Trial of novel leukaemia drug is stopped for second time after two more deaths

BMJ 2016; 355 doi: (Published 25 November 2016) Cite this as: BMJ 2016;355:i6376
  1. Nigel Hawkes
  1. London

A trial that had already been stopped and restarted in July, after three participants died,1 2 has been suspended once again after two more patients died.

Juno Therapeutics of Seattle, Washington, stopped its phase II trial into an immunological treatment for acute lymphocytic leukaemia on 23 November after two patients died. They had symptoms identical to those of the first three patients who died: brain swelling caused by excess fluids (cerebral oedema).

Although patients enlisted in the trial all had a lethal disease and few options left, questions are likely to be asked of the company and the US Food and Drug Administration, which allowed the trial to resume after the first three deaths.

The FDA did so after Juno hypothesised that these deaths had been caused by the use of the anticancer drug fludarabine to precondition the patients. It substituted cyclophosphamide, but this did not eliminate the risk. “The clinical course with these two cerebral oedema patients was very similar to what we saw in July,” said Mark Gilbert, the company’s chief medical officer. “We did not expect the removal of fludarabine to eliminate entirely the risk of neurotoxicity or cerebral oedema.”

He made the remarks in a conference call with industry analysts. The shares of the well funded company, launched on the market on a wave of optimism two years ago, finished the day down by nearly 25%.

The therapy involves engineering T cells taken from a patient’s blood so that they recognise specific antigens on the surface of cancer cells. The process induces the T cells to produce so called chimeric antigen receptors (CARs) on their surface. The modified T cells, called CAR-T, are reintroduced into the bloodstream, where they attack cancer cells. The field is one of the hottest in cancer research, with several companies hoping to produce successful CAR-T products.

Juno, a biotech company formed in 2013 by leading US cancer centres, started with $120m funding and gained another $300m from private investors and $265m by a public placing. It has acquired a series of smaller players and in June 2015 entered a partnership with Cellgene valued at $1 billion over 10 years, one of the largest such deals ever struck. Cellgene will market any products that are licensed.

Much therefore hangs on Juno’s success. Hans Bishop, the company’s chief executive, refused to rule its product dead. Options included continuing the study under a different protocol, starting a new study, or terminating development, he said. “We are faced with a difficult decision,” he admitted.

Juno has several other CAR-T treatments under development, which it claims will not be affected. Other companies involved in the field are Kite Pharma and Novartis. Novartis has said that it remains committed to its CAR-T programme despite its recent decision to close down its cell and gene therapy division.


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