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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]

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

Condition category

Condition code

Blood

Haematological diseases

Cancer

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]

Treatment: Drugs

Intervention code [2]

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]

Time to disease progression by IMWG criteria

Timepoint [1]

Through out the study up to 5 years post completion of therapy

Secondary outcome [1]

Overall survival

Timepoint [1]

Through out the study until death

Secondary outcome [2]

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]

Post Stem cell transplant on day 1 cycle 1, 2, 4 and 12

Secondary outcome [3]

Induction of NKT cell responses post SCT and post dendritic cell vaccination by flow cytometry and NKT cell killing assay

Timepoint [3]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Peter MacCallum Cancer Institute - East Melbourne

Recruitment postcode(s) [1]

3002 - East Melbourne

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Victorian Cancer Agency

Address [1]

12 Victoria Street
Carlton
Melbourne
Victoria 3053

Country [1]

Australia

Funding source category [2]

Government body

Name [2]

Research Infrastructure Support Services

Address [2]

GPO Box 5103 Melbourne, Victoria 3001

Country [2]

Australia

Funding source category [3]

Commercial sector/Industry

Name [3]

Celgene Pty Ltd (Celgene Australia)

Address [3]

Level 7, 607 St Kilda Road
Melbourne ,Victoria, 3004
Australia

Country [3]

Australia

Primary sponsor type

Hospital

Name

Peter MacCallum Cancer Centre

Address

St Andrews Place
East Melbourne
Victoria
3002

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Peter MacCallum Cancer Centre Research Ethics Committee

Ethics committee address [1]

St Andrews Place
East Melbourne
Victoria
3002

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

03/04/2006

Ethics approval number [1]

PMCI 05/56

Summary

Brief summary

This study is evaluating Lenalidomide induction chemotherapy, autologous peripheral stem cell transplant, and adjuvant vaccination with autologous dendritic cells and lenalidomide maintenance in patients with multiple myeloma. Who is it for? You may be eligible to join this study if you are aged above 18 years and have a bone marrow biopsy confirmed diagnosis of multiple myeloma (MM). Trial details Doctors are looking for better ways to improve the duration that the myeloma remains under control. Previous research within Australia and internationally has shown that many blood diseases may be controlled by utilizing the body’s own immune system to fight the abnormal cells. It is possible this may be the case with the vaccine therapy included in this study. In this research project, the researchers will test whether giving a vaccine of immune stimulating cells after treatment with lenalidomide and transplantation followed by lenalidomide maintenance treatment is better than treatment with lenalidomide and transplantation alone or the current standard chemotherapy treatment with transplantation. Lenalidomide is a man-made drug that alters and stimulates the immune system, causes abnormal plasma cells to die, and it may also interfere with the development of tiny blood vessels that help support myeloma cell growth. The researchers running this study believe that the use of lenalidomide may be the best way of controlling myeloma initially and may enhance the effect of the vaccine. The vaccine used in this study is manufactured using a sample of your myeloma cells combined with immune stimulating cells known as dendritic cells. Dendritic cells are normal immune stimulating cells found in everyone. We have the ability to produce large numbers of these cells in the laboratory from your normal white blood cells. We believe that the combination of large number of dendritic cells carrying fragments of the abnormal myeloma cells may be able to increase your immune system’s ability to fight the myeloma cells, which remain after the initial lenalidomide therapy and bone marrow transplant. This vaccine is an experimental treatment. This means that it is not an approved treatment for myeloma in Australia or other parts of the world. This means that it must be tested to see if it is an effective treatment for myeloma. A total of 22 people will take part in the initial research project. 12 people will actively participate in the vaccination part of the study, whilst the other 10 will act as a control group who have treatment with lenalidomide and transplantation for their myeloma and can be compared to the vaccinated group to see if there are any differences between them. A further 20 patients will be recruited into the study to examine the effects of different doses of lenalidomide with or without steroids on the immune system. Thus a total of 42 patients in total will be enrolled.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof Simon Harrison

Address

Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne
Victoria
3002

Country

Australia

Phone

+613 96561076

Fax

+613 96561408

simon.harrison@petermac.org

Contact person for public queries

Name

Claire Coulson

Address

Clinical Trials Unit
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne
Victoria
3002

Country

Australia

Phone

+613 96561111

Fax

Claire.Coulson@petermac.org

Contact person for scientific queries

Name

Simon Harrison

Address

Dept of Haematology
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne
Victoria3002

Country

Australia

Phone

+613 96561076

Fax

+613 96561408

simon.harrison@petermac.org

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

Source	Title	Year of Publication	DOI
Dimensions AI	NKT cells and multiple myeloma	2013	https://doi.org/10.1111/cei.12196
Embase	Spontaneous onset and transplant models of the Vk*MYC mouse show immunological sequelae comparable to human multiple myeloma.	2016	https://dx.doi.org/10.1186/s12967-016-0994-6
Embase	Predicting risk of infection in patients with newly diagnosed multiple myeloma: Utility of immune profiling.	2017	https://dx.doi.org/10.3389/fimmu.2017.01247
Embase	Progression from newly diagnosed multiple myeloma to relapsed refractory multiple myeloma is associated with significant alterations in the CD4+ Treg population phenotype.	2017	https://dx.doi.org/10.1158/1557-3265.HEMMAL17-11
Embase	Cellular immunotherapy as a therapeutic approach in multiple myeloma.	2018	https://dx.doi.org/10.1080/17474086.2018.1483718
Embase	Conventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells.	2020	https://dx.doi.org/10.3389/fimmu.2020.02153
Dimensions AI	Myeloma natural killer cells are exhausted and have impaired regulation of activation	2021	https://doi.org/10.3324/haematol.2020.277525

N.B. These documents automatically identified may not have been verified by the study sponsor.

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