Glossary and FAQs
1. Clinical Studies (general)
Clinical trials of experimental drugs typically are carried out in 3 main steps referred to as Phases 1, 2 and 3. In broad terms, a Phase 1 study seeks to determine how safe the drug is; a Phase 2 study seeks to show that it is able to provide a clinical benefit; a Phase 3 study uses the drug in a way that it would be used on-market to provide statistical evidence of benefit to support an application for marketing approval.
2. Phase 1 Studies
Phase 1 studies with experimental anti-cancer drugs typically are conducted in cancer patients. This is because most anti-cancer drugs are designed to kill cancer cells and that killing action usually means that the drugs have potential side-effects that would be unreasonable to expose healthy patients to. Ethical guidelines mean that patients are eligible only when they have no remaining standard therapeutic options to treat their disease.
Phase 1 studies with experimental anti-cancer drugs usually are conducted in patients with a range of cancer types.
Phase 1 studies often are divided into separate Phase 1a and Phase 1b studies. This is the case with the proposed Georgian study, where we need to check the safety of NOX66 both on its own (Phase 1a) and then in combination with carboplatin (Phase 1b).
In a Phase 1a study, the primary end-points usually are toxicity and how the body treats the drug (known as pharmacokinetics). In the proposed Georgian study, NOX66 will be given on its own at 3 different dosages (low, medium, high) to a total of 15 patients (5 per dose) over a 14-day course of treatment and the ability of the patients to tolerate each dosage determined. Blood and urine also will be collected to help determine how the drug is distributed in the body and how and in what time it is excreted.
In a Phase 1b study, the primary end-point usually is toxicity, but under conditions intended to be encountered in Phase 2 and 3 studies. In the proposed Georgian study, we intend to use NOX66 in combination with chemotherapy drug, carboplatin, for up to 6 months to investigate what if any effect NOX66 has on carboplatin toxicity.
3. Phase 2a Study
Phase 2 studies usually mean using the experimental drug in a way that is designed to show whether it is working, and that usually means testing it in the type of cancer for which it is intended.
Often split into Phase 2a and Phase 2b studies, with Phase 2a being an exploratory study in a small number of patients to confirm issues such as the best clinical target and the optimum drug dosage, before moving onto a larger Phase 2b study. In the proposed Georgian study, the optimal dosage combination of NOX66 + carboplatin will be used in patients with specific types of cancer, based on data generated in the Phase 1b study.
4. Adaptive design
An adaptive clinical trial design is intended to shorten the time it takes to bring a drug through the clinical trial process. It works on the basis of observing outcomes in a study and then modifying the clinical trial in accordance with those observations. Modifications may include drug dosage, sample size and patient selection criteria. These abilities to change are established before the trial begins, with the method of change clearly identified and agreed upon beforehand.
In the case of the Georgian study, an adaptive design means that where we see evidence of significant clinical response with a particular NOX66 + carboplatin dosage combination in a particular cancer type, then we can zero in on that particular dosage/cancer type combination without having to stop the Phase 1 study and submit a Phase 2 protocol to the regulators for consideration.
5. Cytotoxic chemotherapy
The term cytotoxic means to ‘kill a cell.’ Cytotoxic anti-cancer drugs do this by poisoning the cancer cell, resulting in physical damage to the cell. The damage can be sub-lethal, with the outcome generally being that the cancer cell is unable to divide; or, as more usually happens, it is so severe that the cell dies.
There are over 100 different cytotoxic chemotherapies. They mostly fit into 4-5 general families based on how they work. The most common target is the cell’s DNA so that the cell is unable to divide and to function normally. A cell has a number of DNA repair mechanisms that are activated in response to the drug-induced injury, but the purpose of cytotoxic chemotherapy is to create so much damage that it is beyond repair. At that point, the cell becomes stressed and dies.
Carboplatin is one of the most widely used cytotoxic chemotherapy drugs, first introduced in the late-1980s. It is based on a platinum molecule that binds the two strands of DNA in genes and prevents them from functioning. Other platinum-based drugs are cisplatin and oxaliplatin. Carboplatin is used to treat a wide range of solid cancers.
Cytotoxic drugs are general poisons. Their actions do not discriminate between cancer cells and healthy cells. That means that healthy cell DNA is just as susceptible to the damaging effects of drugs such as carboplatin as is cancer cell DNA, with the proviso that DNA is more likely to be damaged when it is dividing. Cytotoxic chemotherapy works on the basis that cancer cells are more likely to be damaged because they are dividing more rapidly than most healthy cells. However, there are certain healthy tissues that also divide fairly actively including the lining of the mouth and gut, bone marrow and hair follicles. Blocking the ability of these tissues to divide produces side-effects such as mouth ulcers, vomiting, diarrhoea, anaemia, low white blood cells (increased susceptibility to infection) and hair loss.
8. Phase 2 metabolism
All foreign chemicals such as drugs are treated with suspicion by the body as potentially harmful, with the body having the primary aim of eliminating them as quickly as possible. The most effective way of doing this is to pass them out through the kidneys into the urine, and to do that the chemical needs to be soluble in water.
About 10% of all drugs we take (like paracetamol, aspirin, codeine), are not soluble in water, and that presents the body with a challenge because they cannot readily be excreted in the urine. So they are attached to compounds which themselves are water-soluble and where the overall combination of the two compounds becomes water-soluble.
Idronoxil is highly insoluble in water and is subject to extensive Phase 2 metabolism, being combined with glucuronic acid. The combined idronoxil + glucuronic acid is able to circulate freely in the blood and to pass out of the body in the urine.
Drugs attached in this way are known as conjugates, and conjugated drugs are inactive…having the second compound attached to make the drug water-soluble makes the combined structure too large to combine to the drug target.