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Trial registered on ANZCTR


Registration number
ACTRN12617001325392
Ethics application status
Approved
Date submitted
12/09/2017
Date registered
15/09/2017
Date last updated
1/11/2018
Date data sharing statement initially provided
1/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
BCT 1703 (DIAmOND): Patients with HER2-positive breast cancer that have progressed on prior trastuzumab therapy will be treated with a combination of tremelimumab and durvalumab, in combination with trastuzumab, to evaluate the efficacy of the combination treatment.
Scientific title
BCT 1703 (DIAmOND): An investigator-initiated, non-randomised, phase II study of combination CTLA-4 and PD-L1 blockade in advanced HER2-positive breast cancers who have progressed on prior trastuzumab-based therapy.
Secondary ID [1] 279908 0
BCT 1703
Universal Trial Number (UTN)
Trial acronym
DIAmOND: Double Immune ActivatiON in her2-positive Disease
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced HER2-positive breast cancer 303097 0
Condition category
Condition code
Cancer 285993 285993 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Induction phase (Weeks 1-16):
* Tremelimumab 75 mg every 4 weeks for 4 doses (intravenous);
* Durvalumab 1500 mg every 4 weeks for 4 doses (intravenous);
* Trastuzumab 2mg/kg every week for 16 weeks (intravenous).

Tremelimumab will be administered first. Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion. The duration will be approximately 1 hour for each infusion. A 1 hour observation period is required after the first infusion of durvalumab and tremelimumab. If no clinically significant infusion reactions are observed during or after the first cycle, subsequent infusion observation periods can be at the Investigator’s discretion (suggested 30 minutes after each durvalumab and tremelimumab infusion).
Trastuzumab is given after Tremelimumab and Durvalumab.

Treatment phase (Weeks 17-52):
* Durvalumab 1120 mg every 3 weeks for 12 doses (intravenous); plus
* Trastuzumab 6 mg/kg every 3 weeks for 12 doses (intravenous).

Durvalumab will be administered first, followed by trastuzumab.

All treatments will be administered by site staff trained in chemotherapy administration.
Intervention code [1] 284231 0
Treatment: Drugs
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 286485 0
Percentage of participants alive and progression free, determined by RECIST 1.1
Timepoint [1] 286485 0
At 12 months from study registration.
Secondary outcome [1] 334418 0
Safety and tolerability as documented according to NCI-CTCAE V4.03 and rates of serious adverse events (SAE)
Timepoint [1] 334418 0
Assessed at each cycle (every 4 weeks during induction phase; every 3 weeks in treatment phase) until 12 months from study registration.
Secondary outcome [2] 334422 0
Median progression free survival (PFS) as determined by the investigator using RECIST 1.1 or death from any cause.
Timepoint [2] 334422 0
Assessed at each cycle (every 4 weeks during induction phase; every 3 weeks in treatment phase) until first occurrence of disease progression.
Secondary outcome [3] 334423 0
Objective response rate (ORR) Complete Response (CR) or Partial Response (PR) as best overall response using RECIST 1.1. or death from any cause.
Timepoint [3] 334423 0
Assessed at each cycle (every 4 weeks during induction phase; every 3 weeks in treatment phase) until 12 months from study registration.
Secondary outcome [4] 334424 0
Duration of response as defined by patients with objective responses (CR or PR as best overall response using RECIST 1.1) and first documentation of progression disease.
Timepoint [4] 334424 0
Assessed at each cycle (every 4 weeks during induction phase; every 3 weeks in treatment phase) until first documentation of progressive disease. In the absence of documented progressive disease, follow up will be censored at date of last disease assessment;
Secondary outcome [5] 334425 0
Time to treatment failure.
Timepoint [5] 334425 0
From time of study registration to cessation of investigational study treatment for any reason, including death.
Secondary outcome [6] 334426 0
Clinical benefit rate (CBR) as defined best overall response of CR, PR or SD disease lasting 24 weeks or longer.
Timepoint [6] 334426 0
Assessed at each cycle (every 4 weeks during induction phase; every 3 weeks in treatment phase) until until first documentation of progressive disease.
Secondary outcome [7] 338217 0
Progression Free Survivial by immune modified RECIST.
Timepoint [7] 338217 0
Assessed at each cycle (every 4 weeks during induction phase; every 3 weeks in treatment phase) until 12 months from study registration.
Secondary outcome [8] 338218 0
Median overall survival
Timepoint [8] 338218 0
From time of study registration to death from any cause.
Secondary outcome [9] 343269 0
12 month estimated overall survival.
Timepoint [9] 343269 0
From registration to 12 months after registration

Eligibility
Key inclusion criteria
1) Written informed consent prior to performing any protocol-related procedures, including screening evaluations.

2) Written consent to biological material submission.

3) Female or Male, age >= 18 years.

4) Local histologically confirmed HER2-positive on ISH testing with ERBB2-amplification as demonstrated by ratio ERBB2/centromeres >= 2.0 or mean gene copy number >= 6, unresectable loco-regional or metastatic breast cancer. HER2 status will be confirmed centrally retrospectively.

5) Locally assessed oestrogen receptor status based on mandatory biopsy. ER-positive is defined as >= 1% (any PR expression). ER-negative is defined as ER < 1% (any PR expression);

6) Must have previously received trastuzumab and pertuzumab in either the (neo)adjuvant or advanced disease setting where appropriate in the first line advanced setting.

7) Must have trastuzumab resistant disease, defined by any of the following:
* Demonstrated progression of disease while on-treatment with trastuzumab (monotherapy or combination-based therapy) or trastuzumab emtansine (TDM-1) for metastatic or unresectable loco-regional disease;
* Recurrence considered incurable while on adjuvant trastuzumab or within 12 months of completing adjuvant trastuzumab;
* Any number of prior lines of anti-HER2 therapy is acceptable. Participants for whom the treatment with the current first-line combination of trastuzumab, pertuzumab and taxanes is not an option (e.g. due to refusal, lack of reimbursement or contraindication) can be considered for enrolment into this study;
* Progression/recurrence must have been demonstrated by radiological or clinical assessment.

8) If a participant has received a subsequent anti-HER2 therapy, she/he must also have progressed on the subsequent therapy. Progression must have been demonstrated by radiological or clinical assessment.

9) Body weight > 30 kg.

10) Able to commence treatment within 7 days of registration.

11) Availability of 2 FFPE tumour biopsies or 15-20 slides for retrospective central testing of HER2 positivity, assessment of PD-L1 status, TIL level, and for translational research taken from unresectable loco-regional or metastatic disease obtained =< 1 year prior to enrolment. Alternatively, new tissue material from a recently obtained surgical or diagnostic biopsy can be submitted. Tissue obtained for the biopsy must not have been previously irradiated.
Note: Submission of a tumour biopsy for central pathology review and translational research is mandatory for this study, however central confirmation of HER2-positivity is not required for eligibility. At least two core biopsies should be available.

12) Measurable disease per RECIST v1.1.

13) Have left ventricular ejection fraction (LVEF) of >= 50% or >= institution lower limit of normal (LLN) as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed within 3 months of registration.

14) Participant has ECOG 0-1.

15) Life expectancy > 3 months.

16) Adequate organ and marrow function as defined below:
* Haemoglobin >= 9.0 g/dL;
* Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3);
* Platelet count >= 75 x 10^9/L (> 75,000 per mm^3)
* Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN). In the case of known Gilbert’s syndrome, a higher serum total bilirubin (< 2 x ULN) is allowed;
* AST (SGOT)/ALT (SGPT) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN;
* Creatinine =< 1.5 x ULN or serum creatinine clearance > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
* International Normalized Ratio (INR) or Prothrombin Time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as INR, PT or APTT is within therapeutic range of intended use of anticoagulant.

17) Agrees to use an effective barrier contraceptive method from screening to 7 months after the last dose of trastuzumab, or 180 days after the last dose of durvalumab + tremelimumab combination therapy, or 90 days after the last dose of durvalumab monotherapy (whichever is longest).

18) Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
* Women < 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
* Women >= 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

19) Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations during both the treatment and follow-up phases.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Previous history of primary HER2 non-amplified invasive breast cancer in the last 5 years.

2) Participation in another clinical study with an investigational product during the last 4 weeks before enrolment.

3) Prior cytotoxic treatment less than 3 weeks before the planned first dose of Durvalumab and Tremelimumab.

4) Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA-4, including tremelimumab.

5) No FFPE material to centrally assess HER2-positivity, PD-L1 expression and TIL levels.

6) Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational study treatment. Note: Local surgery of isolated lesions for palliative intent is acceptable.

7) Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) >=470 ms calculated from a single ECG.

8) Female participants who are pregnant or breastfeeding or male or female participants of reproductive potential who are not willing to employ effective birth control from screening to 7 months after the last dose of trastuzumab, or 180 days after the last dose of durvalumab + tremelimumab combination therapy, or 90 days after the last dose of durvalumab monotherapy – whichever is longest will apply.

9) Interstitial lung disease.

10) History of, or active drug-related pneumonitis requiring treatment with steroids.

11) Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on the baseline brain imaging obtained during the screening period or identified prior to signing the Participant Informed Consent Form. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of =< 10mg/day of prednisone or its equivalent for at least 14 days prior to the start of treatment.

12) Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomization.

13) Leptomeningeal disease.

14) Symptomatic pleural effusion, pericardial effusion, or ascites requiring frequent drainage (< 2 weekly).

15) History of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association functional classification > 3), angina, myocardial infarction or ventricular arrhythmia.

16) Previous severe hypersensitivity reaction to treatment with another monoclonal antibody.

17) Active or uncontrolled infection CTCAE V4.03 grade 2 or higher.

18) Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.

19) Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.

20) Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:
* Patients with vitiligo or alopecia;
* Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement;
* Any chronic skin condition that does not require systemic therapy;
*Patients with celiac disease controlled by diet alone.

21) History of primary immunodeficiency.

22) History of allogeneic organ transplant.

23) Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

24) Chemotherapy, radiotherapy, and/or biological cancer therapy (except trastuzumab and endocrine therapy) within 3 weeks prior to the first study dose and has not recovered to CTCAE V4.03 grade 1 or better from adverse events (except alopecia grade 2). Prior chemotherapy induced neuropathy should be grade 2 or better.

25) Any unresolved toxicity NCI CTCAE Grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Chair and the Director/Deputy Director of Research.

26) Live vaccines within 30 days prior to the first dose of investigational study treatment and during investigational study treatment.

27) Previous or concomitant invasive malignancy (except breast cancer). The exceptions are:
* participants with non-breast malignancy >= 5 years ago, treated with curative intent and without evidence of recurrence;
* basal or squamous cell carcinoma of the skin;
* in situ carcinoma without invasion (includes in situ breast carcinoma).

28) Any condition that, in the opinion of the investigator, would interfere with evaluation of investigational study treatment or interpretation of participant safety or study results.

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
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
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)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 12040 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 12041 0
Bendigo Health Care Group - Bendigo Hospital - Bendigo
Recruitment hospital [3] 12042 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [4] 12043 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [5] 12044 0
Mater Private Hospital - South Brisbane
Recruitment hospital [6] 12045 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [7] 12046 0
Royal Hobart Hospital - Hobart
Recruitment hospital [8] 12047 0
St George Hospital - Kogarah
Recruitment hospital [9] 12048 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [10] 12049 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 24197 0
3084 - Heidelberg
Recruitment postcode(s) [2] 24198 0
3550 - Bendigo
Recruitment postcode(s) [3] 24199 0
6150 - Murdoch
Recruitment postcode(s) [4] 24200 0
5042 - Bedford Park
Recruitment postcode(s) [5] 24201 0
4101 - South Brisbane
Recruitment postcode(s) [6] 24202 0
3000 - Melbourne
Recruitment postcode(s) [7] 24203 0
7000 - Hobart
Recruitment postcode(s) [8] 24204 0
2217 - Kogarah
Recruitment postcode(s) [9] 24205 0
4575 - Birtinya
Recruitment postcode(s) [10] 24206 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 284681 0
Other Collaborative groups
Name [1] 284681 0
Breast Cancer Trials
Address [1] 284681 0
PO Box 283
The Junction NSW 2291
Country [1] 284681 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Breast Cancer Trials
Address
PO Box 283
The Junction NSW 2291
Country
Australia
Secondary sponsor category [1] 295274 0
None
Name [1] 295274 0
Address [1] 295274 0
Country [1] 295274 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286681 0
Peter MacCallum Cancer Centre HREC
Ethics committee address [1] 286681 0
Ethics Committee Secretariat
Peter MacCallum Cancer Centre
Locked Bag 1, A/Beckett Street
Victoria 8006
Ethics committee country [1] 286681 0
Australia
Date submitted for ethics approval [1] 286681 0
03/07/2018
Approval date [1] 286681 0
20/09/2018
Ethics approval number [1] 286681 0
HREC/18/PMCC/126

Summary
Brief summary
This study aims to find out if the combination of trastuzumab (anti-HER2 therapy) with durvalumab (PD-L1 inhibitor) and tremelimumab (CTLA4 inhibitor) will reactivate anti-tumour immune response and improve clinical outcomes in trastuzumab-resistant, advanced HER2-positive breast cancer.

Who is it for?
You may be eligible for this study if you are 18 years or older, male or female, and have HER2-positive metastatic or incurable breast cancer that has progressed on previous trastuzumab treatment.

Trial Details.
Up to 4 weeks before starting study treatment, all participants will have either a CT Scan, MRI, or PET with dedicated CT Scan, provide a research tumour biopsy of the cancer (taken within 1 year of starting the study) and research blood tests.

Study treatment takes place in 2 phases:
1) Induction Phase (weeks 1-16); and
2) Treatment Phase (weeks 17-52).

Induction Phase
During the Induction Phase, participants will receive:
1) 4 doses of durvalumab (1 dose every 4 weeks), administered intravenously;
2) 4 doses of tremelimumab (1 dose every 4 weeks), administered intravenously;
3) 16 doses of trastuzumab (1 dose every week), administered intravenously.

Oestrogen-receptor-positive patients will also start or continue endocrine therapy (aromatase inhibitor and/or GnRH agonist).

Participants will be clinically assessed prior to each study treatment. Two core biopsies, if feasible, will be taken from the same site as the initial biopsy about 3 weeks after starting study treatment. A research blood sample will be taken before the 3rd dose of study treatment.

Treatment Phase
Participants will receive durvalumab and trastuzumab every 3 weeks for 12 doses (total 36 weeks). Tremelimumab will not be given.

Participants will be clinically assessed prior to each study treatment. . A research blood sample will be taken every 9 weeks, before each dose of study treatment.

During the study (Induction and Treatment Phases), heart function tests (ECHO or MUGA) will be performed every 3 months as per standard of care, or as clinically indicated.

The full length of treatment is 52 weeks (1 year). After completing study treatment, patients will be followed every 3 months by either clinic visits or via telephone.
Trial website
www.breastcancertrials.org.au
Trial related presentations / publications
Public notes
Breast Cancer Trials formerly known as Australia & New Zealand Breast Cancer Trials Group.

Contacts
Principal investigator
Name 33755 0
A/Prof Sherene Loi
Address 33755 0
Division of Cancer Medicine, Department of Medical Oncology
Peter MacCallum Cancer Centre
Locked Bag 1, A'Beckett Street
MELBOURNE VIC 8006
Country 33755 0
Australia
Phone 33755 0
+61 3 8559 5935
Fax 33755 0
Email 33755 0
corinna.beckmore@bctrials.org.au
Contact person for public queries
Name 17002 0
Ms Corinna Beckmore
Address 17002 0
BCT
PO Box 283
The Junction NSW 2291
Country 17002 0
Australia
Phone 17002 0
+61 2 4925 5235
Fax 17002 0
Email 17002 0
corinna.beckmore@bctrials.org.au
Contact person for scientific queries
Name 7930 0
A/Prof Sherene Loi
Address 7930 0
Division of Cancer Medicine, Department of Medical Oncology
Peter MacCallum Cancer Centre
Locked Bag 1, A'Beckett Street
MELBOURNE VIC 8006
Country 7930 0
Australia
Phone 7930 0
+61 3 8559 5935
Fax 7930 0
Email 7930 0
corinna.beckmore@bctrials.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
Data sharing process for this study is in development and will be updated as soon as it is available
What supporting documents are/will be available?
Other
'Other' documents specified
Available documents to be confirmed.
Summary results
Not applicable