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A Phase II, Multi-center, Single Arm, Open Label Study of Panobinostat in Combination With Bortezomib and Dexamethasone in Patients With Relapsed and Bortezomib-refractory Multiple Myeloma

Phase 4
18 Years
Open (Enrolling)
Relapsed and Bortezomib Refractory Multiple Myeloma, Refractory Multiple Myeloma, Relapsed Multiple Myeloma

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Trial Information

A Phase II, Multi-center, Single Arm, Open Label Study of Panobinostat in Combination With Bortezomib and Dexamethasone in Patients With Relapsed and Bortezomib-refractory Multiple Myeloma

This is a phase II, two stage, single arm, open label, multi-center study of oral PAN in
combination with BTZ/Dex in patients with relapsed and refractory multiple myeloma, who are
bortezomib-refractory and have received at least 2 prior lines of therapy. Patients must
have been exposed to an iMID (lenalidomide or thalidomide) and progressed on or within 60
days of their last BTZ-containing line of therapy.

Inclusion Criteria:

1. Patient has a previous diagnosis of multiple myeloma, based on IMWG 2003 definitions.
All three of the following criteria must have been met:

- Monoclonal immunoglobulin (M component) on electrophoresis, and on
immunofixation on serum or on total 24 hour urine

- Bone marrow (clonal) plasma cells ≥ 10% or biopsy proven plasmacytoma

- Related organ or tissue impairment (CRAB symptoms: anemia, hypercalcemia, lytic
bone lesions, renal insufficiency, hyperviscosity, amyloidosis or recurrent

2. Patient must have relapsed and refractory MM and must require treatment for the
relapsed disease

3. Patients must have received at least 2 prior lines of therapy which include an IMiD
(thalidomide or lenalidomide)

4. Patient must be refractory to the last bortezomib containing line of therapy given in
the relapsed and refractory setting defined as:

- having progressed on or within 60 days of the last bortezomib-containing line of

5. Patient has measurable disease on M protein at study screening defined by at least
one of the following measurements as per thresholds clarified in IMWG 2003 disease
definitions (Kyle, et al 2003):

- Serum M-protein ≥ 1 g/dL (≥ 10 g/L)

- Urine M-protein ≥ 200 mg/24 h

6. Patients treated with local radiotherapy with or without concomitant exposure to
steroids for pain control or management of cord/nerve root compression, are eligible.
Two weeks must have lapsed since last date of radiotherapy, which is recommended to
be a limited field. Patients who require concurrent radiotherapy should have entry to
the protocol deferred until the radiotherapy is completed and 2 weeks have passed
since the last date of therapy

7. Patient's age is ≥ 18 years at time of signing the informed consent

8. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤

9. Patient has the following laboratory values within 3 weeks before starting study drug
(lab tests may be repeated, as clinically indicated, to obtain acceptable values
before screen fail is concluded but supportive therapies are not to be administered
within the week prior to screening tests for absolute neutrophil count or platelet

- Absolute neutrophil count (ANC) ≥ 1.0 x 109 /L

- Platelet count ≥ 70 x 109 /L

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

- Total calcium (corrected for serum albumin) or ionized calcium ≥ LLN, and not
higher than CTCAE grade 1 in case of elevated value

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

- AST/SGOT and ALT/SGPT ≤ 2.5 x ULN

- Serum total bilirubin ≤ 1.5 ULN (or ≤ 3.0 x ULN if patient has Gilbert syndrome)

- Serum creatinine levels ≤ 2.5 x ULN, or calculated creatinine clearance ≥ 40

10. Patient has provided written informed consent prior to any screening procedures

11. Patient is able to swallow capsules

12. Patient must be able to adhere to the study visit schedule and other protocol

13. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at
within 7 days prior to start of study treatment

Exclusion Criteria:

1. Primary refractory disease (patients that never reached at least an MR for over 60
days under any prior therapy)

2. Patients who have a history of prior MM treatment with a DAC inhibitor including

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

4. Peripheral neuropathy ≥ CTCAE grade 2

5. Patients who will need valproic acid for any medical condition during the study or
within 5 days prior to the first administration of study drug / treatment or who
cannot be switch to safely to alternative anti-epileptic medication

6. Patients who have impaired cardiac function including any of the following:

- Congenital long QT syndrome, complete left bundle branch block or use of a
permanent cardiac pacemaker, history or presence of ventricular
tachyarrhythmias, clinically significant resting bradycardia (< 50 beats per
minute). Right bundle branch block + left anterior hemiblock (bifascicular

- QTcF > 450 msec on screening ECG

- Presence of unstable atrial fibrillation. Patients with stable atrial
fibrillation are allowed in the study provided they do not meet other cardiac or
prohibited drug exclusion criteria

- Previous history of angina pectoris or acute MI within 6 months

- Congestive heart failure (New York Heart Association functional classification

- Patient has any other clinically significant cardiovascular disease (e.g.
uncontrolled hypertension)

7. Patient has an impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of panobinostat (e.g., ulcerative disease,
uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or significant
small bowel resection)

8. Patient has unresolved diarrhea ≥ CTCAE grade 2

9. Patients who have any other concurrent severe and/or uncontrolled medical
condition(s) including, but not limited to: uncontrolled diabetes mellitus, active or
uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease
(e.g. dyspnea at rest from any cause), symptomatic thyroid dysfunction, significant
bleeding tendency, that could cause unacceptable safety risks or compromise
compliance with the protocol

10. Patients who are using medications that have a known relative risk of prolonging the
QT interval or of inducing Torsade de Pointes, where such treatment cannot be
discontinued or switched to a different medication prior to starting study drug

11. Women who are pregnant or breast feeding

12. Patients with evidence of another malignancy not in remission or history of such a
malignancy within the last 5 years (except for treated basal or squamous cell
carcinoma, or in situ cancer of the cervix)

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

14. 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

15. Use of chemo-, biologic or immunologic therapy and/or other investigational agents
while the patient is on study treatment.

16. Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted
only if commenced prior to the start of screening period)

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall response rate (PR+nCR+CR)

Outcome Description:

The primary endpoint for this phase II study of patients with bortezomib-refractory MM is overall response rate (PR+nCR+CR) after a maximum of 8 cycles of therapy as defined by the modified EBMT criteria.

Outcome Time Frame:

after eight cycyles of treatment (24 weeks)

Safety Issue:


Principal Investigator

Novartis Pharmaceuticals

Investigator Role:

Study Director

Investigator Affiliation:

Novartis Pharmaceuticals


United States: Food and Drug Administration

Study ID:




Start Date:

June 2010

Completion Date:

July 2013

Related Keywords:

  • Relapsed and Bortezomib Refractory Multiple Myeloma
  • Refractory Multiple Myeloma
  • Relapsed Multiple Myeloma
  • Multiple Myeloma
  • Relapsed Multiple Myeloma
  • Refractory Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



Medical College of Wisconsin Milwaukee, Wisconsin  53226
Montefiore Medical Center Bronx, New York  10467-2490
Dana Farber Cancer Institute Boston, Massachusetts  02115
UCLA/ University of California Los Angeles Sylmar, California  91342
MD Anderson Cancer Center/University of Texas MD Anderson CC Houston, Texas  77030
Duke University Medical Center Dept. of DUMC (4) Durham, North Carolina  27710
H. Lee Moffitt Cancer Center/University of South Florida Tampa, Florida  33612
Georgia Health Sciences University MedCollege of GA Cancer Ctr 2 Augusta, Georgia  30912
Emory University School of Medicine/Winship Cancer Institute Dept. of Winship Cancer Inst. Atlanta, Georgia  30322
Somerset Hematology Oncology Associates Somerset Hema Oncol Assoc (2) Somerset, New Jersey  08873
Stanford University Medical Center Division of Hematology Stanford, California  94305-5826
Hematology/Oncology of the North Shore Hem/Onc North Shore Skokie, Illinois  60076
Vanderbilt University Medical Center, Clinical Trials Center Vanderbilt UMC Nashville, Tennessee  37212