Clinical Trials /

Defining the HER2 Positive (+) Breast Cancer Kinome Response to Trastuzumab, Pertuzumab, Combination Trastuzumab +Pertuzumab, or Combination Trastuzumab + Lapatinib

NCT01875666

Description:

Kinases are a group of proteins that are important in how cancer cells grow. HER2 is a kind of kinase. This study looks at a new approach to identifying kinases, which may help target therapy more precisely. LCCC1214 is a randomized, multiarm, multicenter, open-label window trial designed to explore the kinome response in Stage I-IV HER2 positive (HER2+) breast cancer patients scheduled to undergo definitive surgery (either lumpectomy, mastectomy or surgical resection of oligometastatic disease). Patients will initiate dosing with either a single HER2-directed agent or a combination of two HER2-directed agents, one week prior to surgery. Forty patients will be randomized to one of four study groups: A) single dose trastuzumab; B) single dose pertuzumab; C) combination single dose trastuzumab plus single dose pertuzumab; or D) combination single dose trastuzumab plus lapatinib daily for 7 days. Pre- and post- dosing tissue will be analyzed for kinome response and resistant signatures. The initiation of study drug will be defined by the surgical schedule; there will be no delays in standard treatment for the purposes of this study.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Defining the HER2 Positive (+) Breast Cancer Kinome Response to Trastuzumab, Pertuzumab, Combination Trastuzumab +Pertuzumab, or Combination Trastuzumab + Lapatinib
  • Official Title: Defining the HER2 Positive (+) Breast Cancer Kinome Response to Trastuzumab, Pertuzumab, Combination Trastuzumab +Pertuzumab, or Combination Trastuzumab + Lapatinib

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1214
  • NCT ID: NCT01875666

Conditions

  • Breast Neoplasms

Interventions

DrugSynonymsArms
TrastuzumabHerceptinTrastuzumab
pertuzumabPerjetapertuzumab
lapatinibTykerbtrastuzumab plus lapatinib

Purpose

Kinases are a group of proteins that are important in how cancer cells grow. HER2 is a kind of kinase. This study looks at a new approach to identifying kinases, which may help target therapy more precisely. LCCC1214 is a randomized, multiarm, multicenter, open-label window trial designed to explore the kinome response in Stage I-IV HER2 positive (HER2+) breast cancer patients scheduled to undergo definitive surgery (either lumpectomy, mastectomy or surgical resection of oligometastatic disease). Patients will initiate dosing with either a single HER2-directed agent or a combination of two HER2-directed agents, one week prior to surgery. Forty patients will be randomized to one of four study groups: A) single dose trastuzumab; B) single dose pertuzumab; C) combination single dose trastuzumab plus single dose pertuzumab; or D) combination single dose trastuzumab plus lapatinib daily for 7 days. Pre- and post- dosing tissue will be analyzed for kinome response and resistant signatures. The initiation of study drug will be defined by the surgical schedule; there will be no delays in standard treatment for the purposes of this study.

Detailed Description

      Until recently, our understanding of the kinome has been limited to just 5-10% of the
      genome-encoded kinases. This limited knowledge prevents a thorough understanding of
      resistance mechanisms, and precludes individualizing HER2-targeted therapy in HER2+ disease.
      Fortunately, we have now developed a chemical proteomics approach to define comprehensive
      kinome activity in cells and tumors (MIB/MS).[1]

      We hypothesize that our proteomics approach can be used to characterize the heterogeneity of
      the kinome activation profiles in HER2+ breast cancer and permit us to identify if adaptive
      response to HER2 inhibition differs depending on the anti-HER2 drug mechanism of action. This
      will allow rational prediction of new combinatorial therapies in future clinical trials.

      To explore kinome activation in this population, we propose a window trial in stage I-IV
      HER2+ patients scheduled to undergo definitive surgery (either lumpectomy, mastectomy or
      surgical resection of oligometastatic disease). Enrolled patients will be randomized to one
      of four treatment arms; A) single dose trastuzumab; B) single dose pertuzumab; C) combination
      trastuzumab + pertuzumab for one dose each; or D) combination single dose trastuzumab plus
      lapatinib daily for one week.

      Dosing in each arm will be initiated 7 days prior to surgery, with pre- and post-dosing
      tissue samples analyzed for kinome response and resistant signatures. To ensure adequate
      levels of trastuzumab and pertuzumab at the time of surgery, a loading dose of each agent (8
      mg/kg IV for trastuzumab, and 840 mg IV fixed dose for pertuzumab) were chosen. The dose of
      lapatinib was based on prior studies of lapatinib administered in combination with
      trastuzumab. Given the varied pharmacokinetic profiles of the three agents and limited
      dosing, we expect exposure levels of the agents to be different relative to respective steady
      state levels. Therefore qualitative rather than quantitative measures will be key.
    

Trial Arms

NameTypeDescriptionInterventions
TrastuzumabActive Comparatorsingle dose intravenous infusion administration of trastuzumab (8 mg/kg)
  • Trastuzumab
pertuzumabActive Comparatorsingle dose infusion of pertuzumab (840 mg)
  • pertuzumab
trastuzumab plus pertuzumabActive Comparatorsingle dose infusion of combination trastuzumab (8 mg/kg) plus pertuzumab (840 mg)
  • Trastuzumab
  • pertuzumab
trastuzumab plus lapatinibActive Comparatorcombination of single dose infusion of trastuzumab (8 mg/kg) plus oral lapatinib (1000 mg daily for 7 days)
  • Trastuzumab
  • lapatinib

Eligibility Criteria

        Inclusion Criteria:

          -  Signed, written informed consent

          -  Age >/= 18 years

          -  Histologically confirmed HER2+ breast cancer: IHC 3+ or fluorescence in situ
             hybridization [FISH] amplified; by clinical assay on either primary or metastatic
             tumor

          -  Stage I-IV disease

               -  For patients with Stage I-IIIc disease:

                    1. Scheduled for lumpectomy or mastectomy

                    2. No prior or current therapy for breast cancer

                    3. Not considered a candidate for therapeutic neoadjuvant treatment

               -  For patients with Stage IV disease:

                    1. Scheduled for surgical resection of oligometastatic disease

                    2. Previously untreated for breast cancer

          -  Normal relevant end organ function as defined by the following:

               -  ANC>1500 cells/mL

               -  Platelets > 100,000 cells/mL

               -  Hemoglobin > 10 g/dL

               -  Total bilirubin ≤ 1.5 x ULN (unless known Gilbert's syndrome)

               -  AST and ALT ≤ 2.5 X ULN

               -  Creatinine ≤ 1.5 X ULN OR Calculated creatinine clearance ≥50 mL/min OR 24-hour
                  urine creatinine clearance ≥50 mL/min

               -  Left Ventricular Ejection Fraction ≥ 50% by ECHO (preferred) or MUGA

          -  For women of childbearing potential, agreement to use an effective form of
             contraception (patient and/or partner, e.g., surgical sterilization, a reliable
             barrier method, birth control pills, or contraceptive hormone implants) and to
             continue its use for the duration of the study treatment, and for a minimum of 6
             months following trastuzumab and/or pertuzumab administration.

          -  Sufficient fresh or frozen tissue remaining from pre-treatment core biopsy/ incisional
             biopsy or willing to undergo biopsy (at UNC via LCCC9819) for research purposes only
             (approximately 10mg or one core's worth of tissue needed)

          -  Surgeon and medical oncologist agree one week window trial is appropriate/safe for the
             patient and that surgery appointment can accommodate treatment schedule as outlined in
             the study schema (section 4.1).

          -  UNC patients must co-enroll into LCCC9819 for collection of tissue samples

        Exclusion Criteria:

          -  Pregnant or lactating female

          -  Prior radiation therapy to the target lesion

          -  Use of any investigational drug within 28 days or five half-lives, whichever is
             shorter, prior to the first dose of study medication; a minimum of 10 days between
             termination of the investigational drug and treatment with study medication is
             required

          -  Any major radiotherapy, tumor-directed systemic or immunotherapy within the last 4
             weeks for any indication

          -  Candidate for therapeutic neoadjuvant treatment

          -  Active infection

          -  Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
             respiratory, hepatic, renal, or cardiac disease)

          -  Required administration of concomitant moderate or strong inhibitors or inducers of
             CYP3A4 for 14 days prior to the first dose of study drug prior amiodarone for up to 6
             months prior to day 1 of study treatment

          -  Inability to take oral medications e.g., impairment of gastrointestinal (GI) function
             or GI disease that may significantly alter the absorption of oral medications (e.g.,
             ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome,
             or small bowel resection)

          -  History or evidence of cardiovascular risk including any of the following:

               -  Current uncontrolled hypertension (systolic >150 mm Hg and/or diastolic >100
                  mmHg) or unstable angina

               -  History of serious cardiac arrhythmia requiring treatment (exceptions: atrial
                  fibrillation, paroxysmal supraventricular tachycardia)

               -  History of myocardial infarction within 6 months of day 1 of dosing

               -  History of CHF of New York Heart Association (NYHA) criteria

          -  Known human immunodeficiency virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
             Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection
             which will be allowed)

          -  Have acute or currently active/requiring anti-viral therapy hepatic or biliary disease
             (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones,
             liver metastases or stable chronic liver disease per investigator assessment).

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study drugs

          -  Psychological, familial, sociological, or geographical conditions that do not permit
             compliance with the protocol

          -  Any other concurrent condition that in the investigator's opinion would jeopardize
             compliance with the protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:difference in kinome activation pre and post treatment
Time Frame:7-10 days prior to surgery and at surgery
Safety Issue:
Description:To identify differential kinome activation before and after treatment with a single dose of trastuzumab, pertuzumab, the combination of trastuzumab + pertuzumab, or the combination of single dose trastuzumab+once daily lapatinib for 7 days, in patients with HER2+ breast cancer

Secondary Outcome Measures

Measure:predictability in kinome activation
Time Frame:kinoming analysis of tissue will be done after subject participation, which will last from 7-10 days prior to surgery.
Safety Issue:
Description:to see if different kinase activation patterns can predict the optimal HER2 inhibition for treatment.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • breast cancer
  • Kinome
  • HER two positive

Last Updated

April 17, 2017