Breast Cancer Chemoprevention by SOM230, an IGF-I Action Inhibitor
| Status: | Terminated |
|---|---|
| Conditions: | Breast Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 21 - Any |
| Updated: | 12/29/2017 |
| Start Date: | June 2011 |
| End Date: | October 2015 |
This will be a proof of principle clinical trial to evaluate the use of pasireotide (SOM230)
in women with ductal carcinoma in situ (DCIS) of the breast. Surgery and radiotherapy are
used as treatment for DCIS and subsequent treatment with antiestrogens has been effective in
reducing the occurrence of invasive breast cancer. Unfortunately, treatment with
antiestrogens carries potential serious side effects and toxicities that are intolerable to
some patients. Preliminary data suggest that inhibition of IGF-1 action in the breast will be
at least as effective as tamoxifen. Pasireotide is a somatostatin analog that prevents
mammary development by inhibiting IGF-1 action directly in the mammary gland and also
indirectly without causing menopausal symptoms. This study is an expansion of work that we
have previously done in women with atypical hyperplasia of the breast, which showed that
treatment with pasireotide for 10 days caused a reduction in the cellularity of these
precancerous lesions. In our present study, women with DCIS will be treated with pasireotide
for 20 days prior to surgical excision. Endpoints will be as follows:
1. To determine whether pasireotide will inhibit cell proliferation and angiogenesis (signs
of tumor growth), and stimulate apoptosis (cell death) in surgically excised tissue in
comparison to core biopsies from women with estrogen receptor (ER) positive DCIS. Both
the core biopsy and surgical excision are standard of care procedures that women with
DCIS have regardless of participation in this trial.
2. To use dynamic contrast enhanced MRI to assess patients before and after treatment with
pasireotide and evaluate for changes in tumor volume and other tumor related features
3. In our previous study we found that many women experienced a slight elevation in blood
sugar with 10 days of treatment with pasireotide. Other work has shown that this effect
often resolves with greater duration of treatment. We are therefore expanding the
duration of treatment in this study to 20 days to assess if the initial hyperglycemia
seen with pasireotide improves as treatment duration progresses.
in women with ductal carcinoma in situ (DCIS) of the breast. Surgery and radiotherapy are
used as treatment for DCIS and subsequent treatment with antiestrogens has been effective in
reducing the occurrence of invasive breast cancer. Unfortunately, treatment with
antiestrogens carries potential serious side effects and toxicities that are intolerable to
some patients. Preliminary data suggest that inhibition of IGF-1 action in the breast will be
at least as effective as tamoxifen. Pasireotide is a somatostatin analog that prevents
mammary development by inhibiting IGF-1 action directly in the mammary gland and also
indirectly without causing menopausal symptoms. This study is an expansion of work that we
have previously done in women with atypical hyperplasia of the breast, which showed that
treatment with pasireotide for 10 days caused a reduction in the cellularity of these
precancerous lesions. In our present study, women with DCIS will be treated with pasireotide
for 20 days prior to surgical excision. Endpoints will be as follows:
1. To determine whether pasireotide will inhibit cell proliferation and angiogenesis (signs
of tumor growth), and stimulate apoptosis (cell death) in surgically excised tissue in
comparison to core biopsies from women with estrogen receptor (ER) positive DCIS. Both
the core biopsy and surgical excision are standard of care procedures that women with
DCIS have regardless of participation in this trial.
2. To use dynamic contrast enhanced MRI to assess patients before and after treatment with
pasireotide and evaluate for changes in tumor volume and other tumor related features
3. In our previous study we found that many women experienced a slight elevation in blood
sugar with 10 days of treatment with pasireotide. Other work has shown that this effect
often resolves with greater duration of treatment. We are therefore expanding the
duration of treatment in this study to 20 days to assess if the initial hyperglycemia
seen with pasireotide improves as treatment duration progresses.
Ductal carcinoma in situ (DCIS) is a direct precursor of invasive breast cancer and is also a
marker of an increased chance of developing invasive cancer in the ipsilateral and
contralateral breast. Surgery and radiotherapy are used as treatment for DCIS and subsequent
treatment with antiestrogens has been effective in reducing the occurrence of invasive breast
cancer in DCIS patients. Unfortunately, treatment with antiestrogens carries potential side
effects and toxicities. The investigators have data to suggest that inhibition of IGF-I
action in the breast will be more effective than antiestrogens, raising hopes it might be
effective enough to stand alone as a treatment. Pasireotide is a somatostatin analog that
prevents mammary development by inhibiting IGF-I action directly in the mammary gland and
also indirectly, without causing menopausal symptoms and signs. As both estrogen (E2) and
progesterone (P) require IGF-I in order to act, part of the inhibitory effect of pasireotide
is on prevention of estrogen action. The investigators have data that indicate that IGF-I
also has direct actions on the breast that are independent of steroid hormones. One example
is that IGF-I has a direct stimulatory effect on mammary development in the absence of E2.
Additionally, IGF-I has effects on ER-negative tumor cell lines that can be reversed by IGF-I
inhibition. If pasireotide inhibited both E2 related and E2 unrelated effects of IGF-I it
would likely be more effective than antiestrogens. Preliminary data in rats show that
pasireotide, at minimum, can entirely substitute for tamoxifen. To determine whether
pasireotide had activities in women at high risk for breast cancer, similar to those observed
in rats, the investigators were awarded a DOD Synergistic Idea grant. Those data are expected
to be reported soon.
The investigators plan to expand this work to determine in principle whether pasireotide has
the potential to treat DCIS. The investigators plan on treating 24 women, with low grade (8),
intermediate grade (8) and high grade (8) ER-positive DCIS tumors. The investigators will
assess its effect on apoptosis, cell proliferation, angiogenesis, ER and PR and
phosphorylation of IGF-IR and IRS-1 before and after 20 days of treatment with pasireotide in
core biopsy vs. surgical excision specimens. These endpoints will be measured by specific
immunohistochemistry. Simultaneously, the investigators will determine whether IGF-I
inhibition will reduce angiogenesis in DCIS using dynamic contrast enhanced MRI (DCE-MRI) at
3.0 Tesla, in addition to mammography. This MRI technique is able to detect early changes of
neo-angiogenesis associated with invasive breast cancers and DCIS. Pasireotide should
theoretically inhibit angiogenesis in these women, as it does in mice. The DCE-MRI may also
show changes in tumor volume, morphologic and kinetic features. Imaging will serve as an
additional measure to monitor response to treatment. Results will be correlated with
pathology and immunohistochemical endpoints.
In our previous work the investigators noted that there was an increase in blood glucose
early after starting pasireotide, but the work of others has indicated that this side effect
lasts only several weeks. The investigators found that suppressed levels of insulin (due to
pasireotide effect on β cells) began to rise by day 10 of treatment. Therefore, extending the
treatment period from 10 to 20 days with daily monitoring of patients will enable us to make
certain that the early elevated glucose associated with pasireotide is only temporary.
Another side effect is reduction in circulating levels of IGF-I. Theoretically, this could
lead to body changes associated with growth hormone deficiency (GHD). Although, tamoxifen and
raloxifene also lower serum IGF-I, and women taking it do not usually complain of symptoms of
GHD, this is an issue that must be further investigated. However, if pasireotide is found to
be effective in the treatment of DCIS, the benefit would likely outweigh the risk.
marker of an increased chance of developing invasive cancer in the ipsilateral and
contralateral breast. Surgery and radiotherapy are used as treatment for DCIS and subsequent
treatment with antiestrogens has been effective in reducing the occurrence of invasive breast
cancer in DCIS patients. Unfortunately, treatment with antiestrogens carries potential side
effects and toxicities. The investigators have data to suggest that inhibition of IGF-I
action in the breast will be more effective than antiestrogens, raising hopes it might be
effective enough to stand alone as a treatment. Pasireotide is a somatostatin analog that
prevents mammary development by inhibiting IGF-I action directly in the mammary gland and
also indirectly, without causing menopausal symptoms and signs. As both estrogen (E2) and
progesterone (P) require IGF-I in order to act, part of the inhibitory effect of pasireotide
is on prevention of estrogen action. The investigators have data that indicate that IGF-I
also has direct actions on the breast that are independent of steroid hormones. One example
is that IGF-I has a direct stimulatory effect on mammary development in the absence of E2.
Additionally, IGF-I has effects on ER-negative tumor cell lines that can be reversed by IGF-I
inhibition. If pasireotide inhibited both E2 related and E2 unrelated effects of IGF-I it
would likely be more effective than antiestrogens. Preliminary data in rats show that
pasireotide, at minimum, can entirely substitute for tamoxifen. To determine whether
pasireotide had activities in women at high risk for breast cancer, similar to those observed
in rats, the investigators were awarded a DOD Synergistic Idea grant. Those data are expected
to be reported soon.
The investigators plan to expand this work to determine in principle whether pasireotide has
the potential to treat DCIS. The investigators plan on treating 24 women, with low grade (8),
intermediate grade (8) and high grade (8) ER-positive DCIS tumors. The investigators will
assess its effect on apoptosis, cell proliferation, angiogenesis, ER and PR and
phosphorylation of IGF-IR and IRS-1 before and after 20 days of treatment with pasireotide in
core biopsy vs. surgical excision specimens. These endpoints will be measured by specific
immunohistochemistry. Simultaneously, the investigators will determine whether IGF-I
inhibition will reduce angiogenesis in DCIS using dynamic contrast enhanced MRI (DCE-MRI) at
3.0 Tesla, in addition to mammography. This MRI technique is able to detect early changes of
neo-angiogenesis associated with invasive breast cancers and DCIS. Pasireotide should
theoretically inhibit angiogenesis in these women, as it does in mice. The DCE-MRI may also
show changes in tumor volume, morphologic and kinetic features. Imaging will serve as an
additional measure to monitor response to treatment. Results will be correlated with
pathology and immunohistochemical endpoints.
In our previous work the investigators noted that there was an increase in blood glucose
early after starting pasireotide, but the work of others has indicated that this side effect
lasts only several weeks. The investigators found that suppressed levels of insulin (due to
pasireotide effect on β cells) began to rise by day 10 of treatment. Therefore, extending the
treatment period from 10 to 20 days with daily monitoring of patients will enable us to make
certain that the early elevated glucose associated with pasireotide is only temporary.
Another side effect is reduction in circulating levels of IGF-I. Theoretically, this could
lead to body changes associated with growth hormone deficiency (GHD). Although, tamoxifen and
raloxifene also lower serum IGF-I, and women taking it do not usually complain of symptoms of
GHD, this is an issue that must be further investigated. However, if pasireotide is found to
be effective in the treatment of DCIS, the benefit would likely outweigh the risk.
Inclusion Criteria:
- 21 years of age and older
- Must sign informed consent, witnessed, and dated prior to entry
- The participant has breast biopsy consistent with Ductal Carcinoma in situ (DCIS)
- Performance Status: ECOG 0-1 unless mobility is limited from chronic physical handicap
- No clinical evidence of other malignancies (except Basal Cell carcinoma)
- Complete blood count, differential and platelet count must be WNL or verified by the
study chair to be related to conditions not interfering with normal health status
- Adequate hepatic and renal function (these must be WNL or verified by study chair to
be related to conditions not interfering with normal health status)
- Normal fasting glucose
- No history of diabetes
- Medically and Psychologically able to comply with all study requirements
- Accessible for Follow up
Exclusion Criteria:
- Less than 21 years of age
- Known invasive breast cancer of any type
- Bilateral prophylactic mastectomy
- Prior malignancy of any type that occurred less than 5 years previously, except for
basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
- Existing non-malignant disease that would preclude the administration of pasireotide
- Pregnancy: All subjects will have a beta-hCG serum pregnancy test to rule out
pregnancy, a history will also be taken to make certain that recent sexual exposure
does not put them at risk for pregnancy. If so a second serum pregnancy test will be
done. Volunteers will be asked to use barrier contraception during study.
- Tamoxifen or other preventive measures within 6 months
- Serious Psychiatric condition or addictive disorder
- Diabetes or elevated fasting blood sugar either by history or by HgbA1c greater than
6.5% or fasting serum glucose greater than 100mg/dL on screening labs. If fasting
serum glucose is greater than 100mg/dL on screening labs, this test will be repeated
to confirm the results
- Inability to inject medication or test for finger stick glucose
- Gall bladder disease
- History of cholecystitis without cholecystectomy
- Electrolyte abnormalities (particularly hypokalemia or hypomagnesemia)
- Contraindication for MRI
- If tumor size is < 1cm on mammography and all calcifications are removed on core
biopsy the patient will be excluded.
QT related exclusion criteria
- QTcF at screening > 450 msec.
- History of syncope or family history of idiopathic sudden death.
- Sustained or clinically significant cardiac arrhythmias.
- Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac
failure, clinically significant/symptomatic bradycardia, or high-grade AV block.
- Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by
diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or
cardiac failure
- Concomitant medication(s) known to increase the QT interval.
Hepatic Related Exclusion Criteria
- Baseline Alanine transaminase (ALT) or Aspartate transaminase (AST) > 2x upper limit
of normal (ULN) without known complications of metastatic liver disease or primary
hepatic disease (e.g. Cushing's disease and Acromegaly studies).
- Baseline Total Bilirubin > 1.5x ULN
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