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Trial registered on ANZCTR


Registration number
ACTRN12621001155886
Ethics application status
Approved
Date submitted
28/06/2021
Date registered
27/08/2021
Date last updated
18/01/2024
Date data sharing statement initially provided
27/08/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase Ib/II study of Azacitidine and Carboplatin priming for Ipilimumab and
Nivolumab re-challenge in patients with advanced melanoma who are
resistant to immunotherapy.
Scientific title
Phase Ib/II study of safety and clinical response to Azacitidine and Carboplatin priming for Ipilimumab and Nivolumab re-challenge in patients with advanced melanoma who are
resistant to immunotherapy.
Secondary ID [1] 303210 0
CA184-602
Universal Trial Number (UTN)
U1111-1262-7878
Trial acronym
PRIME005
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Melanoma 320350 0
Condition category
Condition code
Cancer 318262 318262 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stage 1 of PRIME005 consisted of continuously administered cycles of the following:

Cycles 1 & 2 - oral Azacitidine (200mg or 300mg) daily on days 1-14 and intravenous injection (IVI) Carboplatin AUC 4.5 on day 8 or day 15 over 6 weeks followed by

Cycles 3 & 4 - oral Azacitidine (200mg or 300mg) daily on days 1-14 and IVI Carboplatin AUC 4.5 on day 8 or day 15 with Ipilimumab injection (1mg/kg) and Nivolumab injection (360mg) on day 15 for 6 weeks.

Cycles 5 & 6 - Ipilimumab injection (1mg/kg) and Nivolumab injection (360mg) will be given in combination on day 1 of 21 day cycles.

Maintenance Ipilimumab (every 6 weeks) and Nivolumab (every 3 weeks) will continue for 24 months or until disease progression by iRECIST unless the clinician believes that there is a clinical benefit to continue treatment beyond iRECIST progression and there is no unacceptable toxicity resulting from the treatment.

Participants enrolled in Stage 1 were allocated by the Trial Coordinating Centre to epigenetic and chemotherapy priming at one of the following doses:
Dose 1: 200mg oral Azacitidine daily D1-14 followed by Carboplatin AUC 4 IVI on Day 15
Dose 2: 300mg oral Azacitidine daily D1-14 followed by Carboplatin AUC 4 IVI on Day 8
Dose 3: 300mg oral Azacitidine daily D1-14 followed by Carboplatin AUC 4 IVI on Day 15

Stage 2 (Phase II): Participants will receive epigenetic and chemotherapy priming at the Recommended Phase 2 Dose (RP2D) from Stage 1 of 40mg/m2 azacitidine IVI

Cycles 1 & 2 - Azacitidine (40mg/m2 intravenous injection (IVI)) daily on days 1-5 and IVI Carboplatin AUC 4.5 on day 8 over 6 weeks followed by

Cycles 3 & 4 - Azacitidine (40mg/m2) daily on days 1-5 and IVI Carboplatin AUC 4.5 on day 8 with Ipilimumab injection (1mg/kg) and Nivolumab injection (360mg) on day 15 for 6 weeks.

Cycles 5 & 6 - Ipilimumab injection (1mg/kg) and Nivolumab injection (360mg) will be given in combination on day 1 of 21 day cycles.

Maintenance Ipilimumab (every 6 weeks) and Nivolumab (every 3 weeks) will continue for 24 months or until disease progression by iRECIST unless the clinician believes that there is a clinical benefit to continue treatment beyond iRECIST progression and there is no unacceptable toxicity resulting from the treatment.
Intervention code [1] 319517 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 326244 0
Quantify clinical benefit rate (CBR) using a composite of complete response (CR), partial response (PR) and stable disease (SD)


Timepoint [1] 326244 0
Week 6 & 12 (after 2 and 4 cycles of priming according to RECIST 1.1) and;

Week 12 and 20 (after 2 and 4 cycles of immunotherapy induction according to iRECIST criteria).
Primary outcome [2] 328068 0
Dose-limiting toxicity (DLT) will be determined by the lead Lead Investigator at each visit (using CTCAE v5). DLT is defined as:
- Grade 4 neutropenia lasting >7 days or accompanied by fever
- Grade 3 thrombocytopenia with clinically significant bleeding
- Failure to meet hematologic criteria for starting cycle 2 within 7 days.
- Any non-hematologic adverse event (AE) of grade > 3 that is related to oral azacitidine or to
the combination treatment, except for alopecia, emesis, or diarrhea that responds to clinical
management within 72 hours and non-symptomatic laboratory abnormalities that are not
medically significant.
- Death related to the investigational products (IP).
Timepoint [2] 328068 0
Week 6 - after 2 cycles of oral azacitidine and carboplatin
Primary outcome [3] 328254 0
Calculate Overall Response Rate (ORR) using a composite of CR and PR.
Timepoint [3] 328254 0
Week 6 & 12 (after 2 and 4 cycles of priming according to RECIST 1.1) and;

Week 12 and 20 (after 2 and 4 cycles of immunotherapy induction according to iRECIST criteria).
Secondary outcome [1] 390719 0
The safety profile for epigenetic and chemotherapy priming, immunotherapy induction and
immunotherapy maintenance will be determined by calculating the incidence and recording
the severity of treatment-related adverse events through the clinician-reported CTCAE and
the patient reported Edmonton Symptom Assessment Scale through the Patient Diary.
Timepoint [1] 390719 0
Day 1, 12 and 15 of cycles 1-4 followed by day 1 of cycle 5 onwards until study completion.
Secondary outcome [2] 390720 0
Progression-Free Survival (PFS) in the intent to treat population
Timepoint [2] 390720 0
6 months after first patient in (Day 1, Cycle 1) followed by every 6 months until study completion.
Secondary outcome [3] 390721 0
Overall Survival (OS) in the intent to treat population
Timepoint [3] 390721 0
6 months after first patient in (Day 1, Cycle 1) followed by every 6 months until study completion.
Secondary outcome [4] 390723 0
HLA-A expression (IHC) and methylation of the HLA locus composite analysis in tumour biopsies
Timepoint [4] 390723 0
Baseline, week 6 and week 20
Secondary outcome [5] 390724 0
Immune-response marker (e.g.: PDL-1, PD-1, CD4/CD8, CD68 and HLA-A) levels in blood, tumour and microenvironment.
Timepoint [5] 390724 0
baseline and after: 2 cycles of priming (1 cycle = Azacitidine 40mg/m2 IVI for 5 days followed by Carboplatin AUC 4.5 on Day 8 of 21 day cycle) and; 4 cycles of immunotherapy induction (1 cycle = Ipilimumab 1mg/kg and Nivolumab 360mg on day 1/21 day cycle)
Secondary outcome [6] 399973 0
Pharmacodynamics (PD) from blood assessed by average change in global DNA methylation levels at each timepoint.
Timepoint [6] 399973 0
Baseline, day 1 (30 minutes to 1 hour after dose taken) and day 12 (30minutes to 1 hour after dose taken) of cycles 1-4.

Eligibility
Key inclusion criteria
- Written informed consent to participate in the trial must be given according to ICH GCP and national/local regulations
- Male or Female subjects >= 18 years
- Unresectable or metastatic melanoma
- BRAF mutations status
- ECOG Performance status 0, 1, 2
- Must have failed previous CPI immunotherapy with a combination of anti-PD1 and anti CTLA4 antibodies according to immune response criteria in the BRAF wild type population
OR
- Must have failed previous CPI immunotherapy with a combination of anti- PD1 and anti-CTLA4 antibodies according to immune response criteria as well as targeted therapy with BRAF and MEK inhibitors in the BRAF mutated population
- Patients with asymptomatic brain metastasis are eligible provided they have remained stable for 2 weeks prior to enrolment
- Patients with symptomatic brain metastases are eligible if their brain metastasis have been treated locally and if they are clinically stable for at least 2 weeks prior to enrolment- clinical stability of brain metastasis include the following two criteria:
1. Minimally symptomatic, requiring the equivalent of <= 4 mg dexamethasone daily for at least 7 days prior to enrolment (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
2. Patients that are borderline and not considered for further steroid taper at the start of study enrollment should be discussed with the overall principal investigator/medical monitor of the study before enrollment
- Adequate haematological function defined by absolute neutrophil count (ANC) >=1.0 x 10^9/L, platelet count >= 100 x 10^9/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 >=3 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
- Disease status before first treatment should be documented by full CT scan of chest, abdomen and pelvis and MRI Brain.
- Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the first dose of study treatment
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Uveal melanoma
- Prior organ transplantation, including allogeneic stem-cell transplantation
- Diagnosis of immunodeficiency
- Diagnosis 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
- Patient currently participating or receiving any study therapy or participating in a study of an investigational agent and received study therapy or used an investigational device within 3 weeks prior to the first dose of treatment
- Systemic steroid therapy >30mg/day prednisone equivalent or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study treatment
- Active autoimmune disease that might deteriorate when receiving a CPI at the discretion of the investigator
- Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment or that are well controlled are eligible
- Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered for the purpose of hormonal replacement and at doses <= 30 mg or 30 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
- Significant cardiovascular disease i.e., uncontrolled hypertension/angina/heart failure/arrhythmias, that require a significant change in systemic treatment to stabilize the cardiovascular disease.
- History of immune-related toxicity to previous CPI immunotherapy is not an exclusion criteria provided patients do not have persisting/ active toxicities that are uncontrolled and clinically relevant at the time of enrolment and at the discretion of the investigator.

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 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Stage 1: Primary Outcome Statistical analysis plan:
1. Any of the following occurring after 2 cycles of epigenetic and chemotherapy priming for each participant to be used for calculation of rate of dose-limiting toxicity (DLT).
- Grade 4 neutropenia lasting >7 days or accompanied by fever
- Grade 3 thrombocytopenia with clinically significant bleeding
- Failure to meet hematologic criteria for starting cycle 2 within 7 days.
- Any non-hematologic adverse event (AE) of grade > 3 that is related to oral azacitidine or to the combination treatment, except for alopecia, emesis, or diarrhea that responds to clinical management within 72 hours and non-symptomatic laboratory abnormalities that are not medically significant.
- Death related to the investigational products (IP).
The rate of DLT will be used to inform Phase Ib dose for next participant enrolled.

Rate of DLT = the number of participants experiencing DLT at the current dose/Total number of patients treated at current dose

2. The recommended Phase 2 dose (RP2D) for Stage 2/Phase II will be determined when the rate of DLT for one of the 3 selected dosing schedules is between the boundaries of 0.276 and 0.419 to achieve the target toxicity rate of 0.35 (as per BOIN guidelines). 0.35 rate of DLT was reported in the Phase III trial that led to the FDA approval of oral Azacitidine.
If a RP2D cannot be determined a summary of all AEs and SAEs will be reviewed by the DSMB and amendments made to the protocol to address safety will occur (i.e.: replacement of oral Azacitidine with IV or subcutaneous Azacitidine, dose reduction, dose timing).
The study will stop if the DSMB advises the safety profile cannot be addressed by amendments to the protocol.
Stage 2: Primary Outcome Statistical analysis plan:
Best Overall Response Rate: The BOR rate is defined as the proportion of patients with complete response (CR), partial response (PR), stable disease (SD) evaluated using RECIST 1.1 or iCR, iPR, iSD, iUPD unconfirmed PD (iUPD) or confirmed PD (iCPD) using iRECIST. BOR rate will be calculated using RECIST scores for all Stage 1 and 2 participants that receive the RP2D at week 6 and iRECIST scores at week 12 and week 20.
Waterfall plot of Tumour Shrinkage: Waterfall plot is a data visualization technique that depicts tumour shrinkage that is the best-observed % change of the sum of target lesions from baseline.
Stage 2 Secondary Outcomes: Statistical analysis plan (for all Stage 1 and 2 participants that receive the RP2D):
A summary of all AEs and SAEs will be reviewed by the DSMB and amendments made to the protocol to address safety will occur if advised (i.e.: dose reduction, dose timing). The study will stop if the DSMB advises the safety profile cannot be addressed by amendments to the protocol.
a) Progression-free survival: Will be calculated 6 months after first patient in (Day 1, Cycle 1) followed by every 6 months until study completion. PFS will be calculated as the time from initiation of the trial treatment (Day 1, Cycle 1) to PD or iCPD. Kaplan-Meier plots for sub-groups based on secondary outcome data will be generated every 6 months for the duration of the study.
b) Overall survival: Will be calculated 6 months after first patient in (Day 1, Cycle 1) followed by every 6 months until study completion. Overall survival will be calculated as the time from initiation of the trial treatment (Day 1, Cycle 1) to death from any cause. Kaplan-Meier plots for sub-groups based on secondary outcome data will be generated every 6 months for the duration of the study.
Secondary Outcomes c and d): Data for correlative pre-clinical secondary outcomes will be tested before and after treatment using a paired t-test with Bonferroni correction when required.
Secondary Outcome e) PK/PD data will be assessed by plasma concentration vs time and average change in methylation compared to baseline vs time.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/08/2021
Actual
13/09/2021
Date of last participant enrolment
Anticipated
30/08/2026
Actual
Date of last data collection
Anticipated
30/08/2028
Actual
Sample size
Target
40
Accrual to date
20
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 19812 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [2] 19962 0
Cairns Base Hospital - Cairns
Recruitment postcode(s) [1] 34462 0
2298 - Waratah
Recruitment postcode(s) [2] 34463 0
2298 - Waratah West
Recruitment postcode(s) [3] 34669 0
4870 - Cairns

Funding & Sponsors
Funding source category [1] 307613 0
Commercial sector/Industry
Name [1] 307613 0
Bristol Myers Squibb
Country [1] 307613 0
Australia
Primary sponsor type
University
Name
University of Newcastle
Address
University Dr, Callaghan, NSW Australia 2308
Country
Australia
Secondary sponsor category [1] 308306 0
None
Name [1] 308306 0
Address [1] 308306 0
Country [1] 308306 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307665 0
Bellbery Human Research Ethics Committee
Ethics committee address [1] 307665 0
Ethics committee country [1] 307665 0
Australia
Date submitted for ethics approval [1] 307665 0
12/05/2021
Approval date [1] 307665 0
23/06/2021
Ethics approval number [1] 307665 0
Ethics committee name [2] 309011 0
Royal Brisbane and Women's Hospital Human Research Ethics Committee
Ethics committee address [2] 309011 0
Ethics committee country [2] 309011 0
Australia
Date submitted for ethics approval [2] 309011 0
Approval date [2] 309011 0
12/07/2021
Ethics approval number [2] 309011 0
HREC/2021/QRBW/77577

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

Contacts
Principal investigator
Name 108058 0
Dr Andre van der Westhuizen
Address 108058 0
Medical Oncology and Newcastle Melanoma Unit
Calvary Mater Newcastle
Edith Street, Waratah NSW 2298
Country 108058 0
Australia
Phone 108058 0
+61 249211561
Fax 108058 0
Email 108058 0
andre.vanderwesthuizen@calvarymater.org.au
Contact person for public queries
Name 108059 0
Rochelle Thornton
Address 108059 0
Centre for Drug Repurposing and Medicines Research
University of Newcastle
C/- Hunter Medical Research Institute
Lot 1, Kookaburra Circuit, New Lambton Heights, NSW, 2305
Country 108059 0
Australia
Phone 108059 0
+61240420915
Fax 108059 0
Email 108059 0
CDRMR-PRIME005@newcastle.edu.au
Contact person for scientific queries
Name 108060 0
Nikola Bowden
Address 108060 0
Centre for Drug Repurposing and Medicines Research
University of Newcastle
C/- Hunter Medical Research Institute
Lot 1, Kookaburra Circuit, New Lambton Heights, NSW, 2305
Country 108060 0
Australia
Phone 108060 0
+61 2 40420277
Fax 108060 0
Email 108060 0
CDRMR-PRIME005@newcastle.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will not be shared for this clinical trial. Summary data of all participants will be avaialble.


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.