Clinical Trial Reports

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Phase III

Quality of Life with Sunitinib or Interferon Alfa for Patients with Metastatic Renal Cell Carcinoma

The use of conventional chemotherapy in the treatment of metastatic renal cell carcinoma (mRCC) is not generally considered effective. The five-year survival rate is only as high as 20%. Targeted therapies, such as sunitinib, offer significant promise in mRCC treatment. American researchers performed an interim analysis of a multicenter trial.

The initial randomized study had found that sunitinib treatment was well tolerated and patients had significantly extended progressionfree survival and a higher objective response rate than when using interferon alfa (IFN-alfa). In the present analysis, the researchers compared the quality of life of 375 individuals who were given sunitinib (a starting dose of 50 mg/day for 4 weeks followed by 2 weeks off treatment) or 375 given IFN-alfa (subcutaneous injection on 3 nonconsecutive days/wk or with 3 million units in week 1, 6 million units in week 2, and 9 million units thereafter).

Patients completed three quality-of-life (QoL) questionnaires: (1) Functional Assessment of Cancer Therapy-Kidney Symptom Index-15 item (FKSI-15), (2) the Functional Assessment of Cancer Therapy- General (FACT-G), and (3) the EuroQol Group’s EQ- 5D. For the purposes of this study, the primary QoL endpoint was the FKSI-Disease Related Symptoms (FKSI-DRS) subscale.

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For each cycle a higher (more favorable) FKSI- 15 was reported in subjects in the sunitinib group compared with the IFN-alfa group. The Table shows that sunitinib was favored across all cycles, with an overall mean difference in scores of 1.98 points for FKSI-DRS and 3.27 points for FKSI-15; both are statistically significant (<.0001). After the first treatment cycle, within-group changes over time for postbaseline scores decreased abruptly in both FKSI- 15 and FKSI-DRS. The IFN-alfa treatment group experienced a more pronounced initial decrease, which the clinicians pointed out could be the result of the more toxic nature of IFN-alfa.

In addition to providing significantly superior efficacy when compared with IFN-alfa, sunitinib also offers a better quality of life for patients with advanced mRCC, including superior kidney cancer disease— related symptoms, the researchers concluded.

Cella D, Li JZ, Cappelleri JC, et al. Quality of life in patients with metastatic renal cell carcinoma treated with sunitinib or interferon alfa: Results from a phase III randomized trial.

2008;26:3763-3769.

J Clin Oncol.

Phase II

Children’s Oncology Group Pilot Study

Inhibition of CD22 gene expression has recently been considered a promising target for certain leukemias and lymphomas. How well the humanized monoclonal antibody epratuzumab, which is directed at CD22, is tolerated in children with relapsed acute lymphoblastic leukemia (ALL) was studied by pediatricians at the New York University School of Medicine.

Patients enrolled in the study received epratuzumab 360 mg/m²/dose intravenously twice weekly for four doses, and then a combination of four weekly doses of epratuzumab and standard reinduction chemotherapy. Following the treatment period, the investigators evaluated responses morphologically and by minimal residual disease markers. They also assessed epratuzumab’s CD22 targeting efficiency, which was noted by quantifying changes in CD22 expression using flow cytometry.

This nonrandomized, noncontrolled study comprised 15 patients with CD22-positive ALL marrow relapse. Twelve of these individuals were fully assessable for toxicity. One seizure of unclear etiology (grade 4) and one asymptomatic alanine aminotransaminase level elevation (grade 3) were the two dose-limiting toxicities that arose.

Within 24 hours of receiving epratuzumab therapy, surface CD22 was revealed in only one patient. The clinicians pointed out that this is an indication that the drug effectively targeted the leukemic cells. When chemoimmunotherapy was complete, a complete remission was achieved in nine children, seven of whom did not have evidence of minimal residue disease.

The pediatricians concluded that epratuzumab treatment in children with relapsed CD22-positive ALL is feasible. The patients tolerated the reinduction regimen acceptably, they added, and CD22 was efficiently targeted. A majority of the patients had favorable early responses. They believe that epratuzumab should be the subject of larger-scale, randomized trials.,

Raetz EA, Cairo MS, Borowitz MJ, et al. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: A Children’s Oncology Group Pilot Study.

2008;26:3756-3762.

J Clin Oncol.

Treatment with Gemcitabine and Topotecan for Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Can women with platinum-resistant ovarian or peritoneal cancer benefit from combination therapy with a nucleoside analog and topoisomerase 1 inhibitor? Past studies have yielded limited results using gemcitabine or topotecan, respectively. Therefore, treatment with weekly topotecan and gemcitabine in women with platinum- resistant or refractory ovarian or peritoneal cancer was tested by researchers from the Puget Sound Oncology Consortium, Seattle.

Study participants received gemcitabine 800 mg/m² and topotecan 3.0 or 2.5 mg/m² on days 1 and 8 of a 21-day cycle. Response Evaluation Criteria in Solid Tumors (RECIST) was used to establish the clinical response while Functional Assessment of Cancer Therapy—Ovarian module (FACT-O) was used to measure quality-of-life changes.

Of the 23 enrollees, only one was ineligible because of a concurrent endometrial malignancy, although she was included in the analysis. At baseline, measurable disease was seen in 16 women (70%) whereas seven (30%) had only elevated cancer antigen (CA)- 125 levels. Patients had a median of one prior medical regimen (range, 1-4) and had undergone a median of eight previous chemotherapy cycles (range, 3-39).

The dose of topotecan was lowered from 3.0 mg/m² to 2.5 mg/m² after six patients were subjected to dose delays owing to toxicity and the need for granulocyte colony-stimulating factor. Partial responses were found in four (17%) patients, although only two (9%) were verified before progression. Stable disease was observed in eight (35%) women. Overall, the dose was reduced in only eight of the 107 cycles administered. However, four patients (17%) were removed from the trial because of toxicity (2 each at the higher and lower doses).

The oncologists reported that cancer recurred for the women within a median of three months; median overall survival was 12.6 months. When compared with baseline, the women reported unchanged quality of life during the treatment cycles.

Although a weekly regimen of topotecan and gemcitabine was well tolerated, the best response rate of 17% and a 9% confirmed response rate were not significantly better than reported previously for gemcitabine or topotecan monotherapy, the researchers acknowledged. Therefore, they concluded, the results of this trial do not give persuasive proof that weekly gemcitabine and topotecan can be a promising therapy for patients with resistant or refractory ovarian or peritoneal cancer.

Goff BA, Holmberg LA, Veljovich D, et al. Treatment of recurrent or persistent platinum-refractory ovarian, fallopian tube or primary peritoneal cancer with gemcitabine and topotecan: A phase II trial of the Puget Sound Oncology Consortium.

2008;110:146-151.

Gynecol Oncol.

The Effect of Immunotherapy on Pediatric Sarcoma Survival

Previous studies have demonstrated that patients with metastatic or recurrent Ewing’s sarcoma and alveolar rhabdomyosarcoma have a 5-year survival rate <25%. Researchers primarily from the National Cancer Institute, Bethesda, Maryland, examined a unique immunotherapy regimen that could consolidate remission in these individuals during a phase II trial.

The study group comprised 52 pediatric patients with metastatic or recurrent Ewing’s sarcoma or alveolar rhabdomyosarcoma. Prechemotherapy cells were harvested from the study participants. After standard multimodal therapy was completed, 30 patients received immunotherapy. These individuals were assigned to one of three groups (median age, 16 yr), whereas 22 patients did not receive any immunotherapy (control group: median age, 20 yr). All three of the cohort groups were given autologous T cells, dendritic cells pulsed with peptides derived from tumor-specific translocation breakpoints and E7 (a peptide that can bind HLA-A2), and influenza vaccinations. In addition, moderate-dose recombinant human interleukin-2 (rhIL-2) was administered to cohort 1. Cohort 2 received low-dose rhIL-2. Cohort 3 did not receive interleukin-2.

Influenza-specific immune responses occurred in all immunotherapy recipients. However, of these individuals, only 39% had immune responses to the translocation breakpoint peptides, and E7- specific responses were noted in only 25% of HLA-A2+ patients.

The clinicians found toxicity to be minimal. The overall five-year survival for all patients in the study was 31% and 43% for those who received immunotherapy.

It appears that immunotherapy is feasible for a sizable fraction of patients with high-risk pediatric sarcomas who have good clinical response to frontline cytoreductive therapy. However, the investigators stated, “Improvements in the regimen are needed to induce strong and sustained immune response to tumor antigens in a majority of patients.” They added that the use of more immunogenic antigens and potent dentritic cells in further studies may increase efficacy.

Mackall CL, Rhee EH, Read EJ, et al. A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas

2008;14:4850-4858.

. Clin Cancer Res.

Does Epoetin-Alfa Therapy Affect Cognitive Function in Patients with Cancer?

Previous studies have linked impaired cognition with anemia associated with cancer chemotherapy. Oncologists from the University of Patras Medical School, Patras, Greece, evaluated whether treating the anemia with epoetin alfa treatment also improves cognitive performance in patients with cancer.

Fifty patients were enrolled in this single-arm trial. All had solid tumors and hemoglobin (Hb) levels below 11.0 g/dL. Before initiation of therapy and also at the study completion, they received the Mini-Mental State Examination and the European Organization for Research and Treatment of Cancer (QLQ-C30) questionnaire. The patients were given epoetin alfa 40,000 units once a week for 12 weeks.

The researchers did not observe any change in cognitive function for patients during the treatment period, although hemoglobin levels improved for the majority of patients. When evaluating the group of patients whose hemoglobin levels rose significantly during epoetin alfa treatment versus those whose hemoglobin levels were not affected by treatment, the researchers emphasized that no difference in cognitive performance could be observed.

Although epoetin alfa treatment did not seem to improve cognitive performance even if the anemia was resolved, the investigators wondered whether cognitive function was maintained (i.e., did not worsen) because of epoetin treatment. The researchers believe that this hypothesis would have to be studied in a double-blind, controlled study.

Iconomou G, Koutras A, Karaivazoglou K, et al. Effect of epoetin alfa therapy on cognitive function in anaemic patients with solid tumours undergoing chemotherapy

August 13, 2008 [E-pub ahead of print].

. Eur J Cancer Care.

Inhibition of Tumor Angiogenesis or Its Existing Blood Supply?

First described in the 1970s, the strategy of killing tumors by choking off their blood supply directly led to drugs like bevacizumab, the first of the angiogenesis inhibitors. A new class of similar-acting drugs is in clinical trials, with one difference—instead of attacking the tumor’s ability to grow new vessels, the tumor vascular disrupting agents (VDAs) attempt to kill off the tumor’s existing network of blood vessels.

Oncology & Biotech News

One of the first members of this class, designated ASA404, is being tested in use for several solid tumors. In last month’s , we reported on some positive findings in patients with non—small cell lung cancer (ATTRACT-1 study). Enrollment in multiple phase III investigations in this cancer are now getting underway.

In August, new study results were revealed in a phase II investigation of 74 patients with hormone-refractory prostate cancer, which was first presented at the 2008 annual meeting of the American Society of Clinical Oncologists in June. Patients were given ASA404 1,200 mg/ m2 plus docetaxel or docetaxel alone. Those receiving the combination had a two-year survival of 33% compared with 23% for docetaxel monotherapy. A lower percentage of patients in the combination arm also demonstrated progression in prostatespecific antigen levels.

Another agent, combretastatin A4 phosphate/ CA4P is being tested for use in anaplastic thyroid cancer, and has shown promising results (in 2 patients, tumor blood flow was reduced by three-quarters). Presently, studies are being considered to use the product in combination with angiogenesis inhibitors, an intriguing possibility.

Evidence of activity seen in new data from ASA404 prostate cancer trial. CNNMoney.com August 15, 2008.

Zybrestat—Vascular disrupting agent and cancer therapy. Drug development-technolo gy.com. Accessed August 20, 2008.

Phase I

Combination Therapy for Non-Hodgkin Lymphoma in Children

In adults, four drugs constituting CHOP therapy or R-CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituxan) form the basis of effective treatment of large—cell non-Hodgkin lymphoma (NHL). In children, an alternative induction treatment was tested in a group of patients with newly diagnosed stage III or IV NHL. The activity and toxicity of dexamethasone, high-dose cytarabine, and carboplatin (DAC) as a combination therapy for children with a new diagnosis of large–cell NHL has been studied by clinicians from St. Jude Children’s Research Hospital, University of Tennessee at Memphis College of Medicine.

This pilot study comprised 20 boys and 5 girls (age range, 4.2—17.7 yr) who had St. Jude stage III (n = 21) or stage IV (n = 4) large–cell NHL. At the start of the induction phase, DAC treatment was given in two sequential cycles and included throughout a continuation phase (which also incorporated CHOP). Ten months was the approximate duration of treatment.

Of the 25 patients, 22 (88%) achieved a DAC therapy response (88%), 13 subjects (52%) yielded a complete remission, and eight (36%) had a partial response. Complete remission occurred in 18 patients (73%) and partial remission in three (12%) after further treatment with doxorubicin, cyclophosphamide, vincristine and dexamethasone. Five-year event-free survival was 64%, and the overall survival rate was 80%.

Pediatric patients with large— cell NHL had experienced good remission rates with the regimen and tolerated the DAC therapy well, concluded the authors.

Sandlund JT, Santana VM, Hudson MM, et al. Combination of dexamethasone, high-dose cytarabine, and carboplatin is effective for advanced large-cell non-Hodgkin lymphoma of childhood.

2008;113:782-790.

Cancer.

*SPECIAL REPORT*

Consensus Report by Global Cancer Advocates Urges Stakeholders to Take Action on Behalf of Women Living with Metastatic Breast Cancer

Call-to-Action Addresses Need for Increased Support and Attention to the Metastatic Breast Cancer Community

The Metastatic Breast Cancer Advocacy Working Group, a cooperative of patient advocates from seven countries, released a consensus report urging other advocacy groups; healthcare corporations and professionals; government, academia, and community/religious organizations; and all other relevant breast cancer stakeholders worldwide to take action on three priority areas for women living with metastatic breast cancer (MBC):

• Improve access to tailored information, resources and support for women with MBC• Heighten attention to the MBC community— create a unified voice and platform that speaks to their unique needs• Increase understanding of and access to clinical trials

Breast cancer is the leading cause of cancer death among women worldwide, accounting for an estimated 1.3 million new cases each year. In developed countries, nearly 30% of women with early stage breast cancer will eventually develop metastatic or stage IV breast cancer, the most advanced stage of the disease. Despite the prevalence, women with MBC often report feelings of isolation from the broader breast cancer community, whose public focus and advocacy efforts are largely directed toward early stage disease.

“While there is no cure for MBC, women are living longer with metastatic disease than ever before, due in part to recent advances in treatment and supportive care,” said Dr. Marisa Weiss, Founder and President of Breastcancer.org, leading breast cancer oncologist and member of the MBC Advocacy Working Group. “It is now more critical than ever to address the complex emotional and medical needs of women dealing with metastatic disease through tailored resources and personalized support.”

Over the past three decades, as great strides have been made in detecting and treating breast cancer, public and media attention has transformed the disease into one of the most highly visible women’s health issues. The need now is to accelerate both clinical research and awareness of MBC to advance the care of women living with this stage of the disease.

“The fastest way to identify effective new treatment options is through clinical trials—yet currently enrollment in cancer trials remains alarmingly low. Less than 5% of adult cancer patients participate in clinical trials each year,” said Dr. Weiss. “The global MBC Advocacy Working Group Consensus Report underscores the responsibility oncology health care providers have in empowering patients with the knowledge of their clinical trial options and bridging practical barriers to ensure that all patients have an opportunity to participate in the investigation of tomorrow’s new therapies.”

The Consensus Report was developed following a one-day summit, sponsored by Pfizer Oncology, of the MBC Advocacy Working Group to share insights on the current obstacles and potential solutions for key issues affecting women with MBC.

“For years, the public has perceived women with MBC as being near death, which has contributed to feelings of isolation for these women, many of whom are managing their disease while living full and productive lives,” said Lilla Romeo, New York—based member of the Metastatic Breast Cancer Network and the MBC Advocacy Working Group who has been living with MBC for eight years. “Through partnership and increased collaboration, this Consensus Report is an important stride toward giving a much-needed voice to the MBC community.”

About the Metastatic Breast Cancer Advocacy Working Group

The MBC Advocacy Working Group is a cooperative of patient advocates from seven countries worldwide dedicated to increasing collaboration in an effort to heighten public attention and address the unique needs of women living with MBC. The group was established with sponsorship from Pfizer Oncology and includes individuals from the following advocacy organizations, among others:

• Living Beyond Breast Cancer (US)

• Canadian Breast Cancer Network (Canada)

• Breast Cancer Network of Strength (formerly known as Y-ME National Breast Cancer Organization) (US)

• Grupo Reto (Mexico)

• Breast Cancer Welfare Association (Malaysia)

• Breastcancer.org (US)

• ABCANCER (Brazil)

• Carla Howery, MA, Patient Advocate (US)

• Metastatic Breast Cancer Network (US)

• Europa Donna - The European Breast Cancer Coalition (Head Office, Italy)

• Willow Breast Cancer Support (Canada)

• Young Survival Coalition (US)

• Campaign 2 Control Cancer (Canada)

• CancerCare (US)