International Multicenter Phase I trial of Hydroxyurea in Combination with Dose-Intense Temozolomide in Recurrent Glioblastoma.

More than half of the 19,000 patients in the U.S. and the Netherlands diagnosed
with malignant primary brain tumors each year have glioblastoma (GBM), the most
common primary malignant brain tumor in adults. Glioblastoma is a uniformly
fatal disease with an average survival of less than one year, and even
aggressive treatment with surgery, radiation and/or chemotherapy fails to
extend the life span of patients by more than a few months. Primary treatment
for patients with GBM includes surgical resection. Temozolomide has been
approved for treatment of patients with GBM and is used both in recurrent GBM
as well as in combination with radiotherapy following surgery resulting in an
improvement of survival. However, improvements in median progression-free
survival (PFS) and overall survival (OS) were modest for newly diagnosed GBM
patients (6.9 and 14.6 months, respectively), and all patients ultimately fail.
Following recurrence, there is no identified therapy that has demonstrated
clinical benefit such as improved survival in these patients. Because the
prognosis for such patients is grave, many patients receive experimental
biotherapy or chemotherapy in the setting of clinical trials. However, in
large, pooled databases patients with recurrent GBM treated with various
experimental approaches, only 9-15% were alive and without disease progression
at 6 months. There remains a major unmet need for new treatment options in
glioblastoma.

Hydroxyurea has been previously evaluated in malignant gliomas in combination
with radiation or cytotoxic chemotherapy and has shown limited efficacy.
However, hydroxyurea was not evaluated with an agent with validated efficacy in
glioblastoma such as temozolomide. As a single agent, imatinib did not
demonstrate efficacy in phase II trials of recurrent GBM. However, more
recently, moderate improvements in progression-free survival compared to
historical controls have been observed in small series of recurrent
glioblastoma patients with the combination of daily hydroxyurea and imatinib, a
small molecule selective receptor tyrosine kinase inhibitor of the Bcr- Abl,
c-KIT, c-fms, and platelet-derived growth factor receptor (PDGFR) kinases.
Hydroxyurea penetrates the blood-brain barrier, and enhanced drug delivery
imatinib into the CNS was postulated as a possible reason for the efficacy seen
with this combination.

Dr. Tannous performed an in vitro drug screening to identify compounds that
would overcome resistance to temozolomide using standard glioblastoma cell
lines. In his studies, hydroxyurea potently sensitized temozolomide-resistant
GBM cells to rechallenge with temozolomide in vitro. GBM cells were cultured in
temozolomide until a resistant clone emerged. When combined with hydroxyurea,
temozolomide rechallenge resulted in potent cytotoxicity in vitro.

In addition, temozolomide resistant GBM cells were implanted orthotopically in
mouse brains, and the combination of temozolomide and hydroxyurea resulted in
significant improvement in animal survival. These data were then confirmed
using GBM cells obtained from patient tissue sections from newly diagnosed
tumors with methylated and unmethylated MGMT promoter as well as from recurrent
tumors.

In the animal survival studies, the combination of hydroxyurea and temozolomide
regimen was determined empirically, and the dose of each drug was based on
prior reports using each as a single agent. Hydroxyurea was dosed orally
50mg/kg 4 days/week and temozolomide was dosed 10mg/kg 4 days/week. This
combination was well tolerated with no apparent serious toxicity.

The combination dose regimen and schedule proposed in this study was generated
with the goal of recapitulating the combination regimen used in our animal
survival study which demonstrated efficacy of this combination against
temozolomide-resistant tumors. The dosing in the animal study was daily for 4
of 7 days. Among the various dose-intense temozolomide schedules, we selected
the continuous dose-intense temozolomide regimen (50 mg/m2/day) based on
reports of modest efficacy in recurrent GBM patients who had been previously
treated with different schedules of temozolomide and the relatively mild
myelosuppressive effect of this schedule. This schedule may allow for
concomitant daily dosing with hydroxyurea, which would closely recapitulate the
regimen in our animal studies.

This is a phase I study of hydroxyurea and dose-intense temozolomide in
patients with recurrent glioblastoma that are elegise for re-challenge
temozolomide.

Primary Objective: To determine the maximal tolerated dose and safety profile
of daily hydroxyurea in combination with dose-intense temozolomide (50
mg/m2/day) in patients with recurrent glioblastoma.

Secondary Objectives:
1. To estimate the preliminary median progression-free survival of patients
with recurrent glioblastoma treated with daily hydroxyurea in combination with
dose-intense temozolomide.
2. To estimate the preliminary radiographic response proportion in patients
with measurable disease.
3. To estimate the preliminary median overall survival.
4. Exploratory correlation of treatment outcomes (progression-free and overall
survival with MGMT promoter methylation status in archival tumor specimens.

All patients must have had histological confirmation of glioblastoma by either
biopsy or resection. Patients with progressive disease by standard imaging
criteria or by tissue biopsy will be eligible. Patients must not have had prior
anti-vascular endothelial growth factor (VEGF) therapy as this therapy
interferes with the interpretation of MRI-imaging. After registration, oral
hydroxyurea (dose specified by the Dose Cohort) and oral temozolomide (50
mg/m2/day) will be administered daily in 28-day cycles for 12 cycles or until
unacceptable toxicity, intolerance, progressive disease or withdrawal of
consent. Patients will be treated in dose cohorts of 3 with each cohort
receiving a specific daily dose assignment of hydroxyurea. All patients in the
study will receive temozolomide at 50 mg/m2/day (*dose-intense* schedule). The
dose levels will be increased in a conventional 3+3 design.
Hydroxyurea and temozolomide will be administered every 4 weeks, with 28
consecutive days defined as a treatment cycle. Treatment will be administered
on an outpatient basis. Oral hydroxyurea (dose specified by the Dose Cohort
below) and oral temozolomide (50 mg/m2/day) will be administered daily in
28-day cycles for 12 cycles or until unacceptable toxicity, intolerance,
progressive disease, or withdrawal of consent. Patients will be treated in dose
cohorts of 3 with each cohort receiving a specific daily dose assignment of
hydroxyurea.

All patients in the study will receive temozolomide at 50 mg/m2/day (*dose-
intense* schedule). The starting dose level for hydroxyurea will be 200 mg
daily (QD).

The dose will be escalated in cohorts of at least 3 patients according to the
escalation scheme starting at Dose Cohort 1. All three patients at each dose
level must be followed for at least 4 weeks before any new patients may be
entered at the next dose level. Escalation to the next dose level will occur if
no dose-limiting toxicity (DLT) is observed. If 1 of 3 patients develops DLT
during the first 4 weeks of treatment that Dose Cohort will be expanded by 3
additional patients at the same dose level. The 3 additional patients must be
followed for at least 4 weeks and toxicity must be evaluated before continuing
escalation. If no additional DLT are observed (i.e. 1/6 DLT total in the
expanded Dose Cohort) then 3 new patients may be entered at the next highest
dose level. However, if 1/3 patients experience DLT in this expanded cohort
(i.e. 2/6 DLT total in the expanded Dose Cohort) then this will be declared the
MTD. If 2/3 or 3/6 patients experience DLT at any dose level (above dose level
-1) then the next cohort of 3 patients will be treated at a dose one level
lower than the dose at which 2/3 DLT were observed. All of the above holds for
DLT attributed to hydroxyurea. The dose of hydroxyurea in combination with
temozolomide will not be escalated above 2000 mg QD, the maximum daily dose
when used in monotherapy for other malignancies such as resistant chronic
myelocytic leukemia. We anticipate enrollment of 15-30 patients in this study.

The MTD of hydroxyurea when used in combination with dose-intense temozolomide
identified in this study will be the recommended dose for future phase II
studies.

Hydroxyurea and temozolomide will be administered every 4 weeks, with 28
consecutive days defined as a treatment cycle. Treatment will be administered
on an outpatient basis. Oral hydroxyurea (dose specified by the Dose Cohort
below) and oral temozolomide (50 mg/m2/day) will be administered daily in
28-day cycles for 12 cycles or until unacceptable toxicity, intolerance,
progressive disease, or withdrawal of consent. Patients will be treated in dose
cohorts of 3 with each cohort receiving a specific daily dose assignment of
hydroxyurea.

All patients in the study will receive temozolomide at 50 mg/m2/day (*dose-
intense* schedule). The starting dose level for hydroxyurea will be 200 mg
daily (QD). The dose levels will be increased in a conventional 3+3 design as
follows:

Dose Escalation Schedule

Dose Cohort Hydroxyurea Dose Temozolomide Dose
-1 200 mg, every other day (QOD) 50 mg/m2/day
0 - Starting Dose 200 mg, daily (QD) 50 mg/m2/day
1 400 mg, QD 50 mg/m2/day
2 600 mg, QD 50 mg/m2/day
3 800 mg, QD 50 mg/m2/day
4 1000 mg, QD 50 mg/m2/day
5 1200 mg, QD 50 mg/m2/day
6 1500 mg, QD 50 mg/m2/day
7 1700 mg, QD 50 mg/m2/day
8 2000 mg, QD 50 mg/m2/day

The dose will be escalated in cohorts of at least 3 patients according to the
escalation scheme above starting at Dose Cohort 1. All three patients at each
dose level must be followed for at least 8 weeks before any new patients may be
entered at the next dose level. Escalation to the next dose level will occur if
no dose-limiting toxicity (DLT) is observed (see Section 5.4 for definition of
dose-limiting toxicity). If 1 of 3 patients develops DLT during the first 8
weeks of treatment that Dose Cohort will be expanded by 3 additional patients
at the same dose level. The 3 additional patients must be followed for at least
8 weeks and toxicity must be evaluated before continuing escalation. If no
additional DLT are observed (i.e. 1/6 DLT total in the expanded Dose Cohort)
then 3 new patients may be entered at the next highest dose level. However, if
1/3 patients experience DLT in this expanded cohort (i.e. 2/6 DLT total in the
expanded Dose Cohort) then this will be declared the MTD. If 2/3 or 3/6
patients experience DLT at any dose level (above dose level -1) then the next
cohort of 3 patients will be treated at a dose one level lower than the dose at
which 2/3 DLT were observed. All of the above holds for DLT attributed to
hydroxyurea. The dose of hydroxyurea in combination with temozolomide will not
be escalated above 2000 mg QD, the maximum daily dose when used in monotherapy
for other malignancies such as resistant chronic myelocytic leukemia.

We anticipate enrollment of 15-30 patients in this study.

The MTD of hydroxyurea when used in combination with dose-intense temozolomide
identified in this study will be the recommended dose for future phase II
studies.

The patient will be requested to maintain a medication diary of each dose of
medication. The medication diary will be returned to clinic staff at the end
of each course.

Duration of therapy will depend on individual response, evidence of disease
progression and tolerance. In the absence of treatment delays due to adverse
event(s), treatment may continue for 12 cycles or until one of the following
criteria applies:

• Disease progression

• Intercurrent illness that prevents further administration of treatment

• Unacceptable adverse event(s)

• Participant demonstrates an inability or unwillingness to comply with the
oral medication regimen and/or documentation requirements

• Participant decides to withdraw from the study

• General or specific changes in the participant's condition render the
participant unacceptable for further treatment in the judgment of the treating
investigator

Duration of Follow Up

Following discontinuation of treatment, participants will be followed for two
years for survival and for progression or until death, whichever occurs first.
Follow-up data will be collected as feasible either by follow-up visits, or
telephone contact to the subject*s outside physician monthly for the first 2
months and then every 2 months to assess tumor status. Participants removed
from study for unacceptable adverse event(s) will be followed until resolution
or stabilization of the adverse event.

For participants who continue to be followed by the Investigator and who have
no evidence of progression at the time of treatment discontinuation, repeat
tumor assessments approximately every 8 weeks is suggested in the appropriate
setting.

For participants who are followed by providers other than the Investigator,
follow-up for survival is suggested by telephone contact or other means to
obtain timely regular follow-up data. Follow-up should be monthly for the first
2 months and then every 2 months thereafter.

Participants will be removed from the study when any of the criteria listed in
Section 5.6 applies. The reason for study removal and the date the participant
was removed must be documented in the case report form (CRF). Alternative care
options will be discussed with the participant.

A QACT Treatment Ended/Off Study Form should be filled out when a participant
completes study treatment and again when the participant comes off study. This
form can be found on the QACT website or obtained from the QACT registration
staff.


DOSING DELAYS/DOSE MODIFICATIONS

ANC, platelet count, total white blood cell count, and hemoglobin must be grade
1 or greater prior to the start of each cycle.

In the event of Grade 3 or 4 hematological toxicity (neutropenia,
thrombocytopenia, or anemia), both temozolomide and hydroxyurea must be held
until these counts recover to at least Grade 1. Study drugs may be held for up
to 28 days. Once counts have recovered sufficiently to restart therapy, the
dose of hydroxyurea should be decreased 2 dose levels (see Hydroxyurea Dose
Levels above and Hydroxyurea Dose Reduction Table below for guidance) and the
dose of temozolomide should be continued at the prior dose.

If after 2 successive dose reductions of hydroxyurea the Hydroxyurea Dose
Reduction Table below specifies discontinuation of therapy, then the patient
will be taken off of study for unacceptable toxicity.

If after 2 successive dose reductions of hydroxyurea the participant is
eligible for a 3rd hydroxyurea dose reduction based on the Hydroxyurea Dose
Reduction Table below, the patient will also reduce one Dose Level of
temozolomide.

If the participant requires discontinuation of temozolomide (reached
Temozolomide Dose Level -2), the participant will be taken off study for
unacceptable toxicity.

Dose delays and modifications:

Dose Level Hydroxyurea Dose
-2 Discontinue
-1 200 mg, every other day (QOD)
0 200 mg, daily (QD)
+1 400 mg QD
+2 600 mg QD
+3 800 mg, QD
+4 1000 mg, QD
+5 1200 mg, QD
+6 1500 mg, QD
+7 1700 mg, QD
+8 2000 mg, QD


Dose Level Temozolomide Dose
-2 Discontinue
-1 25 mg/m2/day
0 50 mg/m2/day

Not applicable