A Randomized, Placebo Controlled Phase 3 Study of ABT-414 with Concurrent Chemoradiation and Adjuvant Temozolomide in Subjects with Newly Diagnosed Glioblastoma (GBM) with Epidermal Growth Factor Receptor (EGFR) Amplification (Intellance 1)

Gliomas are the most frequent primary brain tumors in adults, with an annual
incidence between 4 and 5 per 100.000 inhabitants. Glioblastomas represent
60-70% of these tumors. Glioblastomas are the most aggressive primary brain
tumors in adults, with a median survival of 9 to 17 months (when treated). No
curative treatment exists. Fifty to sixty percent of glioblastomas demonstrate
abnormalities of the EGFR pathway: 60% show overexpression of the receptor, in
40-50% the EGFR receptor is amplified, and about 25% of the GBM population
harbors a constitutively activated EGFRvlll mutation in parts of the tumor.
Standard treatment consists of surgical resection to the extent safely feasible
followed by radiation and concomitant and adjuvant TMZ therapy.
ABT-414 is an antibody drug conjugate (ADC) designed for the treatment of
tumors expressing EGFR. ABT-414 consists of: (1) a veneered "humanized"
recombinant lgG1K 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 activated EGFR epitope (even in the absence of the
EGFRvlll mutation), is internalized, and then intracellular enzymes release the
toxin leading to inhibition of microtubule function, the disruption of critical
cellular processes, and cell death.
In an ongoing phase I study in GBM, ABT-414 is given intravenously (IV) every
other week. This is investigated with radiotherapy and daily temozolomide
(RT/TMZ) or with TMZ on day 1-5 every four weeks. In this phase I project,
responses are observed in recurrent glioblastomas. Preliminary results show
that 4 out of 15 recurrent glioblastoma subjects had objective responses, where
these responses occurred in patients with EGFRvlll mutation or amplification.
There are no preliminary results known about the effects with primary
glioblastomas, because no data is present yet about recurrence of the disease.
These data warrant further exploration of ABT-414 in primary GBM with EGFR
amplification, in combination with radiotherapy and TMZ.

To determine whether the addition of ABT-414 to concomitant radiotherapy and
temozolomide prolongs overall survival (OS) in subjects with newly diagnosed
GBM harboring EGFR amplification.

This is a randomized, double-blind, placebo-controlled, multicenter phase 3
study.
The study consists of two arms:

Arm 1:
During the 6 week chemo radiation-phase the subject receives ABT-414 on day 1
of the 1st, 3rd and 5th week. In this period the subject receives standard
radiotherapy and standard TMZ (daily dose lasting 42 days). After a recovery
period of 4 weeks, the adjuvant phase will start where the subject receives TMZ
during 6 cycles of 28 days on day 1-5 of every cycle and ABT-414 on day 1 and
day 15 of every cycle. This will be followed by 6 cycles of 28 days where only
ABT-414 on day 1 and day 15 is given.
Arm 2:
This arm is equal to the first arm, but the ABT-414 infusion will be replaced
by a placebo infusion.
Amendment 3 includes an additional sub-study enrolling approximately 12
subjects with mild to moderate hepatic impairment. These subjects will receive
open label ABT-414 and follow the same procedures and treatments as the blinded
subjects in the blinded study.

Chemo radiation phase:
Subjects will be treated with ABT-414, 2.0 mg/kg or Placebo, intravenous
injection 30 to 40 minutes on day 1 of week 1, 3 and 5. In addition, subjects
receive standard RT and TMZ (75 mg/m2) during the first 6 weeks.
Adjuvant phase:
Subjects will be treated during 12 cycles of 28 days with ABT-414, 1.25 mg/kg
or Placebo, intravenous injection 30 to 40 minutes on day 1 and day 15 of every
cycle. On day 1-5 of the first 6 cycles subjects will receive TMZ 150mg/m2,
with the possibility to increase the dose to 200mg/m2 in subsequent cycles in
case of sufficient tolerance.
The response on the treatment will be assessed by an MRI, which will be
performed every 8 weeks.
The treatment stops after these 12 adjuvant cycles, but in case of a good
response and tolerance of ABT-414 or placebo the treatment can be continued on
request of the investigator and in negotiation with the sponsor.

The subjects participating in the study will have a higher burden because of
participation in the trial. This burden consists of extra visits to the site,
two times an ECG, additional blood draws besides the standard safety labs. Next
to this, the subjects will complete questionnaires (among others HVLT-R and
MDASI-BT) during screening, prior to the adjuvant phase and subsequently every
8 weeks. Furthermore, the subjects will be obliged to use preventive eye drops
in the days surrounding ABT-414 administrations or placebo. Eye examinations
will be performed during screening (1x), the chemo radiation phase (3x) and in
the adjuvant phase. Furthermore an MRI will be made prior to treatment and
subsequently every 8 weeks.

In Arm 1 subjects will receive an intravenous ABT-414 injection every other
week. Risks in this study include toxicity from ABT-414. Next to adverse events
of the standard treatment, such as TMZ and radiotherapy, ABT-414 can give
adverse events. Interim safety data from a phase 1 study with ABT-414 in GBM
patients show the following adverse events: Dry eyes, foreign body sensation in
eyes, keratitis, photophobia, vision blurred, fatigue and headache. The current
data of ABT -414 and the lack of an effective treatment alternative reflect an
acceptable rationale and risk for treating adult patients with GBM with an
elevated expression of EGFR with ABT -414 in the context of a clinical trial.