PAlbociclib and Circulating Tumor DNA for ESR1 Mutation Detection

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Mar 2017 → ongoing

Decision date (initial)

2024-06-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer

External identifiers

EU CT number

2024-510704-37-00

EudraCT number

2016-004360-18

ClinicalTrials.gov

NCT03079011

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Population STEP1 to 3 : To assess the global safety of the combination of palbociclib + endocrine therapy in the whole population of patients, throughout the study, including the potential sequential administration of fulvestrant plus palbociclib, with focus on hematological toxicities.
Population STEP2 : To assess whether a change of the hormone therapy associated with palbociclib (namely, an early switch from aromatase inhibitor with palbociclib to fulvestrant with palbociclib following ctDNA detection) will benefit patients in which rising ESR1 mutations are detected during treatment with palbociclib and aromatase inhibitor.

Secondary objectives 8

1. Population STEP 3 : To assess PFS in patients undergoing a cross-over following RECIST tumor progression in Arm A, from the start of crossover.
2. Population STEP1&2 all included patients : To report the efficacy (progression-free survival (PFS) defined on conventional RECIST criteria) of palbociclib combined with hormone therapy (aromatase inhibitor or fulvestrant), from the date of initial inclusion into the trial.
3. Population STEP2&3 - Arm A & B : To assess whether, in patients with rising ESR1 mutations, the early switch (switch following ctDNA detection) to fulvestrant leads a longer time to strategy failure from randomization, than a late switch (cross-over following RECIST tumor progression)
4. Population STEP2&3 - Arm A & B : To assess whether, in patients with rising ESR1 mutations, the early switch (switch following ctDNA detection) to fulvestrant leads a longer chemotherapy-free survival from randomization, than a late switch (cross-over following RECIST tumor progression).
5. All population STEP 1 to 3 : To obtain additional safety data in a broad patient population treated with palbociclib and hormone therapy (aromatase inhibitor or fulvestrant) in a general oncology practice context.
6. All population STEP1 to 3 : To study the patient’s reported quality of life before and until 2 years of therapy
7. All population STEP1 to 3 : To report the anti-cancer treatments received after the first line therapy, and the overall survival of included patients.
8. Translational objectives (optional translational study) : To report the quantitative and qualitative analyses of circulating tumor DNA detection before and during therapy, the comparison with archived tumor tissue, clinical/pathological characteristics and efficacy of therapy.

Conditions and MedDRA coding

ER+/HER2- metastatic breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 22

1. STEP1 : Women with proven loco-regionally recurrent or metastatic disease adenocarcinoma of the breast not amenable to curative therapy with disease considered potentially sensitive to aromatase inhibitor
2. STEP 1 : Age ≥18 years;
3. STEP 1 : Life expectancy > 3 months;
4. STEP 1 : Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2;
5. STEP 1 : Estrogen Receptor-positive and HER2-negative breast cancer. Where available, assessment of Estrogen Receptor status should be based on the most recent tumor sample; to be considered as ERpositive, the most recent breast cancer tissue examined must display at least 10% of cancer cells with positive ER staining;
6. STEP 1 : Tumor block (primary tumor or metastasis) available;
7. STEP 1 : No prior systemic anti-cancer therapy for metastatic or advanced disease (chemotherapy targeted therapy or hormone therapy); prior initiation of LHRH agonist or bone-directed agents is however allowed);
8. STEP 1 : Menopausal patients or patients with suppressed ovarian function
9. STEP 1 : Patients may have measurable (according to Response Evaluation Criterion in Solid Tumors (RECIST v1.1) or not measurable disease
10. STEP 1 : Adequate organ and marrow function as defined : Hemoglobin ≥ 90 g/L; Absolute neutrophil count ≥ 1.5 G/L; Platelet count ≥ 100 G/L; Serum bilirubin ≤ 1.5 × ULN. This will not apply to patients with confirmed Gilbert’s syndrome; ALT and AST ≤ 3 × ULN; Alkaline phosphatase ≤ 2.5× ULN; Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 60 mL/min as determined by Cockcroft-Gault (using actual body weight) formula for females [creatinine clearance =Weight (kg) × (140 - Age) × 0.85 (mL/min)/ (72 × serum creatinine (mg/dL))
11. STEP 1 : Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and any protocol-related procedures including screening evaluations;
12. STEP 1 : Resolution of all acute toxic effects or prior anti-cancer therapy or surgical procedures to NCI-CTCAE version 4.03 grade 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion);
13. STEP 1 : Written informed consent obtained prior to performing any protocol-related procedures including screening evaluations;
14. STEP 1 : Patient affiliated to a social security system.
15. STEP 2 : Patients included and treated within the PADA-1 protocol, who received a combination of aromatase inhibitor and palbociclib;
16. STEP 2 : Detection of a rise in circulating ESR1 mutation as defined in the protocol;
17. STEP 2 : Absence of concomitant RECIST 1.1 proven tumor progression;
18. STEP 2 : Life expectancy > 3 months;
19. STEP 2 : Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2;
20. STEP 2 : Patients who have been properly informed and have signed the informed consent of the randomized part of the protocol.
21. STEP 3 : Patients who have been included in the PADA-1 study, who were randomized for the no-change arm (Arm A) upon rising ESR1 ctDNA;
22. STEP 3 : Patients who have recent documented tumor progression (RECIST 1.1).

Exclusion criteria 21

1. STEP 1 : Locally advanced breast cancer or loco-regional relapse amenable for any treatment with curative intent;
2. STEP 1 : HER2-positive or equivocal tumor status either on the primary or on the recurrent tumor, defined as IHC3+, Fish/Cish amplified or Fish/Cish equivocal according to the ASCO2015 criteria;
3. STEP 1 : Prior endocrine therapy in the metastatic setting is not allowed;
4. STEP 1 : Prior treatment with any CDK 4/6 inhibitor in the adjuvant or metastatic setting (neoadjuvant/preoperative treatment is allowed); however, prior therapy with another targeted treatment in the adjuvant setting is allowed;
5. STEP 1 : Visceral crisis: Advanced, symptomatic, visceral spread that is at risk of life-threatening complication in the short term and that requires chemotherapy;
6. STEP 1 : Any major surgery (defined as requiring general anaesthesia) or significant traumatic injury within 4 weeks of treatment initiation or patients that may require major surgery during the course of the study; however, surgical diagnostic procedure is allowed (even if under general anaesthesia);
7. STEP 1 : Known active, bleeding diathesis;
8. STEP 1 : Any serious known concomitant systemic disorder incompatible with the study (at the discretion of investigator), previous history of bleeding diathesis, or anti-coagulation treatment (the use of low molecular weight heparin is allowed);
9. STEP 1 : Patients unable to swallow tablets;
10. STEP 1 : History of mal-absorption syndrome or other condition that would interfere with enteral absorption;
11. STEP 1 : Chronic daily treatment with corticosteroids with a dose of ≥ 10mg/day methylprednisolone equivalent (excluding inhaled steroids);
12. STEP 1 : Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral oedema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable and off anticonvulsants and steroids for at least 4 weeks before treatment start;
13. STEP 1 : Known hypersensitivity to letrozole, anastrozole, exemestane, fulvestrant, palbociclib or any of their excipients;
14. STEP 1 : Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia);
15. STEP 1 : Patients treated within the last 7 days prior to treatment start in the trial with drug that are known to be CYP3A4 inhibitors, drugs that are known to be CIP3A4 inducers, or with patients who underwent a grapefruit and grapefruit juice cure;
16. STEP 1 : Patients already included in another therapeutic trial evaluating an investigational medicinal product or having received an investigational medicinal product within 3 months;
17. STEP 1 : History of previous: Any stage II, III, IV cancer within 5 years preceding patient enrollment in the trial – however multiple breast cancers (controlateral/ipsilateral cancers/local relapses) are allowed pending all tumor masses were ER+; Any history of hematological malignancy.
18. STEP 1 : Persons deprived of their freedom or under guardianship or incapable of giving consent;
19. STEP 1 : Pregnancy or lactation period. Women of childbearing potential must implement adequate nonhormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization; LHRH agonist cannot be considered as an efficient contraceptive measure) during study treatment and for 90 days after discontinuation. A serum pregnancy test must be negative in premenopausal women or women with amenorrhea of less than 12 months.
20. STEP 2 : Patients who have stopped the aromatase inhibitor therapy for more than 4 consecutive weeks;
21. STEP 2 : Patients with a visceral crisis linked to their underlying breast cancer;

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The Progression-Free Survival (PFS) will be measured from the time of randomization (following rising ESR1 mutation detection) to the time of tumor progression (as assessed by the investigator per RECIST v1.1 criteria (Eisenhauer 2009)) or death (whichever comes first) – in randomized patients. Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor assessments as primary data source.
2. The safety will be assessed by the collection of grade ≥3 adverse events, using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 – in all included patients. The co-primary analysis will focus on grade ≥3 hematological toxicities and their associations with baseline characteristics.

Secondary endpoints 8

1. Progression-Free Survival will be measured from the time of cross-over to the time of tumor progression (as assessed by the investigator per RECIST 1.1) or death (whichever comes first) – in all patients undergoing the crossover.
2. Progression-Free Survival will be measured from the time of inclusion to the time of tumor progression (as assessed by the investigator per RECIST 1.1) or death (whichever comes first) – in all included patients including those switched to fulvestrant.
3. Time to strategy failure will be measured from the time of randomization until palbociclib+endocrine therapy discontinuation or death (whichever comes first)– in all randomized patients.
4. Chemotherapy-free survival will be measured from the time of randomization until the date of chemotherapy initiation or death (whichever comes first)– in all randomized patients. Anticancer treatments received after the study treatment discontinuation will be described.
5. Description of all extra-hematological grade ≥3 toxicities and SAEs incidence rate in the overall population and each treatment step.
6. Overall Survival measured from the date of inclusion to that of the patient’s death – in all included patients.
7. Quality of life score obtained through self-administered QLQ-C30 questionnaire at baseline, at randomization, and every 2 cycles until disease progression (including patients who perform a late switch from arm A to B) or until two years after inclusion whatever the step if patient did not undergo disease progression or rising ctDNA before 2 years.
8. Translational end points : ctDNA detection at different time points.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 82 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications