PREVENTION OF TOXICITIES INDUCED BY PLATINUM-BASED AGENTS
Platinum-Based Agents Overview
Platinum-based antineoplastic drugs are chemotherapeutic agents used to treat various cancers. These agents are estimated to be used in almost 50% of all cancer patients and include cisplatin, oxaliplatin, and carboplatin among others. Platinum-based antineoplastic agents cause cross linking of DNA that inhibits DNA repair and/or DNA synthesis in cells thereby inhibiting rapidly growing cells. These actions create enormous oxidative stress and damage in both normal and cancerous cells.
Toxicities associated with platinum-based agents include mucositis (oral ulceration/inability to swallow), nephrotoxicity (kidney damage), myelosuppression (low blood cell count), ototoxicity (hearing loss), nausea, vomiting, alopecia (hair loss), secondary malignancy (cancer), and many more. Many of these side effects can be life-threatening and have a significant adverse effect on the patient’s quality of life. 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 platinum-based agents. Specifically, Matrix Biomed, Inc. is currently conducting trials on the most widely used platinum-based agent, cisplatin.
Preclinical Evidence Supporting TEMPOL’s Protection Against Cisplatin Toxicities
A study conducted by the Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Ana P. Cotrim, D.D.S., Ph.D and her team found that TEMPOL prevents oral mucositis in mice after exposure to ionizing radiation ± cisplatin, see table below. (Cotrim 2012)
In another study, TEMPOL was effective against cisplatin-induced kidney damage, marked by a prevention in the elevation of serum creatinine, urea, glucosuria, and proteinuria, see table below.
In mice administered cisplatin alone, 29% died whereas in mice administered TEMPOL plus cisplatin, there were no observed mortalities. Furthermore, comparing mice administered TEMPOL plus cisplatin with mice administered cisplatin alone, there is a similar reduction in tumor volume, see table below. (Ahmed 2014)
72 hours after single IP cisplatin injection (25 mg/kg). Tempol 100mg/kg/d po for 4 days starting 1 day before cisplatin. N= 10-12 mice +/- SEM.
* = p<0.05 versus normal or control. # = p< 0.05 versus cisplatin.
Clinical Trial Design
Matrix Biomed, Inc. has been granted phase IIb approval for the prevention of mucositis in head and neck cancer patients receiving both chemotherapy and radiotherapy. Oral mucositis is one of the most common, debilitating complications of cancer treatment, particularly chemotherapy and radiation. It can lead to several problems, including pain, often requiring opioid analgesia, malnutrition as a result of a patient’s inability to swallow sometimes requiring intubation and hospitalization, and increased risk of infection due to open sores in the oral mucosa. It has a significant adverse effect on the patient’s quality of life and can be dose-limiting (i.e., requiring a reduction in subsequent chemotherapy doses).
- Objective: Prevention of Cisplatin and Radiation Induced Toxicities
- Stage: Phase IIb
- Study Population: Patients with head and neck cancer receiving radiation and cisplatin treatment
- Number of Patients: 120 patients (1:1 Randomization; TEMPOL oral solution v Placebo)
- Primary Endpoint: Reduction in incidence of severe mucositis based on the WHO Scoring System
- Secondary Endpoints:
- Reduction in duration of severe oral mucositis
- Prevention and/or reduction of cisplatin induced nephrotoxicity (kidney damage)
- Prevention and/or reduction of cisplatin induced ototoxicity (hearing loss)
Noteworthy: Approval of this clinical trial protocol is significant because the FDA is generally unwilling without overwhelming evidence to approve a phase II trial on a compound to be delivered before radiation or chemotherapy. Here, based on the wealth of preclinical data, the FDA has approved 120 patients to receive TEMPOL before both radiation and chemotherapy. This study is designed to meet FDA requirements for Breakthrough Therapy and Fast-Track Designations.