis and refractory kidney cancer. Phase III trials both in patients with poor prognosis and in patients progressing on prior VEGF therapy show a survival benefit (as a result of mTOR inhibitor therapy).” Further clinical trials are needed, advised Dr. Figlin, to explore tumor characteristics and molecular context so that we can get information regarding resistance mechanisms likely to develop against mTOR inhibition and learn what patient groups will most likely benefit from mTOR inhibitor therapy.

Dr. Figlin reported that the latest NCCN guidelines indicate mTOR inhibitors as first-line therapy in poor risk patients (with both clear and non-clear cell mRCC, as second-line therapy after cytokine failure (and following sorafenib or sunitinib failure), and as second-line therapy after two tyrosine kinase inhibitor failures.

Correction: A longer version of this article appeared in the May issue of

with an error in the data presented in the table. We are sorry for any inconvenience this may have caused.

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