Description

Dacetuzumab is a monoclonal antibody that specifically binds to and works against a molecule called a CD40 receptor, which appears in abnormally high amounts in multiple myeloma cells, as well as in the cells of other blood cancers such as non-Hodgkin’s lymphoma. When dacetuzumab binds to CD40 receptors in a myeloma cell, the cell dies and does not multiply.

Mechanism of Action

Dacetuzumab kills myeloma cells by recruiting the body’s immune cells in two mechanisms, antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. It also acts in direct signal transduction, releasing chemical signals into the myeloma cell it binds to that tell the cell to die.

History

Though dacetuzumab is still in its early stages of clinical study, the idea for its action is older. Over the past decade, scientists have been interested in targeting CD40 for cancer therapy because of its abundance in the cells of certain blood cancers, and because it appears to be involved in cell growth.

In 2004, Seattle Genetics, in collaboration with Genentech, began a Phase 1 study of dacetuzumab’s safety and effectiveness in relapsed and refractory multiple myeloma. The results were published in February in the journal Haematologica ^[1] (pdf). Seattle Genetics now has two more Phase 1 trials underway, studying dacetuzumab with Velcade ^[2] (bortezomib) and Revlimid ^[3] (lenalidomide).

Usage in Multiple Myeloma

Dacetuzumab is in Phase 1 testing for multiple myeloma. The two trials that are now underway both study the drug as a treatment for people with relapsed or refractory multiple myeloma; study participants must have tried at least one previous treatment. The two current trials also both study dacetuzumab in combination with another drug, either Velcade or Revlimid. A previous lab experiment, published in the journal Cancer Research ^[4] in 2005, showed that dacetuzumab may work especially well with Revlimid.

Dosage & Administration

Because dacetuzumab is still under study, no optimal dosages have been established yet. Clinical trials have tested different dosages.

Seattle Genetic Inc.’s first clinical trial of dacetuzumab studied varying weekly doses of the drug, ranging up to 16 mg/kg. The study participants received the drug intravenously. Those who were taking higher doses also took a steroid to reduce the risk of cytokine release syndrome, a side effect of antibody treatments like dacetuzumab.

In one current ongoing trial, study participants receive dacetuzumab intravenously in doses ranging from 2 mg/kg to 12 mg/kg for eight 28-day cycles of treatment, taking fewer doses in later cycles. They receive dacetuzumab on Days 1, 4, 8, 15 and 22 of Cycle 1; then on Days 1, 8, 15 and 22 of Cycles 2 through 4; then just Days 1, 8 and 15 during Cycles 5 through 8. At the same time, they take up to 25 mg of Revlimid daily and 40 mg of dexamethasone ^[5] (Decadron) weekly.

In the other ongoing dacetuzumab trial, study participants take increasing intravenous doses of both dacetuzumab and Velcade. The ClinicalTrials.gov ^[6] description of this trial does not give any specific doses.

Side Effects

When used in combination with Revlimid and dexamethasone, the most common harmful effects were mild to moderate fatigue, low white blood cell counts, diarrhea, constipation, and headache. Less than 6 percent of patients stopped treatment because of their side effects. One patient developed a painful viral skin rash called herpes zoster and another developed kidney failure and needed dialysis.

When used alone, the most common side effects were fatigue, headache, nausea and anemia. Most participants had mild to moderate side effects, though 30 percent had more severe ones. Treatment was discontinued by 14 percent of patients because of their side effects and by 11 percent because their myeloma progressed.

Drug Interactions

No drug interactions have been reported at this time.

Precautions

No precautions have been reported at this time.

Ongoing Clinical Trials

Closed
Phase 1:

• Seattle Genetics Inc., Genentech: Study of Dacetuzumab in Patients with Refractory or Recurrent Multiple Myeloma (NCT00079716 ^[7])
• Seattle Genetics Inc., Genentech: Study of Dacetuzumab, Revlimid, and Dexamethasone in Patients With Multiple Myeloma (NCT00525447 ^[8])

For a more detailed listing of clinical trials involving dacetuzumab, please check the U.S. government’s clinical trials ^[9] Web site.

Clinical Trial Results

Dacetuzumab, Revlimid, and Weekly Dexamethasone in Relapsed or Refractory Multiple Myeloma: Multiple Responses Observed in a Phase 1b Study (2009): Among 33 people with relapsed or refractory multiple myeloma, 12 achieved partial response and one achieved complete response after treatment with dacetuzumab, Revlimid, and dexamethasone. The other study participants had stable disease (10 participants), minimal response (4 participants), or progressive disease (2 participants). Scientists were unable to evaluate four participants’ responses and have yet to evaluate the response of three more participants. For more information on this ongoing clinical trial, please see the related American Society of Hematology Annual Meeting ^[10] abstract.

A Phase 1 Multidose Study of Dacetuzumab in Patients with Multiple Myeloma (February 2010): After treatment with varying doses of dacetuzumab alone, nine out of 44 study participants reached the study’s best response—stable disease. This study helped established the safety of dacetuzumab, allowing the current dacetuzumab clinical trials to move forward. For more information, please see the full study published in Haematologica ^[1].

Patient Assistance Programs

Chronic Disease Fund, Inc.
877-968-7233
www.cdfund.org ^[11]

HealthWell Foundation
800-675-8416
www.healthwellfoundation.com ^[12]

Links of Interest

Seattle Genetics Inc.’s List of Published Research on Dacetuzumab
http://www.seagen.com/product_pipeline_scientific_publications.shtml#SGN-40 ^[13]

How Monoclonal Antibody Treatments for Cancer Work, by the Mayo Clinic
http://www.mayoclinic.com/health/monoclonal-antibody/CA00082 ^[14]