1B-13-2 Core Biopsies of Breast Tumor Tissue Repository
The response to treatment varies considerably among breast cancer patients. Markers that can predict response to specific therapies have been difficult to identify and validate for several reasons: cell and animal models do not reflect human biology well, tumor tissue that has been fixed in preservative limits their analysis, and differences within tumors that may control drug response are not easily assessed in tissue sections. The study of human breast tumor tissue in patients at baseline and at timepoints following medical therapies can provide valuable insights into markers and pathways that mediate drug response and resistance. We aim to create a repository for future studies to develop and refine tissue assays and to generate pilot data on mediators of drug response/resistance that can then be validated on larger tissue cohorts from clinical trial databases and other outside repositories. In contrast to the more general breast and womens program tissue repository, this proposal is specifically for collecting core tumor biopsies performed on patients with breast cancers who are receiving anti-cancer therapy. The objective of this proposal is to prospectively obtain and bank core biopsies of breast cancers at the timepoints of diagnostic biopsy, surgery for tumor removal, and following chemotherapy in order to facilitate research focusing on tumor changes that drive drug resistance and spread to other organs.Patients enrolled in this registry will have suspected or known breast cancer and be able to provide additional core biopsy specimens over and above those needed for diagnosis and other required tests. There will be 4 groups of patients enrolled: 1) patients newly diagnosed with early stage breast cancer who will have surgery before receiving any chemotherapy, 2) patients newly diagnosed with breast cancer who will be receiving standard of care chemotherapy before surgery or patients with advanced disease that cannot be removed with surgery, 3) patients being evaluated for a suspicious breast mass that has a high likelihood of being cancer, and 4) patients with breast cancer that has returned or worsened. Consenting patients will have additional core needle biopsies of suspected or known breast tumors collected by the pathologist assigned to the case. Up to 6 additional core biopsies will be obtained through a single opening in the skin under ultrasound guidance by the research radiologist. For patients in whom a full diagnosis is not yet established, the additional core biopsy specimens will be held until the pathologist verifies that the diagnostic biopsy is sufficient for all needed diagnostic tests. If patients consent, another set of biopsies will be done at the time when their disease returns or worsens. Blood samples will be collected at baseline and at the time when disease returns or worsens. Medical records will be reviewed to collect information about medical history, family history, diagnosis, cancer treatments, lab test results, medications used, tumor measurements, and death. Participants will be followed every 6 months through chart review and telephone calls.Interested investigators and / or researchers who would like to obtain tissue or blood samples and / or associated data will submit their IRB-approved protocols for consideration to the Core Biopsy Steering Committee.
A Randomized, Phase II Clinical Trial of a Controlled Diet Prior to Selected Chemotherapy Treatment in Breast and Prostate Cancer to Evaluate the Impact on Toxicity and Efficacy
I. To obtain preliminary estimates of the impact of a restricted diet on toxicity and
efficacy of chemotherapy for breast and prostate cancer.
II. To evaluate the compliance with a controlled diet intervention.
III. To investigate changes in plasma insulin, glucose, insulin-like growth factor 1 (IGF1)
and IGF binding protein (IGFBP) levels in subjects who consume a restricted diet compared to
Patients are randomized to 1 or 2 treatment arms.
ARM I: Patients eat a special low-calorie diet during 3 days prior to chemotherapy, during
the 12 weeks of chemotherapy, and 24 hours after chemotherapy. Patients are provided with
all meals and all food to be consumed and maintain a diary of the food consumed and
appropriate amounts. Patients meet with the study dietician within 3 weeks of enrollment
and prior to, or on the day of, their first course of chemotherapy on study and at the start
of each subsequent course.
ARM II: Patients eat a normal diet and receive dietary advice which may include consultation
with a nutritionist. Patients maintain a diary of the food consumed and appropriate amounts.
A Phase I/II Trial of Temsirolimus Plus Neratinib for Patients With Metastatic HER2-Amplified or Triple Negative Breast Cancer
Phase I Design
A standard, 3+3, dose escalation schedule will be used. Between 6 and 12 patients will
likely be necessary to determine the MTD of temsirolimus in combination with neratinib.
There will be no intrapatient dose escalation. The starting dose of temsirolimus is 8 mg
administered intravenously weekly (dose level 1). Three patients will initially be enrolled
in each cohort. The Phase I portion is closed to enrollment.
Phase II Design
The phase II portion of this trial will be comprised of two cohorts—HER2-amplified and
triple negative breast cancer—each of which has a Simon two-stage design to determine the
efficacy of temsirolimus when administered in combination with neratinib. Both pathologic
subtypes of patients will be studied separately though accrual will be simultaneous.
Response (RECIST criteria) will be assessed every 8 weeks (every 2 cycles) after the start
of therapy. As of 2/10/12, the Triple-negative cohort is closed to accrual. The HER2-
amplified cohort will continue to enroll as planned up to a total of 34 patients.
A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients With 1-3 Positive Nodes, Hormone Receptor-Positive and HER2-Negative Breast Cancer With Recurrence Score (RS) of 25 or Less. RxPONDER: A Clinical Trial Rx for Positive Node, Endocrine Responsive Breast Cancer
I. To determine the effect of chemotherapy in patients with node positive breast cancer who
do not have high Recurrence Scores (RS) by Oncotype DX. In patients with 1-3 positive nodes,
and hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative
breast cancer with RS =< 25 treated with endocrine therapy we will test whether the
difference in disease-free survival for patients treated with chemotherapy compared to no
chemotherapy depends directly on the magnitude of RS. If benefit depends on the RS score,
the trial will determine the optimal cutpoint for recommending chemotherapy or not.
I. To compare overall survival (OS), distant disease-free survival (DDFS), and local
disease-free interval (LDFI) by receipt of chemotherapy or not and its interaction with RS.
II. To compare the toxicity across the treatment arms. III. To perform other assays or tests
(in particular the PAM50 risk of relapse score) as they are developed and validated that
measure potential benefit of chemotherapy and compare them to Oncotype DX.
IV. To determine the impact of management with Oncotype DX on patient-reported anxiety
(co-primary Health-Related Quality of Life [HRQL] outcome) prior to screening, after
disclosure of test results, and during the randomized trial.
V. To determine the impact of Oncotype DX on the initial management cost of node-positive,
HR-positive, HER2-negative breast cancer.
VI. To compare patient-reported utilities (e.g., QOL) for those randomized to chemotherapy
versus no chemotherapy.
VII. To estimate the cost-effectiveness of management with Oncotype DX vs usual care using
modeling and DFS information from the trial.
VIII. To determine the role of other assays (e.g., PAM50) as predictors of DFS, DDFS, and
LDFI of patients randomized to chemotherapy versus no chemotherapy.
IX. To determine the impact of treatment with chemotherapy versus no chemotherapy on
patient-reported fatigue and cognitive concerns (secondary HRQL outcomes).
X. To determine the impact of management with Oncotype DX on patient-reported decision
conflict, perceptions regarding Oncotype DX testing, and survivor concerns prior to
screening, after disclosure of test results, and during the randomized trial (secondary HRQL
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive a protocol-approved chemotherapy regimen based on the patient and/or
physician preference. Patients then receive a protocol-approved adjuvant endocrine therapy
comprising tamoxifen citrate, an aromatase inhibitor (anastrozole, letrozole, or
exemestane), or both for 5-10 years in the absence of disease progression or unacceptable
ARM II: Patients receive a protocol-approved endocrine therapy comprising tamoxifen citrate,
an aromatase inhibitor (anastrozole, letrozole, or exemestane), or both for 5-10 years in
the absence of disease progression or unacceptable toxicity.
Patients may complete health-related quality-of-life (QOL) questionnaires at baseline and
periodically during study. Information on Medicare and/or insurance coverage and on health
coverage decisions may also be collected periodically.
After completion of study therapy, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then yearly for at least 15 years.
A Randomized Phase III Trial of the Value of Early Local Therapy for the Intact Primary Tumor in Patients With Metastatic Breast Cancer
- To evaluate whether early local therapy comprising surgery of intact primary disease
compared to local palliative therapy only in patients with stage IV breast cancer,
whose disease does not progress during initial optimal systemic therapy, will result in
- To compare the time to uncontrolled chest wall disease between patients treated with
- To determine whether there is a difference in health-related quality-of-life (HRQOL)
between patients treated with these regimens.
- To determine whether the absolute value of circulating tumor cells (CTC) burden at 6
months following randomization (time +6) will be lower in the palliative therapy arm
than in early local therapy arm, and whether this value is inversely related to
survival (lower CTC, longer survival).
- To collect tumor and blood specimens for future exploration of the biological
interactions between the primary tumor and metastatic lesions and the effect of primary
OUTLINE: This is a multicenter study. Patients are stratified according to hormone receptor
and treatment plan (ER+ or PR+, HER2-, endocrine therapy alone vs ER+ or PR+, and HER2-,
chemotherapy and/or endocrine therapy vs ER- or PR-, and HER2- vs HER2+), and number of
involved organ systems with distant disease (regional nodes in the axillary,
supraclavicular, and internal mammary locations are not considered distant sites) (1 vs >
1). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive standard palliative therapy, if needed, to address symptoms
such as tumor ulceration, pain, bulky adenopathy causing arm symptoms, and other
similar situations. Therapy may consist of radiotherapy alone, surgery alone, or a
combination of both.
- Arm II: Patients undergo surgery comprising breast-conserving therapy (BCT) or total
mastectomy according to patient and treating physician preference. Surgery is to occur
no later than 10 weeks after completion of 32 weeks of systemic therapy. Free surgical
margins must be achieved with re-excision or mastectomy for patients undergoing BCT.
After completion of BCT, patients undergo radiotherapy once a day, 5 days per week.
Patients who had mastectomy undergo radiotherapy at the discretion of treating
Patients may undergo blood and tumor tissue sample collection for circulating tumor cells
(CTC) burden and future studies.
Patients complete the Functional Assessment of Cancer Therapy - Breast Trial Outcome Index
(FACT- TOI) and FACT - General (22) and the Breast Cancer Subscale (FACT-B) quality-of-life
questionnaires at baseline and periodically during study.
After completion of study therapy, patients are followed up periodically for 5 years.
Combined Exercise Program for Early Breast Cancer Survivors
I. To determine whether a 16-week exercise intervention will improve components of
metastasis (MetS) in breast cancer survivors soon after completion of cancer-related
treatments by measuring changes in body composition, waist circumference, blood pressure,
and serum levels of insulin, glucose, lipids, C-reactive protein, and hemoglobin A1c
II. To determine whether a 16-week exercise intervention will improve physical fitness in
breast cancer survivors soon after completion of cancer-related treatments by measuring
cardiorespiratory fitness and muscle strength.
III. To assesses the feasibility of a supervised exercise intervention in early breast
IV. To determine whether a 16-week exercise intervention will result in a reduction in
adipose tissue inflammation in obese breast cancer survivors soon after completion of
cancer-related treatments by measuring ATM phenotype and ATM cytokine expression.
V. To determine whether breast cancer survivors can maintain positive benefits of an
exercise intervention following a 12-week follow-up period by measuring changes in body
composition, waist circumference, blood pressure, and serum levels of insulin, glucose,
lipids, C-reactive protein, and HbA1c, cardiorespiratory fitness and muscle strength.
Patients are randomized to 1 of 2 arms.
Arm I (Control): Patients refrain from increasing physical activity levels for 16 weeks.
Arm II (Exercise): Patients participate in supervised exercise sessions over 60 minutes
thrice weekly and are encouraged to participate in a home-based exercise session over 30-45
minutes once weekly for 16 weeks.
1B-12-6 Light-Scattering Spectroscopy for the Detection of Stage II-III Breast Cancer: A Pilot Study
Breast cancer is the second leading cause of cancer death in women, and is the most frequently diagnosed cancer among women. The most common method for breast cancer screening is mammography, which is an x-ray of the breast. Although a mammogram may find tumors that are too small to feel, it has limitations as a screening test. These include the use of x-ray radiation and uncomfortable compression of an individuals breast. Also, the ability of a mammogram to find breast cancer may depend on the size of the tumor, the density of the breast tissue, and the skill of the radiologist. Mammograms are less likely to find breast tumors in women younger than 50 years than in older women. This may be because younger women have denser breast tissue that appears white on a mammogram resulting in missed cancers or in the discovery of later stage cancers. Light-scattering spectroscopy (LSS) is based on the science of diffusion in which light is scattered from its point of origin and interacts with another medium. When a beam of light comes into contact with an object, the light is absorbed, reflected, and/or scattered. After the light has been scattered, the measurements can be collected and analyzed. Recent advances have allowed for the noninvasive detection of precancerous lesions by using LSS. This approach has been validated for detection of precancerous polyps in the colon and pancreatic cancer.We propose a pilot study to predict the presence of breast cancer through the assessment of the tissue in the nipple using LSS, thereby eliminating the need for any direct examination or radiographic imaging of the inside of the breast. The objective of this study is to evaluate whether LSS can reliably distinguish between two subject groups: those with clinical confirmed stage II or stage III breast cancer and those without breast cancer. If successful, this technology could lead to a safer, less expensive method of breast cancer screening.Patients who agree to take part will have two assessments with the LSS probe done on each breast. They will not be followed after the assessments and their participation will end once the assessments have been completed.The data will be coded, classified, and ranked for each group. These results will be compared to the tumor status of each breast and the number of correct classifications counted. The accuracy of the classifications will be associated with the ability of the device to predict the presence of disease. Optical markers will also be analysed using multivariate analyses. The results will be evaluated and will be used to determine if the device warrants further investigation in this type of cancer.
1B-12-10 Phase II Trial of Metronomic Capecitabine and Cyclophosphamide with Lapatinib and Trastuzumab in Patients with HER2 Positive Metastatic Breast Cancer Who Have Progressed on a Previous Trastuzumab-Based Regimen
Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in women. About 20% of patients will initially be diagnosed with breast cancer that has spread (metastatic), and 20-80% of patients initially diagnosed with localized disease will ultimately develop metastatic disease. Despite recent advances in therapy, metastatic breast cancer (MBC) remains an incurable disease and further improvements in systemic therapy are needed. Chemotherapy is usually given at the highest possible dose that does not cause life-threatening side effects. This dose does not target tumor cells specifically, but damages normal cells and results in toxic side effects that require time between each dose for recovery. Metronomic chemotherapy is an emerging new model in cancer therapy, in which low doses of chemotherapy drugs are given at frequent intervals. The major advantage of metronomic chemotherapy is the low toxicity, which significantly improves patients quality of life, allows for longer administration of chemotherapy drugs without dose reductions or delays, and provides opportunities to combine different classes of drugs that would otherwise be difficult with full dose regimens. Metronomic chemotherapy has been found to have moderate activity with low toxicity in several phase II clinical trials in patients with MBC and improved activity was seen in studies when it was combined with targeted therapies. Human epidermal growth factor receptor 2 (HER2) is overexpressed in about 20-30% of all breast cancers and is associated with earlier recurrence and shorter overall survival. Trastuzumab, a targeted therapy against HER2, improves survival in HER2 positive patients and when combined with chemotherapy has response rates that are 60-70%. However, patients eventually progress after initial response, but trastuzumab is usually continued in these patients even after their disease progresses. Lapatinib is an orally active small molecule that inhibits the tyrosine kinases of HER2 and epidermal growth factor receptor type 1 (EGFR). A phase III, randomized, open-label study showed that lapatinib in combination with capecitabine is also active in women with HER2-positive MBC who had previously received trastuzumab and is now the standard treatment in patients whose disease has progressed after treatment with trastuzumab. Other studies combining trastuzumab with lapatinib suggest that inhibiting HER2 with both drugs is better than using either drug alone in the treatment of HER2-positive breast cancer.This study proposes a phase II clinical trial using metronomic chemotherapy (capecitabine and cyclophosphamide), in combination with dual HER2 inhibition (lapatinib and trastuzumab), in HER2 positive MBC patients previously treated with trastuzumab. The primary objective of this study is to estimate the progression free survival (PFS) in patients with MBC that is HER2 positive and who have had previous treatment with trastuzumab.Patients who will be enrolled for this study will have laboratory confirmed HER2-positive breast cancer whose disease has spread and have had prior treatment with trastuzumab. Once participants sign the informed consent and are deemed eligible for the study, participants will receive either cyclophosphamide, cytoxan, lapatinib, and trastuzumab. They will take cyclophosphamide, cytoxan, lapatinib once a day and receive an injection of trastuzumab every 21 days. Every 21 days is called a cycle. During the study, participants will have the following procedures done during each cycle: a physical exam, blood tests, performance status, assessment of side effects, and review of medications. They will have tumor assessments every 2 cycles with radiographic scans and MUGA or Echo to assess heart function every 3 cycles. Participants will stop taking study drug(s) if their disease worsens, they have another illness which prevents them from taking the study drug(s), they cannot tolerate the side effects, they withdraw from the study, or their study doctor thinks that being on the study is no longer in their best interest. Participants will be followed every 3 months for one year after stopping the study drugs.The primary endpoint for participants is PFS. One-sided one-sample logrank test will be used to evaluate the improvement in PFS compared to the reported historical PFS rate. One futility analysis will be performed during the trial, at the end of the 1st year after enrollment starts using the Hazard Ratio for progression.
A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral Lucitanib in Patients With FGF Aberrant Metastatic Breast Cancer
Lucitanib is a selective, orally available tyrosine kinase inhibitor targeting FGFR1-3,
VEGFR1-3, and PDGFRα and β, with activity in relevant cell lines and animal models.
The first in human trial of lucitanib demonstrated that daily dosing with lucitanib can
provide durable clinical responses in patients with FGFR1- or 11q (FGF3, FGF4, Cyclin D1, or
FGF19)-amplified breast cancer. RECIST partial responses (PRs) were also observed in
patients not known to have FGF abnormalities.
Based on these results, is study is designed to explore the safety and anti-tumor activity
of daily lucitanib in breast cancer patients with and without alterations of the FGF
Effect of Preoperative Breast MRI on Surgical Outcomes, Costs and Quality of Life of Women With Breast Cancer
This is a randomized trial of preoperative breast MRI in patients deemed eligible for breast
conserving surgery by conventional clinical criteria will provide important information
about the clinical and biologic relevance of occult disease identified by MRI alone.
Patients will be assigned to standard pre-operative breast cancer disease assessment without
the addition of MRI prior to breast conserving surgery or standard pre-operative breast
cancer disease assessment with the use of MRI prior to breast conserving surgery.
The primary objective is to compare the rates of local-regional recurrence (LRR) following
attempted breast conserving therapy in a cohort of women with triple negative or HER-2
amplified breast cancer randomized to preoperative staging with mammography (control arm) or
mammography plus breast MRI (MRI arm).
Secondary objectives are:
- To compare the re-operation rates following attempted breast conserving therapy between
women assessed preoperatively with breast MRI to those assessed without the use of
- To compare local recurrence rates between women who undergo BCT on the control arm to
women who undergo BCT on the MRI arm
- To compare the conversion rate to mastectomy secondary to persistent positive margins
or poor cosmesis within the first 6 months of attempting BCT (prior to the
administration of RT) between women assessed preoperatively with breast MRI to those
assessed without the use of breast MRI
- To compare the contralateral breast cancer rates in women randomized to preoperative
breast MRI to those not receiving pre-operative breast MRI
- To compare the disease-free survival rates between women assessed preoperatively with
breast MRI to those assessed without the use of breast MRI
- To compare breast cancer specific and overall survival outcomes of women assessed
preoperatively with breast MRI to those assessed without the use of breast MRI
- To estimate the rate of MRI-guided localization assisted surgery
- To estimate the rate of multi-centric disease in the index breast for women in the MRI
- To evaluate the accuracy of index lesion characteristics and other factors in
predicting multi-centricity in the cohort randomized to breast MRI
- To assess the positive predictive values (PPV) of MRI in detecting ipsilateral
multi-centric disease and contralateral disease in women with breast cancer undergoing
preoperative breast MRI
- To estimate the false positive rate for detection of multiple foci of breast cancer by
All registered patients will be monitored for relapse and survival for 5 years from the date
of surgery. Patients will be followed a minimum of every 4 months for the first 2 years from
diagnosis and a minimum of every 6 months during years 3-5. Patients will be monitored for
local, regional, distant relapse and vital status.
1B-13-8 Real Time Contrast Enhanced Ultrasound and Ultrasound-Based Elastography: Novel Techniques in Assessment of Treatment Response to Neoadjuvant Chemotherapy for Breast Cancer
I. To establish a quantitative prediction rule for accurate and early prediction of the
pathologic tumor response assessed post-surgery, using the change of contrast enhanced
ultrasound (CEUS) assessed tumor size and perfusion characteristics before (baseline) and
2-3 weeks following initiation of neoadjuvant chemotherapy (NAC).
II. To assess the agreement between CEUS based classification rule and pathologically
determined treatment response (baseline versus pre-surgical scan).
III. To establish a quantitative prediction rule for accurate and early prediction of the
pathologic tumor response assessed post-surgery, using the change in propagation velocity of
a shear mechanical wave in tissue before (baseline) and 2-3 weeks following initiation of
IV. To assess the agreement between shear wave elastography (SWE) based classification rule
and pathologically determined treatment response (baseline versus pre-surgical scan).
I. To explore the role of combined CEUS + SWE features obtained at early treatment phase
(2-3 weeks following initiation of NAC), in accurately predicting the pathologically
determined tumor response.
II. To investigate the agreement in assessment of therapy response to NAC between CEUS
versus contrast enhanced magnetic resonance imaging (CE MRI) and SWE versus CE MRI for
baseline versus pre-surgery scan and to identify discordant cases using scatter plot and
Patients undergo dynamic contrast-enhanced ultrasound imaging and shear wave elastography at
baseline, 2-3 weeks after initiation of chemotherapy, and before surgery.
A Randomized Phase III Trial Comparing Axillary Lymph Node Dissection to Axillary Radiation in Breast Cancer Patients (CT1-3 N1) who Have Positive Sentinel Lymph Node Disease after Neoadjuvant Chemotherapy
- All patients will undergo surgery to identify sentinel lymph node(s). If a lymph node
(sentinel or non-sentinel) is determined to be positive on intra-operative pathology
the patient will be registered/randomized intra-operatively.
- Patients who do not have a sentinel lymph node identified will not be
registered/randomized to the study.
- Patients whose sentinel lymph node status is cannot be/is not determined intra-
operatively, and have not undergone ALND, but had at least one lymph node (sentinel or
non-sentinel) found to be positive on final pathology review will be
- Patients whose sentinel lymph node status is found to be negative intra-operatively and
have not undergone ALND, but had at least one lymph node (sentinel or non-sentinel)
found to be positive on final pathology review will be registered/randomized
- ALND is not to be performed prior to registration/randomization.
- Patients who are determined to have negative lymph nodes on final pathology will not be
registered/randomized, but can be offered participation in another cooperative group
The primary and secondary objectives of the study are described below. Please see the "Arms"
section for a detailed description of the treatment regimens.
- To evaluate whether radiation to the undissected axilla and regional lymph nodes is not
inferior to axillary lymph node dissection with radiation to the regional lymph nodes
but not to the dissected axilla in terms of invasive breast cancer recurrence-free
interval in patients with positive SLN(s) after completion of neoadjuvant chemotherapy
- To evaluate whether radiation to the undissected axilla and regional lymph nodes is not
inferior to axillary lymph node dissection with radiation to the regional lymph nodes
but not to the dissected axilla in terms of the incidence of invasive loco-regional
recurrences in patients with a positive SLN(s) after completion of neoadjuvant
- To obtain an estimate of the distribution of residual disease burden scores for each
- To estimate the distribution of overall survival for each treatment arm
Patients may receive adjuvant and ancillary therapy as appropriate per the protocol.
- Adjuvant endocrine therapy: Patients with hormone receptor (ER and/or PR) positive
disease should receive a minimum of 5 years of standard endocrine therapy (experimental
agents/regimens are not permitted). Endocrine therapy should begin following completion
of neoadjuvant chemotherapy and surgery, either before, during or after radiation
therapy at the discretion of the oncologist. Selection of the agents is at the treating
- Patients with HER 2 positive disease should complete a total of one year of trastuzumab
therapy (over the neoadjuvant and adjuvant period).
- Chemotherapy, biologic therapy or vaccine therapy in the adjuvant setting is not
Patients who wish to receive any of these therapies after surgery must go off study at the
time of their initiation.
- Patients should receive full supportive care, including transfusions of blood and blood
products, erythropoetin (unless otherwise specified in the protocol), antibiotics,
antiemetics, etc. when appropriate.
Patients are followed up for 5 years after completion of radiation therapy.
0C-14-2: An Open-Label, Phase 2 Study of Neratinib in Patients with Solid Tumors with Somatic Human Epidermal Growth Factor Receptor (Egfr, Her2, Her3) Mutations or EGFR Gene Amplification
This is an open-label, non-randomized, multicenter, multinational, Phase 2 study exploring the efficacy and safety of neratinib as monotherapy or in combination with other therapies in patients with ERBB mutation-positive or EGFR gene amplified solid tumors.
Neratinib (PB-272) is a small molecule that inhibits EGFR, HER2, and HER4. Aberrant expression of EGFR, HER2, and HER3 are linked to development of many epithelial cancers including colorectal, gastric, breast and head and neck cancers. Preclinical data suggest that neratinib will have antitumor activity in EGFR- and/or HER2-expressing carcinoma cell lines.
The study will include the following cohorts of patients with tumors harboring somatic ERBB (EGFR, ERBB2, ERBB3) mutations or EGFR gene amplification.
1. Bladder/Urinary Tract
ERBB2 Mutant - Neratinib 240mg daily + Paclitaxel 80mg/m^2 IV on Days 1, 8, and 15 of every 4 week cycle
2. Biliary Tract
ERBB2 mutant HR Negative- Neratinib 240mg daily
a. ERBB2 mutant HR Negative - Neratinib 240mg daily
b. ERBB2 mutant HR Positive - Neratinib 240mg daily + Fulvestrant 500mg on Days 1, 15 of the first month, then Day 1 of every 4 week cycle
ERBB2 mutant - Neratinib 240mg daily
ERBB2 mutant - Neratinib 240mg daily
ERBB2 mutant - Neratinib 240mg daily
7. Solid tumors (NOS)
ERBB2 Mutant - Neratinib 240 mg daily
*Cohorts given combination therapy are "Combination Therapy" and all cohorts given Neratinib alone are labeled "Monotherapy."
The following cohorts have closed to accrual:
1. EGFR mutation and/or EGFR amplification
Primary brain tumors
Cohort: Primary brain tumors (glioblastoma multiforme [GBM] Grade III, glioma, gliosarcoma)
Closed to Accrual
The trial will consist of a screening period, a treatment period, safety follow-up and end of treatment (EOT) assessments, follow-up for disease progression every 8 weeks, and a survival follow-up period.
Treatment will consist of neratinib by mouth with food once daily in the morning administered on a continuous basis or combination therapy as listed above.
The primary endpoint of this study for all cohorts is to determine the objective response rate at 8 weeks (ORR8) following treatment with neratinib.
The secondary objectives of this study are:
To determine the confirmed objective response rate (ORR) according to RECIST v1.1 or other defined response criteria with neratinib monotherapy and combination therapy.
To determine the clinical benefit rate (CBR) of neratinib monotherapy and combination therapy.
To determine PFS.
To determine change in tumor growth rate for patients with primary brain tumors.
To determine the duration of response (DOR) of neratinib monotherapy and combination therapy, defined as the time from which measurement criteria are met for overall response of CR and PR until the first date of documented disease progression.
To determine overall survival (OS).
To determine the role of dual modality PET/CT scans in measuring metabolic response to neratinib monotherapy and combination therapy.
To assess the safety profile and tolerability of neratinib monotherapy and combination therapy.
To assess Patient Reported Outcomes using the EuroQol EQ-5D-5L instrument.
A Simon 2-stage optimal design will be used to determine whether neratinib has sufficient activity to warrant further development in the following cohorts: colorectal, endometrial, gastroesophageal, ovarian, and listed breast cancers. At the end of the trial, a 2-sided 80% confidence interval for Objective Response Rate will be determined for each cohort separately using the method of Koyama and Chen (2008).
Patient-related outcomes (EQ-5D-5L instrument) will be summarized and plotted over time. Changes from baseline will be provided with both point estimates and confidence intervals.
All analyses are descriptive and no formal testing is planned.
Recruiting | Any Cancer Condition or Solid Tumor | Multisite