Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12612000779875
Ethics application status
Approved
Date submitted
19/07/2012
Date registered
23/07/2012
Date last updated
24/07/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
To explore the tolerance and activity of increasing doses of Panobinostat when given in combination with Bortezomib, Cyclophosphamide and Dexamethasone to patients with symptomatic Multiple Myeloma who have had no previous treatment.
Scientific title
A Multicenter, Phase I/II dose escalation study to evaluate the toxicity of once weekly Panobinostat combined with Bortezomib, Cyclophosphamide and Dexamethasone in Treatment Naive Myeloma patients
Secondary ID [1] 280860 0
None
Universal Trial Number (UTN)
U1111-1132-7140
Trial acronym
PANACHE (Panobinostat Auckland Haematology Study)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma (Treatment Naive) 286931 0
Condition category
Condition code
Cancer 287261 287261 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Panobinostat (LBH589) in an oral formulation (capsules)

In Phase I, there will be three dose levels studied. At dose level 1, participants will receive 20 mg of Panobinostat on days 1, 8, 15 and 22 (a weekly regime). If this dose is well tolerated a second group of patients will be recruited and the dose increased to 25 mg of Panobinostat weekly and finally, a third group of patients will receive 30 mg of study drug. The VCD regimen is the same for all patients with all drugs given weekly and each 4-week block considered as one cycle.
Patients will receive a total of 6 cycles (6 months) of treatment at their allocated dose of Panobinostat combined with VCD

In Phase II, 10 patients will be treated at the maximum tolerated dose level of Panobinostat (determined from Phase I) in combination with VCD
This group of patients will also receive a total of 6 cycles (6 months) of treatment.

Dosages of the other components also given weekly are
Velcade (Bortezomib) 1.6mg/m2 (subcutaneously)
Cyclophosphamide 300mg/m2 (orally)
Dexamethasone 40mg (orally)
Intervention code [1] 285288 0
Treatment: Drugs
Comparator / control treatment
There is no control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 287539 0
Primary endpoint is to determine the toxicity of escalating doses of Panobinostat combined with VCD in treatment naive myeloma patients

Safety measurements will be assessed prior to drug administration and at designated intervals throughout the study. The following safety evaluations will be performed during the course of the study.
Physical examinations
Vital signs
ECG, Cardiac Echo
ECOG performance status
Laboratory studies: complete blood counts, serum chemistries, urinalysis, coagulation studies, pregnancy test, disease staging/ assessment
Skeletal Survey's

All Adverse events will be assessed and graded using the Common Terminology Criteria for Adverse Events v4.0 (CTCAE)
Timepoint [1] 287539 0
During treatment and upto 30 days post last dose of study drug.
Secondary outcome [1] 298353 0
To determine treatment response to 6 cycles of P-VCD.
This will be measured by
Laboratory studies: complete blood counts, serum chemistries, disease staging/ assessment
Skeletal Survey's
Patients will be monitored for response with each cycle and fully restaged at completion or change of therapy
Timepoint [1] 298353 0
During the 6 months of treatment
Secondary outcome [2] 298404 0
To determine progression free and overall survival
This will be determined by Laboratory tests done at each follow up visit
Timepoint [2] 298404 0
2 years post treatment

Eligibility
Key inclusion criteria
Subjects must meet all of the following inclusion criteria to be eligible for the study.
1.Patient has a diagnosis of multiple myeloma, based on IMWG 2003 definitions all three of the following criteria had been met:
a.Monoclonal immunoglobulin (M component) on electrophoresis, and on immunofixation on serum or on total 24 hour urine (or demonstration of M protein in cytoplasm of plasma cell for non secretory myeloma) .
b.Bone marrow (clonal) plasma cells equal to or greater than 10% or biopsy proven plasmacytoma
c.Related organ or tissue impairment (CRAB symptoms: anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity, amyloidosis or recurrent infections)

2.Patient has measurable disease at study screening defined by at least one of the following measurements as per IMWG 2003 criteria (Kyle, et al 2003):
a.Serum M-protein equal to or greater than 1 g/dL or 10 g/L
b.Urine M-protein equal to or greater than 200 mg/24 h

3.Patients myeloma is treatment naive with the exception of:
a. less than two weeks of steroid therapy
b.the patient has been treated with local radiotherapy with or without concomitant exposure to steroids for pain control or management of cord/nerve root compression, is eligible. Two weeks must have lapsed since last date of radiotherapy, which is recommended to be a limited field. Patient 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
4.Patient’s must be at least 18 years old at time of signing the informed consent
5.Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) equal to or less than 2
6.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 failure at screening is concluded but supportive therapies are not to be administered within the week prior to screening tests for ANC or platelet count)
a.Absolute neutrophil count (ANC) equal to or greater than 1.5 x 109 /L
b.Platelet count equal to or greater than 100 x 109 /L
c.Serum potassium, magnesium, phosphorus , within normal limits (WNL) for institution.
d.Total calcium (corrected for serum albumin) or ionized calcium greater or equal to lower normal limits (greater than LLN) for institution, 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 less than LLN.
e.AST and ALT equal to or less than 2.5 x ULN
f.Serum total bilirubin equal to or less than 1.5 ULN (or equal to or less than 3.0 x ULN if patient has Gilbert syndrome)
g.Calculated creatinine clearance equal to or greater than 40 ml/min
7.Patient has provided written informed consent prior to any screening procedures
8.Patient is able to swallow capsules
9.Patient must be able to adhere to the study visit schedule and other protocol requirements
10.Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at baseline
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria
1.Patient has shown intolerance to dexamethasone or cyclophosphamide or components of these drugs
2.Patient has greater than 2 grade peripheral neuropathy or grade 1 peripheral neuropathy with pain on clinical examination within 14 days before randomization
3.Patient needing valproic acid for any medical condition during the study or within 5 days prior to first administration of panobinostat/study treatment.
4.Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted)
5.Patient has secondary primary malignancy less than 3 years before first dose of study treatment (except for treated basal or squamous cell carcinoma, or in situ cancer of the cervix).
6.Patient who received prior anti-myeloma chemotherapy or medication including IMiDs prior to start of study.
7.Patient who received experimental therapy or biologic immunotherapy including monoclonal antibodies less than 4 weeks prior to start of study.
8.Prior radiation therapy less than 4 weeks or limited field radiotherapy less than 2 weeks prior start of study or the patient has not recovered from all therapy-related toxicities associated with radiation treatments to < grade 2 CTCAE.
9.Patient has undergone major surgery less than 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy to < grade 2 CTCAE
10.Patients with evidence of mucosal or internal bleeding
11.Patient has unresolved diarrhea less than CTCAE grade 2
12.Patient has impaired cardiac function, including any one of the following:
a.LVEF < LLN of institutional norm, as determined by ECHO
b.obligate use of a permanent cardiac pacemaker
c.congenital long QT syndrome
d.history or presence of ventricular tachy-arrhythmias
e.resting bradycardia defined as < 50 beats per minute
f.QTcF > 450 msec on screening ECG
g.complete left bundle branch block (LBBB), bifascicular block
h.any clinically significant ST segment and/or T-wave abnormalities
i.presence of unstable atrial fibrillation (ventricular response rate > 100 bpm). Patients with stable atrial fibrillation can be enrolled provided they do not meet other cardiac exclusion criteria.
j.myocardial infarction or unstable angina pectoris less than 6 months prior to starting study drug
k.symptomatic congestive heart failure (New York Heart Association class III-IV)
l.other clinically significant heart disease and vascular disease (e.g. uncontrolled hypertension
m.Patient taking medications with relative risk of prolonging the QT interval or inducing Torsade de pointes, if such treatment cannot be discontinued or switched to a different medication prior to starting study drug.
13.Patient has 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 stomach and/or small bowel resection)
14.Patient has any other concurrent severe and/or uncontrolled medical conditions (e.g.,uncontrolled diabetes, active or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease including dyspnea at rest from any cause, uncontrolled thyroid dysfunction) that could cause unacceptable safety risks or compromise compliance with the protocol
15.Patient has a known history of HIV seropositivity or history of active/treated hepatitis B or C (a test for screening is not required)
16.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 3 months after the study evaluation completion treatment, of which one must be a barrier method. 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.patient has had menses at any time in the preceding 12 consecutive months.
17.Patient is a male not willing to use a barrier method of contraception (a condom) during the study and for 3 months after the study evaluation completion treatment

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not Applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
This study was withdrawn by Novartis Pharmaceuticals. This was due to delays in the development program of Panobinostat. and so the company decided not to proceed with the study.
Date of first participant enrolment
Anticipated
1/02/2014
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
37
Accrual to date
Final
Recruitment outside Australia
Country [1] 4411 0
New Zealand
State/province [1] 4411 0

Funding & Sponsors
Funding source category [1] 285645 0
Commercial sector/Industry
Name [1] 285645 0
Novartis Pharmaceuticals Australia Pty Limited
Country [1] 285645 0
Australia
Primary sponsor type
Other
Name
North Shore Haematology Clinical Trial Unit
Address
North Shore Hospital
124 Shakespeare Road,
Takapuna,
Auckland 0622
Country
New Zealand
Secondary sponsor category [1] 284480 0
None
Name [1] 284480 0
Address [1] 284480 0
Country [1] 284480 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287644 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 287644 0
Ethics committee country [1] 287644 0
New Zealand
Date submitted for ethics approval [1] 287644 0
15/08/2012
Approval date [1] 287644 0
05/12/2012
Ethics approval number [1] 287644 0

Summary
Brief summary
The purpose of this research study is to monitor the side effects and tolerance of a gradual increase in the dose of Panobinostat when given in combination with Bortezomib (Velcade), Cyclophosphamide and Dexamethasone or VCD, in people who have symptomatic Multiple Myeloma that has not been previously treated. The effect of using Panobinostat in combination with Bortezomib has been studied and shown to produce a good response. The study will also monitor the disease response, progression free survival and overall survival It is being conducted over 4 sites in New Zealand. In Phase I, there will be three dose levels studied. At dose level 1, participants will receive 20 mg of Panobinostat on days 1, 8, 15 and 22 (a weekly regime). If this dose is well tolerated a second group of patients will be recruited and the dose increased to 25 mg of Panobinostat weekly and finally, a third group of patients will receive 30 mg of study drug. The VCD regimen is the same for all patients with all drugs given weekly and each 4-week block considered as one cycle
In Phase II, 10 patients will be treated at the maximum tolerated dose level of Panobinostat in combination with VCD and be monitored for disease response with each cycle, and undergo a complete disease reassessment on completion or change of therapy. Patients in Phase I or Phase II will receive a total of 6 cycles of treatment. An Autologous Bone Marrow Transplant and/or additional chemotherapy may be given as consolidation therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34448 0
Dr David Simpson
Address 34448 0
North Shore Hospital
124 Shakespeare Road
Takapuna
Auckland 0622
Country 34448 0
New Zealand
Phone 34448 0
+64 9 486 8920
Fax 34448 0
Email 34448 0
david.simpson@waitematadhb.govt.nz
Contact person for public queries
Name 17695 0
Mrs Elizabeth Thatcher
Address 17695 0
North Shore Hospital
124 Shakespeare Road
Takapuna, Auckland 0622
Country 17695 0
New Zealand
Phone 17695 0
+64 (9) 486 8920 ext 2185
Fax 17695 0
+64 (9) 488 4641
Email 17695 0
elizabeth.thatcher@waitematadhb.govt.nz
Contact person for scientific queries
Name 8623 0
Dr Dr David Simpson
Address 8623 0
North Shore Hospital
124 Shakespeare Road
Takapuna, Auckland 0622
Country 8623 0
New Zealand
Phone 8623 0
+64 (9) 486 8920
Fax 8623 0
+64 (9) 488 4641
Email 8623 0
david.simpson@waitematadhb.govt.nz

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

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