Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000344796
Ethics application status
Approved
Date submitted
26/03/2013
Date registered
28/03/2013
Date last updated
28/03/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase II Study of Lenalidomide Induction, Autologous Peripheral Stem Cell Transplant and Adjuvant Vaccination with Autologous Dendritic Cells and Lenalidomide Maintenance in Multiple Myeloma.
Scientific title
A Phase II Study of Lenalidomide Induction, Autologous Peripheral Stem Cell Transplant and Adjuvant Vaccination with Autologous Dendritic Cells and Lenalidomide Maintenance in Multiple Myeloma.
Secondary ID [1] 282196 0
PMCI 05/56
Universal Trial Number (UTN)
U1111-1141-1254
Trial acronym
LITVacc Study.
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 288707 0
Condition category
Condition code
Blood 289056 289056 0 0
Haematological diseases
Cancer 289057 289057 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1 (n=12)
Induction. Low dose Lenalidomide (15mg, oral tablet, D1-21) and low dose dexamethasone (20mg oral tablet weekly) 4 x 28 day cycles.
Autologous Peripheral Stem Cell Transplant 4-6 weeks following completion of induction chemotherapy (Minimum target CD34+ stem cell administration will be 2 x 10^6/kg).
Maintenance commences 4-5 weeks post transplant. Adjuvant Vaccination with Autologous tumour cell lysate pulsed Dendritic Cells ( SCI, 1x10e6 cells) monthly x 6
Lenalidomide (25mg, oral tablet, D1-21) minimum 12 x 28 day cycles or until disease progression.

Arm 2 (n=10)
Induction. Low dose Lenalidomide (15mg, oral tablet, D1-21), low dose dexamethasone (20mg, oral tablet, weekly) 4 x 28 day cycles.
Autologous Peripheral Stem Cell Transplant 4-6 weeks following completion of induction chemotherapy (Minimum target CD34+ stem cell administration will be 2 x 10^6/kg).
Maintenance commences 4-5 weeks post transplant. Lenalidomide ( 25mg, oral tablet, D1-21) minimum 12 x 28 day cycles or until disease progression.

Arm 3 (n=10)
Induction. Lenalidomide (25mg, D1-21) and low dose dexamethasone (20mg weekly) 4 x 28 day cycles.
Autologous Peripheral Stem Cell Transplant 4-6 weeks following completion of induction chemotherapy (Minimum target CD34+ stem cell administration will be 2 x 10^6/kg). Maintenance commences 4-5 weeks post transplant. Lenalidomide (25mg, oral tablet, D1-21) minimum 12 x 28 day cycles or until disease progression.

Arm 4 (n=10)
Induction. Lenalidomide (25mg, oral tablet, D1-21). 4 x 28 day cycles. Dexamethasone (40mg, oral tablet, weekly) only added if less than MR after 2 cycles and PR after 4 cycles. Maximum 6 cycles.
Autologous Peripheral Stem Cell Transplant 4-6 weeks following completion of induction chemotherapy (Minimum target CD34+ stem cell administration will be 2 x 10^6/kg).
Maintenance commences 4-5 weeks post transplant. Lenalidomide (25mg, oral tablet, D1-21) minimum 12 x 28 day cycles or until disease progression.
Intervention code [1] 286801 0
Treatment: Drugs
Intervention code [2] 286802 0
Treatment: Other
Comparator / control treatment
Arms 1 and 2 sequential recruitment. Then Arms 3 and 4 randomised. Comparison between all arms and historical control group of patients previously transplanted in our centre without maintenance lenalidomide N =30 in the previous 2 years.
Control group
Active

Outcomes
Primary outcome [1] 289171 0
Time to disease progression by IMWG criteria
Timepoint [1] 289171 0
Through out the study up to 5 years post completion of therapy
Secondary outcome [1] 301956 0
Overall survival
Timepoint [1] 301956 0
Through out the study until death
Secondary outcome [2] 301957 0
Induction of myeloma specific T cell immune responses by t cell killing assay by flow cytometry and cytokine release by intracellular cytokine staining.
Timepoint [2] 301957 0
Post Stem cell transplant on day 1 cycle 1, 2, 4 and 12
Secondary outcome [3] 301958 0
Induction of NKT cell responses post SCT and post dendritic cell vaccination by flow cytometry and NKT cell killing assay
Timepoint [3] 301958 0
post SCT and post dendritic cell vaccination day 1 cycle 1, 2, 4 and 12.

Eligibility
Key inclusion criteria
1. The patient has a bone marrow biopsy confirmed diagnosis of multiple myeloma (MM)
2. Understand and voluntarily sign an informed consent form.
3. Age 18 years or over at the time of signing the informed consent form.
4. Able to adhere to the study visit schedule and other protocol requirements.
5. The diagnostic marrow demonstrates >50% plasmacytosis on immunohistology with anti-CD138 in the 1st 2 cohorts of patients. For the additional cohorts of newly diagnosed patients, <50% plasma cell infiltrate is permitted.
6. Patient is eligible (on normal disease and performance status criteria) for autologous SCT
7. All previous cancer therapy, including radiation, hormonal therapy and surgery, must have been discontinued at least 4 weeks prior to treatment in this study. Under exceptional circumstances and only with the specific permission of the PI, a single course of Dexamethasone 20mg/day x4 days (or equivalent) is allowed in the 4 weeks prior to the start of therapy.
8. Should have measurable disease as per Blade/ EBMT criteria.
9. ECOG performance status of less than or equal to 2 at study entry.
10. Laboratory test results within these ranges:
Absolute neutrophil count greater than or equal to 1.5 x 109/L
Platelet count greater than or equal to 100 x 109/L
Serum creatinine less than or equal to 2.0 mg/dL
Total bilirubin less than or equal to 1.5 mg/dL
11. Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. The two methods of reliable contraception must include one highly effective method (i.e. intrauterine device (IUD), hormonal [birth control pills, injections, or implants], tubal ligation, partner’s vasectomy) and one additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of contraceptive methods if needed.

Before starting study drug:
Female Subjects:
a. FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to starting study drug. The first pregnancy test must be performed within 10-14 days prior to the start of study drug and the second pregnancy test must be performed within 24 hours prior to the start of study drug. The subject may not receive study drug until the Investigator has verified that the results of these pregnancy tests are negative.
b. Will be warned that sharing study drug is prohibited and will be counselled about pregnancy precautions and potential risks of foetal exposure.
c. Must agree to abstain from donating blood during study participation and for at least 28 days after discontinuation from the study.
Male Subjects:
d. Must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.
e. Will be warned that sharing study drug is prohibited and will be counselled about pregnancy precautions and potential risks of foetal exposure.
f. Must agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation from the study.


During study participation and for 28 days following discontinuation from the study:
All Subjects:
a. No more than a 28-day supply of study drug will be dispensed at a time.
Female Subjects:
b. FCBP with regular cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 days while on study, at study discontinuation, and at day 28 following discontinuation from the study. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study discontinuation, and at days 14 and 28 following discontinuation from the study.
c. In addition to the required pregnancy testing, the Investigator must confirm with FCBP that she is continuing to use two reliable methods of birth control at each visit.
d. Counselling about pregnancy precautions and the potential risks of foetal exposure must be conducted at a minimum of every 28 days. During counselling, subjects must be reminded to not share study drug and to not donate blood.
e. Pregnancy testing and counselling must be performed if a subject misses her period or if her pregnancy test or her menstrual bleeding is abnormal. Study drug treatment must be discontinued during this evaluation.
f. Females must agree to abstain from breastfeeding during study participation and for at least 28 days after discontinuation from the study.
Male Subjects:
Counselling about the requirement for latex condom use during sexual contact with females of childbearing potential and the potential risks of foetal exposure must be conducted at a minimum of every 28 days. During counselling, subjects must be reminded to not share study drug and to not donate blood, sperm, or semen.

If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a male study subject during study participation, study drug must be immediately discontinued.

12. Disease free of prior malignancies for = 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma “insitu” of the cervix or breast
13. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation. (patients intolerant to ASA may use warfarin or low molecular weight heparin).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
2. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide).
3. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
4. Use of any other experimental drug or therapy within 28 days of baseline.
5. Known hypersensitivity to thalidomide.
6. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
7. Any prior use of lenalidomide.
8. Concurrent use of other anti-cancer agents or treatments.
9. Known positive for HIV or infectious hepatitis, type A, B or C.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Cohorts 1 and 2 have sequential recruitment. When complete cohorts 3 and 4 are randomised by closed envelope method
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Cohorts 1 and 2 have sequential recruitment. When complete cohorts 3 and 4 are randomised by simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation) and closed envelope method
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Datasets to be analysed
Cohort sizes have been chosen on pragmatic grounds. The Division of Haematology and Medical Oncology performs approximately 30 autologous stem cell transplants in MM patients each year. It is expected that it will take two years to accrue 10 patients in each of the prospectively enrolled cohorts.

With 10 patients in each prospectively enrolled cohort accrued over 2 years and followed up for a minimum of 2 years, a comparison (two-sided log-rank test, a=0.05) of PFS between the two cohorts will have 80% power in, for example, this underlying scenario – 50% surviving progression-free at 3 years in patients without DC vaccination and 95% surviving progression-free at 3 years in patients with DC vaccination.

With 10 patients in the DC vaccination cohort, accrued over 2 years and followed up for a minimum of 2 years, and 20 patients in the historical cohort, also accrued over, say, 2 years and followed up for a minimum of 2 years, a comparison (two-sided log-rank test, a=0.05) of PFS between the vaccinated cohort and the historical cohort will have 80% power in, for example, this underlying scenario – 50% surviving progression-free at 3 years in patients in the historical cohort and 89% surviving progression-free at 3 years in the DC vaccination cohort.

Statistical Methodology
PFS and OS curves for each cohort will be estimated using the Kaplan-Meier method. The comparison of PFS and OS between the vaccination cohort and each of the comparator cohorts, the unvaccinated prospectively enrolled cohort and the historical cohort, will be based on log-rank tests.

The numbers and function of CD3 T cell populations and NKT cells in patients in each of the prospectively enrolled cohorts (with and without DC vaccination) will be compared at each time point, on which immunological monitoring is scheduled, using two-sample t-tests and a variance-stabilizing transformation may be required for these comparisons. Graphical and repeated measures analyses will also be used to summarise the individual patient profiles in each cohort.

Exploratory analyses of the relationship between the presence and/or enhancement of NKT cell numbers and function and both PFS and OS will of necessity be confined to patients in the two prospectively enrolled cohorts and will use Cox proportional hazards regression models - time-varying covariates will be considered.

All statistical tests will be two-sided, a=0.05, and no adjustments will be made for multiple testing.

Two-sample t-tests (two-sided, a=0.05) for the comparison of immunological results at each scheduled time point will have 80% power for an effect size of 1.33

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/10/2007
Actual
4/12/2007
Date of last participant enrolment
Anticipated
1/12/2012
Actual
30/10/2012
Date of last data collection
Anticipated
Actual
Sample size
Target
42
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 797 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment postcode(s) [1] 6619 0
3002 - East Melbourne

Funding & Sponsors
Funding source category [1] 286956 0
Government body
Name [1] 286956 0
Victorian Cancer Agency
Country [1] 286956 0
Australia
Funding source category [2] 286957 0
Government body
Name [2] 286957 0
Research Infrastructure Support Services
Country [2] 286957 0
Australia
Funding source category [3] 286958 0
Commercial sector/Industry
Name [3] 286958 0
Celgene Pty Ltd (Celgene Australia)
Country [3] 286958 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
St Andrews Place
East Melbourne
Victoria
3002
Country
Australia
Secondary sponsor category [1] 285743 0
None
Name [1] 285743 0
Address [1] 285743 0
Country [1] 285743 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289007 0
Peter MacCallum Cancer Centre Research Ethics Committee
Ethics committee address [1] 289007 0
Ethics committee country [1] 289007 0
Australia
Date submitted for ethics approval [1] 289007 0
Approval date [1] 289007 0
03/04/2006
Ethics approval number [1] 289007 0
PMCI 05/56

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

Contacts
Principal investigator
Name 38438 0
A/Prof Simon Harrison
Address 38438 0
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne
Victoria
3002
Country 38438 0
Australia
Phone 38438 0
+613 96561076
Fax 38438 0
+613 96561408
Email 38438 0
[email protected]
Contact person for public queries
Name 38439 0
Claire Coulson
Address 38439 0
Clinical Trials Unit
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne
Victoria
3002
Country 38439 0
Australia
Phone 38439 0
+613 96561111
Fax 38439 0
Email 38439 0
[email protected]
Contact person for scientific queries
Name 38440 0
Simon Harrison
Address 38440 0
Dept of Haematology
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne
Victoria3002
Country 38440 0
Australia
Phone 38440 0
+613 96561076
Fax 38440 0
+613 96561408
Email 38440 0
[email protected]

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
Dimensions AINKT cells and multiple myeloma2013https://doi.org/10.1111/cei.12196
EmbaseSpontaneous onset and transplant models of the Vk*MYC mouse show immunological sequelae comparable to human multiple myeloma.2016https://dx.doi.org/10.1186/s12967-016-0994-6
EmbasePredicting risk of infection in patients with newly diagnosed multiple myeloma: Utility of immune profiling.2017https://dx.doi.org/10.3389/fimmu.2017.01247
EmbaseProgression from newly diagnosed multiple myeloma to relapsed refractory multiple myeloma is associated with significant alterations in the CD4+ Treg population phenotype.2017https://dx.doi.org/10.1158/1557-3265.HEMMAL17-11
EmbaseCellular immunotherapy as a therapeutic approach in multiple myeloma.2018https://dx.doi.org/10.1080/17474086.2018.1483718
EmbaseConventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells.2020https://dx.doi.org/10.3389/fimmu.2020.02153
Dimensions AIMyeloma natural killer cells are exhausted and have impaired regulation of activation2021https://doi.org/10.3324/haematol.2020.277525
N.B. These documents automatically identified may not have been verified by the study sponsor.