Solid Tumors Clinical Trial
Official title:
A Phase I Study of Doxorubicin-loaded Anti-EGFR Immunoliposomes in Patients With Advanced Solid Tumors
Verified date | September 2014 |
Source | University Hospital, Basel, Switzerland |
Contact | n/a |
Is FDA regulated | No |
Health authority | Switzerland: Swissmedic |
Study type | Interventional |
Background: Site-specific delivery of anti-cancer therapeutics is paramount for both
reducing nonspecific toxicities and increasing efficacy of chemotherapeutic agents. Due to
their small molecular size and nonspecific mechanisms of action, most conventional
chemotherapies result in significant toxicities that limit the effectiveness of treatment
and reduce the overall quality of life for cancer patients. Encapsulation of these toxic
agents inside lipid-based carrier systems (so-called liposomes) results in passive targeting
of the compounds to solid tumors. The preferential delivery of liposomal drugs to solid
tumors is mostly due to altered barrier-properties of tumor-associated vessels. This results
in both an improved delivery and at the same time a significantly milder toxicity profile.
Recently, the specificity of delivery was further increased by attaching monoclonal
antibodies or antibody fragments to the surface of liposomes (=immunoliposomes,
antibody-linked nanoparticles). Antibody-coated immunoliposomes attach more selectively to
antigens expressed on the target cells and they are internalized more efficiently.
Furthermore, there is evidence that drug resistance, a major challenge in cancer treatment,
may be overcome by such delivery systems. A logical and accessible target, such as EGFR, is
overexpressed on a variety of primary human cancer cells and it is involved in signaling
pathways that contribute both to tumor initiation and tumor progression. Recently, the
investigators have tested immunoliposomes against the epidermal growth factor receptor
(EGFR) in a preclinical setting. Based on the preclinical results we have initiated this
phase I clinical trial.
Study hypothesis: The investigators hypothesize that anti-EGFR-immunoliposomes selectively
deliver cytotoxic compounds to EGFR-overexpressing tumors cells. Specific delivery is
supposed to increase efficacy while reducing side-effects of the compound. The primary
objective of this phase 1 trial is the determination of the maximum tolerated dose (MTD) for
future phase 2 trials of this nanoparticle.
Status | Completed |
Enrollment | 26 |
Est. completion date | March 2010 |
Est. primary completion date | March 2010 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years and older |
Eligibility |
Inclusion Criteria: 1. Histologically proven locally advanced or metastatic solid tumor. 2. ECOG Performance = 2. 3. No additional standard therapy available for the patient. 4. EGFR overexpression (according to DAKO EGFR pharmDx - Test) determined in the most recently evaluable tumor tissue. 5. No concomitant anti-tumor therapy (steroids are permitted - in breast cancer and prostate cancer, steroid dose needs to remain stable during the study period). 6. At least four weeks since termination of any previous anti-tumor treatment (6 weeks in the case of nitrosoureas or mitomycin C). 7. In patients with previous anthracycline exposure, a normal echocardiogram (LVEF > 50%) is required. 8. Age = 18. 9. Male or female. 10. Female and male patients of reproductive age must be using effective contraception. 11. Willing and able to sign an informed consent prior to participation in the study and to comply with the protocol for the duration of the study. Exclusion Criteria: 1. Pregnancy and/or breastfeeding. 2. Patients with the following laboratory values - neutrophils < 1.5 x 109/L - platelets < 100 x 109/L - serum creatine > 3.0 x upper normal limit - ALAT, ASAT > 3.0 x upper normal limit (5.0 x in patients with liver metastases as the only likely cause of enzyme alteration) - alkaline phosphatase > 3.0 x upper normal limit (5.0 x in patients with liver or bone metastases as the only likely cause of enzyme alteration) - bilirubin > 3.0 x upper normal limit 3. Participation in any investigational drug study within 4 weeks preceding treatment start. 4. Patients with clinically significant and uncontrolled renal- or hepatic disease. 5. Clinically significant cardiac disease: congestive heart failure (New York Heart Association class III or IV); symptomatic coronary artery disease; cardiac arrhythmia not well controlled with medication; myocardial infarction within the last 12 months. 6. Any serious underlying medical condition (at the judgement of the investigator) which could impair the ability of the patient to participate in the trial (e.g. active autoimmune disease, uncontrolled diabetes, etc.). 7. Any concomitant drugs contraindicated when administering Erbitux™ or Caelyx™ according to the Swissmedic-approved product information. 8. A cumulative doxorubicin dose of > 300 mg/m2 BSA (or cardiotoxic anthracycline-equivalent). 9. Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and precluding informed consent or interfering with compliance. 10. Brain metastases. |
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
Switzerland | University Hospital | Basel |
Lead Sponsor | Collaborator |
---|---|
University Hospital, Basel, Switzerland |
Switzerland,
Mamot C, Drummond DC, Greiser U, Hong K, Kirpotin DB, Marks JD, Park JW. Epidermal growth factor receptor (EGFR)-targeted immunoliposomes mediate specific and efficient drug delivery to EGFR- and EGFRvIII-overexpressing tumor cells. Cancer Res. 2003 Jun 15;63(12):3154-61. — View Citation
Mamot C, Drummond DC, Noble CO, Kallab V, Guo Z, Hong K, Kirpotin DB, Park JW. Epidermal growth factor receptor-targeted immunoliposomes significantly enhance the efficacy of multiple anticancer drugs in vivo. Cancer Res. 2005 Dec 15;65(24):11631-8. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Determination of the maximum tolerated dose (MTD) | The MTD is defined through the occurrence of two dose limiting toxicities (DLTs) at a specific dose level. DLT are defined as any grade 4 toxicity, any grade 3 toxicity lasting more than one week or/and febrile neutropenia grade 3 (defined as neutrophils < 1.0 x 10e9/l and fever > 38.5 °C). Nausea, vomiting, anorexia, and alopecia (grade 2) will be excluded as dose limiting toxicities. Similarly, adverse events that are clearly related to the primary tumor, such as progression of disease will not be considered as DLTs. | after completion of the 1st cycle (day 28) | Yes |
Secondary | CT scans for efficacy | every 2 months for 6 months and then every 3 months for a total of one year | No |
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