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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
23/01/2020
Date data sharing statement initially provided
26/11/2018
Date results information 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
Gender
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
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)
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
Address [1] 294090 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
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
55 Commercial Rd, Melbourne VIC 3004
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
The primary purpose of this trial is to determine the maximum tolerated dose of stereotactic ablative radiotherapy (SABR) in combination with immunotherapy for the treatment of metastatic melanoma, and to determine whether the treatment has any clinical efficacy.

Who is it for?
You may be eligible to enroll in this trial if you are aged 18 or over and have been diagnosed with non-oligometastatic stage IV melanoma.

Study details
You will be participating in a phase I study. Although SABR is generally safe on its own, it is not clear how safe it is in combination with immune activating drugs. To find out we will start by giving a very low dose of SABR, which we think will be safe for almost all patients and slowly increase the dose to a level, which we think will be effective.
Patients participating in this study will all receive a drug that activates their immune system and you will discuss this further with your doctor. These drugs will be delivered in a standard fashion, with at least 4 doses delivered every 3 weeks for up to 2 years or until you no longer are gaining benefit.. By participating in this study, a few days before you receive the drug you will receive SABR to one of your disease sites.
You will be followed up for up to 5 years on this study

It is hoped that findings from this trial will provide information on the maximum tolerated dose, and the level of efficacy of each dose level of SABR with immunotherapy for the treatment of metastatic melanoma.
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
S.Senthi@alfred.org.au
Contact person for public queries
Name 67543 0
Mrs 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
r.smith@alfred.org.au
Contact person for scientific queries
Name 67544 0
Dr 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
S.Senthi@alfred.org.au

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?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 501 0
Study protocol
Citation [1] 501 0
Link [1] 501 0
Email [1] 501 0
Other [1] 501 0
Type [2] 502 0
Informed consent form
Citation [2] 502 0
Link [2] 502 0
Email [2] 502 0
Other [2] 502 0
Type [3] 503 0
Ethical approval
Citation [3] 503 0
Link [3] 503 0
Email [3] 503 0
Other [3] 503 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Yes
Results – basic reporting
Results – plain English summary