| Conditions: |
|
Breast Cancer - Breast Tumors - Breast Neoplasms |
| Purpose: |
|
Background:
- GRN1005 is an experimental cancer treatment drug that may help treat breast cancer that
has spread to the brain. It contains a chemical that may help the drug enter the brain and
stop tumor cells from dividing. Researchers want to test GRN1005 alone and with another drug
called Herceptin. Herceptin is designed to treat a specific type of breast cancer, and will
not be given to all study participants.
Objectives:
- To see if GRN1005 is a safe and effective treatment for breast cancer that has spread
to the brain.
- To see if GRN1005 plus Herceptin is a safe and effective treatment for specific types
of breast cancer that has spread to the brain.
Eligibility:
- Individuals at least 18 years of age who have breast cancer that has spread to the brain.
Design:
- Participants will be screened with a physical exam and medical history. Blood, urine,
and tumor samples will be collected. Imaging studies will be used to identify where the
cancer has spread.
- Participants will be put in one of two groups for treatment. One group will receive
GRN1005 alone. The other group will receive GRN1005 plus Herceptin. Participants will
be assigned to these groups based on their type of breast cancer.
- All participants will have one dose of GRN1005 every 3 weeks for six cycles of
treatment. After six cycles, they will continue GRN1005 treatment as long as the side
effects are not severe and the cancer does not spread.
- The GRN1005 plus Herceptin group will also receive Herceptin either every week or every
3 weeks, as chosen by the study doctor.
- Treatment will be monitored with frequent blood tests and imaging studies. Tumor
samples may also be collected.
- Participants will continue treatment as long as the side effects are not severe and the
cancer does not spread....
|
| Study Summary: |
|
Background:
Among women with advanced breast cancer, the long-term cumulative risk of developing brain
metastases from breast cancer is estimated at 10 -15%. The 5-year cumulative incidence of
brain metastases in triple-negative (human epidermal growth factor receptor 2
[HER2]-negative, estrogen receptor [ER]-negative and progesterone receptor [PgR]-negative)
breast cancer has been reported as 10%, but has been reported up to 46% following the
diagnosis of metastatic breast cancer. In HER2-positive disease, this incidence may be up to
34% following the diagnosis of metastatic breast cancer and has recently been estimated as
almost 50% based on data in long-term follow-up of patients with both early and advanced
HER2-positive disease.
Brain metastases are associated with considerable morbidity and mortality. Currently, there
is no approved drug therapy for brain metastases. Conventional cytotoxic drugs penetrate the
brain poorly and intra-cranial response rates are low and of short duration. Given the poor
prognosis of patients with brain metastases and the lack of effective drug treatment
options, there is a need for development of new therapeutic agents.
We are proposing to study (18)F-FLT to determine if amount of change in the uptake in the
brain metastases from breast cancer after one dose of therapy with GRN1005, correlates with
intracranial response. FLT-PET utilizes a radiolabeled form of thymidine, which is
incorporated into DNA in proliferating cells. (18)F-FLT uptake correlates better than
(18)F-FDG with proliferation, tumor progression, and survival. Because CNS uptake of FLT is
low in contrast to FDG, this makes it potentially useful in evaluating CNS metastases. We
would like to see which of these imaging modalities is superior in detection of brain
metastases, and monitoring response to therapy.
Objectives:
- To determine in a preliminary manner whether change in the FLT-PET/CT uptake after 1
cycle of therapy with GRN1005 is associated with intra-cranial tumor response.
Intracranial disease will be evaluated according to modified RECIST v1.1 for central
nervous system (CNS) disease.
- To determine in a preliminary manner whether treatment with GRN1005 is associated with
a significant change in FLT-PET uptake of intra-cranial tumor.
- To determine in a preliminary manner whether change in the FLT-PET/CT uptake with
GRN1005 is associated with 3-month intra-cranial progression free survival and 6 month
overall survival.
- To compare brain metastasis detection by standard contrast-enhanced MRI vs. FLT-PET,
brain tumor protocol MRIs (DCE-MRI and DSC-MRI).
- To compare response assessment in CNS metastases by standard MRI vs. volumetric MRI vs
brain tumor protocol MRIs.
Eligibility:
- Patients with history of WBRT for intra-cranial lesions, must have WBRT completed > 28
days prior to enrollment to the study.
- Be at least 18 years of age
- Have a Karnofsky Performance Score (KPS) greater than or equal to 80%
- Histologically or cytologically-documented breast cancer (HER2 status and ER/PgR status
must be known)
- At least one radiologically-confirmed and measurable metastatic brain lesion
- Patients must be neurologically stable
Design:
- Phase II, multi-center, open label study to evaluate the efficacy, safety, and
tolerability of GRN1005 in patients with brain metastases from breast cancer with or
without prior WBRT
- Patients will be evaluated in two separate cohorts according to HER2 status; each
cohort will include approximately 50 patients (total of about 100 patients).
- Cohort 1 will include HER2-negative breast cancer patients
- Cohort 2 will include HER2-positive breast cancer patients
- Cohort 2 will receive trastuzumab in combination with GRN1005 for management of
extra-cranial disease from HER2-positive metastatic breast cancer according to
standard-of-care practice.
- At least 25 patients per cohort (approximately half) of the patients must have had
prior WBRT.
- A total of about 100 patients will be enrolled at approximately 25 study centers in
North America.
- Ten patients will be enrolled to NCI site and will undergo (18)FLT imaging studies.
|
| Criteria: |
|
- INCLUSION CRITERIA:
Patients must meet all the following criteria for study enrollment. Informed consent must
be obtained before any study specific evaluations are performed (unless performed as
standard-of-care).
1. Adult patients (greater than or equal to 18 years)
2. Willing and able to sign an informed consent
3. Histologically or cytologically-documented breast cancer (HER2 status and ER/PgR
status must be known)
4. Brain metastases from breast cancer with or without prior WBRT
5. At least one radiologically-confirmed and measurable metastatic brain lesion (greater
than or equal to 1.0 cm in the longest diameter) by Gd-MRI of the brain < 14 days
prior to first dose of GRN1005 (Cycle 1, Day 1)
? Metastatic brain lesions previously treated with SRS are not allowed as target or
as non-target lesions
6. Patients must be neurologically stable, defined as being on stable doses of
corticosteroids and anticonvulsants (not EIAEDs, including phenytoin, phenobarbitol,
carbamazepine, fosphenytoin, primidone, oxcarbazepine) for greater than or equal to 5
days prior to obtaining the baseline Gd-MRI of the brain and greater than or equal to
5 days prior to first dose of GRN1005 (Cycle 1, Day 1)
7. Karnofsky Performance Score (KPS) greater than or equal to 80% (which is equivalent
to Eastern Cooperative Oncology Group [ECOG] Performance Status of 0 or 1)
8. No presence of rapid uncontrolled systemic disease or tumor-related complications
which, in the opinion of the Investigator, might restrict life expectancy to less
than 3 months in the absence of effective therapy
9. Completed WBRT for intra-cranial lesions greater than or equal to 28 days prior to
first dose of GRN1005 (Cycle 1, Day 1)
10. Completed cytotoxic chemotherapy greater than or equal to 21 days (for an every
3-week regimen) or greater than or equal to 14 days (for an every 2-week or weekly
regimen) prior to first dose of GRN1005 (Cycle 1, Day 1); all clinically significant
toxicities (excluding alopecia) must have resolved to less than or equal to CTCAE
v4.0 Grade 1.
11. Completed treatment with non-cytotoxic systemic drugs (e.g., targeted drugs) greater
than or equal to 14 days for small molecules and greater than or equal to 28 days
prior to first dose of GRN1005 (Cycle 1, Day 1) for monoclonal antibodies (e.g.,
bevacizumab), with the exception of trastuzumab and bisphosphonates. All clinically
significant toxicities (excluding alopecia) must have resolved to less than or equal
to CTCAE v4.0 Grade 1.
12. Adequate laboratory test results for organ systems less than or equal to 7 days prior
to first dose of GRN1005 (Cycle 1, Day 1), as follows:
1. Absolute neutrophil count (ANC) greater than or equal to 1.5 times 10(9)/L
2. Hgb greater than or equal to 9.0 g/dL
3. Platelets greater than or equal to 100 times 10(9)/L
4. Total bilirubin < 1.6 mg/dl or < the upper limit of normal (ULN). Serum
bilirubin < 2 times ULN for patients with Gilbert's syndrome
5. Aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT)
< 2.5 times ULN. AST, ALT < 5 times ULN for patients with documented liver
metastases
6. Alkaline phosphatase < 2.5 times ULN. For patients with documented liver or
bone metastases, alkaline phosphatase < 5 times ULN
7. Serum creatinine < 1.5 mg/dL or creatinine clearance greater than or equal to
45 mL/min
13. Negative pregnancy test less than or equal to 72 hours prior to Cycle 1, Day 1 of
GRN1005 (for all women of reproductive potential)
14. Patients with HER2-positive disease should be willing and able to receive trastuzumab
in accordance with standard institutional practice and prescribing information
15. For patients with CNS disease requiring immediate neurosurgical intervention (e.g.,
resection, shunt, etc.), > 2-week recovery is mandated and patients should be
clinically stable following the intervention
4.1.3. Exclusion Criteria
Patients who meet any of the following criteria will be excluded from screening and study
entry:
1. NCI CTCAE v4.0 Grade greater than or equal to 2 neuropathy
2. CNS disease requiring immediate neurosurgical intervention (e.g., resection, shunt
placement, etc.)
3. Known leptomeningeal disease
4. Known severe hypersensitivity or allergy to paclitaxel or any of its components
5. For HER2-positive MBC patients, known severe hypersensitivity or allergy to
trastuzumab or any of its components
6. Treatment with P450 CYP 3A4 or 2C8 enzyme-inducing anticonvulsant drugs less than or
equal to 14 days prior to first dose of GRN1005 (Cycle 1, Day 1)
7. Patients with the presence of an infection including abscess or fistulae, or
infection with hepatitis B or C or HIV
8. Any evidence of severe or uncontrolled systemic disease, such as clinically
significant cardiovascular (including arrhythmias), pulmonary, hepatic, renal, or
metabolic disease; wound-healing disorders; ulcers; or bone fractures
9. History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or
evidence of clinically significant interstitial lung disease on chest CT scan
10. Severe conduction disturbance including clinically significant QTc prolongation >
450 ms (unless pacemaker in place)
11. Women or men of reproductive potential not consenting to use double-barrier
contraceptive methods (e.g., diaphragm plus condom) or abstinence during the study,
from screening until 3 months after the last GRN1005 administration, and if
applicable, for 6 months after the last trastuzumab administration
12. Women who are pregnant or breast-feeding
13. Prior GRN1005 treatment
14. Unable or unwilling to comply with the study protocol requirements.
|
| NCT ID: |
|
NCT01557530 |
| Primary Contact: |
|
Principal Investigator
Susan E Bates, M.D.
National Cancer Institute (NCI)
Robin R. Frye, R.N.
Phone: (301) 402-5958
Email: fryer@mail.nih.gov
|
| Backup Contact: |
|
Email: sebates@helix.nih.gov
Susan E Bates, M.D.
Phone: (301) 402-0984
|
| Location Contact: |
|
Bethesda, Maryland 20892
United States
For more information at the NIH Clinical Center contact National Cancer Institute Referral Office
Phone: (888) NCI-1937
Site Status: Recruiting |