Phase I Study of Mesenchymal Stromal Cells-Derived Exosomes With KrasG12D siRNA for Metastatic Pancreas Cancer Patients Harboring KrasG12D Mutation
Overview
- Phase
- Phase 1
- Intervention
- Mesenchymal Stromal Cells-derived Exosomes with KRAS G12D siRNA
- Conditions
- Not specified
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 28
- Locations
- 1
- Primary Endpoint
- Overall survival (OS)
- Status
- Recruiting
- Last Updated
- 5 months ago
Overview
Brief Summary
This phase I trial studies the best dose and side effects of mesenchymal stromal cells-derived exosomes with KrasG12D siRNA (iExosomes) in treating participants with pancreatic cancer with KrasG12D mutation that has spread to other places in the body. iExosomes may work better at treating pancreatic cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To identify the maximum tolerated dose (MTD) of mesenchymal stem cell (MSC)-derived exosomes loaded with small interference RNA (siRNA) against KrasG12D (iExosomes) in metastatic pancreatic ductal adenocarcinoma (PDAC) patients with KrasG12D mutation. II. To identify the dose-limiting toxicities (DLT) of mesenchymal stem cell (MSC)-derived exosomes loaded with siRNA against KrasG12D (iExosomes) in metastatic PDAC patients with KrasG12D mutation. SECONDARY OBJECTIVES: I. Evaluate the pharmacokinetic profile of iExosomes. II. Assess the overall response rate of iExosomes in the chosen patient population. III. Assess the disease control rate (partial response + stable disease) with therapy. IV. Determine median progression-free survival (PFS) with this treatment. V. Determine the median overall survival (OS) with this treatment. EXPLORATORY OBJECTIVES: I. Evaluate optional tissue collection and serum-derived exosomes and circulating-free deoxyribonucleic acid (DNA) (cfDNA) for detection of DNA and ribonucleic acid (RNA) showing KrasG12D sequence; evaluate DNA and RNA showing KrasG12D sequence in optional tissue collection. II. Evaluate the siRNA content in blood and optional tissue collection. OUTLINE: This is a dose-escalation study. Participants receive mesenchymal stromal cells-derived exosomes with KrasG12D siRNA intravenously (IV) over 15-20 minutes on days 1, 4, and 10. Treatment repeats every 14 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Participants who respond may continue 3 additional courses. After completion of study treatment, participants are followed up at 30 days, then every 3 months for up to 1 year.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients with histologically confirmed metastatic pancreatic ductal adenocarcinoma harboring KrasG12D mutation
- •Patients must have documented progression or stable disease on one or more lines of systemic therapy. If stable disease, patient must have completed at least 4 months of chemotherapy with cytotoxic therapy
- •KrasG12D mutation status will be informed from any previous routine molecular profiling (using commercial assays such as Foundation One, Caris, Oncomine or other) of tissue or blood. Additional KrasG12D mutation status may be confirmed using tissue biopsy or blood prior to enrolling into the trial
- •ECOG (Eastern Cooperative Oncology Group) performance status of 0-1
- •Absolute neutrophil count (ANC) more or equal to 1,500 cells/mm3
- •Platelets more or equal to 100,000/ul
- •Hemoglobin more than 9.0 g/dL
- •Total bilirubin between 1 and 1.5 mg/dL
- •AST (aspartate aminotransferase) and ALT (alanine transaminase) less than 2.5 x ULN (upper limit of normal)
- •Alkaline phosphatase less than 2.5 x ULN
Exclusion Criteria
- •Concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study such as unstable angina, myocardial infarction within 6 months, unstable symptomatic arrhythmia, uncontrolled diabetes, serious active or uncontrolled infection
- •Pregnancy (positive pregnancy test) or lactation
- •Known CNS (central nervous system) disease, except for treated brain metastasis. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (magnetic resonance imaging-MRI or computerized tomography-CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; gamma knife, linear accelerator \[LINAC\], or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded
Arms & Interventions
Treatment (iExosomes)
Participants receive mesenchymal stromal cells-derived exosomes with KrasG12D siRNA IV over 15-20 minutes on days 1, 4, and 10. Treatment repeats every 14 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Participants who respond may continue 3 additional courses.
Intervention: Mesenchymal Stromal Cells-derived Exosomes with KRAS G12D siRNA
Outcomes
Primary Outcomes
Overall survival (OS)
Time Frame: Up to 1 year
Estimated using the Kaplan-Meier product limit estimator.
Progression-free survival (PFS)
Time Frame: Up to 1 year
Estimated using Kaplan-Meier product limit estimator.
Minimal residual disease rate in high-risk patients
Time Frame: Up to 1 year
Will be modeled using logistic regression.
Maximum Tolerated Dose Determined by Dose Limiting Toxicity
Time Frame: First 4 weeks of treatment
Dose limiting toxicity graded according to the NCI CTCAE, Version 4.0