Abstracts of Clinical Meeting on 12-July-2002
A Phase I Study Of An Immunomodulatory Drug (CC-4047), A Structural Analogue Of Thalidomide, In Relapsed / Refractory Multiple Myeloma
Steve Schey, Consultant Haematologist, Guy's & St Thomas' NHS Trust, London, SE1 9RT
CC-4047 is an immunomodulatory drug chemically-linked, but functionally distinct from thalidomide with approximately 5000-fold greater inhibition of tumour necrosis factor alpha (TNF-α) activity than thalidomide and has an excellent toxicity and safety profile in early human volunteer studies.
Presented is a Phase I dose escalation study in relapsed/refractory multiple myeloma designed to identify the maximum tolerated dose (MTD) and evaluate the safety of CC-4047 when given orally for 4 weeks. Patients were enrolled in cohorts of 3 at each dose level: 1mg/day, 2mg/d, 5mg/d and 10mg/d. Secondary end-points were disease response and pharmacokinetics.
Results: 18 patients entered the study, (median age 67-years, range 55 years to 81-years) with a median of 2 prior chemotherapy regimens (range 2-4). 2 patients had undergone previous autologous stem cell transplantation and 3 patients had received prior thalidomide. At the 1 mg dose level, 1 patient developed a DVT proven on ultrasonography. 3 additional patients were entered at 1 mg/d with no DLT in the 28-day study period. There were no DLTs at the 2mg or 5mg dose levels. At the 10mg dose level, two patients developed grade IV neutropenia, 3 further patients were then enrolled at 5mg dose level, at this level 2/3 patients developed grade 3 neutropenia establishing MTD at the 2mg dose level with additional patients to be enrolled at 2mgmg/d for confirmation. No significant neuropathy, somnolence or constipation has been reported in any of the cohorts. All patients at all dose levels reported an improvement in their clinical health while on treatment. The median duration of therapy is 19 weeks (range 3-44). The M-protein response on trial was as follows: <25% in 8/18 (44%), >25-50% in 7/18 (39%) and >50% in 3/18 (17%). On a named patient basis, 8/18 developed >50% M-protein response including one CR and two near CRs.
Conclusion: CC-4047 has an acceptable toxicity profile with anti-tumour activity and should be evaluated in future phase II studies in haematologic and solid tumour malignancies.
This study is currently being extended to allow for the evaluation of dose escalation using an alternate day dosing regime.