Joe, Christine or Lani....BRAIN MET CLINICAL TRIALS~ANYWHERE???

[Believe51]

Looking for clinical trials for BRAIN METS somewhere close to home but will go anywhere.

Also need to get into Dana Farber again. I will know more after 1:00 today. Need to see Dr Wiener this time, sorry we did not have him in the beginning and I do regret that very very much.

Any sugggestions or thoughts??>>Believe51

[hutchibk]

Eric Winer is the way to go, Marie. I talked to him at SABCS last December and he is a gem! If anyone knows brain mets trials, he would be the one. And he might even have some himself. Also, you might contact Kent Osborne at Baylor College of Medicine Breast Center in Houston. He or his other docs may have something cooking. But, I just don't know if you need anything experimental just yet - as there are so many very solid options available that are working wonderfully for many of us!

[schoonder]

Believe51

I searched clinicaltrials.gov registry using search keys brain and her2 and found following six active trials.
Use of other search keys, like brain and met will probably result in other trials. I hope that this helps.
http://www.clinicaltrials.gov/ct2/re...her2&recr=Open

[Lani]

of the one with WBR or SBR--they only allowed 1-3 brain mets

Another was for lapatinib after failure of WBR or SBR

I didn't get a chance yet for a full review but thought of Dr. Wicha of Michigans new gamma secretase inhibitor trial against cancer stem cells as the gamma secretase inhibitors have been investigated for Alzheimers and must therefore cross the blood brain barrier.

So for I just found this notch inhibitor trial, but will get back on the web later and try to find Dr. Wicha (of U of Michigan)'s trial

Here is the notch inhibitor--don't know if it crosses the blood-brain barrier--
and unfortunately it is only Phase I--will keep looking

A Notch Signalling Pathway Inhibitor for Patients With Advanced Breast Cancer
Basic Trial Information
Trial Description
Summary
Eligibility Criteria
Trial Contact Information

Basic Trial Information

Phase
Type
Status
Age
Sponsor
Protocol IDs



Phase I


Treatment


Active


18 and over


Pharmaceutical / Industry


2005_008
MK0752-014, NCT00106145


Trial Description


Summary

An investigational study to determine the safety/tolerability, and efficacy of a notch signaling pathway inhibitor in patients with metastatic or locally advanced breast cancer and other advanced solid tumors.

Eligibility Criteria

Inclusion Criteria:

Women or men greater than or equal to 18 years of age
ECOG status less than or equal to 2 (a measurement to determine your ability to perform daily activities)
In Part I of the study, patients must have metastatic or locally advanced breast cancer or other solid tumors, and have failed at least one prior systemic therapy.
In Part II of the study, patients must have metastatic or locally advanced breast cancer.
Exclusion Criteria:

Patient has had an investigational treatment in the preceding 30 days
Uncontrolled congestive heart failure or myocardial infarction (heart attack) within 3 months of study start
History of hepatitis B or C or HIV
Trial Contact Information


Trial Lead Organizations/Sponsors

Merck and Company, Incorporated

Medical Monitor Study Director

Toll Free Number Ph: 1-888-577-8839

Trial Sites

U.S.A.

Colorado

Denver

Call for Information
Florida

Tampa

Call for Information
Massachusetts

Boston

Call for Information
Michigan

Detroit

Call for Information
New York

Troy

Call for Information
Texas

Austin

Call for Information
Bedford

Call for Information
Dallas

Call for Information
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00106145
Information obtained from ClinicalTrials.gov on August 15, 2008

Note: Information about this trial is from the ClinicalTrials.gov database. The versions designated for health professionals and patients contain the same text. Minor changes may be made to the ClinicalTrials.gov record to standardize the names of study sponsors, sites, and contacts. Cancer.gov only lists sites that are recruiting patients for active trials, whereas ClinicalTrials.gov lists all sites for all trials.

[Joe]

Trials specific to Dana Farber:

http://www.clinicaltrials.gov/ct2/re...ND+dana+farber

Joe

[Lani]

1: J Neurooncol. 2006 Sep 26; [Epub ahead of print] Links
A lipoxygenase inhibitor in breast cancer brain metastases.

Flavin DF.
Foundation for Collaborative Medicine and Research, 24 Midwood Drive, Greenwich, CT, 06831, USA, Dana_FK@hotmail.com.
The complication of multiple brain metastases in breast cancer patients is a life threatening condition with limited success following standard therapies. The arachidonate lipoxygenase pathway appears to play a role in brain tumor growth as well as inhibition of apoptosis in in-vitro studies. The down regulation of these arachidonate lipoxygenase growth stimulating products therefore appeared to be a worthwile consideration for testing in brain metastases not responding to standard therapy. Boswellia serrata, a lipoxygenase inhibitor was applied for this inhibition. Multiple brain metastases were successfully reversed using this method in a breast cancer patient who had not shown improvement after standard therapy. The results suggest a potential new area of therapy for breast cancer patients with brain metastases that may be useful as an adjuvant to our standard therapy.
PMID: 17001517 [PubMed - as supplied by publisher]

[Lani]

I found refererences to posts of mine re Temodar/Xeloda , Boswellia serrata , etc

You might want to start there until I can look further....

[Lani]

paper inquiring as to whether clinical trials are beginning...

Mol Pharmacol. 2008 Feb;73(2):338-48. Epub 2007 Nov 1. Links

Comment in:
Mol Pharmacol. 2008 Feb;73(2):271-3.
Cellular and in vivo activity of JNJ-28871063, a nonquinazoline pan-ErbB kinase inhibitor that crosses the blood-brain barrier and displays efficacy against intracranial tumors.

Emanuel SL, Hughes TV, Adams M, Rugg CA, Fuentes-Pesquera A, Connolly PJ, Pandey N, Moreno-Mazza S, Butler J, Borowski V, Middleton SA, Gruninger RH, Story JR, Napier C, Hollister B, Greenberger LM.
Bristol-Myers Squibb, Oncology Drug Discovery, Princeton, NJ 08543, USA. stuart.emanuel@bms.com
JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.
PMID: 17975007 [PubMed - indexed for MEDLINE]

[Lani]

intrathecal delivery of herceptin (ie, into the cerebrospinal fluid)

Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11719-23. Epub 2006 Jul 25. Links

Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption.

Kinoshita M, McDannold N, Jolesz FA, Hynynen K.
Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood-brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood-brain barrier under image guidance by using an MRI-guided focused ultrasound blood-brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system.
PMID: 16868082 [PubMed - indexed for MEDLINE

[Lani]

1: Oncol Rep. 2006 May;15(5):1373-7. Links

Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer.

Stemmler HJ, Schmitt M, Harbeck N, Willems A, Bernhard H, Lässig D, Schoenberg S, Heinemann V.
Department of Internal Medicine III, Ludwig-Maximilians-University of Munich, Klinikum Grosshadern, D-81377 Munich, Germany. joachim.stemmler@med.uni-muenchen.de
Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). A 39-year-old female presenting with HER2-overexpressing MBC and suffering from meningeal carcinomatosis was treated with the humanized antibody trastuzumab directed to HER2 by intrathecal administration. The patient was diagnosed with HER2-overexpressing stage III breast cancer in December 2003. In August 2004, the patient developed a singular intracerebral metastasis which was resected by neurosurgery followed by whole-brain radiotherapy. Since MRI and cerebrospinal fluid (CSF) analyses indicated meningeal carcinomatosis, the patient was commenced on trastuzumab (6 mg/kg q3w) and capecitabine (2.500 mg/m2 d1-14, q3w). Prompted by clinical deterioration, 5 repeated doses of intrathecal methotrexate (15 mg/dose) were administered, yet without clinical improvement. There is initial evidence that trastuzumab does not reach an adequate concentration in CSF after intravenous application. Nevertheless, infiltration of trastuzumab into CSF is facilitated under conditions of an impaired blood-brain barrier, as it is known for meningeal carcinomatosis. For patients with leptomeningeal disease, intrathecal application of trastuzumab may provide an interesting therapeutical approach for patients with HER2 overexpressing metastatic breast cancer. Therefore, an Ommaya reservoir for intrathecal treatment with trastuzumab was placed surgically and intrathecal therapy was begun with escalating doses of trastuzumab (5-20 mg), which proved to be effective and well tolerated by the patient. Within 2 weeks after treatment, the patients' condition improved significantly and cell counts in CSF obtained from the Ommaya reservoir remained low for 11 months after first diagnosis of meningeal carcinomatosis when clinical symptoms and MRI indicated progression of meningeal and cerebral disease.
PMID: 16596213 [PubMed - indexed for MEDLINE]
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[Lani]

Also many papers I have read agree that Herceptin should be continued in those who developed brain mets while on Herceptin--don't know if any trials allow Lapatinib/Xeloda while continuing herceptin. I believe the thinking is that the radiation treatment (whole brain or cyber/gammaknife) make the blood brain barrier more permeable (easier for things to get across) including herceptin.


Clin Breast Cancer. 2003 Jun;4(2):114-9. Links

Increased rate of brain metastasis with trastuzumab therapy not associated with impaired survival.

Lower EE, Drosick DR, Blau R, Brennan L, Danneman W, Hawley DK.
University of Cincinnati Medical Center, Department of Internal Medicine, OH, USA. lowere@uc.edu
Trastuzumab is important for treatment of metastatic breast cancer patients with tumors that overexpress HER2/neu, but its penetration to the brain is poor. The aims of this study are to determine the prevalence of bone and brain metastasis during therapy, to compare the survival of breast cancer patients with brain metastasis who received trastuzumab to those patients not receiving trastuzumab, and to assess the impact of brain metastasis on the overall survival of trastuzumab patients. Of 103 patients treated with trastuzumab, 16 had brain metastasis and 43 had bone metastasis at the beginning of trastuzumab. The control group consisted of 196 patients with metastatic breast cancer who had never received trastuzumab. Six had brain metastasis and 75 had bone metastasis at the beginning of therapy. During therapy, only 9 of 60 trastuzumab patients (15%) developed bone metastasis, while 170 of 186 control patients (91%; c2 = 129.8, P < 0.0001) developed bone metastasis. In addition, 22 of 87 trastuzumab patients (25%) and 58 of 190 control patients (31%) subsequently developed brain metastasis. Control patients without brain metastasis experienced significantly better survival (median survival = 928 days) than those with brain metastasis (median survival = 639 days, c2 = 8.34, P < 0.005). There was no difference in survival for trastuzumab-treated patients if they acquired brain metastasis (median survival = 1400 days) or no brain metastasis (median survival > 2000 days, c2 = 0.12, P > 0.05). Patients receiving trastuzumab were unlikely to develop new bone metastasis but were as likely as control patients to develop brain metastasis. However, patients who developed brain metastasis experienced better survival compared with those patients with brain metastasis who never received trastuzumab.
PMID: 12864939 [PubMed - indexed for MEDLINE]
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[Breast Cancer Res. 2005]
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[Lani]

Did you ever get the result of your OWN biopsy?

[Lani]

Perform your original search, her2+ breast cancer brain metastases, in Ann Oncol Search


Annals of Oncology Advance Access published online on July 29, 2008
Annals of Oncology, doi:10.1093/annonc/mdn539
\

Articles by Park, I. H.
Articles by Shin, K. H.


© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Trastuzumab treatment beyond brain progression in HER2-positive metastatic breast cancer

I. H. Park1, J. Ro1,*, K. S. Lee1, B. H. Nam2, Y. Kwon1 and K. H. Shin1
1 Center for Breast Cancer, National Cancer Center, Goyang, Gyeonggi, Korea
2 Center for Clinical Trials, National Cancer Center, Goyang, Gyeonggi, Korea

* Address for correspondence: Dr J. Ro, Center for Breast Cancer, National Cancer Center, 111 Jungbalsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Korea. Tel: +82-31-920-1610; E-mail: jungsro@ncc.re.kr

Background: Although trastuzumab therapy improves survival in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, 40% of patients develop brain metastasis (BM) even when extracranial disease is under control. We studied whether trastuzumab therapy beyond or after BM was beneficial to patients with BM.

Patients and methods: The effect of trastuzumab on survival after BM was analyzed in 78 HER2-positive breast cancer patients. Patients were grouped according to trastuzumab therapy; no treatment and treatment before and after BM were diagnosed.

Results: Overall survival after the diagnosis of BM as well as time to progression (TTP) of intracranial tumors was prolonged in patients who received trastuzumab after BM was diagnosed. Conversely, BM occurred much later in patients who received trastuzumab before BM. In the multivariate Cox regression model, age at BM <50 years, disease-free interval 24 months, TTP of intracranial tumor 4.8 months, and trastuzumab treatment after BM were significantly associated with longer survival after the onset of BM.

Conclusions: Trastuzumab therapy after the onset of BM in HER2-positive breast cancer patients is associated with a significant survival benefit after BM diagnosis compared with patients who never received or completed trastuzumab before the BM diagnosis.

brain metastasis, HER2-positive breast cancer, trastuzumab

Received for publication May 21, 2008. Accepted for publication June 30, 2008.

[Lani]

http://www.touchbriefings.com/pdf/2789/Cameron.pdf

[Lani]

ABSTRACT #1003 - "Multicenter phase I clinical trial of daily and weekly RAD001 (everolimus) in combination with weekly paclitaxel and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab"
Fabrice Andre, MD, PhD, Institut Gustave Roussy, Villejuif, France
This multicenter Phase I-II trial evaluated daily RAD001 (5 mg, 10 mg) and weekly RAD001 (30 mg, 50 mg and 70 mg) regimens in combination with paclitaxel (80 mg/m2, IV over 60 min on days 1, 8 and 15 q4w) and trastuzumab (4 mg/kg loading dose, IV over 90 min on day 1 [if patient was not already receiving trastuzumab], followed by weekly 2 mg/kg IV over 30 min) in heavily pretreated patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab. Thirteen heavily pretreated patients were assessable for efficacy to date: treatment arms included five patients assigned to RAD001 5 mg daily, one to 10 mg daily and seven to 30 mg weekly. Among the five patients allocated to the 5 mg daily arm, four patients had confirmed partial responses (including three complete responses, yet to be confirmed); the one patient on 10 mg daily showed stable disease at the first assessment; and of the seven patients evaluated in the RAD001 weekly treatment arm, two patients had confirmed partial response and four patients had long disease stabilization, including complete disappearance of brain metastasis in one patient. The most commonly reported adverse events were neutropenia and mouth sores.
"These preliminary results are very exciting given that the women in the study were heavily pretreated, had documented resistance to trastuzumab and most were also taxane-resistant," said Fabrice Andre, MD, PhD, Institut Gustave Roussy, Villejuif, France. "If confirmed in Phase II and III clinical trials, RAD001 will be a major addition to the existing arsenal of breast cancer therapy."

[Lani]

Marie--glad you were so happy with your (own) biopsy results

[Believe51]

You guys are the best, looks like no xanax for me today, I will be too busy investigating options. Oh...and Lani..looks like Santa came early this year..LOL>>Believe51