Clinical Trials /

Palbociclib Plus Letrozole in Hormone Receptor Positive Residual Disease After Neoadjuvant Chemotherapy

NCT04130152

Description:

PROMETEO II is a single-arm window of opportunity trial to evaluate biologic and anti-proliferative effects of palbociclib and letrozole in HR+/HER2-negative operable breast cancer (BC) patients with residual disease after neoadjuvant chemotherapy (NAC) and help to identify biomarkers for better patient selection.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Palbociclib Plus Letrozole in Hormone Receptor Positive Residual Disease After Neoadjuvant Chemotherapy
  • Official Title: Palbociclib in Combination With Letrozole in Patients With Hormone Receptor (HR) Positive/Human Epidermal Growth Factor Receptor 2 (HER2) Negative Residual Disease After Standard Neoadjuvant Chemotherapy (PROMETEO II)

Clinical Trial IDs

  • ORG STUDY ID: SOLTI-1710
  • SECONDARY ID: 2019-001275-36
  • NCT ID: NCT04130152

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
PalbociclibIbrancePalbociclib + Letrozole
LetrozolePalbociclib + Letrozole

Purpose

PROMETEO II is a single-arm window of opportunity trial to evaluate biologic and anti-proliferative effects of palbociclib and letrozole in HR+/HER2-negative operable breast cancer (BC) patients with residual disease after neoadjuvant chemotherapy (NAC) and help to identify biomarkers for better patient selection.

Detailed Description

      This is a single-arm window of opportunity trial to evaluate biologic and anti-proliferative
      effects of palbociclib and letrozole in HR+/HER2-negative operable BC patients with residual
      disease after NAC and help to identify biomarkers for better patient selection.

      The primary endpoint will be the Complete Cell Cycle Arrest (CCCA) determined by Ki67<2.7%,
      centrally assessed at surgery after 4 weeks of palbociclib and letrozole.

      Tumor measurement will be performed by magnetic resonance imaging (MRI) for disease
      evaluation at screening at the end of NAC. The biopsy after chemotherapy will only be done if
      the tumor is equal or larger than 1 cm in its greatest diameter by MRI. Ki67% ≥ 10% after NAC
      by local determination will be necessary to be included in the study.

      Patients will be administered palbociclib at a dose of 125 mg once daily, day 1 to day 21
      followed by 7 days off treatment in a 28-day cycle and letrozole: oral, 2.5 mg per day
      continuously, one cycle of treatment.

      After finalization of the neoadjuvant treatment, patients will undergo surgery. Surgery
      specimens will be collected for histological examination and biomarker analysis

      The end of the study is defined as the date of post-surgery visit and will take place 4 weeks
      (+/- 7days) after the surgery in order to monitor the patient's safety and collect the
      surgery information.
    

Trial Arms

NameTypeDescriptionInterventions
Palbociclib + LetrozoleExperimentalPalbociclib 125 mg once daily, day 1 to day 21, followed by 7 days off treatment in a 28-day cycle Letrozole: oral, 2.5 mg per day continuously. during the 28-day cycle. If the patient is pre-menopausal, ovarian suppression with luteinizing hormone-releasing hormone (LHRH) analogues (ie, triptorelin 3.75 mg intra-muscular (IM) or Goserelin 3,6 mg SC) must be initiated at least 2 weeks before palbociclib plus letrozole administration.
  • Palbociclib
  • Letrozole

Eligibility Criteria

        Inclusion Criteria:

          1. Written and signed informed consent for all study procedures according to local
             regulatory requirements prior to beginning specific protocol procedures.

          2. Female patients age ≥ 18 years.

          3. Pre and post-menopausal women.

          4. ECOG (Eastern Cooperative Oncology Group) Performance Status of 0 to 1.

          5. Histologically confirmed non-metastatic primary HR-positive/HER2 negative breast
             cancer with all the following characteristics:

               -  Breast cancer eligible for surgery.

               -  ER-positive and/or progesterone receptor (PgR) positive and HER2-negative tumor
                  by American Society of Clinical Oncology (ASCO) /College of American Pathologists
                  (CAP) guidelines, ER and PgR defined as IHC nuclear staining >1% and HER2
                  negative and Ki-67 >10%, locally assessed.

               -  Ki67% ≥ 10% after neoadjuvant chemotherapy locally assessed.

               -  A lesion that can be accurately and serially measured in at least 1 dimension and
                  for which the longest diameter is ≥ 1 cm as measured by MRI after neoadjuvant
                  chemotherapy.

          6. Completed ≥80% total dose of an anthracycline/taxane-based neoadjuvant regimen
             planned. The allowed chemotherapy regimens will be AC (cyclophosphamide, doxorubicin)
             or EC (epirubicin, cyclophosphamide) 4 cycles followed by weekly paclitaxel x 12 or AC
             or EC 4 cycles followed by docetaxel 4 cycles. It would be acceptable to change the
             administration sequence to paclitaxel followed by AC/EC. AC can be given either a
             standard dose or in a dose dense schedule. Paclitaxel could be administered as a
             solvent-based or Nanoparticle albumin-bound (Nab) formulation.

          7. Availability of a recent formalin-fixed paraffin-embedded (FFPE) tumor sample before
             NAC and a research tumor biopsy after NAC. Minimal sample requirements are to have at
             least 2 tumor cylinders with a minimal tissue surface of 10 mm2 tissue, containing at
             least 10% tumor cells and having enough tissue to do at least 2 cuts of 10 μm each.

          8. Adequate organ function determined within 28 days prior to enrollment, defined as
             follows:

               -  Hematological

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

                    -  Platelet count ≥ 100 x 109/L

                    -  Hemoglobin ≥ 9 g/dL (red blood cell transfusion and/or erythropoietin
                       allowed)

               -  Renal

                  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN), or 24-hour creatinine
                  clearance ≥ 60 mL/min for subject with creatinine levels >1.5 x ULN. (Note:
                  Creatinine clearance does not need to be determined if the baseline serum
                  creatinine is within normal limits. Creatinine clearance should be calculated per
                  institutional standard).

               -  Hepatic

                    -  Serum bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with
                       total bilirubin level > 1.5 x ULN

                    -  Aspartate aminotransferase (AST) ≤ 2.5 x ULN

                    -  Alanine aminotransferase (ALT) ≤ 2.5 x ULN Coagulation International
                       normalization ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN

          9. Serum or urine pregnancy test must be negative within 7 days prior to randomization in
             women of childbearing potential. If the urine pregnancy test is positive or cannot be
             confirmed as negative, a serum pregnancy test will be required. Pregnancy testing does
             not need to be pursued in patients who are judged as postmenopausal before
             randomization, as determined by local practice, or who have undergone bilateral
             oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing
             potential randomized to the treatment must use adequate contraception for the duration
             of protocol treatment.

         10. Absence of 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.

         11. Resolution of all acute toxic effects of prior anti-cancer therapy to NCI CTCAE
             version 5.0 Grade ≤ 1 (except alopecia or other toxicities not considered a safety
             risk for the patient at investigator´s discretion).

        Exclusion Criteria:

          1. Non-operable, locally advanced breast cancer (inoperable stage III) after NAC.

          2. Bilateral or metastatic invasive breast cancer at the time of the diagnosis.

          3. Multicentric or multifocal breast cancer before NAC.

          4. Known severe hypersensitivity reactions to compounds similar to palbociclib or to
             excipients or to endocrine treatments.

          5. History of any previous treatment using Aromatase inhibitors (AI) o selective estrogen
             receptor modulator (SERMs) in the past 5 years.

          6. Prior therapy with palbociclib or any cyclin-dependent kinase (CDK) inhibitor.

          7. Concurrent treatment with other experimental drugs. Participation in another clinical
             trial with any investigational not marketed drug within 30 days prior to
             randomization.

          8. Patients receiving any medications or substances that are strong inhibitors or
             inducers of CYP3A isoenzymes within 7 days of randomization.

          9. Any surgery (not including minor procedures such as primary tumor core biopsy, fine
             needle aspiration) within 4 weeks of start of study treatment; or not fully recovered
             from any side effects of previous procedures.

         10. Sentinel lymph node biopsy is not allowed before NAC.

         11. Diagnosis of any previous malignancy within the last 3 years, except for adequately
             treated basal cell carcinoma, or squamous cell skin carcinoma, or in situ cervical
             carcinoma

         12. Malabsorption syndrome or other condition that would interfere with enteric
             absorption.

         13. Clinically significant history of liver disease, including viral or other hepatitis,
             current alcohol abuse, or cirrhosis.

         14. Uncontrolled electrolyte disorders (eg, hypocalcemia, hypokalemia, hypomagnesemia).

         15. Any of the following within 6 months of randomization: myocardial infarction,
             severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 5.0 Grade
             ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft,
             symptomatic congestive heart failure, cerebrovascular accident including transient
             ischemic attack, or symptomatic pulmonary embolism.

         16. Corrected QT interval (QTc) greater than 480 msec or a family or personal history of
             long or short QT syndrome, Brugada syndrome or know history of QTc prolongation, or
             Torsade de Pointes (TdP).

         17. Uncontrolled current illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, diabetes, or psychiatric illness/social situations that would limit
             compliance with study requirements. Ability to comply with study requirements is to be
             assessed by each investigator at the time of screening for study participation.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Cell Cycle Arrest (CCCA)
Time Frame:Ki67 changes will be determined from baseline biopsy at the end of NAC and 4 weeks later at surgery
Safety Issue:
Description:Complete Cell Cycle Arrest (CCCA) determined by Ki67< 2.7% at surgery following treatment with palbociclib plus letrozole, by central laboratory

Secondary Outcome Measures

Measure:Residual Cancer Burden (RCB)
Time Frame:At surgery, 4 weeks after palbociclib and letrozole treatment
Safety Issue:
Description:Rate of RCB score 0 or 1 (RCB 0/1) after neoadjuvant treatment, according to the MD Anderson Cancer Center procedures, as per local assessment
Measure:Pathological complete response (pCR)
Time Frame:At surgery, 4 weeks after palbociclib and letrozole treatment
Safety Issue:
Description:Rate of pCR (ypT0/TisypN0) defined as the complete absence of invasive carcinoma in the breast and axillary lymph nodes on histological examination at the time of definitive surgery, irrespective of in situ carcinoma in the breast and in the breast and axilla by local evaluation.
Measure:Incidence, duration and severity of Adverse Events (AEs)
Time Frame:Up to 4 weeks
Safety Issue:
Description:Incidence and severity of treatment-emergent and treatment-related adverse events assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 5.0, including dose reductions, delays and treatment discontinuations.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:SOLTI Breast Cancer Research Group

Trial Keywords

  • Palbociclib, residual disease, Neoadjuvant treatment, Ki67

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