Trial Information

A Phase I Study of Doxorubicin-loaded Anti-EGFR Immunoliposomes in Patients With Advanced Solid Tumors

C225-ILS-DOX

This is a phase 1 trial of anti-EGFR-immunoliposomes, an investigative nanoparticle targeted
against EGFR-overexpressing tumor cells. The investigators have constructed anti-EGFR
immunoliposomes by using Fab' fragments of the chimeric MAb cetuximab (C225, cetuximab,
erbitux™, ImClone Systems Corp., NY, USA; Merck KGaA, Darmstadt, Germany), which were
covalently conjugated to the liposome membrane. This approach was designed to provide
maximal drug delivery to cancer cells via a receptor-targeted and internalizing drug carrier
that is stable, non-immunogenic, long-lived with extended blood and tissue residence times
and capable of delivering large payloads of diverse types of drugs.

Based on extensive preclinical studies, the investigators decided to perform a
first-in-human clinical trial in patients with EGFR-overexpressing solid tumors who have
already received all available standard treatments. The therapeutic compound tested in the
trial is C225-ILs-dox, a doxorubicin-loaded anti-EGFR-immunoliposome. Doxorubicin is one of
the most active agents in many human tumors, and a high percentage of these malignancies do
express EGFR. Therefore, the targeting of doxorubicin to EGFR-expressing tumors via the
EGFR-specific antibody C225 should enhance the specificity and efficacy of chemotherapy,
while the encapsulation of the cytotoxic drug within pegylated liposomes should at the same
time decrease its toxicity.

This is a single center, open study. The aim of the trial is the definition of the maximum
tolerated dose (MTD) for future phase 2 studies. Secondary endpoints include the overall
response rate, the time-to-progression and the assessment of the pharmakokinetic of the
compound. The trials follows a canonical 3+3 design and allows an additional recruitment of
up to 6 patients on the dose level defined as the MTD. Planned dose levels are as follows:

Level 1 = 5 mg/m2 Level 2 = 10 mg/m2 Level 3 = 20 mg/m2 Level 4 = 30 mg/m2 Level 5 = 40
mg/m2 Level 6 = 50 mg/m2 Level 7 = 60 mg/m2 Level 8 = 70 mg/m2 Level 9 = 80 mg/m2

At each dose level, 3 patients may be enrolled simultaneously. Escalation to the next higher
dose will be allowed after patient 3 of a given dose level has received at least one full
cycle of therapy if no dose limiting toxicity (DLT) occured at a given dose level. The
decision to enter a next dose level will be made by the study team after reviewing all
available toxicity data of the previous groups. A DLT is 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. In addition, preexisting toxicities must be taken into account when defining and
analyzing DLTs.

Patients will be treated until disease progression but for a maximum of 6 cycles. Patients
having completed the treatment phase (24 weeks) and showing complete or partial response as
well as stable disease will enter the observation phase of the study. This phase will end 12
months after the last patient has been included. At any time during treatment phase or
observation phase, patients with signs of disease progression according to RECIST criteria
for reporting results of cancer treatment or having discontinued treatment due to
unacceptable toxicity will go off study and be treated at the investigator's discretion.