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RecruitingLast updated: 9 January 2024

PARAGON II: This phase II study is evaluating the effectiveness of hormone therapy (letrozole) when combined with targeted therapy (alpelisib or ribociclib) in post-menopausal women with advanced gynaecological cancers that are hormone-receptor positiveThe 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)

Clinical summary

Summary

Eligible participants will be allocated to one of two treatment groups based on their PIK3CA mutation status. Participants in the PIK3CA mutation group will receive letrozole (2.5mg) oral tablets once daily continuously, plus alpelisib (300mg) oral tablet once daily continuously until disease progression or intolerance. Participants in the PIK3CA non-mutated wild-type/unknown group will receive letrozole (2.5mg) oral tablet once daily continuously, plus ribociclib (600mg) 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.

Conditions

This trial is treating patients with hormone-receptor positive endometrial cancer, endometrial stromal sarcoma, leiomyosarcoma, granulosa cell tumours, low grade epithelial cancer of the ovary, platinum resistant high-grade epithelial cancers of the ovary, fallopian tube and peritoneum,, and other gynaecological cancers

Cancer

Multi-Cancer Multi-Cancer

Age

People18+

Phase

II

Trial Acronym

PARAGON II

More information

Trial Identifiers

Use the hyperlinks, where available to access additional clinical trial information.

Trial sponsor

University of Sydney,Australia New Zealand Gynaecological Oncology Group (ANZGOG)

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)

Eligibility

Inclusion

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%.

Exclusion

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.

Inclusion

  • You have had treatment, but your cancer has come back.
  • Your cancer has spread to other parts of the body.

Exclusion

  • You have been diagnosed with a prior or secondary type of cancer.
  • You have certain types of non-cancer medical conditions.
  • You have had certain treatments, surgical procedures or drugs.
Message

Clinical trials have complex eligibility criteria.

Ask your doctor if this trial could be right for you.

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