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A Phase I/II Trial of Romidepsin (Depsipeptide) and Bortezomib in Patients With Relapsed Myeloma

Phase 1/Phase 2
18 Years
Open (Enrolling)
Multiple Myeloma

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Trial Information

A Phase I/II Trial of Romidepsin (Depsipeptide) and Bortezomib in Patients With Relapsed Myeloma

Several groups have explored the possible synergistic interactions between proteasome and
HDAC inhibitors in malignant hematopoietic cells. Bortezomib and HDACIs synergistically
induce apoptosis, mitochondrial injury (via BAX), ROS generation and oxidative injury in
human leukemia and myeloma cells.

In view of this evidence, we are proposing a trial to examine the clinical effects of
combined romidepsin and bortezomib in patients with relapsed/refractory MM. However, there
are currently no data as to whether these drugs are safe to administer in combination or at
what dose toxicity they may become unacceptable.

Trial Design Open label, single centre, single arm, phase I/II dose escalation trial of
bortezomib-dexamethasone with the addition of romidepsin followed by maintenance therapy
until disease progression.

Primary objective:

• To determine the maximum tolerated dose (MTD) of romidepsin administered with Bortezomib
in patients with relapsed multiple myeloma by the assessment of adverse events and abnormal
laboratory values.

Primary endpoint:

• Toxicity evaluation at each of four dose levels presented in the dose-escalation schedule

Secondary objective:

• To determine the efficacy of this combination at the MTD in terms of (i) overall response,
(ii) time to progression and (iii) overall survival

Secondary endpoints:

- Overall response (OR), defined as the best response on treatment based on M Protein
response criteria with CR documented to EMBT standard and in conjunction with soft
tissue plasmacytomas response criteria and corrected serum calcium level.

- Time to progression (TTP), defined as the time from commencement of treatment to the
date of first evidence of progressive disease.

- Overall survival (OS), defined as the time from commencement of treatment to the date
of death from any cause

Inclusion Criteria:

1. Patient was previously diagnosed with multiple myeloma based on standard criteria
treated with at least one, but less than 4 lines of therapy, and currently requires
further treatment because of relapse from CR or PD.

2. Patient previously treated with bortezomib will be included in the study, if the
duration of response was >6mths from the completion of therapy.

3. Patient's age is > 18 yrs

4. Patient is, in the investigator's opinion, willing and able to comply with the
protocol requirements.

5. Patient has given voluntary written informed consent.

6. Female patients of child-bearing potential and male patients with female partners of
child-bearing potential, one of whom has not undergone surgical sterilisation must
agree to use 2 simultaneous methods of contraception. For female patients, a negative
pregnancy test is to be performed within 7 days prior to administration of study

7. Patient has measurable disease.

- serum monoclonal protein (SEP) > 5 g/L

- serum-free light chains (SFLC) > 100 mg/L

- urine-free light chains (UFLC) > 200 mg/24hr

- measurable soft tissue (not bone) plasmacytoma (STPC)

8. Patient has a Karnofsky performance status ≥80%.

9. Patient has a life-expectancy >3 months.

10. Patient has the following laboratory values within 14 days before study drug

- Platelet count ≥50 × 109/L without transfusion support within 7 days

- Hemoglobin ≥75 g/L without transfusion support within 7 days

- Absolute neutrophil count (ANC) ≥0.75 × 109/L without the use of growth factors.

- Corrected serum calcium <14 mg/dL (3.5 mmol/L).

- Serum potassium ≥ 4.0 mmol/L and serum magnesium ≥ 0.85 mmol/L (electrolytes can
be corrected with supplementation. See section 9.7).

- Aspartate transaminase (AST): ≤2.5 × the upper limit of normal (ULN).

- Alanine transaminase (ALT): ≤2.5 × the ULN.

- Total bilirubin: ≤1.5 × the ULN.

- Calculated or measured creatinine clearance: ≥20 mL/minute.

Exclusion Criteria:

1. Prior severe allergic reactions to bortezomib (Velcade), romidepsin, boron or

2. Neuropathy > Grade 3 or Neuropathy of Grade 2 with pain > Grade 1 by NCI-CTCAE
criteria (v3.0).

3. Patients with the following cardiac risk factors will be excluded from the study (as
per the previous NCI trials):

- Congenital long QT syndrome

- QTc interval > 480 milliseconds

- Patients who have had a myocardial infarction within 12 months of study entry.

- Patients who have active coronary artery disease, e.g. angina as defined by
Canadian Class II-IV (Appendix 3).

- Patients with an ECG showing evidence of cardiac ischemia (ST depression of ≥ 2

- Patients with congestive heart failure that meets NYHA Class II to IV
definitions (Appendix 4) and/or ejection fraction < 45% by MUGA scan or < 50% by
echocardiogram and/or MRI.

- Patients with a history of sustained VT, VF, Torsade de Pointes, or cardiac
arrest unless currently addressed with an automatic implantable cardioverter
defibrillator (AICD).

- Patients with dilated, hypertrophic, or restrictive cardiomyopathy from prior
treatment or other causes (in doubt, see ejection fraction criteria above).

- Patients with uncontrolled hypertension, i.e. SBP ≥ 160 mm Hg or DBP ≥ 95 mm Hg.

- Patients with cardiac arrhythmia requiring anti-arrhythmic medication other than
beta blocker or calcium channel blocker. Patients in whom digitalis cannot be
discontinued are excluded from study.

- Patients with Mobitz II second degree heart block, that do not have a pacemaker.

Note: Patients with other cardiac disease may be excluded at the discretion of the
principal investigator following consultation with cardiologist.

4. Pregnancy in female patients

Type of Study:


Study Design:

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

Outcome Measure:


Outcome Time Frame:

Until progression

Safety Issue:


Principal Investigator

Simon J Harrison, MBBS, PhD.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Peter MacCallum Cancer Centre, Australia


Australia: Department of Health and Ageing Therapeutic Goods Administration

Study ID:




Start Date:

November 2006

Completion Date:

January 2012

Related Keywords:

  • Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell