Relapse and / or Refractory Myeloma Clinical Trial
Official title:
Phase 2 Study of Daratumumab in Combination With Thalidomide and Dexamethasone in Relapse and / or Refractory Myeloma
Myeloma patients who relapse after prior treatment with bortezomib and lenalidomide have
survival of less than 1 year. A number of new drugs have been approved for the treatment of
relapse myeloma in the last couple of years, including, Elotuzumab, Panobinostat, Ixazomib,
carfilzomib and Pomalidomide. However, most of these drugs either do not have good single
agent activity or still belongs to the category of immunomodulatory drugs or proteasome
inhibitors. Daratumumab is a monoclonal antibody against CD38 that is highly expressed on
myeloma plasma cells. In phase ½ studies, it has impressive single agent activity in relapse
and refractory myeloma with a very acceptable toxicity profile. This set the stage for
combinations with daratumumab to increase efficacy and improve outcome of patients with
myeloma. The use of immunomodulatory drugs, such as thalidomide and lenalidomide, has been
shown to augment NK cell activity. NK cells are important mediator of antibody dependent
cellular cytotoxicity. We therefore hypothesize that the combination of Daratumumab with
thalidomide may therefore improve the efficacy of the treatment.
In this study, we will plan to perform a phase II trial using the Daratumumab, Thalidomide,
Dexamethasone combination in 100 myeloma patients with relapse myeloma in Asia.
Daratumumab is a humanized antibody against CD38 which is expressed on myeloma cells.
Daratumumab exhibited single agent activity in myeloma and is a promising new treatment.
Recently, 2 phase 1 / 2 studies establishes the dosing regimen for Daratumumab and impressive
single agent activity of about 30% response rates in patients who relapse after prior
lenalidomide and bortezomib. Daratumumab also appear to be well tolerated. The most common
toxicity is infusion-related and almost all confined to the first cycle. On the whole these
are manageable with early intervention, concurrent corticosteroids and anti-histamines as
well as slowing infusion rate. More recently, early results from 2 randomise study comparing
Daratumumab plus lenalidomide and dexamethasone compared to lenalidomide and dexamethasone,
and Daratumumab plus bortezomib and dexamethasone compared to bortezomib and dexamethasone,
showed that the addition of Daratumumab significantly improved response and progression free
survival, including a high minimal residual disease (MRD) negative rate of more than 20% in
the relapse myeloma populations.
In addition, the use of immunomodulatory drugs, such as thalidomide and lenalidomide, has
been shown to augment NK cell activity. NK cells are important mediator of antibody dependent
cellular cytotoxicity, which is an important mechanism of action for Daratumumab.
Furthermore, in the studies using another antibody target SLAMF7, Elotuzumab, the addition of
dexamethasone greatly improve efficacy. Furthermore, thalidomide plus dexamethasone
combination have a long history in myeloma and is relatively well tolerated and
cost-effective. We therefore propose to add Daratumumab to thalidomide and dexamethasone, as
this combination will be relatively easy to deliver in the Asian population because of
availability and there is good rationale that such a combination will be synergistic and
well-tolerated
Patients will be assessed every 28 days (+/-10 days). Patients shall receive the treatment
until disease progression, unacceptable toxicity as determined by treating physician,
withdrawal of consent or mortality (whichever occurs first). After disease progression, the
treating physician should provide long-term follow-up data on disease status and survival.
For patients who discontinued treatment before disease progression occurred, disease
assessment measurements shall be performed once every 28 days (+/- 10 days) until disease
progression. After patients have documented progression of disease, they will be followed for
survival every 3 months (+/-10 days) until study closure or until patients withdraws consent,
is lost to follow-up or until death, whichever comes first. For any patient who is lost to
follow-up, the study site shall attempt to ascertain survival information via public database
search.
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