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Ovarian Cancer (Expert Forum)
parpinhibitor for brac1&2 pos patients azd2281
Answered by
Annekathryn Goodman, M.D. - Gynecologic Cancers, Complex Gynecologic, Surgeries, Palliative Care, Acupuncture
Massachusetts General Hospital Cancer Center
Boston - MA
This forum is for questions and support regarding ovarian cancer issues, such as: Biopsy, Chemotherapy, Clinical Trials, Genetics, Hysterectomy,Immunotherapy, Ovarian Cancer Types, Radiation Therapy, Risk Factors, Screening, Staging, Surgery.
Doctor's Answer
by Annekathryn Goodman, M.D., May 10, 2008 10:49AM
, May 10, 2008 10:49AM
Hi There,
I do not have the full data from the phase 2 study. I can say that our experience at MGH has been that of the women enrolled on the study, one women had a great response for six months before her cancer recurred. she had only had one prior line of chemotherapy with carboplatin and taxol one year earlier.
All the other women enrolled on the study had been heavily pretreated with multiple lines of chemotherapy, some up to 12 previous lines. some of them were extremely ill from their cancer. The parp inhibitor did not help them at all.
It is hard to make broad statements about this interesting new treatment based on this experience.
We will have to wait for the publication of the study to see how many women received this drug, how many previous lines of chemo had they received, how ill were they and so on to get some statistics.
I have pasted a summary of what was reported at ASCO 2007 below
take care
Oncology Times:Volume 29(18)25 September 2007p 52-53
Targeting DNA Repair in BRCA Mutation Carriers
[ASCO Annual Meeting]
Tuma, Rabiya S. PhD
CHICAGO-A new targeted drug that blocks DNA repair appears safe and shows preliminary evidence of activity in familial ovarian cancer patients, researchers reported here at the ASCO Annual Meeting.
Already several drugs in this same class are being tested in early clinical trials. Researchers say that they expect that the agents will work in BRCA-associated ovarian and breast cancers and that they may increase the potency of DNA-damaging agents in other cancers.
The new drugs inhibit an enzyme called poly(ADP-ribose) polymerase (PARP), which is critical for repairing single-strand DNA breaks. Preclinical studies have shown that the agents are particularly toxic to cells that lack either BRCA1 or BRCA2 genes, which disrupt another type of DNA repair called homologous recombination.
BRCA1- or -2-deficient cells are approximately 400 to more than 1,000-fold more sensitive to PARP inhibition than wild type and, importantly, heterozygous BRCA cells, which showed no increase in sensitivity, said the researcher who presented the early clinical trial data, Timothy A. Yap, MD, of the Drug Development Unit at the Royal Marsden NHS Foundation Trust.
It was hypothesized that targeted inhibition of BRCA-deficient cells with a PARP inhibitor would result in a selective and less toxic therapy.
To test that hypothesis, Dr. Yap and colleagues enrolled 56 patients in a Phase I study of AZD2281 (formerly called KU-005943) at Royal Marsden Hospital and the Netherlands Cancer Institute. In the initial dose-escalation phase, patients with any solid tumor type were eligible for entry; however during an expansion phase of the trial, only patients with BRCA1 or 2 associated breast and ovarian cancers were eligible.
Thirteen of the patients in the study had confirmed BRCA1 mutations, including nine patients with ovarian cancer, one each with breast cancer, fallopian tube cancer, primary peritoneal, and small cell lung cancer. Four patients carried BRCA2 mutations, including one with ovarian cancer, two with breast cancer, and one with prostate cancer. Additionally, one ovarian cancer patient has a family history that is consistent with a BRCA mutation, but she declined to be tested.
The drug appeared to be well tolerated, Dr. Yap said, with most toxicities limited to Grade 1 or 2. Nineteen patients (35%) had some nausea, which was the most common side effect. Fifteen patients (28%) had fatigue of any grade, seven (12%) had vomiting, five (9%) reported taste alteration, and five had (9%) anorexia.
In terms of Grade 3 or higher non-dose limiting toxicities, two patients (4%) had Grade 3 fatigue, one (2%) had nausea, one (2%) had vomiting, one (2%) had dizziness, and another had Grade 3 thrombocytopenia.
Additionally one patient with small-cell lung cancer died of a respiratory infection while on therapy, although clinicians concluded that it was not related to the drug.
Three dose-limiting toxicities were reported at 400 and 600 mg twice daily dosing, including one patient with neurocognitive impairment, which was characterized by low mood and occurred with Grade 3 fatigue, and one patient with Grade 3 sleepiness.
All of these problems resolved within 24 hours of stopping the drug. One patient had Grade 4 thrombocytopenia, which resolved within two weeks of stopping therapy. Based on these data, the dose for subsequent enrollment and trials was set at 200 mg twice-daily continuous dosing.
There was evidence of anti-tumor activity, particularly in patients with BRCA 1 or 2 mutations. Five patients with hereditary ovarian cancer had partial responses by Response Evaluation Criteria in Solid Tumors, as did one patient with BRCA-associated fallopian cancer. Three of these individuals are still on therapy, at 17, 20, and 31 weeks.
Additionally, five patients have stable disease, with one ovarian and one breast cancer patient continuing on therapy at 15 and 10 weeks, respectively. One BRCA-mutation carrier with ovarian cancer has had a CA-125 response and continues on therapy at 28 weeks.
Dr. Yap said that the research team fully expects that the drug will also show efficacy in BRCA-related breast cancer, but the three patients with that malignancy in the study started on the trial only recently and so are not yet evaluable.
Dr. Yap showed CT scans of several tumors before and after treatment, including a brain scan of a patient with a BRCA-related breast cancer. After six weeks on treatment, a brain metastasis shrank from 6.5 mm to 3 mm, indicating that the drug can cross the blood-brain barrier, he said.
To find out whether the drug was inhibiting the target enzyme, Dr. Yap and colleagues tested peripheral blood mononuclear cells (PBMCs) and tumor biopsies with an antibody that binds to a modified form of the PARP enzyme, called PAR, which is formed during the first step in PARP-mediated DNA repair. In five of six tumor samples analyzed, they found more than 55% inhibition of PARP. There was as much as 85% enzyme inhibition in PBMCs.
Interestingly, Dr. Yap said, the team assayed for a downstream product of PARP inhibition, called gH2AX, in the follicle of plucked eyebrow hairs. Our results are still preliminary, but we are cautiously optimistic that this may provide a non-invasive way of detecting target inhibition with this drug, he said.
We have observed substantial inhibition of the target in both tumor and surrogate tissue. And encouragingly we have also observed compelling efficacy data in hereditary ovarian cancer
I do not have the full data from the phase 2 study. I can say that our experience at MGH has been that of the women enrolled on the study, one women had a great response for six months before her cancer recurred. she had only had one prior line of chemotherapy with carboplatin and taxol one year earlier.
All the other women enrolled on the study had been heavily pretreated with multiple lines of chemotherapy, some up to 12 previous lines. some of them were extremely ill from their cancer. The parp inhibitor did not help them at all.
It is hard to make broad statements about this interesting new treatment based on this experience.
We will have to wait for the publication of the study to see how many women received this drug, how many previous lines of chemo had they received, how ill were they and so on to get some statistics.
I have pasted a summary of what was reported at ASCO 2007 below
take care
Oncology Times:Volume 29(18)25 September 2007p 52-53
Targeting DNA Repair in BRCA Mutation Carriers
[ASCO Annual Meeting]
Tuma, Rabiya S. PhD
CHICAGO-A new targeted drug that blocks DNA repair appears safe and shows preliminary evidence of activity in familial ovarian cancer patients, researchers reported here at the ASCO Annual Meeting.
Already several drugs in this same class are being tested in early clinical trials. Researchers say that they expect that the agents will work in BRCA-associated ovarian and breast cancers and that they may increase the potency of DNA-damaging agents in other cancers.
The new drugs inhibit an enzyme called poly(ADP-ribose) polymerase (PARP), which is critical for repairing single-strand DNA breaks. Preclinical studies have shown that the agents are particularly toxic to cells that lack either BRCA1 or BRCA2 genes, which disrupt another type of DNA repair called homologous recombination.
BRCA1- or -2-deficient cells are approximately 400 to more than 1,000-fold more sensitive to PARP inhibition than wild type and, importantly, heterozygous BRCA cells, which showed no increase in sensitivity, said the researcher who presented the early clinical trial data, Timothy A. Yap, MD, of the Drug Development Unit at the Royal Marsden NHS Foundation Trust.
It was hypothesized that targeted inhibition of BRCA-deficient cells with a PARP inhibitor would result in a selective and less toxic therapy.
To test that hypothesis, Dr. Yap and colleagues enrolled 56 patients in a Phase I study of AZD2281 (formerly called KU-005943) at Royal Marsden Hospital and the Netherlands Cancer Institute. In the initial dose-escalation phase, patients with any solid tumor type were eligible for entry; however during an expansion phase of the trial, only patients with BRCA1 or 2 associated breast and ovarian cancers were eligible.
Thirteen of the patients in the study had confirmed BRCA1 mutations, including nine patients with ovarian cancer, one each with breast cancer, fallopian tube cancer, primary peritoneal, and small cell lung cancer. Four patients carried BRCA2 mutations, including one with ovarian cancer, two with breast cancer, and one with prostate cancer. Additionally, one ovarian cancer patient has a family history that is consistent with a BRCA mutation, but she declined to be tested.
The drug appeared to be well tolerated, Dr. Yap said, with most toxicities limited to Grade 1 or 2. Nineteen patients (35%) had some nausea, which was the most common side effect. Fifteen patients (28%) had fatigue of any grade, seven (12%) had vomiting, five (9%) reported taste alteration, and five had (9%) anorexia.
In terms of Grade 3 or higher non-dose limiting toxicities, two patients (4%) had Grade 3 fatigue, one (2%) had nausea, one (2%) had vomiting, one (2%) had dizziness, and another had Grade 3 thrombocytopenia.
Additionally one patient with small-cell lung cancer died of a respiratory infection while on therapy, although clinicians concluded that it was not related to the drug.
Three dose-limiting toxicities were reported at 400 and 600 mg twice daily dosing, including one patient with neurocognitive impairment, which was characterized by low mood and occurred with Grade 3 fatigue, and one patient with Grade 3 sleepiness.
All of these problems resolved within 24 hours of stopping the drug. One patient had Grade 4 thrombocytopenia, which resolved within two weeks of stopping therapy. Based on these data, the dose for subsequent enrollment and trials was set at 200 mg twice-daily continuous dosing.
There was evidence of anti-tumor activity, particularly in patients with BRCA 1 or 2 mutations. Five patients with hereditary ovarian cancer had partial responses by Response Evaluation Criteria in Solid Tumors, as did one patient with BRCA-associated fallopian cancer. Three of these individuals are still on therapy, at 17, 20, and 31 weeks.
Additionally, five patients have stable disease, with one ovarian and one breast cancer patient continuing on therapy at 15 and 10 weeks, respectively. One BRCA-mutation carrier with ovarian cancer has had a CA-125 response and continues on therapy at 28 weeks.
Dr. Yap said that the research team fully expects that the drug will also show efficacy in BRCA-related breast cancer, but the three patients with that malignancy in the study started on the trial only recently and so are not yet evaluable.
Dr. Yap showed CT scans of several tumors before and after treatment, including a brain scan of a patient with a BRCA-related breast cancer. After six weeks on treatment, a brain metastasis shrank from 6.5 mm to 3 mm, indicating that the drug can cross the blood-brain barrier, he said.
To find out whether the drug was inhibiting the target enzyme, Dr. Yap and colleagues tested peripheral blood mononuclear cells (PBMCs) and tumor biopsies with an antibody that binds to a modified form of the PARP enzyme, called PAR, which is formed during the first step in PARP-mediated DNA repair. In five of six tumor samples analyzed, they found more than 55% inhibition of PARP. There was as much as 85% enzyme inhibition in PBMCs.
Interestingly, Dr. Yap said, the team assayed for a downstream product of PARP inhibition, called gH2AX, in the follicle of plucked eyebrow hairs. Our results are still preliminary, but we are cautiously optimistic that this may provide a non-invasive way of detecting target inhibition with this drug, he said.
We have observed substantial inhibition of the target in both tumor and surrogate tissue. And encouragingly we have also observed compelling efficacy data in hereditary ovarian cancer