the Marsden Hospital in London. They analysed the outcomes of 212 patients who took part in these trials. Arkenau et al. describe them thus:
A total of 148 patients (70%) were treated in ‘first in human trials’ involving biological agents (132 patients ) or new cytotoxic compounds (16 patients ) alone and 64 patients (30%) received chemotherapy‐based regimens with or without biological agents.
I have highlighted their use of the terms ‘patients’ and ‘treated’. (This type of terminology was common when Rachel Ballinger and I did our analysis of communication between trial doctors and potential trial participants – I shall describe this later in Chapter 14) These terms perpetuate the therapeutic misconception – ‘I am still a patient being treated’.
Arkenau et al. evaluated the tumours before the third cycle of the trial – between weeks 6 and 8. They reported a ‘partial response’ in 19 people (9.4%), stable disease in 88 people (44%), and progression of disease in 95 (47%). ‘The 30‐ and 90‐day mortality was 1.9% (4 out of 212) and 18.3% (39 out of 212), respectively. Treatment related mortality was 0.47% (1 out of 212) and 11.8% (25 out of 212) of the patients have been withdrawn from an ongoing study due to toxicity’ (Arkenau et al. 2008). So, half a percent of people died because of the effects of the trial agents (or ‘treatments’ as they were described). They concluded:
This analysis demonstrated that treatment within the context of a phase I trial could be considered as a valuable therapeutic option. Interestingly, those trials incorporating classical cytotoxics were associated with a better outcome. Clearly, this relates to patient selection, particularly when the trial may involve the use of a cytotoxic in chemonaive cases. The treatment in our cohort was generally well tolerated and treatment‐related deaths and toxicities were low. Moreover, a significant number of patients achieved disease control for a significant duration. However, the challenge remains in appropriate patient selection and for this, the use of an objective clinical score could be a helpful tool.
(Arkenau et al. 2008)
Now, here is a challenge for you: (i) What sense do you make of these findings? (ii) What is missing from these trials? (My thoughts are given at the end of the chapter.)
Phase II Clinical Trials
If Phase I trials show that a new agent is relatively safe, the next step in the development of a new drug is a Phase II trial. These specifically check effectiveness – to see if it does what we want it to do. But these trials continue to monitor the safety and side effects of the developing treatment. Larger numbers are recruited into these trials. The CRUK literature defines them like this:
Phase II trials aim to find out:
if the new treatment works well enough to be tested in a larger Phase III trial;
which types of cancer the treatment works for;
more about side effects and how to manage them;
more about the best dose to use.
These treatments have been tested in Phase I trials, but may still have side effects that the doctors don't know about. Treatments can affect people in different ways.
Phase II trials are usually larger than phase I. There may be up to 100 or so people taking part. Sometimes in a phase II trial, a new treatment is compared with another treatment already in use, or with a dummy drug (placebo).
Some Phase II trials are randomised. This means the researchers put the people taking part into treatment groups at random.
(CRUK 2020)
Again, the principles are the same for cancer drug trials as for other drug trials except that cancer drug trials usually recruit people with cancer and do not pay them; whereas, in other drug trials, healthy volunteers are recruited to take part and they are paid.
Safety in Clinical Trials
There have been some tragic events during Phase I and Phase II trials. Some have been noted above in relation to Phase I oncology trials. But other trials involving heathy volunteers have ended in tragedy. I have selected a few to illustrate this.
TGN 1412 Trial
Six healthy young male volunteers at a contract research organisation were enrolled in the first Phase I clinical trial of TGN1412, a novel superagonist anti‐CD28 monoclonal antibody that directly stimulates T cells. Within 90 minutes after receiving a single intravenous dose of the drug, all six volunteers had a systemic inflammatory response characterised by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhoea, erythema, vasodilatation, and hypotension. Within 12–16 hours after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. Severe and unexpected depletion of lymphocytes and monocytes occurred within 24 hours after infusion. All six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high‐dose methylprednisolone, and an anti‐interleukin‐2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days. Despite evidence of the multiple cytokine‐release syndrome, all six patients survived. Documentation of the clinical course occurring over the 30 days after infusion offers insight into the systemic inflammatory response syndrome in the absence of contaminating pathogens, endotoxin, or underlying disease. (Suntharalingam et al. 2006)
Fialuridine
Before it was trialled on human subjects, Fialuridine was tested on animals, including mice, rats, dogs, monkeys, and woodchucks. Those tests found that animals could survive doses which were a hundred times more than those given to humans without any toxic reactions. A Phase II trial on human subjects was conducted. In week 13 one of the subjects suddenly developed hepatic toxicity and lactic acidosis. The trial was stopped. But seven more subjects became ill and five died. Two had to have liver transplants. These totally unforeseen consequences led to a review of protocols for testing potent biological molecules on human subjects. Attarwala (2010) concluded, ‘Though there is always a risk involved with clinical trials, these risks can be potentially reduced if more scientific research toward development of animal models closely mimicking drug behavior in humans can be developed.’
BIA 10–2474 Trial
In one phase trial, BIA 10‐2474 (an orally administered reversible FAAH inhibitor) was given to healthy volunteers with a view to assessing its safety.
‘Single doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10‐2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10‐2474 per day (6 participants)’. ‘They had received the highest cumulative dose (250 to 300 mg) administered to humans’ (Kerbrat et al. 2016). In this final cohort, four of the six participants developed an acute,
