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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00532389




Registration number
NCT00532389
Ethics application status
Date submitted
18/09/2007
Date registered
20/09/2007
Date last updated
3/11/2014

Titles & IDs
Public title
Safety Study of LBH589 When Given in Combination With Bortezomib in Adult Patients With Multiple Myeloma
Scientific title
A Phase Ib, Multi-center, Open-label, Dose-escalation Study of Oral LBH589 When Administered in Combination With Bortezomib in Adult Patients With Multiple Myeloma
Secondary ID [1] 0 0
2006-006638-16
Secondary ID [2] 0 0
CLBH589B2207
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - LBH589

Experimental: Panobinostat (LBH589) -


Treatment: Drugs: LBH589


Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
To determine the MTD of panobinostat with bortezomib
Timepoint [1] 0 0
throughout the study
Secondary outcome [1] 0 0
The safety and tolerability of the study continuous Panobinostat treatment in dose escalation phase and non continuous schedule of panobinostat in dose expansion phase
Timepoint [1] 0 0
throughtout the study
Secondary outcome [2] 0 0
To characterize the PK profile of bortezomib; the PK profile of panobinostat with and without bortezomib; the PK profile of bortezomib and panobinostat with and without dexamethasone
Timepoint [2] 0 0
cycle 1 & cycle 2
Secondary outcome [3] 0 0
To assess the preliminary efficacy of the study treatment
Timepoint [3] 0 0
throughout the study

Eligibility
Key inclusion criteria
Inclusion criteria:

1. Patients must have a diagnosis of active multiple myeloma according to the
International Myeloma Working Group criteria (IMWG., 2003), and be deemed by the
investigator as requiring treatment.

2. Patients must have received at least one prior line of therapy and includes patients
whose disease has relapsed as well as relapsed-refractory MM . (Durie et. al., 2006).
One prior line of therapy may consist of induction followed by autologous stem cell
transplantation.

3. Patients must be suitable (according to their local product information and applicable
health authority recommendations) for treatment with BTZ. Note: patients previously
treated with BTZ are eligible to participate in the trial.

4. Patients enrolled to dose expansion phase must have measurable M component at entry
according to the IMWG Criteria (Durie et al, 2006) including at least one of the
following:

- Serum M-protein by sPEP = 1 g/dL (> 10g/l)

- For patients with IgA M-protein whose sPEP is not providing sufficiently precise
quantification due to confounded migration of M-protein with serum beta
globulins, a quantification by nephelometry / turbidometry is permitted and must
show serum M-protein = 1 g/dL

- Urine M-protein by uPEP = 200 mg/24 h

- Serum FLC assay: Involved FLC level = 100 mg/L, provided serum FLC ratio is
abnormal. (abnormal if FLC ratio is <0.26 or >1.65 )

5. Adults = 18 years old

6. ECOG Performance Status = 2

7. Life expectancy > 12 weeks

8. Patients must have the following laboratory values:

- ANC = 1.5 x 109/L

- Platelets = 100x 109/L

- Calculated CrCl = 30 mL/min (MDRD Formula)

- AST and ALT = 2.5 x ULN

- Serum bilirubin = 1.5 x ULN

- Serum potassium, magnesium, phosphorous, within normal limits (WNL) for
institution

- Total calcium (corrected for serum albumin) or ionized calcium equal to lower
normal limits for institution or greater (= LLN) but not higher than CTCAE grade
1

- Note: Potassium, calcium, magnesium, and/or phosphorous supplements may be given
to correct values that are < LLN.

9. Baseline MUGA or ECHO must demonstrate LVEF = the lower limit of the institutional
normal

10. All patients (dose-escalation and dose-expansion patients) must be willing to undergo
a mandatory bone marrow aspirate sampling at baseline (for cytology) and another later
in the study if the patient eventually goes on to experience a CR or PR. For patients
who join the study at the dose-expansion phase, they must also give consent to have an
extra volume of sample taken for exploratory biomarker testing. Potential
dose-expansion phase patients who do not consent for this biomarker sample collection
will not be eligible to participate in the trial (Note: One extra bone aspirate sample
at C2D1 is optional as per the protocol).

11. Able to sign informed consent and to comply with the protocol

12. Patient is able to swallow capsules
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:

1. Prior exposure to a HDAC inhibitor compound used in the treatment of MM

2. Patients with Refractory MM (i.e. patients refractory to all prior therapies) who
under all prior previous lines of therapy have :

- either never reached a response better than SD

- or whose disease progressed from any best response while still under therapy

- or whose disease progressed within 60 days of last dose of therapy

3. Patients who have had prior allogeneic stem cell transplantation and show evidence of
active graft-versus-host disease or of graft-versus-host disease that requires
immunosuppressive therapy.

4. Patient has grade 1 peripheral neuropathy with pain or grade = 2 peripheral neuropathy
on clinical examination within 14 days before first study treatment

5. Impaired cardiac function or clinically significant cardiac diseases, including any
one of the following:

- Patients with congenital long QT syndrome

- History or presence of sustained ventricular tachyarrhythmia. (Patients with a
history of atrial arrhythmia are eligible but should be discussed with the
Sponsor prior to enrollment)

- Any history of ventricular fibrillation or torsade de pointes

- Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR =
50 bpm.

- Screening ECG with a QTc > 450 msec

- Right bundle branch block + left anterior hemiblock (bifascicular block)

- Patients with myocardial infarction or unstable angina = 6 months prior to
starting study drug

- Other clinically significant heart disease (e.g., CHF NY Heart Association class
III or IV , uncontrolled hypertension, history of labile hypertension, or history
of poor compliance with an antihypertensive regimen)

6. Impairment of GI function or GI disease that may significantly alter the absorption of
PAN

7. Patient has unresolved diarrhea = CTCAE grade 2

8. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
diabetes, active or uncontrolled infection, acute diffuse pulmonary disease,
pericardial disease, uncontrolled thyroid dysfunction ) including abnormal laboratory
values, that could cause unacceptable safety risks or compromise compliance with the
protocol

9. Patients using medications that have a relative risk of prolonging the QT interval or
inducing torsade de pointes if treatment cannot be discontinued or switched to a
different medication prior to starting study drug

10. Patients who need valproic acid for any medical condition during the study or within 5
days prior to the first PAN treatment.

11. Patients who have received targeted agents within 2 weeks or within 5 half-lives of
the agent and active metabolites (which ever is longer) and who have not recovered
from side effects of those therapies.

12. Patients who have received either immunotherapy within = 8 weeks; chemotherapy within
= 4 weeks; or radiation therapy to > 30% of marrow-bearing bone within = 2 weeks prior
to starting study treatment; or who have not yet recovered from side effects of such
therapies.

13. Patients who have received steroids (e.g. Dex) = 2 weeks prior to starting study
treatment or who have not recovered from side effects of such therapy. Concomitant
therapy medications that include corticosteroids are allowed if patients receive < 10
mg of prednisone or equivalent as indicated for other medical conditions, or up to 100
mg of hydrocortisone as pre-medication for administration of certain medications or
blood products while enrolled in this study.

14. Patients who have undergone major surgery = 4 weeks prior to starting study drug or
who have not recovered from side effects of such therapy

15. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)not
willing to use a double method of contraception during the study and for 3 months
after treatment. One of these methods of contraception must be a barrier method. WOCBP
are defined as women who have not undergone a hysterectomy or who have not been
naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses
any time in the preceding 12 consecutive months). Women of childbearing potential must
have a negative serum pregnancy test within 7 days of the first administration of oral
PAN

16. Male patients whose sexual partners are WOCBP not using a double method of
contraception during the study and for 3 months after treatment. One of these methods
of contraception must be a condom

17. Patients with a prior malignancy with in the last 3 years (except for basal or
squamous cell carcinoma, or in situ cancer of the cervix)

18. Patients with any significant history of non-compliance to medical regimens or
unwilling or unable to comply with the instructions given to him/her by the study
staff.

19. Patients who have shown intolerance to BTZ or to Dex or components of these drugs or
has any contraindication to one or the other drug, following locally applicable
prescribing information

Other protocol defined inclusion/exclusion criteria may apply

Study design
Purpose of the study
Treatment
Allocation to intervention
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
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
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)
ACT
Recruitment hospital [1] 0 0
Novartis Investigative Site - Canberra
Recruitment postcode(s) [1] 0 0
2606 - Canberra
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Florida
Country [2] 0 0
United States of America
State/province [2] 0 0
Massachusetts
Country [3] 0 0
United States of America
State/province [3] 0 0
New Jersey
Country [4] 0 0
United States of America
State/province [4] 0 0
Washington
Country [5] 0 0
Canada
State/province [5] 0 0
British Columbia
Country [6] 0 0
Canada
State/province [6] 0 0
Quebec
Country [7] 0 0
Germany
State/province [7] 0 0
Berlin
Country [8] 0 0
Germany
State/province [8] 0 0
Kiel
Country [9] 0 0
Germany
State/province [9] 0 0
Leipzig
Country [10] 0 0
Germany
State/province [10] 0 0
München
Country [11] 0 0
Germany
State/province [11] 0 0
Wuerzburg
Country [12] 0 0
Italy
State/province [12] 0 0
BO
Country [13] 0 0
Italy
State/province [13] 0 0
TO
Country [14] 0 0
Spain
State/province [14] 0 0
Castilla y Leon
Country [15] 0 0
Spain
State/province [15] 0 0
Catalunya

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This study comprises of a dose-escalation and dose expansion phase and will determine the
maximum tolerated dose of oral Panobinostat on a continuous schedule in adult in combination
with bortezomib. Safety, tolerability, PK and PD profile of the combined treatments will be
assessed as secondary objectives. Dose expansion phase will explore in a non continuous
Panobinostat schedule with bortezomib and dexamethasone, safety and tolerability and PK
profile of Panobinostat and Bortezomib with and without Dexamethasone
Trial website
https://clinicaltrials.gov/show/NCT00532389
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications