Multiple Myeloma Clinical Trial
Official title:
An Open-label Phase II Study of the Efficacy of Combination Bortezomib-containing Regimens in the Treatment of Newly Diagnosed Patients With t (4; 14) Positive Multiple Myeloma
Given the disappointing results with routine ASCT in t(4;14) patients, we propose this open label phase II study of bortezomib along with dexamethasone and pegylated liposomal doxorubicin (Doxil/Caelyx), referred to as the DBd regimen, for 4 cycles, followed by post-induction therapy with cyclophosphamide + bortezomib + prednisone (referred to as the CyBorP regimen) for 8 cycles. Since patients with t(4;14) remain at high risk for relapse, maintenance therapy with dexamethasone weekly will be given until disease progression.
PROTOCOL SYNOPSIS A. TITLE: An Open-Label Phase II Study of the Efficacy of Combination
Bortezomib-containing Regimens in the Treatment of newly diagnosed patients with t (4;14)
positive Multiple Myeloma.
B. RATIONALE: Between 15 and 20% of myeloma patients exhibit a t(4;14), which results in
translocation of the receptor tyrosine kinase (TK) fibroblast growth factor receptor 3
(FGFR3) from chromosome 4 to the Immunoglobulin H (IgH) locus. The presence of a t(4;14)
appears to confer an extremely poor prognosis. Patients with this abnormality do not
experience prolonged remissions after a single autologous stem cell transplant (ASCT) using
high-dose melphalan, and the optimal therapy of this group has not yet been defined.
Specifically, data from Princess Margaret Hospital and the Mayo Clinic both indicate that the
median progression-free survival (PFS) is only about 8 months and overall survival 18-22
months after ASCT. Unpublished data from the French Francophone Myeloma Intergroup (IFM)
studies suggest that tandem transplants may improve these results modestly, but the outcome
is still inferior compared with other cytogenetic subgroups.
Initial unpublished observations suggested that t(4;14) patients with relapsed/refractory
disease were uniquely sensitive to the new agent bortezomib. More recent information in
larger numbers of patients indicates that responses to single agent bortezomib are seen in up
to 50-65% of t(4;14) patients; the duration of response is similar to that seen in other
subsets, i.e. in the range of 5-7 months. Combinations of bortezomib with agents such as
doxorubicin, pegylated liposomal doxorubicin, thalidomide, cyclophosphamide, melphalan,
thalidomide and corticosteroids have been evaluated in a number of clinical studies in
recurrent myeloma, and the response rates (RR) appear to be improved compared to single agent
bortezomib, and toxicity has been acceptable.
In newly diagnosed myeloma patients, combinations such as vincristine, doxorubicin,
dexamethasone (VAD) and thalidomide + dexamethasone are often utilized before ASCT. A study
by Hussein et al. substituted pegylated liposomal doxorubicin for the conventional
formulation of doxorubicin and noted a similar response rate with less grade 3/4 neutropenia,
alopecia and sepsis; in addition, patients do not necessarily require a central venous
catheter. More recently, Cavenagh et al. has reported remarkable activity with the so-called
PAD regimen of bortezomib, doxorubicin and dexamethasone, with a combined Complete Remission
(CR) + Partial Response (PR) rate of 67% following 1 cycle, and 93% after 4 cycles, with no
impairment of the ability to collect blood stem cells for ASCT. Preliminary data from an
ongoing Canadian phase II study of Doxil/Caelyx + Bortezomib + Dexamethasone (DBd), in which
pegylated liposomal doxorubin, bortezomib and dexamethasone are combined, has produced
encouraging results to date with minimal toxicity. In that study, DBd therapy was given for 4
cycles before ASCT independently of cytogenetic classification.
Given the disappointing results with routine ASCT in t(4;14) patients, we propose this open
label phase II study of bortezomib along with dexamethasone and pegylated liposomal
doxorubicin (Doxil/Caelyx), referred to as the DBd regimen, for 4 cycles, followed by
post-induction therapy with cyclophosphamide + bortezomib + prednisone (referred to as the
CyBorP regimen) for 8 cycles. Since patients with t(4;14) remain at high risk for relapse,
maintenance therapy with dexamethasone weekly will be given until disease progression. This
approach will test the hypothesis that bortezomib-based therapy can improve the outcome of
newly diagnosed t(4;14) multiple myeloma patients.
C. OBJECTIVES OF THE STUDY: To evaluate the efficacy of the DBd regimen given as induction
therapy, followed by post-induction therapy with CyBorP and maintenance therapy with
dexamethasone in t(4;14) positive multiple myeloma (MM) patients.
Primary Objectives
- To determine the time to progression (TTP) with this treatment regimen. Secondary
Endpoints
- To determine the objective response rate following DBd induction therapy
- To determine the duration of response following DBd induction therapy
- To determine the objective response rate following CyBorP post-induction therapy
- To determine the duration of response following CyBorP post-induction therapy
- To determine PFS
- To determine overall survival
- To determine the safety profile of this regimen
- To examine the ability of bortezomib based regimens to repress FGFR3 signaling
D. STUDY DESIGN: This is an open-label, Phase II study of induction therapy with bortezomib,
pegylated liposomal doxorubicin (Doxil/Caelyx) and dexamethasone as initial therapy in
patients with t(4;14). Each 21 day-cycle consists of bortezomib 1.3 mg/m2 (given as an I.V.
bolus on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 to 21). DOXIL/CAELYX
30 mg/m2 will be given after bortezomib as at least a 1-hour I.V. infusion on Day 4 of each
21-day cycle. Dexamethasone 40 mg PO will be given on days 1-4, days 8-11 and days 15-18
during the first cycle. For the subsequent 3 cycles, dexamethasone 40 mg PO will be given on
days 1-4 and days 11-14. Patients who do not experience disease progression may undergo
elective, as per the attending physician's discretion, stem cell mobilization followed by
stem cell collection and cryopreservation. Patients will then receive post-induction therapy
with cyclophosphamide + bortezomib + prednisone (1.5 mg/m2 bortezomib on days 1, 8, and 15
I.V. + cyclophosphamide 300 mg/m2 PO weekly + prednisone 100 mg PO on alternate days) for 8
monthly 28 day cycles, followed by maintenance therapy with 40 mg of dexamethasone weekly per
month until disease progression occurs.
E. PATIENT CHARACTERISTICS: Untreated multiple myeloma patients who are t(4;14) positive by
fluorescence in situ hybridization (FISH) will be considered for the study. Exclusion
criteria include inadequate liver function aspartate aminotransferase (AST} and alanine
aminotransferase (ALT) > 2.5 times the upper limit of normal), thrombocytopenia (platelets <
50 X 109/L), neutropenia (absolute neutrophil count < 1.0 x 109/L), pregnant or lactating
women, and women of childbearing potential (WCBP) who are not using adequate contraception
and Left Ventricular Ejection Fraction (LVEF) below the institutional Lower Limit Normal
(LLN) or less than 40%; whichever value is higher. A patient may have received up to 4 months
of other anti myeloma therapy, as part of the induction therapy, prior enrollment and still
be considered eligible to participate in the study, as long as the patient's multiple myeloma
has not progressed in the current regimen and the other eligibility criteria are met.
F. STATISTICAL PLAN: The TTP from initiation of chemotherapy in patients treated with ASCT
for this subset is approximately 12 months. An increase in TTP from 12 to 21 months would be
of clinical significance. Using an 80% power to detect this time difference in a two-sided
comparison patient, a sample size of 36 evaluable patients is required. This calculation
assumes that each patient will be evaluated at a fixed time of 24 months. Assuming a 20%
drop-out rate, a total sample size of 45 patients will be required.
G. STUDY DESIGN: It is assumed that the new regimen will not be of further interest in
t(4;14) positive myeloma patients if the TTP from the time of starting induction therapy is
less than 21 months. Each patient will be followed every month until disease progression and
then after every 6 moths up to 5 years for survival. An interim analysis will also be
performed after 12 patients have completed the post-induction therapy with cyclophosphamide +
bortezomib + prednisone (CyBorP).
H. PATIENT ACCRUAL AND STUDY DURATION: Patients with t(4;14) represents only 15% of all
myeloma patients, as such, accrual will be highly dependant on number of participating
centers. It is estimated that approximately 350 newly-diagnosed patients will require
cytogenetic screening in order to meet the accrual target. Accrual is expected to be complete
within 48 months. Additional time is required, of course, to allow the response data to
mature. All patients registered in the study will be accounted for (screen failures +
enrolled patients). The number of patients who are not evaluable, who died or withdrew before
treatment began will be specified. The distribution of follow-up times will be described and
the number of patients lost to follow-up will be monitored.
I. EFFICACY PARAMETERS: Beginning in cycle 1, the response to treatment will be determined
during each cycle using the International Myeloma Working Group uniform response criteria for
multiple myeloma as outlined in Section 11.0. Responses will be assessed by monoclonal
protein, monoclonal paraprotein (M protein) quantification from serum and a 24-hour urine
collection (including immunofixation, if needed), bone marrow plasma cells, assessment of
lytic lesions, and soft tissue plasmacytomas. For patients with light chain disease or
non-secretory myeloma, a serum sample for Free Lite chain testing will be obtained and the
results will be compared to the levels reported quantified in the urine.
J. REGISTRATION: Patients will be registered by completing the eligibility and enrollment
checklist and forwarding it by fax to the Multiple Myeloma Research Coordinator at Princess
Margaret Hospital at 416-946-4419, between the hours of 9 am and 4 pm Eastern Standard Time,
up to 5 business days prior commencement of cycle 1 day 1. The research coordinator should
also be contacted by phone at 416 946-4627. The checklist will be verified and a patient
number will be assigned for eligible patients.
K. SAMPLE PROCESSING: Centralized screening will be employed at Princess Margaret Hospital.
Following informed consent site should send two fresh heparinized (green top tube) marrow
samples (5cc per tube or best available) by overnight courier (see Appendix VI for shipping
and notification instructions) for t4;14 screening test. Tri-color fluorescence in situ
hybridization (FISH) for t(4;14) will be performed and reported back to referring site within
5-7 working days.
;
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT05027594 -
Ph I Study in Adult Patients With Relapsed or Refractory Multiple Myeloma
|
Phase 1 | |
Completed |
NCT02412878 -
Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma
|
Phase 3 | |
Completed |
NCT01947140 -
Pralatrexate + Romidepsin in Relapsed/Refractory Lymphoid Malignancies
|
Phase 1/Phase 2 | |
Recruiting |
NCT05971056 -
Providing Cancer Care Closer to Home for Patients With Multiple Myeloma
|
N/A | |
Recruiting |
NCT05243797 -
Phase 3 Study of Teclistamab in Combination With Lenalidomide and Teclistamab Alone Versus Lenalidomide Alone in Participants With Newly Diagnosed Multiple Myeloma as Maintenance Therapy Following Autologous Stem Cell Transplantation
|
Phase 3 | |
Active, not recruiting |
NCT04555551 -
MCARH109 Chimeric Antigen Receptor (CAR) Modified T Cells for the Treatment of Multiple Myeloma
|
Phase 1 | |
Recruiting |
NCT05618041 -
The Safety and Efficay Investigation of CAR-T Cell Therapy for Patients With Hematological Malignancies
|
N/A | |
Active, not recruiting |
NCT03844048 -
An Extension Study of Venetoclax for Subjects Who Have Completed a Prior Venetoclax Clinical Trial
|
Phase 3 | |
Recruiting |
NCT03412877 -
Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Neoantigens in People With Metastatic Cancer
|
Phase 2 | |
Completed |
NCT02916979 -
Myeloid-Derived Suppressor Cells and Checkpoint Immune Regulators' Expression in Allogeneic SCT Using FluBuATG
|
Phase 1 | |
Recruiting |
NCT03570983 -
A Trial Comparing Single Agent Melphalan to Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM) as a Preparative Regimen for Patients With Multiple Myeloma Undergoing High Dose Therapy Followed by Autologous Stem Cell Reinfusion
|
Phase 2 | |
Terminated |
NCT03399448 -
NY-ESO-1-redirected CRISPR (TCRendo and PD1) Edited T Cells (NYCE T Cells)
|
Phase 1 | |
Completed |
NCT03665155 -
First-in- Human Imaging of Multiple Myeloma Using 89Zr-DFO-daratumumab, a CD38-targeting Monoclonal Antibody
|
Phase 1/Phase 2 | |
Completed |
NCT02812706 -
Isatuximab Single Agent Study in Japanese Relapsed AND Refractory Multiple Myeloma Patients
|
Phase 1/Phase 2 | |
Active, not recruiting |
NCT05024045 -
Study of Oral LOXO-338 in Patients With Advanced Blood Cancers
|
Phase 1 | |
Active, not recruiting |
NCT03989414 -
A Study to Determine the Recommended Dose and Regimen and to Evaluate the Safety and Preliminary Efficacy of CC-92480 in Combination With Standard Treatments in Participants With Relapsed or Refractory Multiple Myeloma (RRMM) and Newly Diagnosed Multiple Myeloma (NDMM)
|
Phase 1/Phase 2 | |
Active, not recruiting |
NCT03792763 -
Denosumab for High Risk SMM and SLiM CRAB Positive, Early Myeloma Patients
|
Phase 2 | |
Withdrawn |
NCT03608501 -
A Study of Ixazomib, Thalidomide and Dexamethasone in Newly Diagnosed and Treatment-naive Multiple Myeloma (MM) Participants Non-eligible for Autologous Stem-cell Transplantation
|
Phase 2 | |
Recruiting |
NCT04537442 -
Clinical Study to Evaluate the Safety and Efficacy of IM21 CAR-T Cells in the Treatment of Elderly Patients With Relapsed or Refractory Multiple Myeloma
|
Phase 1 | |
Completed |
NCT02546167 -
CART-BCMA Cells for Multiple Myeloma
|
Phase 1 |