Trial Information

AMD3100 With Busulfan, Fludarabine and Thymoglobulin for Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndromes

This is a single centre phase I/II study which will be conducted in two stages. The ability
of AMD3100 to augment the antileukemic effect of chemotherapy and stem cell transplantation
in patients with MDS or with AML in first or subsequent relapse, second or greater remission
or primary induction failure will be assessed.

The primary objective in Stage 1 is to determine an acceptably safe dose, utilizing the
continual reassessment method (CRM).The CRM is a model-based statistical procedure for
conducting phase I clinical trials that assigns doses to successive cohorts of patients
based on the doses given and outcomes observed (toxicity or no toxicity) of all previous
patients. In this sense, the method is "outcome-adaptive." The CRM relies on a simple
Bayesian model for the probability of toxicity as a function of dose. As the dose-toxicity
data in the trial accumulate the Bayesian model "learns" about the relationship between dose
and probability of toxicity. Numerous computer simulation studies (and the references
therein) have shown that the CRM has greatly superior properties compared to conventional
"3+3" algorithms. This is due to the facts that conventional algorithms are not model-based,
they only use data from the most recent 6 patients, and they tend to stop the trial very
early, with the consequences that they are very likely to give very unreliable estimates of
the toxicity probability at each dose and provide an unreliable recommended maximum
tolerated dose (MTD).

Under the particular version of the CRM being used in this trial, following treatment of the
first cohort of three patients at the initial dose level 80 µg/kg, the following decisions
are possible:

- If 0 of the first 3 patients (#1, 2 and 3) experience toxicity, then the method will
escalate and the second cohort of patients (#4, 5 and 6) will be treated at the second
dose level, 160 µg/kg.

- If either 1 or 2 of the first 3 patients experience toxicity, then the method will stay
at the starting dose, so the second cohort will be treated at the lowest dose level, 80
µg/kg.

- If all 3 of the first 3 patients experience toxicity, then the posterior probability
that the lowest dose is unacceptably toxic will be 0.951, and since this exceeds the
decision cut-off 0.90 in the protocol the phase I trial will be terminated with the
conclusion that the lowest dose level 80 µg/kg is excessively toxic.

If the trial continues, for all successive cohorts after the first, since the decision of
which dose to assign utilizes all of the dose-toxicity data from all patients treated
previously, there are too many possibilities to enumerate. For example, there are 12
possible outcomes for the second cohort, and this number increases exponentially as the
trial progresses. However, at any point in the trial, the estimated probability of toxicity
at each dose based on the most recent data may easily be estimated and this information made
available to the investigators. Additional safety provisions are that the middle dose of 160
µg/kg may not be skipped when initially escalating from 80 µg/kg, and the trial will be
terminated early with no dose chosen if the lowest dose is excessively toxic.

The primary objective in Stage 2 is to determine progression free survival post-allogeneic
transplant, in terms of time to treatment failure and survival. Stage 1 will include both
prognostic subgroups CR and not in complete remission (NCR). In Stage 2, different
monitoring rules will be used in CR and NCR subgroups to reflect their very different
historical failure rates. Additionally, all patients treated at the dose selected in Stage 1
will be counted as members of the Stage 2 sample.