Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000226505
Ethics application status
Approved
Date submitted
11/02/2015
Date registered
11/03/2015
Date last updated
21/01/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 2 Clinical Trial of Dichloroacetate in Plateau Phase Myeloma - DiCAM
Scientific title
In 'plateau phase' myeloma patients does 3 months of oral dichloroacetate lead to a reduction in residual disease burden as assessed by serum paraprotein or light chain levels.
Secondary ID [1] 286081 0
Nil
Universal Trial Number (UTN)
U1111-1166-4468
Trial acronym
DiCAM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Plasma Cell Myeloma (aka Multiple Myeloma) 294080 0
Condition category
Condition code
Cancer 294386 294386 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oral Dichloroacetate as the sodium salt, administered by mouth for 3 months.
Dose will be 25mg/kg twice daily loading for 3 days then reduce to 6.25mg/kg twice daily.

A single boost of 25mg/kg on day 8 will occur followed by return to maintenance dose of 6.25mg/kg twice daily.

Adherence monitoring will be by capsule count with dispensing of new medication as well as pharmacokinetic monitoring of plasma levels.
Intervention code [1] 291118 0
Treatment: Drugs
Comparator / control treatment
Nil
Control group
Uncontrolled

Outcomes
Primary outcome [1] 294232 0
Overall response rate (ORR) defined as the proportion of patients achieving at least a 25% (and 1g/L) reduction in serum paraprotein or 25% reduction in difference between involved serum light chains (at least 100mg/mL)
Timepoint [1] 294232 0
After 3 months of DCA administration
Secondary outcome [1] 312852 0
Genotyping of Glutathione S Transferase Zeta (GSTZ1) and correlation of GSTZ1 genotype with DCA pharmacokinetics in vivo

DNA will be isolated from blood samples drawn for plasma DCA levels, and GSTZ1 genotypes determined by PCR.
Plasma DCA levels will be assessed by mass spectrometry on plasma samples.
Timepoint [1] 312852 0
Multiple timepoints throughout treatment (Day 1 at 1,2,3,4,5,6 hours post dose, Day 2 trough, Day 8 trough and at 1,2,3,4,5,6 hours, Day 28 trough, Day 56 trough and Day 84 trough)

Eligibility
Key inclusion criteria
*Diagnosis of Plasma Cell Myeloma (at any time) according to WHO criteria
*Aged 18 years or older
*Eastern Co- operative Oncology Group Performance status less than 2
*Life expectancy due to myeloma or co- morbid conditions in the opinion of the treating physician likely to exceed 3 months

AND

* has measurable residual disease i.e.
**Quantifiable serum paraprotein on electrophoresis at least 1g/L OR
**Elevated free kappa (>21mg/L) or lambda light chains (>30mg/L) AND a minimum difference between level of involved/uninvolved light chain of 150mg/L AND an abnormal serum free light chain ratio (normal range = 0.26-1.26)
AND
* is in a ‘Plateau- Phase’ i.e.
** A period of neither progression nor response at least 28 days following the last change in myeloma treatment
**Progression defined as per IWMG

*an increase in the paraprotein by >= 25% and at least 5g/L

*In light chain only patients, >25% increase in difference between involved and uninvolved light chain level, with an absolute increase of >0.1g/L

*development of new lytic lesions

*development of new end organ damage (Renal disease, marrow failure, lytic lesions, hypercalcaemia) attributable to myeloma or new plasmacytomas

**Response defined as reduction in the paraprotein by at least 25% OR in the case of light chain only myeloma, at least 25% decrease in the difference between the involved and uninvolved light chain and an absolute reduction of at least 100mg/L.

* Blood samples to assess for plateau phase must be at least 28 days apart
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
*Unable to give informed consent
*Non-secretory myeloma
*Receipt of any active anti-myeloma therapy (excluding bisphosphonates) in the 16 weeks prior to enrolment, with the exception that patients on stable doses of long- term maintenance therapy will be allowed (no dose alteration in the prior 8 weeks).

*Pregnant or breastfeeding
*Unwilling to avoid pregnancy and use birth control (if applicable) during the study and for 4 weeks after completion of the study
*Unable to swallow capsules
*Major surgery within the last 28 days
*Enrolled in another trial or have discontinued from another clinical trial within the last 14 days
*Any serious pre-existing medical condition that, in the opinion of the study doctor would keep you from being on this trial
*Any peripheral motor or sensory neuropathy, neuralgia or paraesthesia (of grade 3 or worse)
*Any pre-existing severe ataxia or tremor (grade 3 or worse)
*Known history of liver disease (cirrhosis established by imaging studies or biopsy) or abnormal liver function tests within the last 14 days (AST or ALT > 3 x ULN or ALP >2.5 x ULN or total bilirubin > 1.5 x ULN)
*Any more than moderate renal impairment i.e. Calculated Creatinine Clearance by Cockcroft Gault formula of greater than or equal to 30 mL/min
*Inadequate cardiac function defined as:
**Electrocardiographic (ECG) evidence of
***Acute ischemia
***Active clinically significant conduction system abnormalities
***>Grade 2 (>480 ms) (QTc) prolongation
***Uncontrolled angina or severe ventricular arrhythmias
***Myocardial infarction within the last 6 months
***Class 3 or higher New York Heart Association Congestive Heart Failure

*Haematological
**Haemoglobin < 80g/L
**Absolute Neutrophil Count (ANC) less than 1.0 x 10^9/L
**Platelet Count less than 50 x 10^9/L
*Any active fungal, bacterial and/or known active viral infection including HIV or hepatitis (A, B, or C).
*A second malignancy which in the opinion of the investigator may affect the interpretation of results

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)
Referred patients will be consented and screened for suitability. All patients will be allocated in an unblinded fashion to study drug.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Simons minimax 2 stage design
- initial recruitment & evaluation of 15 patients for treatment response.

Recruitment of a further 10 participants only if first cohort shows evidence of efficacy.
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
A Simon’s Mini-max 2-stage design will be used to conduct the trial. This trial design will optimise safety by exposing fewer patients to a potentially inactive treatment.
With this study design a total of 25 patients are needed to achieve 80% power with an alpha of 0.05.
The null hypothesis is that <10% of patients respond to the DCA i.e. H0: patients achieving ORR < 10% of study participants.
The alternative hypothesis is that at least 30% of patients will have a response to the DCA: Ha: patients achieving ORR = 30% of study participants
The decision to terminate the study and reject the drug after the first stage of the study will be based on the number of responses observed. If at least 1 of the first 15 evaluable patients in stage 1 achieve a response as defined above, the study will continue to stage 2 until a total of 25 evaluable patients have been recruited.
If in the final analysis more than 5 patients have an ORR then the null hypothesis will be rejected i.e. confirming evidence of the efficacy of DCA in deepening responses in plateau phase patients.
The primary efficacy analysis of ORR will be performed when the required number of evaluable patients has been enrolled. The study population is defined as all registered patients who have received at least 12 weeks of treatment. A final evaluation of the proportion of patients achieving ORR will be calculated and a corresponding 95% CI reported.
The expected enrolment period is 12 months. To account for potential non-adherence or early dropout, we envisage that up to an additional 5 patients may be enrolled in the first stage and that these additional enrolments may continue, only until such time as 15 patients have successfully completed the 3 month exposure to the study drug. Once the first 15 patients have completed this treatment period, no further enrolment will occur until the initial efficacy analysis is complete.


Simple descriptive statistics will be used to measure efficacy (proportion of patients achieving a response).

Secondary analyses of response according to myeloma characteristics (cytogenetics where available, prior treatment type etc) will also occur

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
16/03/2015
Actual
28/05/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
25
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT
Recruitment hospital [1] 3438 0
The Canberra Hospital - Garran
Recruitment postcode(s) [1] 9205 0
2605 - Garran

Funding & Sponsors
Funding source category [1] 290725 0
Government body
Name [1] 290725 0
The Canberra Hospital Private Practice Fund
Country [1] 290725 0
Australia
Primary sponsor type
Hospital
Name
Department of Haematology - Capital Region Cancer Services- The Canberra Hospital
Address
Capital Region Cancer Services Building
Level 5

Yamba Dr, GARRAN ACT 2602
Country
Australia
Secondary sponsor category [1] 289416 0
None
Name [1] 289416 0
Address [1] 289416 0
Country [1] 289416 0
Other collaborator category [1] 278344 0
Individual
Name [1] 278344 0
Dr Anneke Blackburn
Address [1] 278344 0
Cancer Metabolism and Genetics Group
Department of Cancer Biology and Therapeutics
John Curtin School of Medical Research Building 131, Garran Rd
Australian National University, PO Box 334, Canberra ACT 0200
AUSTRALIA
Country [1] 278344 0
Australia
Other collaborator category [2] 278356 0
Individual
Name [2] 278356 0
Dr Lucy Coupland
Address [2] 278356 0
Post-Doctoral Researcher
Cancer & Vascular Biology Group,
The John Curtin School of Medical Research, Building 131, Garran Rd,
ACTON ACT 2601


Country [2] 278356 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292362 0
ACT Health Human Research Ethics Committe (HREC)
Ethics committee address [1] 292362 0
Ethics committee country [1] 292362 0
Australia
Date submitted for ethics approval [1] 292362 0
Approval date [1] 292362 0
17/09/2014
Ethics approval number [1] 292362 0
ETH 7.14.166

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 307 307 0 0
/AnzctrAttachments/367868-DiCAM Protocol - Version 1 0.docx
Attachments [2] 308 308 0 0
/AnzctrAttachments/367868-12 10 - eth 7 14 166 - Bennett - oos approval (2).pdf

Contacts
Principal investigator
Name 54530 0
Dr Samuel Bennett
Address 54530 0
Haematology Department
Capital Region Cancer Services

Yamba Dr, GARRAN ACT 2602
Country 54530 0
Australia
Phone 54530 0
+61 2 6174 8547
Fax 54530 0
Email 54530 0
[email protected]
Contact person for public queries
Name 54531 0
Samuel Bennett
Address 54531 0
Haematology Department
Capital Region Cancer Services

Yamba Dr, GARRAN ACT 2602
Country 54531 0
Australia
Phone 54531 0
+61 2 6174 8547
Fax 54531 0
Email 54531 0
[email protected]
Contact person for scientific queries
Name 54532 0
Anneke Blackburn
Address 54532 0
Cancer Metabolism and Genetics Group
Department of Cancer Biology and Therapeutics
John Curtin School of Medical Research
Building 131, Garran Rd.
Australian National University
Acton ACT 2601
AUSTRALIA
Country 54532 0
Australia
Phone 54532 0
+61 2 6125 4710
Fax 54532 0
+61 2 6125 4712
Email 54532 0
[email protected]

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

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AILong-term stabilization of stage 4 colon cancer using sodium dichloroacetate therapy2016https://doi.org/10.12998/wjcc.v4.i10.336
Dimensions AILong-term stabilization of metastatic melanoma with sodium dichloroacetate2017https://doi.org/10.5306/wjco.v8.i4.371
EmbaseGSTZ1 genotypes correlate with dichloroacetate pharmacokinetics and chronic side effects in multiple myeloma patients in a pilot phase 2 clinical trial.2019https://dx.doi.org/10.1002/prp2.526
N.B. These documents automatically identified may not have been verified by the study sponsor.