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Trial registered on ANZCTR


Registration number
ACTRN12616001164482
Ethics application status
Approved
Date submitted
12/08/2016
Date registered
26/08/2016
Date last updated
30/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase IIb, open label, sequential cohort study comparing KappaMab alone to KappaMab in combination with lenalidomide and low dose dexamethasone (MRd) in Relapsed Refractory Multiple Myeloma
Scientific title
A Phase IIb, open label, sequential cohort study comparing KappaMab alone to KappaMab in combination with lenalidomide and low dose dexamethasone (MRd) in Relapsed Refractory Multiple Myeloma
Secondary ID [1] 289920 0
Nil
Universal Trial Number (UTN)
U1111-1186-3669
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsed/Refractory Multiple Myeloma 299891 0
Condition category
Condition code
Cancer 299794 299794 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
KappaMab 10mg/kg Cycle 1: Days 8, 15, 22, 29, Cycle 2: Days 1, 8, 15, 22, Cycle 3 onwards: Day 1, i.v. infusion. (Cycle 1 is 35 days to allow Len/Dex to start 7 days prior to KappaMab, all other cycles 28 days).
Lenalidomide: 25mg Cycle 1: Days 1-28 Cycle 2: Days 1-21, tablet, adherence monitored through drug packet return
Dexamethasone: 40mg All cycles Days 1, 8, 15, 22 (and Cycle 1 – Day 29) tablet, adherence monitored through drug packet return
First 30 participants receiving KappaMab only, next 30 participants receiving KappaMab in combination with Len/Dex

Treatment to continue until unacceptable toxicity, disease progression or death.
Intervention code [1] 295604 0
Treatment: Drugs
Comparator / control treatment
KappaMab 10mg/kg Cycle 1 and 2 : Days 1, 8, 15, 22, Cycle 3 onwards: Day 1, i.v. infusion. (All cycles 28 days).

Treatment to continue until unacceptable toxicity, disease progression or death.
Control group
Active

Outcomes
Primary outcome [1] 299258 0
To establish the clinical benefit rate (CBR = minimal response + partial response + very good partial response + complete response) of KappaMab alone and in combination with lenalidomide and dexamethasone (MRd) in RRMM

Outcome assessed through bone marrow and blood chemistry analysis and medical record review.
Timepoint [1] 299258 0
Response assessment made every 4 weeks on study until 12 months after recruitment of final study subject
Secondary outcome [1] 326662 0
To determine the safety of KappaMab in combination with lenalidomide and low dose dexamethasone (MRd) in relapsed refractory multiple myeloma, in particular, incidence of immunological AEs and development of anti-human chimera antibodies (HACA).

Antibodies and adverse reactions assessed through blood and other medical testing and observation. AEs may possibly include infusion related reactions, allergic reactions, blood related reactions and heart, musculoskeletal and skin problems.
Timepoint [1] 326662 0
Response assessment made every 4 weeks on study until 12 months after recruitment of final study subject.
Secondary outcome [2] 326663 0
To evaluate the kinetics of response and loss of response (time to response, time to disease progression [PFS], overall survival [OS]) between the group of patients receiving single agent KappaMab vs. the group receiving MRd. Responses assessed through bone marrow and blood chemistry analysis and medical record review.
Timepoint [2] 326663 0
Response assessment made every 4 weeks on study until 12 months after recruitment of final study subject.
Secondary outcome [3] 326664 0
To obtain mechanistic correlates of immunological synergies between KappaMab and lenalidomide as biomarkers of therapeutic responses. Exploratory biomarkers will include: induction of KMA expression, baseline and dynamic expression of key IMiD targets (e.g. cereblon, IKZF1, IKZF3, cMYC, IRF4) and modulation of MM immunogenicity (by FACS analysis for HLA class I/II expression, co-stimulatory markers and checkpoint regulators including PD1/PDL1), BM cytotoxic effector cell populations for quantitation and functional assays of T- and NK- function including autologous PC co-cultures and chromium release assays vs. human myeloma cell lines and K562 targets.
Timepoint [3] 326664 0
Every 12 weeks on study until 12 months after recruitment of final study subject
Secondary outcome [4] 326665 0
To correlate clinical responses with biomarkers of IMiD activity to establish 'on target' mechanisms of synergy in vivo, ie: IMiD-related MM effects and non-MM autonomous activities.

Exploratory biomarkers will include: induction of KMA expression, baseline and dynamic expression of key IMiD targets (e.g. cereblon, IKZF1, IKZF3, cMYC, IRF4) and modulation of MM immunogenicity (by FACS analysis for HLA class I/II expression, co-stimulatory markers and checkpoint regulators including PD1/PDL1), BM cytotoxic effector cell populations for quantitation and functional assays of T- and NK- function including autologous PC co-cultures and chromium release assays vs. human myeloma cell lines and K562 targets.

Clinical responses as per International Myeloma Working Group response criteria assessed through bone marrow and blood chemistry analysis and medical record review.
Timepoint [4] 326665 0
Every 12 weeks on study until 12 months after recruitment of final study subject
Secondary outcome [5] 326667 0
To establish novel pharmacodynamic (PD) biomarkers of MRd (KappaMab, Lenalidomide and Dexamethasone) activity, patterns of clonal evolution during therapy and candidate mechanisms of MRd resistance. This is an exploratory outcome examining dynamic changes in SFLC (‘Flare’) and selected cytokines (e.g. HGF, CXCL9, CXCL10, CCL27 and MIF) correlated with clinical response. Assessment through lab analysis of blood samples.
Timepoint [5] 326667 0
Every 12 weeks on study until 12 months after recruitment of final study subject or disease progression.

Eligibility
Key inclusion criteria
1. Age 18 years and above.

2. Confirmed diagnosis of MM as per IMWG criteria,

3. ECOG performance status 0-2

4. Relapsed and/or refractory kappa restricted MM

5. Received 1-3 prior lines of therapy
a. Induction + ASCT + maintenance = 1 line of therapy
b. (No prior lenalidomide therapy)

6. Adequate liver and kidney function (<2 x institutional upper limit of normal)

7. Platelet count > 75 x 10^9/L, absolute neutrophil count > 1.0 x 109/L

8. No contraindication to the use of KappaMab, lenalidomide or dexamethasone

9. Patient has voluntarily agreed and has given written informed consent.

10. Life expectancy of > 8 weeks

11. Patient must be > 2 weeks from prior chemotherapy, radiotherapy, biological therapy, immunotherapy, major surgery or any other investigational anti-cancer therapy prior to the first dose of study drug

12. All females of childbearing potential (FOCBP)** must agree to have two medically supervised negative pregnancy tests : one at screening, patient undertaking contraceptive controls and one 24 hours prior to dosing of study drug. Patient must use two reliable methods of contraception simultaneously or to practice complete abstinence from any sexual contact during the following time periods related to this study: 1) for at least 28 days before starting study; 2) while participating in the study; 3) dose interruptions; and 4) for at least 28 days after study treatment discontinuation. The two methods of reliable contraception must include one highly effective method and one additional effective method to prevent pregnancy, not plan on conceiving children during or within 6 months following lenalidomide

13. All male participants must practice complete abstinence 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 28 days following study drug discontinuation, even if he has undergone a successful vasectomy.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients with monoclonal gammopathy of uncertain significance.

2. Primary amyloidosis

3. Patients who have received prior allogeneic transplantation

4. Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

5. Patients with a prior malignancy within the last 5 years (except for basal or squamous cell carcinoma or in situ cancer of the cervix).

6. Pregnant or lactating women.

7. Known hepatitis B, Hepatitis C, HIV infection, other immunosuppressive therapy or autoimmune disease

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
Other
Other design features
First 30 participants will receive KappaMab only, and the next 30 participants will receive KappaMab in combination with Len/Dex.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 6475 0
The Alfred - Prahran
Recruitment hospital [2] 6477 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [3] 6478 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 9060 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 14030 0
3004 - Prahran
Recruitment postcode(s) [2] 14033 0
3065 - Fitzroy
Recruitment postcode(s) [3] 14034 0
3168 - Clayton
Recruitment postcode(s) [4] 17554 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 294291 0
Commercial sector/Industry
Name [1] 294291 0
Celgene Pty Ltd
Address [1] 294291 0
Level 7, 607 St Kilda Rd, Melbourne, VIC, 3004
Country [1] 294291 0
Australia
Funding source category [2] 294292 0
Commercial sector/Industry
Name [2] 294292 0
HaemaLogiX
Address [2] 294292 0
145/4 Cornwallis street, Eveleigh, NSW, 2015
Country [2] 294292 0
Australia
Primary sponsor type
Hospital
Name
Dr Andrew Spencer - Alfred Hospital
Address
Alfred Hospital, 55 Commercial Road, Melbourne, VIC, 3004
Country
Australia
Secondary sponsor category [1] 293131 0
None
Name [1] 293131 0
Address [1] 293131 0
Country [1] 293131 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295719 0
Alfred Health Human Research Ethics Committee
Ethics committee address [1] 295719 0
Alfred Hospital, 55 Commercial Road, Melbourne, VIC, 3004
Ethics committee country [1] 295719 0
Australia
Date submitted for ethics approval [1] 295719 0
21/07/2016
Approval date [1] 295719 0
19/09/2016
Ethics approval number [1] 295719 0
HREC/16/Alfred/116

Summary
Brief summary
The primary purpose of this trial is to evaluate the safety and efficacy of KappaMab in combination with Lenalidomide and Dexamethasone for the treatment of relapsed/refractory multiple myeloma.

Who is it for?
You may be eligible to participate in this trial if you are aged 18 or over with relapsed/refractory kappa restricted multiple myeloma for which you have received Received 1-3 prior lines of therapy.

Study details
Half of the participants in the study will be administered KappaMab only and half will be administered with KappaMab in combination with Lenalidomide and Dexamethasone. KappaMab will be administered weekly for the first eight weeks of study and every 28 days therafter. Lenalidomide will be taken for the first 28 days of study and the first 21 days of cycle 2. Dexamethasone will be taken weekly for the duration of the study. Participants will have blood samples taken once per month along with a medical exam in order for researchers to monitor whether the treatment is safe and whether it is effectively treating the myeloma.

It is hoped that the findings of this trial will establish the benefits of a KappaMab and Lenalidomide based immune-oncology approach for the treatment of multiple myeloma patients relatively early in their disease course.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 68214 0
Prof Andrew Spencer
Address 68214 0
Alfred Health, Commercial Road, Melbourne, Victoria, 3004
Country 68214 0
Australia
Phone 68214 0
+61 3 90763451
Fax 68214 0
+61 3 90762298
Email 68214 0
aspencer@netspace.net.au
Contact person for public queries
Name 68215 0
Ms Nola Kennedy
Address 68215 0
Alfred Health, Commercial Road, Melbourne, Victoria, 3004
Country 68215 0
Australia
Phone 68215 0
+61 3 90762217
Fax 68215 0
+61 3 90765531
Email 68215 0
n.kennedy@alfred.org.au
Contact person for scientific queries
Name 68216 0
Prof Andrew Spencer
Address 68216 0
Alfred Health, Commercial Road, Melbourne, Victoria, 3004
Country 68216 0
Australia
Phone 68216 0
+61 3 90763451
Fax 68216 0
+61 3 90762298
Email 68216 0
aspencer@netspace.net.au

No data has been provided for results reporting
Summary results
Not applicable