Author:

Rachel Brazil

Introduction

The importance of platinum-based chemotherapies cannot be underestimated – they are given to about 40% of patients who receive chemotherapy. Much of the research and development leading to the first platinum drug, cisplatin, was carried out in the US, but its discovery launched major research efforts in both the UK and France, producing new generations of platinum drugs with superior properties

Carboplatin ‒ the second generation

The second generation platinum-based chemotherapy is used to treat ovarian, lung head and neck and brain cancers, and neuroblastoma. It was developed in the UK and approved in the UK in 1986 and in the US in 1989. Although it exhibits similar activity to cisplatin, it causes significantly less severe side-effects.

“Of course, a lot of people thought, well, maybe we could make an analogue to cisplatin that is less toxic,” says Calvert, “and that's how carboplatin came about.” The second generation platinum drug was developed by a UK team, stemming from work carried out by Mike Cleare as a postdoctoral researcher in Rosenberg’s Michigan lab.

Cleare recollects that Rosenberg came to London to meet representatives of Rustenburg Platinum Mines (mines in South Africa that are still one of the major sources of platinum) and the UK precious metals and chemical company, Johnson Matthey, where Cleare was working as a young researcher. “He sold them a pitch that it would be good for public relations to support platinum being used for potential cancer therapies,” remembers Cleare. Rustenburg agreed to fund a postdoctoral research fellowship through Johnson Matthey. “The first thing I knew about it was when I got a phone call to say would I go and meet with Rosenberg and see if I would like to go out there.”

With cisplatin research already underway, Cleare’s role was to study the relationship between chemical structure and reactivity, with the aim of finding better platinum drug candidates. “I must have made hundreds of platinum compounds,” he says. He discovered that changing the ligands around the platinum atom could change the reactivity of the complexes, but it did not change the anti-cancer properties. It did, however, cause a significant change in the toxicity and the side-effects.

The mission for Cleare then shifted from looking for more active platinum complexes to finding one that was less toxic but still sufficiently active. “We found that some molecules fitted the bill, and in particular those with bidentate carboxylate ligands seemed to have a happy medium of lower toxicity combined with good therapeutic activity,” says Cleare, who adds that this may be connected to enzyme activity that is able to chemically react with these bidentate ligands. The problem was that many of these complexes are insoluble and therefore unsuitable for developing into drugs.

Example of bidenate ligand

Using the non-planar cyclobutane dicarboxylic acid (CBDCA) ligand, however, Cleare found the resulting molecular complex ‒ carboplatin ‒ was unable to ‘close pack’ and form crystals, rendering it soluble. It was also lipophilic (fat soluble) which is important for its uptake by cells. With this combination of properties Cleare had found a potential alternative to cisplatin. But it wasn’t until he returned to the UK that the development of carboplatin became a priority.

Carboplatin

After two years in Rosenberg’s lab, Cleare returned to Johnson Matthey in the UK to continue the work, teaming up with the Institute of Cancer Research (ICR). “That's where we really got stuck into seriously looking at this very valuable heap of work, and with the ICR’s help we managed to focus on selecting a second-generation compound.

“Although it was made by an Englishman and devised by English people, the chemical was made in Michigan State University and the patent was held by them,” clarifies Calvert. Cleare is named on the fundamental composition patent for carboplatin, along with Rosenberg and others working in his lab involved with the initial work. But as Cleare adds: “Without the European institutions, carboplatin, which turned out to be just as important as cisplatin, and in many ways better, would never have happened.”

One significant factor in this was the multi-centre research collaboration known as the Rustenburg Platinum Group, funded by Johnson Matthey and Rustenburg Platinum Mines, and coordinated by Cleare with researchers from the ICR, led first by Tom Connors and then by Ken Harrap when Connors retired in 1978. The group ‒ was an early example of ‘team science’ with participants from multiple institutions. In addition to further basic research, in 1976 the group started developing carboplatin, with clinical trials at the Royal Marsden. In a meeting held by the Wellcome Trust in 2006, group member Andrew Thomson (1940-2021) commented that the Rustenburg Platinum Group helped the clinical work go much more rapidly.

The eventual success was due to luck but also persistence. The ICR’s Connors was aware of the toxicity and damaging side-effects experienced by patients in the first cisplatin trials. He decided there was a case to test out the more selective and less toxic analogue that Cleare had developed. “We came to terms with the fact that it wouldn’t have a particularly different spectrum of activity, but it would be much easier to use because of its reduced toxicity; it had a better window between activity and toxicity,” explains [Mike Cleare](@mike -cleare).

“There was a shortlist of about eight platinum compounds, and eventually we chose carboplatin as being the best one on the basis of studies which today you would think were very rough really,” says Calvert. Bristol Myers, which had licensed the second-generation platinum compound, was not initially interested. It was already developing cisplatin and the focus was less on quality of life than on finding a complex with a different spectrum of activity.

Bristol Myers was also developing another platinum compound called spiroplatin or TNO-6, licensed from the Netherlands Cancer Institute. The company hoped this reactive complex (with a sulfate ligand) would remain active in cancer that became resistant to cisplatin. A response in breast cancer had been reported in phase I trials, but by 1992 further trials were stopped when little anti-tumour activity was found and there was severe and unpredictable renal toxicity.

Going it alone, early phase trials of carboplatin started in 1979 at the Royal Marsden, led by Calvert (the first phase I trial of his career). Without Bristol Myers, all trial phases were carried out under a clinical trial exemption (CTX) – a now defunct mechanism by which clinicians could take personal responsibility for prescribing a drug, with Johnson Matthey doing the chemistry needed for the eventual regulatory approval. “We were widely pilloried in the academic community for doing this,” says Calvert. The team’s papers and abstracts were often not accepted at conferences.

But the trials showed evidence of activity as well as reduced toxicity compared with cisplatin. Carboplatin was much better for people in almost all respects, from its nephrotoxicity, through to the nausea and vomiting and hearing loss caused by cisplatin. Calvert also carried out a phase II trial in ovarian cancer, supported by Eve Wiltshaw, who had previously conducted trials on cisplatin. “She collaborated with me and passed me a lot of patients with ovarian cancer who, for one reason or another, hadn’t done well on cisplatin. And we just got a stunning number of tumour responses. It was obvious fairly quickly that we were sitting on a really active drug,” says Calvert.

“People began to realise that carboplatin did actually work, and the mood changed a bit and then Bristol Myers Squibb took an interest,” recalls Calvert. Carboplatin was approved in the UK in 1986, and in the US in 1989. But this was not the end of the story, as persuading clinicians to prescribe the drug ‒ especially those in the US ‒ was initially hard, because it was difficult to calculate the right dose for each patient. “It became obvious that there was huge variation in individual people’s tolerance,” explains Calvert. Dosage tolerance was related not only to the size of a patient but to the rate at which the drug could be cleared from the body. “I thought, we should be able to work out a formula based on kidney function.”

Calvert sought help from his mother, a mathematician, to solve the relevant differential equations. “She posted me a book and said: ‘Read it and you can learn how to solve them.’ So I did, and found a formula to dose carboplatin, which is now used all over the world.” There were several other contributions to creating dosing formulas, notable from pharmacology expert Merrill Egorin at the University of Pittsburgh in the US, and Etienne Chatelut at the Toulouse Cancer Research Centre in France. But things changed when Bristol Myers Squibb marketing manager Frank Pasqualone took Calvert to the US to explain the ‘Calvert formula’ to senior oncologists. “That's what really turned it around and made it into a successful drug.” Cleare agrees: “The person who really made it all happen clinically was Hilary Calvert, whom I call Mr Carboplatin.”

See here for more about what is known widely as the Calvert formula and here.

In 1991, the team was awarded the Queen’s Award for Technological Achievement in the UK. But carboplatin owes its existence, says Cleare, to a European approach to drug discovery. “The European approach is slightly different; it’s a bit more open minded and flexible particularly with regards to goals and objectives. When I look back on it there was definitely a bit of competition with Europe wanting to develop carboplatin as a better version of the US-developed cisplatin.” Today the drug remains one of the most commonly prescribed anticancer drugs, particularly in combination with paclitaxel to treat ovarian cancer, and also for lung cancers.

The UK team continued work to find a superior third-generation platinum complex, funded with a $5m grant from Bristol Myers Squibb. They had some candidates: satraplatin was developed as an orally administered drug and, during clinical trials, was found to remain active in cisplatin-resistant cells; picoplatin also showed activity in cisplatin-resistant cancers. But despite early trials, neither drug became commercially available. “They just weren’t sufficiently differentiated to be picked up,” says Cleare. “To get a third-generation compound it’s got to have outstandingly improved activity, and these didn’t.”

See also this personal reflection on carboplatin by Calvert, which is dedicated to Martin Gore, who worked on the early studies and went on to become medical director of the Royal Marsden; and also a lecture on the 40th anniversary of the approval of cisplatin and the evolution to carboplatin, also by Calvert.