Prague, Czech Republic: Researchers in the UK and the United States have
found that a drug composed of an antibody carrying a highly toxic
anti-cancer agent is well tolerated by patients at much higher doses than
have been used before.
The drug, BB-10901 (huN901-DM1), is being tested in a phase I clinical trial
in patients who have relapsed or failed to respond to previous treatment for
a range of cancers, such as small cell lung cancer (SCLC), other tumours in
the lungs of neuroendocrine origin and non-pulmonary small cell carcinomas.
Although the trial is not designed to test the efficacy of the drug,
researchers report promising clinical responses in patients, including one
patient who has remained in remission for more than a year.
Dr Paul Lorigan reported to the EORTC-NCI-AACR [1] Symposium on Molecular
Targets and Cancer Therapeutics in Prague today (Friday): "The results are
important in that, in contrast to a prior regimen investigated in a phase I
trial in the United States, significantly higher dose intensity is achieved
with the current schedule. This has implications for the design of future
trials with this agent, especially as the amount of the drug given is likely
to be important in determining clinical response and outcome. In addition,
the presence of a durable, complete response as well as other hints of
clinical activity are very encouraging.
"The tolerability of this agent compares very favourably with that of
standard chemotherapy. The lack of clinically significant bone marrow
toxicity by BB-10901 raises the possibility that such an agent could be used
either alone or in combination with standard chemotherapy in future clinical
trials."
Dr Lorigan, a senior lecturer in medical oncology at the Christie Hospital,
Manchester, UK, worked with colleagues in the UK and USA to investigate
different dose levels, any adverse effects and how the drug was cleared from
the body (pharmacokinetics). The drug, also known as huN901-DM1, is an
immunoconjugate - a hybrid molecule specifically designed to deliver a
potent cell-killing agent to cancer cells - and is created by attaching a
cytotoxic drug DM1 to a monoclonal antibody, huN901. It binds to cells that
have the molecule CD56 on their cell surfaces and the DM1 then can kill the
cells. Several tumours are CD56 positive, including SCLC, neuroendocrine
tumours, Wilms' tumours, and multiple myeloma.
The researchers gave the drug by intravenous infusions for three consecutive
days every three weeks. The researchers initially enrolled four patients at
each dose level (4, 8, 16, 24, 36, 48, 60, 75 milligrams per squared metre
of body surface area (mg/m2)). When a patient experienced a dose-limiting
toxicity the cohort was enlarged to six patients at that dose. So far, 40
patients have been treated.
Adverse effects were seen in six patients and included constipation,
fatigue, leg pain, headache, inflamed pancreas, hypotension and myocardial
infarction. Dr Lorigan said: "In general, the study drug was well
tolerated, particularly when compared to standard chemotherapy. There was
no clinically significant myelosuppression, most probably because the
immunoconjugate is targeted at the tumour rather than the normal cells.
Also, there was no clinical evidence of serious allergic or infusion
reactions. The one side effect we have seen at higher doses is headache.
This seems to be reduced if we increase the infusion time, and it may
respond to other medication given with the study drug - we are investigating
this further."
One patient with metastatic, recurrent Merkel cell carcinoma (a rare,
aggressive cancer that develops on, or just beneath, the skin and in hair
follicles) had a durable, complete response and remains in clinical
remission more than a year after treatment. "This patient had numerous
prior relapses and had failed standard chemotherapy," said Dr Lorigan.
Eight patients had stable disease lasting between six and 21 weeks.
"It is difficult to draw any reliable conclusions from an early phase study
such as this, but we are encouraged to see early signs of activity. While
some tumours treated were indolent, others such as extensive SCLC were very
aggressive. The presence of stable disease in a patient with SCLC over six
cycles of therapy is very encouraging," he continued.
Pharmacokinetics showed that drug was able to tackle tumour cells expressing
CD56 more effectively at the higher doses. The researchers have not reached
the maximum tolerated dose yet and are continuing to enrol new patients.
"We are considering amending the protocol and adding three patients at 75
mg/m2/day, with pre-medication prior to infusions of BB-10901. While we
have not seen dose-limiting toxicity at this level with the slower infusion
(without pre-medication), we have seen headache in two patients, which is a
moderate adverse effect. We anticipate that pre-medication will ameliorate
or prevent this symptom. If well tolerated, we would then increase the dose
to 94 mg/m2/day," said Dr Lorigan.
He concluded: "Treatment options for these patients are limited and we are
encouraged by the early results with this novel agent. We are grateful to
the patients, their families, the investigators, clinical staff, and our
colleagues at ImmunoGen (the sponsor of the clinical study) for their
participation and continued support of this trial."
Abstract no: 649
1. EORTC [European Organisation for Research and Treatment of Cancer,
NCI [National Cancer Institute], AACR [American Association for Cancer
Research].
EORTC-NCI-AACR