Clinical Trials /

Neratinib and Paclitaxel With or Without Pertuzumab and Trastuzumab Before Combination Chemotherapy in Treating Patients With Metastatic or Locally Advanced Breast Cancer

NCT03101748

Description:

This phase I/II trial studies the side effect and best dose of neratinib and to see how well it works with paclitaxel and with or without pertuzumab and trastuzumab before combination chemotherapy in treating patients with breast cancer that has spread to other places in the body. Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with pertuzumab and trastuzumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as paclitaxel, doxorubicin hydrochloride, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving neratinib, pertuzumab, trastuzumab, paclitaxel and combination chemotherapy may work better in treating patients with breast cancer.

Related Conditions:
  • Breast Carcinoma
  • Inflammatory Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1b Study of Neratinib, Pertuzumab and Trastuzumab With Taxol (3HT) in Primary Metastatic and Locally Advanced Breast Cancer, and Phase II Study of 3HT Followed by AC in HER2 + Primary IBC, and Neratinib With Taxol (NT) Followed by AC in HR+ /HER2- Primary IBC
  • Official Title: A Phase 1b Study of Neratinib, Pertuzumab and Trastuzumab With Taxol (3HT) in Primary Metastatic and Locally Advanced Breast Cancer, and Phase II Study of 3HT Followed by AC in HER2 + Primary IBC, and Neratinib With Taxol (NT) Followed by AC in HR+ /HER2- Primary IBC

Clinical Trial IDs

  • ORG STUDY ID: 2016-0537
  • SECONDARY ID: NCI-2017-00813
  • NCT ID: NCT03101748

Conditions

  • Malignant Neoplasm of Breast

Interventions

DrugSynonymsArms
NeratinibGroup A: HER2-Positive Breast Cancer
PaclitaxelTaxolGroup A: HER2-Positive Breast Cancer
PertuzumabPerjetaGroup A: HER2-Positive Breast Cancer
TrastuzumabHerceptinGroup A: HER2-Positive Breast Cancer
DoxorubicinDoxorubicin Hydrochloride, Adriamycin PFS, Adriamycin RDF, Adriamycin, RubexGroup B: HER2+ Locally Advanced Inflammatory Breast Cancer
CyclophosphamideCytoxan, NeosarGroup B: HER2+ Locally Advanced Inflammatory Breast Cancer

Purpose

The goal of this clinical research study is to learn if adding neratinib to either taxol (paclitaxel) or to the combination of pertuzumab, trastuzumab, and paclitaxel can help to control metastatic or locally advanced breast cancer when given before other standard chemotherapy (doxorubicin and/or cyclophosphamide) and surgery. Researchers also want to find the highest tolerable dose of neratinib that can be used in these study drug combinations. The safety of these drug combinations will also be studied. This is an investigational study. Pertuzumab and trastuzumab are FDA approved and commercially available for the treatment of HER2-positive breast cancer. Paclitaxel, doxorubicin, and cyclophosphamide are FDA approved and commercially available for the treatment of breast cancer. Neratinib is not FDA approved or and commercially available. The drug combinations are investigational and are currently being used for research purposes only. The study doctor can describe how the study drugs are designed to work. Up to 99 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

      Study Groups:

      If participant is found to be eligible to take part in this study, participant will be
      assigned to 1 of 3 study groups based on participant's screening results:

        -  If participant is in Group A or B, participant will receive neratinib, paclitaxel,
           pertuzumab, and trastuzumab. The difference between these 2 groups is that the dose of
           neratinib and paclitaxel may be different for participants in Group A, but all
           participants in Group B will receive the same dose.

        -  If participant is in Group A, participant will be assigned to a dose level of neratinib
           based on when participant joins this study. Up to 5 dose levels of neratinib will be
           tested. Up to 20 total participants will be enrolled in Group A. The first group of
           participants will receive the lowest dose level. Each new group will receive a higher
           dose than the group before it, if no intolerable side effects were seen. This will
           continue until the highest tolerable dose of neratinib is found. Participant will
           receive 4 cycles of the study treatment. At the completion of the 4th cycle, depending
           on participant's response, participant's doctor may decide to continue up to 4
           additional cycles of the study therapy or start another treatment.

        -  If participant is in Group B, participant will receive doxorubicin and cyclophosphamide
           after receiving 4 cycles of the drugs listed above.

        -  If participant is in Group C, participant will receive neratinib and paclitaxel followed
           by doxorubicin and cyclophosphamide.

      Study Drug Administration:

      All participants will take neratinib 1 time a day by mouth for the first week as a 1-week
      "pre-cycle". After that, all study cycles will be 21 days long and participant's drug
      administration schedule will depend on what group participant is in.

      If participant is in Group A:

        -  Participant will take neratinib tablets 1 time a day by mouth with food at the same time
           each day (in the morning, if possible) during Cycles 1-4 (or up to 8 cycles). The study
           doctor will tell participant how many tablets participant needs to take every day.

        -  Participant will receive paclitaxel by vein over about 1-3 hours on Days 1, 8, and 15 of
           Cycles 1-4 (or up to 8 cycles).

        -  Participant will receive pertuzumab by vein over about 1 hour on Day 1 of Cycles 1-4.

        -  Participant will receive trastuzumab by vein over about 1-2 hours on Day 1 of Cycles 1-4
           (or up to 8 cycles).

      If participant is in Group B:

        -  Participant will take neratinib tablets 1 time a day by mouth with food at the same time
           each day (in the morning, if possible) during Cycles 1 - 4. The study doctor will tell
           participant how many tablets participant needs to take every day.

        -  Participant will receive paclitaxel by vein over about 1-3 hours on Days 1, 8, and 15 of
           Cycles 1-4.

        -  Participant will receive pertuzumab by vein over about 1 hour on Day 1 of Cycles 1-4.

        -  Participant will receive trastuzumab by vein over about 1-2 hours on Day 1 of Cycles
           1-4.

        -  Participant will receive standard-of-care doxorubicin and cyclophosphamide by vein over
           about 90 minutes on Day 1 of Cycles 5 - 8.

      If participant is in Group C:

        -  Participant will take neratinib tablets 1 time a day by mouth with food at the same time
           each day (in the morning, if possible) during Cycles 1 - 4. The study doctor will tell
           participant how many tablets participant needs to take every day.

        -  Participant will receive paclitaxel by vein over about 1 - 3 hours on Days 1, 8, and 15
           of Cycles 1 - 4.

        -  Participant will receive standard-of-care doxorubicin and cyclophosphamide by vein over
           about 90 minutes on Day 1 of Cycles 5 - 8.

      If participant is in Group B or C, participant will have standard-of-care surgery after
      participant finishes receiving doxorubicin and cyclophosphamide. Participant will receive a
      separate consent form for the surgery that describes the procedure and its risks.

      Participant will have a medication diary to record the information about taking neratinib.

      Participant should bring this diary and the medication bottles with the leftover drug to the
      clinic at the beginning of each cycles.

      Length of Study:

      Participant will receive up to 8 cycles of study drugs. Participant will no longer be able to
      take the study drugs if the disease gets worse, if intolerable side effects occur, or if
      participant is unable to follow study directions.

      Participation on the study will be over after the follow-up period.

      Study Visits:

      Before participant receives study drug, at the end of the "pre-cycle", and then after Cycle
      4, blood (about 3 teaspoons) will be drawn for research purposes, including genetic research.

      If participant is in Group A:

        -  Before Day 1 of Cycle 1, participant will have a breast core biopsy to collect tissue
           for biomarker testing.

        -  Blood ( about 3 teaspoons) will be collected for research purposes, including genetic
           research.

        -  Before Day 1 of each cycle, and then before participant begins the next treatment,
           participant will have a physical exam including a breast and lymph node exam.

        -  Before Day 1 of Cycle 1 and then before participant begins the next treatment after
           Cycle 4, the study doctor will take pictures of both of participant's breasts.

        -  On Days 1, 8, and 15 of each cycle and before participant begins the next treatment
           after Cycle 4, blood (about 1-3 tablespoon) will be drawn for routine tests.

        -  Before Day 1 of Cycle 1, and then before participant begins the next treatment after
           Cycle 4, participant will have a mammogram of the involved breast and an ultrasound of
           the involved breast and lymph nodes, or breast MRI if the doctor thinks it is needed.

        -  Participant will have a CT scan or PET CT scan or bone scan or chest X-ray after every 3
           cycles if participant's doctor think it needed

        -  After Cycle 4, participant will have a MUGA scan or echocardiogram (ECHO) to check
           participant's heart function.

        -  After Cycle 4 and participant still has breast tumor, participant will have another
           biopsy to collect tissue for biomarker testing.

      If participant is in Group B or C:

        -  Before Day 1 of Cycle 1, participant will have a breast core biopsy to collect tissue
           for biomarker testing.

        -  Blood ( about 3 teaspoons) will be collected for research purposes, including genetic
           research.

        -  Before Day 1 of each cycle and before surgery, participant will have a physical exam
           including a breast and lymph node exam.

        -  Before Cycle 1 and Cycle 5, and then before surgery, the study doctor will take pictures
           of both of participant's breasts.

        -  On the day of each cycle participant is receiving chemotherapy and then before surgery,
           blood (about 1-3 tablespoon) will be drawn for routine tests.

        -  Before Day 1 of Cycle 1, before participant begins receiving doxorubicin and
           cyclophosphamide, and then before surgery, participant will have a mammogram of the
           involved breast and an ultrasound of the involved breast and lymph nodes, or breast MRI
           if the doctor thinks it is needed.

        -  After Cycle 4, participant will have a MUGA scan or echocardiogram (ECHO) to check
           participant's heart function. Participant may have a MUGA scan or ECHO every 3 months
           thereafter if the doctor thinks it is needed.

        -  During surgery, breast tissue samples will be collected to identify tumors for routine
           testing and for biomarker testing. No additional breast tissue will be removed in
           addition to what would already be removed during surgery.

      Follow-Up:

      If participant is in Group A:

      °About 1 month after the last dose of study drug, participant will be asked about
      participant's health and any side effects participant may have had. Participant may be asked
      during a routine clinic visit or participant may be called by a member of the study staff. If
      participant is called, each call should last about 2 minutes.

      If participant is in Group B or C:

        -  About 1 month after surgery, participant will be asked about participant's health and
           any side effects participant may have had. Participant may be asked during a routine
           clinic visit or participant may be called by a member of the study staff. If participant
           is called, each call should last about 2 minutes.

        -  Then participant will be followed every 6 months for 2 years for disease status.
           Participant may be asked during a routine clinic visit or participant may be called by a
           member of the study staff. If participant is called, each call should last about 2
           minutes.
    

Trial Arms

NameTypeDescriptionInterventions
Group A: HER2-Positive Breast CancerExperimentalGroup A consists of HER2-positive metastatic or locally advanced breast cancer patients. All participants take Neratinib 1 time a day by mouth for the first week as a 1-week "pre-cycle". After that, all study cycles are 21 days long. Participants take Neratinib tablets 1 time a day by mouth with food at the same time each day (in the morning, if possible) during Cycles 1 - 4. Participants receive Paclitaxel by vein over about 1-3 hours on Days 1, 8, and 15 of Cycles 1 - 4. Participants receive Pertuzumab by vein over about 1 hour on Day 1 of Cycles 1 - 4. Participants receive Trastuzumab by vein over about 1-2 hours on Day 1 of Cycles 1 - 4. All participants take Neratinib 1 time a day by mouth for the first week as a 1-week "pre-cycle". After that, all study cycles will be 21 days long.
  • Neratinib
  • Paclitaxel
  • Pertuzumab
  • Trastuzumab
Group B: HER2+ Locally Advanced Inflammatory Breast CancerExperimentalGroup B consists of HER2+ locally advanced inflammatory breast cancer (IBC) patients. All participants take Neratinib 1 time a day by mouth for the first week as a 1-week "pre-cycle". After that, all study cycles are 21 days long. Participants take Neratinib tablets 1 time a day by mouth with food at the same time each day (in the morning, if possible) during Cycles 1 - 4. Participants receive Paclitaxel by vein over about 1-3 hours on Days 1, 8, and 15 of Cycles 1-4. Participants receive Pertuzumab by vein over about 1 hour on Day 1 of Cycles 1 - 4. Participants receive Trastuzumab by vein over about 1 - 2 hours on Day 1 of Cycles 1 - 4. Participants receive standard-of-care Doxorubicin and Cyclophosphamide by vein over about 90 minutes on Day 1 of Cycles 5 - 8.
  • Neratinib
  • Paclitaxel
  • Pertuzumab
  • Trastuzumab
  • Doxorubicin
  • Cyclophosphamide
Group C: HER2-/ER+ Locally Advanced IBC PatientsExperimentalGroup C consists of HER2-negative/ER-positive (HER2-/ER+) locally advanced IBC patients. All participants take Neratinib 1 time a day by mouth for the first week as a 1-week "pre-cycle". After that, all study cycles are 21 days long. Participants take Neratinib tablets 1 time a day by mouth with food at the same time each day (in the morning, if possible) during Cycles 1 - 4. Participants take Neratinib tablets 1 time a day by mouth with food at the same time each day (in the morning, if possible) during Cycles 1 - 4. Participants receive Paclitaxel by vein over about 1 - 3 hours on Days 1, 8, and 15 of Cycles 1 - 4. Participants receive standard-of-care Doxorubicin and Cyclophosphamide by vein over about 90 minutes on Day 1 of Cycles 5 - 8.
  • Neratinib
  • Paclitaxel
  • Doxorubicin
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

          1. Histological confirmation of breast cancer

          2. 18 years of age or older

          3. Able to provide written informed consent for the trial

          4. Performance status of </= 1 on the ECOG performance scale

          5. Able to swallow oral medication

          6. LVEF assessment by 2-D echocardiogram or MUGA scan performed within 90 days prior to
             registration must be >/= 50%

          7. 7. Adequate organ function as determined by the following laboratory values: Absolute
             neutrophil count >/= 1,500 /uL, Platelets >/= 100,000 / uL, Hemoglobin >/=9 g/dL,
             Creatinine clearance >/= 50 ml/min, Total bilirubin </= 1.5 X ULN, for patients with
             congenital unconjugated hyperbilirubinemia (Crigler-Najjar syndrome type 1 and 2,
             Gilbert syndrome) that transient hyperbilirubinemia can occur due to physiological
             condition, as long as there is clear documentation of diagnosis, allowed to be
             enrolled if direct (conjugated) bilirubin is ≤ 1.5 X ULN, Alanine aminotransferase and
             aspartate aminotransferase </= 2.5 X ULN except in patients with AST/ALT elevation
             that is declared to be caused due to liver metastasis, they are allowed to be enrolled
             as long as <5 x ULN.

          8. Subject of Childbearing potential should is willing to use effective methods of birth
             control or be surgically sterile, or abstain from heterosexual activity during study
             and at least 4 months after the last dose of study drug. Subject of childbearing
             potential is defined as has not been surgically sterilized or free from menses for > 1
             year.

          9. Subject of childbearing potential is willing to use effective methods of birth control
             include: 1) Use of hormonal birth control methods: pills, shots/injections, implants
             (placed under the skin by a health care provider), or patches (placed on the skin); 2)
             Intrauterine devices (IUDs); 3) Using 2 barrier methods (each partner must use 1
             barrier method) with a spermicide. Males must use the male condom (latex or other
             synthetic material) with spermicide. Females must choose either a Diaphragm with
             spermicide, or Cervical cap with spermicide, or a sponge (spermicide is already in the
             contraceptive sponge). Female patients of childbearing potential must have a negative
             urine pregnancy test no more than 21 days prior to starting study drug; 4) For male
             participant, they must agree and commit to use a barrier method of contraception while
             on treatment and for 3 months after the last dose of investigational product.

         10. Cohort 1: Phase 1b: Subject must have HER2 + (regardless of hormonal receptor status)
             primary metastatic or locally advanced breast cancer (IBC or Non-IBC). HER2 positive
             status is defined as strongly positive (3+) staining score by IHC, or gene
             amplification using FISH, if performed. If IHC is equivocal (2+), assays using FISH
             require gene amplification based on recent ASCO-CAP guideline: dual-probe HER2/CEP17
             ratio is >/=2.0 and/or an average HER2 copy number >/= 6.0 signals/cell. IBC is
             determined by using international consensus criteria: Onset: Rapid onset of breast
             erythema, edema and/or peau d'orange, and/or warm breast, with/without an underlying
             breast mass. Duration: History of such findings no more than 6 months. Extent erythema
             occupying at least 1/3 of whole breast. Pathology: Pathologic confirmation of invasive
             carcinoma

         11. Cohort 1: Phase II: Patient must have HER2+ (regardless of hormonal receptor status)
             stage III IBC.

         12. Cohort 2 Patient must have HER2-/HR+ stage III IBC. HER2 negative status, which
             determined by assays using IHC require negative (0 or 1+) staining score. If IHC is
             equivocal (2+) staining score, assays using FISH require the absence of gene
             amplification: dual-probe HER2/CEP17 ratio is < 2.0 and an average HER2 copy number
             <4.0 signals/cell. If HER2 testing result is confirmed at MDACC, it does not require
             centralized repeat testing. Hormone receptor (HR) positivity is determined by ER
             >/=10% and /or PR >/=10% by IHC staining.

        Exclusion Criteria:

          1. Excisional biopsy or lumpectomy for the current breast cancer.

          2. Any other previous malignancies (except for cervical in situ cancers treated only by
             local excision, and basal and squamous cell carcinomas of the skin) within 5 years.

          3. Any other previous antitumor therapies for the current cancer event. This exclusion
             does not apply to phase Ib part of cohort 1.

          4. Breast-feeding at screening or planning to become pregnant during the course of
             therapy.

          5. History of active or known autoimmune disease that can cause diarrhea like (but not
             limited to) Addison's Disease, Celiac Disease/Gluten Intolerance/Irritable Bowel
             Syndrome, Scleroderma.

          6. Active infection or chronic infection requiring chronic suppressive antibiotics.

          7. Known hepatitis B or hepatitis C with abnormal liver function tests.

          8. Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of
             the stomach or small bowel, or other disease or condition significantly affecting
             gastrointestinal function.

          9. Persistent >/= grade 2 diarrhea regardless of etiology.

         10. Sensory or motor neuropathy >/= grade 2

         11. Conditions that would prohibit intermittent administration of corticosteroids for
             paclitaxel premedication. However, corticosteroid can be dropped after confirming of
             no asthma like reaction to paclitaxel after 3 doses.

         12. Uncontrolled hypertension defined as a systolic BP > 150 mmHg or diastolic BP > 90
             mmHg, with or without anti-hypertensive medications.

         13. Cardiac disease (history of and/or active disease) that would preclude the use of any
             of the drugs included in the treatment regimen. This includes but is not confined to:
             (A)Active cardiac diseases including: • symptomatic angina pectoris within the past
             180 days that required the initiation of or increase in anti-anginal medication or
             other intervention; • ventricular arrhythmias except for benign premature ventricular
             contractions; • supraventricular and nodal arrhythmias requiring a pacemaker or not
             controlled with medication; • conduction abnormality requiring a pacemaker; • valvular
             disease with documented compromise in cardiac function; and • symptomatic
             pericarditis. (B) History of cardiac disease: • myocardial infarction documented by
             elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV
             function; • history of documented CHF; and • documented cardiomyopathy.

         14. If you are pregnant, you will not be enrolled on this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of Neratinib in Combination with Paclitaxel, Pertuzumab, and Trastuzumab in HER2-positive (HER2+) Primary Metastatic or Locally Advanced Breast Cancer
Time Frame:42 days
Safety Issue:
Description:MTD is defined as the highest dose for which the posterior probability of toxicity is closest to 20%. The phase Ib portion of the trial uses the Bayesian modified Toxicity Probability Interal (mTPI)[34] dose-escalation algorithm to determine the MTD of Neratinib from among four doses.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS) Rate of HER2+ Primary de novo Metastatic and Locally Advanced Inflammatory Breast Cancer (IBC) Patients, and HER2-/ER+ IBC Patients Treated with Neratinib Plus Anthracycline and Taxane Based Chemotherapy
Time Frame:2 years
Safety Issue:
Description:Progression-free survival (PFS) estimated by the Kaplan-Meier method, and distributions compared using the log-rank test.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Malignant neoplasm of breast
  • Metastatic breast cancer
  • Locally advanced breast cancer
  • HER2-positive
  • HER2+
  • HER2-negative/ER-positive
  • HER2-/ER+
  • Locally advanced inflammatory breast cancer
  • IBC
  • Neratinib
  • Paclitaxel
  • Taxol
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • Adriamycin
  • Rubex
  • Pertuzumab
  • Perjeta
  • Trastuzumab
  • Herceptin
  • Cyclophosphamide
  • Cytoxan
  • Neosar

Last Updated

February 2, 2018