38 Oncology & Biotech News | 12.09

Studies from Around the GlobeStories written by Stanton R. Mehr

CliNiCAlTriAlrepOrTS

Exercise Maintains Function, Improves QoL for Patients With Lymphoma Exercise training in patients with lymphoma can maintain physical function and quality of life (QoL), according to a new study from the Univer-sity of Alberta, Edmonton, Canada. From 2005 to 2008, experts trained in physical education performed a controlled trial comprising 122 patients with lymphoma. Each patient was classified by disease type and current treatment status. Sixty-two were randomly assigned to receive usual care, and 60 were placed in a program of supervised exercise training for 12 weeks. The primary study measure was the Trial Outcome Index–Anemia scale, a patient-reported physical-function rating. Secondarily, the patients were assessed for body composi-tion, fitness, QoL, and psychosocial functioning. Patients were re-assessed just after the 12-week program ended (n = 117) and again after 6 months (n = 110).

The investigators reported a 92% median adherence to the aerobic exercise regimen. As assessed at 12 weeks, the group performing

aerobic exercise had significantly higher physi-cal functioning scores compared with the group receiving usual care (mean score difference, +9.0; P = .02). This change likely resulted from improved

cardiovascular fitness. At six months after discontinuing the exercise program, the posi-tive effects of aerobic exercise started to disappear, but the im-provement in overall QoL scores, depression levels, and happiness levels remained significant.

The use of an aerobic ex-ercise program did not affect chemotherapy completion rate, response to treatment, or risk of disease progression or recur-rence. The authors concluded that aerobic exercise training should be considered in appro-

priate patients with lymphoma to help maintain QoL and cardiovascular fitness.

Courneya KS, Sellar CM, Stevinson C, et al. Randomized controlled trial of the effects of aerobic exercise on physical functioning and quality of life in lymphoma patients. J Clin Oncol. 2009;27(27):4605-4612.

Intra-arterial Bevacizumab Delivered Directly into the Brain TumorThe antiangiogenesis agent bevacizumab (Avastin) is approved for intravenous use in patients with glioblastoma multiforme (GBM). Its limits in cross-ing the blood-brain barrier may hamper its effec-tiveness, however, and systemic administration is associated with cytotoxic effects. To address these issues, neurosurgeons at New York-Presbyterian Hospital/Weill Cornell Medical Center, New York City, are seeking a more direct route of administration. In a phase I study of 5 patients with GBM, bevacizumab was injected through a microcatheter ap-proximately the width of a human hair, placed via the carotid artery in arterial targets at the tumor site. An agent to open the blood-brain barrier temporarily is first infused, followed by the antiangiogenesis agent itself.

Early reports have been promising, but the op-timal dosing of directly injected bevacizumab for the intra-arterial cerebral infusion is still unknown. After completion of the phase I study, a phase II clinical trial will investigate the optimal dosing and efficacy in patients with GBM, anaplastic astrocy-toma, or anaplastic mixed oligoastrocytoma.

Patient receives world’s first delivery of intra-arterial Avastin directly into a malignant brain tumor: New York-Presbyterian/Weill Cornell study opens blood-brain barrier to deliver high-dose chemotherapy to malignant brain tumors (press release). Available at: http://nyp.org/news/hospital/intra-arterial-avastin.html. Accessed Novem-ber 17, 2009.

Measures Improved After 12 Weeks of Aerobic Exercise in Lymphoma Patients

• Cardiovascular fitness• Depression• Fatigue• General health• Happiness• Lean body mass• Overall quality of life• Physical functioning

United states

canada

Glioblastoma multiforme

12.09 l www.Onclive.com 39

United states/finland

Lower Cholesterol Levels May Reduce Risk of Aggressive Prostate CancerKeeping cholesterol levels down may be a key to avoid-ing aggressive prostate can-cer. According to 2 studies published in Cancer Epide-miology Biomarkers & Pre-vention, men with high levels of high-density lipoprotein (HDL) and men with total cho-lesterol levels <200 mg/dL have significantly lower rates of some prostate cancers.

In the first study, epidemiol-ogists and clinicians from the Johns Hopkins Medical Insti-tutions, Baltimore, Maryland, retrospectively analyzed data for 5586 men 55 years and older assigned to a placebo group in a large 1990s fed-eral cancer prevention study. They found that men with low cholesterol levels (<200 mg/dL) had less than half the risk of developing high-grade prostate tumors as those with high-serum cholesterol ≥200 mg/dL. Although cho-lesterol levels had no affect on the men’s overall chances of developing the disease, the likelihood of developing high-grade tumors (Gleason score 8–10) was 59% lower in the men who had cholesterol levels <200 mg/dL.

The second study, from the National Cancer Institute, Bethesda, Maryland, analyzed data for more than 29,000 male smokers from Finland to determine whether ingesting beta-carotenes lowered the risk of developing prostate cancer. As part of the study protocol, HDL levels were measured at baseline. The researchers found that par-ticipants with the highest HDL levels were 11% less likely to develop the disease than those with the lowest levels. They noted that total choles-terol concentration was as-sociated with decreased risk of multiple cancers.

Although nutritional guidelines do not exist for prostate cancer prevention, research suggests that lim-iting circulating lipid lev-els can decrease the risk of some cancer types, which

these findings seem to support. The investigators concede that these two studies are not definitive; neither database included information on how many men in the study were taking statins or looked at the effects of other lifestyle factors on cancer risk.

Platz EA, Till C, Goodman PJ, et al. Men with low se-rum cholesterol have a lower risk of high-grade pros-

tate cancer in the placebo arm of the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev. 2009;18(11):2807-2813.

Ahn J, Lim U, Weinstein SJ, et al. Prediagnostic to-tal and high-density lipoprotein cholesterol and risk of cancer. Cancer Epidemiol Biomarkers Prev. 2009;18(11):2814-2821.

40 Oncology & Biotech News | 12.09

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Primary central nervous system (CNS) lymphoma is often treated with chemo-therapy plus high-dose methotrexate. Oncologists from the International Extra-nodal Lymphoma Study Group, Switzer-land, sought to determine whether adding high-dose cytarabine to methotrexate therapy would result in superior outcomes in these patients.

They conducted an open-label, random-ized, phase II trial enrolling 79 patients (age range, 18-75 y) from 6 countries. All of these newly diagnosed patients had non-Hodgkin lymphoma localized to the CNS, cranial nerves, or eyes only. Each patient demon-strated performance scores of ≤3.

Patients were randomly assigned to 4 courses of treatment every 3 weeks with either 3.5 g/m2 of methotrexate on day 1 (n = 40) or 3.5 g/m2 of methotrexate on day 1 plus 2 g/m2 cytarabine twice a day on days 2 and 3 (n = 39). After the courses were completed, all patients received whole-brain irradiation.

switzerland

Combining Cytarabine & Methotrexate Therapy to Treat CNS Lymphoma

MethotrexateMethotrexate + Cytarabine P Value

Overall response, % 40 69 .009

Complete response, % 18 46 .006

Partial response, % 22 23 NA

Grade 3-4 hematologic AEs, % 15 92 NA

AE-related deaths 1 4 NA

AE indicates adverse event.

Remission Rates in Primary CNS Lymphoma

taiwan

Universal Hepatitis B Vaccine & the Long-Term Incidence of Hepatic CancerSome Southeast Asian countries that have particularly high rates of hepatitis infection have introduced universal vaccination programs for hepatitis B, a major cause of hepatocellular cancer (HCC). Taiwan introduced such a program in 1984, and data are beginning to illuminate the long-term outcomes of this public health intervention.

In a population-based study, pediatricians from the National Taiwan University Hospital, Taipei, used two national HCC registries to review the clinical status of 1958 patients (age range, 6-29 y) who received a diagnosis of HCC between 1983 and 2004. In addi-tion, specific prenatal maternal hepatitis B antigen characteristics were compared for 64 patients with HCC and 5.5 million Taiwanese who were vaccinated under the program.

When stratified by age, the researchers confirmed that vaccinated children had a lower incidence of HCC. They found one case of cancer in 589,207 person-years among those who were vaccinated compared with one case in 176,793 person-years among those who were not vaccinated (RR, 0.31; P <.001). Incomplete vaccination was associated with a higher risk of developing HCC (odds ratio [OR], 4.32).

This finding, however, did not represent the great-est risk factor for developing HCC in vaccinated pa-tients. In patients born to a mother seropositive for hepatitis B s antigen, the OR for hepatic cancer was 29.50. The OR of HCC for children born to mothers with prenatal maternal hepatitis B e antigen (HBeAg)

seropositivity was 5.13 in those who received hepati-tis B immunoglobulin at birth and 9.43 in those who did not. The researchers pointed out that although vaccination is strongly associated with a lower risk of HCC, the mother’s hepatitis antigen status during pregnancy plays a large role in assessing the child’s risk of developing HCC.

A related economic study, also conducted by re-searchers at the National Taiwan University, found that under universal hepatitis B vaccination in a location with high prevalence of hepatitis B virus and HBeAg, the average person vaccinated gained 3.9 life-years. They also found that the program

ultimately costs less overall than having no vaccina-tion program.

Chang MH, You SL, Chen CJ, et al. Decreased inci-dence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst. 2009;101(19):1348-1355.

Hung HF, Chen TH. Probabilistic cost-effectiveness analysis of the long-term effect of universal hepatitis B vaccination: an experience from Taiwan with high hepatitis B virus infection and hepatitis B e antigen pos-itive prevalence. Vaccine. 2009;27(48):6770-6776.

The researchers reported significantly higher rates (P = .006) of complete remission in the combination treatment group, at 46%, compared with 18% in the monotherapy group. The rate of partial responses was similar between both groups, with 22% of patients receiving methotrexate alone and 23% of those receiv-ing methotrexate plus cytarabine experiencing a partial response.

The clinicians were not surprised to find that the combination therapy was more toxic, with 92% of

those in the combination group experi-encing grade 3-4 hematological adverse effects compared with only 15% in the methotrexate group; they reported that 4 patients in the combination group and 1 in the monotherapy group died as a result of these toxicities.

This international investigation revealed that the addition of high-dose cytarabine to a methotrexate regimen offers better like-lihood of complete and partial responses in patients with CNS lymphoma than methotrexate alone. They did note that the

side-effect profile is not unmanageable, although the risk of death seemed higher in the combination treatment group.

Ferreri AJ, Reni M, Foppoli M, et al. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with pri-mary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009;374(9700):1512-1520.

Hepatitis B, countries or areas at risk

Countries or areas with moderate to high risk.

The risk of infection is based on the estimated prevalance rate of antigen to hepatitis B virus surface antigen (HBsAG)–a marker of chronic HBV infection–among population. This marker is based on limited data and may not reflect current prevalence.

Source: World Health Organization/CDC Map Production: Public Health Information and Geographic Information Systems (GIS) World Health Organization

O 1,250 2,500 5,000 Kilometers

42 Oncology & Biotech News | 12.09

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aUstralia

LHRH Agonists in Early Estrogen Receptor–Positive Breast Cancer It has long been thought that the use of luteinizing hormone–releasing hormone (LHRH) agonists should be helpful in pre-menopausal women with estrogen receptor (ER)–positive breast cancer, but their place in therapy has not been solidified. On-cologists from the Sydney Cancer Center, New South Wales, Australia, researched the Cochrane Database, MEDLINE, EMBASE, and abstracts from major cancer research meetings to conduct a literature review on the clinical benefits of LHRH-agonist treat-ment in such tumors, particularly relative to standard treatment over 5 years with tamoxifen.

The oncologists included in the search all randomized trials involving LHRH agonists as adjuvant treatment in premenopausal women with early-stage breast cancer. This included trials of LHRH compared with other monotherapy, in combination with chemotherapy versus another treatment or in combination with chemotherapy plus an antiestrogenic treatment (eg, tamoxifen) compared with other intervention. A meta-analysis was not possible owing to the variability in reporting of outcomes from each trial.

They culled 14 randomized, controlled trials comprising more than 13,000 premenopausal women with operable breast cancer, most of whom were determined to be ER-positive. Goserelin was

the most common LHRH agonist tested. The authors concluded that overall, available data support the use of an LHRH agonist plus chemotherapy and tamoxifen, with a trend toward “improved recurrence-free and overall survival” in patients who received this combination compared with chemotherapy alone, but more data are needed to clearly define this approach.

Too few data exist to support the superiority of LHRH mono-therapy versus tamoxifen alone, although a trend was observed suggesting comparable progression-free survival. In addition, insufficient data were available to support recommending LHRH plus tamoxifen therapy over tamoxifen monotherapy because the treatment protocols tested at the time are now obsolete.

The authors pointed out that tamoxifen therapy combined with LHRH agonists resulted in a better adverse effects profile compared with chemotherapy alone. They concluded, however, that “definitive comparisons against current clinical standards of care,” including third-generation chemotherapy regimens and tamoxifen, are required before determining what place LHRH has in the adjuvant setting. The researchers emphasized the need for randomized controlled trials that definitively compare “a variety of combinations of LHRH agonists and antiestrogenic strategies to the current standard of 5 years of tamoxifen.”

Goel S, Sharma R, Hamilton A, et al. LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women. Cochrane Database Syst Rev. 2009;(4):CD004562.

In 2008, the FDA converted accelerated

approval of denileukin diftitox (Ontak),

an infused biologic agent, to full

approval after a phase III clinical trial

demonstrated safety and efficacy in

patients with persistent or recurrent

cutaneous T-cell lymphoma (CTCL)

who express the interleukin-2 receptor

CD25+. At the time, lead investigator

Francine M. Foss, MD, professor of

Medicine, Hematologic Malignancies at

Yale Cancer Center, described denileukin

diftitox as “the most extensively studied

agent in CTCL.”

At the recent 51st ASH Annual Meeting

and Exposition, Dr Foss presented

combined data on the efficacy of

this agent from two

clinical trials of patients

with relapsed and/

or refractory stage IB-

IVA or stage I-III CTCL

and from a rollover

trial involving patients

who had progressed

after treatment with

denileukin diftitox.

Cumulatively these trials

included 263 intent-to-

treat (ITT) patients, of

which 227 were CD25+

and 36 were CD25-. All had been

treated previously with one or more

regimens. Patients received 9 µg/kg (n

= 80) or 18 µg/kg (n = 183) of denileukin

diftitox daily for 5 days in 21-day

cycles. In the 18 µg/kg dosing groups,

29 patients had progressed on a 9 µg/

kg-dose of denileukin diftitox.

The overall rate of complete

response (CR) was 9.1%, achieved

by 24 patients (median age, 59 y).

Dr Foss and colleagues described

these responses as “durable.” The

mean number of prior regimens for the

patients who achieved CR was 3.6,

with 37% having received >3 prior

therapies. Although denileukin diftitox

is not indicated for CD25- disease,

3 of the 24 CRs were seen in CD25-

patients. While most (n = 18) of the

CRs occurred with the 18 µg/kg dose,

the ratio of CR to number of patients

means the difference in CR between

the two doses was not significant

(P = .56). Looking at just the cohort

of patients who received the higher

dose, researchers said no significant

difference in CR was observed

between CD25+ and CD25- patients

(P = .64). The rate of CR

was also similar between

patients with early stage

and advanced stage

CTCL (10.7% vs 8.9%,

respectively).

In the 9 µg/kg group,

the median time to response (TTR)

for CD25+ patients was 53.5 days

compared with 41 days in the 18 µg/

kg group. CD25- patients who received

18 µg/kg had a median TTR of 43 days.

Duration of response trended longer in

the CD25+ patients, at 57 to >1325 days

compared with 190-400 days for the

CD25- patients.

At the time data were presented, 7 of

the 24 patients who achieved CR had

progressed, with 17 remaining in CR.

Median PFS had not been reached.

Notable treatment-related adverse

affects among the patients achieving CR

included 3 hypersensitivity reactions and

3 incidents of capillary leak syndrome.

Investigators concluded, “These studies

demonstrate clinical benefit of denileukin

diftitox with CR in both early and

advanced CTCL at both 9 and 18 µg/kg

doses.”

Foss F, Duvic M, Olsen E, et al. Complete

responses with denileukin diftitox in

cutaneous T-cell lymphoma studies.

Presented at: 51st ASH

Annual Meeting and

Exposition, December 5-8,

2009, New Orleans, LA.

Complete Response by CD25 Status

CD25+ CD25-

Overall 227 36

Rollover trial 29 36

18 µg/kg dose 118 36

CR 21 3

Response duration 57->1325 d 190-400 d

Denileukin Diftitox Produces Complete Response in CTCL

United states

Shom Goel, MD

The researchers concluded that “definitive comparisons

against current clinical standards of care,” including

third-generation chemotherapy regimens and tamoxifen, are required before determining what place LHRH has in the

adjuvant setting.

“These studies demonstrate clinical benefit of denileukin diftitox with CR in both early and advanced CTCL at both 9

and 18 µg/kg doses.”–Francine M. Foss, MD

12.09 l www.Onclive.com 43

Long-Term Effectiveness of Immunotherapy in Lymphoma Associated with Epstein-Barr VirusTargeted immunotherapy has the poten-tial to devastate tumor cells in a number of cancers while sparing healthy tissue and is an attractive area for research and development. Researchers from the Bay-lor College of Medicine, Houston, Texas, recently reported promising results us-ing specialized white blood cells (WBC) to treat or prevent lymphoma associated with the Epstein-Barr virus (EBV) in pa-tients who had undergone a hematopoi-etic stem-cell transplant. Because of their compromised immune status, patients undergoing stem-cell transplantation are at higher risk for EBV infection and subse-quently EBV-associated lymphoma.

The researchers tested whether EBV-specific cytotoxic T-lymphocyte treat-ment could control or eliminate EBV lym-phomas. They accrued 101 patients who were undergoing hematopoietic stem-cell transplant for other disorders and con-sidered at high risk for EBV lymphoma and an additional 13 patients with a lym-phoma diagnosis. None of the 101 at-risk patients who received the treatment pro-phylactically developed EBV lymphoma, whereas 11 of the 13 patients (85%) with confirmed lymphoma who were treated therapeutically attained a sustained com-plete remission.

The researchers hypothesized that time to treatment may be key to a successful outcome. In this trial, the cytotoxic T-lymphocyte lines were infused soon after stem-cell transplantation, while patients’ WBC count was still low. Therefore, the cells that were infused could increase at a faster rate and could become involved in anti-tumor and anti-viral effects.

Leen AM, Christin A, Myers GD, et al. Cy-totoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation. Blood. 2009; 114(19):4283-4292.

Oral Mucositis Prevention for Patients with Colorectal CancerOral mucositis, often grade 2 or worse, remains a com-mon adverse effect of chemotherapy. Human intestinal trefoil factors are regulatory peptides involved in mu-cosal protection and repair in the gastrointestinal tract. An oral spray containing recombinant human intestinal trefoil factor (rhITF) was tested by an international team of researchers for the treatment and prevention of oral mucositis caused by chemotherapy in patients with col-orectal cancer.

The phase II study group comprised 99 patients with moderate-to-severe oral mucositis (grade ≥2) in the first cycle of chemotherapy. Individuals were randomized to receive treatment with a placebo or rhITF at a relatively low dose (10 mg/mL) or a high dose (80 mg/mL) by oral spray (300 μL, 8 times/d) for 14 consecutive days in the second chemotherapy cycle. An assessment for safety and for oral mucositis incidence and severity was performed at multiple times for 21 days after beginning therapy.

Leukemia cells containing Epstein-Barr virus.

At the recent ECCO/ESMO Congress, investigators

presented data from a phase II study that demonstrated a

combination of farletuzumab (MORAb-003) with standard

platinum-based chemotherapy and a taxane was highly

effective and relatively safe in platinum-sensitive patients

experiencing their first ovarian cancer relapse. Platinum-

sensitive patients who relapse typically have better

outcomes than women who are only partially platinum-

sensitive or platinum-resistant. Data were presented by

Deborah Armstrong, MD, associate professor of oncology,

Johns Hopkins Kimmel Cancer Center.

The multinational open label study included 44 patients

from the United States, Germany, and The Netherlands.

All the women received farletuzumab in combination

with platinum-based chemotherapy and a taxane. The

preliminary analysis included data for 41 patients. Dr

Armstrong said the overall response rate was 69.8%,

with someone seeing their tumors disappear entirely.

Another 23% achieved stable disease. For more than

20% of patients, the duration to their second relapse was

at least as long as the time to initial relapse, with median

progression-free survival of 10.3 months.

CA-125, a tumor marker used to track

the risk of recurrence in women with

ovarian cancer, dropped to normal levels

in 90.2% of the patients. In an interview

with Oncology & Biotech News, Martin

D. Phillips, MD, chief medical officer

and senior vice president of Clinical

Development for Morphotek Inc, the company that is

developing farletuzumab, said while these are only interim

data, “There was a high response rate by both the biomarker,

CA-125, and by computed tomography scans in patients

with relapsed platinum-sensitive ovarian cancer when

farletuzumab was given in combination with platinum and

taxane.” He described the response as “higher than what

When patients at high risk of oral mucositis were treat-ed with low-dose rhITF, the incidence was reduced by 75% (P <.001); those in the high-dose group were 81% less likely to develop oral mucositis (P = .002). The fre-quency of patients with mucositis ≥grade 2 was 48.5% in the placebo group compared with 9.1% in the low-dose group and 12.1% in the high-dose rhITF treatment group. Statistically significant reductions in the severity of oral mucositis were seen in patients treated with rhITF com-pared with placebo when the area under the curve was assessed. Only 6% of patients experienced treatment-related adverse events, which were all mild to moderate. Rates did not differ significantly between the two treat-ment groups. Investigators concluded that the spray form of rhITF was safe and effective at decreasing the rate of chemotherapy-related oral mucositis in patients with colorectal cancer.

Peterson DE, Barker NP, Akhmadullian LI, et al. Phase II, randomized, double-blind, placebo-controlled study of recombinant human intestinal trefoil factor oral spray for prevention of oral mucositis in patients with colorec-tal cancer who are receiving fluorouracil-based chemo-therapy. J Clin Oncol. 2009;27(26):4333-4338.

Farletuzumab Produces 70% Response Rate in Relapsed Ovarian Cancer

would be expected for women at this stage of ovarian cancer.”

Dr Armstrong noted that farletuzumab did not increase

toxicity significantly more than expected from the taxane

and platinum regimen. As Dr Phillips explained, “There were

very few serious or severe adverse events attributed to

farletuzumab in this study. Farletuzumab is given in addition

to standard chemotherapy, so we expect to see the adverse

effects of those drugs in any case.”

Farletuzumab is a humanized monoclonal antibody that

targets the folate receptor alpha. “This is an area of active

research,” Dr Phillips said. “The amount of scientific literature

on the role of folate receptor alpha is expanding rapidly.” He

said farletuzumab appears to have at least two mechanisms:

“Engagement of the patient’s own immune system by

antibody-dependent and complement-dependent cytotoxicity

and interference with the activity of lyn kinase [a member of

the src family of kinases].” Dr Phillips said these and other

mechanisms are still being investigated.

The data from this study are only preliminary, Dr Phillips

cautioned, and final data will be needed to conclusively say

what role farletuzumab might eventually play at the practice

level. “About 20% of patients had a second remission that

was as long as or longer than their first,” he said, noting

that this is a promising result. “A phase III study to confirm

these findings is in progress.” The phase III study is actively

accruing patients in 25 countries in North and South

America, Europe, Asia, and Australia. Dr Phillips said, “We

expect to enroll about 900 patients by mid-2011.” More

information on the phase III trial of farletuzumab is available

at www.clinicaltrials.gov, ID NCT00849667.

Armstrong DK, Coleman R, White AJ, et al. Efficacy and

safety of farletuzumab, a humanized monoclonal antibody to

folate receptor alpha, in platinum-sensitive relapsed ovarian

cancer subjects: preliminary data from a phase-2 study. Euro

J of Cancer Suppl. 2009;2(7):S449.

Martin D. Phillips, MD

MUltinatiOnal

United states

United states