In stage II, a variable cohort sizes of up to five patients will be considered. Patients are screened for eligibility before they are formally registered. During screening, it is expected to transpire that some patients will be ineligible. To maximise recruitment and reduce trial suspension period between cohorts in this rare disease, the flexibility of variable cohort sizes will be allowed for by screening cohorts of up to five patients. Screening slots will be allocated so that the sum of: a) the number of patients already receiving treatment in the current cohort; and (b) the number of patients in screening; does not exceed five. If a patient is screened and proves to be eligible, they will be recruited to the trial. The first three patients in a cohort will receive the dose-level allocated to the cohort. Patients who are inevaluable, as described immediately above, can be replaced. If a fourth or fifth patient is recruited to a cohort and the dose allocated to the cohort is not yet regarded as tolerable, the fourth and fifth patients will receive the next dose-level below. Otherwise, they will receive the same dose level as the previous patients in the cohort. The aim of the described strategy is to maximise recruitment but not expose more than three patients to a dose that has not yet been demonstrated tolerable. The model will usually be updated after every 2 to 3 evaluable patients and subsequent recommended doses will be assigned to patients iteratively until the maximum sample size is reached, or the trial is stopped early because there is a high chance that the lowest dose is too toxic.