ANZCTR - Registration

Please note the ANZCTR will be unattended from Friday 20 December 2024 for the holidays. The Registry will re-open on Tuesday 7 January 2025. Submissions and updates will not be processed during that time.

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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]

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

Condition category

Condition code

Cancer

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]

Treatment: Drugs

Intervention code [2]

Treatment: Other

Comparator / control treatment

No control group. Dose escalated Stereotactic Ablative Radiotherapy

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

Follow up every 3 weeks to assess toxicities and blood samples to assess immune response whilst receiving immunotherapy

Secondary outcome [1]

To determine the clinical activity of SABR with Immunotherapy

Timepoint [1]

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]

To determine biologic activity of SABR with Immunotherapy

Timepoint [2]

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]

To determine survival benefit of Immunotherapy and SABR

Timepoint [3]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

The Alfred - Prahran

Recruitment postcode(s) [1]

3004 - Prahran

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC

Address [1]

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

Hospital

Name

Alfred Health Radiation Oncology

Address

55 Commercial Rd, Melbourne VIC 3004

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred Hospital Ethics Committee

Ethics committee address [1]

55 Commercial Rd, Melbourne VIC 3004

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

26/02/2016

Approval date [1]

06/03/2016

Ethics approval number [1]

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

Dr Sasha Senthi

Address

Alfred Hospital, 55 Commercial Rd, Melbourne VIC 3004

Country

Australia

Phone

+61 (3) 9076 2337

Fax

+61 (3) 9076 2916

S.Senthi@alfred.org.au

Contact person for public queries

Name

Robin Smith

Address

Alfred Hospital, 55 Commercial Rd, Melbourne VIC 3004

Country

Australia

Phone

+61 (3) 9076 2337

Fax

+61 (3) 9076 2916

r.smith@alfred.org.au

Contact person for scientific queries

Name

Sasha Senthi

Address

Alfred Hospital, 55 Commercial Rd, Melbourne VIC 3004

Country

Australia

Phone

+61 (3) 9076 2337

Fax

+61 (3) 9076 2916

S.Senthi@alfred.org.au

Data sharing statement

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

No/undecided IPD sharing reason/comment

Patient confidentiality

What supporting documents are/will be available?

Doc. No.	Type	Attachment
501	Study protocol	371121-(Uploaded-26-11-2018-13-13-56)-Study-related document.pdf
502	Informed consent form	371121-(Uploaded-26-11-2018-13-15-05)-Study-related document.pdf
503	Ethical 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

Source	Title	Year of Publication	DOI
Embase	Stereotactic Radiation Therapy Combined With Immunotherapy Against Metastatic Melanoma: Long-Term Results of a Phase 1 Clinical Trial.	2020	https://dx.doi.org/10.1016/j.ijrobp.2020.05.022
Embase	Blood T-cell profiling in metastatic melanoma patients as a marker for response to immune checkpoint inhibitors combined with radiotherapy.	2022	https://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.

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Documents added manually

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