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Trial registered on ANZCTR


Registration number
ACTRN12621000639820
Ethics application status
Approved
Date submitted
11/02/2021
Date registered
28/05/2021
Date last updated
7/04/2024
Date data sharing statement initially provided
28/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase II basket study of an ARomatase inhibitor plus PI3KCA inhibitor or CDK4/6 inhibitor in women with hormone receptor positive recurrent/metastatic Gynaecological Neoplasms (PARAGON-II)
Scientific title
The activity and tolerability of Aromatase inhibitor plus PI3KCA inhibitor or CDK4/6 inhibitor in women with hormone receptor positive recurrent/metastatic gynaecological neoplasms (PARAGON-II) .
Secondary ID [1] 303187 0
None
Universal Trial Number (UTN)
Trial acronym
PARAGON-II
Linked study record
This trial builds on the PARAGON study (ACTRN12610000796088) that treated more than 300 patients with HR+ gynaecological cancers with an aromatase inhibitor. The study aims to investigate if the combination treatments of letrozole plus alpelisib, and letrozole plus ribociclib, will lead to an increase in overall response rates, as compared to historical controls from the PARAGON trial, in HR+ advanced gynaecological cancers that are either PIK3CA-mutated or PIK3CA non-mutated.

Health condition
Health condition(s) or problem(s) studied:
Platinum resistant high-grade epithelial cancers of ovary 321226 0
Low grade epithelial cancers of ovary 321272 0
Endometrial cancer 320319 0
Leiomyosarcomas 321270 0
Other gynaecological cancers (excluding endometrial cancers) 321273 0
Platinum resistant high-grade epithelial cancers of fallopian tube 321267 0
Platinum resistant high-grade epithelial cancers of primary peritoneum 321268 0
Endometrial stromal sarcomas 321269 0
Granulosa cell tumours 321271 0
Condition category
Condition code
Cancer 319042 319042 0 0
Womb (Uterine or endometrial cancer)
Cancer 319061 319061 0 0
Other cancer types
Cancer 319043 319043 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will have letrozole 2.5 mg daily continuously until disease progression, unmanageable toxicity, or withdrawal for another reason. Participants will be allocated to these 2 treatment groups based on PIK3CA mutation status:
- PIK3CA mutant group (cohort A and F) will receive letrozole 2.5 mg oral tablet once daily continuously, plus alpelisib 300 mg oral tablet once daily continuously until disease progression or intolerance
- PIK3CA non-mutated wild-type/unknown group (cohort B, C, D and E) will receive letrozole 2.5 mg oral tablet once daily continuously, plus ribociclib 600 mg oral capsule once daily with a 3-week-on/1-week-off schedule until disease progression or intolerance. Oral letrozole will continue during the 1 week off ribociclib treatment.

The study cohorts are as follows:
(A) PIK3CA mutated endometrial cancers
(B) PIK3CA wild-type/unknown endometrial cancers
(C) PIK3CA wild-type/unknown platinum resistant high-grade epithelial cancers of ovary, fallopian tube and primary peritoneum
(D) PIK3CA wild-type/unknown endometrial stromal sarcomas, leiomyosarcomas, granulosa cell tumours
(E) PIK3CA wild-type/unknown low grade epithelial cancers of ovary
(F) PIK3CA mutated gynaecological cancers (excluding endometrial cancers)
Intervention code [1] 319492 0
Treatment: Drugs
Comparator / control treatment
Comparison will be made against data collected from the PARAGON trial (ACTRN12610000796088) conducted from 2011 to 2020.
Control group
Historical

Outcomes
Primary outcome [1] 326470 0
Effects on Objective Response Rate (ORR) according to RECIST 1.1 in participants with target lesions, and CA125 progression defined by GCIG criteria in participants with ovarian cancer who have no target lesions.

ORR in each cohort is defined as the proportion of participants with an objective tumour response (CR + PR) at 12 weeks divided by the total number of participants with measurable disease at baseline in that cohort.
The study database will record the number of participants with an objective tumour response at 12 weeks and the number of participants with measurable disease at baseline in that cohort.

For ovarian cancer/fallopian tube cancer/primary peritoneum cancer patients (cohort C), ORR is determined by RECIST and for those with no measurable disease by CA125 (Composite Outcome).

For endometrial and rare gynaecological cancers (cohorts A, B, D, F), ORR is determined by RECIST
Timepoint [1] 326470 0
12 weeks post baseline
Secondary outcome [1] 391602 0
Progression Free Survival.
PFS is defined as the interval from date of registration to the date of first evidence of disease progression (assessed according to RECIST 1.1. criteria and radiological responses) or death, whichever occurs first.
PFS at 6-months refers to the proportion of participants who have not progressed and are alive at that time. Participants who discontinue study drugs for any reason, but have no documented progression, will be censored at the time of commencing alternative anti-cancer therapies. Evidence of disease progression will be assessed according to radiological findings.
Timepoint [1] 391602 0
6 months post registration
Secondary outcome [2] 391601 0
Duration of response.
The study database will record the participant's objective tumour response and disease progression. This will be assessed according to RECIST 1.1. criteria and radiological responses will be captured in the study database.
Timepoint [2] 391601 0
Duration of response is defined as time between the first documented objective tumour response to therapy and subsequent disease progression.
Secondary outcome [3] 391600 0
Disease control rate.
Disease control rate (DCR) is defined as the proportion of participants experiencing a Complete Response, Partial Response, or stable disease at 12 weeks. This will be assessed according to RECIST 1.1. criteria and radiological responses will be captured in the study database.
Timepoint [3] 391600 0
12 weeks post baseline
Secondary outcome [4] 393383 0
MOST-T24(v2) to measure symptom benefit in patients with recurrent ovarian cancer receiving palliative chemotherapy.
Timepoint [4] 393383 0
From baseline, and within +/- 7 days of week 7 and 13, and then once every 12 weeks (i.e. week 25 onwards) until disease progression for a maximum of 36 months
Secondary outcome [5] 391604 0
Effects on safety and tolerability of treatment (rates of adverse events as per CTCAE v5.0).
Adverse events will be recorded in the study database.
Timepoint [5] 391604 0
AEs will be recorded from the first dose of study treatment until 90 days after cessation of study treatment.
Secondary outcome [6] 393382 0
QLQ-OV28 to assess a comprehensive range of relevant issues: abdominal/gastrointestinal symptoms, peripheral neuropathy, hormonal/menopausal symptoms, body image, attitude to disease/treatment and sexual functioning.
Timepoint [6] 393382 0
From baseline, and within +/- 7 days of week 7 and 13, and then once every 12 weeks (i.e. week 25 onwards) until disease progression for a maximum of 36 months
Secondary outcome [7] 393381 0
EORTC QLQ-C30 to assess the different domains of QOL.
Timepoint [7] 393381 0
From baseline, and within +/- 7 days of week 7 and 13, and then once every 12 weeks (i.e. week 25 onwards) until disease progression for a maximum of 36 months

Eligibility
Key inclusion criteria
1. People aged 18 years and older with one of the following histologically-proven gynaecological cancers with recurrence/metastases:
a. Endometrial cancer, where chemotherapy is not clinically indicated. Participants who were previously treated with chemotherapy and/or immunotherapy and/or multikinase inhibitor (either in adjuvant or metastatic setting) and/or a progestogen and/or aromatase inhibitor will be eligible;
b. Platinum-resistant, high-grade epithelial cancer of the ovary, fallopian tube or primary peritoneum, defined as disease recurrence within 6 months of completion of previous line platinum-based chemotherapy and in whom chemotherapy is not clinically indicated and who have not had prior endocrine therapy as treatment for platinum-resistant ovarian cancer;
c. Low grade serous ovarian cancer where chemotherapy is not clinically indicated or previously treated with up to two-lines of endocrine therapy, provided they have not progressed within 6 months of aromatase inhibitor. Prior chemotherapy or targeted treatment (e.g. KRAS/MEK inhibitor) will also be permitted;
d. Rare gynaecological cancers defined as Low grade endometroid ovarian cancer, Endometrial Stromal Sarcoma, Leiomyosarcoma or Granulosa Cell Tumour, where chemotherapy is not clinically indicated. Participants who were previously treated with one-line chemotherapy (either in adjuvant or metastatic setting), and/or a progestogen and/or aromatase inhibitor will also be eligible.
2. Post-menopausal as defined by:
(i) age 60 or more, or
(ii) age 45–59 and satisfying the following criteria: Amenorrhoea for at least 12 months and FSH in post-menopausal range with an intact uterus, or
(iii) age 18 or more, and having had a bilateral oophorectomy
3. Evaluable disease defined as:
- measurable disease as per RECIST v1.1, and/or
- elevated CA125 as per GCIG criteria (for ovarian/fallopian tube/primary peritoneal cancer subgroups only), and/or
- elevated (above the institutional ULN) total inhibin and/or inhibin A and/or inhibin B (for granulosa cell sub-group only).
4. ECOG performance status of 0-2.
5. Tumours must be hormone receptor positive (either oestrogen-positive, or progesterone-positive, or both). At least 10% of tumour cells must stain positive for oestrogen-receptor and/or progesterone-receptor, or an Allred Histoscore of 3 or more.
6. Archival tumour block/slides must be confirmed available at registration. If archival tissue is not available, a recent tissue biopsy is required. Participants are not permitted to be enrolled without available tissue, archival or recent biopsy.
7. Adequate bone marrow function defined as;
- haemoglobin greater than or equal to 9.0 g/dL,
- platelets greater than or equal 100 x 10^9/L, and
- ANC greater than or equal to 1.5 x 10^9/L
8. Adequate renal function with creatinine clearance greater than or equal to 30 ml/min.
9. INR less than or equal to 1.5 (unless the participant is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study treatment)
10. Participants must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of study treatment:
- Potassium,
- Magnesium, and
- Total Calcium (corrected for serum albumin).
11. Adequate liver function defined as:
- Total bilirubin less than ULN except for participants with Gilbert’s syndrome who may only be included if the total bilirubin is less than or equal to 3.0 × ULN or direct bilirubin less than or equal to 1.5 × ULN.
- Aspartate transaminase (AST) less than 2.5 × ULN, except for participants with liver metastasis, who are only included if the AST is less than 5 × ULN
- Alanine transaminase (ALT) less than 2.5 × ULN, except for participants with liver metastasis, who are only included if the ALT is less than 5 × ULN
12. Standard 12-lead ECG values defined as the mean of the triplicate ECGs:
- QTcF interval at screening less than 450 msec (QT interval using Fridericia’s correction),
- Mean resting heart rate 50-90 bpm (determined from the ECG).
13. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
14. Signed, written informed consent.

Inclusion criteria specific only to cohorts A, B and F only
15. Glycosylated Haemoglobin (HbA1c) less than or equal to 8.5%.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Participant has a known hypersensitivity to letrozole or any of its excipients.
2. Participants currently receiving any hormone replacement therapy for management of post-menopausal symptoms. [Note: A washout period of 4 weeks is required.]
3. Untreated osteoporosis.
4. Specific comorbidities or conditions (e.g. psychiatric) that might limit the ability of the participant to comply with the protocol.
5. Other non-malignant co-morbidities or conditions that may compromise assessment of key outcomes.
6. Life expectancy of less than 3 months.
7. Other active malignancy as assessed by treating clinician.
8. Active hepatitis B or C infection (defined as detectable level for hepatitis B DNA or hepatitis C RNA).
9. Participant with liver failure with Child Pugh score B or C.
10. Known serologically positive for human immunodeficiency virus (HIV).
11. Participants unable to swallow orally administered medications and participants with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel resection).
12. Clinically significant, uncontrolled heart disease and/or cardiac repolarisation abnormality, including any of the following:
- History of documented angina pectoris, myocardial infarction, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to study entry,
- Documented cardiomyopathy,
- History of congestive heart failure, known Left Ventricular Ejection Fraction less than 50%,
- Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
i) Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcaemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia,
ii) Concomitant medication(s) with a known risk to prolong QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting study treatment),
iii) Inability to determine the QTcF interval
- 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),
- Systolic blood pressure greater than 160 or less t han 90 mmHg,
- On screening, in participants without pacemaker, any of the following cardiac parameters: PR interval greater than 220 msec, QRS interval greater than 109 msec, or QTcF greater than 450 msec.
13. Participants receiving any prohibited medications which cannot be discontinued 7 days prior to study enrolment; with the exception of prior chemotherapy which requires at least 28-day washout prior to study enrolment.
14. Participant has not recovered from acute toxicities related to prior anti-cancer therapies. Exception to this criterion: participants with Grade 1 taxane-induced neuropathy, any grade of alopecia, amenorrhea or other toxicities not considered a safety risk for the participant as per Investigator’s discretion, are allowed to enter the study.
15. Participant has not received extended-field radiotherapy less than or equal to 4 weeks or limited field radiotherapy less than or equal to 2 weeks prior to registration, and has not recovered to Grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the participant at Investigator’s discretion). [Note: Participants in whom greater than or equal to 25% of the bone marrow has been previously irradiated are also excluded.]
16. Participants with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
- At least 4 weeks from the prior therapy completion (including radiation and/or surgery) to starting the study treatment and
- Clinically stable CNS tumour at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases.
17. Surgery within 14 days of starting study drug or is still recovering from major side effects.
18. Participant is currently receiving or has received systemic corticosteroids =2 weeks prior to starting study drug, or who has not fully recovered from side effects of such treatment.
Note: The following uses of corticosteroids are permitted: a short duration (<5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).

Exclusion criteria specific only to ribociclib arm (cohorts B, C, D, E)
19. Participant is currently receiving any of the following substances and cannot be discontinued 7 days prior to cycle 1 day 1 (C1D1):
• Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, pomelos, star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of CYP3A4/5,
• Medications that have a narrow therapeutic window and are predominantly metabolised through CYP3A4/5.
20. Participant has a known hypersensitivity to ribociclib or to any of its excipients.


Exclusion criteria specific only to alpelisib and letrozole arm (cohorts A and F)
21. Participant has currently documented pneumonitis/interstitial lung disease (the chest CT scan performed before start of study treatment for the purpose of tumour assessment should be reviewed to confirm that there are no relevant pulmonary complications present).
22. Participant has a history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis.
23. Participant has a history of severe cutaneous reaction, such as Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
24. Participant has a known hypersensitivity to alpelisib or to any of its excipients.
25. Prior therapy with an inhibitor of PI3K, AKT, CDK4/6 or mTOR.
26. Participants with an established diagnosis of diabetes mellitus type I or not controlled type II (based on HbA1c; see Inclusion Criterion 15).
27. Participant with unresolved osteonecrosis of the jaw.

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
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Analyses will be performed for each cohort. The number and percentage of participants achieving efficacy outcomes of ORR and DCR will be calculated with corresponding 95% confidence intervals. Rates will be based on participants receiving at least 2 weeks (intention-to-treat) of treatment, as well as participants who were on study for at least 6 weeks (evaluable for response/clinical benefit). A similar approach will be used for reporting of adverse events involving all participants who receive a single cycle of study treatment. Analyses of progression-free survival and response duration will be analysed using the Kaplan-Meier method. Kaplan-Meier survival curves will be constructed for graphical display and the median reported with 95% CI. HRQOL will be analysed using change scores, t tests and suitable regression methods. Comparisons will be 2-tailed, using a nominal significance level of 0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/08/2022
Actual
4/08/2022
Date of last participant enrolment
Anticipated
1/08/2024
Actual
Date of last data collection
Anticipated
1/11/2024
Actual
Sample size
Target
182
Accrual to date
100
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 22965 0
Royal Hospital for Women - Randwick
Recruitment hospital [2] 23536 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [3] 22964 0
Prince of Wales Hospital - Randwick
Recruitment hospital [4] 23731 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 24949 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [6] 22963 0
Border Medical Oncology - Albury
Recruitment hospital [7] 24457 0
Royal Hobart Hospital - Hobart
Recruitment hospital [8] 23226 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [9] 22893 0
Westmead Hospital - Westmead
Recruitment hospital [10] 22894 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [11] 22892 0
Newcastle Private Hospital - New Lambton Heights
Recruitment hospital [12] 26379 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [13] 24126 0
Wollongong Hospital - Wollongong
Recruitment hospital [14] 25530 0
Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [15] 24458 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [16] 24125 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 40040 0
4101 - South Brisbane
Recruitment postcode(s) [2] 38199 0
2145 - Westmead
Recruitment postcode(s) [3] 38270 0
2031 - Randwick
Recruitment postcode(s) [4] 38198 0
2305 - New Lambton Heights
Recruitment postcode(s) [5] 39634 0
2500 - Wollongong
Recruitment postcode(s) [6] 38952 0
2065 - St Leonards
Recruitment postcode(s) [7] 39633 0
6009 - Nedlands
Recruitment postcode(s) [8] 38594 0
3000 - Melbourne
Recruitment postcode(s) [9] 42352 0
5042 - Bedford Park
Recruitment postcode(s) [10] 38200 0
3168 - Clayton
Recruitment postcode(s) [11] 38269 0
2640 - Albury
Recruitment postcode(s) [12] 40601 0
2485 - Tweed Heads
Recruitment postcode(s) [13] 41352 0
2050 - Camperdown
Recruitment postcode(s) [14] 40039 0
7000 - Hobart
Recruitment postcode(s) [15] 39170 0
4029 - Herston
Recruitment outside Australia
Country [1] 26240 0
New Zealand
State/province [1] 26240 0
Auckland

Funding & Sponsors
Funding source category [1] 307593 0
Government body
Name [1] 307593 0
Australian Government - Medical Research Future Fund (MRFF)
Country [1] 307593 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
University of Sydney, Camperdown NSW 2006
Country
Australia
Secondary sponsor category [1] 308284 0
Other Collaborative groups
Name [1] 308284 0
Australia New Zealand Gynaecological Oncology Group
Address [1] 308284 0
Level 6, Chris O'Brien Lifehouse
119-143 Missenden Road
Camperdown, NSW 2050
Country [1] 308284 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307648 0
Sydney Local Health District (SLHD) - RPA Zone Research Ethics and Governance
Ethics committee address [1] 307648 0
Ethics committee country [1] 307648 0
Australia
Date submitted for ethics approval [1] 307648 0
27/01/2021
Approval date [1] 307648 0
11/05/2021
Ethics approval number [1] 307648 0
X21-0018

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

Contacts
Principal investigator
Name 107998 0
A/Prof Chee Khoon Lee
Address 107998 0
NHMRC Clinical Trials Centre
Level 6, Chris O'Brien Lifehouse
119-143 Missenden Road
Camperdown NSW 2050
Country 107998 0
Australia
Phone 107998 0
+61 2 9562 5365
Fax 107998 0
Email 107998 0
chee.lee@sydney.edu.au
Contact person for public queries
Name 107999 0
PARAGON-II Trial Operations Coordinator
Address 107999 0
NHMRC Clinical Trials Centre
Level 6, Chris O'Brien Lifehouse
119-143 Missenden Road
Camperdown NSW 2050
Country 107999 0
Australia
Phone 107999 0
+61 2 9562 5000
Fax 107999 0
Email 107999 0
paragon2.study@sydney.edu.au
Contact person for scientific queries
Name 108000 0
Katrina Diamante
Address 108000 0
NHMRC Clinical Trials Centre
Level 6, Chris O'Brien Lifehouse
119-143 Missenden Road
Camperdown NSW 2050
Country 108000 0
Australia
Phone 108000 0
+61 2 9562 5000
Fax 108000 0
Email 108000 0
paragon2.study@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Currently no plan and participant informed consent will be required.


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseNovel therapeutics in low-grade serous ovarian cancer.2023https://dx.doi.org/10.1136/ijgc-2022-003677
N.B. These documents automatically identified may not have been verified by the study sponsor.