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Trial registered on ANZCTR


Registration number
ACTRN12612000746831
Ethics application status
Approved
Date submitted
28/06/2012
Date registered
13/07/2012
Date last updated
13/07/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase I/II trial to determine the Safety, Toxicity and Efficacy of Iodine-131-Rituximab and the Histone Deacetylase Inhibitor Panobinostat in Relapsed and Refractory Indolent B-cell Lymphoma
Scientific title
A Phase I/II trial to determine the Safety, Toxicity and Efficacy of Iodine-131-Rituximab and the Histone Deacetylase Inhibitor Panobinostat in Relapsed and Refractory Indolent B-cell Lymphoma
Secondary ID [1] 280689 0
None
Universal Trial Number (UTN)
Trial acronym
BCELLI Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsed and Refractory Indolent B-cell Lymphoma 286717 0
Condition category
Condition code
Cancer 287019 287019 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All patients will receive oral panobinostat (20 or 30 or 40mg in 5, 15 and 20mg tablets) which will commence on day one on a Monday and will continue to be given on Monday, Wednesday and Friday weekly for four weeks. A tracer activity of 200 MBq131I-rituximab will be administered intravenously after an intravenous dose of 375 mg/m2 rituximab unlabeled antibody, with both given on day four. Whole-body imaging and background scans will be performed within one hour in the administering department, and be repeated four and seven days later under the same imaging conditions. The residence time of 131I-rituximab is calculated from whole-body gamma camera counts at these time points. The radio-immunotherapeutic dose will be administered intravenously on day 11 (+/- one day dependant on availability of single isolation room) after an additional 375 mg/m2 loading dose of intravenous unlabeled rituximab on the same day. The administered activity is estimated to deliver a whole-body radiation absorbed dose of 0.75 Gy. During rituximab infusions cardiac monitoring in the form of regular blood pressure and pulse monitoring will take according to institutional practice.

After administration of therapeutic 131I-rituximab patients will be treated according to institutional and state practice, and will either require isolation until radiation levels fall below mandated thresholds (approximately five days), or will be allowed home.

Prophylactic Lugols iodine 10 drops per day will commence on day three and continue until day 21 in order to block thyroid uptake of radio-iodine.

There are two phases for this study;

The aim of the study is to evaluate the safety and exclude a clinically unacceptable rate of hematological and non-hematological toxicity of the combination of 131I-rituximab and panobinostat in patients with relapsed and refractory indolent B-cell NHL.
Three dose levels of panobinostat will be considered in phase I of the study, which is the dose finding phase. This will be followed by phase II, which consists of an expanded cohort at the phase I determined dose of panobinostat.
For the first 3 patients in the pilot phase, a dose of 30mg panobinostat will be used with a standard dose of 131I-rituximab (dose level 1).
If 0/3 patients have a DLT then a second cohort will be opened at dose level 2 starting immediately.

If 1/3 patients has a DLT then a further 3 patients will be enrolled at dose level 1. If there are no further DLTs then the current dose will be declared to be the final dose, and the phase II part of the study will begin. If there are >2/6 DLT’s in total then the panobinostat dose will be reduced to 20mg monday/wednesday/friday for ongoing patients and a new pilot cohort of three patients will be enrolled at dose level -1.

If > 2/3 patients or the first two patients accrued have a DLT then the panobinostat dose will be reduced to 20mg monday/wednesday/friday for ongoing patients and a new pilot cohort of three patients will be enrolled at dose level -1.

For patients enrolled at dose level -1 (20mg panobinostat)

If 0/3 patients have a DLT then the current dose will be declared to be the final dose and expansion to phase II study at dose level -1 will start immediately
If 1/3 patients have a DLT then a further 3 patients will be enrolled at the current dose level. If there are no further DLTs then the current dose will be declared to be the final dose and the phase II study will begin at dose level -1.

If >2/6 or > 2/3patients have a DLT then the study will be terminated.

For patients enrolled at dose level 2 (40mg panobinostat)

If 0/3 patients have DLTs then the current dose will be declared to be the final dose and expansion to phase II will start at 40mg.

If 1/3 patients has DLT then a further 3 patients will be enrolled to the current cohort. If there are no further DLTs then the current dose will be declared to be the final dose and the phase II study will begin at 40mg.

If there are >2/6 patients in total with DLTs then dose level 1 will be declared to be the final dose and the phase II part of the study will begin at 30mg of panobinostat.
Prior to initiation of phase II, the safety monitoring committee will review data to ensure safety. If committee approved, patients will be accrued following the completion of the phase I cohort(s). The schedule of treatment will be identical to the pilot group, whilst the dose of panobinostat will be 20mg (dose level -1), 30mg (dose level 1) or 40 mg (dose level 2) dependent on the outcome of the pilot phase.
Intervention code [1] 285101 0
Treatment: Drugs
Comparator / control treatment
Not applicable
Control group
Uncontrolled

Outcomes
Primary outcome [1] 287359 0
The primary objective is the evaluation of the incidence of dose limiting toxicities (DLTs) from day 1 of study treatment to 12 weeks post treatment.

For both phases DLTs are defined as the occurrence of any one or more of the following:

Study drug (any or all of 131I-rituximab, rituximab and panobinostat) related Grade 4 hematological toxicity lasting seven or more days as determined by Monday/Wednesday/Friday testing, i.e. on at least 4 consecutive tests, up to and including week 12.

Study drug related (any or all of 131I-rituximab, rituximab and panobinostat) Grade 4 biochemical toxicity of any duration within the first 12 weeks post commencement of panobinostat).

Study drug related (any or all of 131I-rituximab, rituximab and panobinostat) Grade 3 or 4 other toxicity (i.e. other than hematological or biochemical) of any duration as assessed by NCI CTCAE version 4, up to and including week 12.

Study drug related (any or all of 131I-rituximab, rituximab and panobinostat) infection requiring intravenous antibiotics or hospitalization, up to and including week 12.

QTcF prolongation up to and including week 12.

The most common expected adverse events are thrombocytopenia (when on the drug) and non-specific QT abnormalities on ECG for panobinostat, and anaemia and thrombocytopenia (6-8 weeks after drug) for 131-I-riuximab. Patients have a weekly physical assessment for 12 weeks and a full blood count taken three times per week. ECGs are taken on day one and five of the first week of panobinostat, following a defined protocol used in other panobinostat studies.
Timepoint [1] 287359 0
day 1 of treatment to 12 weeks post treatment
Secondary outcome [1] 297999 0
- To determine the association of the absolute peripheral blood lymphocyte number as well as the intensity of CD20 expression at study entry on peripheral blood B-cells with each of response and PFS.
Timepoint [1] 297999 0
- Lymphocyte subset analysis and CD20 expression assessed day one and four and week 12. response assessed at week 12 and PFS at relapse.
Secondary outcome [2] 297998 0
- To determine the duration of response after combination therapy with 131I-rituximab and panobinostat in patients who achieve a response (CR/Cru and PR).
Timepoint [2] 297998 0
from confirmed response at week 12 to documented disease relapse.
Secondary outcome [3] 297986 0
- To determine the CR/CRu rate by CT and CT-PET after combination therapy with 131I-rituximab. CT response as defined by the IWG criteria (Standardised Response Criteria determined by consensus of an International Working Group), will be used for the primary determination of response rate
Timepoint [3] 297986 0
The primary indicator of efficacy of the investigation therapy will be the CR/CRu rate as assessed by CT criteria at 12 weeks after therapy.

The CT response (CR, CRu, PR, SD or progressive disease [PD]) at 12 weeks will be assessed.

PFS will initially be characterised for each of the above subsets using a Kaplan-Meier curve one year after the last patient on study has had his or her initial response assessment, and then again at three years after the enrolment of the last patient.

Duration of response will initially be characterised using a Kaplan-Meier curve one year after the last patient on study has had his or her initial response assessment, and then again at three years after the enrolment of the last patient.

Further objectives for both phase I and phase II of the study include measuring the rate of molecular response for all patients positive at baseline, regardless of phase at three months with the drug combination.
Secondary outcome [4] 297997 0
- To determine the PFS (Progression Free Survival) in all patients who achieve a CT response of CR, CRu, PR or SD to combination therapy with 131I-rituximab and panobinostat.
Timepoint [4] 297997 0
from day 1 to documented disease relapse

Eligibility
Key inclusion criteria
Inclusion criteria:
Histologically confirmed relapsed indolent B-cell NHL.
Measurable disease by CT criteria.
One or more lines of previous therapy.
Age >18 years.
ECOG performance status <2.
Protocol defined adequate bone marrow function, serum electrolyte levels and hepatic function.
Written informed consent.
A negative serum pregnancy test in women.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria:
Chemotherapy or radiotherapy <4 weeks previously.
Previous HDACi (excluding prior valproate therapy).
Stable platelet count<100x109/L and neutrophils<1.5x109/L.
Previously diagnosed myelodysplasia (MDS).
Another malignancy <3 years previously
Major surgery less than or equal to 2 weeks prior to starting study drug.
Patients with evidence of significant bleeding.
Unresolved diarrhoea.
A protocol defined history of significant heart disease
Use of medications at risk of causing prolonged QT interval.
Impaired gastrointestinal (GI) function or disease that may significantly alter the absorption of panobinostat
Any concurrent severe and/or uncontrolled medical conditions.
Hepatitis B, C, or HIV positivity.
Pregnant or breast feeding women.

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)
Each patient must meet the eligibility requirements of the protocol.
This study has two phases, a pilot dose finding phase (phase I), and provided there is no excess toxicity, a 2nd phase (phase II), which is a single arm study of 131I-rituximab and panobinostat.

The following describes the dose escalation and de-escalation rules that are to be applied in this study.

For patients enrolled at dose level 1 (30mg panobinostat)

If 0/3 patients have a DLT then a second cohort will be opened at dose level 2 starting immediately.

If 1/3 patients has a DLT then a further 3 patients will be enrolled at dose level 1. If there are no further DLTs then the current dose will be declared to be the final dose, and the phase II part of the study will begin. If there are >2/6 DLT’s in total then the panobinostat dose will be reduced to 20mg monday/wednesday/friday for ongoing patients and a new pilot cohort of three patients will be enrolled at dose level -1.

If > 2/3 patients or the first two patients accrued have a DLT then the panobinostat dose will be reduced to 20mg monday/wednesday/friday for ongoing patients and a new pilot cohort of three patients will be enrolled at dose level -1.

For patients enrolled at dose level -1 (20mg panobinostat)

If 0/3 patients have a DLT then the current dose will be declared to be the final dose and expansion to phase II study at dose level -1 will start immediately

If 1/3 patients have a DLT then a further 3 patients will be enrolled at the current dose level. If there are no further DLTs then the current dose will be declared to be the final dose and the phase II study will begin at dose level -1.

If >2/6 or > 2/3patients have a DLT then the study will be terminated.

For patients enrolled at dose level 2 (40mg panobinostat)

If 0/3 patients have DLTs then the current dose will be declared to be the final dose and expansion to phase II will start at 40mg.

If 1/3 patients has DLT then a further 3 patients will be enrolled to the current cohort. If there are no further DLTs then the current dose will be declared to be the final dose and the phase II study will begin at 40mg.

If there are >2/6 patients in total with DLTs then dose level 1 will be declared to be the final dose and the phase II part of the study will begin at 30mg of panobinostat.

Prior to initiation of phase II, the safety monitoring committee will review data to ensure safety. If committee approved, patients will be accrued following the completion of the phase I cohort(s). The schedule of treatment will be identical to the pilot group, whilst the dose of panobinostat will be 20mg (dose level -1), 30mg (dose level 1) or 40 mg (dose level 2) dependent on the outcome of the pilot phase.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable, dose escalation as above
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
Recruiting
Date of first participant enrolment
Anticipated
25/05/2012
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 5405 0
3002

Funding & Sponsors
Funding source category [1] 285463 0
Commercial sector/Industry
Name [1] 285463 0
Novartis Pharmaceuticals Australia Pty Limited
Country [1] 285463 0
Australia
Funding source category [2] 285459 0
Hospital
Name [2] 285459 0
Peter MacCallum Cancer Centre
Country [2] 285459 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
St Andrews Place, East Melbourne, Victoria 3002
Country
Australia
Secondary sponsor category [1] 284317 0
None
Name [1] 284317 0
Address [1] 284317 0
Country [1] 284317 0
Other collaborator category [1] 276864 0
Commercial sector/Industry
Name [1] 276864 0
Novartis Pharmaceuticals Australia Pty Limited
Address [1] 276864 0
Novartis Pharmaceuticals Australia Pty Limited
54 Waterloo Road
North Ryde NSW 2113
Country [1] 276864 0
Australia
Other collaborator category [2] 276865 0
Hospital
Name [2] 276865 0
Fremantle Hospital
Address [2] 276865 0
Fremantle Hospital
Alma Street, Fremantle,
Western Australia 6160
Country [2] 276865 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287474 0
Peter MacCallum Cancer Centre
Ethics committee address [1] 287474 0
Ethics committee country [1] 287474 0
Australia
Date submitted for ethics approval [1] 287474 0
Approval date [1] 287474 0
05/05/2011
Ethics approval number [1] 287474 0
10/90
Ethics committee name [2] 287475 0
Fremantle Hospital and Health Service
Ethics committee address [2] 287475 0
Ethics committee country [2] 287475 0
Australia
Date submitted for ethics approval [2] 287475 0
Approval date [2] 287475 0
18/08/2011
Ethics approval number [2] 287475 0
1/11/0224

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34326 0
Address 34326 0
Country 34326 0
Phone 34326 0
Fax 34326 0
Email 34326 0
Contact person for public queries
Name 17573 0
Dr Michael Dickinson
Address 17573 0
Peter MacCallum Cancer Centre
St Andrews Place, East Melbourne, Victoria 3002
Country 17573 0
Australia
Phone 17573 0
+61396561111
Fax 17573 0
Email 17573 0
Michael.Dickinson@petermac.org
Contact person for scientific queries
Name 8501 0
Dr Michael Dickinson
Address 8501 0
Peter MacCallum Cancer Centre
St Andrews Place, East Melbourne, Victoria 3002
Country 8501 0
Australia
Phone 8501 0
+61396561111
Fax 8501 0
Email 8501 0
Michael.Dickinson@petermac.org

No information has been provided regarding IPD availability


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No Supporting Document Provided


Results publications and other study-related documents

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