By Nancy Roach, Chair, C3 Board of Directors

C3 has submitted comment to the Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC), recommending that FDA implement a Special Restriction Distribution Program for Erythropoiesis Stimulating Agents (ESAs), to maximize patient safety and ensure the rapid collection of patient information.

ESAs, better known under brand names, Procrit, Epogen and Aranesp, were approved by the Food and Drug Administration (FDA) to reduce the need for blood transfusions and have been used widely to aid with chemotherapy-induced anemia. Research results have indicated that higher doses of ESAs could actually cause a patient’s cancer to grow faster, and increase mortality, pointing out the need for future research to nail down the risk/benefit ratio of ESA use.

C3, in partnership with other advocacy organizations, has been working with FDA and ESA manufacturers (Amgen and Johnson & Johnson) to ensure that patients are helped, not harmed, by these supportive care drugs.

ODAC will be meeting on March 13, 2008 to discuss new research findings, future research plans and the current clinical situation. Carlea Bauman, C3 President, will speak during the open public hearing. In addition, C3 has submitted comments identifying questions such as:

• What is the plan for answering the question of whether ESAs have a tumor-promoting effect?
• What is the plan for answering the question of whether ESAs provide patient benefit when dosed according to the FDA label?
• What is the appropriate clinical use of ESAs pending the answers to these questions?

Ultimately, C3 recommends that ESA use be closely monitored, similar to the way that thalidomide use is monitored.

For additional information, see:

• www.ESAFacts.org presented by the Marti Nelson Cancer Foundation
• Briefing information from the May 10, 2007 ODAC meeting

Disclosure: C3 believes in fully disclosing sources of financial support, per our disclosure policy which can be viewed here. In 2006 and 2007, C3 received funding from Amgen in the form of a charitable donation. Since the May 2007 Oncology Drug Advisory Committee (ODAC) meeting, C3 has met with Amgen and Johnson & Johnson (J&J) to increase our understanding of these issues and express our concerns. J&J held a meeting on February 19, 2008 in Washington, DC, and paid the travel expenses of a C3 Board member so that she could attend the meeting.

Amgen has opened a Phase II clinical trial to study the safety and effectiveness of Vectibix (panitumumab) combined with FOLFIRI chemotherapy as second-line treatment for colorectal cancer that has spread to organs beyond the colon or rectum. 

150 patients will be recruited from the United States, and will receive FOLFIRI — Irinotecan, leucovorin, and continuous infusion 5FU – plus Vectibix (panitumumab)

Who is eligible?

• Patients with confirmed colorectal cancer that has spread to organs beyond the colon (metastatic disease); and
• Patients whose tumor has been removed by surgery and who have paraffin-embedded tumor tissue available; and
• Patients with cancer that can be seen by scans, and which cannot be removed by surgery alone; and
• Patients whose overall organ functioning is adequate based on blood tests; and
• Patients who have received first-line treatment of FOLFOX – oxaliplatin, leucovorin and continuous infusion 5FU – plus Avastin (bevacizumab), and who had to discontinue FOLFOX plus Avastin because:
  • Their cancer progressed; or
  • They were unable to tolerate treatment

Who is not eligible?

• Patients who have received radiotherapy within two weeks of starting the trial; or
• Patients who have taken CYP3A4 enzyme inducers, inhibitors, and substrates (eg, phenytoin, phenobarbital, carbamazepine, ketoconazole, rifampin, rifabutin, and St. John’s Wort) within two weeks of starting the trial; or
• Patients who have had systemic infections and are taking antibiotics within 2 weeks of starting the trial; or
• Patients with a history of:
  • cardiovascular disease; or
  • pneumonitis or pulmonary fibrosis
• Patients who have had a significant thromboembolic event such as pulmonary embolism or deep vein thrombosis within 8 weeks of starting the trial; or
• Patients who have had significant bleeding within 6 weeks of starting the trial; or
• Patients with active or uncontrolled gastroduodenal ulcer(s) within 4 weeks of starting the trial; or
• Patients with a condition that could increase the risk of toxicity (eg, dihydropyrimidine deficiency, significant ascites, or pleural effusion); or
• Patients who have had major surgery (requiring general anesthesia), open biopsy, or significant traumatic injury within 4 weeks of starting the trial; or
  Patients who experienced treatment toxicities which were unable to be controlled; or
• Patients who have had prior treatment that included irinotecan, any anti-EGFr therapy, or vaccine for the treatment of mCRC

The trial will examine:

• If patients with specific genetic mutations in their tumors have different responses to the combination of FOLFIRI plus Vectibix
• Safety

For more information about the trial, call Amgen at 1-866-572-6436

Disclosure: C3 has accepted funding for projects and educational programs from Amgen in the form of unrestricted educational grants. C3 has ultimate authority over website content.

Amgen has opened a Phase II clinical trial to compare the safety and effectiveness of Vectibix (panitumumab) combined with FOLFIRI chemotherapy with the combination of Avastin (bevacizumab) plus FOLFIRI as second-line treatment for colorectal cancer that has spread to organs beyond the colon or rectum. 

Two hundred patients will be recruited from the United States, and will be randomized to receive either:

• FOLFIRI — Irinotecan, leucovorin, and continuous infusion 5FU – plus Avastin (bevacizumab)
• FOLFIRI plus Vectibix (panitumumab)

Who is eligible?

• Patients with confirmed colorectal cancer that has spread to organs beyond the colon (metastatic disease); and
• Patients whose cancer cannot be removed by surgery alone; and
• Patients whose overall organ functioning is adequate based on blood tests; and
• Patients who have received first-line treatment of at least 4 cycles of FOLFOX – oxaliplatin, leucovorin and continuous infusion 5FU – plus Avastin (bevacizumab), and who had to discontinue FOLFOX plus Avastin because:
  • Their cancer progressed; or
  • They were unable to tolerate treatment

Who is not eligible?

• Patients who experienced treatment toxicities which were unable to be controlled; or
• Patients who have had prior treatment that included irinotecan, any anti-EGFr therapy, or vaccine for the treatment of metastatic colorectal cancer.

The trial will examine:

• Amount of tumor shrinkage
• How long tumors either shrink or do not grow
• Safety

For more information about the trial, call Amgen at 1-866-572-6436

Disclosure: C3 has accepted funding for projects and educational programs from Amgen in the form of unrestricted educational grants. C3 has ultimate authority over website content.

As reported in a C3 post on June 26, a phase IV clinical trial* was closed after an interim analysis indicated that the use of calcium/magnesium to reduce neuropathy caused by FOLFOX might also reduce the effectiveness of this chemotherapy treatment.

In this trial*, patients receiving FOLFOX and bevacizumab chemotherapy were also randomized to Magnesium Sulfate and Calcium Gluconate before and after oxaliplatin in a double-blind placebo controlled fashion.  The preliminary data from the first 174 patients on the trial showed that patients who had received calcium/magnesium had significantly less tumor shrinkage than patients who did not receive calcium/magnesium.  The data is based on scans of patients’ tumors.

As a result, the trial was closed and all patients on the trial will receive future treatment without calcium/magnesium.

The data will be verified as follows:

• An independent committee of expert radiologists is being convened;
• The committee will examine all scans from the trial. Their examination will be blinded (they will not know which patients received which treatment); and
• The results of their examinations will be analyzed, and compared to the preliminary data.

The verification process is expected to take several months.  Final results may be available in early 2008.

On July 31, the Journal of Clinical Oncology published a letter from the trial’s primary investigators.  The investigators say the following:

At present, bearing in mind the preliminary and unconfirmed nature of these data, we would like our colleagues to be aware of this unexpected finding. Oncologists should recognize the possibility that calcium and magnesium may reduce the activity of FOLFOX and bevacizumab in the treatment of colorectal cancer and exercise appropriate clinical judgment when using these agents in the neuroprotective setting until definitive data are available. For the time being, we would urge that calcium and magnesium salts particularly be avoided in the adjuvant setting, where reduced efficacy could lead to reduced benefit, and be reserved for those with symptomatic acute neurotoxicity.

Full letter text available here. 

C3 asked sanofi-aventis (the manufacturer of oxaliplatin) how this information was being disseminated to the oncology community. Sanofi-aventis indicated that its sales force was carrying the information to oncologists and oncology nurses, and that these efforts would continue.

WHAT THIS MEANS TO PATIENTS:
If you are receiving calcium-magnesium as treatment for neuropathy related to your FOLFOX regimen, talk to your doctor to be sure that s/he is aware of this preliminary data.  If your doctor is unaware, s/he can contact sanofi-aventis Medical Information Service at 1-800-633-1610 option 1 for additional information.

While this data is preliminary, patients and doctors should take it into account when planning treatment.

Source:
Sanofi-aventis website
Hochster et al, Journal of Clinical Oncology, July 31 2007

* CONCEPT Trial – a Phase IV, Randomized, Prospective Multicenter comparison of an Intermittent Schedule of Oxaliplatin combined with 5-Fluorouracil/Leucovorin (FOLFOX) / Bevacizumab Versus the Conventional Mode of Administration of FOLFOX/Bevacizumab PLUS Neuroprophylaxis With Calcium/Magnesium for the Optimization of First-Line Therapy of Metastatic Colorectal Cancer.  Available here.

Disclosure: C3 has accepted funding for projects and educational programs from sanofi-aventis in the form of charitable donations. C3 has ultimate authority over website content.

Anne Brady Moore lost her mom to colorectal cancer and her dad to bladder cancer.  Read how one woman is making a difference in her community.

We need more people like Anne Brady spreading the word that colorectal cancer is preventable, beatable and treatable. Find out what you can do to make a difference in your community.