Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001530819
Ethics application status
Approved
Date submitted
18/08/2021
Date registered
10/11/2021
Date last updated
7/02/2024
Date data sharing statement initially provided
10/11/2021
Date results information initially provided
7/02/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
The efficacy of Isatuximab plus Pomalidomine and Dexamethasone in patients with amyloid light-chain (AL) amyloidosis who have not responded to previous therapy
Scientific title
ALLG MM24: A phase 2, open label, multicenter, single-stage study to evaluate the efficacy of Isatuximab plus Pomalidomide and Dexamethasone (IPd), in patients with amyloid light chain (AL) amyloidosis not in very good partial response (VGPR) or better after any previous therapy
Secondary ID [1] 305065 0
IFM 2020-01/ALLG MM24
Universal Trial Number (UTN)
Trial acronym
IsAMyP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Amyloid light chain (AL) Amyloidosis 323271 0
Condition category
Condition code
Cancer 320844 320844 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patient eligible to enter the study will receive 9 to 12 cycles (according to response) of intravenous Isatuximab (10 mg/kg) and Pomalidomide 4 mg (oral tablet) daily from day 1 to day 21 and Dexamethasone (oral) 10-20 mg weekly on days 1, 8, 15 and 22. Note dexamethasone is 10mg if patients are equal to or greater than 75 years of age.

Each cycle will be of 28 days duration.

During cycle 1, Isatuximab will be administered weekly on days 1, 8, 15, and 22 then days 1 and 15 in subsequent cycles from cycle 2 to 9 or 12.

For each individual patient, the treatment period will be 12 months, unless complete response at the completion of 9 cycles, disease progression or unacceptable toxicity occurs.

The duration of follow-up for overall survival will be 1 year after the last patient enters overall survival follow-up.

Drug accountability will be performed by the administering sites.
Intervention code [1] 321459 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328642 0
To assess if hematologic response of(VGPR or better i.e. dFLC < 40mg/L, CR including modified CR*, low dFLC response (dFLC <10mg/L), iFLC <30mg/L) achieved after 6 cycles of Isa-Pd.

* If iFLC < ULN and serum and urine immunofixation are negative, then neither a normal uFLC level nor a normal FLC ratio are required for complete response (CR)
Timepoint [1] 328642 0
After 6 cycles of therapy
Secondary outcome [1] 399800 0
To assess Overall Response Rate )VGPR, CRm moedified CR*, low dFLC response (dFLC <10mg/L), iFLC < 10mg/L and PR) at the completion of the 1st, 2nd, 4th, 6th, 9th and 12th cycles.
*If iFLC <ULB and serum and urine immunofixation are negative, then niether a normal uFLC level nor a normal FLC ratio are required for complete response (CR).

Response to trial treatment will be assessed using markers in the blood and urine. . Markers used to assess response are free light chains.

Timepoint [1] 399800 0
At the end of the 1st, 2nd, 4th, 6th, 9th and 12th cycle of treatment
Secondary outcome [2] 399801 0
To assess efficacy measures including when trial treatment has completed:
- Progression-free survival
PFS will be assessed using hematologic and urine markers (FLC) as per criteria for treatment response.
Timepoint [2] 399801 0
1 year after treatment has completed
Secondary outcome [3] 399802 0
To determine safety and tolerability of the trial treatment by reviewing the number of side effects and treatment patterns eg whether treatment was modified or discontinued. Side effects will be assessed by the treating clinician at the patients regular clinic visits.
Timepoint [3] 399802 0
This endpoint will be assessed when all patients have completed 30 days post treatment completion.
Secondary outcome [4] 400813 0
To assess efficacy measures including when trial treatment has completed:
- Relapse-free survival (RFS) in responding population measured from the date of best response.
RFS will be assessed using hematologic and urine markers (FLC)
Timepoint [4] 400813 0
When all patients have completed 12 month of follow up post treatment
Secondary outcome [5] 400814 0
To assess efficacy measures including when trial treatment has completed:
Organ response rate (Appendix 3)

This outcome will be assessed using hematologic and urine markers (FLC)
Timepoint [5] 400814 0
When all patients have completed 12 months of follow up post treatment
Secondary outcome [6] 400815 0
To assess efficacy measures including when trial treatment has completed:
Overall survival
Timepoint [6] 400815 0
Measured from date of inclusion when all patients have completed 1 year of follow up post treatment
Secondary outcome [7] 400816 0
To assess efficacy measures including when trial treatment has completed:
Time to and the duration of response

This outcome will be assessed using hematologic and organ responses to assess against criteria for CR, PR etc. Blood and urine samples will be used to assess response.
Timepoint [7] 400816 0
When all patients have completed 1 year of follow up post treatment

Eligibility
Key inclusion criteria
1. Minimum age of 18 years
2. Histologic diagnosis of AL amyloidosis;
3. Patients should have received at least one line with an alkylating agent and/or a PI, and Dexamethasone and not be in VGPR (or better) at the time of inclusion (patients who did not reach VGPR before, or patients in VGPR or better before but with a hematological relapse at the time of inclusion can be included);
4. Measurable hematologic disease: difference between involved and uninvolved free light chain (FLC) > 50 mg/L with an abnormal k/l ratio;
5. Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system)
6. Wash-out period of at least 4 weeks from previous antitumor therapy or any investigational treatment or 5 half-lives from previous antibodies, whichever is longer.
7. Adequate bone marrow function prior to 1st drug intake (C1D1), without transfusion or growth factor support within 5 days prior to 1st drug intake, defined as:
- Absolute neutrophils count equals to 1000/mm3,
- Platelets equal to or greater than 75000/mm3,
- Hemoglobin equal to or greater than 8.0 g/dL,
8. Adequate organ function defined as:
- Serum ASAT or ALAT equal to or less than 3.0 X Upper Limit of the normal range (ULN),
- Serum total bilirubin level < 1.5 x ULN, unless for subjects with Gilbert’s syndrome where the direct bilirubin should then be equal to or less than 2.0 x ULN.
9. ECOG status equal to or less than 2
10. Male participants must agree to use contraception during the intervention period and for at least 5 months after the last dose of isatuximab/dexamethasone and refrain from donating sperm during this period.
11. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. AL amyloidosis with isolated soft tissue involvement
2. Bone marrow plasma cells >30% and clinically symptomatic multiple myeloma with lytic bone lesions
3. NT-proBNP > 8500 ng/L and hs-troponin I > 100 ng/L or hs- troponin T > 50 ng/L (cardiac stage IIIb patients)
4. Repetitive ventricular arrhythmias on 24h Holter ECG despite anti-arrhythmic treatment sustained ventricular tachycardia, aborted ventricular fibrillation, atrioventricular nodal or sinoatrial nodal dysfunction with no pacemaker
5. Chronic atrial fibrillation with uncontrolled heart rate
6. Significant cardiac dysfunction; myocardial infarction within 12 months; unstable poorly controlled angina pectoris
7. Uncorrected valvular disease unrelated to AL amyloid cardiomyopathy
8. QT interval as corrected by Fridericia’s formula > 550 msec without pacemaker,
9. Undergoing dialysis
10. Ongoing toxicity (excluding alopecia and those listed in eligibility criteria) from any prior therapy > G1 (NCI-CTCAE v5.0)
11. Supine systolic blood pressure < 90 mmHg, or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of < 80 mmHg despite medical management (i.e. midodrine, fludrocortisones) in the absence of volume depletion
12. Previous anti-CD38 therapy or Pomalidomide therapy (if refractory to Pomalidomide)
13. Hypersensitivity to IMiD® defined as any hypersensitivity reaction leading to stop IMiD® within the 2 first cycles or toxicity, which does meet intolerance definition
14. Hypersensitivity or history of intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, polysorbate 80, poloxamer 188, sucrose or any of the other components of study treatment that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents
15. History of malignancy (other than AL amyloidosis) within 3 years before the date of inclusion
16. Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose the patient to excessive risk or may interfere with compliance or interpretation of the study results
17. Active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics
18. Received any investigational drug within 14 days or 5 half-lives of the investigational drug prior to initiation of study intervention, whichever is longer. In case of very aggressive disease (i.e acute leukemia) delay could be shortened after agreement between sponsor and investigator, in absence of residual toxicities from previous therapy
19. Known positive for HIV or active hepatitis A, B or C:
Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA

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 2
Type of endpoint/s
Statistical methods / analysis
All quantitative data will be described using median, interquartile range and range, and qualitative data will be described using count and percentages and the analysis will be performed on an intention-to-treat basis.

The primary endpoint will be assessed by the percentage of patients reaching VGPR or better at the completion of 6 cycles. All time to event endpoints (such as PFS and OS) will be estimated using Kaplan Meier method. For safety analysis, the rate of severe adverse events will be tabulated as count and percent. All tests will be two-tailed, and values of p < 0.05 will be considered significant, and statistical analyses.


Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
7/04/2022
Actual
16/05/2022
Date of last participant enrolment
Anticipated
28/06/2023
Actual
27/10/2023
Date of last data collection
Anticipated
31/08/2024
Actual
Sample size
Target
16
Accrual to date
Final
16
Recruitment outside Australia
Country [1] 24048 0
France
State/province [1] 24048 0

Funding & Sponsors
Funding source category [1] 309461 0
Commercial sector/Industry
Name [1] 309461 0
Sanofi
Country [1] 309461 0
France
Funding source category [2] 309465 0
Charities/Societies/Foundations
Name [2] 309465 0
Leukaemia Foundation
Country [2] 309465 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Intergroupe francophone du myelome
Address
75 avenue Parmentier
75544 Paris Cedex 11
Country
France
Secondary sponsor category [1] 310431 0
Other Collaborative groups
Name [1] 310431 0
Australasian Leukaemia and Lymphoma Group
Address [1] 310431 0
35 Elizabeth Street
Richmond
VIC 3121
Country [1] 310431 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309253 0
South Metropolitan Health Service (SMHS)
Ethics committee address [1] 309253 0
SMHS Research Ethics and
Governance Unit
Level 3, Perkins Murdoch Campus
Fiona Stanley Hospital Campus
11 Robin Warren Drive
Murdoch WA 6150
Ethics committee country [1] 309253 0
Australia
Date submitted for ethics approval [1] 309253 0
28/09/2021
Approval date [1] 309253 0
05/11/2021
Ethics approval number [1] 309253 0

Summary
Brief summary
This study aims to assess the effect of Isatuximab (an immunological treatment) in combination with Pomalidomide and Dexamethasone for the treatment of patients with amyloid light-chain (AL) amyloidosis who have not responded to previous treatments.

Who is it for?
You may be eligible for this study if you are aged 18 or older, you have been diagnosed with AL amyloidosis and you have not had a successful response to previous targeted treatments.

Study details
Participants who choose to enrol in this study will all receive 9 to 12 cycles (each cycle is 28 days) of Isatuximab (administered into a vein) and oral Pomalidomide from day 1 to day 21 and oral Dexamethasone weekly on days 1, 8, 15 and 22. For each participant, the treatment period will be 12 months, unless complete response is observed at the completion of 9 cycles, there is disease progression or unacceptable toxicity occurs. Participants will be asked to provide blood and urine samples and other procedures at certain timepoints to assess how they are responding to treatment and to check for any side effects.

It is hoped this research will determine whether Isatuximab is effective at treating AL amyloidosis, and determine the maximum number of treatment cycles needed. If Isatuximab is found to be an effective treatment, it may be used to improve the health outcomes of future patients with AL amyloidosis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113502 0
Dr Simon Gibbs
Address 113502 0
Box Hill Hospital,
8 Arnold Street,
Box Hill
Victoria, 3128
Country 113502 0
Australia
Phone 113502 0
+613 90949502
Fax 113502 0
Email 113502 0
[email protected]
Contact person for public queries
Name 113503 0
Ms Delaine Smith
Address 113503 0
Australasian Leukaemia & Lymphoma Group
35 Elizabeth Street,
Richmond
VIC 3121
Country 113503 0
Australia
Phone 113503 0
+613 8373 9701
Fax 113503 0
Email 113503 0
[email protected]
Contact person for scientific queries
Name 113504 0
Ms Delaine Smith
Address 113504 0
Australasian Leukaemia & Lymphoma Group
35 Elizabeth Street,
Richmond
VIC 3121
Country 113504 0
Australia
Phone 113504 0
+613 8373 9701
Fax 113504 0
Email 113504 0
[email protected]

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 publically. 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.