A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABT-414 for Subjects with Glioblastoma Multiforme

GBM is the most common and most aggressive type of primary brain tumor in
adults, affecting 8,000 to 10,000 people per year in North America alone.
Treatments may include surgical resection of the tumor, chemotherapy, radiation
therapy, and immunotherapy. Despite advances in treatments, the prognosis of
patients with GBM remains poor. The current standard-of-care therapy for newly
diagnosed glioblastoma following surgical debulking is radiation therapy (RT)
in combination with temozolomide (TMZ), followed by 6 months of further
temozolomide monotherapy.

GBM tumors have unique molecular characteristics that can influence outcome and
inform treatment decisions. Phosphatase and
tensin homolog (PTEN) and EGFR expression have correlated with outcome
measures. GBM tumors, particularly those with EGFR amplification, have a high
rate of EGFRde2-7 mutation expression (up to 40% in the overall population and
up to 60% of more in the EGFR amplification population). The presence of this
mutation confers a worse prognosis.

ABT-414 is an antibody drug conjugate (ADC) designed for the treatment of
tumors expressing EGFR, consisting of: 1) a veneered "humanized" recombinant
IgG1* antibody that has binding properties specific to a unique epitope of
human EGFR with 2) non-cleavable maleimido-caproyl linkers each attached to 3)
a potent antimicrotubule agent, monomethylauristatin F (MMAF). The antibody
binds to the EGFR epitope, is internalized, and then intracellular enzymes
release the toxin leading to inhibition of microtubule function, the disruption
of critical cellular
processes and cell death.

ABT-414 is expected to be a more potent and tumor-specific antibody-drug
conjugate than other EGFR antibodies and will be broadly applicable to a wide
variety of EGFR-expressing tumor subsets. When compared to other EGFR directed
molecules, nonclinical studies to date have confirmed that ABT-414 has potency
greater than what is observed with clinically available agents in a variety of
human xenograft animal models, with at least an equivalent toxicity profile.

The evaluation of the safety and pharmacokinetics of ABT-414 in combination
with radiation plus temozolomide or temozolomide alone for subjects with
Glioblastoma Multiforme.

Approximately 200 subjects will be enrolled at approximately 18 research sites.

The study will consist of three arms, which will be enrolled in parallel, as
well as Expanded Cohorts per arm. The first arm (Arm A) will evaluate the
toxicities, PK, MTD, and RPTD of ABT-414 when administered every other week in
combination with standard of care radiation and temozolomide in a population of
subjects with newly diagnosed GBM. The second arm (Arm B) will evaluate the
toxicities, PK, MTD, and RPTD of ABT-414 when administered every other week in
combination with temozolomide in a population of subjects with GBM that have
either just completed adjuvant radiation and temozolomide therapy or in
subjects with recurrent GBM.
The third arm (Arm C) will evaluate the toxicities, PK, MTD, and RPTD of
ABT-414 when administered every other week as monotherapy in subjects with
recurrent GBM.

Once the RPTD is determined, the recommended Phase 2 dose (RPTD) of ABT-414
will be evaluated in Expanded Cohorts for each respective arm. In Expanded
Cohort A, approximately 12 additional subjects will be included. In expanded
cohorts B and C, an additional of approximately 50 subjects will be included.

Subjects will receive ABT-414 every other week by IV injection as monotherapy
or together with the standard of care medication (Temozolomide with or without
radiotherapy). Subjects can continue the use of ABT-414 progression of disease
or severe adverse events.

ABT-414 is an ADC that has demonstrated robust preclinical efficacy in a broad
range of tumor types, including glioblastoma cell lines that have a high degree
of EGFR expression. ABT-414 also demonstrates a favorable EGFR binding ratio of
tumor to normal tissue. These data together reflect an acceptable rationale and
risk for treating adult patients with cancer that has a moderate to high level
of EGFR expression with ABT-414 in the context of a clinical trial.

The subjects participating in the study will have a higher burden because of
participation in the trial. This burden exists of extra study visits and blood
draws. The subjects do not need to complete diaries or questionnaires. Other
than that, the subjects will receive the standard treatment.