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Trial registered on ANZCTR


Registration number
ACTRN12614001181695
Ethics application status
Approved
Date submitted
14/10/2014
Date registered
11/11/2014
Date last updated
5/11/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot study of patients with oligometastases from breast cancer treated with stereotactic ablative body radiosurgery in combination with the anti-PD-1 antibody MK-3475.
Scientific title
A pilot study to assess the safety and feasibility of stereotactic ablative body radiosurgery combined with MK-3475 in patients with oligometastases from breast cancer.
Secondary ID [1] 285477 0
Nil
Universal Trial Number (UTN)
U1111-1162-6800
Trial acronym
BOSTON II
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Breast Cancer (1-5 metastases) 293255 0
Condition category
Condition code
Cancer 293526 293526 0 0
Breast
Cancer 293725 293725 0 0
Bone

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stereotactic ablative body radiotherapy (SABR) is a new form of cancer treatment involving high precision radiotherapy. Standard radiotherapy treatment is usually delivered in small doses over many treatments (usually 5 to 20 treatments). SABR treatment is different as it uses a dose of radiation delivered in 1 or 2 treatments that is much higher than standard radiotherapy dosages with the aim of destroying all cancer cells at the site of treatment. The total dose of radiation may be 5-10 times higher than standard radiotherapy doses. SABR treatment appears to be effective in controlling cancer in other sites elsewhere in the body, including the lung, kidney and the liver. We aim to test the ability of this new technique to control the cancer spots that have spread from the breast to the bones and lymph nodes and that are being treated with SABR.

The investigational drug (MK-3475) is a type of monoclonal antibody. An antibody is a common type of protein made in the body in response to a foreign substance. Antibodies attack foreign substances and protect against infection. A monoclonal antibody is a laboratory-produced antibody that is carefully engineered to attach to your cancer cells. Monoclonal antibodies mimic the antibodies your body naturally produces as part of your immune system's response to germs, vaccines, and other invaders. There are now several approved monoclonal antibodies for the treatment of cancer or other diseases.

MK-3475 is a monoclonal antibody that works against a protein called PD-1 on the surface of the cancer cells. It is thought that cancer cells with increased levels of PD-1 avoid detection by the body’s immune system. The study drug (MK-3475) is being tested to see if it can decrease the level of PD-1 in your cancer and allow the body’s immune system to identify and work against the tumour cells.


1) Screening Assessments:

Initially you will be assessed to check that you are eligible to join the study. This screening period may last for a number of weeks and will involve the following procedures.

A) Physical Assessment: Including height, weight, pulse rate and blood pressure assessment. You will also be asked questions about your medical history and the medicines you currently take. Finally, your doctor will assess your performance status (by asking questions about your general well-being).

B) Disease Assessment: Your breast cancer will be assessed by:
* Radiology scans such as a CT (computed tomography) scan of the chest, abdomen and pelvis.
* Whole body bone scan
* Nuclear medicine scans such as a FDG (fluorodeoxyglucose) - PET (positron emission tomography)/computed tomography (CT).
* X-rays (if necessary)

* Tumour Tissue: If you decide to participate in this study, your doctor will be required to send a sample of your tumour to a central laboratory, which was previously collected when you were diagnosed with metastatic breast cancer. This sample (which has already been taken from you) is currently stored in a pathology laboratory and we will request this sample to be sent to our central laboratory with your permission.

If your tumour starts to grow again at a location where it is readily accessible, your doctor may propose to take a biopsy again. We would like to collect a sample of this biopsy as well to determine in which way the tumour has changed.

C) Routine Blood Samples: Before entering the study, blood will be taken (approximately 15-30mls or approximately 2 tablespoons) to check for; blood cell counts, liver, pancreas, kidney and thyroid function, HIV, Hepatitis B, Hepatitis C, a breast cancer tumour marker called cancer antigen 15-3 (CA15-3), as well as a pregnancy test if you are able to become pregnant. Blood samples will be taken at every 3 weeks while treatment is continuing to monitor your haematology and serum chemistry levels.


2) STUDY TREATMENT:

If you decide to participate in the study and meet the criteria to take part in the study, you will be treated according to the following schema:

A) SABR TREATMENT

Prior to your SABR treatment, you will be required to fill out a pain rating scale, which may take up to 2 minutes of your time. You will have either a single session of SABR treatment (20Gy in 1 fraction per area to be treated) or in some cases where there is not enough time available or for technical reasons you may be required to return for two or three sessions (i.e. You may receive 28Gy in 2 fractions).

In order to deliver this treatment, you may need to attend a ‘planning CT scan’ session, where you will receive a CT scan and your body measurements are taken in the position that you will be lying in for your radiotherapy. This visit takes approximately one hour. Once the radiotherapy treatment has been planned, a further ‘mock-up’ visit may be required to ensure that the radiotherapy plan can be smoothly delivered when it comes to the time of treatment. This session will take between 45 minutes and 90 minutes. When the treatment starts, the total time required to deliver the treatment will be approximately one hour.

B) MK-3475 TREATMENT

MK-3475 (200mg) will be given to you by a needle in your vein (called venous infusion) over a period of 30mins, with the first dose starting a maximum of 5 days after completing SABR treatment, and delivered once every three weeks for a total of 8 cycles (i.e. 1 cycle every 3 weeks for a total of 8 cycles).

Treatment with MK-3475 will continue until you have completed 6 months of treatment, or until your cancer spreads further to other parts of your body, or you experience intolerable side effects. If you stop treatment for any reason prior to completing the 6 months of MK-3475 treatment, you will be offered alternative treatment options by your study doctor.

During the 6 months of MK-3475 treatment, you will be required to have a doctor’s visit every 3 weeks. Overnight stay in the hospital is not anticipated, but may become necessary. Routine blood tests, including liver, thyroid and kidney function, will be carried out during treatment at each visit before you receive MK-3475. If you develop side effects, more frequent examinations may be necessary.

Your physician will document your general condition and all hospital stays during the clinical trial. He/she will similarly ask you about all side effects which you experienced and about all medications or treatments which you received since your last visit.

Your doctor may suggest other tests, such as a CT scan if appropriate. The regular doctor’s visits are part of your standard medical care and are handled the same way as if you did not take part in the study.

If you complete the 6 months of MK-3475 treatment and your cancer has responded, but sometime in the future your cancer returns or grows (should this happen), you will be given the option to receive a further course of MK-3475 treatment by your study doctor.


3) CLINIC VISITS/FOLLOW-UP:

After your SABR treatment is completed, you will be asked to attend the hospital for a check-up at approximately 1 month, and every 3 months until two years from the date that SABR treatment was completed. Some of these visits may coincide with the 3-weekly visits required during the MK-3475 treatment, and if so, you won’t be required to come to the hospital twice.

At each visit, a doctor will review your general health and whether anything new has happened to you since the last study visit (including any bad reactions or injuries), any side effect’s you may be experiencing, an assessment of how well you can perform daily activities and a review of any further anti-cancer treatments you may have undergone.

At every follow-up visit, you will be expected to fill out a questionnaire to nominate your current pain rating, which will take about 2 minutes of your time.


A) RADIOLOGICAL INVESTIGATIONS:

The following radiological investigations will be undertaken during and after your treatment on this study:

* CT Scan and Whole Body Bone Scan: You will a CT scan and whole body bone scan at 6, 12 and 24 months post end of SABR treatment unless there is evidence that your disease has progressed, in which case the scans may be done earlier.

Intervention code [1] 290414 0
Treatment: Drugs
Intervention code [2] 290415 0
Treatment: Other
Comparator / control treatment
Uncontrolled
Control group
Uncontrolled

Outcomes
Primary outcome [1] 293361 0
The primary objective is to determine the safety profile of stereotactic ablative body radiosurgery (SABR) in combination with MK-3475 treatment in patients with oligometastatic breast cancer.
Timepoint [1] 293361 0
Safety will be evaluated using CTCAE version 4.0 in all patients who have received at least one SABR treatment and one dose of MK-3475. Acute AE are defined as AE’s occurring from the time from 1st SABR treatment to 30 days post end of MK-3475 treatment and long term AE are defined as AE’s occurring after 30 days post end of MK-3475 treatment. AE assessments will be conducted from time of study consent, during treatment, at 1 month post end of treatment, and at every 3 months until 2 years from the date that SABR was completed.
Secondary outcome [1] 310843 0
To evaluate changes in immunological markers in tumor tissue, and immune subsets in peripheral blood from patients over serial time-points, including at time of progression.
Timepoint [1] 310843 0
Blood samples will be collected (50ml) at baseline (prior to first SABR), prior to the first dose of MK-3475, prior to cycle 2 of MK-3475, at disease progression (if this occurs) and then every 3 months up to two years post end of SABR treatment. These will be analysed for the following (this is a non-exhaustive list):
i. Absolute lymphocyte counts using a blood analyser.
ii. The presence of CD8+ T cells by flow cytometric analysis.
iii. Change in frequency of tumor reactive T cells. These may include markers for HLA-DR, CD4+, CD8+ T cells, PD-1, TIM-3 signifying antigen presentation and experience.
Secondary outcome [2] 310844 0
To evaluate effectiveness of the treatment combination as assessed by pain ratings as well as tumor response in the irradiated lesions.
Timepoint [2] 310844 0
Effectiveness of treatment will be evaluated using two methods; a) Numerical Rating Pain Scale and B) Local and distant progression free survival (LPFS and DPFS).
a. Pain will be evaluated pre and post using the Numerical Rating Pain Scale at the following time points: pre-SABR treatment, at approx. 1 month (around cycle 2 of Pembrolizumab), 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months and at 24 months after the end of treatment.
b. Treatment efficacy will also be assessed by the local progression disease free survival (LPFS) and distant progression free survival (DPFS). LPFS and DPFS will be measured from date of commencement of treatment to the date of first local progression or date of death for patients without local/distant progression. Time to progression in other sites will also be recorded. LPFS and DPFS will be assessed by clinical (i.e. physical examinations) and radiological assessments (via a CT scan, WBBS and/or FDG PET/CT scans) at 3, 9, 15, 18 and 21 months post SABR treatment unless evidence of progression earlier or clinically inappropriate. Re-staging will also occur using CT scan and WBBS scan at 6, 12 and 24 Months post end of SABR treatment if no evidence of progression has occurred earlier.

Eligibility
Key inclusion criteria
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be 18 years of age on day of signing informed consent.
3. Have histologically or cytologically confirmed breast cancer. Oligometastatic lesions do not need to be biopsied but they must be strongly suspected to represent metastatic disease.
4. CT scan (Chest, Abdo + Pelvis), Whole Body Bone scan, and FDG-PET scan evidence of 1 to 5 metastases within 8 weeks of study registration.
Note: At least 1 of the 5 metastases must be deemed suitable for SABR treatment.
5. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumour lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Participants for whom newly-obtained samples cannot be provided (e.g. inaccessible or participant safety concern) may submit an archived specimen only upon agreement from the study P.I’s.
6. Have a performance status of 0-2 on the ECOG Performance Scale.
7. Demonstrate adequate organ function.
8. Life expectancy > 12 months.
9. Be willing and able to comply with all study requirements, including treatment, attending assessments and follow-up.
10. Female patients of childbearing potential must have a negative urine or serum pregnancy within 7 days of study registration and re-tested within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
11. Female patients of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through to 120 days after the last dose of MK-3475. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
12. Male patients must agree to use an adequate method of contraception starting with the first SABR treatment, through to 120 days after the last dose of MK-3475.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous high dose radiotherapy (BED > 20Gy) to an area to be treated which includes vertebral bodies.
2. Evidence of brain metastases.
3. Intention to treat with any chemotherapy agent within +/- 3 weeks of study treatment.
4. Evidence of Spinal Cord Compression.
5. Spinal Instability Neoplastic Score greater than or equal to 7 unless lesion reviewed by a neurosurgical service and considered stable. A dose of 28Gy in 2 fractions can be considered after review at SABR chart round.
6. Surgical fixation of bone lesion required for stability.
7. Lytic metastases in a long bone (femur or humerus) that erodes the cortex.
8. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and is planned to receive study therapy or used an investigational device within 4 weeks of study treatment.
9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy at time of study registration.
10. Has a plan to receive or did receive a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study treatment or has not recovered from adverse events (i.e. AEs not at = Grade 1 or at baseline values) due to agents administered more than 4 weeks earlier.
11. Is planned to receive chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study treatment or who has not recovered from adverse events (i.e. AEs not at = Grade 1 or at baseline values) due to a previously administered agent.
12. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
13. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to study registration and any neurological symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
14. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
15. Has known history of, or any evidence of active, non-infectious pneumonitis.
16. Has an active infection requiring systemic therapy.
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient’s participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
19. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through to 120 days after the last dose of trial treatment.
20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
21. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
22. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
23. Has a plan to receive or has received a live vaccine within 30 days prior to study treatment.
24. Has a known history of active TB (Bacillus Tuberculosis).
25. Known hypersensitivity to MK-3475 or its excipients.

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)
Following informed consent, the Participant Information & Consent Form will be signed and dated (with a witness). Once it is confirmed that the patient meets all inclusion criteria and none of the exclusion criteria, they will be registered onto the study. This is a non-randomised trial and there are no allocation concealment procedures
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A - This is a non-randomised study.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
This is a single institution, single arm pilot study to determine the safety profile of stereotactic ablative body radiosurgery (SABR) in combination with MK-3475 treatment in patients with oligometastatic breast cancer.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
This is a single arm pilot study to determine safety profile of SABR in combination with MK-3475 in patients with oligometastatic breast cancer.

A) The Primary Endpoint is Safety of the Combination:
Safety will be assessed using CTCAE v4.0 and the maximum acute toxicity grade will be derived. The proportion of patients who suffer from grade 3 or higher acute toxicities will be provided along with its exact 95% CI.

A summary table (overall, acute and long term) will be evaluated using CTCAE version 4.0. Adverse events (worst grade per patient) will be tabulated for all patients who have received at least one dose of MK-3475 and completed at least one SABR treatment. If patients are retreated with MK-3475, toxicities occurring during or after second treatment with MK-3475 will be reported separately from the long term toxicities.

B) Secondary Endpoints are to Examine the Biological Effects of the Combination:
The chief secondary endpoints are descriptive and are to evaluate immune responses and efficacy of the treatment (local and distant tumor responses). We will be looking for consistent changes in immunity and reporting efficacy as stated below. This data will provide the scientific rationale for moving to a larger, appropriately powered trial to look specifically at efficacy.

C) Anti-Tumor Immunity:
Host anti-tumor immunity measured at the designated time points (baseline, prior to first dose MK-3475, on treatment, post treatment and at 24 months or at time of progression if that comes before the 24 month time period) will be described as change over time using linear mixed models. The linear mixed model will include time as fixed effect and patients as random effect. Mean and 95% confidence intervals will be calculated for each time point and the data will be displayed graphically. Variable transformation may be required for some of the collected variables. If the assumptions of the model do not hold, simple descriptive statistics will be provided for each variable at each time point.

D) Efficacy:
The efficacy of the treatment will be evaluated by:
i) Pain will be described as change over time using linear mixed models. The linear mixed model will include time as fixed effect and patients as random effect. Mean and 95% confidence intervals will be calculated for each time point and the data will be displayed graphically. Variable transformation may be required for some of the collected variables. If strong floor effect is observed or if the assumptions of the model do not hold, simple descriptive statistics will be provided for each variable at each time point
ii) Kaplan-Meier methods will be used to describe LPFS and DPFS at 1 and 2 years. This will be estimated from the Kaplan-Meier curve, along with the corresponding 95% confidence interval.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/02/2015
Actual
2/11/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
15
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 3047 0
Peter MacCallum Cancer Institute - East Melbourne

Funding & Sponsors
Funding source category [1] 290088 0
Charities/Societies/Foundations
Name [1] 290088 0
National Breast Cancer Foundation
Country [1] 290088 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
C/O Monash Cancer Centre
Radiation Oncology and Cancer Imaging
823-865 Centre Road,
East Bentleigh, VIC 3165
Country
Australia
Secondary sponsor category [1] 288787 0
None
Name [1] 288787 0
Address [1] 288787 0
Country [1] 288787 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291796 0
Peter MacCallum Cancer Centre Ethics Committee
Ethics committee address [1] 291796 0
Ethics committee country [1] 291796 0
Australia
Date submitted for ethics approval [1] 291796 0
01/12/2014
Approval date [1] 291796 0
10/07/2015
Ethics approval number [1] 291796 0
PMCC 14/157

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

Contacts
Principal investigator
Name 52026 0
A/Prof Sherene Loi
Address 52026 0
Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Melbourne, Victoria, 8006
Country 52026 0
Australia
Phone 52026 0
+613 9656 1111
Fax 52026 0
+613 9656 1411
Email 52026 0
[email protected]
Contact person for public queries
Name 52027 0
Sherene Loi
Address 52027 0
Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Melbourne, Victoria, 8006
Country 52027 0
Australia
Phone 52027 0
+613 9656 1111
Fax 52027 0
+613 9656 1411
Email 52027 0
[email protected]
Contact person for scientific queries
Name 52028 0
Sherene Loi
Address 52028 0
Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Melbourne, Victoria, 8006
Country 52028 0
Australia
Phone 52028 0
+613 9656 1111
Fax 52028 0
+613 9656 1411
Email 52028 0
[email protected]

No information has been provided regarding IPD availability


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No Supporting Document Provided



Results publications and other study-related documents

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