A Phase I/II Trial of Romidepsin (Depsipeptide) and Bortezomib in Patients With Relapsed Myeloma
Several groups have explored the possible synergistic interactions between proteasome and
HDAC inhibitors in malignant hematopoietic cells. Bortezomib and HDACIs synergistically
induce apoptosis, mitochondrial injury (via BAX), ROS generation and oxidative injury in
human leukemia and myeloma cells.
In view of this evidence, we are proposing a trial to examine the clinical effects of
combined romidepsin and bortezomib in patients with relapsed/refractory MM. However, there
are currently no data as to whether these drugs are safe to administer in combination or at
what dose toxicity they may become unacceptable.
Trial Design Open label, single centre, single arm, phase I/II dose escalation trial of
bortezomib-dexamethasone with the addition of romidepsin followed by maintenance therapy
until disease progression.
• To determine the maximum tolerated dose (MTD) of romidepsin administered with Bortezomib
in patients with relapsed multiple myeloma by the assessment of adverse events and abnormal
• Toxicity evaluation at each of four dose levels presented in the dose-escalation schedule
• To determine the efficacy of this combination at the MTD in terms of (i) overall response,
(ii) time to progression and (iii) overall survival
- Overall response (OR), defined as the best response on treatment based on M Protein
response criteria with CR documented to EMBT standard and in conjunction with soft
tissue plasmacytomas response criteria and corrected serum calcium level.
- Time to progression (TTP), defined as the time from commencement of treatment to the
date of first evidence of progressive disease.
- Overall survival (OS), defined as the time from commencement of treatment to the date
of death from any cause
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Simon J Harrison, MBBS, PhD.
Peter MacCallum Cancer Centre, Australia
Australia: Department of Health and Ageing Therapeutic Goods Administration