Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001158752
Ethics application status
Approved
Date submitted
21/07/2022
Date registered
24/08/2022
Date last updated
13/02/2024
Date data sharing statement initially provided
24/08/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
MM25: A phase 1b/II study of the efficacy of Venetoclax, Iberdomide and Dexamethasone (IberVenD) for patients in first or second relapse of Multiple Myeloma with t(11;14)
Scientific title
MM25: A phase 1b/II study of the efficacy of Venetoclax, Iberdomide and Dexamethasone (IberVenD) for patients in first or second relapse of Multiple Myeloma with t(11;14)
Secondary ID [1] 307775 0
ALLG Viber-M MM25
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsed Multiple Myeloma 326644 0
Refractory Multiple Myeloma 327247 0
Condition category
Condition code
Cancer 323886 323886 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an adverse event-adaptive trial design for safety purposes. There will be intra-patient dose escalation over the first three cycles, i.e. all patients will start at ‘combination level 1’ during cycle 1, if there is no treatment-related Grade 3 neutropenia or Grade 4 thrombocytopenia, as per Common terminology criteria for adverse events version 6 (CTCAE v6), dose will be escalated to ‘combination level 2’ during cycle 2, then ‘combination level 3’ during cycle 3, respectively:

• Cycle 1 (combination level 1)*: Iberdomide 1.3mg + Venetoclax 200mg
• Cycle 2 (combination level 2): Iberdomide 1.3mg + Venetoclax 400mg
• Cycle 3 onwards (combination level 3): Iberdomide 1.6mg + Venetoclax 400mg
All patients will receive dexamethasone in each treatment combination level.
*Note: In case of treatment related Grade 3 neutropenia or Grade 4 thrombocytopenia at ‘combination level 1’, then the dosing level will be deescalated to ‘combination level -1’: Iberdomide 1.0mg + Venetoclax 200mg.

Dosing will be done on a 28-day cycle:
- Venetoclax given orally from days 1-28
-Iberdomide given orally from days 1-21
-Dexamethasone given orally, 40mgs weekly (20mg for patients >75 years of age)

Participants will continue on treatment until one of the following criteria applies:
• Disease progression
• Intercurrent illness that prevents further administration of treatment
• Unacceptable AE(s)
• Patient decides to withdraw from treatment or the study, or
• General or specific changes in the patient's condition render the patient unacceptable for further treatment in the opinion of the investigator.

Compliance will be monitored via drug accountability exercises completed by the participating site and the sponsor.
Intervention code [1] 323782 0
Treatment: Drugs
Comparator / control treatment
'No control group'
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331707 0
To assess the efficacy of Iberdomide, Venetoclax and Dexamethasone combination therapy in relapsed/refractory multiple myeloma patients with t(11;14).
Timepoint [1] 331707 0
The primary endpoint is the proportion of patients who have achieved very good partial response (VGPR) or better. An assessment of efficacy will be performed after 20 patients have completed cycle 3 or been withdrawn due to unacceptable toxicity or progressive disease. Samples (serum, bone marrow and urine samples) will be collected at the start of each 28-day cycle to measure these endpoints.



Patients will be classified as VGPR (or better) based on the International Myeloma Working Group (IMWG) Response Criteria. VGPR equals yes at any stage during the study, if their response is VGPR or complete response (CR) or stringent complete response (sCR). Otherwise the patient will be classified as VGPR equals No.

VGPR according to IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or greater than or equal to reduction in serum M-protein plus urine M-protein level less than 100mg/24 hours.

CR according to IMWG criteria is defined as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than 5 percent plasma cells in bone marrow.

sCR according to IMWG criteria is defined below plus normal Free Light Chain (FLC) ratio and absence of clonal cells in bone marrow by immunochemistry or immunofluorescence.

The proportion of patients classified as VGPR = yes will be estimated and presented with exact 90% confidence limits. If the historical value of 36% is below the lower confidence limit then the result will be consistent with a better response rate than seen with the historical Venetoclax and Dexamethasone regime.
Secondary outcome [1] 410824 0
To assess the depth of response to Iberdomide, venetoclax and dexamethasone in this patient population.
Timepoint [1] 410824 0
At each assessment timepoint the depth of response will be determined using the IMWG response criteria (VGPR, CR and sCR) and Minimal residual disease (MRD) .

VGPR according to IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or greater than or equal to reduction in serum M-protein plus urine M-protein level less than 100mg/24 hours.

CR according to IMWG criteria is defined as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than 5 percent plasma cells in bone marrow.

sCR according to IMWG criteria is defined below plus normal FLC ratio and absence of clonal cells in bone marrow by immunochemistry or immunofluorescence.


Frequency tables will be produced by timepoint to show the distribution of patients across response assessment. For all patients their overall response will be the best assessment documented at any post-baseline assessment time. Frequency tables will be produced for Overall response rate.

The proportion of patients who are MRD negative at any time during the study will be presented with exact 90% confidence limits (as described for the primary endpoint).

Samples (serum, bone marrow and urine samples) will be collected at the following timepoints: Day 1 of each cycle, within 2 weeks of completion of cycle 6, at serological complete response (CR), progressive disease and end of treatment (within 3 weeks of last dose of study drug).

PET plus or minus contrast enhanced Computerised tomography of neck-chest-abdomen and pelvis (CT NCAP) will be used for the measurement of plasmacytomas in
patients with extramedullary disease. This will be done every 3 months from intervention commencement until the end of treatment to assess response to treatment.
Secondary outcome [2] 410825 0
To assess progression free survival (PFS) outcomes to Iberdomide, venetoclax and dexamethasone in this patient population.

Disease progression will be measured according to the IMWG response criteria. The following criteria will have to be met to be deemed progressive disease:

Increase of greater than or equal to 25 per cent from lowest response value in any one or more of the following:
•Serum M-component and/or (the absolute increase must be greater than or equal to 0.5 g/dL)
•Urine M-component and/or (the absolute increase must be greater than or equal to 200 mg/24 hours)
•Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved serum FLC levels. The absolute increase must be greater than 10 mg/dL.
•Bone marrow plasma cell percentage; the absolute percentage must be greater than or equal to 10%
•Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. This will be determined by whole body PET/CT.


Timepoint [2] 410825 0
Progression free survival (PFS) will be defined as the time (in days) from the date of commencement on study treatment to the date of progression or death from any cause. A Kaplan Meier plot will be presented, using the product limit method. If possible, the median PFS (and 90% confidence intervals) will be reported. The proportion of patients progression free at 6, 12 and 24 months post-intervention commencement will be estimated and presented with 90% confidence limits using the lifetable method.
Secondary outcome [3] 410826 0
To assess overall survival (OS) outcomes to Iberdomide, venetoclax and dexamethasone in this patient population.
Timepoint [3] 410826 0
Overall survival (OS) will be defined as the time (in days) from the date of commencement on study treatment to the date of death from any cause. Analysis will be as per the analysis for PFS.

Overall survival will be measured at 6, 12 and 24 months post-intervention commencement.
Secondary outcome [4] 411984 0
To assess the safety and tolerability of Iberdomide, venetoclax and dexamethasone combination therapy.
Timepoint [4] 411984 0
The assessment of safety will be based mainly on the frequency of adverse events (AEs) and clinical laboratory assessments. All the safety analyses will be based on the safety set.

All AEs recorded during the study will be summarised for the safety set in total. The incidence of treatment-emergent AEs (new or worsening from baseline) will be summarised by system organ class, severity (based on CTCAEc5 grades), type of AE, and relation to the study regime. Summaries will be presented by timeframe (and overall) for events which occur during cycle 1, during cycles 2-6, during later cycles and during follow-up. Deaths reportable as SAEs and non-fatal serious AEs will be listed by patient and tabulated by type of AE.
For patients with multiple episodes of the same event, the event will be summarised by the worst severity recorded.
In addition, the incidence of adverse events of special interest (AESI), specifically Grade 3 neutropenia with fever, Grade 4 neutropenia, Grade 4 thrombocytopenia and Grade 3 non-haematological toxicities (related to treatment), events which would influence dose escalation in the first 3 cycles, will be presented by cycle (across the first 3 cycles), for cycles 4-6, for all subsequent cycles combined.

All laboratory values will be classified by the reporting laboratory as within normal range, below the normal range or above the normal range. Shift tables will be presented by timepoint to show changes in category compared with baseline. In addition, for all out of range values, the investigator will classify the result as clinically significant (or not). All clinically significant out of range values will be reported as adverse events.

All adverse events will be assessed ongoing from the commencement of the intervention until completion of study (within 3 weeks of last drug dose on trial), withdrawal, disease progression or death.

Haematology, biochemistry and renal function laboratory values will be assessed for safety on Day 1 of each treatment cycle until end of treatment (within 3 weeks of last drug dose on trial), withdrawal, disease progression or death
Secondary outcome [5] 411985 0
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) will be assessed and scored as a composite secondary outcome.

This assessment will be done to determine changes in patient-reported quality of life (QOL).
Timepoint [5] 411985 0
Responses to QOL measurements using EORTC QLQ-C30

The EORTC QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Scores for each item will be derived according to the author's instructions. For each scale a general linear mixed model (GLMM) will be fitted with change in score (from baseline) as the outcome variable and timepoint as a factor. Baseline will be included as a covariate. Other relevant prognostic factors recorded at baseline may be included (full details to be provided in the SAP). From the model the estimated change from baseline at each timepoint will be estimated and presented with 90% confidence limits.

Quality of life questionnaires will be administered on Day 1 of each treatment cycle until end of treatment (within 3 weeks of last drug dose on trial), withdrawal or disease progression




Secondary outcome [6] 412552 0
European Organisation for Research and Treatment of Cancer assessment of quality of life of myeloma patients (EORTC QLQ – MY20). will be assessed and scored as a composite secondary outcome.

This assessment will be done to determine changes in patient-reported quality of life (QOL).
Timepoint [6] 412552 0
Responses to QOL measurements using EORTC QLQ – MY20

The EORTC OLO-MY20 module comprises 24 questions addressing four domains of QOL important in myeloma: a pain scale, treatment side effects, social support and future perspective. Scores for each item will be derived according to the author’s instructions and a GLMM fitted as described above.

Quality of life questionnaires will be administered on Day 1 of each treatment cycle until end of treatment (within 3 weeks of last drug dose on trial), withdrawal or disease progression

Eligibility
Key inclusion criteria
1. Males or females, age 18 years or older, capable of giving consent
2. ECOG performance status of 0 to 2.
3. Have confirmed MM as defined by IMWG criteria and have had 1 to 2 prior lines of therapy
4. Have measurable disease defined by having at least one of the following:
o Serum M-protein concentration of greater than or equal to 5g/L
o Urine M-protein excretion of greater than or equal to 200mg/24 hours
o Involved serum free light chain (SFLC) greater than or equal to 100mg/L and an abnormal SFLC ratio ( less than 0.26 or
greater than 1.65)
5. Positive for t(11;14) by fluorescence-in-situ-hybridisation (FISH) testing on bone marrow aspirate sample
6. Adequate bone marrow function
7. Adequate liver function (ALT/AST equal to 2.5 x Upper limit of normal, Bilirubin equal to 1.5 x Upper limit of normal)
8. Adequate renal function (creatinine clearance equal to 30ml/minute)
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following applies
o Is not a woman of childbearing potential (WOCBP) or
o Is a WOCBP and is using a contraceptive method that is highly effective (with failure rate of less than 1%/year) during the study intervention and for at least 4 months after the last dose of the study drug
10. A male participant is eligible to participate if they agree to refrain from donating sperm AND either agree to be abstinent from heterosexual intercourse or agree to use barrier contraception when engaging in sexual activity with a WOCBP (including pregnant females). This female partner must also be using an additional method of highly effective contraceptive method (with failure rate of less than 1%/year).
11. Willing and able to comply with all study requirements, including treatment (e.g. able to swallow tablets), timing and/or nature of required assessments
12. Signed, written informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous treatment with Bcl-2 inhibitor or CELMod
2. Any of the following conditions: Non-secretory Multiple Myeloma, solitary plasmacytoma or plasma cell leukaemia.
3. Known Central nervous system involvement
4. Systemic anti-myeloma therapy within less than or equal to 14 days with the exception of corticosteroids equivalent to dexamethasone less than or equal to 160mg in total within last 4 weeks.
5. Major surgery within 14 days of initiating study treatment
6. Radiotherapy within 14 days of initiating study treatment
7. Female patients who are lactating or have a positive serum pregnancy test during screening period.
8. Evidence of cardiovascular risk:
o Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block;
o History of myocardial infarction, acute coronary syndrome (including unstable angina), coronary angioplasty, or stenting or bypass grafting within the last 6 months;
o Class III of IV heart failure defined by New York Heart Association functional classification system
9. Known immediate or delayed hypersensitivity or allergy to previous drugs chemically related to venetoclax and/or Iberdomide.
10. Acute infections requiring antibiotic, antifungal or antiviral therapy within 1 week prior to first dose.
11. Known HIV infection.
12. Hepatitis B surface antigen positivity or Hepatitis B DNA positivity at screening or within 3 months prior to first dose of study treatment. Participants with positive Hepatitis B core antibody testing can be enrolled if Hepatitis B DNA negative and receiving Hepatitis B prophylaxis.
13. Known gastrointestinal disease or procedure that could interfere with the oral absorption or tolerance of iberdomide or venetoclax.
14. Use of a strong or moderate CYP3A inhibitor or inducer within 1 week prior to starting first dose of study treatment.
15. Diagnosed or treated for another malignancy within 2 years before study enrolment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
16. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Based on a phase II study by Kaufman et al. of venetoclax in combination with dexamethasone as targeted therapy for t(11;14) in Relapsed/refractory multiple myeloma, 36% of patients achieved VGPR. We expect that addition of Iberdomide to venetoclax/dexamethasone will be more effective. A VGPR of 55% or more is considered clinically meaningful.

A total of 42 patients provides 80% power to distinguish a VGPR rate of 55% from a historical value of 36%, with a one-sided alpha of 0.05, assuming the normal approximation to the binomial. To allow for a 15% screen fail rate, we aim to recruit screen a total of 50 participants.

Main analysis and read out of outcomes will be performed when the final patient recruited has had 6 months of treatment, developed progressive disease (so treatment has ceased), died or withdrawn , whichever occurs first.

Categorical data will be summarized using frequency tables (frequencies and percentages). For continuous data, descriptive statistics (n, mean, standard deviation, median, 25th and 75th percentiles, minimum and maximum) will be presented.

Baseline and demographic information:
All baseline information, including medical history, prior treatment, diagnostic information, demographics will be summarised using frequency tables or descriptive statistics, as applicable for the type of data.

Treatment:
The total number of cycles received (irrespective of dose) will be presented using frequency tables. Further summaries of treatment received will be defined in the Statistical analysis plan.

Efficacy assessment:
The primary endpoint is the proportion of patients who have achieved very good partial response (VGPR) or better.

Patients will be classified as VGPR (or better) equals yes if, at any stage during the study, their response is VGPR or CR or sCR. Otherwise the patient will be classified as VGPR equals No. The proportion of patients classified as VGPR equals yes will be estimated and presented with exact 90% confidence limits. If the historical value of 36% is below the lower confidence limit then the result will be consistent with a better response rate than seen with the historical Venetoclax Dexamethasone (VenDex) regime.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/06/2023
Actual
19/07/2023
Date of last participant enrolment
Anticipated
25/01/2025
Actual
Date of last data collection
Anticipated
31/08/2027
Actual
Sample size
Target
50
Accrual to date
8
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 24848 0
New Zealand
State/province [1] 24848 0

Funding & Sponsors
Funding source category [1] 311682 0
Other Collaborative groups
Name [1] 311682 0
Australasian Leukaemia & Lymphoma Group
Country [1] 311682 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia & Lymphoma Group
Address
Ground Floor, 35 Elizabeth St, Richmond VIC 3121
Country
Australia
Secondary sponsor category [1] 313137 0
None
Name [1] 313137 0
Address [1] 313137 0
Country [1] 313137 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311046 0
St Vincent's Hospital Melbourne Human Research Ethics Committee
Ethics committee address [1] 311046 0
Ethics committee country [1] 311046 0
Australia
Date submitted for ethics approval [1] 311046 0
05/10/2022
Approval date [1] 311046 0
23/11/2022
Ethics approval number [1] 311046 0
217/22

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 119806 0
Prof Hang Quach
Address 119806 0
Department of Haematology, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065.
Country 119806 0
Australia
Phone 119806 0
+61 3 92312030
Fax 119806 0
Email 119806 0
Hang.Quach@svha.org.au
Contact person for public queries
Name 119807 0
Delaine Smith
Address 119807 0
Australasian Leukaemia and Lymphoma Group
Ground Floor, 35 Elizabeth Street,
Richmond
VIC 3121
Country 119807 0
Australia
Phone 119807 0
+61 3 8373 9701
Fax 119807 0
Email 119807 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 119808 0
Delaine Smith
Address 119808 0
Australasian Leukaemia and Lymphoma Group
Ground Floor, 35 Elizabeth Street,
Richmond
VIC 3121
Country 119808 0
Australia
Phone 119808 0
+61 3 8373 9701
Fax 119808 0
Email 119808 0
delaine.smith@allg.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual patient data will not be shared publicly. Aggregate patient data and final results will be presented in the final report


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.