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Trial registered on ANZCTR


Registration number
ACTRN12618000053224
Ethics application status
Approved
Date submitted
15/12/2017
Date registered
16/01/2018
Date last updated
12/09/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Early phase II study of Azacitidine and Carboplatin priming for Avelumab in patients with advanced melanoma who are resistant to immunotherapy.
Scientific title
PRIME002: Early phase II study of Azacitidine and Carboplatin priming for Avelumab in patients with advanced melanoma who are resistant to immunotherapy.
Secondary ID [1] 293618 0
Nil known
Universal Trial Number (UTN)
U1111-1206-6838
Trial acronym
PRIME002
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic melanoma 305885 0
Immunotherapy resistant 305886 0
Condition category
Condition code
Cancer 305080 305080 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
First month- Azacitidine 40mg/m2 Intravenous Injection (IVI)/day for 5 days (Day 1-Day 5) followed by Carboplatin AUC 5 IVI on Day 8; Week 3 and Week 4- no treatment

Second month- repeat above starting at Week 5, Day 29

Third to sixth months – Avelumab 10mg/kg every 2 weeks for 6 cycles (12 weeks) IVI/day on Day 1 of each cycle followed by biopsies and RECIST 1.1 criteria assessment 3 months after starting Avelumab.

Sixth month until disease progression, patient withdrawal or death – Avelumab 10mg/kg IVI/day on Day 1 of each 14 day cycle. Treatment will be stopped if there is disease progression according to immune response criteria.



All doses administered and logged on site by study staff.
Intervention code [1] 299880 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 304261 0
Quantify response as complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1
Timepoint [1] 304261 0
Week 9 - after 2 cycles of azacitidine/carboplatin;
Primary outcome [2] 304410 0
Quantify response as complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1
Timepoint [2] 304410 0
Week 22 - after 6 cycles of immunotherapy (Avelumab)
Primary outcome [3] 304411 0
Determine overall response rate (ORR) according to RECIST 1.1
Timepoint [3] 304411 0
Week 9 - after 2 cycles of azacitidine/carboplatin;
Week 22 - after 6 cycles of immunotherapy (Avelumab)
Secondary outcome [1] 341392 0
Tumour biopsy will be used for analysis of DNA methylation whole genome bisulfite sequencing or ELISA assays
Timepoint [1] 341392 0
Week -2: baseline before treatment biopsy
Week 9: after 2 cycles of azacitidine/carboplatin
Week 22: after 6 cycles of Avelumab
Secondary outcome [2] 341393 0
Blood collected will be tested for immune activation profile using custom designed flow cytometry assays. All data will be tested before and after treatment using paired t-test with Bonferroni correction.
Timepoint [2] 341393 0
Week -2: baseline before treatment
Week 9: after 2 cycles of azacitidine/carboplatin
Every 2 weeks from week 10 onwards: with every administration of Avelumab
Secondary outcome [3] 341395 0
Safety assessment for azacitidine/carboplatin using National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) grades for hematological or renal toxicity, nausea, constipation, fatigue, anorexia, diarrhoea, vomiting and dizziness and any other adverse event.
Timepoint [3] 341395 0
Week 1, 2, 5, 6, 9: assessment of adverse events related to azacitidine/carboplatin
Secondary outcome [4] 341873 0
Blood collected will be tested for INF gamma signature using custom designed flow cytometry assays. All data will be tested before and after treatment using paired t-test with Bonferroni correction.
Timepoint [4] 341873 0
Week -2: baseline before treatment
Week 9: after 2 cycles of azacitidine/carboplatin
Every 2 weeks from week 10 onwards: with every administration of Avelumab
Secondary outcome [5] 341874 0
Immune-response markers will be assessed in tumour biopsies using standard immunohistochemistry. All data will be tested before and after treatment using paired t-test with Bonferroni correction
Timepoint [5] 341874 0
Week -2: baseline before treatment biopsy
Week 9: after 2 cycles of azacitidine/carboplatin
Week 22: after 6 cycles of Avelumab
Secondary outcome [6] 341875 0
Tumour biopsy will be used for analysis of XPC mRNA by qPCR and protein levels by immunohistochemistry.
Timepoint [6] 341875 0
Week -2: baseline before treatment biopsy
Week 9: after 2 cycles of azacitidine/carboplatin
Week 22: after 6 cycles of Avelumab
Secondary outcome [7] 341884 0
Safety assessment for avelumab using National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) grades for infusion-related reactions, hematological, renal, cardiac or hepatic toxicity, diarrhea/colitis, rash, pneumonitis, endocrinopathy and any other adverse event.
Timepoint [7] 341884 0
Week 10 and every 2 weeks onwards until disease progression, withdrawal from study or death

Eligibility
Key inclusion criteria
• Unresectable or metastatic melanoma
• Primary resistance to previous anti-PD1 immunotherapy
• Male or Female subjects aged>= 18 years
• Before study enrolment written informed consent to participate in the trial must be given according to ICH/GCP and national/local regulations
• Adequate haematological function defined by absolute neutrophil count (ANC) > 1.5 x 109/L, platelet count) > 100 x 109/L, and haemoglobin) > 9g/dL (may have been transfused)
• Adequate hepatic function defined by a total bilirubin level <1.5 x the upper limit of normal (ULN) range and AST and ALT levels <2.5 x ULN for all subjects
• Adequate renal function defined by an estimated creatinine clearance of greater than 30mL/min according to the Cockcroft-Gault formula or local institutional method
• Tumour material is mandatory for subcutaneous or lymph node disease - tumour tissue selected must not be previously irradiated; treatment should start only after complete wound healing from surgery
• Disease status before first treatment should be documented by full CT scan of chest, abdomen and pelvis and MRI brain. PET scans will also be done before first treatment to help with monitoring disease response in subcutaneous/ lymph node metastases
• BRAF mutation status
• ECOG Performance Status 0,1,2
• Patient is not currently participating and receiving study therapy or has not participated in a study of an investigational agent and received study therapy or used and investigation device within 4 weeks prior to first dose of treatment
• Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the first dose of study treatment
• Effective contraception for both male and female subjects if the risk of conception exists (Note: The effects of the trial drug on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use effective contraception, defined as 2 barrier methods, or 1 barrier method with a spermicide, an intrauterine device, or use of oral
• female contraceptive. Effective contraception must be used 30 days prior to first trial drug administration, for the duration of trial participation, and at least for 30 days after stopping trial participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately.
• [For female participants] If you do become pregnant whilst participating in the research project, you should advise your study doctor immediately. Your study doctor will withdraw you from the research project and advise on further medical attention should this be necessary. You must not continue in the research if you become pregnant.
• [For male participants] You should advise your study doctor if you father a child while participating in the research project. Your study doctor will advise on medical attention for your partner should this be necessary.
• Female patients who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 120 days after the last dose of the study drug
• Aboriginal Torres Strait Islander patients must be offered the option of having the Aboriginal Liaison Officer or a friend/relative be present during consenting process
• Patients with a primary language other than English must be offered an interpreter during the consenting process.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Mucosal or ocular melanoma
• All subjects with brain metastases, except those meeting the following criteria:
- Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment
- No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
- Subjects must be either off steroids or on a stable or decreasing dose of <10mg daily prednisone (or equivalent)
• Prior organ transplantation, including allogenic stem-cell transplantation
• Diagnosis of immunodeficiency
• History of HIV; positive test for HBV surface antigen and/or confirmatory HCV RNA (if anti-HCV antibody tested positive) or any other significant acute or chronic infections
• Systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
- Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
- Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses 10 mg equivalent prednisone per day
- Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
• Known severe hypersensitivity reactions to monoclonal antibodies (Grade >3 NCI-CTCAE v4.03), any history of anaphylaxis, or uncontrolled asthma (3 or more features of partially controlled asthma)
• Persisting toxicity related to prior therapy of Grade>1 NCI-CTCAE v 4.03, alopecia and sensory neuropathy Grade <2 is acceptable
• Active infections requiring systemic therapy
• Significant cardiovascular disease i.e uncontrolled hypertension/angina/heart failure/arrhythmias
• History of immune related toxicity to previous immunotherapy of grade 2 or higher except endocrinology related toxicity that is treated and stable and on replacement therapy for adrenal, pituitary or thyroid deficiency (thyroxine, insulin or physiologic corticosteroid therapy allowed). Subjects requiring hormone replacement with corticosteroids are eligible if the steroid are administered only for the purpose of hormonal replacement and at doses less or equal to 10 mg or 10 mg equivalent prednisone per day. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) are acceptable
• Patients who received treatment with live vaccines within 30 days prior to first dose of study medication
• History of hematologic or primary solid tumour malignancy, unless no evidence of that disease for 3 years
• Pregnancy or lactation
• Known alcohol or drug use
• Any psychiatric condition that would prohibit the understanding or rendering of informed consent
• Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines

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
Initial recruitment (Stage 1): 10 patients will be recruited initially to assess objective response rate (ORR) and adverse events. If a favourable or stable ORR is detected in the first 10 patients and there are minimal grade 4 or persistant grade 3 adverse events, the trial will expand to recruit 30 patients (Stage 2).
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
• Objective response rate (ORR): The ORR is defined as the proportion of patients with tumour size reduction of 10% after onset of treatment until documented tumour progression. ORR will be calculated using RECIST scores at weeks -1, 9 and 22.
• Before-after study (paired t-test): RECIST scores will undergo paired t-test analysis to determine statistical differences in response based on tumour size. The results of the before-after study will be used to calculate the sample size for a large multi-centre Phase 2 trial.
• Waterfall plot of Tumor Shrinkage: Waterfall plot is a data visualization technique that depicts tumor shrinkage that is the best observed % change of sum of target lesions from baseline.
• Overall survival: Will be calculated at each RECIST data collection point (weeks -1, 9 and 22) and every 6 months until study completion. Overall survival will be calculated as the time from initiation of the trial treatment to death from any cause. Kaplin-Meier plots for sub-groups based on secondary outcome data will be generated every 6 months for the duration of the study.
• Secondary outcomes: All data for secondary outcomes will be tested before and after treatment using paired t-test with Bonferroni correction.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 9571 0
Calvary Mater Newcastle - Waratah
Recruitment postcode(s) [1] 18325 0
2298 - Waratah

Funding & Sponsors
Funding source category [1] 298230 0
Charities/Societies/Foundations
Name [1] 298230 0
Ramaciotti Foundation
Address [1] 298230 0
Perpetual Trustees
GPO Box 4171, Sydney NSW 2001
Country [1] 298230 0
Australia
Funding source category [2] 298234 0
Charities/Societies/Foundations
Name [2] 298234 0
Hunter Medical Research Institute
Address [2] 298234 0
Lot 1, Kookaburra Cct
New Lambton Heights NSW 2308
Country [2] 298234 0
Australia
Primary sponsor type
Hospital
Name
Calvary Mater Hospital Newcastle
Address
Edith Street, Waratah NSW 2298. Australia
Country
Australia
Secondary sponsor category [1] 297352 0
None
Name [1] 297352 0
Address [1] 297352 0
Country [1] 297352 0
Other collaborator category [1] 279870 0
University
Name [1] 279870 0
University of Newcastle
Address [1] 279870 0
University Dr, Callaghan, NSW 2304
Country [1] 279870 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299239 0
North Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 299239 0
Research Office
Level 13, Kolling Building
Royal north Shore Hospital
St Leonards, NSW, 2065
Ethics committee country [1] 299239 0
Australia
Date submitted for ethics approval [1] 299239 0
Approval date [1] 299239 0
13/10/2017
Ethics approval number [1] 299239 0
RESP/17/43

Summary
Brief summary
This is a study of two medications that may increase the sensitivity of metastatic melanomas to a currently used immunotherapy.

Who is it for?
You may be eligible for this study if you are 18 years or older and have an unresectable or metastatic melanoma which has primary resistance to previous immunotherapy (anti-PD1 therapy).

Study details
All participants in the study will receive a course of the two study drugs (azacitidine and carboplatin) for 8 weeks, before a ongoing course of immunotherapy (avelumub). Over the course of the study, blood samples and tumour biopsies will be taken to assess the treatment’s effect on the melanoma.

It is hoped this study will provide evidence of these study substances increasing the sensitivity of melanomas to the anti-PDL1 antibody class of immunotherapy agents.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 79766 0
Dr Andre van der Westhuizen
Address 79766 0
Medical Oncology and Newcastle Melanoma Unit
Calvary Mater Newcastle
Edith Street, Waratah NSW 2298. Australia
Country 79766 0
Australia
Phone 79766 0
+61249211561
Fax 79766 0
Email 79766 0
andre.vanderwesthuizen@calvarymater.org.au
Contact person for public queries
Name 79767 0
A/Prof Nikola Bowden
Address 79767 0
Hunter Medical Research Institute
Lot 1 Kookaburra Circuit
New Lambton Heights, NSW 2308
Country 79767 0
Australia
Phone 79767 0
+61240420277
Fax 79767 0
Email 79767 0
nikola.bowden@newcastle.edu.au
Contact person for scientific queries
Name 79768 0
A/Prof Nikola Bowden
Address 79768 0
Hunter Medical Research Institute
Lot 1 Kookaburra Circuit
New Lambton Heights, NSW 2308
Country 79768 0
Australia
Phone 79768 0
+61240420277
Fax 79768 0
Email 79768 0
nikola.bowden@newcastle.edu.au

No information has been provided regarding IPD availability
Summary results
No Results