ANZCTR - Registration

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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

23/11/2022

Date data sharing statement initially provided

18/11/2021

Date results information initially provided

18/11/2021

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]

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

Immunotherapy resistant

Condition category

Condition code

Cancer

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]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Quantify response as complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1

Timepoint [1]

Week 9 - after 2 cycles of azacitidine/carboplatin;

Primary outcome [2]

Quantify response as complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1

Timepoint [2]

Week 22 - after 6 cycles of immunotherapy (Avelumab)

Primary outcome [3]

Determine overall response rate (ORR) according to irRECIST

Timepoint [3]

Week 9 - after 2 cycles of azacitidine/carboplatin;
Week 22 - after 6 cycles of immunotherapy (Avelumab)

Secondary outcome [1]

Tumour biopsy will be used for analysis of DNA methylation whole genome bisulfite sequencing or ELISA assays

Timepoint [1]

Week -2: baseline before treatment biopsy
Week 9: after 2 cycles of azacitidine/carboplatin
Week 22: after 6 cycles of Avelumab

Secondary outcome [2]

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]

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]

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]

Week 1, 2, 5, 6, 9: assessment of adverse events related to azacitidine/carboplatin

Secondary outcome [4]

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]

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]

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]

Week -2: baseline before treatment biopsy
Week 9: after 2 cycles of azacitidine/carboplatin
Week 22: after 6 cycles of Avelumab

Secondary outcome [6]

Tumour biopsy will be used for analysis of XPC mRNA by qPCR and protein levels by immunohistochemistry.

Timepoint [6]

Week -2: baseline before treatment biopsy
Week 9: after 2 cycles of azacitidine/carboplatin
Week 22: after 6 cycles of Avelumab

Secondary outcome [7]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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 40 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

Stopped early

Data analysis

Data analysis is complete

Reason for early stopping/withdrawal

Participant recruitment difficulties

Date of first participant enrolment

Anticipated

1/02/2018

Actual

22/03/2018

Date of last participant enrolment

Anticipated

31/12/2019

Actual

11/01/2021

Date of last data collection

Anticipated

28/05/2023

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD

Recruitment hospital [1]

Calvary Mater Newcastle - Waratah

Recruitment hospital [2]

Cairns Base Hospital - Cairns

Recruitment postcode(s) [1]

2298 - Waratah

Recruitment postcode(s) [2]

4870 - Cairns

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Ramaciotti Foundation

Address [1]

Perpetual Trustees
GPO Box 4171, Sydney NSW 2001

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Hunter Medical Research Institute

Address [2]

Lot 1, Kookaburra Cct
New Lambton Heights NSW 2308

Country [2]

Australia

Funding source category [3]

Commercial sector/Industry

Name [3]

Merck KGaA

Address [3]

Frankfurter Str. 250, 64293 Darmstadt, Germany

Country [3]

Germany

Primary sponsor type

University

Name

University of Newastle

Address

University Dr, Callaghan, NSW, 2308 Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

North Sydney Local Health District Human Research Ethics Committee

Ethics committee address [1]

Research Office
Level 13, Kolling Building
Royal north Shore Hospital
St Leonards, NSW, 2065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

13/10/2017

Ethics approval number [1]

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

Dr Andre van der Westhuizen

Address

Medical Oncology and Newcastle Melanoma Unit
Calvary Mater Newcastle
Edith Street, Waratah NSW 2298. Australia

Country

Australia

Phone

+61249211561

Fax

[email protected]

Contact person for public queries

Name

A/Prof Nikola Bowden

Address

Hunter Medical Research Institute
Lot 1 Kookaburra Circuit
New Lambton Heights, NSW 2308

Country

Australia

Phone

+61240420277

Fax

[email protected]

Contact person for scientific queries

Name

A/Prof Nikola Bowden

Address

Hunter Medical Research Institute
Lot 1 Kookaburra Circuit
New Lambton Heights, NSW 2308

Country

Australia

Phone

+61240420277

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Study results article	Yes		Published July 27, 2022 Andre van der Westhuize... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Retreatment with immune checkpoint inhibitors in solid tumors: a systematic review.	2020	https://dx.doi.org/10.1177/1758835920975353
Embase	Interrogating epigenome toward personalized approach in cutaneous melanoma.	2021	https://dx.doi.org/10.3390/jpm11090901
Dimensions AI	Sequential azacitidine and carboplatin induces immune activation in platinum-resistant high-grade serous ovarian cancer cell lines and primes for checkpoint inhibitor immunotherapy	2022	https://doi.org/10.1186/s12885-022-09197-w
Dimensions AI	1374TiP PRIME002: Early phase II study of azacitidine and carboplatin priming for avelumab in patients with advanced melanoma who are resistant to immunotherapy	2019	https://doi.org/10.1093/annonc/mdz255.062
Dimensions AI	1375TiP Pembrolizumab (pembro) plus lenvatinib (len) for first-line treatment of patients (pts) with advanced melanoma: Phase III LEAP-003 study	2019	https://doi.org/10.1093/annonc/mdz255.063
Dimensions AI	1376TiP Proof of concept study with the histone deacetylase inhibitor vorinostat in patients with resistant BRAFV600 mutated advanced melanoma	2019	https://doi.org/10.1093/annonc/mdz255.064
Dimensions AI	1373TiP ILLUMINATE 301: A randomized phase III study of tilsotolimod in combination with ipilimumab compared with ipilimumab alone in patients with advanced melanoma following progression on or after anti-PD-1 therapy	2019	https://doi.org/10.1093/annonc/mdz255.061

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically