Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001458820
Ethics application status
Approved
Date submitted
31/08/2021
Date registered
26/10/2021
Date last updated
3/05/2022
Date data sharing statement initially provided
26/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and Tolerability of Hydroxychloroquine in Participants with Multiple Myeloma and Partial Response or Less to Carfilzomib
Scientific title
Phase I Clinical Trial to Determine Dosing Schedule of Hydroxychloroquine in Participants with Multiple Myeloma and Partial Response or Less to Carfilzomib
Secondary ID [1] 305188 0
none
Universal Trial Number (UTN)
Trial acronym
CHARMM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 323463 0
Myeloma 323464 0
Condition category
Condition code
Cancer 321016 321016 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All study participants will initially receive 2 cycles of once-weekly intravenous Carfilzomib and oral Dexamethasone as per the standard of care. During the rest period of Cycle 2, disease response assessment will be performed according to the International Myeloma Working Group (IMWG) Criteria for Response Assessment. Each cycle is 28 days.
Participants who achieve a very good partial response (VGPR) or above will continue receiving once-weekly Carfilzomib and Dexamethasone (without Hydroxychloroquine), as per the standard of care and at the discretion of the treating physician. Participants who achieve a partial response (PR) or below will undergo additional assessments before beginning treatment with oral Hydroxychloroquine and continued once-weekly Carfilzomib and Dexamethasone. The dose of Hydroxychloroquine that a participant will receive is dependent on the stage of dose-escalation: Level -1, 200 mg every other day; level 1 (starting dose) 200 mg once daily; level 2, 200 mg twice daily; level 3, 200 mg three times daily; level 4, 400 mg twice daily. The duration of combined treatment will be a maximum of 10 cycles.

Carfilzomib 20 mg/m2 will be given as the starting dose on Cycle 1 Day 1, followed by escalation to 70 mg/m2 for all subsequent doses, if tolerated. Participants will continue to receive Carfilzomib at 70 mg/m2 until treatment discontinuation.

Strategies to monitor adherence include checking patient records, medication diary and counting hydroxychloroquine tablets at the end of each cycle.
Intervention code [1] 321589 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328795 0
Incidence and severity of adverse events.
The tool to measure severity of adverse events is the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0.
Timepoint [1] 328795 0
Once every cycle till 12 months from the end of treatment.
Primary outcome [2] 329078 0
Disease response as per the International Myeloma Working Group criteria.
Timepoint [2] 329078 0
Disease response is measured based on laboratory markers collected just prior to the administration of the next cycle. It is measured every cycle or once a month till 12 months from the end of treatment.
Primary outcome [3] 329079 0
Change in heart function in participants on Hydroxychloroquine and Carfilzomib
Timepoint [3] 329079 0
ECG is performed at the start of each cycle of combined Hydroxychloroquine and Carfilzomib.
Echocardiogram is performed at cycle 2, 4 and 7 in participants on combined Hydroxychloroquine and Carfilzomib.
Secondary outcome [1] 400388 0
The outcome assessed is autophagic activity from cellular assay using blood and bone marrow biopsy samples.
Timepoint [1] 400388 0
Blood samples are collected every cycle of treatment until end of treatment. Bone marrow samples are collected a screening , after cycle 2 and 4 .

Eligibility
Key inclusion criteria
• Written informed consent given by the participant or next of kin, legal guardian or appointed public guardian
• Males and females aged greater than 18
• Disease status: Progressive multiple myeloma according to the IMWG Criteria for Response Assessment after at least one prior line of therapy and satisfies the PBS criteria for Carfilzomib treatment
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
• Left ventricular ejection fraction greater than or equal to 40%, assessed by echocardiogram or multi-gated acquisition scan
• Absolute neutrophil count greater than or equal to 1 x 109/L within 21 days prior to Cycle 1 Day 1
• Haemoglobin greater than or equal to 80 g/L within 21 days prior to Cycle 1 Day 1
• Platelet count greater than or equal to 50 x 109/L (or greater than or equal to 30 x 109/L if myeloma involvement in the bone marrow is greater than 50%), within 21 days prior to Cycle 1 day 1
• Calculated or measured creatinine clearance of greater than or equal to 15 mL/min within 21 days prior to Cycle 1 Day 1
• Adequate hepatic function within 21 days prior to Cycle 1 Day 1, with bilirubin < 1.5 times the upper limit of normal, and aspartate aminotransferase and alanine aminotransferase < 3 times the upper limit of normal.
• Female patients of child-bearing potential must have a negative serum pregnancy test within 21 days prior to Cycle 1 Day 1 and agree to use an effective method of contraception during the study and for 3 months following the last dose of drug
o Postmenopausal females (> 45 years old and without menses for > 1 year) and surgically sterilised females are exempt from any pregnancy test.
• Male patients must agree to use an effective method of contraception during the study and for 3 months following the last dose of drug
Minimum age
19 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Written informed consent not obtained
• ECOG performance status greater than or equal to 2
• Known hypersensitivity to 4-aminoquinoline compounds or Hydroxychloroquine
• Known hypersensitivity to sulfobutyl betadex sodium (a cyclodextrin used to solubilise Carfilzomib)
• G6PD deficiency
• Pre-existing maculopathy of the eye
• Currently on a clinical trial for any other anti-cancer drug or anti-myeloma chemotherapy
• Has active congestive heart failure (New York Heart Association Functional Classification of Heart Failure Class III to IV, symptomatic ischaemia or conduction abnormalities uncontrolled by conventional intervention
• Has had myocardial infarction within 4 months prior to Cycle 1 Day 1
• Prolonged QT interval on electrocardiogram
• Pre-existing proarrhythmic conditions (e.g., bradycardia < 50 bpm)
• Any history of ventricular dysrhythmia
• Uncorrected hypokalaemia and/or hypomagnesaemia
• Uncontrolled hypertension (greater than or equal to 140/90 mmHg within 21 days prior to Cycle 1 Day 1)
• Platelet count < 50 x 109/L and neutrophil count < 0.5 x 109/L (except in patients with cytopenia thought to be attributed to multiple myeloma)
• Currently pregnant or lactating
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
• Waldenstrom macroglobulinemia
• Second malignancy within the past 3 years except the following:
o Adequately treated basal cell or squamous cell skin cancer
o Carcinoma in situ of the cervix
o Prostate cancer with Gleason score < 6 and stable prostate-specific antigen over 12 months
o Breast carcinoma in situ with full surgical resection
o Treated medullary or papillary thyroid cancer
• Has myelodysplastic syndrome
• Chemotherapy with approved or investigational anticancer therapeutics within 7 days prior to screening bone marrow biopsy
• Glucocorticoid therapy (prednisolone > 30 mg/day or equivalent) within 7 days prior to screening bone marrow biopsy
• Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to screening bone marrow biopsy and Cycle 1 Day 1 (i.e., prior radiation must have been to < 30% of bone marrow)
• Immunotherapy within 21 days prior to screening bone marrow biopsy and Cycle 1 Day 1
• Major surgery (excluding kyphoplasty) within 14 days prior to screening bone marrow biopsy and Cycle 1 Day 1
• Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 7 days prior to screening bone marrow biopsy and Cycle 1 Day 1
• Known HIV seropositive, hepatitis C infection (except for patients who have had hepatitis C treatment and have cleared blood hepatitis C viral RNA) and/or hepatitis B (except for patients with hepatitis B surface antigen or core antibody receiving and responding to antiviral therapy directed at hepatitis B)
• Known cirrhosis
• Ongoing graft-vs-host disease
• Taking any prohibited concomitant medication that cannot be stopped for the duration of the study
• Any other clinically significant medical condition or psychiatric condition (in the investigator’s opinion) that may interfere with protocol adherence or a patient’s ability to give or withdraw informed consent
• Any other diseases, clinical features and laboratory abnormalities that contraindicates the use of investigational drug and /or renders the participant at high risk of complications.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The total number of participants to be recruited into this study is estimated to be between 36 to 48 participants. This estimation is not based on statistical calculations, but rather based on the dose escalation rules involved in a convention 3+3 study design, with 4 planned dose levels to be tested (200mg, 400mg, 600mg, 800mg).
A minimum of 3 participants are required to be assigned to and assessed in each dose level, with the potential for 3 additional participants to be assigned to each dose level to further evaluate toxicity.
If no additional participants are required in any dose level, a minimum of 12 participants must be recruited to fulfill all 4 dose levels. If 3 extra participants are required in each dose level, a total of 24 participants must be recruited.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/06/2022
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
36
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 20445 0
Liverpool Hospital - Liverpool
Recruitment postcode(s) [1] 35214 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 309573 0
Government body
Name [1] 309573 0
South Western Sydney Local Health District
Country [1] 309573 0
Australia
Primary sponsor type
Government body
Name
South Western Sydney Local Health District
Address
South Western Sydney Local Health District
Liverpool Hospital
Liverpool NSW 2170
Country
Australia
Secondary sponsor category [1] 310578 0
None
Name [1] 310578 0
Address [1] 310578 0
Country [1] 310578 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309349 0
Bellberry Limited
Ethics committee address [1] 309349 0
Ethics committee country [1] 309349 0
Australia
Date submitted for ethics approval [1] 309349 0
30/11/2021
Approval date [1] 309349 0
28/04/2022
Ethics approval number [1] 309349 0

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

Contacts
Principal investigator
Name 113862 0
Dr Silvia Ling
Address 113862 0
Haematology Consulting Rooms
Liverpool Hospital
Campbell Street
Liverpool Hospital
NSW 2170
Country 113862 0
Australia
Phone 113862 0
+61287385167
Fax 113862 0
+61287385176
Email 113862 0
[email protected]
Contact person for public queries
Name 113863 0
Silvia Ling
Address 113863 0
Haematology Consulting Rooms
Liverpool Hospital
Campbell Street
Liverpool Hospital
2170
Country 113863 0
Australia
Phone 113863 0
+61287385167
Fax 113863 0
+61287385176
Email 113863 0
[email protected]
Contact person for scientific queries
Name 113864 0
Silvia Ling
Address 113864 0
Haematology Consulting Rooms
Liverpool Hospital
Campbell Street
Liverpool Hospital
NSW 2170
Country 113864 0
Australia
Phone 113864 0
+61287385167
Fax 113864 0
+61287385176
Email 113864 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No individual participant data will be available as the number of participants is small and there is a risk of privacy breach


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
No additional documents have been identified.