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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03464942




Registration number
NCT03464942
Ethics application status
Date submitted
21/02/2018
Date registered
13/03/2018
Date last updated
13/03/2018

Titles & IDs
Public title
Stereotactic Radiation and Immunotherapy in Patients With Advanced Triple Negative Breast Cancer
Scientific title
A Randomised Phase II Trial Comparing the Efficacy of Single-fraction or Multi-fraction SABR (Stereotactic Ablative Body Radiotherapy) With AteZolizumab in Patients With Advanced Triple nEgative Breast Cancer
Secondary ID [1] 0 0
17/013
Universal Trial Number (UTN)
Trial acronym
AZTEC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Other - SABR
Treatment: Drugs - Atezolizumab

Active Comparator: Single Dose - SABR 20Gy given as a single dose (to 1 -4 metastases with at least 1 untreated metastasis) followed by atezolizumab (1200 mg) every 3 weeks for 24 months.

Active Comparator: Fractionated Dose - SABR 24Gy given as 3 fractions (to 1 -4 metastases with at least 1 untreated metastasis) followed by atezolizumab (1200 mg) every 3 weeks for 24 months.


Treatment: Other: SABR
Single Dose Group: this group will receive 20 Gy of radiation in a single dose within 10 days of randomisation Fractionated Dose: Participants in this dose will receive a total of 24Gy of radiation given as 3 separate fractions of 8 Gy each.

Treatment: Drugs: Atezolizumab
All participants will commence atezolizumab (within 5 days of last SABR dose) 1200 mg every 3 weeks for 24 months

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

Outcomes
Primary outcome [1] 0 0
Progression Free Survival - To assess the progression free survival of SABR at a dose of 24Gy in 3# followed by atezolizumab and SABR at a dose of 20Gy in 1# followed by atezolizumab in patients with advanced triple negative breast cancer (TNBC).
Timepoint [1] 0 0
24 months
Secondary outcome [1] 0 0
Best Objective Response (BOR) between different SABR regimens + atezolizumab - Best objective response (BOR) rate: confirmed complete response (CR) or partial response (PR) as per RECIST 1.1
Timepoint [1] 0 0
24 months
Secondary outcome [2] 0 0
Incidence of treatment emergent adverse events (safety and tolerability) - Toxicities will be assessed using NCI-CTCAE version 4.03. Tolerability is defined as the time until ceasing treatment due to toxicity.
Timepoint [2] 0 0
24 months
Secondary outcome [3] 0 0
Progression Free Survival Comparison between different SABR regimens + atezolizumab - To compare the progression free survival between arms
Timepoint [3] 0 0
24 Months
Secondary outcome [4] 0 0
Duration of Response (DOR) between different SABR regimens + atezolizumab - Duration of response (DoR), defined as time from first occurrence of documented response to disease progression or death in participants who achieve a PR or better as per RECIST 1.1.
Timepoint [4] 0 0
24 months
Secondary outcome [5] 0 0
Disease Control Rate (DCR) between different SABR regimens + atezolizumab - Disease control (DC), defined as achieving a CR, PR or have had stable disease (SD) for at least 21 weeks prior to any evidence of disease progression, based on RECIST 1.1
Timepoint [5] 0 0
24 months
Secondary outcome [6] 0 0
Time to Treatment Failure between different SABR regimens + atezolizumab - Time to treatment failure (TTF) defined as the time from randomization until cessation of atezolizumab for any reason including disease progression, treatment toxicity, participant preference or death.
Timepoint [6] 0 0
24 months
Secondary outcome [7] 0 0
Overall Survival between different SABR regimens + atezolizumab - Overall survival, defined as the time from randomization to the date of death from any cause
Timepoint [7] 0 0
24 months

Eligibility
Key inclusion criteria
1. Participants with a histological or cytological diagnosis of Stage IV TNBC breast
cancer (see Appendix 7), defined by ER <1%, PR <1% and HER2 negative on IHC and/or
non-amplified by ISH by local lab testing.

2. Written informed consent.

3. Male or female participants aged = 18 years and < 70 years.

4. No more than one prior chemotherapy line in the incurable disease setting. For the
purposes of this trial, adjuvant or neoadjuvant chemotherapy does not count as a prior
line of therapy but chemotherapy given for residual disease post neoadjuvant
chemotherapy is considered as one line.

5. Must be 6 or more months from prior adjuvant, neoadjuvant or post neoadjuvant
chemotherapy last dose.

6. At least one measurable lesion as per RECIST 1.1 (see Appendix 1) that is not planned
to receive SABR.

7. CT scan (CAP), while body bone scan, and FDG-PET scan evidence of = 2 metastases (with
= 1 amenable to SABR).

8. Be willing to provide tissue from a newly obtained core biopsy of a metastatic tumour
lesion. Newly-obtained is defined as a specimen obtained up to 60 days prior to
randomisation. Patients for whom newly-obtained samples cannot be provided (e.g.
inaccessible or patient safety concern) may submit an archived specimen only upon
agreement from the CPI).

9. ECOG performance status 0 - 1 (see Appendix 6).

10. Expected life expectancy > 6 months.

11. Female participants of childbearing potential must have a negative urine or serum
pregnancy within 7 days of trial randomisation.

12. Female participants 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 trial through to 5 months after the last dose of atezolizumab.

13. Male participants must agree to use an adequate method of contraception starting with
the first SABR treatment, through to 120 days after the last dose of atezolizumab.

14. Adequate Organ Function as defined in the table below:

- Absolute neutrophil count (ANC) = 1.5 x 109/L,

- Platelets = 100 x 109/L,

- Hemoglobin* = 90 g/L OR = 9 g/dL (Without transfusion or EPO dependency (within 7
days of assessment),

- Serum creatinine = 1.5 X ULN OR Measured or calculated Creatinine Clearance** =
60 mL/min if Serum Creatinine >1.5

- X ULN (Creatinine clearance should be calculated per institutional standard. GFR
can also be used in place of creatinine or creatinine clearance - see Attachment
5 - Cockcroft-Gault Formula),

- Serum Total Bilirubin = 1.5 X ULN OR Direct bilirubin = ULN if Serum Total
Bilirubin > 1.5 ULN

In participants with known Gilbert's syndrome:

- Serum Total Bilirubin = 3.0 X ULN AND Direct Bilirubin = 1.5 X ULN,

- Aspartate Aminotransferase (AST/SGOT) and Alanine Aminotransferase (ALT/SGPT) = 2.5 X
ULN OR = 4.0 X ULN if liver metastases are present,

- Albumin > 221 µmol/L OR > 2.5 mg/dL,

- International Normalised Ratio (INR) OR Prothrombin Time (PT) OR Activated Partial
Thromboplastin Time (PTT) = 1.5 X

- ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is
within therapeutic range of intended use of anticoagulants,

- Lactate dehydrogenase (LDH) =2.5 x ULN
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous radiotherapy (BED > 30Gy) to an area to be treated.

2. Evidence of active brain metastases. Participants with previously treated brain
metastases (with surgical resection, stereotactic radiosurgery or palliative whole
brain radiotherapy) may participate, provided they have stable brain metastases
defined as 2 imaging studies documenting stability of brain metastasis(es) over > 4
weeks.

3. Intention to treat or requirement for treatment with any chemotherapy agent within ± 3
weeks of trial treatment.

Note: bisphosphonates or RANKL inhibitors are allowed.

4. Evidence of Spinal Cord Compression.

5. Spinal Instability Neoplastic Score = 7 (see Appendix 4), in a lesion scheduled for
SABR treatment unless lesion reviewed by a neurosurgical service and considered
stable.

6. Untreated lytic metastases in the neck of the femur that erodes the cortex that is
scheduled for SABR treatment.

7. Is currently participating and receiving trial therapy or has participated in a trial
of an investigational agent and is planned to receive trial therapy or used an
investigational device within 4 weeks of trial treatment

8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(> or equal to 10mg prednisolone daily) or any other form of immunosuppressive therapy
at time of trial treatment. Note: There must be no intention to commence systemic
long-term steroid therapy or any form of immunosuppressive therapy within 7 days prior
to the planned first dose of atezolizumab treatment. Note: Single (once off) doses of
prophylactic steroid therapy are acceptable.

9. Is planned to receive chemotherapy, targeted small molecule therapy, or radiation
therapy within 3 weeks prior to trial 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.

10. Has a known additional malignancy that is progressing or requires active treatment.

11. Has uncontrolled pleural effusion, pericardial effusion, or ascites requiring
recurrent drainage procedures (once monthly or more frequently).

Note: Participants with indwelling catheters (e.g., PleurX) are allowed.

12. Has uncontrolled hypercalcemia (> 1.5mmol/L ionized calcium or serum calcium
>2.99mmol/L or corrected serum calcium >ULN) or symptomatic hypercalcemia requiring
continued use of bisphosphonate therapy or denosumab. Note: Participants who are
receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events
and who do not have a history of clinically significant hypercalcemia are eligible.

13. Has a significant cardiovascular disease, such as New York Heart Association cardiac
disease (Class II or greater), myocardial infarction within 3 months prior to Cycle 1,
Day 1, unstable arrhythmias or unstable angina. Note: Participants with a known left
ventricular ejection fraction (LVEF) < 40% will be excluded.

Note: Participants with known coronary artery disease, congestive heart failure not
meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is
optimized in the opinion of the treating physician, in consultation with a
cardiologist if appropriate.

14. Has a history of autoimmune disease, including but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid
syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis.

Note: Participants with a history of autoimmune hypothyroidism on a stable dose of
thyroid replacement hormone are eligible Note: Participants with controlled Type 1
diabetes mellitus on a stable insulin regimen are eligible Note: Participants with
eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic
manifestations only (e.g., participants with psoriatic arthritis would be excluded)
are permitted provided that they meet the following conditions:

- Rash must cover less than 10% of body surface area (BSA).

- Disease is well controlled at baseline and only requiring low potency topical
steroids.

- No acute exacerbations of underlying condition within the previous 12 months (not
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids,
biologic agents, oral calcineurin inhibitors, high-potency or oral steroids).

15. Has a history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
pneumonitis, organising pneumonia (i.e., bronchiolitis obliterans, cryptogenic
organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.

Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

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 participant's
participation for the full duration of the trial, or is not in the best interest of
the participant 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 5 months after or 120 days after the last dose of trial treatment, for
women and men respectively.

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. Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or
anticipation that such a live attenuated vaccine will be required during the study -
Influenza vaccination should be given during influenza season only (example:
approximately March to October in the Southern Hemisphere). Participants must not
receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to
Cycle 1, Day 1 or at any time during the study treatment or within 5 months after the
last dose of atezolizumab.

24. Has a known history of active TB (Bacillus Tuberculosis).

25. Known hypersensitivity to atezolizumab or its excipients.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
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] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne

Funding & Sponsors
Primary sponsor type
Other
Name
Peter MacCallum Cancer Centre, Australia
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Trans-Tasman Radiation Oncology Group (TROG)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This is a multi-centre, open label, phase 2, randomised controlled trial of patients with
advanced triple negative breast cancer (TNBC) who have received no more than one line of
chemotherapy (not including neoadjuvant or adjuvant therapy) who will be randomised to be
treated with SABR 20Gy in 1# followed by atezolizumab or SABR 24Gy in 3# followed by
atezolizumab.
Trial website
https://clinicaltrials.gov/show/NCT03464942
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Sherene Loi, Prof
Address 0 0
Peter MacCallum Cancer Centre, Australia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Sherene Loi, Prof
Address 0 0
Country 0 0
Phone 0 0
+61 3 8559 5935
Fax 0 0
Email 0 0
sherene.loi@petermac.org
Contact person for scientific queries

No data has been provided for results reporting
Summary results
Not applicable