Phase II Study of RO4929097 to Eradicate Residual Disease in Patients With Multiple Myeloma Post Single Autologous Stem Cell Transplant
I. To determine the efficacy of RO4929097 in eradicating residual/persistent disease
(conversion of VGPR to CR or sCR status) in multiple myeloma patients status post single
high-dose melphalan/autologous stem cell rescue with residual/persistent disease
I. To determine the safety of single agent RO4929097 post-autologous stem cell transplant in
multiple myeloma patients.
II. To analyze Notch receptor and ligand protein expression in pre-transplant, pre-treatment
with RO4929097, and post-treatment bone marrow biopsy samples.
III. To isolate and identify clonogenic multiple myeloma progenitor cells from bone marrow
aspirate and/or peripheral blood at the following time points: pre-transplant, day 100
post-transplant, and post-treatment staging bone marrow biopsy.
IV. To analyze Notch receptor and ligand protein expression on isolated clonogenic
progenitor myeloma cells.
V. To characterize the tumor xenograft-initiating potential of clonogenic myeloma cells in
adult Casper zebrafish and SCID-hu model and evaluate the drug toxicity and therapeutic
potential of RO4929097 with this model.
VI. To analyze anti-angiogenic effects of RO4929097 as measured by reduction in microvessel
density and VEGFR-1 expression in pre-treatment and post-treatment bone marrow biopsy
VII. To determine whether measurement of soluble surrogate markers of angiogenesis prior to
and following treatment with RO4929097 provide an early marker of disease response to Notch
OUTLINE: This is a multicenter study.
STEM CELL TRANSPLANTATION AND CHEMOTHERAPY: Patients undergo standard mobilization and
collection of autologous peripheral stem cells (>= 4.0 x 10^6 CD34+ cells/kg). Patients then
receive high-dose melphalan IV on days -3 and -2 and undergo autologous stem cell
transfusion on day 0. Patients with progressive disease, stable disease, partial response,
stringent complete response, or complete response are taken off study; patients with
residual/persistent disease (very good partial response [VGPR]*) continue to therapeutic
NOTE: *Patients who meet the criteria for VGPR but have findings of abnormal bone marrow
cytogenetic study demonstrating >= 10% metaphase cells positive for either high-risk
chromosomal abnormalities or persistent disease-related chromosomal abnormalities (e.g.,
chromosome del 13; del17p, t(4;14), t(14;16), t(6;14) or complex cytogenetics) will have a
repeat bone marrow biopsy assessment with cytogenetics within 2-3 weeks. If the repeat
biopsy findings suggest persistent high-risk cytogenetic findings, then the patient is
considered eligible to receive RO4929097 to eradicate residual disease.
THERAPEUTIC TREATMENT: Beginning 100-110 days after transplantation, patients receive oral
RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for at least 4 weeks.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Overall response rate of gamma-secretase/Notch signalling pathway inhibitor RO4929097 in eradicating residual/persistent disease, defined as conversion from VGPR to CR or sCR
A Simon's 2-stage optimal Phase II design will be used to monitor the study.
Up to 42 days
Cancer Institute of New Jersey
United States: Food and Drug Administration
|H. Lee Moffitt Cancer Center and Research Institute||Tampa, Florida 33612|
|Cancer Institute of New Jersey||New Brunswick, New Jersey 08901|