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Phase I Exploratory Study of Panobinostat IV in Combination With Bortezomib in Relapsed/Refractory Multiple Myeloma Patients

Phase 1
18 Years
Open (Enrolling)
Multiple Myeloma

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Trial Information

Phase I Exploratory Study of Panobinostat IV in Combination With Bortezomib in Relapsed/Refractory Multiple Myeloma Patients

The objective of this study is to identify the maximum tolerated dose (MTD) and assess the
feasibility and toxicity experience for patients with refractory multiple myeloma treated
with bortezomib and one of three doses of panobinostat IV.

Sample Size:

This study will accrue up to 18 patients, in 3 groups of up to 6 patients each, depending on
experiences of DLT. Patients will be studied as follows, Group 1: Bortezomib 1.0 mg/m2 and
panobinostat IV 5 mg/m2 IV, Group 2: Bortezomib 1.0 mg/m2and panobinostat IV 10 mg/m2 IV,
Group 3: Bortezomib 1.0 mg/m2 and panobinostat IV 15 mg/m2 IV and Group 4: Bortezomib 1.0
mg/m2 and panobinostat IV 20 mg/m2 IV. Bortezomib will be given on days 1, 4, 8, and 11
during cycle 1 and cycle 2, and panobinostat will be given on days 1 and 8 of the second

If the MTD is not reached with the first group, the second group will be enrolled and will
receive bortezomib1.0 mg/m2 with escalation of panobinostat IV as described above.

Patient population:

Patient's with relapsed/refractory multiple myeloma with at least one line of prior therapy.

Inclusion and exclusion criteria:

Patients must have baseline evaluations performed prior to the first dose of study drug and
must meet all inclusion and exclusion criteria. Results of all baseline evaluations, which
assure that all inclusion and exclusion criteria have been satisfied, must be reviewed by
the principal investigator prior to enrollment of that patient. In addition, the patient
must be thoroughly informed about all aspects of the study, including the study visit
schedule and required evaluations and all regulatory requirements for informed consent. The
written informed consent must be obtained from the patient prior to enrollment. The
following criteria apply to all patients enrolled onto the study unless otherwise specified.

Inclusion Criteria:

1. Patients with relapsed/refractory multiple myeloma to at least one line of prior

2. Male or female patients aged ≥ 18 years old

3. Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed

4. Patients are allowed to receive growth factors (erythropoietin hormones, GCSF and

5. Patients must meet the following laboratory criteria:

- ANC ≥ 1.5 x 109/L

- Hemoglobin ≥ 9 g/dl

- Platelets ≥ 100x 109/L

- Calculated CrCl > 50 mL/min (MDRD Formula)

- AST and ALT ≤ 2.5 x ULN

- Serum bilirubin < 2.0 x ULN

- Albumin > 3.0 g/dl

- Serum potassium ≥ LLN for the institution

- Total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN, for
the institution

- Serum magnesium ≥ LLN for the institution

- Serum phosphorus ≥ LLN for the institution

- TSH ≤ LLN and free T4 within normal limits. Patients are permitted to receive
thyroid hormone supplements to treat underlying hypothyroidism

6. Baseline MUGA or ECHO must demonstrate LVEF ≥ the lower limit of the institutional

7. History of histologically documented MM with relapsed or progressive disease after at
least one line of prior therapy

8. Patient has measurable disease in which to capture response, defined as one or more
of the following:

1. Serum M-protein level ≥ 0.5 gm/dl (10.0 g/L) measured by serum protein
electrophoresis or immunoglobulin electrophoresis; or

2. Urinary M-protein excretion ≥ 200 mg/24 hrs; or

3. Bone marrow plasmacytosis of ≥ 30% by bone marrow aspirate and/or biopsy; or

4. Serum Free Light Chains (By the Freelite test) > 2X ULN, in the absence of renal

9. Performance status of ≤ 2 as per ECOG scale, unless PS of 3-4 based solely on bone

10. Patients must have signed an IRB approved written informed consent form and
demonstrate willingness to meet follow-up schedule and study procedure obligations

Exclusion Criteria:

1. Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer

2. Patients who have received Velcade within 2 months of enrollment

3. Patients who will need valproic acid for any medical condition during the study or
within 5 days prior to first panobinostat IV treatment

4. Peripheral neuropathy > grade 2.

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 Novartis
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. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
diabetes or active or uncontrolled infection) including abnormal laboratory values,
that could cause unacceptable safety risks or compromise compliance with the protocol

7. 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

8. Concomitant use of CYP3A4 inhibitors (See Appendix 2)

9. 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.

10. Patients who have received either immunotherapy (e.g. vaccines) 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.

11. Patients with an active bleeding tendency or is receiving any treatment with
therapeutic doses of sodium warfarin (Coumadin®) or coumadin derivatives. Low doses
of Coumadin® (e.g. ≤ 2.0 mg/day) to maintain line patency (if applicable) is allowed.

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

13. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)
not using an effective method of birth control. WOCBP are defined as sexually mature
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 24hrs of receiving the first dose of study

14. Male patients whose sexual partners are WOCBP not using effective birth control

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

16. Patients with known positivity for human immunodeficiency virus (HIV) ) or hepatitis
C; baseline testing for HIV and hepatitis C is not required

17. 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

18. No concomitant use of bisphosphonates is allowed

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To assess the toxicity of bortezomib combined with one of 3 doses of panobinostat IV in patients with relapsed/refractory multiple myeloma, and to find the most appropriate doses of bortezomib and panobinostat IV in the combination.

Outcome Time Frame:

June, 2012

Safety Issue:


Principal Investigator

Mauizio Zangari, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Utah


United States: Food and Drug Administration

Study ID:




Start Date:

April 2009

Completion Date:

December 2013

Related Keywords:

  • Multiple Myeloma
  • cancer
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



Huntsman Cancer Hospital Salt Lake City, Utah  84112