Trial Title:
Testing the Combination of Two Approved Drugs and One Experimental Drug in Patients With Relapsed or Refractory Multiple Myeloma
NCT ID:
NCT06232044
Condition:
Recurrent Multiple Myeloma
Refractory Multiple Myeloma
Conditions: Official terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Dexamethasone
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Iberdomide
Description:
Receive PO
Arm group label:
Phase I (iberdomide, belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm II (iberdomide, belantamab mafodotin)
Intervention type:
Biological
Intervention name:
Belantamab Mafodotin
Description:
Receive IV
Arm group label:
Phase I (iberdomide, belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm I (belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm II (iberdomide, belantamab mafodotin)
Intervention type:
Drug
Intervention name:
Dexamethasone
Description:
Receive PO
Arm group label:
Phase I (iberdomide, belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm I (belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm II (iberdomide, belantamab mafodotin)
Intervention type:
Procedure
Intervention name:
Echocardiography
Description:
Undergo ECHO
Arm group label:
Phase I (iberdomide, belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm I (belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm II (iberdomide, belantamab mafodotin)
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Phase I (iberdomide, belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm I (belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm II (iberdomide, belantamab mafodotin)
Other name:
CT Scan
Other name:
CAT Scan
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Phase I (iberdomide, belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm I (belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm II (iberdomide, belantamab mafodotin)
Other name:
MRI
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography
Description:
Undergo PET
Arm group label:
Phase I (iberdomide, belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm I (belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm II (iberdomide, belantamab mafodotin)
Other name:
PET Scan
Intervention type:
Procedure
Intervention name:
Bone Marrow Biopsy
Description:
Undergo Bone Marrow Biopsy
Arm group label:
Phase I (iberdomide, belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm I (belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm II (iberdomide, belantamab mafodotin)
Intervention type:
Procedure
Intervention name:
Bone Marrow Aspiration
Description:
Undergo Bone Marrow Aspirate
Arm group label:
Phase I (iberdomide, belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm I (belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm II (iberdomide, belantamab mafodotin)
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Phase I (iberdomide, belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm I (belantamab mafodotin, dexamethasone)
Arm group label:
Phase II, Arm II (iberdomide, belantamab mafodotin)
Summary:
This phase I/II trial tests the safety, side effects, best dose, and effectiveness of
iberdomide in combination with belantamab mafodotin and dexamethasone in treating
patients with multiple myeloma (MM) that has come back after a period of improvement
(relapsed) or that does not respond to treatment (refractory). Multiple myeloma is a
cancer that affects white blood cells called plasma cells, which are made in the bone
marrow and are part of the immune system. Multiple myeloma cells have a protein on their
surface called B-cell maturation antigen (BCMA) that allows the cancer cells to survive
and grow. Immunotherapy with iberdomide, may induce changes in body's immune system and
may interfere with the ability of cancer cells to grow and spread. Belantamab mafodotin
has been designed to attach to the BCMA protein, which may cause the myeloma cell to
become damaged and die. Dexamethasone is in a class of medications called
corticosteroids. It is used to reduce inflammation and lower the body's immune response
to help lessen the side effects of chemotherapy drugs. Iberdomide plus belantamab
mafodotin may help slow or stop the growth of cancer in patients with multiple myeloma.
Detailed description:
PRIMARY OBJECTIVES:
I. To determine maximum tolerated dose (MTD) of iberdomide (CC-220) in combination with
belantamab mafodotin and dexamethasone in patients with relapsed or refractory multiple
myeloma (RRMM). (PHASE I) II. To determine whether the combination of belantamab
mafodotin/ iberdomide/dexamethasone improves progression-free survival (PFS) relative to
belantamab mafodotin/dexamethasone in patients with RRMM. (PHASE II)
SECONDARY OBJECTIVES:
I. To summarize the incidence and cause for treatment delays, modifications and
omissions. (PHASE I) II. To assess treatment response. (PHASE I) III. To obtain an
estimate of the progression-free survival (PFS) and overall survival (OS) distribution.
(PHASE I) IV. To determine minimal residual disease (MRD) negativity. (PHASE I) V. To
observe and record anti-tumor activity. (PHASE I) VI. To determine whether the
combination of belantamab mafodotin/ iberdomide/dexamethasone improves overall survival
(OS) compared to belantamab mafadotin/dexamethasone in patients with RRMM. (PHASE II)
VII. To evaluate the safety profile. (PHASE II) VIII. To estimate the ORR (per
International Myeloma Working Group [IMWG] criteria), duration of response (DoR), and
time to relapse (TTR). (PHASE II) XI. To determine MRD status. (PHASE II)
EXPLORATORY OBJECTIVES:
I. To examine changes in T, NK, and B-cell subsets and quantitative immunoglobulin levels
after 1, 3, 6 and 12 cycles of treatment.
II. To investigate whether BCMA protein expression on MM cells at diagnosis as well as at
relapse or end of study (including loss of expression) is associated with outcome (OS and
PFS).
OUTLINE: This is a phase I, dose-escalation study of iberdomide followed by a phase II
study.
PHASE I: Patients receive iberdomide orally on days 1-21 and 29-49, belantamab mafodotin
intravenously (IV) on day 1, and dexamethasone orally (PO) on days 1, 8, 15, 22, 29, 36,
43, and 50 of each cycle. Cycles repeat every 56 days in the absence of disease
progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) during
screening as clinically indicated and computed tomography (CT), magnetic resonance
imaging (MRI) and/or positron emission tomography (PET) scans during screening and as
clinically indicated on study. Patients also undergo a bone marrow biopsy and aspiration
and blood sample collection throughout trial.
PHASE II: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive belantamab mafodotin IV on day 1 and dexamethasone PO on days 1,
8, 15, 22, 29, 36, 43, and 50 of each cycle. Cycles repeat every 56 days in the absence
of disease progression or unacceptable toxicity. Patients who progress may cross over to
Arm II. Patients undergo ECHO during screening as clinically indicated and CT, MRI and/or
PET scans during screening and as clinically indicated on study. Patients also undergo a
bone marrow biopsy and aspiration and blood sample collection throughout trial.
ARM II: Patients receive iberdomide orally on days 1-21 and 29-49, belantamab mafodotin
IV on day 1, and dexamethasone PO on days 1, 8, 15, 22, 29, 36, 43, and 50 of each cycle.
Cycles repeat every 56 days in the absence of disease progression or unacceptable
toxicity. Patients undergo ECHO during screening as clinically indicated and CT, MRI
and/or PET scans during screening and as clinically indicated on study. Patients also
undergo bone marrow biopsy and aspiration and blood sample collection throughout trial.
After completion of study treatment, patients are followed up every 6 months for 3 years
from study entry.
Criteria for eligibility:
Criteria:
- Documentation of disease: Diagnosis of multiple myeloma and have relapsed or
refractory disease according to the IMWG criteria where:
- Progression of myeloma is defined by IMWG criteria as recurrence of disease
after prior response, indicated as any of the following:
- ≥ 25% increase in M-protein (must be at least 0.5g/dl above nadir from
last treatment regimen).
- 25% difference between involved and uninvolved serum free light chains
from its nadir or
- The development of new plasmacytomas or hypercalcemia.
- Refractory myeloma as defined by IMWG criteria as disease which become
non-responsive or progresses on therapy or within 60 days of last treatment in
patients who had achieved a minimal response or better on prior therapy.
- Measurable disease defined by IMWG criteria as:
- Serum M-protein ≥ 0.5 g/dL.
- Urine monoclonal protein ≥ 200 mg/24h.
- Serum free light chains (FLC) assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l)
and serum free light chain ratio is abnormal.
- Two or more prior lines of therapies, triple-class exposed (exposed /refractory to
an immunodulatory derivative (IMiD) and/or proteasome inhibitors (PI) and/or to
daratumumab or other anti-CD38 monoclonal antibody).
- No prior exposure to iberdomide or belamaf.
- No prior BCMA-directed therapy.
- No prior treatment with a monoclonal antibody within 2 weeks of registration.
- No history of severe allergic reaction (including erythema nodosum) to lenalidomide,
pomalidoimide or other prior IMiD therapy.
- No prior allogeneic stem cell transplant. NOTE: Participants who have undergone
syngeneic transplant will be allowed only if no history of or no currently active
GvHD.
- Participant must not have received a live or live-attenuated vaccine within 30 days
prior to registration.
- No plasmapheresis within 7 days prior to registration.
- Age ≥ 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
- Absolute neutrophil count (ANC) ≥ 1,000/mm^3.
- Platelet count ≥ 75,000/mm^3 (or ≥ 50,000/mm^3 in Phase II if bone marrow (BM)
plasma cells > 50%).
- Calculated (Calc.) creatinine clearance ≥ 30 mL/min using Cockcroft-Gault equation.
- Spot urine (albumin/creatinine ratios) < 500 mg/g (56 mg/mmol) OR urine dipstick ≥
1+ if confirmed.
- Total bilirubin ≤ 2 mg/dL.
- Aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤ 2.5 x upper limit of
normal (ULN).
- Not pregnant and not nursing, because this study involves an investigational agent
whose genotoxic, mutagenic and teratogenic effect on the developing fetus and
newborn are unknown. FCBP (female of childbearing potential) is a female who: 1) has
achieved menarche (first menstrual cycle) at some point, 2) has not undergone a
hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the
surgical removal of both ovaries) or 3) has not been naturally postmenopausal
(amenorrhea following cancer therapy does not rule out childbearing potential) for
at least 24 consecutive months (ie, has had menses at any time during the preceding
24 consecutive months). Women of childbearing potential (WOCBP):
- Must use a contraceptive method that is highly effective (with a failure rate
of < 1% per year), preferably with low user dependency during the intervention
period and for at least 4 months after the last dose of study intervention and
agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during
this period. The investigator should evaluate the effectiveness of the
contraceptive method in relationship to the first dose of study intervention.
- The effects of iberdomide on the developing human fetus are unknown.
Immunodulatory derivative (IMiD) agents as well as other therapeutic agents
used in this trial are known to be teratogenic. Females of child-bearing
potential 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 iberdomide, and must either commit to continued abstinence from
heterosexual intercourse or begin two acceptable methods of birth control, one
highly effective method and one additional effective method at the same time,
at least 28 days before she starts taking iberdomide. Examples of highly
effective methods are intrauterine device, hormonal contraceptives, tubal
ligation, or partner's vasectomy. Examples of barrier method are male condom,
diaphragm, or cervical cap. 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 successful vasectomy. All patients must be counseled at a
minimum of every 28 days about pregnancy precautions and risk of fetal
exposure.
- Should a woman become pregnant or suspect she is pregnant while she or her
partner are participating in this study, she should inform her treating
physician immediately. FCBP must use adequate contraception for at least 4
months after discontinuation from study. Because of the potential for serious
adverse reactions in a breastfed child, women are advised not to breastfeed
during treatment and for at least 3 months after the last dose.
- The investigator is responsible for review of medical history, menstrual
history, and recent sexual activity to decrease the risk for inclusion of a
woman with a nearly undetected pregnancy. Nonchildbearing potential is defined
as follows (by other than medical reasons):
- ≥ 45 years of age and has not had menses for > 1 year
- Patients who have been amenorrhoeic for < 2 years without history of a
hysterectomy and oophorectomy must have a follicle stimulating hormone value in
the postmenopausal range upon screening evaluation
- Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation.
Documented hysterectomy or oophorectomy must be confirmed with medical records
of the actual procedure or confirmed by an ultrasound. Tubal ligation must be
confirmed with medical records of the actual procedure.
- Male patients must agree to use an adequate method of contraception for the
duration of the study and for 6 months afterwards.
- Male participants: contraceptive use should be consistent with local
regulations regarding the methods of contraception for those participating in
clinical studies: Male participants are eligible to participate if they agree
to the following during the intervention period and for 6 months after the last
dose of study treatment to allow for clearance of any altered sperm:
- Refrain from donating sperm PLUS, either:
- Be abstinent from heterosexual intercourse as their preferred and usual
lifestyle (abstinent on a long term and persistent basis) and agree to remain
abstinent. OR
- Must agree to use contraception/barrier as detailed below:
- Agree to use a male condom, even if they have undergone a successful vasectomy,
and female partner to use an additional highly effective contraceptive method
with a failure rate of < 1% per year as when having sexual intercourse with a
woman of childbearing potential (including pregnant females).
- Archival tissue must be available for submission for the mandatory correlative
studies.
- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial.
* Patients with treated brain metastases are eligible if follow up brain imaging
after central nervous system (CNS) directed therapy shows no evidence of
progression.
- No patients with uncontrolled human immunodeficiency virus (HIV), hepatitis C and B.
Testing for HIV and hepatitis C and B are not required prior to registration.
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral
load within 6 months are eligible for this trial.
- No positive hepatitis C antibody test result or positive hepatitis C ribonucleic
acid (RNA) test result at screening or within 3 months prior to registration unless
the participant can meet the following criteria:
- RNA test negative.
- Successful anti-viral treatment (usually 8 weeks duration) is required,
followed by a negative hepatitis C virus (HCV) RNA test after a washout period
of at least 4 weeks.
- Patients with hepatitis B will be excluded unless the following criteria can be met.
- Serology: Hepatitis B core antibody positive (HbcAb)+, hepatitis B surface
antigen (HbsAg)-.
- Screening: Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) undetectable.
- During study treatment: Monitoring per protocol.
- During study treatment: Antiviral treatment instituted if HBV DNA becomes
detectable.
- Serology: HBsAg+ at screen or within 3 months prior to registration.
- Screening: HBV DNA undetectable.
- Screening: Highly effective antiviral treatment started at least 4 weeks prior
to first registration.
- Screening: Baseline imaging per protocol.
- Screening: Participants with cirrhosis are excluded.
- During study treatment: Antiviral treatment maintained throughout study
treatment.
- During study treatment: Monitoring and management per protocol. ** Note:
Presence of isolated hepatitis (Hep) B surface antibody (HBsAb) indicating
previous vaccination will not exclude a participant.
- No patients with unacceptable cardiac risk factors defined by any of the following
criteria:
- Evidence of current clinically significant uncontrolled arrhythmias, including
clinically significant electrocardiogram (ECG) abnormalities such as 2nd degree
(Mobitz Type II) or 3rd degree atrioventricular (AV) block.
- History of myocardial infarction, acute coronary syndromes (including unstable
angina), coronary angioplasty, or stenting or bypass grafting within three (3)
months of Screening.
- Class III or IV heart failure as defined by the New York Heart Association
functional classification system [Error! Reference source not found., 1994].
- Uncontrolled hypertension.
- Patients with congenital long QT syndrome, QTcF interval QTcF > 480 msec (the
QT interval values must be corrected for heart rate by Fridericia's formula
[QTcF]).
- Any history of ventricular fibrillation or torsade de pointes.
- Symptomatic bradycardia defined as heart rate (HR) < 50 bpm with associated
dizziness/syncope.
- Left ventricular ejection fraction < 30%.
- No patients who have received targeted (non-monoclonal antibodies [mAb]) or
investigational agents within 2 weeks prior to rgistration and who have not
recovered from side effects of those therapies.
- No patients who have undergone major surgery ≤ 2 weeks prior to registration or who
have not recovered from the side-effects of surgery.
- No known medical condition causing an inability to swallow oral formulations of
agents.
- No active bacterial, viral or fungal infection (s) present.
- Patients cannot have a Child-Pugh score greater than 1 (absent ascites, total
bilirubin < 2, international normalized ratio (INR) <1.7 (unless on
anticoagulation), and no encephalopathy; esophageal or gastric varices, and
cirrhosis. Note: Stable non-cirrhotic chronic liver disease (including Gilbert's
syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is
acceptable if otherwise meets entry criteria.
- No presence of active renal condition (infection, requirement for dialysis or any
other condition that could affect participant's safety). Participants with isolated
proteinuria resulting from MM are eligible, provided they fulfill inclusion
criteria.
- No evidence of active mucosal or internal bleeding.
- No known immediate or delayed hypersensitivity reaction or idiosyncratic reactions
to belamaf or drugs chemically related to belamaf, or any of the components of the
study treatment.
- Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly,
endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or active
plasma cell leukemia at the time of screening.
- Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on
this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14
days prior to registration on the study. Chronic concomitant treatment with strong
CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to
the start of study treatment. Participant must not have current corneal epithelial
disease except mild changes in corneal epithelium. For belantamab mafodotin,
concomitant administration with strong inhibitors of OATP should be avoided.
- RE-REGISTRATION ELIGIBILITY CRITERIA: Patients must meet criteria for progression of
myeloma as defined by IMWG criteria indicated as any of the following:
- ≥ 25% increase in M-protein (must be at least 0.5 g/dl above nadir from last
treatment regimen).
- 25% difference between involved and uninvolved serum free light chains from its
nadir or
- The development of new plasmacytomas or hypercalcemia not due to other causes.
In the absence of progression by serum M protein or free light chain, biopsy of
new plasmacytoma of extramedullary disease is warranted.
- If refractory myeloma, it should be defined by IMWG criteria as disease which
has become non-responsive or progressive on belamaf/dexamethasone.
- RE-REGISTRATION ELIGIBILITY CRITERIA: Measurable disease defined by IMWG criteria
as:
- Serum M-protein ≥ 0.5 g/dL.
- Urine monoclonal protein ≥ 200 mg/24h.
- Serum FLC assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l) and serum free
light chain ratio is abnormal.
- PET/CT or MRI findings consistent with (c/w) disease progression.
- RE-REGISTRATION ELIGIBILITY CRITERIA: Absolute neutrophil count (ANC) ≥ 1,000/mm^3.
- RE-REGISTRATION ELIGIBILITY CRITERIA: Platelet Count ≥ 75,000/mm^3 (or ≥ 50,000/mm^3
if BM plasma cells > 50%).
- RE-REGISTRATION ELIGIBILITY CRITERIA: Calc. creatinine clearance ≥ 30 mL/min using
Cockcroft-Gault equation.
- RE-REGISTRATION ELIGIBILITY CRITERIA: Total bilirubin ≤ 2 mg/dL.
- RE-REGISTRATION ELIGIBILITY CRITERIA: AST/ALT ≤ 2.5 x upper limit of normal (ULN).
- RE-REGISTRATION ELIGIBILITY CRITERIA: Alkaline phosphatase ≤ 3 x ULN.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
August 30, 2024
Completion date:
August 1, 2030
Lead sponsor:
Agency:
Alliance for Clinical Trials in Oncology
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
Alliance for Clinical Trials in Oncology
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06232044
