Intrathecal Pertuzumab and Trastuzumab in Patients With New Untreated Asymptomatic or Low Symptomatic Brain Metastasis in HER2 Positive Breast Cancer
The purpose of this research study is to determine how well pertuzumab and trastuzumab works in treating breast cancer that has spread to the brain. Pertuzumab and trastuzumab are treatments that stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2).
Pertuzumab and trastuzumab have been found to be very effective for HER2-positive breast cancer and are FDA approved for treatment of metastatic breast cancer outside of the brain when given through the vein. This suggests that pertuzumab and trastuzumab may help shrink or stabilize HER2-positive breast cancer that has spread to the brain in this research study.
In this research study, the investigators are looking to see whether pertuzumab and trastuzumab will work to decrease the size of or stabilize breast cancer that has spread to the brain.
|HER2 Positive Untreated Metastatic Breast Cancer Asymptomatic or Low Symptomatic Brain Metastasis in Breast Cancer||Drug: Pertuzumab Drug: Trastuzumab||Phase 1|
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Dose Escalation Trial of Intrathecal Pertuzumab and Trastuzumab in Patients With New Untreated Asymptomatic or Low Symptomatic Brain Metastasis|
- Safety as measured by adverse events [ Time Frame: Baseline up to 36 weeks ]Adverse events will be closely monitored and assessed for all subjects on study treatment. The main observational portion of study will be complete at 36 weeks. However, subjects will be allowed to continue on treatment for as long as they are receiving clinical benefit and any adverse events occurring during this time will be assessed. Following discontinuation of study treatment, patient follow-up will take place every 3 months.
- Maximum tolerated dose as measure by dose limiting toxicity [ Time Frame: Baseline up to 36 weeks ]
Toxicity will be graded according to the NCI-CTC version 4 and will be assessed weekly for the first six weeks of treatment and then every 21 days. A DLT is defined as any grade 3 or higher non-hematologic toxicity or grade 4 hematologic toxicity that occurs within the first 6 weeks of treatment that is assessed as possibly related to the intrathecal therapy. Any treatment delays occurring during the first six weeks of treatment that are due to study treatment-related toxicity will also be considered a DLT.
The main portion of study will be complete at 36 weeks. However, subjects will be allowed to continue on treatment for as long as they are receiving clinical benefit.
- Response rate as measured by brain MRI [ Time Frame: Every 6 weeks from Baseline up to 36 weeks ]
Complete Response (CR): Radiographic complete response (RCR), 100% reduction in tumor, with complete clearing of MRI scan evidence of disease on 2 consecutive scans 6 weeks apart with stable or improved clinical function.
Partial Response (PR): Radiographic stability of disease (RSD), > 50% but < 100% reduction in tumor, with improved clinical function.
Stable Disease (SD): Radiographic stability of disease (RSD), < 50% reduction in tumor or < 25% increase in size of tumor, with stable clinical function.
Progressive Disease (PD): Radiographic progressive disease (RPD), > 25% increase in size of tumor, and/or the presence of declining clinical function attributable to the CNS metastasis. Other indications of progression include development of new CNS metastases or increase in size of previous CNS metastasis. Changes in size of previous CNS metastasis must measure > 25% increase in the largest unidimensional measurement in the absence of new neurologic symptoms.
- Changes in cell-free circulating tumor DNA (ctDNA) in response to treatment [ Time Frame: Baseline up to 36 weeks ]
|Study Start Date:||May 2016|
|Estimated Study Completion Date:||August 2019|
|Estimated Primary Completion Date:||February 2019 (Final data collection date for primary outcome measure)|
Experimental: Intrathecal Pertuzumab and Trastuzumab
Four cohorts will enroll in a dose escalation of pertuzumab and a consistent dose of trastuzumab. The cohorts will be assigned as follows:
Cohort: Intrathecal Dose:
Pertuzumab will be administered intrathecally via a lumber puncture. The dosing cohorts are described above in the arm description.
Other Name: PerjetaDrug: Trastuzumab
Trastuzumab will be administered intrathecally via a lumber puncture. The dosing cohorts are described above in the arm description.
Other Name: Herceptin
Intrathecal administration of pertuzumab and trastuzumab will occur via lumbar puncture (spinal tap) under fluoroscopic guidance by interventional radiology at Duke University Medical Center. The spinal needle will be inserted into the spinal column and 7 mL of cerebrospinal fluid (CSF) will be collected. Once the CSF is removed, the intrathecal pertuzumab and trastuzumab will be administered using aseptic technique. At certain time points the CSF will be analyzed for free cell DNA. If subjects consent, the CSF fluid will also be stored for additional future research.
Patients will be treated using a 3+3 dose-escalation design. Patients will not be accrued to the next cohort (dose escalation) until at least one patient on the previous cohort has been followed for six weeks. If a dose limiting toxicity (DLT) is seen in a patient then the cohort will be expanded by an additional 3 patients to allow for 1 in 6 patients per cohort to have a DLT before dose escalation. Dose limiting toxicity will be assessed weekly during the first six weeks of the treatment.
Patients will be treated weekly for the first six weeks and then every 3 weeks (q21 days). Once the maximum tolerated dose is reached, an additional 12 patients will be enrolled in the cohort at the maximum tolerated dose. The maximum number of enrolled patients is 36. Dosing is as follows: Cohort 1 - 80mg IT trastuzumab, 10mg IT pertuzumab, cohort 2 - 80mg IT trastuzumab, 20mg IT pertuzumab, cohort 3 - 80mg IT trastuzumab, 40mg IT pertuzumab, cohort 4 - 80mg IT trastuzumab, 80mg IT pertuzumab. If the lowest dose level is found to be too toxic, the trial will stop without finding a maximum tolerated dose.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02598427
|Contact: Kim Rileyemail@example.com|
|Contact: Sheryl Cummings, MS, BSN, RN, OCNfirstname.lastname@example.org|
|United States, North Carolina|
|Duke University Medical Center||Recruiting|
|Durham, North Carolina, United States, 27710|
|Contact 919-660-1278 email@example.com|
|Contact: Sheryl Cummings 919-613-4579 firstname.lastname@example.org|
|Principal Investigator: Kimberly Blackwell, MD|
|Sub-Investigator: P. Kelly Marcom, MD|
|Sub-Investigator: Gretchen Kimmick, MD|
|Sub-Investigator: Kelly Westbrook, MD|
|Principal Investigator:||Kimberly Blackwell, MD||Duke University|