This study has been transitioned to CTIS with ID 2024-512354-21-00 check the CTIS register for the current data. Primary objectivesTo evaluate the efficacy (rate of improvement in response from PR to >= VGPR; from VGPR to >=CR; from CR to sCR…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Response improvement rate within 6 months will be measured as the number of
subjects that improve response according to IMWG criteria (from PR to >=VGPR;
from VGPR to >=CR; from CR to >sCR) within the end of sixth cycle of treatment.
Dose reductions/discontinuation rate within 6 months will be measured as the
number of subjects that discontinued treatment or have a dose modification
within the end of sixth cycle of treatment.
Secondary outcome
TTP will be measured by protocol from the date of start of therapy and
according to ITT from the date of eligibility confirmation to the date of first
observation of PD, or deaths for PD. Subjects who have not progressed or who
withdraw from the study or die from causes other than PD will be censored at
the time of the last disease assessment. Subjects lost to FU will also be
censored at the time of last complete disease assessment.
PFS will be measured by protocol from the date of start of therapy and
according to ITT from the date of eligibility confirmation to the date of first
observation of PD, or death from any cause as an event. Subjects who have not
progressed or who withdraw from the study or who were lost to FU will be
censored at the time of the last disease assessment.
TNT will be measured by protocol from the date of start of therapy and
according to ITT from the date of eligibility confirmation to the date of next
anti-myeloma therapy. Death due to any cause before starting therapy will be
considered an event. Subjects who have not progressed or who withdraw from the
study will be censored at the time of the last disease assessment. Subjects
lost to FU will also be censored at the time of last contact.
PFS2 will be measured by protocol from the date of start of therapy and
according to ITT from the date of eligibility confirmationto the date of
observation of second disease progression (i.e. progression after the second
line of therapy) or death to any cause as an event. In case of date of second
progression is not available, date of start of third line treatment can be
used. Subjects who have not progressed or who withdraw from the study will be
censored at the time of the last complete disease assessment. All subjects who
were lost to follow-up prior to the end of the study, have not progressed, and
are still alive will also be censored at the time of last contact.
OS is defined by protocol from the date of start of therapy and according to
ITT from the date of eligibility confirmation to the date of death, regardless
cause of death. Subjects who withdraw consent will be censored at the time of
withdrawal. Subjects who are still alive at the cut-off date of final analysis
will be censored at the date of last contact. Subjects lost to FU will also be
censored at the time of last contact.
Response rate (sCR, CR, VGPR) will be evaluated according to IMWG Response
criteria
Rate of NGF Minimal residual disease (MRD) conversion from positive to negative
The MRD conversion rate at 6 months is determined as the proportion of subjects
with MRD negativity (>=10-5 sensitivity level, by NGF) after 6 months converted
from status as Positive at screening.
The MRD conversion rate at 12 months is determined as the proportion of
subjects with MRD negativity (>=10-5 sensitivity level, by NGF) after 12 months
converted from status as Positive at screening. Subjects who withdraw from the
study or are lost to follow up before post 12 months MRD evaluation, the best
MRD assessment will be considered.
The best MRD conversion rate within 12 months is determined as the proportion
of subjects with MRD negativity (>=10-5 sensitivity level, by NGF) within 12
months converted from status as Positive at screening. The best MRD assessment
will be considered. Subjects who withdraw from the study or are lost to follow
up before MRD evaluation, the best MRD assessment will be considered.
The analysis of safety as defined by type, frequency and severity will be done
primarily by tabulation of the incidence of AEs as defined by the National
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE),
version 5.0. In the by-subject analysis, a subject having the same event more
than once will be counted only once. AEs will be summarized by worst CTCAE grade
Dose reduction will be done primarily by tabulation of the incidence of subject
with at least one dose reduction and causes.
Relative dose will be evaluated consider the ratio between the administered and
the planned dose.
Time to discontinuation for toxicity will be measured from the date of first
dose of study drugs to the date of discontinuation due to AE or Death for
AE/SPM. Subjects who discontinued drugs due to PD, or death for cause other
than AE/SPM will be considered a competing event. Subjects has not discontinued
and are still alive and on treatment at the cut-off date of final analysis will
be censored at the cut-off date. All subjects who were lost to FU will also be
censored at the time of last contact.
Quality of life defined by EORTC QLQ-C30.
Determine whether tumor response and outcome (PFS, PFS2, TTP, TNT and OS) may
change in subgroups with different prognosis according to current prognostic
factors.
Background summary
Multiple myeloma (MM) is the second most common hematologic malignancy,
characterized by the malignant proliferation of clonal plasma cells in the bone
marrow microenviroment, monoclonal protein in blood or urine, and associated
organ dysfunction or myeloma defining events (1). The annual incidence rates in
Western countries is of 5.6 cases per 100.000 people. The median age at
diagnosis is 70 years (2).
High-dose therapy with autologous stem cell transplantation (ASCT) is the
standard of care for eligible newly diagnosed MM patients. Induction generally
consists of 3-6 cycles of therapy with immunomodulatory agents (thalidomide or
lenalidomide) or chemotherapy (cyclophosphamide or doxorubicine) plus
proteasome inhibitor (bortezomib). High dose melphalan (200 mg/m2-Mel200) is
the standard conditioning myeloablative regimen. Two courses of Mel200 followed
by autologous stem cell transplantation (ASCT) can be considered in high-risk
patients. Post ASCT consolidation treatment with a regimen similar or equal to
the one administered as induction may be considered, according to drug
availability, but data on impact on progression free survival (PFS) and overall
survival (OS) are conflicting. Post ASCT maintenance with lenalidomide
continuous therapy is the current standard of care (3).
Iberdomide
Iberdomide (CC-220) is an orally available agent which binds to the cereblon E3
ubiquitin ligase complex, resulting in proteasomal degradation of Ikaros and
Aiolos, which are key transcriptional regulators in cells of the immune system,
including B cells, T cells, monocytes, and plasmacytoid dendritic cells.
Iberdomide is a potent antiproliferative agent in B cell-derived tumors,
including MM and lymphoma tumor cell lines.
Thus, iberdomide, sharing a similar mechanism of action with lenalidomide and
thalidomide, but with greater potency and unique pharmacokinetic (PK)
properties, may show clinical benefit in a similar set of hematological
diseases.
Iberdomide is being studied in an ongoing Phase 1b/2a study in subjects with
MM, MM-001, which consists of 2 parts: Part 1 dose escalation of iberdomide in
relapsed and refractory multiple myeloma (RRMM) as monotherapy (Cohort A),
iberdomide in combination with dexamethasone (Cohort B; Iber + dex), iberdomide
in combination with dexamethasone and daratumumab (Cohort E; IberDd),
iberdomide in combination with dexamethasone and bortezomib (Cohort F; IberVd),
and iberdomide in combination with dexamethasone and carfilzomib (Cohort G;
IberKd); and Part 2 expansion of the recommended phase 2 dose (RP2D), Iber +
dex in RRMM subjects (Cohort D), Iber + dex in RRMM subjects previously exposed
to B cell maturation antigen (BCMA)-targeted therapies (Cohort I), IberVd in
subjects with newly diagnosed multiple myeloma (NDMM) who are not eligible for
autologous stem cell transplant (ASCT) (Cohort J1), IberVd in NDMM subjects who
are eligible for ASCT (Cohort J2), and IberDd in subjects with NDMM who are not
eligible for ASCT (Cohort K).
As of the clinical cutoff date of 02 Jun 2021, a total of 342 subjects have
been enrolled in the MM-001 study: 209 subjects in Part 1 (dose escalation) and
133 patients in Part 2 (dose expansion). At the time of data extract, dose
escalation was ongoing in all cohorts in Part 1 with the exception of the Iber
monotherapy cohort, where 1 mg dose level was deemed tolerable in subjects with
RRMM, the Iber + dex cohort, where a 1.6 mg dose of iberdomide was selected as
the RP2D, and the IberDd cohort, where a 1.6 mg dose was selected as the RP2D.
Dose expansion in Part 2 was also ongoing with Iber + dex in RRMM subjects
(Cohort D) and in RRMM subjects previously exposed to BCMA-targeted therapies
(Cohort I).
The Iber + dex cohorts are the most advanced cohort in terms of enrollment and
data availability. In Cohort B in part 1, 90 subjects were enrolled and treated
with Iber+ dex at doses ranging from 0.3 to 1.6 mg. A total of 89 (98.9%)
subjects treated in cohort B experienced at least 1 TEAE.
The most frequently reported TEAEs (occurring in >= 20% of all subjects in
Cohort B) were neutropenia, (47.8%), thrombocytopenia (40.0%), anemia, (38.9%),
fatigue, (36.7%), insomnia, (32.2%), leukopenia (30%), diarrhea, (23.3%), back
pain, muscle spasms, and pyrexia (22.2% each), and arthraligia, cough, and
dyspnea (21.1% each). Infections occurred in 56 (62.2%) subjects. Grade 3 or 4
TEAEs were reported in 83.3% of subjects and the most common Grade 3 or 4 TEAEs
were neutropenia, (42.2%), anemia, (26.7%), thrombocytopenia, (14.4%),
leukopenia (13.3%), pneumonia, (11.1%), and lymphopenia (10.0%).. Five subjects
had TEAEs that led to death, 4 of which were related to progression of MM and 1
subject experienced sudden death with unknown causes. Serious TEAEs occurred in
53.3% of subjects. In the Infections and Infestations SOC were the most
commonly reported, with a total of 23 (25.6%) subjects, reporting a TEAE within
this SOC. Pneumonia was the only PT within this SOC reported for more than 2
subjects. TEAEs reported for more than 2 subjects in other SOCs included back
pain (4 subjects, 4.4%), acute kidney injury (4 subjects, 4.4%), febrile
neutropenia, (3 subjects, 3.3%), and pyrexia (3 subjects, 3.3%) The TEAEs that
led to iberdomide dose discontinuation were anemia, progressive multifocal
leukoencephalopathy, lower respiratory tract infection, pyrexia, neutropenia,
and thrombocytopenia.
In Cohort A, 29 subjects were enrolled and treated with Iber monotherapy in 6
dose levels (from 0.3 mg to 1.0 mg). The MTD was not reached; however, given
the better clinical efficacy and availability of iberdomide in combination with
other agents in RRMM, further dose escalation was not continued with iberdomide
monotherapy. The most frequently reported all-causality TEAEs were hematologic
in nature or general conditions, including neutropenia and fatigue (55.2%
each), anemia and back pain (37.9% each), thrombocytopenia, arthralgia, and
constipation (27.6% each), muscle spasms and nausea (24.1% each), and upper
respiratory tract infection and musculoskeletal chest pain (20.7% each). Among
all Cohort A subjects, the most common Grade 3/4 TEAEs were hematologic in
nature (neutropenia, 48.3%; anemia, 20.7%; thrombocytopenia, 17.2%). Grade 3/4
TEAEs in the SOC of Infections and Infestations were reported in 27.6% of all
subjects in Cohort A. As of the data cutoff date of 02 Jun 2021, 1 (3.4%)
subject in Cohort A died while on treatment due to plasma cell myeloma. SAEs
were reported for approximately half of the subjects in Cohort A (13 subjects,
44.8%), with Infections and Infestations SOC the most commonly reported, with a
total of 8 (27.6%) subjects. The pharmacokinetics (PK) of iberdomide were
characterized in clinical studies in healthy subjects. Following oral
administration of iberdomide in healthy subjects, systemic exposure increased
in a doseproportional manner. The median time to reach the maximum observed
plasma concentration (Cmax) was 2.5 to 4 hours. After repeated QD oral doses,
steady state appeared to have been achieved by Day 7 with an approximately
2-fold accumulation ratio (AUC). Following single oral dose administration of
iberdomide to healthy subjects, the geometric mean terminal half-life (t1/2)
was approximately 9 to 13 hours. Co-administration with a high-fat meal did not
change the overall exposure of iberdomide.
Based on results from a radiolabeled human mass balance study, intact parent
molecule in urine and feces constitute 16% and 11% respectively, indicating the
absorbed drug is extensively metabolized and excreted mostly as metabolites.
Iberdomide and metabolite M12 were the predominant
components in human plasma comprising approximately 59% and 14% of circulating
total radioactivity exposure, respectively. Single-dose PK of iberdomide was
characterized in subjects with normal, mild, moderate, a
Study objective
This study has been transitioned to CTIS with ID 2024-512354-21-00 check the CTIS register for the current data.
Primary objectives
To evaluate the efficacy (rate of improvement in response from PR to >= VGPR;
from VGPR to >=CR; from CR to sCR) of three different dose levels
of Iberdomide in maintenance treatment after ASCT
Secondary objectives
To determine:
• Rate of NGF MRD conversion from positive to negative
• Rate of adverse events
• Safety and efficacy in different subset of subjects with different prognostic
features
• Time to Progression (TTP)
• Progression Free Survival (PFS)
• Time to next therapy (TNT)
• Progression Free Survival 2 (PFS2)
• Overall survival (OS)
• Pharmacokinetics (PK) of iberdomide
Study design
This is a non-randomized phase II trial evaluating three dose levels of
Iberdomide (1.3 mg, 1.0 mg and 0.75 mg). Newly diagnosed MM subjects who
achieved at least a partial response after induction with protesome inhibitor
and immunomodulatory agents followed by ASCT +/- consolidation will be assigned
to the three different dose levels. Patients will be allocated in a 1:1:1 ratio
to each cohort with a fixed sequence: Cohort 1, Cohort 2 and Cohort 3. Subjects
will be allocated using a web-based, computer generated, procedure completely
concealed to study participants An interim analysis will be conducted when the
first 20 patients in each cohort have received at least 3 cycles of maintenance
treatment or discontinued treatment. In case of excess toxicity IDMC could
recommend to preliminary stop enrollment in cohort.
Details of all treatments (dose and schedule) are given in Section 9.
Intervention
Iberdomide will be given orally, from day 1 to 21 of a 28-day cycle,
continuously, until progressive disease (PD) or unacceptable toxicity.
The trial will start by enrolling 3 parallel cohorts of subjects, receiving the
following doses of iberdomide:
1. 1.3 mg/day
2. 1.0 mg/day
3. 0.75 mg/day
Study burden and risks
By participating in this study patients will not be asked to deviate
significantly from the standard practice in terms fo their disease follow up.
In particular visits to the hospital are confined to once per month to monitor
the study activities and of course their status and safety of the medication.
Furthermore the investigations to be performed during those visits do not
differ from the standard practice for Multiple Myeloma.
By receiving iberdomide thyere is a possibility that patients may experience
some adverse reactions. Very common adverse reactions with ibedomide treatment
include neturopenia, thrombocytopenia, anemia and infections and common ones
include skin rash. Treating physician will always safeguard the health and best
interested of the patients in the study and, furthermore, as per local
requirement, an independent physician will be available to provide independent
advice to the patients.
Erasmus MC, dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Erasmus MC, dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
• Subjects with newly diagnosed MM, requiring therapy due to the presence of
CRAB symptoms or myeloma defining events and measurable disease (sPEP >=0.5 g/dL
and/or uPEP >= 200 mg/24h and/or FLC involved >= 10 mg/dL with abnormal FLC
ratio) before induction therapy with a PI and IMID-containing regimen-
• Subjects with complete baseline evaluation at the time of diagnosis according
to revised International Staging System (R-ISS) (cytogenetic profile, ISS and
LDH)
• Subjects treated with proteasome inhibitor plus immunomodulatory drug-based
induction (3-6 cycles), followed by single or double autologous stem cell
transplant (ASCT) with melphalan as condItioning regimen +/- consolidation.
• Subjects within 15 months from diagnosis and 120 days after last ASCT or
consolidation treatment, if performed, who achieved at least a partial response
(PR) after ASCT, according to IMWG criteria
• Subjects willing and able to follow the trial procedures
• Subjects must understand and voluntary sign an ICF prior to any study related
assessment/procedurs being conducted
• Age >=18 years
• ECOG performance status 0-1
• A female of childbearing potential (FCBP) is a female who: 1) has achieved
menarche at some point, 2) has not undergone a hysterectomy or bilateral
oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following
cancer therapy does not rule out childbearing potential) for at least 24
consecutive months (i.e., has had menses at any time in the preceding 24
consecutive months) and must:
a. Have two negative pregnancy tests as verified by the Investigator prior to
starting study treatment. She must agree to ongoing pregnancy testing during
the course of the study, and after end of study treatment. This applies even if
the subject practices true abstinence* from heterosexual contact.
b. Either commit to true abstinence* from heterosexual contact (which must be
reviewed on a monthly basis and source documented) or agree to use, and be able
to comply with two forms of contraception: one highly effective, and one
additional effective (barrier) measure of contraception without interruption 28
days prior to starting investigational product, during the study treatment
(including dose interruptions), and for at least 28 days after the last dose of
CC-220. Contraception requirements are detailed in Appendix H.
• Male subjects must:
a. Practice true abstinence* (which must be reviewed on a monthly basis and
source documented) or agree to use a condom during sexual contact with a
pregnant female or a female of childbearing potential while participating in
the study, during dose interruptions and for at least 90 days following the
last dose of study treatment, even if he has undergone a successful vasectomy.
* True abstinence is acceptable when this is in line with the preferred and
usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of contraception.]
• Males must agree to refrain from donating sperm while on study treatment,
during dose interruptions and for at least 90 days following last dose of study
treatment.
• All subjects must agree to refrain from donating blood while on study
treatment, during dose interruptions and for at least 28 days following the
last dose of study treatment.
• All male and female subjects must follow all requirements defined in the
Pregnancy Prevention Program (v5.1). See Appendix I for CC-220 Pregnancy
Prevention Plan for Subjects in Clinical Trials.
• Subject agree to refrain from donating blood while on iberdomide, during dose
interruption and for at least 28 days following the last iberdomide dose
• Baseline values:
ANC >=1.0 x 109/L without use of growth factors;
PLTs>=75 x109/L (transfusions within 14 days from Day1 cycle 1 to achieve this
cut off are not allowed);
Hb >8 g/dL (transfusions within 14 days from Day1 cycle 1 to achieve this cut
off are not allowed);
• Life expectancy >= 3 months
Exclusion criteria
• Systemic AL amyloidosis or plasma cell leukemia (>2.0x109/L circulating
plasma cells by standard differential) or Waldenstrom*s macroglobulinemia
• Subject has known meningeal involvement of multiple myeloma
• History of active malignancy during the past 5 years, except squamous cell
and basal cell carcinomas of the skin and carcinoma in situ of the cervix or
breast and incidental histologic finding of prostate cancer (T1a or T1b using
the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer
that is cured, or malignancy that in the opinion of the local investigator,
with concurrence with the principal investigator, is considered cured with
minimal risk of recurrence within 3 years.
• Subject with any one of the following: clinically significant abnormal
electrocardiogram (ECG) findings at screening; congestive heart failure (New
York Heart Association Class III or IV); myocardial infarction within 12 months
prior to starting iberdomide; unstable or poorly controlled angina pectoris,
including Prinzmetal variant; clinically significant pericardial disease
• Peripheral neuropathy of >=grade 2.
• Subject has any concurrent severe and/or uncontrolled medical condition or
psychiatric disease that is likely to interfere with study procedures or
results, or that in the opinion of the investigator would constitute a hazard
for participating in this study or that confounds the ability to interpret data
from the study.
• Subjects with gastrointestinal disease that may significantly alter the
absorption of iberdomide
• Subject with known history of anaphylaxis or hypersensitivity to thalidomide,
lenalidomide, pomalidomide
• Subject with known or suspected hypersensitivity to excipients contained in
the formulation of iberdomide
• Subjects has current or prior use of immunosuppressive medication within 14
days prior to starting therapy with iberdomide (exceptions are intranasal,
inhaled, topical or local steroids injections; systemic corticosteroids at
doses not exceeding 10 mg/day of prednisone or equivalent; steroids as
premedication for hypersensitivity reactions)
• Subject has taken a strong inhibitor or inducer of CYP3A4/5 including
grapefruit, St John*s wort or related products within 2 weeks prior to dosing
and during the course of study
• Subject known to test positive for HIV or have active hepatitis A, B or C
• Subjects is unable or unwilling to undergo protocol required thromboembolism
prophylaxis
• Subject is a female who is pregnant nursing or breastfeeding or who intends
to become pregnant during the participation
• Baseline lab values:
- Creatinine clearance <=30 ml/min.
- Significant hepatic dysfunction (total bilirubin > 1.5x ULN or AST/ALT > 2.5x
ULN), or > 3.0 mg/dL for subjects with documented Gilbert*s syndrome unless
related to myeloma
- Corrected serum calcium>13.5 mg/dL (3.4 mmol/L)
• Any clinical condition at screening that would preclude subject from
completing the study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 2020-003091-40 |
| EU-CTR | CTIS2024-512354-21-00 |
| EudraCT | EUCTR2020-003091-40-NL |
| CCMO | NL75594.029.20 |