Trial Information

Mechanistic Study: Pharmokinetics of 4-hydroxycyclophosphamide in Patients Receiving Cyclophosphamide for the SCOT Trial

The purpose of this study is to determine the plasma concentration and exposure time
required for cyclosphosphamide to produce optimal immunosuppressive activity with minimal
toxicity in subjects with severe systemic sclerosis.

Secondary objectives are:

1. To determine whether the initial cyclophosphamide exposure affects the pharmacokinetics
of a second dose in the cyclophosphamide arm.

2. To evaluate the effect of this high dose cyclophosphamide regimen on myelosuppression
as assessed by total white cell count and that of polymorphic mononuclear cells at
approximately 24 and 48 hours post-dose in the transplant arm.

Recruitment for this study will be limited to participants who have elected to participate
in the SCOT study and have been randomized to one of the SCOT treatment arms. Participants
will be recruited after randomization to ensure balance on the two arms for this mechanistic
study and must agree to participate and sign an informed consent for this mechanistic study
prior to initiation of treatment on either arm. Fifty participants, 25 from each arm, will
be recruited for this sub-study. It will be conducted at the participating SCOT transplant
and rheumatology centers.

In Arm 1 (the transplant arm), as part of the conditioning regimen, cyclophosphamide at a
dose of 60 mg/kg will be infused over 1 to 2 hours (on 2 consecutive days), and blood
collection will occur prior to dosing and at Hours 2, 4, 6, 8, 10, and 23 after completion
of the first infusion for measurement of 4-OH-CP pharmacokinetics. Additionally, blood
collection will occur at approximately 24 and 48 hours in the transplant arm to obtain white
cell count and differential (including polymorphic mononuclear cell counts).

In Arm 2 (the high-dose cyclophosphamide arm), an initial cyclophosphamide dose of 500 mg/m2
will be infused over 1 to 2 hours, and blood collection will occur prior to dosing and at
Hours 0.5, 1, 2, and 24 after completion of drug infusion for measurement of 4-OH-CP
pharmacokinetics. For the second monthly infusion, a cyclophosphamide dose of 750 mg/m2 will
be infused with blood collection occurring at the same time points as those for the first
dose.