Clinical Trials /

Study of Palbociclib and Trastuzumab With Endocrine Therapy in HER2-positive Metastatic Breast Cancer

NCT02448420

Description:

PATRICIA is a phase II, open-label, multicentre, Simon's two-stage-design study of the combination of palbociclib plus trastuzumab, with or without letrozole, in post-menopausal patients with HER2-positive locally advanced or metastatic breast cancer (MBC) who have received chemotherapy and treatment with trastuzumab for their metastatic disease. Cohorts A, B1 and B2 based on their HR status and treatment allocation were planned. The aim of the PATRICIA study is to test the hypothesis that the addition of Palbociclib to standard therapy is well tolerated and can provide a benefit in progression-free survival. Based on interim results from this trial that support the benefit of CDK4 / 6 inhibition in luminal disease, two additional cohorts will be included.

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Palbociclib and Trastuzumab With Endocrine Therapy in HER2-positive Metastatic Breast Cancer
  • Official Title: A Phase II Trial of Palbociclib in Combination With Trastuzumab and Endocrine Therapy in Patients With Previously-treated Locally Advanced or Metastatic HER2-positive Breast Cancer (PATRICIA II)

Clinical Trial IDs

  • ORG STUDY ID: SOLTI-1303
  • SECONDARY ID: 2014-005006-38
  • NCT ID: NCT02448420

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
PalbociclibIbranceArm C1: Palbociclib, trastuzumab and endocrine therapy
TrastuzumabHerceptin, trastuzumab biosimilarArm C1: Palbociclib, trastuzumab and endocrine therapy
Endocrine therapyETArm C1: Palbociclib, trastuzumab and endocrine therapy
ChemotherapyCTArm C2: Treatment based of physician's choice
Antibody-Drug ConjugatesTrastuzumab emtansine (TDM-1)Arm C2: Treatment based of physician's choice

Purpose

PATRICIA is a phase II, open-label, multicentre, Simon's two-stage-design study of the combination of palbociclib plus trastuzumab, with or without letrozole, in post-menopausal patients with HER2-positive locally advanced or metastatic breast cancer (MBC) who have received chemotherapy and treatment with trastuzumab for their metastatic disease. Cohorts A, B1 and B2 based on their HR status and treatment allocation were planned. The aim of the PATRICIA study is to test the hypothesis that the addition of Palbociclib to standard therapy is well tolerated and can provide a benefit in progression-free survival. Based on interim results from this trial that support the benefit of CDK4 / 6 inhibition in luminal disease, two additional cohorts will be included.

Detailed Description

      After the amendment of PATRICIA study, two additional cohorts will be included:

        -  Cohort C1: will include patients with OR+, HER2 positive, Luminal intrinsic subtype
           determined by PAM50 who will receive trastuzumab + palbociclib + endocrine therapy (ET)

        -  Cohort C2: will include patients with OR+, HER2 positive, Luminal intrinsic subtype
           determined by PAM50 who will receive treatment of physician's choice.

      When the recruitment of those cohorts C begins, the recruitment in cohorts A and B will be
      closed.

      For cohorts C, an adaptive design will be applied to compare arms of treatment in patients
      with Luminal subtype locally advanced or metastatic breast cancer (MBC).

      All patients in those cohorts will have histologically- confirmed HR+/HER2-positive and
      PAM50-confirmed Luminal intrinsic subtype breast adenocarcinoma, and must have received at
      least 1 (and no more than 4) previous lines of anti-HER2 regimens for locally advanced
      disease or MBC (including prior treatment with a taxane, trastuzumab and Antibody-Drug
      conjugate).

      Stratification factors will include number of previous regimens for advanced breast cancer
      (one and two vs three and four) and presence of visceral disease (yes vs no).

      Treatment in all cohorts will be administered until progression, unacceptable toxicity,
      patient consent withdrawal, or death 516 patients will be screened and a total of 232
      patients will be included. The inclusion period will be divided in two phases. During phase I
      it is planned to include 60 patients in 24 months; considering early stopping rule according
      to SF rate. During phase II, the trial will continue until the final evaluable number of
      patients are included.
    

Trial Arms

NameTypeDescriptionInterventions
Arm C1: Palbociclib, trastuzumab and endocrine therapyExperimentalHR positive, HER2 positive, Luminal intrinsic subtype determined by PAM50 who will receive trastuzumab + palbociclib + endocrine therapy Trastuzumab or biosimilar: intravenous trastuzumab loading dose of 8mg/kg followed by 6 mg/kg once every 3 weeks; or subcutaneous trastuzumab 600mg every 3 weeks. Palbociclib:oral, 125 mg/d for 3 weeks, followed by one week off, in 4-week cycles. Endocrine therapy: either an Aromatase Inhibitor, Fulvestrant or Tamoxifen.
  • Palbociclib
  • Trastuzumab
  • Endocrine therapy
Arm C2: Treatment based of physician's choiceActive ComparatorHR positive, HER2 positive, Luminal intrinsic subtype determined by PAM50 who will receive Treatment based of physician's choice from the following options: TDM1 or chemotherapy (gemcitabine, vinorelbine, capecitabine, eribulin or a taxane) in combination with trastuzumab.
  • Trastuzumab
  • Chemotherapy
  • Antibody-Drug Conjugates

Eligibility Criteria

        Inclusion Criteria

          1. Written signed Informed Consent for all study procedures in accordance with the local
             administrative requirements prior to starting the protocol-specific procedures.

          2. Male or female patients. Premenopausal or postmenopausal women.

          3. Age 18 years or older.

          4. ECOG performance status 0 to 2 (Appendix 1).

          5. Invasive HER2 positive breast cancer, according to the central laboratory, defined
             according to ASCO/CAP criteria (Wolff et al. Arch Pathol Lab Med 2018;)

          6. Hormone receptor positive (HR+), determined locally according to ASCO/CAP guidelines;
             OR or PgR considered positive in case of ≥1% of cell nuclei positive.

          7. Centrally confirmed Luminal intrinsic subtype as per PAM50 analysis (i.e. Luminal A or
             Luminal B).

          8. Histologically confirmed adenocarcinoma of the breast, metastatic or locally advanced.

               1. Patients with locally advanced disease must have recurrent or progressive disease
                  unsuitable for resection with curative intent. Patients with standard curative
                  options available will not be eligible.

               2. In patients with bilateral breast cancer, HER2+ positivity must be demonstrated
                  in both sites or in a metastatic biopsy.

          9. All patients must have received at least 1(maximum 4) previous lines of systemic
             treatment for metastatic or locally advanced disease, at least one of which must have
             included trastuzumab. Previous use of other anti-HER2 treatment, alone or in
             combination with chemotherapy, is permitted, including lapatinib, neratinib,
             pertuzumab or T-DM1. Previous use of any chemotherapy or hormone agent is permitted.

         10. Tumour tissue available for biomarker analysis, obtained from metastatic lesions
             (preferably) or from the primary tumour.

         11. Measurable or non-measurable (but evaluable) disease according to RECIST 1.1 criteria
             (Appendix 5).

         12. Adequate organ function, defined as:

               1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.

               2. Haemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted).

               3. Platelets > 100,000/mm3

               4. Creatinine ≤ 1.5 x normal value

               5. AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis)

               6. Alkaline phosphatase ≤2.5 x ULN. Alkaline phosphatase may be more than 2.5 x ULN
                  only in the case of bone metastases, and AST and ALT less than 1.5 x ULN.

               7. Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient
                  has Gilbert's syndrome).

         13. Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic
             ventriculography (MUGA).

         14. Absence of psychological, family, sociological or geographical conditions that could
             potentially hinder compliance with the study protocol and follow-up schedule. These
             situations must be discussed with the patient before she is included in the study.

         15. If female of childbearing potential, must have a negative result of serum pregnancy
             test performed within 7 days prior to first dose of study treatment.

         16. Participants with a history of treated CNS metastases are eligible, provided they meet
             all of the following criteria:

               -  Disease outside the CNS is present.

               -  No evidence of interim progression between the completion of CNS-directed therapy
                  and the screening radiographic study.

               -  No history of intracranial hemorrhage or spinal cord hemorrhage.

               -  Stable doses or no need of corticosteroids and anti-convulsants for symptomatic
                  control

               -  Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 of
                  study treatment; and recovery from any significant (Grade ≥ 3) acute toxicity

        Exclusion criteria

          1. Treatment with any investigational anticancer drug within 14 days of the start of
             study treatment.

          2. Patient has received more than 4 previous lines of treatment (anti-HER2 drug +/-
             chemotherapy) for metastatic breast cancer or locally advanced disease. Exclusively
             hormonal treatments will not be taken into account.

          3. Previous treatment with a cyclin-dependent kinase inhibitor.

          4. History of other malignant tumours in the past 5 years, with the exception of
             adequately treated in situ carcinoma of the cervix, non-melanoma carcinoma of the
             skin, uterine cancer in stage I or other malignant tumours with an expected curative
             outcome.

          5. Radiation therapy for metastases outside the brain carried out in the 21 days prior to
             inclusion in the study and/or patients who have received radiation to > 30% of the
             bone marrow.

          6. Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 21 days
             prior to inclusion in the study. Biphosphonates will be permitted for the prevention
             of bone events.

          7. History of exposure to cumulative anthracycline doses greater than follows:

               1. Adriamycin > 400 mg/m2

               2. Epirubicin > 720 mg/m2

               3. Mitoxantrone > 120 mg/m2

               4. Idarubicin > 90 mg/m2

               5. If another anthracycline or more than one anthracycline has been used, the
                  cumulative dose must not exceed the equivalent of 400 mg/m2 of adriamycin.

          8. Cardiopulmonary dysfunction, defined as:

               1. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg)
                  despite optimum medical treatment.

               2. Angina pectoris or arrhythmia poorly controlled with optimum medical treatment.

               3. History of congestive heart failure NCI CTCAE version 4.0 grade ≥ 3 NYHA class ≥
                  2.

               4. History of LVEF decrease to < 40% or symptomatic congestive heart failure during
                  prior treatment with trastuzumab.

               5. Myocardial infarction within 6 months before randomisation.

               6. Resting dyspnoea due to complications of the malignant disease, requiring
                  continuous oxygen therapy.

          9. Any other severe, uncontrolled disease (pulmonary, cardiac, metabolic, or
             haematological disorder, wound healing disorders, ulcers, bone fractures, infectious
             processes).

         10. Major surgery in the 28 days prior to randomisation or foreseeable during study
             treatment period.

         11. Infection with HIV or active Hepatitis B and/or Hepatitis C.

         12. History of trastuzumab intolerance, including grade 3-4 infusion reaction or
             hypersensitivity.

         13. Known hypersensitivity to any of the study drugs, including inactive ingredients.

         14. Inability, in the opinion of the investigator, to comply with the protocol
             requirements or any comorbidity that might hinder study follow-up, response evaluation
             or the informed consent process.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival (PFS)as Assessed by the Investigator [ Time Frame: From randomization date to date of first documentation of progression or death
Time Frame:From randomization date to date of first documentation of progression or death , whichever came first, assessed up to 5 years
Safety Issue:
Description:This will be defined as the proportion of patients alive and without progression (according to RECIST v1.1 criteria)

Secondary Outcome Measures

Measure:Rate of Disease control rate (DCR) in both treatment arms
Time Frame:up to 5 years
Safety Issue:
Description:Number of patients with objective response (complete or partial) or stable disease according to RECIST 1.1 criteria for at least 8 weeks.
Measure:Rate of Overall tumour objective response rate (ORR) in both treatment arms.
Time Frame:up to 5 years
Safety Issue:
Description:Number of patients who achieve complete or partial response according to RECIST 1.1 criteria during treatment.
Measure:Safety profile in both treatment arms: Percentage of Participants with Adverse Events
Time Frame:up to 5 years
Safety Issue:
Description:Measurements used to assess the safety profile will include adverse events of any grade, grade 3 and 4 adverse events, withdrawals due to adverse events and dose reductions due to adverse events. CTCAE v.4.03 will be used to evaluate AE grade.
Measure:12-month Overall Survival in both treatment arms.
Time Frame:up to 5 years
Safety Issue:
Description:Measured as time between treatment start and all-cause death.
Measure:Change From Baseline Between Treatment Comparison in Functional Assessment of Cancer Therapy FACT-B to assess patient reported breast cancer specific health related quality of life (HRQOL) and general health status in both treatment arms.
Time Frame:From the date of randomization up to 5 years
Safety Issue:
Description:The FACT-B consists of the Functional Assessment of Cancer Therapy-General (FACT-G) (27-items) and a breast-specific module: a 10-item instrument designed to assess patient concernsrelating to BC. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. Patients are asked to respond to a Likert scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much.
Measure:Change From Baseline Between Treatment Comparison in Euroqol-5D (EQ-5D) to assess patient reported breast cancer specific health related quality of life (HRQOL) and general health status in both treatment arms.
Time Frame:From the date of randomization up to 5 years
Safety Issue:
Description:The EuroQol EQ-5D is designed to assess health status in terms of a single index value or utility score. It contains 5 descriptors of current health state (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with each dimension having 5 levels of function (1=no problem, 2=slight problem, 3=moderate problem, 4=severe problem, and 5=unable/extreme). The scores on the 5 descriptors are summarized to create a single summary score. The EQ-5D also includes a visual analog scale (VAS), in which the patients self-rate their overall health status on a scale from 0 (worst imaginable) to 100 (best imaginable).
Measure:To investigate baseline tumor and blood biomarkers as predictors of response or resistance to the study treatment.
Time Frame:up to 5 years
Safety Issue:
Description:The codeset of 110 genes include the 50 genes assessed in the PAM50 intrinsic subtype predictor platform and the expression of 60 additional genes covering a significant biological variation of gene signatures relevant in breast cancer. Peripheral blood samples will be collected, and plasma extracted for circulating tumoral DNA (ctDNA) determination.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:SOLTI Breast Cancer Research Group

Last Updated

October 21, 2019