Phase I/II study of combined treatment with AT-101, cisplatin and radiotherapy in patients with locally advanced head and neck cancer

Despite significant improvements in the treatment of patients with inoperable
head and neck cancer, recurrence rates remain a major obstacle. Thus, there is
a clear need to develop new therapeutic approaches to further enhance the
anti-tumor efficacy of existing standard regimens, such as cisplatin-based
chemoradiotherapy. Overexpression of anti-apoptotic members of the Bcl-2 family
is frequently observed in HNSCC and has been associated with resistance to
radio- and chemotherapy and poor prognosis.
From structure-studies and binding assays, it was shown that AT-101 is a potent
inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-XL, and Mcl-1. In
experimental and preclinical studies, AT-101 demonstrated pro-apoptotic
properties in a dose dependent manner, with selective cytotoxic activity
towards malignant cells. It has shown limited antitumor effects when used as
single agent after oral administration and preliminary evidence of efficacy
when combined with docetaxel in HRPC. However, after concurrent administration
of AT-101 with radiation or cisplatin-chemotherapy the anti-proliferative
effects were significantly enhanced in preclinical experimental studies.
Because AT-101 is able to enhance both radiation- and chemotherapy-induced
tumor regression, it is an attractive drug for concomitant use with concurrent
cisplatin-based chemoradiotherapy. From preclinical studies and phase I
clinical data it can be concluded that oral administration of (±)-Gossypol and
AT-101 are well tolerated.
For this study oral administration of AT-101, concurrently with 3-weekly
cisplatin i.v. and radiation is proposed to allow optimal interaction. Two
schedules of AT-101 will be tested in parallel: First, daily administration of
AT-101 for two weeks, every 3 weeks will be tested in a dose-escalating
manner. Second, a pulse dose regimen of oral administration of AT-101 will be
given, consisting of 3 consecutive days of oral AT-101 BID, every 3 weeks. The
administration of cisplatin, concurrently with radiation is standard practice
in HNSCC.
Because there are no safety data on concurrent administration of AT-101 and
cisplatin-based chemoradiation in patients with advanced solid tumors, it is
necessary to evaluate tolerability and toxicity prior to initiation of phase
II-III studies. Toxicity profiles of AT-101, cisplatin and radiation do not
show substantial overlap, and therefore a combined approach is justified. In
order to be able to fully understand the pro-apoptotic properties of AT-101,
the first group of patients will be treated without AT-101, with concurrent
chemoradiation only. This will enable us to investigate changes in the
biomarkers from the translational research, relative to baseline values, i.e.
without the addition of AT-101. The starting dose of oral AT-101 at 10 mg/day
is based on previous experience within phase I studies and preclinical data.
Dosages will be subsequently increased in a dose-escalating manner.

Primary objective:

The main objective of this study is to assess the feasibility, tolerability and
the maximum tolerated dose (MTD) of oral AT-101 in combination with concurrent
cisplatin-based chemotherapy and radiotherapy (RT) in advanced HNSCC, as a
guidance for the recommended dose in future studies.

Secondary objectives:

Additional objectives include the exploration of mechanisms, involved in the
therapeutic effect of the different modalities in this combined modality
treatment, exploration of pharmacokinetics of AT-101, and documentation of
therapeutic effects.

This is a single center, uncontrolled phase I/II dose-escalation combination
study with a sequential group design using 2 parallel schedules of AT-101.
Treatment will consist of a fixed regimen of concurrent cisplatin-based
chemoradiation and dose-escalated AT-101. RT will be given to a total dose of
70 Gy in 35 fractions in an overall treatment time of 7 weeks. Cisplatin will
be given 3-weekly intravenously (i.v.), 100 mg/m2, 1-2 hour before RT, for a
total of 3 courses, with additional hydration. AT-101 will be according to two
parallel schedules as defined below.

1. In the first schedule, AT-101 will be given daily orally 4 hours before RT
in a dose escalating manner, for 2 weeks every 3 weeks on radiation-treatment
days only. Courses will begin on cisplatin dosing days (days 1, 22, and 43). A
run-in period of 1 week of AT-101 alone will used before chemoradiation is
started, without delaying the start of chemoradiation.

2. In the second, parallel schedule, pulse dose of AT-101 is given, using
higher doses of AT-101 on 3 consecutive days, every 3 weeks. In this schedule,
no run-in period with AT-101 alone is used.

Starting Dose of AT-101
The starting dose of AT-101 will be 0 mg po daily. This will represent the
population of 3 patients within the two parallel groups with baseline values
for the biomarker studies. There will be no delay in enrollment between this
dose level and the first dose levels that include AT-101.
In the daily administration group, the initial patients treated with AT-101
will receive a dose of 10 mg po daily. In the pulse dose group, the initial
patients treated with AT-101 will receive a dose of 20 mg BID for 3 days
orally. Enrollment into this group will proceed in parallel to enrollment into
the daily administration group.

Methods and Endpoints
The rate of subject entry and escalation to the next dose level will depend
upon assessment of the safety profile of patients entered at the previous dose
level. There will be no delay in enrollment between dose level 0 and subsequent
dose groups, as dose level 0 does not include the investigational product.
Toxicity will be evaluated according to the NCI Common Terminology Criteria for
Adverse Events (CTCAE), Version 3.0. A minimum of three patients will be
entered on each dose level. Decision on further escalation will be made no
sooner than 4 weeks after completion of a dose level and will be based on the
toxicity assessment in that first cycle and the documentation of any DLT (for
definitions see below). Patients will be enrolled separately in the two
parallel groups, i.e. when the required number of patients has been entered in
a dose level, the next eligible patient will be entered in the parallel study
using the above stated guidelines for subsequent enrolment and expansion into
the new cohort.

Extent of burden comprises:

- additional questions during routine follow up pertaining to toxicity
- additional blood sampling for pharmacokinetics: 14 vena punctures.
- 2 skin biopsies

There is a strong need for more effective therapeutic strategies for locally
advanced head and neck cancer. Given recent insights into mechanisms of
treatment resistance and the availability of novel targeted agenst, the testing
of new combined modality approaches is of pivotal importance. The toxicity
profile of the study medication is known and acceptable and does not overlap
with that of standard chemoradiotherapy, justifies the extra (minimal) burden
to the patients.