Patient case: 32-year-old male with dilated cardiomyopathy; genetic feature: LMNA

Clinical trial: Neoadjuvant Letrozole and Palbociclib in Patients With Stage II-IIIB Breast Cancer, HR+, HER2 -

Summary: This is an international, multicenter, open-label, non-comparative, Simon´s two-stage design, phase II clinical trial.

Detailed description: Primary objective:
  • To explore after 6 months of treatment the ability of palbociclib in combination with letro-zole to induce global molecular changes measured by either the Oncotype DX Breast Recurrence Score® (the "Assay") test result at surgery (post-treatment Recurrence Score® (RS) result), or pathological Complete Response (pCR) in patients with aggres-sive luminal tumors (pre-treatment RS result 18-25 or 26-100, and Ki67>20).
  Secondary objectives:
  BIOLOGY
  -  To explore the ability of palbociclib in combination with letrozole to induce global mo-lecular changes measured by post-treatment RS result, in patients with aggressive luminal tumors (pre-treatment RS result 18-25 and Ki67>20) after 6 months of treatment.
  -  To explore the ability of palbociclib in combination with letrozole to induce global mo-lecular reduction measured by either the post-treatment RS result, and/or Residual Cancer Burden (RCB), and/or Ki67 in patients with aggressive luminal tumors (pre-treatment RS result 18-25 or 26-100 and Ki67>20) after 6 months of treatment.
  -  To verify the ability of palbociclib in combination with letrozole to induce global mo-lecular reduction (measured as either post-treatment RS≤25 or RCB score of 0-I) in >35% of patients in cohort B with pre-treatment RS 26-100;
  -  To verify the ability of palbociclib in combination with letrozole to induce increase in RS result (measured as post-treatment RS 26-100) in <3% of patients in cohort A with pre-treatment RS 18-25;
  -  To evaluate the concordance rate between the RCB score (0- I vs. II-III) and the post-treatment RS result in both cohorts of patients after treatment with palbociclib in com-bination with letrozole;
  -  To evaluate the concordance rate between the preoperative endocrine prognostic index (PEPI) score and post-treatment RS result in both cohorts of patients after treatment with palbociclib in combination with letrozole;
  -  To evaluate the concordance rate between the pCR and the post-treatment RS re-sult in both cohorts of patients after treatment with palbociclib in combination with letro-zole;
  -  To determine the change in RS result as measured by median absolute value or median percentage after 6 months of treatment: from pre-treatment RS 18-25 to post-treatment RS 0-17 for patients in cohort A and from pre-treatment RS 26-100 to post-treatment RS≤25 for patients in cohort B.
  EFFICACY
  -  To determine the Overall Response Rate (ORR) of patients treated with palbociclib in combination with letrozole.
  -  To evaluate the Duration of Response (DoR) of palbociclib in combination with letrozole.
  -  To evaluate the Time to Response (TTR) of palbociclib in combination with letrozole.
  -  To assess the Clinical Benefit Rate (CBR) of palbociclib in combination with letrozole.
  -  To evaluate the Maximum Tumor Shrinkage of palbociclib in combination with letrozole.
  SAFETY
  • To assess the safety and tolerability of palbociclib in combination with letrozole.
  This is an international, multicenter, open-label, non-comparative, Simon's two-stage design, phase II clinical trial to explore the ability of palbociclib in combination with letrozole to in-duce global molecular changes as measured by the Assay after 6 months of treatment, or pCR (invasive) or microscopic residual infiltration where the post-treatment RS result is not feasible in patients with cT2-4, cN0-2, M0 early breast tumors.
  A two-stage Simon's statistical design will be used for both cohorts (minimax design in co-hort B and optimal design in cohort A). A total of 66 patients will be enrolled into this trial, N=33 patients in cohort with high-risk tumors (Cohort B: pre-treatment RS>25) and N=33 patients in cohort with intermediate-risk tumors (Cohort A: pre-treatment RS18-25).
  The accrual goal will be of 26 patients (N=13 patients in each cohort) during the first stage. The interim analysis has been planned after 15 patients (cohort B) and 9 patients (cohort A) will be available for biological response evaluation, and in case of positive findings, the trial will recruit additional 40 patients (N=20 patients in each cohort).
  -  The study would be defined as positive at final analysis in the cohort B (pre-treatment RS>25), if 8 or more than 8 patients with biological signal (post-treatment RS≤25) are observed (≥28.6%) among 28 evaluable patients.
  -  The study would be defined as positive at final analysis in the cohort A (pre-treatment RS18-25), if 25 or more than 25 patients with biological stabilization (post-treatment RS≤25) are observed (≥89.3%) among 28 evaluable patients.
  Study treatment management
  After signing the informed consent form (ICF) and confirmed pre-eligibility, patients with HR- positive/HER2-negative early breast cancer, with Ki67≥20% and no substantial axillary lymph node involvement who meet standard clinical criteria for NCT will be pre-registered in the study. Patients will undergo baseline tumor biopsy (1st biopsy time-point), that will be used to perform central pathology confirmation of HR, HER2, and Ki67 levels (approximately within 7-10 working days) as well as central assessment of RS (approximately within 12-15 working days). Since patient pre-registration patients will receive up to 4 weeks of endocrine therapy, consisting of letrozole alone, and Luteinizing Hormone-Releasing Hormone (LHRH) agonist if premenopausal. Patients are eligible to enter one of the two cohorts according to RS assessments as follow:
  -  Cohort A: patients with intermediate risk tumors (pre-treatment RS18-25);
  -  Cohort B: patients with high risk tumors (pre-treatment RS26-100). Patients with low risk tumors (pre-treatment RS≤18) will be considered not eligible.
  Patients allocated into Cohort A/B will receive palbociclib in combination with letrozole during 24 weeks (6 cycles). In detail, letrozole administration will consist on 2.5 mg tablet orally once daily, beginning on day 1 and continuing through day 28 of every 28-day cycle. Pa-tients will receive palbociclib capsules orally once daily (QD) (starting dose at 125mg) for 21 days every four weeks.
  Premenopausal women must also be treated with LHRH agonist during the treatment phase.
  Additionally, a tumor biopsy sample is mandatory after 14 days of neoadjuvant treatment with palbociclib plus letrozole (2nd biopsy time-point). If tumor Ki67>10% at Day 14 Cycle 1, study therapy will be discontinued due to inadequate response and patient will exit the study to receive an alternative treatment as per investigator choice. Patients with Ki67≤10% (or indeterminant) at Day 14 Cycle 1 will continue palbociclib and letrozole for 22-weeks un-less patients experience intolerable side effects, disease progression, or withdrew consent.
  After 6 cycles of palbociclib plus letrozole, patients will have definitive breast surgery and a tumor biopsy (3rd biopsy time-point) is mandatory to determine study objectives as defined in Section 4. Surgery will occur within 7 days (+/- 3 days) after completion of 6th cycle of pre-operative treatment. Patients must receive additional palbociclib plus letrozole treatment (with LHRH agonist if premenopausal) until surgery. Furthermore, in patients who experiment AEs≥grade 3, surgery should not occur until AE recovery but not later than 3 weeks. If sur-gery is delayed, patients must receive additional palbociclib plus letrozole treatment until immediately before surgery.

Eligibility: Inclusion Criteria:
  -  Patients must meet ALL of the following inclusion criteria to be eligible for enrolment into the study:
  1. Female patients over 18 years of age.
  2. Patients have been informed about the nature of study, have agreed to participate in the study, and have signed the informed consent form prior to participation in any study-related activities.
  3. Premenopausal and postmenopausal women. Premenopausal women must be treated with LHRH analogue since patient pre- registration. Premenopausal or postmeno-pausal status should have been established before starting study treatment with letrozole plus palbociclib based on the following classification:
  1. Postmenopausal status is defined as either:
  -  Prior bilateral oophorectomy; Or
  -  Age>60 years; Or
  -  Age<60 years and amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression, and follicle-stimulating hormone (FSH) and estradiol in postmenopausal range.
  2. Premenopausal status is defined as all those women who do not meet any of above criteria.
  4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
  5. HR-positive (estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive) EBCs (breast cancers that have at least 1% of cells staging positive for ER and PgR should be considered ER-positive and PgR-positive according to the National Compre-hensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guide-lines). ER and/or PgR status must be centrally confirmed by using immunohistochemistry (IHC) testing and Allred score of 6-8.
  6. Patients with HER2-negative breast cancer through in situ hybridization test (fluores-cence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], or silver en-hanced in situ hybridization [SISH]) or negative immunohistochemical status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required. HER2 status must be centrally confirmed.
  7. Ki67 levels ≥ 20% confirmed by IHC testing in a central laboratory.
  8. Tumor size >2,0 cm (T2-4 according to TNM staging system, but always >2,0 cm).
  9. Limited node involvement (N0-2, according to TNM staging system), as assessed by a sentinel lymph node biopsy, an axillary dissection, or both, and as defined by the Sixth Edition of the American Joint Committee on Cancer (AJCC) staging criteria.
  10. No metastatic disease (M0, according to TNM staging system).
  11. Available pre-treatment tissue sample (biopsy) material (formalin- fixed paraffin-embedded (FFPE)) for RS central evaluation by the Assay.
  12. Patients agree to collection of tissue biopsy from the primary breast cancer at the time of study inclusion (screening), at Cycle 1 Day 14 of treatment, and after 24 weeks, or if experience intolerable side effects, disease progression, or withdraw during 24 weeks of study treatment.
  13. Patients must have biopsable and measurable disease (according to RECIST criteria v.1.1).
  14. No prior chemotherapy, endocrine or radiation therapy for current disease.
  15. Adequate organ function:
  1. Hematological: White blood cell (WBC) count ≥ 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5x 109/L, platelet count ≥ 75.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).
  2. Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (x ULN) (or total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN in patients with well-documented Gilbert's syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transami-nase (ALT) ≤ 3 times ULN.
  3. Renal: Serum creatinine ≤ 1.5 x ULN.
  16. Resolution of all acute toxic effects of prior surgical proce-dures to grade ≤1 as determined by the NCI CTCAE v.5.0.
  Exclusion Criteria:
  -  Patients will be excluded from the study if they meet ANY of the following criteria:
  1. Metastatic progression (M1, according to TNM staging system).
  2. Substantial nodal involvement (N>2, according to TNM staging system).
  3. Non-large tumor (T0-1, according to TNM staging system).
  4. Bilateral breast carcinoma.
  5. Inflammatory carcinoma (T4d, according to TNM staging system).
  6. Patients with exclusive non-measurable/evaluable disease.
  7. Known hypersensitivity to any palbociclib excipients.
  8. Known hypersensitivity to any letrozole excipients.
  9. Formal contraindication to endocrine therapy.
  10. Patients unable to swallow tablets.
  11. Other malignancies within the past five years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix.
  12. Previous radiotherapy on the ipsilateral chest wall for the treatment of any other malignance.
  13. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within four weeks of start of study treatment, or patients who have not recovered from the side effects of any major surgery, or patients that may require major surgery during the course of the study.
  14. Have a serious concomitant systemic disorder (i.e., active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator).
  15. Patients with an active bleeding diathesis, previous history of bleeding diathesis, or anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon as it is used as prophylaxis intention).
  16. History of malabsorption syndrome or other condition that would interfere with enteral absorption.
  17. Chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day methylpredniso-lone equivalent (excluding inhaled steroids).
  18. QTc interval > 480 msec on basal assessments, personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
  19. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (i.e., hypocalcemia, hypokalemia, or hypomagnesemia).
  Participation in the treatment phase of an interventional trial within 30 days prior to study treatment start.

Relevance to patient case: not relevant