Safety Study of LBH589 When Given in Combination With Bortezomib in Adult Patients With Multiple Myeloma

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT00532389

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

3.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: LBH589	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

62 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official 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

Study Start Date :

Oct 1, 2007

Actual Primary Completion Date :

Oct 1, 2013

Actual Study Completion Date :

Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Panobinostat (LBH589)	Drug: LBH589

Arm

Intervention/Treatment

Experimental: Panobinostat (LBH589)

Drug: LBH589

Outcome Measures

Primary Outcome Measures

To determine the MTD of panobinostat with bortezomib [throughout the study]

Secondary Outcome Measures

The safety and tolerability of the study continuous Panobinostat treatment in dose escalation phase and non continuous schedule of panobinostat in dose expansion phase [throughtout the study]
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 [cycle 1 & cycle 2]
To assess the preliminary efficacy of the study treatment [throughout the study]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

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.
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.
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.
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 )

Adults ≥ 18 years old
ECOG Performance Status ≤ 2
Life expectancy > 12 weeks
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.

Baseline MUGA or ECHO must demonstrate LVEF ≥ the lower limit of the institutional normal
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).
Able to sign informed consent and to comply with the protocol
Patient is able to swallow capsules

Exclusion criteria:

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

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

Impairment of GI function or GI disease that may significantly alter the absorption of PAN
Patient has unresolved diarrhea ≥ CTCAE grade 2
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
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
Patients who need valproic acid for any medical condition during the study or within 5 days prior to the first PAN treatment.
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.
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.
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.
Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
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
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
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)
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.
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Innovative Medical Research of South Florida Dept.ofInnovativeMedResearch	Miami Shores	Florida	United States	33138
2	Dana Farber Cancer Institute Clinical Research Coordinator	Boston	Massachusetts	United States	02115
3	Hackensack University Medical Center Multiple Myeloma Division	Hackensack	New Jersey	United States	07601
4	Swedish Medical Center Dept.ofSwedishMedicalCtr.	Seattle	Washington	United States
5	Novartis Investigative Site	Canberra	Australian Capital Territory	Australia	2606
6	Novartis Investigative Site	Vancouver	British Columbia	Canada	V5Z 1M9
7	Novartis Investigative Site	Montreal	Quebec	Canada	H1T 2M4
8	Novartis Investigative Site	Berlin		Germany	10117
9	Novartis Investigative Site	Kiel		Germany	24105
10	Novartis Investigative Site	Leipzig		Germany	04103
11	Novartis Investigative Site	München		Germany	80336
12	Novartis Investigative Site	Wuerzburg		Germany	97070
13	Novartis Investigative Site	Bologna	BO	Italy	40138
14	Novartis Investigative Site	Torino	TO	Italy	10126
15	Novartis Investigative Site	Salamanca	Castilla Y Leon	Spain	37007
16	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036