Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001064493
Ethics application status
Approved
Date submitted
19/07/2016
Date registered
9/08/2016
Date last updated
2/07/2021
Date data sharing statement initially provided
26/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase I Stereotactic Radiotherapy dose escalation study with Immune pathway activation for metastatic Melanoma
Scientific title
Treating metastatic melanoma with Stereotactic ABlative Radiotherapy and IMmune Pathway ACTivation: A phase I dose-escalation trial (SABR IMPACT I)
Secondary ID [1] 289713 0
None
Universal Trial Number (UTN)
U1111-1185-5624
Trial acronym
SABR-IMPACT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Melanoma 299531 0
Condition category
Condition code
Cancer 299510 299510 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a prospective phase I dose-escalation study. Patients will receive a single fraction of SABR to a single site at an increasing dose and at different times while on Immunotherapy. A minimum of 3 patients will be enrolled at each increasing dose level, if safe and no grade 3 toxicities occur as assessed by the PI, the next 3 patients will be enrolled at the increased dose level until MTD is established. If these are tolerated, patients will receive SABR before each cycle, delivered to a different site at the highest possible dose tolerated by that site.
For SABR:
All SABR treatments will be delivered in the week before up to the same day as immunotherapy
Level 1: 10Gy to a single site before cycle 1
Level 2: 15Gy to a single site before cycle 1
Level 3a: 20Gy to a single site before cycle 1
Level 3b: 20Gy to a single site before cycle 2
Level 3c: 20Gy to a single site before cycle 3
Level 3d: 20Gy to a single site before cycle 4
Level 4: 24Gy to a single site before cycle 1 (peripheral lung and liver only)
Level 5: 27Gy to a single site before cycle 1 (peripheral lung and liver only)
Level 6: 30Gy to a single site before cycle 1 (peripheral lung and liver only)
Level 7: Highest SABR dose before as many cycles as possible

The PI or treatung Radiation Oncologist will decide the site to receive SABR

For Immunotherapy:
Patients will be treated according to Medical Oncology standard of care. Each patients treating doctor will decide which drug is most appropriate for each individual case.

*Ipilimumab will consist of four cycles of 3mg/kg, delivered IV every 3 weeks until progression.
*Nivoloumab will be delivered as per expanded access program, with a dose of 3mg/kg IV every two weeks for up to 96 weeks or until progression
*Pembrolizumab will be delivered as per expanded access program, with a dose of 2mg/kg IV every three weeks for up to 2 years or until progression
A standard 3+3 design will be used, whereby at least 3 patients are enrolled into each dose level. If no patients experience grade 3 or higher toxicity, escalation to the next level is permitted. If 1 out of 3 patients experience toxicity a further 3 patients are enrolled at that dose level and if none of these experience toxicity, escalation is permitted. If 2 of 3 or 2 of 6 patients experience toxicity, then escalation ceases and the prior dose level is defined as maximum tolerated dose.
Intervention code [1] 295344 0
Treatment: Drugs
Intervention code [2] 295535 0
Treatment: Other
Comparator / control treatment
No control group. Dose escalated Stereotactic Ablative Radiotherapy
Control group
Uncontrolled

Outcomes
Primary outcome [1] 298991 0
The maximum tolerated dose (MTD) of SABR with immunotherapy will be assessed using the standard 3+3 design, with toxicity assessed as per CTCAE criteria by the treating radiation oncologist
Timepoint [1] 298991 0
Follow up every 3 weeks to assess toxicities and blood samples to assess immune response whilst receiving immunotherapy
Secondary outcome [1] 326424 0
To determine the clinical activity of SABR with Immunotherapy
Timepoint [1] 326424 0
Clinical activity will be assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1).
Restaging will be done every 3 months with a CT scan or MRI if indicated for up to 5 years
Secondary outcome [2] 326455 0
To determine biologic activity of SABR with Immunotherapy
Timepoint [2] 326455 0
Peripheral blood will be collected prior to each dose of Immunotherapy and the immune monitoring profile will be assessed.
This will be done every 3 weeks prior to treatment for the entire time the patient is receiving treatment with Immunotherapy
Secondary outcome [3] 326511 0
To determine survival benefit of Immunotherapy and SABR
Timepoint [3] 326511 0
Survival will be determined through clinic visits every 3 weeks whilst on Immunotherapy treatment. Following treatment clinic visits will occur 3 monthly for 2 years, then 6 monthly until 5 years.

Eligibility
Key inclusion criteria
*Aged 18 or older.
*Willing and able to provide informed consent.
*Histologically confirmed metastatic melanoma.
*At least one extra-cranial metastasis that is symptomatic or imminently symptomatic and may impact quality of life or ability to tolerate ongoing treatment.
*Non-oligometastatic disease (defined more than 5 total metastasis, or more than 3 metastasis in any organ system) and
1. At least one extra-cranial metastasis that can be treated with a SABR dose of at least 20Gy (as determined by a Radiation Oncologist).
2. Intracranial disease control (defined as surgery and/or stereotactic radiotherapy to all intracranial sites).
3. At least one extra-cranial metastasis that will not be treated with SABR to monitor response.
*Able to tolerate treatment with Immunotherapy (as determined by a Medical Oncologist).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
*Patient with a life expectancy less than 3 months, including those with malignant pleural or pericardial effusions.
*Patients requiring immediate surgical intervention
1. Clinical or radiologic evidence of spinal cord compression
2. Dominant brain metastasis requiring surgical decompression
*Pregnant or lactating females
*Significant auto-immune diseases including inflammatory bowel disease, rheumatoid arthritis and Systemic Lupus Erythematosus

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
Other
Other design features
This group of patients will be treated with Immunotherapy and a dose escalation of SABR from 10Gy to a maximum of 30Gy in a single dose
Phase
Phase 1
Type of endpoint/s
Efficacy
Statistical methods / analysis
Using a standard 3+3 design, if 2 of 3 patients develop DLT at a particular dose, we can conclude with 90% confidence that the true probability of DLT at that dose is greater than 20%. Similarly, if 0 of 3 patients develop DLT at a particular dose, we can conclude with 90% confidence that the true probability of DLT at that dose is less than 55%. Expanding to 6 patients, when 1 of 3 patients develop DLT this ensures that there is a 91% probability escalation will be halted when the true probability of DLT is less than 10% and 92% probability escalation will not proceed when the true probability of DLT is greater than 60%.
Biologic endpoints will be correlated with clinical and survival endpoints using the Student’s t-test or Fisher’s Exact Test.
Survival will be calculated using the Kaplan-Meier method and differences compared using the log-rank test. A Cox multivariable regression analysis will be used to determine baseline and treatment factors predictive of survival.
A power calculation was not performed as this is a phase 1 study assessing safety

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
18/04/2016
Date of last participant enrolment
Anticipated
Actual
14/08/2018
Date of last data collection
Anticipated
Actual
26/11/2018
Sample size
Target
30
Accrual to date
Final
31
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 6226 0
The Alfred - Prahran
Recruitment postcode(s) [1] 13641 0
3004 - Prahran

Funding & Sponsors
Funding source category [1] 294090 0
Government body
Name [1] 294090 0
NHMRC
Country [1] 294090 0
Australia
Primary sponsor type
Hospital
Name
Alfred Health Radiation Oncology
Address
55 Commercial Rd, Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 292923 0
None
Name [1] 292923 0
Address [1] 292923 0
Country [1] 292923 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295506 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 295506 0
Ethics committee country [1] 295506 0
Australia
Date submitted for ethics approval [1] 295506 0
26/02/2016
Approval date [1] 295506 0
06/03/2016
Ethics approval number [1] 295506 0
545/14

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

Contacts
Principal investigator
Name 67542 0
Dr Sasha Senthi
Address 67542 0
Alfred Hospital, 55 Commercial Rd, Melbourne VIC 3004
Country 67542 0
Australia
Phone 67542 0
+61 (3) 9076 2337
Fax 67542 0
+61 (3) 9076 2916
Email 67542 0
[email protected]
Contact person for public queries
Name 67543 0
Robin Smith
Address 67543 0
Alfred Hospital, 55 Commercial Rd, Melbourne VIC 3004
Country 67543 0
Australia
Phone 67543 0
+61 (3) 9076 2337
Fax 67543 0
+61 (3) 9076 2916
Email 67543 0
[email protected]
Contact person for scientific queries
Name 67544 0
Sasha Senthi
Address 67544 0
Alfred Hospital, 55 Commercial Rd, Melbourne VIC 3004
Country 67544 0
Australia
Phone 67544 0
+61 (3) 9076 2337
Fax 67544 0
+61 (3) 9076 2916
Email 67544 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
Patient confidentiality


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
501Study protocol    371121-(Uploaded-26-11-2018-13-13-56)-Study-related document.pdf
502Informed consent form    371121-(Uploaded-26-11-2018-13-15-05)-Study-related document.pdf
503Ethical approval    371121-(Uploaded-26-11-2018-13-18-29)-Study-related document.pdf



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseStereotactic Radiation Therapy Combined With Immunotherapy Against Metastatic Melanoma: Long-Term Results of a Phase 1 Clinical Trial.2020https://dx.doi.org/10.1016/j.ijrobp.2020.05.022
EmbaseBlood T-cell profiling in metastatic melanoma patients as a marker for response to immune checkpoint inhibitors combined with radiotherapy.2022https://dx.doi.org/10.1016/j.radonc.2022.06.016
N.B. These documents automatically identified may not have been verified by the study sponsor.