Trial Title:
A Study of Venetoclax in Combination With Isatuximab and Dexamethasone for Relapsed/Refractory Multiple Myeloma
NCT ID:
NCT06115135
Condition:
Multiple Myeloma in Relapse
Multiple Myeloma, Refractory
Conditions: Official terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Venetoclax
Conditions: Keywords:
Multiple Myeloma
MM
RRMM
Relapsed/Refractory Multiple Myeloma
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Venetoclax
Description:
All subjects in Dose Level 0 will receive 1) venetoclax, PO, at 400 mg every day (QD) on
Days 1-28 of a 28-day cycle, 2) dexamethasone 40 mg IV, once weekly on Days 1, 8, 15, and
22 of a 28-day cycle; and 3) isatuximab 10mg/kg, IV, on Days 1, 8, 15, and 22 of the
first 28-day cycle, and then Days 1 and 15 during subsequent 28-day cycles.
Arm group label:
open-label
Other name:
VENCLEXTA
Summary:
A phase 2 study of venetoclax in combination with isatuximab and dexamethasone for
relapsed/refractory multiple myeloma patients with t(11;14)
Detailed description:
Despite recent advances in treating MM that have improved outcomes, patients with this
B-cell malignancy inevitably become refractory to therapy, and thus, must rely on
additional treatment options for long-term management of their disease.
Venetoclax is an oral BCL-2 inhibitor which has been recently demonstrated to show
clinical activity for the treatment of MM. The BCL-2 family of proteins are critical
regulators of apoptosis which include both anti-apoptotic (e.g. BCL-2, MCL-1 and BCL-XL)
and pro-apoptotic (e.g. BAK and BAX) elements. The upregulation of anti-apoptotic
proteins has been reported for most cancers, but high BCL-2 levels have been especially
prevalent in human lymphoid malignancies including chronic lymphocytic leukemia, for
which venetoclax is currently indicated. BCL-2 is also overexpressed especially in the
subset of MM patients with t(11;14) translocations, a cytogenetic abnormality found in
approximately 20% of MM patients.
Venetoclax as a single agent has been shown to induce apoptosis not only in human MM cell
lines and primary MM tumor cell samples, but also specifically in RRMM patients. Clinical
activity with single-agent venetoclax was mostly limited to those with (11;14)
translocations, with 12 of 14 responses occurring among patients with that cytogenetic
marker in the single-agent clinical trial of this BCL-2 inhibitor for patients with RRMM
(#NCT01794520) as reported by Kumar et al.7 Resistance to venetoclax as a single agent
has been shown to be mediated by MCL-1, with low BCL-2/MCL-1 ratios indicating resistance
and high ratios indicating an increased sensitivity to this BCL-2 inhibitor. Furthermore,
MCL-1 silencing was shown to heighten sensitivity to BCL-2 inhibitors, and MM xenograft
models co-expressing BCL-2 with MCL-1 were resistant to venetoclax.
The therapeutic landscape of MM has evolved even more with the discovery and validation
of monoclonal antibodies in the treatment of MM. The first two monoclonal antibody-based
therapies to show promising activity for treating MM patients were elotuzumab, which
targets SLAMF7, and daratumumab, which targets CD38. A recent phase 1 study showed high
response rates among RRMM patients with t(11;14) who were treated with daratumumab,
dexamethasone and venetoclax.2 The most recent addition to the collection of the
antibody-based therapies is a humanized IgG1 monoclonal antibody that binds selectively
to a unique epitope on the human CD38 receptor, isatuximab (SAR-650984). A dose finding
phase 2 trial of isatuximab as a single agent was well tolerated and showed clinical
activity for heavily pre-treated patients with RRMM.3 Furthermore, a phase 1b study
examining combination therapy consisting of isatuximab with lenalidomide and
dexamethasone showed promising activity and good tolerability for heavily previously
treated patients with RRMM. Based on the results of two phase 3 studies, the antibody has
been FDA-approved in combination with pomalidomide or carfilzomib for treating RRMM
patients.
Notably, the investigators reported two cases of patients with RRMM who achieved rapid
complete remissions to therapy with venetoclax at low doses (100 mg) in combination with
bortezomib, dexamethasone and the anti-CD38 antibody daratumumab after failing multiple
treatment regimens including bortezomib, dexamethasone and daratumumab. The investigators
have recently reported on a larger retrospective study of RRMM patients receiving this
combination. The response rate was 80% among those harboring the t(11;14) marker whereas
it was only 31% among those lacking this chromosomal translocation. Responses were
observed among patients who failed prior anti-CD38 antibody treatments. These results
suggest that low doses of venetoclax may help overcome resistance to other anti-MM agents
for the treatment of RRMM patients especially those with the t(11;14) chromosomal marker.
Therefore, in this phase 2 trial, The investigators will evaluate the safety and efficacy
of isatuximab, venetoclax and dexamethasone for treating patients with RRMM and show the
t(11;14) marker.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Have a diagnosis of MM based on standard criteria as follows, both criteria a and b
must be met:
c. Clonal BM plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma
d. Any or more of the following myeloma defining events: i. Evidence of end organ damage
that can be attributed to the underlying plasma cell proliferative disorder,
specifically:
1. Hypercalcemia: serum calcium >2.75 mmol/L (>11 mg/dL) or >0.25 mmol/L (>1 mg/dL)
higher than the upper limit of normal
2. Renal insufficiency: creatinine clearance < 40mL/min or serum creatinine > 177
mmol/L (> 2mg/dL)
3. Anemia: hemoglobin value of >2 g/dL below the lower limit of normal, or a hemoglobin
value <10 g/dL
4. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT
ii. Clonal BM plasma cell percentage > 60% iii. Involved: uninvolved SFLC ratio >100
(involved FLC level must be >100 mg/L) iv. > 1 focal lesion on MRI studies (at least
5 mm in size)
2. Show the t(11;14), confirmed by FISH or cytogenetic analysis , to be performed
within 28 days prior to baseline. If performed more than 28 days prior, it should be
repeated at the investigator's discretion
3. Absolute neutrophil count ≥ 1.5 x 10/L
4. Platelet count ≥ 75 x 109/L
5. Hemoglobin ≥ 8.0 g/dL within 21 days prior to enrollment.
6. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute as calculated
by Cockcroft-Gault method
7. Total bilirubin levels ≤ 2.0 mg/dL (normal levels)
8. AST (SGOT) and ALT (SGPT) ≤ 2 x ULN
9. Serum potassium within the normal range
10. Female of childbearing potential (FCBP)† must have a negative serum or urine
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to
and again within 24 hours of starting and must either commit to continued abstinence
from heterosexual intercourse or use acceptable methods of birth control, one highly
effective method and one additional effective method AT THE SAME TIME, and at least
28 days before she starts taking treatment drugs. FCBP must also agree to ongoing
pregnancy testing. Men must agree to use a latex condom during sexual contact with a
FCBP even if they have had a vasectomy. All subjects must be counseled at a minimum
of every 28 days about pregnancy precautions and risks of fetal exposure.
Contraception measures should be continued for 3 months following the treatment
completion.
- A FCBP (female of childbearing potential) is a sexually mature woman who has not
undergone a hysterectomy or bilateral oophorectomy; or has not been naturally
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time
in the preceding 24 consecutive months
11. Eastern Cooperative Oncology Group (ECOG) performance score less than or equal
to 2
12. Participant must have received at least 3 lines of prior treatment for MM,
including regimens that contained a proteasome inhibitor, lenalidomide, and
glucocorticosteroids
13. Participant currently has documented progressive MM per IMWG criteria
14. Subject must be ≥ 18 years of age
15. Subject must voluntarily sign and date an informed consent
Exclusion Criteria:
1. Participant has a history of intolerability to any of the study drugs
2. Participant has any of the following conditions: amyloidosis, POEMS syndrome
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin
changes), known human immunodeficiency viral (HIV) infection, active hepatitis B or
C infection based on blood screen tests, significant cardiovascular disease,
including uncontrolled angina, severe or uncontrolled arrhythmia, recent myocardial
infarction within 6 months of screening, or congestive heart failure New York Heart
Association (NYHA) Class greater than or equal to 3, major surgery within 4 weeks
prior to screening, acute infections requiring parenteral therapy (antibiotic,
antifungal, or antiviral) within 14 days prior to screening, peripheral neuropathy
greater than or equal to Grade 3 or greater than or equal to Grade 2 with pain
within 2 weeks prior to screening, uncontrolled diabetes or uncontrolled
hypertension within 14 days prior to screening, any other medical condition that, in
the opinion of the Investigator, would adversely affect the participant's
participation in the study
3. Participant has a history of other active malignancies, including myelodysplastic
syndrome (MDS), within the past 3 years prior to study entry, with the following
exceptions: previous malignancy with no evidence of disease confined and surgically
resected (or treated with other modalities) with curative intent and unlikely to
impact survival during the duration of the study
4. If participant had prior allogeneic stem cell transplant (SCT), participant has
evidence of ongoing graft-versus-host disease (GvHD)
5. Participants that are pregnant or breast feeding
6. Participants with hypersensitivity to any study medications and/or their excipients
7. Treatment with an anti-CD38 antibody (daratumumab or isatuximab) within the last six
months
8. Treatment with an anti-CD38 antibody (daratumumab or isatuximab), alone or in
combination, without achieving a best response of at least a MR
9. Treatment with venetoclax
10. Participants that are refractory to anti-CD38 antibody treatment [i.e. disease
progression (i.e., PD, per IMWG criteria) while receiving a CD38 MoAb or within 60
days of treatment (PD after 60 days after CD38 MoAb treatment is allowed)]
11. Treatment with any of the following within 7 days prior to the first dose of study
drug:
1. Steroid therapy for anti-neoplastic intent
2. Moderate or strong cytochrome P450 3A (CYP3A) inhibitors or inducers
12. Administration or consumption of any of the following within 3 days prior to the
first dose of study drug:
d. Grapefruit or grapefruit products e. Seville oranges (including marmalade
containing Seville oranges) f. Star fruit
13. Additional prior and concomitant therapy excluded and cautionary medications:
c. Excluded: i. Anticancer therapies including chemotherapy, radiotherapy, or other
investigational therapy, including targeted small molecule agents: Excluded 5
half-lives prior to first dose and throughout venetoclax administration ii. Biologic
agents (e.g., monoclonal antibodies) for anti-neoplastic intent: Excluded 28 days
prior to first dose and throughout venetoclax administration
d. Cautionary during the study: i. Strong and Moderate CYP3A inhibitors: Exclude
during ramp-up phase and consider alternative medications. If subject requires use
of these medications at the cohort designated dose, use with caution and reduce the
venetoclax dose by 50% for moderate inhibitors and at least 75% for strong
inhibitors during co-administration. After discontinuation of CYP3A inhibitor, wait
for 2 to 3 days before venetoclax dose is increased back to the initial
maintenance/target dose.
ii. Strong and Moderate CYP3A inducers: Exclude during ramp-up phase and consider
alternative medications. If subject requires use of these medications at the cohort
designated dose, use with caution and contact AbbVie medical monitor for guidance.
iii. Additional: Warfarin, P-gp substrates, BCRP substrates, OATP1B1/1B3 substrates,
P-gp inhibitors, BCRP inhibitors
Gender:
All
Minimum age:
N/A
Maximum age:
N/A
Healthy volunteers:
No
Start date:
March 1, 2024
Completion date:
December 31, 2026
Lead sponsor:
Agency:
Oncotherapeutics
Agency class:
Industry
Source:
Oncotherapeutics
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06115135
