Panobinostat and Letrozole in Treating Patients With Metastatic Breast Cancer
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|ClinicalTrials.gov Identifier: NCT01105312|
Recruitment Status : Completed
First Posted : April 16, 2010
Results First Posted : June 27, 2017
Last Update Posted : June 27, 2017
RATIONALE: Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. Giving panobinostat together with letrozole may be an effective treatment for breast cancer.
PURPOSE: This phase I/II trial is studying the side effects and best dose of panobinostat when given together with letrozole and to see how well it works in treating patients with metastatic breast cancer.
|Condition or disease||Intervention/treatment||Phase|
|Breast Cancer||Drug: letrozole Drug: panobinostat Genetic: RNA analysis Genetic: microarray analysis Genetic: reverse transcriptase-polymerase chain reaction Other: enzyme-linked immunosorbent assay Other: immunohistochemistry staining method Other: laboratory biomarker analysis||Phase 1 Phase 2|
- To determine the maximum-tolerated dose of panobinostat in combination with letrozole in patients with metastatic breast cancer. (Phase I)
- To determine the safety of this regimen in these patients. (Phase I)
- To assess the confirmed response rate and safety profile of this regimen in patients with triple-negative disease. (Phase II)
- To assess the therapeutic effects of this regimen in these patients. (Phase I)
- To examine the duration of response, clinical benefit rate, and time to treatment failure in patients treated with this regimen. (Phase II)
- To examine the time to progression, progression-free survival, and overall survival of patients treated with this regimen. (Phase II)
- To examine the estrogen, progesterone, and HER2 status of tumor at primary compared to metastatic tissue, and possibly after treatment. (exploratory)
- To bank paraffin-embedded tissue blocks/slides and blood products for future studies. (exploratory)
- To determine expression levels of biomarkers of treatment response (i.e., ER, PR, aromatase, NFkappaB, Ki67, and Caspase 3) in accessible tumors pre- and post-therapy via immunohistochemistry. (exploratory)
- To determine whether ELISA for KLK11 in serum can be used as marker of activity of letrozole and LBH589. (exploratory) The Phase I portion of this study closed and the Phase II portion of the study opened as per NCCTG Addendum 6, effective January 23, 2012.
OUTLINE: This is a multicenter, phase I dose-escalation study of panobinostat followed by a phase II study. (The Phase I portion of this study closed and the Phase II portion of the study opened as per NCCTG Addendum 6, effective January 23, 2012.)
Patients receive oral panobinostat once daily on days 1, 3, and 5 in weeks 1-4 and oral letrozole once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Tumor tissue and blood samples are collected and banked for future biomarker and other analysis. Samples are also analyzed for biomarkers utilizing immunohistochemistry, microarray, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA).
After completion of study therapy, patients are followed up every 3-6 months for up to 5 years.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||28 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I/II Study of Panobinostat (LBH589) and Letrozole in Patients With Triple Negative Metastatic Breast Cancer|
|Actual Study Start Date :||September 2010|
|Actual Primary Completion Date :||August 2013|
|Actual Study Completion Date :||September 3, 2013|
U.S. FDA Resources
Experimental: panobinostat (LBH589) and letrozole
Each patient will receive panobinostat (LBH589) and letrozole. Patients will be administered LBH589 PO, 3 days per week for a total of 4 weeks. Patients will also be administered letrozole 2.5 mg PO Days 1-28 every 4 weeks. There are two phases of the study. The first phase determines the maximum tolerated dose for LBH589 in combination with letrozole. The second phase is to assess and confirm the response rate and safety profile of LBH589 in combination with letrozole.
|Drug: letrozole Drug: panobinostat Genetic: RNA analysis Genetic: microarray analysis Genetic: reverse transcriptase-polymerase chain reaction Other: enzyme-linked immunosorbent assay Other: immunohistochemistry staining method Other: laboratory biomarker analysis|
- Maximum-tolerated Dose (Phase I) [ Time Frame: Up to 2.5 months ]
MTD is defined as the dose level below the lowest dose that induces dose limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6
> new patients). If dose-limiting toxicity (DLT) is not seen in any of the 3 patients, 3 new patients will be accrued and treated at the next higher dose level. If DLT are seen in 2 or 3 of 3 patients treated at a given dose level, then the next 3 patients will be treated at the next lower dose level, if only 3 patients were enrolled and treated at this lower dose level. The number of DLT's will be reported here.
- Response Rate (Phase II) [ Time Frame: from baseline up to 5 years post-registration ]
A confirmed response is defined to be a CR or PR (as determined by RECIST (version 1.1 criteria) noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Response will be evaluated using all cycles of treatment. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluable for response.
A CR is defined as:
All of the following must be true:
- Disappearance of all non-nodal target lesions
- Each target lymph node must have reduction in short axis to <1.0 cm
A PR is defined as:
At least a 30% decrease in the sum of the longest diameters of the non-nodal target lesions and the short axes of the target lymph nodes taking as reference the BSD (Section 11.41)
- Survival Time (Phase II) [ Time Frame: from baseline up to 5 years post-registration ]Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier
- Time-to-disease Progression (Phase II) [ Time Frame: from baseline up to 6 months ]
Time-to-disease progression (TTP) is defined as the time from registration to documentation of disease progression. If a patient dies without a documentation of disease progression, the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death. The distribution of TTP will be estimated using the method of Kaplan-Meier. Progression is defined as at least one of the following:
- At least one new malignant lesion or a lymph node whose short axis has increased to >1.5 cm
- At least a 20% increase in the sum of diameters of target lesions taking as reference the MSD. In addition, the sum must also demonstrate an absolute increase of at least 0.5 cm
- Progression-free Survival (Phase II) [ Time Frame: from baseline up to 6 months ]Progression-free survival (PFS) is defined as the time from registration to progression or death due to any cause. PFS at 6 months will be estimated. The distribution of PFS will be estimated using the method of Kaplan-Meier.
- Duration of Response (Phase II) [ Time Frame: from baseline up to 5 years post-registration ]Duration of response is defined for all evaluable patients who have achieved a confirmed response as the date at which the patient's objective status is first noted to be a CR or PR to the earliest date progression is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier.
- Clinical Benefit Rate [ Time Frame: from baseline up to 6 months ]Clinical benefit rate will be estimated by the total number of patients with an objective status of CR, PR, or SD for duration of at least 6 months divided by the total number of evaluable patients. All evaluable patients will be used for this analysis. Exact binomial 95% confidence intervals for the true clinical benefit rate will be calculated.
- Time to Treatment Failure [ Time Frame: from baseline up to 5 years post-registration ]Time to treatment failure (TTF) is defined as the time from the date of registration to the date at which the patient is removed from treatment due to progression, unacceptable adverse events, or refusal. The distribution of TTF will be estimated using the method of Kaplan-Meier
- Confirmed Response Rate (Phase I) [ Time Frame: from baseline up to 5 years ]A confirmed response is defined to be a CR or PR (as determined by RECIST criteria) noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Response will be evaluated using all cycles of treatment. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluable for response. The number of confirmed responses will be reported here.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01105312
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|Study Chair:||Winston Tan, MD, FACP||Mayo Clinic|