A Study Inhibiting Telomerase to Reverse Trastuzumab Resistance in HER2+ Breast Cancer

Study Overview
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Brief Summary
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A study to evaluate safety and biologic effects of giving GRN163L in combination with trastuzumab in patients diagnosed with HER2+ metastatic breast cancer that is resistant to therapy with trastuzumab.

Official Title
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A Phase I Study Inhibiting Telomerase to Reverse Trastuzumab Resistance in HER2+ Breast Cancer

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: GRN163L in combination with trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females 18 years or older at the time of consent. ECOG performance status of 0-2 within 21 days of study registration. Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease. NOTE: locally recurrent disease must not be amenable to surgery or radiation with curative intent. Measurable or evaluable disease according to RECIST v1.1 within 35 days prior to study registration. Disease must be amenable to biopsy (image-guided or via direct visualization of superficial lesions) with minimal risk to the patient. NOTE: Patients with disease limited to the lung and/or pleura are excluded. Disease must be HER2+ as defined by IHC 3+ or FISH ratio > 2.0. Resistant to trastuzumab as defined as (1) progression within 12 months of completing adjuvant/neoadjuvant trastuzumab or (2) progression on trastuzumab administered for metastatic disease. Prior treatment with lapatinib or investigational HER2 targeted therapies is allowed but not required. There are no limits on the number of regimens or other prior anti-HER2 therapies patients have received. LVEF ≥ Lower Limit of Normal based on MUGA or ECHO within 35 days prior to study registration Females of childbearing potential and males must be willing to use an effective method of contraception from the time consent is signed until 6 months after treatment discontinuation. Methods of contraception include hormonal birth control (oral contraceptives, patch, injection, vaginal ring or implant), two barrier methods of birth control, abstinence and/or other methods as determined by the treating physician. Females of childbearing potential must have a negative pregnancy test within 14 days prior to registration for protocol therapy. NOTE: Females are considered of child bearing potential unless they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal (> 12 months since last menses). Laboratory values must be obtained within 21 days of study registration: Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 Platelets ≥ 100 K/mm3 Hemoglobin (Hgb) ≥ 9.0 g/dL (may be transfused) Serum creatinine < 3.0 mg/dL Total Bilirubin ≤ 1.5 x ULN AST/SGOT ≤ 2.5 x ULN. If liver metastases is present, AST ≤ 5 x ULN ALT, SGPT ≤ 2.5 x ULN. If liver metastases is present, ALT ≤ 5 x ULN Exclusion Criteria: No Investigational therapy within 4 weeks of study registration No hormonal therapy within 2 weeks of study registration No cytotoxic chemotherapy within 2 weeks of study registration. No prior treatment with GRN163L No prior history of severe reaction to trastuzumab, as determined by the treating physician. No history of clinically significant cardiac dysfunction, including: Current uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg), or unstable angina History of symptomatic CHF (Grade >3 by NCI CTCAE or Class >II by NYHA criteria [see Appendix IV]) or serious cardiac arrhythmia requiring treatment within 12 months of study registration, with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia History of myocardial infarction within 6 months of study registration No history of cerebrovascular accident within 12 months of study registration No active CNS metastases. Patients with previously treated CNS metastases who do not require chronic steroids or anticonvulsants are eligible. Prior radiation therapy must not have involved > 25% of bone marrow due to potential myelosuppression with GRN163L. See bone marrow chart in Appendix III NOTE: Radiation therapy within 2 weeks of study registration is not allowed. Females must not be breastfeeding. No clinically significant active infection, as determined by the treating physician

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GRN163L + Trastuzumab<br> | Drug: GRN163L in combination with trastuzumab<br>* GRN163L will be administered in escalating dose cohorts on Day 1 of each 21-day cycle prior to trastuzumab infusion. Trastuzumab will be a administered day 1 of each 21-day cycle after GRN163L. There will be a 30 minute observation period between the end of the GRN163L infusion and the beginning of the trastuzumab infusion.<br>* Other names: Herceptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the dose-limiting toxicity of GRN163L in combination with trastuzumab in patients with refractory HER2+ metastatic disease |  | End of Study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure the concentration of trastuzumab and GRN163L from blood samples immediately before and after infusion on day 1, weekly during cycle 1, and immediately prior to cycle 2 | PK data will be described using means, standard deviations, medians, minimums and maximums. | Until cycle 2 | 
| Tumor biopsy and bone marrow aspirate assayed for telomerase activity prior to treatment and immediately prior to planned cycle 2 | Telomerase activity data will be described using means, standard deviations, medians, minimums and maximums. | Until cycle 2 | 
| Flow cytometry to compare cell cycle distribution in tumor and bone marrow prior to treatment and immediately prior to cycle 2. | Marrow (and tumor when sufficient sample is available) will be analyzed via flow cytometry to determine cell distribution. Percentage of cells at each cycle will be described using means, standard deviations, medians, minimums and maximums. | Until cycle 2 | 
| Tumor samples analyzed for activation of HER2 family signaling protein activation (phosphorylation) status prior to treatment and immediately prior to cycle 2. | HER2 family signaling protein activation will be described using means, standard deviations, medians, minimums and maximums. | Until cycle 2 | 
| Determine objective response rate (ORR) and progression free survival (PFS) of GRN163L in combination with trastuzumab in this patient population |  | End of Study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Breast Tumors, Cancer of Breast, Cancer of the Breast, Genes, HER-2, Genes, HER2