Clinical Trials News

Immutep Announces Positive Interim Results In Phase I/II Chemoimmunotherapy Trial In Breast Cancer

2009-01-06T13:25:00.000-08:00

Immutep S.A. announced today interim results from its ongoing Phase I/II chemoimmunotherapy clinical trial in metastatic breast carcinoma. ImmuFact IMP321 was administered the day after weekly paclitaxel for six months. The interim results show a clinical response rate of 50 per cent compared to 25 per cent with paclitaxel alone. In addition, a robust immune response was observed in clinically-responding patients.

IMP321 is a first-in-class immunopotentiator that agonizes MHC class II molecules thereby stimulating antigen-presenting cells, such as dendritic cells and monocytes, leading to markedly improved cytotoxic CD8 T-cells responses against tumours.

Chemoimmunotherapy is a new approach to the treatment of cancer. Chemotherapy drugs induce tumour cell apoptosis and cause modulation of the immunological environment combined with a burst of tumour antigen release. The resulting T-cell immune response contributes to the regression of the tumour and, importantly, may seek out and destroy metastases. However, this initial immune response needs to be sustained and amplified by a T-cell booster that is non-toxic and can be given repeatedly, such as ImmuFact IMP321.

The design of the study is a multi-centre open-label fixed dose-escalation trial. One of the lead centre's main Principal Investigators, Maya Gutierrez, is coordinating the team carrying out the trial at the René Huguenin Cancer Centre, Saint Cloud, near Paris.

Patients receive 6 cycles of low-dose weekly paclitaxel at Day 1, Day 8 and Day 15 of a 4-week cycle as first line chemotherapy plus bi-weekly IMP321 administered the day after the paclitaxel to make a total of 12 injections of IMP321 over 24 weeks. Three dose levels of IMP321 are being studied in three cohorts of 8 patients each. The interim results are based on tumour regression under RECIST criteria in the first two cohorts of 16 patients out of the total of 24 compared to the historical control group which is the weekly paclitaxel arm of a recent randomised phase III study (N. Engl. J. Med. 2007; 357:2666-76). The improvement is statistically significant with a p-value of 0.03.

"Such sequential chemo- and then non-toxic immunotherapeutic combos may be a way to improve the response rate and/or consolidate or stabilize the partial tumour responses obtained with chemotherapy alone," said Dr Maya Gutierrez, Principal Investigator of this Phase I trial. "We are very pleased to be testing this innovative therapeutic approach at our Institute."

"Boosting the dendritic cell network when it is loaded with tumour antigens following chemotherapy with repeated injections of IMP321 is an effective way to amplify the cytotoxic CD8 T-cell responses observed in first-line chemotherapy," said Frédéric Triebel, Scientific & Medical Director of Immutep. "A similar approach will shortly be tested in the first trial of IMP321 in the USA in pancreatic cancer patients receiving first-line gemcitabine."

"These positive results have encouraged us to engage in discussions with potential partners over Immutep's plans for the advanced development stages of IMP321 as we continue to collect data from this study at the highest dose," added John Hawken, CEO.

For further information please visit the web-site http://www.immutep.com

Metastatic Breast Cancer and Chemoimmunotherapy

Metastatic breast cancer remains incurable. The failure of current approaches is generally attributed to the outgrowth of breast tumour cells that are inherently resistant to standard treatments. Manipulating the immune system to recognize and eradicate breast tumour cells is a highly attractive alternative approach to disease management. Active immunization offers multiple theoretical advantages over all other therapies, including low toxicity. The sustained antitumour effect due to immunological memory would obviate the requirement for prolonged, repetitive cycles of therapy.

The objective of chemo-immunotherapy is to amplify natural pre-existing T-cell responses specific for any known or unknown tumour antigen and to recruit and amplify new tumour-specific T-cell responses resulting from the use of cytotoxic drugs known to induce tumour cell apoptosis. The direct cytolytic effect of some cytotoxic drugs, such as paclitaxel, can enhance antigen presentation by inducing tumour cell apoptosis. This mechanism of therapeutic synergy has been shown with cyclophosphamide, doxorubicin, or paclitaxel when given with dendritic cell-based vaccines. Until 8 years ago, it was thought that the T-cell depletion caused by chemotherapy would make immunotherapy ineffective. However it has now been shown that, on the contrary, the vigorous T-cell repopulation following depletion can be directed against the tumour, the so-called "rebound" effect.

Soluble LAG-3 protein is a prognostic factor in breast cancer

ImmuFact IMP321 is closely related to the soluble form of the LAG-3 (Lymphocyte Activation Gene-3) protein which is a prognostic indicator for survival in breast cancers expressing oestrogen or progesterone receptors. This was shown is a study carried out by researchers at the René Huguenin Cancer Centre and Pr. Frédéric Triebel when he was at the Pharmacy Faculty of University Paris 11. These results paved the way for the current clinical trial.

Relapse In Early Breast Cancer Patients Following Endocrine Therapy, Prediced By New Model

2008-09-24T12:21:00.000-07:00

Researchers have developed and validated a model that predicts relapse in women with stage 2 or 3 breast cancer who have been treated with endocrine therapy prior to surgical removal of the tumor, according to a study published online September 23 in the Journal of the National Cancer Institute. The preoperative endocrine prognostic index (PEPI) may help identify women who can safely avoid chemotherapy and those women at high risk of relapse who should be considered for aggressive therapy.
Oncologists increasingly treat women with stage 2 and 3 estrogen receptor (ER)-positive breast cancer with endocrine therapy, such as tamoxifen or letrozole, prior to surgery to shrink the tumor. Researchers have not known whether a woman's response to such therapy correlated with her risk of relapse in the future.

In the current analysis, Matthew Ellis, Ph.D., of the Washington University School of Medicine in St. Louis and colleagues examined surgical tumor samples from two previous studies in which women received endocrine treatment for several months prior to surgery. The team analyzed tumor samples from posttreatment surgery for ER status, histological grade, pathological grade, tumor size, nodal stage, treatment response, and Ki67 expression level, which is an indicator of cell proliferation. They tested these characteristics for an association with relapse-free survival and overall survival in 158 women treated in the P024 neoadjuvant trial and used the data to develop PEPI. They validated the model in 203 women previously treated in another clinical trial known as IMPACT.

Pathological tumor stage, nodal status, Ki67 expression level, and ER status in posttreatment specimens were independently associated with relapse-free survival; the PEPI model incorporates these characteristics. PEPI was a statistically significant predictor of relapse-free survival in the women in the IMPACT study. None of the women with the lowest PEPI score in the IMPACT trial had relapsed during the follow-up period, which was a median of 60.3 months. The researchers need longer follow-up data to validate PEPI's ability to predict overall survival.

"Of particular note, patients with low pathological stage (stage 1 or 0) and a favorable biomarker profile (PEPI score 0) at surgery had such a low rate of relapse that further adjuvant systemic therapy beyond continuation of an endocrine agent appears unnecessary," the authors write. "In striking contrast, patients with high pathological stage disease at surgery and a poor biomarker profile (PEPI group 3) had a statisti¬cally significant higher risk of early relapse, more typical of ER [negative] disease, and therefore should be offered all appropriate adjuvant treatments available."

Given the robust associations, the researchers suggest that prospective validation of the model is warranted. If validated in a prospective manner, PEPI could help guide individual treatment and assess novel endocrine therapies in future clinical trials.

Peregrine Pharmaceuticals Completes Patient Enrollment In First Stage Of Bavituximab Phase II Breast Cancer Trial

2008-04-30T11:14:00.000-07:00

Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM), a clinical stage biopharmaceutical company developing monoclonal antibodies for the treatment of cancer and hepatitis C virus infection (HCV), announced that it has completed enrollment in the first stage of its Phase II trial of bavituximab in combination with chemotherapy in patients with advanced breast cancer. The main objective of the safety and efficacy study is to assess the overall response rate to the combination of bavituximab with docetaxel, a chemotherapy drug commonly used to treat breast cancer.
"We are very pleased that patient enrollment in this trial has proceeded quickly, reflecting the enthusiasm and efficiency of our clinical colleagues in Europe and the level of patient interest in a potential new therapy for this difficult disease," said Steven W. King, president and CEO of Peregrine. "We look forward to providing an update on the trial as patients continue to be dosed in the study and tumor response data is generated."

As part of this trial's two-stage design, 15 patients with locally advanced or metastatic breast cancer have been enrolled initially. The primary objective of the multi-center, open-label study is to assess overall tumor response rate to the combination of bavituximab with docetaxel. The study may be expanded to include up to an additional 31 subjects if promising results are seen in the first 15 patients. Patients enrolled in the trial will remain in the study until disease progression.

Secondary objectives of the Phase II study include measuring time to tumor progression, duration of response, overall patient survival and safety parameters. Patients may continue to receive bavituximab alone after completion of chemotherapy as long as the cancer does not progress and side effects are acceptable.

Tumor response in this study will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) parameters. The trial is being conducted in the Republic of Georgia according to International Conference on Harmonization (ICH) and Good Clinical Practices (GCP) standards.

The National Cancer Institute estimates that approximately 178,480 U.S. women were diagnosed with cancer of the breast in 2007 and about 40,460 women died of the disease. According to the World Health Organization, breast cancer is the most commonly diagnosed cancer in women, and is second only to lung cancer as a leading cause of female cancer deaths.

Bavituximab is a monoclonal antibody that binds to a phospholipid called phosphatidylserine that is usually located inside normal cells, but which becomes exposed on the outside of the cells that line the blood vessels of tumors, creating a specific target for anti-cancer treatments. Bavituximab is believed to help mobilize the body's immune system to destroy the blood vessels needed for tumor growth and spread. In a Phase Ib pilot trial in advanced cancer patients, bavituximab plus chemotherapy appeared to have a safety profile consistent with chemotherapy alone and showed positive signs of clinical activity, achieving objective response or disease stabilization in 50% of the evaluable patients. Peregrine has received regulatory approval to conduct three Phase II trials to study the anti-tumor effects of bavituximab in combination with chemotherapy. These include two breast cancer protocols and a non-small cell lung cancer protocol. Bavituximab is in clinical trials in the U.S. in patients with advanced solid tumors and in patients co-infected with HCV and HIV.

Side Effects But No Extra Efficacy From New Chemotherapy Combo, In Early Breast Cancer Patients

2008-04-18T04:13:00.000-07:00

Adding capecitabine, a drug that inhibits DNA synthesis and slows the growth of tumour tissue, to docetaxel, in patients with early breast cancer, leads to more toxicities and does not improve the efficacy of treatment, a German scientist told the 6th European Breast Cancer Conference (EBCC-6). Previously, such a combination had improved patient survival in metastatic disease, where the cancer has spread to other parts of the body.

Professor Gunter von Minckwitz, Chairman of the German Breast Group, Neu-Isenberg, Germany, and his team set out to look at the use of the combination in early breast cancer. "We recruited 1510 patients with previously untreated primary tumours," he said. "Each received the normal preoperative treatment of four cycles of epirubicin and cyclophosphamide. We then randomised them to either four cycles of docetaxel alone, four cycles of simultaneous docetaxel and capecitabine, or four cycles of docetaxel followed by four cycles of capecitabine. If capecitabine were to improve outcomes, we wanted to see how best to use it - simultaneously or in sequence."

The scientists planned to study the pathologic response at surgery - the way, if any, in which the tumour had reacted to the administration of the chemotherapy drug.

"However, we found no difference in efficacy between the three arms of the trial with regard to pathologic response, clinical response, and rate of breast conservations," said Professor von Minckwitz. "The overall rate of pathologic complete responses (pCRs) - no cancer in the breast or lymph nodes - was 29.7%."

Nor did the length of treatment appear to make a statistically significant difference. What the scientists did find was that the addition of capecitabine to the chemotherapy regime produced more non-haematological toxicities - for example hand-foot syndrome, a skin reaction that appears on the palms of the hands and soles of the feet, and which can be very painful if untreated. They also found increased rates of nail changes, stomatitis (inflammation of the mucous lining the mouth and throat), and diarrhoea.

The scientists now intend to follow up their work by correlating the response at the time of surgery with the long-term outcomes for patients. "Although it is the best indication we have at present, it is still uncertain whether pCR is a reliable predictor of long-term activity," said Professor von Minckwitz.

Given the lack of extra efficacy of adding capecitabine to docetaxel, and the additional toxicities that it produces, the scientists say that they would not recommend using it as preoperative treatment in early breast cancer. "Prolongation of chemotherapy also has the effect of reducing patient compliance, so, given all these factors we would recommend staying with current standard treatments - epirubicin and cyclophosphamide followed by a taxane, or TAC, another commonly used three-drug combination of docetaxel, doxorubicin and cyclophosphamide," said Professor von Minckwitz.

Results From Breast Cancer Pilot Study Presented By NovoCure

2008-04-15T05:36:00.001-07:00

NovoCure has announced that it presented the results from a single-arm pilot trial evaluating the Novo-TTF, a non-invasive portable medical device, combined with neo-adjuvant chemotherapy for the treatment of patients with locally advanced breast cancer. Tumor volume shrank by 86-100 percent in the first four patients treated with the combined therapy, and one patient has experienced a complete response

The data, which was presented during the annual meeting of the American Association for Cancer Research, also indicated that the Novo-TTF device can be safely combined with chemotherapy. It should be noted that these results are preliminary and the study is ongoing. In addition, NovoCure presented in vitro data from studies of the Novo-TTF treatment combined with chemotherapy to treat breast cancer and non-small cell lung cancer cells in culture, as well as animal data from VX2 tumors. The in vitro data demonstrated that the combination of chemotherapy with the Novo-TTF may produce additive as well as synergistic effects of one treatment plus the other.

The Novo-TTF device disrupts cancer cell proliferation and tumor growth by creating low intensity, intermediate frequency, alternating electric fields in the region of a tumor. These electric fields exert forces on the dividing cancer cells that prevent tumor growth. In pre-clinical and clinical studies to date, the electric fields have shown no effect on non-dividing, healthy cells in the same region, suggesting that the device can treat cancer without harming surrounding tissue, unlike chemotherapy. Chemotherapy is typically associated with high toxicity that kills both healthy and cancerous cells. The Novo-TTF is currently an investigational medical device and is not yet FDA approved.

"We are delighted that the American Association of Cancer Research gave us the opportunity to present publicly, for the first time, preliminary human data related to the combination of low intensity, intermediate frequency, alternating electric fields and chemotherapy agents for breast cancer patients," said Professor Yoram Palti, M.D., Ph.D. and NovoCure founder. "These results add to the growing body of evidence that the Novo-TTF may be a valuable option for patients with solid tumor cancer."

NovoCure also continues to develop the Novo-TTF as a treatment for glioblastoma multiforme (GBM) brain tumors. NovoCure recently published data from its human pilot study for patients with GBM tumors that recurred after surgery and radiation. The results of this study preliminarily indicate that the Novo-TTF more than doubled the median overall survival rates for recurrent GBM patients relative to historical data.

NovoCure is currently conducting a Phase III clinical trial at more than 20 centers in the US and Europe for patients with recurrent glioblastoma. Please refer to http://www.novocuretrial.com/ for more information on this trial.

Possible Cause Of "Chemo Brain" In Breast Cancer Patients

2008-03-21T05:38:00.000-07:00

Thanks to early diagnosis and chemotherapy, more women survive breast cancer than ever before. However, following treatment, approximately 25 percent of survivors experience mild to moderate memory, concentration and cognitive problems known as "chemobrain".

"Several studies have investigated chemotherapy's cause and effect on memory problems, but until now scientists had no clue what changes in the brain lead to memory loss," Jame Abraham, M.D., director of the Comprehensive Breast Cancer Program at West Virginia University's Mary Babb Randolph Cancer Center, said.

Abraham and his research team conducted one of the first chemobrain studies of its kind. The study documented the extent of changes to the brain's white matter in women who received chemotherapy for breast cancer.

The preliminary study involved ten breast cancer patients who had received chemotherapy and complained of cognitive changes. A control group of nine healthy women of similar age, education and IQ, who never received chemotherapy, was also studied.

All participants were screened for medical, neurologic and psychiatric conditions that could affect brain structure or function. Participants were tested for depression, anxiety and processing speed.

Each participant also participated in a diffusion tensor imaging (DTI) MRI scan. The DTI was used to assess changes in the white matter of the brain.

"The images indicated differences in the white matter in the front part of the brain in women who had received chemotherapy," said Marc Haut, Ph.D., of WVU's departments of Behavioral Medicine and Psychiatry, Neurology and Radiology. "This difference in white matter correlated with how quickly the breast cancer patients could process information."

"Women who received chemotherapy performed significantly worse in speed of processing than their counterparts in the control group," said Abraham. "Our preliminary findings suggest that chemotherapy may change the brain and those changes affect the patient's cognitive skills."

Morgantown resident Sharon Palmatory, a patient of Dr. Abraham, recently finished chemotherapy treatments. She had very few side effects during chemotherapy, but after treatment experienced trouble remembering names and numbers.

"I can't multi-task anymore; I can only focus on one thing at a time. It's frustrating because I am used to being in control," Palmatory said.

In some patients chemobrain can have a significant and serious affect on their everyday life.

"I feel like I'm always lagging behind in processing information," she said. "It's good to know that Dr. Abraham and others are studying this problem; they can let women receiving chemo know that they may experience memory loss."

WVU researchers also concluded that changes in the white matter of the brain do not appear to be caused by depression or anxiety.

Abraham and Haut are leading several chemobrain studies funded by the U.S. Department of Defense and the WVU Department of Radiology. Their article is published in Clinical Breast Cancer, Volume 8, Number 1, February 2008.

WVU co-authors include Maria Moran, Ph.D., Department of Behavioral Medicine and Psychiatry and Department of Radiology; Shannon Filburn, Clinical Trials Research Unit; and Susan Lemiuex, Center for Advanced Imaging and Department of Radiology. Hiroto Kuwabara, Ph.D., Department of Radiology at Johns Hopkins University, is also a co-author.

West Virginia University Health Sciences Center
PO Box 9083
Morgantown, WV 26506-9083
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http://www.hsc.wvu.edu