Anti-EGFR Immunoliposomes in Solid Tumors

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.

Sex

All

Minimum age

18 Years

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.

• BACKGROUNDMamot 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. PMID 12810643
• BACKGROUNDMamot 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. doi: 10.1158/0008-5472.CAN-05-1093. PMID 16357174
• DERIVEDMamot C, Ritschard R, Wicki A, Stehle G, Dieterle T, Bubendorf L, Hilker C, Deuster S, Herrmann R, Rochlitz C. Tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded anti-EGFR immunoliposomes in advanced solid tumours: a phase 1 dose-escalation study. Lancet Oncol. 2012 Dec;13(12):1234-41. doi: 10.1016/S1470-2045(12)70476-X. Epub 2012 Nov 13. PMID 23153506