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HR+/HER2- Advanced Breast Cancer and Endocrine Resistance (PASIPHAE)

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ClinicalTrials.gov Identifier: NCT03322215
Recruitment Status : Recruiting
First Posted : October 26, 2017
Last Update Posted : September 18, 2020
Sponsor:
Information provided by (Responsible Party):
Theodoros Foukakis, Karolinska University Hospital

Brief Summary:

This is a randomized, 2-arm, open-label, multicenter, international phase II trial. A total of 196 patients will be included.

The study will include patients with metastatic Hormone Receptor positive / Human Epidermal Growth Factor Receptor (HER2) negative breast cancer with progressive disease after endocrine treatment.

Patients will be randomized (1:1) between two treatment arms: A. palbociclib + fulvestrant and b. capecitabine.


Condition or disease Intervention/treatment Phase
Breast Cancer Metastatic Drug: Palbociclib Drug: Fulvestrant Drug: Capecitabine Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 196 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, International, Multicenter, Open-labeled, Randomized Trial of PAlbociclib and Fulvestrant vs. Standard Oral Capecitabine In Patients With Hormone Receptor (HR)+ / HER2- Advanced Breast Cancer and Documented Endocrine Resistance
Actual Study Start Date : October 24, 2017
Estimated Primary Completion Date : October 31, 2021
Estimated Study Completion Date : October 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Palbociclib and fulvestrant

Combination of palbociclib and fulvestrant

Palbociclib:

125 mg capsule administered orally once daily for 21 consecutive days followed by 7 days off treatment. Dose modification is recommended based on individual safety and tolerability.

Fulvestrant:

500 mg administered intramuscularly on days 1 and 15 of cycle 1, and then on day 1 of each subsequent 28-day cycle.

Drug: Palbociclib
75-125 mg capsule orally once daily for 21 consecutive Days followed by 7 Days of treatment.
Other Name: Ibrance

Drug: Fulvestrant
500 mg intramuscularly Days 1 and 15 of cycle 1, and then on Day 1 of each subsequent 28-days cycle.
Other Name: Faslodex

Active Comparator: Capecitabine
1,000 mg/m2 tablet administered orally twice daily for 2 weeks followed by one week of rest. Depending on adverse reactions, both dose escalation and dose reductions will be performed.
Drug: Capecitabine
Oral tablet 500 - 1,250 mg/m2 twice Daily, for 2 weeks followed by 1 week of rest.
Other Name: Xeloda




Primary Outcome Measures :
  1. Progression free survival (PFS), as assessed locally by the investigator. [ Time Frame: Time from the date of randomization to the date of progression, assessed up to 5 years. ]
    Time to progression will be measured according to the RECIST criteria (version 1.1). Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and - together with other lesions that are denoted as non-target lesions - followed until disease progression.


Secondary Outcome Measures :
  1. Health related quality of life score EuroQol (EQ-5D) [ Time Frame: Baseline to progression up to 2 years ]
    Change from baseline to Health related quality of life score EuroQol (EQ-5D)

  2. Health related quality of life score EORTC QLQ-C30 [ Time Frame: Baseline to progression up to 2 years ]
    European Organisation for Research and Treatment of Cancer Quality of Life Instrument (EORTC QLQ-C30).

  3. Health related quality of life score EORTC QLQ-BR23 [ Time Frame: Baseline to progression up to 2 years ]
    European Organisation for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ-BR23).

  4. Correlation of efficacy measures with tumor Biomarkers [ Time Frame: Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years.. ]
    PgR IHC status (10% cut-off), will be correlated with PFS

  5. Correlation of efficacy measures with tumor Biomarkers [ Time Frame: Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years. ]
    Ki67 IHC status, will be correlated with PFS

  6. Correlation of efficacy measures with tumor Biomarkers [ Time Frame: Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years. ]
    ESR1 DNA somatic mutation status, will be correlated with PFS

  7. Correlation of efficacy measures with tumor Biomarkers [ Time Frame: Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years. ]
    Somatic mutations in cancer genes identified by sequencing, will be correlated with PFS

  8. Correlation of efficacy measures with tumor Biomarkers [ Time Frame: Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years. ]
    SET index, will be correlated with PFS

  9. Overall survival (OS) [ Time Frame: Time from randomization to death from any cause, assessed up to 5 years. ]
    Overall survival from time of randomization to death from any cause.

  10. 1-year survival [ Time Frame: Time from randomization to death from any cause, assessed up to 5 years. ]
    1-year survival rate from time of randomization to death from any cause.

  11. 2-year survival [ Time Frame: Time from randomization to death from any cause, assessed up to 5 years. ]
    2-year survival rate from time of randomization to death from any cause.

  12. Objective response [ Time Frame: From randomization until end of treatment, assessed up to 5 years. ]
    Objective tumor response will be measured according to the RECIST criteria (version 1.1). Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and - together with other lesions that are denoted as non-target lesions - followed until disease progression.

  13. Duration of response [ Time Frame: From randomization until end of treatment, up to 5 years. ]
    Response duration will be measured from the time measurement criteria for complete response (CR)/ partial response (PR) (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented.

  14. Clinical Benefit Rate [ Time Frame: From randomization until end of treatment, up to 5 years. ]
    Clinical Benefit Rate is defined as CR+PR+stable disease (SD) for > 24 weeks

  15. Frequency of adverse events (AE) [ Time Frame: From randomization until 28 days after the last dose of study medication, assessed up to 5 years. ]
    Adverse events will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0



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:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Women 18 years or older.
  2. Postmenopausal, defined by at least one of the following criteria:

    1. Prior bilateral oophorectomy
    2. Age ≥60
    3. Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and estradiol in the postmenopausal range according to the local laboratory reference. Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol are needed to ensure postmenopausal status. OR Pre/perimenopausal if treated with goserelin that was initiated at least 4 weeks prior to randomization.
  3. Locally advanced or metastatic breast cancer deemed not amenable to curative surgery or curative radiation therapy.
  4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  5. Known estrogen-receptor positive and/or progesterone receptor positive breast cancer reported by local laboratory.
  6. Known HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing.
  7. Documented resistance to endocrine therapy (tamoxifen or aromatase inhibitors) defined as:

    1. Recurrence while on or within 12 months after the end of adjuvant endocrine treatment OR
    2. Progression while on or within 1 month after the end of endocrine treatment for advanced disease
  8. Previous chemotherapy for breast cancer including an anthracycline and a taxane (only one line for metastatic disease) is permitted.
  9. Radiological or other objective evidence (eg. new skin lesions or new lymph node lesions) of recurrence during or after the most recent systemic therapy for recurrent / metastatic disease prior to randomization.
  10. At least one tumor lesion accessible for biopsy that is a non-bone lesion or a predominantly lytic bone lesion, and that measures at least 10 mm in largest diameter. This lesion must not have been treated previously with irradiation (although the area may have been irradiated before the occurrence of the lesion).
  11. Patient is interested to participate in the trial, including the obligatory biopsies at a metastatic site/site before the start of study treatment.
  12. Clinically and/or radiographically documented measurable disease according to RECIST v1.1 criteria or bone-only disease with at least one predominantly lytic or mixed bone lesion. For measurable disease, at least one site of disease must have largest tumor diameter of at least:

    1. 10 mm if measured by CT-scan, ultrasound, or physical exam
    2. 20 mm if measured by Chest X-ray
    3. 15 mm if suspiciously enlarged lymph node (short axis) see Eisenhauer et al. for more details All radiology studies must be performed within 28 days prior to registration (35 days if negative).
  13. Adequate bone-marrow, hepatic and renal function defined as laboratory tests within 7 days prior to enrollment:

    1. Hematology: Absolute granulocytes > 1.5 x 109/L, Platelets > 100 x 109/L
    2. Biochemistry: Bilirubin ≤ 1.5 x upper limit of normal (ULN), Serum creatinine ≤ 1.5 x ULN.
  14. 14. APTT and INR ≤ 1.5 x ULN or institution accepted values for biopsy within 7 days prior to enrollment.
  15. Signed written informed consent provided by the patient.

Exclusion Criteria:

  1. Previous treatment with a CDK4/6 inhibitor, mTOR or PI3K inhibitor, fulvestrant or capecitabine. Short-term (<28 days) exposure to mTOR or PI3K inhibitor in the (neo)adjuvant setting is allowed.
  2. More than one prior chemotherapy lines for metastatic breast cancer. Previous (neo)adjuvant chemotherapy or for radically treated local or regional relapse is allowed in addition to one prior chemotherapy line for metastatic breast cancer Note: A chemotherapy line in advanced disease is an anticancer regimen that contains at least one chemotherapy agent and is given for 21 days or longer. If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease progression and the decision for its discontinuation was taken within 21 days after starting it, then this regimen does not count as a "prior line of chemotherapy". Chemotherapy regimens composed of more than one drug are considered as one line of therapy.
  3. No measurable lesions amenable to biopsy (e.g. pleural effusion, ascites, skin rash, sclerotic bone etc).
  4. CNS metastases unless asymptomatic and adequately controlled with surgery or radiotherapy. Stable CNS disease is defined as CNS metastases or cord compression that have been definitively treated and the patient is clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization.
  5. Leptomeningeal carcinomatosis
  6. Advanced, symptomatic visceral spread (visceral crisis) with risk of life-threatening complications in the short term.
  7. Concurrent malignancy of any site, except adequately controlled limited basal cell carcinoma or squamous-cell carcinoma of the skin, in situ melanoma or carcinoma in situ of the cervix.
  8. Active cardiac disease or a history of cardiac dysfunction including any of the following:

    1. History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry
    2. History of documented congestive heart failure (New York Heart Association functional classification III-IV)
    3. Documented cardiomyopathy
    4. QTc > 480 msec as measured by Bazett's formula, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
    5. Uncontrolled hypertension.
  9. Patients being treated with drugs recognized as strong inhibitors or inducers of the isoenzyme CYP3A (including, but not limited, to - see table 6 - Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Ritonavir, Telithromycin) continuously for at least 7 days during any time period in the last 2 weeks prior to randomization.
  10. Subjects with known dihydropyrimidine dehydrogenase (DHPD) deficiency or previous severe reactions to a fluoropyrimidine.
  11. Known abnormalities in coagulation such as bleeding diathesis or ongoing treatment with anticoagulants that preclude intramuscular administration of drugs.
  12. Ongoing pregnancy or lactation.
  13. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
  14. A previous metastatic tumor biopsy reported to be negative for both estrogen receptor and progesterone receptor (i.e. <1% for both), or positive for HER2 status (amplified ERBB2).

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): NCT03322215


Contacts
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Contact: Theodoros Foukakis, MD PhD +468 517 795 53 theodoros.foukakis@ki.se

Locations
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Sweden
Sahlgrenska University Hospital Recruiting
Göteborg, Sweden, 413 45
Contact: Barbro Linderholm, MD PhD    + 46 31 342 79 41    barbro.linderholm@oncology.gu.se   
Principal Investigator: Barbro Linderholm, MD PhD         
Skåne University Hospital Recruiting
Malmö, Sweden, 205 02
Contact: Marie Klintman, MD PhD    +46 46 17 85 54    marie.klintman@med.lu.se   
Principal Investigator: Marie Klintman, MD PhD         
S:t Görans Hospital Recruiting
Stockholm, Sweden, 112 19
Contact: Hanjing Xie, MD PhD       Hanjing.Xie@capiostgoran.se   
Contact: Maria Enkullen-Moskovits       Maria.Enkullen-Moskovits@capiostgoran.se   
Principal Investigator: Hanjing Xie, MD PhD         
Karolinska University Hospital Recruiting
Stockholm, Sweden
Contact: Theodoros Foukakis, MD PhD       theodoros.foukakis@ki.se   
Principal Investigator: Theodoros Foukakis, MD PhD         
Uppsala University Hospital Recruiting
Uppsala, Sweden, 751 85
Contact: Henrik Lindman, MD PhD       henrik.lindman@igp.uu.se   
Principal Investigator: Henrik Lindman, MD PhD         
United Kingdom
NHS Grampian Not yet recruiting
Aberdeen, United Kingdom, AB15 6RE
Contact: Trevor McGoldrick, MD PhD         
Principal Investigator: Trevor McGoldrick, MD PhD         
Western General Hospital Not yet recruiting
Edinburgh, United Kingdom, EH1 3EG
Contact: David Cameron, MD PhD       D.Cameron@ed.ac.uk   
Contact: Peter Hall, MD PhD       peter.hall@nhslothian.scot.nhs.uk   
Principal Investigator: Peter Hall, MD PhD         
Sub-Investigator: David Cameron, MD PhD         
Beatson Not yet recruiting
Glasgow, United Kingdom, G12 0XH
Contact: Iain MacPherson, MD PhD         
Principal Investigator: Iain MacPherson, MD PhD         
NHS Ayshire and Arran Not yet recruiting
Kilmarnock, United Kingdom, KA2 OBE
Contact: Lucy Scott, MD PhD         
Principal Investigator: Lucy Scott, MD PhD         
Sponsors and Collaborators
Theodoros Foukakis
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Responsible Party: Theodoros Foukakis, Principal Investigator, Karolinska University Hospital
ClinicalTrials.gov Identifier: NCT03322215    
Other Study ID Numbers: 2016-002893-11
First Posted: October 26, 2017    Key Record Dates
Last Update Posted: September 18, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Theodoros Foukakis, Karolinska University Hospital:
palbociclib
fulvestrant
capecitabine
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Capecitabine
Fulvestrant
Palbociclib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors