New Clinical Trial -- Trying to Arrest Drug Resistance

[Cynthia]

Friends,

It has been a while since I posted. I hope all is well. Sadly my work is preventing me from attending San Antonio this year. I will miss seeing so many of you there but eagerly await your reports.

I received the following information from a colleague who does lots of advocacy work in the cancer research field. She asked that I post the following information about a new Phase II clinical trial of capecitabine and lapatinib with or without IMC-A12 in patients with HER2 positive breast cancer previously treated with trastuzumab and an anthracycline and/or taxane. I understand that the trial is looking at whether resistance to Herceptin and/or Lapatinib can be blocked. (I will posts this on the clinical trials site as well.)

Best regards,

Cynthia

New clinical trial to test co-inhibition of insulin-like growth factor receptor (IGF-1R) and human epidermal growth factor (HER2) in patients with metastatic HER2 positive breast cancer

North Central Cancer Treatment Group (NCCTG) Clinical trial N0733 was recently activated at more than 140 sites within NCCTG and the National Cancer Institute’s Cancer Trials Support Unit. This study is a Phase II clinical trial of capecitabine and lapatinib with or without IMC-A12 in patients with HER2 positive breast cancer previously treated with trastuzumab and an anthracycline and/or taxane. The study is projected to enroll 154 patients.

Study objectives

“The primary objective of the trial is to determine the six month progression free survival for capecitabine plus lapatinib with or without IMC-A12,” says Paul Haluska, Jr., M.D., Ph.D., an oncologist at Mayo Clinic in Rochester, Minn. “The study will also include analysis of additional clinical parameters such as response rate, overall survival and duration of response.”

In addition, the trial includes correlative studies to determine if clinically important “crosstalk” can be identified in circulating tumor cells and if circulating markers of sensitivity to IGF-1R targets can be measured in patient serum.

Study background

Metastatic breast cancer is an incurable disease, and within the subtypes of breast cancer, those that express the HER2 protein have the worst prognosis. Treatments targeting HER2, including trastuzumab and lapatinib, have made a dramatic improvement in the outcome for these patients. However, resistance to these therapies ultimately leads to cancer progression in these patients.

Data from Mayo Clinic laboratory studies and results from others have implicated that the insulin-like growth factor (IGF) pathway is a major contributor to the resistance to HER2 targeted therapy through so-called “crosstalk signaling.” Through this crosstalk, blocking HER2 signaling in tumors can be overcome by IGF-1 signaling. Similarly, blocking IGF-1 signaling can be overcome by HER2 signaling.
“Indeed, we have shown that blocking both the HER2 and IGF receptor (IGF-1R) simultaneously leads to profound anti-tumor effects in tumor models in the laboratory,” says Dr. Haluska. “With the clinical development of the IGF-1R monoclonal antibody inhibitor, IMC-A12, we have the opportunity to test whether this synergistic activity of combined IGF-1R and HER2 blockage will have improved clinical benefit over blocking HER2 alone.”

Clinical trial N0733 will test this theory. Trial participants will be patients with HER2 positive metastatic breast cancer who have had their tumors progress on chemotherapy and trastuzumab. These patients will receive lapatinib, a dual epidermal growth factor (EGFR), HER2 inhibitor, plus capecitabine, which is a standard regimen for this patient population, plus or minus IMC-A12.

Significance for future research

“Should IGF-1R inhibition increase the activity of lapatinib plus capecitabine, this could have a major impact on our understanding of how HER2 positive breast cancers overcome HER2 targeted therapy and improve the clinical outcomes in these patients,” says Dr. Haluska. “Positive results in this study would then lead to further clinical investigations to determine whether co-inhibition of IGF-1R/HER2 leads to improved survival compared to inhibition of HER2 alone.”

For more information about clinical trial N0733, visit the NCCTG Web site at http://ncctg.mayo.edu.

[chrisy]

Cynthia,

Missed seeing you in SA...

This is exciting stuff - trying to close another door is a good thing! Someone in the Alamo Hot Topics briefing made the comment that "all these survival mechanisms are achilles heels". The sooner they can get to the point of closing off enough pathways to make it just lay down and die, the better!