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PAlbociclib and Circulating Tumor DNA for ESR1 Mutation Detection (PADA-1)

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ClinicalTrials.gov Identifier: NCT03079011
Recruitment Status : Active, not recruiting
First Posted : March 14, 2017
Last Update Posted : March 4, 2019
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
UNICANCER

Brief Summary:
This study is a randomized, open-label, multicentric, phase III trial conducted in patients receiving aromatase inhibitor and palbociclib as first line therapy for estrogen receptor (ER)-positive HER2-negative metastatic breast cancer and which aims to evaluate, at the onset of ESR1 mutations in circulating tumor DNA, the efficacy of a change of the hormone therapy (aromatase inhibitor (AI) changed to fulvestrant) combined to palbociclib, together with the safety of hormone therapy and palbociclib combination in the overall population.

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Drug: Palbociclib 125mg Drug: Aromatase Inhibitors Drug: Fulvestrant Injectable Product Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 800 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Step 1: 800 patients screened for circulating blood ESR1 mutation detection at regular intervals will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off (28-day cycle) + AI (letrozole, anastrozole or exemestane) administered once daily in a continuous scheme (EoT if RECIST tumor progression or ESR1 mutation detection)

Step 2: 160 Patients with a rising circulating ESR1 mutation and without tumor progression will be randomized (1:1):

  • ARM A: no change in therapy. EoT if tumor progression or possibility of a cross-over (step 3)
  • ARM B: palbociclib 125 mg + fulvestrant 500 mg administered intramuscularly on D1,15 and 29 and once monthly thereafter. EoT if RECIST tumor progression
  • Step 3 (cross over): 80 patients who have been randomized in arm A will be offered to be treated by fulvestrant + palbociclib, after having progressed under AI + palbociclib. The EoT will occur at the tumor progression under fulvestrant + palbociclib
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized, Open Label, Multicentric Phase III Trial to Evaluate the Safety and Efficacy of Palbociclib in Combination With HTdriven by ctDNA ESR1 Mutation Monitoring in ER+, HER2-negative Metastatic Breast Cancer Patients
Actual Study Start Date : March 22, 2017
Estimated Primary Completion Date : April 15, 2022
Estimated Study Completion Date : April 15, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: A- palbociclib + AI
After randomization, the patient will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with an aromatase inhibitor (letrozole, anastrozole or exemestane, according to physician's choice and according their respective summary product characteristics) administered once daily in a continuous scheme.
Drug: Palbociclib 125mg
Palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle

Drug: Aromatase Inhibitors
Letrozole: 2.5 mg once daily on a continuous scheme (tablets, per os) Anastrozole:1 mg once daily on a continuous scheme (tablets , per os) Exemestane: 25 mg once daily on a continuous scheme (tablets, per os)
Other Name: Letrozole, Anastrozole or exemestane

Experimental: B- Palbociclib + fulvestrant
After randomization, the patient will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with fulvestrant, a selective estrogen receptor down-regulator, 500 mg administered intramuscularly on Days 1, 15, and 29 and once monthly thereafter.
Drug: Palbociclib 125mg
Palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle

Drug: Fulvestrant Injectable Product
500 mg by intramuscular injection on days 1 and 15 of cycle one and then on day one of each subsequent cycle (28 days)

Experimental: Selection - Palbociclib + AI
All patients included into the study will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with an aromatase inhibitor (letrozole, anastrozole or exemestane, according to physician's choice and according their respective summary product characteristics) administered once daily in a continuous scheme
Drug: Palbociclib 125mg
Palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle

Drug: Aromatase Inhibitors
Letrozole: 2.5 mg once daily on a continuous scheme (tablets, per os) Anastrozole:1 mg once daily on a continuous scheme (tablets , per os) Exemestane: 25 mg once daily on a continuous scheme (tablets, per os)
Other Name: Letrozole, Anastrozole or exemestane




Primary Outcome Measures :
  1. Co-primary :safety until randomization [ Time Frame: an average of 24 months ]
    Safety: global safety of the combination of palbociclib + endocrine therapy in the whole population of patients, throughout the study with focus on hematological toxicities. Safety of patients will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

  2. Co-primary : efficacy from randomization [ Time Frame: an average of 12 months (until disease progression) ]
    Efficacy: 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. Progression-Free Survival (PFS) will be measured from the time of randomization to the time of tumor progression (as assessed by the investigator per RECIST v1.1) or death (whichever comes first) - in randomized patients.


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: from inclusion to death of the patient (average of 36 months) ]
    Overall Survival measured from the date of inclusion to that of the patient's death - in all included patients

  2. quality of life by quality of life questionnaire (QLQ)-C30 [ Time Frame: at baseline, at randomization, and every 2 cycles until disease progression an average of 24 months ]
    To study the patient's reported quality of life before and throughout therapy. 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).

  3. other line of therapy [ Time Frame: during follow-up (2 years) ]
    To report the anti-cancer treatments received after the first line therapy, and the overall survival of included patients.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Women with proven loco-regionally recurrent or metastatic adenocarcinoma of the breast not amenable to curative therapy with disease considered potentially sensitive to aromatase inhibitors Note: patients relapsing while on adjuvant tamoxifen or other non-aromatase inhibitor adjuvant endocrine therapy are eligible for the present study; patient relapsing after 6 years or more under adjuvant aromatase inhibitor are eligible.
  2. Age ≥18 years;
  3. Life expectancy >3 months;
  4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2;
  5. Estrogen Receptor (ER)-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 ER-positive, the most recent breast cancer tissue examined must display at least 10% of cancer cells with positive ER staining;
  6. Tumor block (primary tumor or metastasis) available;
  7. 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. Menopausal patients or patients with suppressed ovarian function Women with bilateral oophorectomy

    Postmenopausal women, as defined by any of the following criteria:

    Age 60 or over;

    Age 50 to 59 years and meets one of the following criteria:

    Amenorrhea for ≥24 months and follicle-stimulating hormone within the postmenopausal range; patients with hysterectomy or chemotherapy-induced amenorrhea must display follicle-stimulating hormone within the postmenopausal range; Other women, provided they are being treated with monthly LHRH analogues (first injection performed ≥7 days before the treatment initiation) and are willing to continue to receive LHRH agonist therapy for the duration of the trial;

  9. Patients may have measurable (according to Response Evaluation Criterion in Solid Tumors (RECIST v1.1) or not measurable disease Patients with only blastic bone lesions are not eligible; Patients with only pleural, cardiac or peritoneal effusion or meningeal carcinomatosis are not eligible;
  10. Adequate organ and marrow function as defined below:

    Hemoglobin ≥90 g/L Absolute neutrophil count ≥1.5 G/L Platelet count ≥100 G/L Serum bilirubin ≤1.5 × upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome.

    ALT and AST ≤3 × ULN; Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone or liver metastases present) 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. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and any protocol-related procedures including screening evaluations;
  12. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.0 Grade 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion);
  13. Written informed consent obtained prior to performing any protocol-related procedures including screening evaluations;
  14. Patient affiliated to a social security system.

Exclusion Criteria:

  1. Locally advanced breast cancer or loco-regional relapse amenable for any treatment with curative intent;
  2. 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. Prior endocrine therapy in the metastatic setting is not allowed;
  4. 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. Visceral crisis: Advanced, symptomatic, visceral spread that is at risk of life-threatening complication in the short term and that requires chemotherapy;
  6. 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 performed under general anaesthesia);
  7. Known, active bleeding diathesis;
  8. Any serious known concomitant systemic disorder (e.g. known active infection including HIV, or cardiac disease) 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. Patients unable to swallow tablets;
  10. History of mal-absorption syndrome or other condition that would interfere with enteral absorption;
  11. Chronic daily treatment with corticosteroids with a dose of ≥ 10mg/day methylprednisolone equivalent (excluding inhaled steroids);
  12. Known active uncontrolled or symptomatic central nervous system (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. Known hypersensitivity to letrozole, anastrozole, exemestane, fulvestrant, palbociclib or any of their excipients;
  14. QTcF >480 msec on basal assessment, personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP);
  15. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia);
  16. 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, drugs that are known to prolong the QT interval; who underwent a grapefruit cure;
  17. Patients already included in another therapeutic trial evaluating an investigational medicinal product or having received an investigational medicinal product within 3 months;
  18. History of previous:

    Any other stage II, III, IV cancer within 5 years preceding patient enrollment in the trial - however, multiple primary breast cancers (controlateral/ipsilateral cancers/local relapses) are allowed pending all tumor masses were ER+; Any history of hematological malignancy;

  19. Persons deprived of their freedom or under guardianship or incapable of giving consent;
  20. Pregnancy or lactation period. Women of childbearing potential must implement adequate non-hormonal 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03079011


Locations
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France
Centre Leon Berard
Lyon, France
Institut Curie
Paris, France, 75005
Gustave Roussy
Villejuif, France, 94805
Sponsors and Collaborators
UNICANCER
Pfizer
Investigators
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Principal Investigator: François-Clément BIDARD, MD PhD Institut Curie

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Responsible Party: UNICANCER
ClinicalTrials.gov Identifier: NCT03079011     History of Changes
Other Study ID Numbers: UC-0140/1615 - UCBG3-05
First Posted: March 14, 2017    Key Record Dates
Last Update Posted: March 4, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by UNICANCER:
ESR1 mutation detection, ctDNA
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Letrozole
Fulvestrant
Palbociclib
Anastrozole
Exemestane
Aromatase Inhibitors
Antineoplastic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Protein Kinase Inhibitors