PREVENTION OF TOXICITIES INDUCED BY ANTHRACYCLINES
Anthracycline drugs are chemotherapeutic agents used to treat various cancers. Anthracyclines are some of the most widely used chemotherapeutic agents and include doxorubicin, epirubicin, daunorubicin, and idarubicin among others. Anthracyclines intercalate between DNA/RNA base pairs inhibit topoisomerase II thereby preventing replication of DNA and inhibiting rapidly growing cells. These actions create enormous oxidative stress and damage in both normal and cancerous cells.
Toxicities associated with anthracycline agents, such as doxorubicin, include neutropenia (low neutrophil count), anemia (low red blood cells), leukopenia (low white blood cells), pruritus (itchy skin), stomatitis (mouth inflammation), thrombocytopenia (low platelets), cardiotoxicity (damage to the heart), myelosuppression (low blood cell count), reduction in brain function and size, alopecia (hair loss), secondary malignancy (cancer), and many more. Furthermore, these side effects are often dose-limiting requiring a reduction in subsequent chemotherapy that may impact the overall success of the cancer treatment regimen.
Matrix Biomed, Inc.’s development program is directed to providing relief from toxicities associated with all anthracyclines. Specifically, Matrix Biomed, Inc. is currently developing clinical trials for the most widely used anthracycline, doxorubicin.
Preclinical Evidence Supporting TEMPOL’s Protection Against Doxorubicin Toxicities
In a study conducted by Dr. Jennifer S. Dickey of the FDA and her team discovered that TEMPOL exhibited cardioprotective and chemotherapeutic effects in a syngeneic breast tumor preclinical model. As predicted, tumor reduction and cardiomyopathy were demonstrated by doxorubicin. TEMPOL accumulated in the mitochondria of the tumor and cardiac tissue. TEMPOL ameliorated doxorubicin-induced cardiomyopathy without altering the antitumor activity lowering the average lesion score, see table below. TEMPOL also increased the pro-survival autophagy marker LC3-II and decreased the apoptosis marker caspase-3 in the heart, independently and in combination with doxorubicin.
Clinical Trial Design
Matrix Biomed, Inc. is finalizing a protocol for submission to the FDA for the prevention of anthracycline-induced cardiotoxicity in end stage breast cancer patients. Additional endpoints will be directed to the prevention and reduction of neutropenia and myelosuppression. TEMPOL has been shown to prevent and reduce doxorubicin-induced cardiotoxicity.
- Objective: Prevention of Doxorubicin Induced Toxicities
- Stage: Phase IIb
- Study Population: Women with Breast Cancer Receiving Doxorubicin Treatment
- Number of Patients: 120 (1:1 randomization Tempol capsules v Placebo)
- Primary Endpoint: Reduction in Doxorubicin induced cardiotoxicity (damage to the heart)
- Secondary Endpoints:
- Attenuation of the decrease in neutrophil count (white blood cell)
- Attenuation of the reduction in brain size and function
Noteworthy: The only approved compounds to prevent doxorubicin induced cardiotoxicity have substantial side effects and are limited to higher cumulative doxorubicin dose regimens. TEMPOL is well tolerated at the anticipated clinical dose for preventing doxorubicin induced toxicities. This study is designed to support FDA Breakthrough Therapy and Fast-Track Designations.