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Trial registered on ANZCTR


Registration number
ACTRN12619001117101
Ethics application status
Approved
Date submitted
31/07/2019
Date registered
12/08/2019
Date last updated
26/11/2023
Date data sharing statement initially provided
12/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
BCT 1901 (CAPTURE): Women or men with oestrogen receptor positive, HER2 negative advanced breast cancer and PIK3CA mutant circulating DNA will be randomised to evaluate treatment with alpelisib plus fulvestrant compared with capecitabine on progression free survival.
Scientific title
BCT 1901 (CAPTURE): A phase II randomised study to evaluate alpelisib plus fulvestrant versus capecitabine in oestrogen receptor positive, HER2-negative advanced breast cancer patients with PIK3CA mutant circulating DNA.
Secondary ID [1] 298709 0
BCT 1901
Universal Trial Number (UTN)
Trial acronym
CAPTURE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Breast Cancer 313614 0
Condition category
Condition code
Cancer 312047 312047 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Alpelisib at a dose of 300 mg will be administered by oral tablet once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in combination with fulvestrant 500 mg intramuscular every 28 days.

Pre- or peri-menopausal women will also receive a 3.6 mg goserelin implant under the skin every 28 days.

Participants will be given a patient diary to monitor their alpelisib administration; the diary will be checked at each treatment visit.

Treatment will continue until one of the following criteria applies:
* Documented disease progression#;
* Intercurrent illness that prevents further administration of treatment;
* Unacceptable adverse event(s) or toxicity;
* Withdrawal of consent;
* Investigator decision;
* Protocol non-compliance.
# Study treatment may continue after a restaging scan showing RECIST 1.1 progressive disease, if the investigator considers the participant to be experiencing ongoing clinical benefit, for up to 8 weeks or until confirmation of progressive disease on a subsequent staging scan (whichever comes first), after discussion with BCT and the Study Chairs.

All participants who discontinue treatment for reasons other than disease progression will continue to be followed for documentation of progression by RECIST 1.1 until disease progression, death, withdrawal of consent, or loss to follow-up. If a participant starts a new antineoplastic treatment without withdrawing consent, the participant will continue to be followed until disease progression, death, withdrawal of consent or loss to follow-up.
Intervention code [1] 314969 0
Treatment: Drugs
Comparator / control treatment
Capecitabine at a dose of 1000 mg/m^2 will be administered by oral tablet twice daily on Day 1 to 14 of a 21 day cycle.

Participants will be given a patient diary to monitor their capecitabine administration; the diary will be checked at each treatment visit.
Treatment will continue until one of the following criteria applies:
* Documented disease progression#;
* Intercurrent illness that prevents further administration of treatment;
* Unacceptable adverse event(s) or toxicity;
* Withdrawal of consent;
* Investigator decision;
* Protocol non-compliance.
# Study treatment may continue after a restaging scan showing RECIST 1.1 progressive disease, if the investigator considers the participant to be experiencing ongoing clinical benefit, for up to 8 weeks or until confirmation of progressive disease on a subsequent staging scan (whichever comes first), after discussion with BCT and the Study Chairs .
Control group
Active

Outcomes
Primary outcome [1] 320684 0
Progression Free Survival (PFS) measured as per RECIST 1.1
Timepoint [1] 320684 0
The duration of time from randomisation until the date of progression or death from any cause.
Secondary outcome [1] 372476 0
Objective Response Rate (ORR) measured as per RECIST 1.1; the percentage of participants who have achieved either complete response (CR) or partial response (PR) to the therapeutic intervention; the denominator is randomised participants.
Timepoint [1] 372476 0
The time from randomisation to the date of either complete response (CR) or partial response (PR).
Secondary outcome [2] 372477 0
Clinical Benefit Rate (CBR) measured as per RECIST 1.1; the percentage of participants who have achieved either complete response (CR), partial response (PR) or stable disease (SD) for at least 6 months (24 weeks) to the therapeutic intervention; the denominator is randomised participants.
Timepoint [2] 372477 0
Complete response (CR), partial response (PR), or stable disease (SD) for at least 24 weeks.
Secondary outcome [3] 372478 0
Duration of Response (DoR) measured as per RECIST 1.1.
Timepoint [3] 372478 0
The time from the first documentation of objective tumour response (PR or CR) to the first documentation of objective tumour progression. DoR assessment will be limited to participants who achieved either a complete response (CR) or partial response (PR).
Secondary outcome [4] 372479 0
Safety of combination treatment with alpelisib plus fulvestrant measured by adverse events and laboratory abnormalities graded according to the NCI-CTCAE v5.0.

Adverse events will be assessed by clinical examination and participant self-report and described by:
1) NCI-CTCAE V5.0 terms – Common Terminology Criteria for Adverse Events;
2) Duration (start and end dates);
3) Severity Grade;
4) Relationship to study treatment (suspected/not suspected);
5) Action taken with regard to study treatment (e.g. omitted, discontinued);
6) Whether the event was reported as a Serious Adverse Event (SAE).

For potential Adverse Events for CAPTURE, please see list of side effects (Cancer Fields).
Timepoint [4] 372479 0
Frequency of adverse events from the date pre-screening informed consent is signed and up to 28 days after completion of study treatment.
Secondary outcome [5] 372482 0
Tolerability of combination treatment with alpelisib plus fulvestrant measured by adverse events and laboratory abnormalities graded according to the NCI-CTCAE v5.0.

Adverse events will be assessed by clinical examination and participant self-report and described by:
1) NCI-CTCAE V5.0 terms – Common Terminology Criteria for Adverse Events;
2) Duration (start and end dates);
3) Severity Grade;
4) Relationship to study treatment (suspected/not suspected);
5) Action taken with regard to study treatment (e.g. omitted, discontinued);
6) Whether the event was reported as a Serious Adverse Event (SAE).

For potential Adverse Events for CAPTURE, please see list of side effects (Cancer Fields).
Timepoint [5] 372482 0
Dose reductions and drug interruptions due to adverse events events from the date pre-screening informed consent is signed and up to 28 days after completion of study treatment.

Eligibility
Key inclusion criteria
PRE-SCREENING
For inclusion in the pre-screening, participants must fulfil all the following criteria:
1. Female or Male, >= 18 years.
2. Advanced (locoregionally recurrent not amenable to curative therapy, or metastatic) ER-positive, HER2-negative breast cancer, histologically defined as:
a. ER positive: Locally assessed oestrogen receptor status based on assessment of primary or metastatic disease. ER-positive is defined as >=10% (any PR expression) by immunohistochemistry irrespective of staining intensity.
b. HER2 negative:
i. IHC 1+, as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of invasive tumour cells; OR
ii. IHC 0, as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within <= 10% of the invasive tumour cells; OR
iii. ISH (FISH or SISH) negative based on:
* Single-probe average HER2 copy number < 4.0 signals/cell, OR
* Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell.
3. ECOG performance status of 0–1.
4. No more than two prior lines of endocrine therapy for treatment of advanced disease setting (no prior fulvestrant).
5. No more than one line of chemotherapy for treatment of advanced breast cancer (no prior capecitabine).

RANDOMISATION
In addition to the above listed pre-screening inclusion criteria, participants must fulfil all of the following criteria prior to randomisation:
1. PIK3CA mutation (PIK3CA E542K, E545K, H1047L or H1047R mutation) identified through ctDNA testing.
2. Progression of disease during or after CDK4/6 inhibitor (i.e. ribociclib, palbociclib, abemaciclib) AND AI therapy (i.e. letrozole, anastrozole, exemestane) in the (neo) adjuvant OR advanced disease setting.
3. Evaluable disease (i.e. at least one measurable or non-measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
4. Adequate organ function:
a. Haematology: Absolute neutrophil count >= 1.5 × 10^9/L, Platelets >= 90 × 10^9/L, Haemoglobin >= 9.0 g/dL
b. Hepatic Function:
i. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 × ULN. If the participant has liver metastases, ALT and AST <= 5 × ULN. In addition, the elevated ALT or AST values must be stable for 2 weeks without evidence of biliary obstruction by imaging;
ii. Total bilirubin < 2 x ULN (any elevated bilirubin should be asymptomatic at screening)except for participants with Gilbert’s syndrome who may only be included if the total bilirubin is <= 3.0 × ULN or direct bilirubin <= 1.5 × ULN.
c. Renal Function; Creatinine Clearance >= 35 mL/min using Cockcroft-Gault formula;
d. Calcium (corrected for serum albumin) and magnesium with normal limits or <= Grade 1 according to NCI-CTCAE V5.0 if judged clinically not significant by the investigator;
e. Potassium within normal limits, or corrected with supplements;
f. Blood Chemistry;
i. Fasting plasma glucose (FPG) <= 6.0 mmol/L and Glycosylated Haemoglobin (HbA1c) <= 6.5% (both criteria have to be met);
ii. Fasting Serum amylase <= 2 × ULN;
iii. Fasting Serum lipase <= ULN.
5. Participants with metastatic CNS tumours may participate in this study if they are:
a. Four weeks from completion of prior therapy for CNS disease (including radiation and surgery) to starting study treatment;
b. Clinically stable with respect to the CNS tumour at the time of screening as determined by clinical examination and brain imaging (MRI or CT);
c. Not receiving steroid therapy at commencement of study treatment.
6. Female participants must have confirmation of menopausal status.
a. Participants assigned fulvestrant should be functionally postmenopausal. Pre- or peri-menopausal women can be enrolled if amenable to be treated with goserelin.
b. Female participants will be clinically defined as pre- or peri-menopausal unless one of the following criteria is met for the definition of postmenopausal:
i. Prior surgical bilateral oophorectomy;
ii. Age >= 60 years;
iii. Age 50 to 59 years with oestradiol, FSH and LH levels within the laboratory’s reference range for postmenopausal females (in the absence of ovarian suppression).
N.B. Female participants < 50 years will be considered pre- or peri-menopausal regardless of oestradiol, FSH and LH levels. This is because of the difficulties in ascertaining if menopause is permanent in women, particularly in those < 50 years, who have received prior chemotherapy and/or GnRH agonists and/or oral endocrine therapy.
13. Signed informed consent and is willing and able to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations;
a. Must also consent for donation of archival diagnostic tumour specimens, if available, for further correlative science research as specified in the protocol and Participant Information Sheet and Consent Form.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any disease burden that makes participants ineligible for endocrine therapy as per the investigator’s best judgement.
2. Prior treatment with capecitabine, fulvestrant, any PI3K, mTOR or AKT inhibitor.
3. Known hypersensitivity or contra-indication to alpelisib, fulvestrant or capecitabine.
4. Concurrently using other anti-cancer therapy. Exception: goserelin.
5. Previous or concomitant invasive malignancy. The exceptions are:
a. participants with non-breast malignancy >= 3 years ago, treated with curative intent and without evidence of recurrence;
b. basal or squamous cell carcinoma of the skin or non-melanomatous skin cancer;
c. in situ carcinoma without invasion (includes in situ breast carcinoma);
d. curatively resected cervical cancer.
6. Radiotherapy <= 2 weeks prior to randomisation, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia).
7. Prior endocrine therapy <= 2 weeks prior to randomisation. Exception: goserelin.
8. Prior chemotherapy <= 2 weeks prior to randomisation.
9. Surgery <= 2 weeks prior to randomisation or has not recovered from major side effects.
10. Not recovered from all toxicities related to prior anticancer therapy to NCI-CTCAE V5.0 Grade <= 1. Exception: patients with any grade of alopecia or menopausal symptoms.
11. Participation in a prior investigational study within 30 days prior to the start of study treatment or within 5 half-lives of the investigational product, whichever is longer.
12. Established diagnosis of type I diabetes mellitus, type II diabetes mellitus requiring anti-hyperglycaemic medication or any participant with HbA1c > 6.5%.
13. Currently documented pneumonitis/interstitial lung disease.
14. Child Pugh score B or C.
15. Clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following:
a. History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis, or myocardial infarction within 6 months prior to the start of study treatment;
b. History of documented congestive heart failure (New York Heart Association functional classification III-IV);
c. Left Ventricular Ejection Fraction (LVEF) < 50% as determined by echocardiogram (ECHO);
d. Clinically significant cardiac arrhythmias, (e.g. ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block without pacemaker in place);
e. Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) >= 160 mmHg and/or Diastolic Blood Pressure (DBP) >= 100 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening;
f. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or corrected QT interval > 470msec at screening (using Fridericia correction);
g. Bradycardia (heart rate < 50 at rest), by ECG or pulse.
16. History of acute pancreatitis within 1 year of screening or a past medical history of chronic pancreatitis.
17. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs based on investigator discretion.
18. Known history of Human Immunodeficiency Virus (HIV) infection (testing not mandatory).
19. Other non-malignant systemic diseases (cardiovascular, renal, hepatic, lung, etc.) that would prevent prolonged follow-up.
20. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, lung disease, liver 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 participant to give written informed consent.
21. Currently receiving any of the following medications and cannot be discontinued 7 days prior to randomisation:
a. Strong inducers of CYP3A4;
b. Inhibitors of Breast Cancer Resistance Protein (BCRP).
22. Unresolved osteonecrosis of the jaw.
23. History of Stevens-Johnson-Syndrome (SJS), Erythema Multiforme (EM), or Toxic Epidermal Necrolysis (TEN).
24. Currently receiving or has received systemic corticosteroids <= 2 weeks prior to randomisation, or who has not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways disease), eye drops or local injections (e.g. intra-articular).
25. Pregnant or lactating at the time of randomisation. A pregnancy test is recommended for women of child-bearing potential who are sexually active and not using reliable contraceptive methods.
26. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 6 months after stopping the study treatment. Highly effective contraception methods include:
a. Total abstinence;
b. Female sterilisation (bilateral oophorectomy, total hysterectomy or tubal ligation at least 6 weeks prior to screening);
c. Male partner sterilisation (at least 6 months prior to screening) if the sole partner of a female participant on the study.
d. Copper (non-hormonal) intra-uterine device (IUD).
27. Sexually active males unless they are sterilized (at least 6 months prior to screening) or use a condom during intercourse while taking drug and for at least 6 months after stopping alpelisib and/or Fulvestrant medication and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. In addition, male participants must not donate sperm during study and up to the time period specified above.
28. Not able to understand and to comply with study instructions and requirements.

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
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2020
Actual
3/08/2020
Date of last participant enrolment
Anticipated
30/06/2025
Actual
Date of last data collection
Anticipated
30/06/2026
Actual
Sample size
Target
66
Accrual to date
46
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 15747 0
Ballarat Health Services (Base Hospital) - Ballarat Central
Recruitment hospital [2] 15748 0
Border Medical Oncology - Albury
Recruitment hospital [3] 15749 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [4] 15750 0
Epworth Richmond - Richmond
Recruitment hospital [5] 15751 0
Peninsula Oncology Centre - Frankston
Recruitment hospital [6] 15752 0
Latrobe Regional Hospital - Traralgon
Recruitment hospital [7] 15753 0
Liverpool Hospital - Liverpool
Recruitment hospital [8] 15754 0
Maroondah Hospital - Ringwood East
Recruitment hospital [9] 15755 0
Mater Sydney - North Sydney
Recruitment hospital [10] 15756 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [11] 15757 0
Nepean Hospital - Kingswood
Recruitment hospital [12] 15758 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [13] 15759 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [14] 15760 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [15] 15761 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [16] 15762 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [17] 15763 0
Southwest Health Care - Warrnambool - Warrnambool
Recruitment hospital [18] 15764 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [19] 15765 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [20] 15766 0
Westmead Hospital - Westmead
Recruitment hospital [21] 20601 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [22] 22663 0
Icon Cancer Centre Hobart - Hobart
Recruitment postcode(s) [1] 29178 0
3350 - Ballarat Central
Recruitment postcode(s) [2] 29179 0
2640 - Albury
Recruitment postcode(s) [3] 29180 0
2298 - Waratah
Recruitment postcode(s) [4] 29181 0
3121 - Richmond
Recruitment postcode(s) [5] 29182 0
3199 - Frankston
Recruitment postcode(s) [6] 29183 0
3844 - Traralgon
Recruitment postcode(s) [7] 29184 0
2170 - Liverpool
Recruitment postcode(s) [8] 29185 0
3135 - Ringwood East
Recruitment postcode(s) [9] 29186 0
2060 - North Sydney
Recruitment postcode(s) [10] 29187 0
3168 - Clayton
Recruitment postcode(s) [11] 29188 0
2747 - Kingswood
Recruitment postcode(s) [12] 29189 0
3000 - Melbourne
Recruitment postcode(s) [13] 29190 0
2444 - Port Macquarie
Recruitment postcode(s) [14] 29191 0
4102 - Woolloongabba
Recruitment postcode(s) [15] 29192 0
5011 - Woodville
Recruitment postcode(s) [16] 29193 0
0810 - Tiwi
Recruitment postcode(s) [17] 29194 0
3280 - Warrnambool
Recruitment postcode(s) [18] 29195 0
6008 - Subiaco
Recruitment postcode(s) [19] 29196 0
2010 - Darlinghurst
Recruitment postcode(s) [20] 29197 0
2145 - Westmead
Recruitment postcode(s) [21] 35393 0
5112 - Elizabeth Vale
Recruitment postcode(s) [22] 37940 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 303262 0
Government body
Name [1] 303262 0
National Health and Medical Research Council
Country [1] 303262 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] 303489 0
None
Name [1] 303489 0
Address [1] 303489 0
Country [1] 303489 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303800 0
Peter MacCallum Cancer Centre HREC
Ethics committee address [1] 303800 0
Ethics committee country [1] 303800 0
Australia
Date submitted for ethics approval [1] 303800 0
11/11/2019
Approval date [1] 303800 0
12/12/2019
Ethics approval number [1] 303800 0
HREC/57079/PMCC-2019

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

Contacts
Principal investigator
Name 94854 0
Prof Sarah-Jane Dawson
Address 94854 0
Department of Medical Oncology
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 94854 0
Australia
Phone 94854 0
+61 3 8559 7132
Fax 94854 0
Email 94854 0
[email protected]
Contact person for public queries
Name 94855 0
Corinna Beckmore
Address 94855 0
Breast Cancer Trials
PO Box 283
The Junction NSW 2291
Country 94855 0
Australia
Phone 94855 0
+61 2 4925 5235
Fax 94855 0
Email 94855 0
[email protected]
Contact person for scientific queries
Name 94856 0
Sarah-Jane Dawson
Address 94856 0
Department of Medical Oncology
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 94856 0
Australia
Phone 94856 0
+61 3 8559 7132
Fax 94856 0
Email 94856 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Anonymised Individual Patient Data (IPD) collected during the trial.
When will data be available (start and end dates)?
Data will be made available for request after publication of the main/final study results; no end date.

Note that there may be additional circumstances preventing BCT from sharing requested data as outlined in the BCT Data Sharing Guidelines.
Available to whom?
Researchers who submit a research proposal and BCT Data Request Application, which is assessed by BCT to have appropriate scientific value. Refer to the BCT Data Sharing Guidelines.
Available for what types of analyses?
To achieve the aims in the approved proposal.
How or where can data be obtained?
Subject to approval by Breast Cancer Trials [email protected] (refer to BCT Data Sharing Guidelines).


What supporting documents are/will be available?




Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.