Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma
I. To assess the safety and tolerability of AMG 386 (trebananib) 15 mg/kg weekly in
combination with bevacizumab 10 mg/kg every 2 weeks (Cohort 1). (closed to accrual 10/2/12)
II. To assess the efficacy of AMG 386 in combination with bevacizumab 10 mg/kg every 2 weeks
compared to bevacizumab monotherapy in bevacizumab-naïve patients, as measured by 6-month
progression-free survival (PFS6) (Cohort 2).
I. To further assess the toxicity profile (Cohorts 1 and 2). II. To assess feasibility of
AMG 386 15 mg/kg weekly in combination with bevacizumab 10 mg/kg every 2 weeks (Cohort 1
[closed to accrual 10/2/12]), as measured by the percentage of patients requiring dose
reduction/interruption or discontinuation in the first 2 and subsequent cycles.
III. To determine the radiographic response rate (RR), median progression-free survival
(PFS), and overall survival (OS) in bevacizumab-naïve patients (Cohort 2).
IV. To assess the efficacy of AMG 386 15 mg/kg weekly in combination with bevacizumab 10
mg/kg every 2 weeks in patients who have progressed while on bevacizumab, as measured by
overall survival (OS) (cross-over from placebo arm of Cohort 2).
V. To correlate outcome to treatment with tumor genotype, expression profile, and
circulating angiogenesis biomarkers in tumor specimens (Cohort 2).
VI. To determine the RR, PFS6, and PFS in patients who have progressed while on bevacizumab
therapy and receive AMG 386 in combination with bevacizumab (cross-over from placebo arm of
VII. To determine the serum pharmacokinetics of AMG 386 in patients receiving bevacizumab
(Cohort 1 and cross-over from placebo arm of Cohort 2).
OUTLINE: This is a safety study (cohort 1 [closed to accrual 10/2/12]) followed by a
randomized study (cohort 2).
Cohort 1: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and
15 and trebananib IV over 30-60 minutes on days 1, 8, 15, and 22. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity. (closed to accrual
Cohort 2: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive bevacizumab and trebananib as in Cohort 1.
ARM II: Patients receive bevacizumab as in Arm I and placebo IV over 30-60 minutes on days
1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity. Patients with disease progression may cross over to Arm I.
After completion of study treatment, patients are followed up at 30 days, every 2 months for
1 year, every 6 months for 1 year, and then annually thereafter.
An Open-Label, Phase 1/2A Dose Escalation Study of Safety and Efficacy of NEO100 in Recurrent Grade IV Glioma
Perillyl alcohol has previously been tested in 15 clinical studies in > 600 subjects This
includes 13 studies in 255 subjects using oral administration sponsored by the National
Cancer Institute and two studies in > 350 subjects using intranasal administration in Brazil.
NEO100 is a highly purified (>99%) form of perillyl alcohol. Studies in Brazil suggest
improved survival for patients with recurrent glioblastoma. Doses of 96 mg qid, 144mg qid,
192mg qid, and 288 mg qid administered intranasally to patients with recurrent GBM for up to
6 months, disease progression or death. From 3 to 6 patients will be evaluated after first
cycle (28 days) until MTD is reached. MRI with gadolinium will be at base line, and at the
beginning of even cycles. A total of 25 patients will be treated at the MTD. PK studies will
be conducted during Phase 1 at first dosing, and after first dose of 3rd cycle.
A Phase II Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma
This Phase II study will enroll patients into three groups. Group 1 are patients who have
never been treated with bevacizumab. These patients will be randomly assigned to receive
either rindopepimut/GM-CSF or KLH, each along with bevacizumab. Treatment assignment for
Group 1 will be blinded. Group 2 and Group 2C patients are those who are refractory to
bevacizumab (experienced recurrence or progression of glioblastoma while on bevacizumab or
within 2 months of discontinuing bevacizumab). These patients will all receive
rindopepimut/GM-CSF along with bevacizumab. Patients will be treated until disease
progression or intolerance and all patients will be followed for survival. Patients may be
treated with other therapies that are not part of the study after discontinuing treatment
with the study vaccine.
A Phase II/III Randomized Trial of Veliparib or Placebo in Combination With Adjuvant Temozolomide in Newly Diagnosed Glioblastoma With MGMT Promoter Hypermethylation
I. Test whether the experimental combination of ABT-888 (veliparib) combined with TMZ
(temozolomide), compared to the control of placebo combined with TMZ, significantly extends
overall survival in newly diagnosed glioblastoma multiforme (GBM) patients with tumor MGMT
I. Test whether the experimental treatment significantly extends progression-free survival.
II. Test whether the experimental treatment improves objective tumor response. III. Test
whether the experimental treatment is associated with significantly greater rates of grade 3
or higher adverse events.
I. Evaluate the utility of dynamic susceptibility contrast (DSC) and diffusion weighted
imaging (DWI) magnetic resonance imaging (MRI) techniques in defining time to progression in
the setting of a large multi-institutional clinical trial.
II. Test the concordance between site-determined MGMT methylation status and central
laboratory determination of MGMT status in cases with local testing.
III. Evaluate whether genetic or epigenetic alterations in deoxyribonucleic acid (DNA) repair
or replication genes are associated with overall survival, progression-free survival, and
objective tumor response.
IV. Test whether polymorphisms in MGMT, PARP1, or other DNA repair proteins, are associated
with overall survival, progression-free survival, objective tumor response, or rates of grade
3 or higher adverse events.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5 and veliparib PO
twice daily (BID) on days 1-7. Treatment repeats every 28 days for 6 courses in the absence
of disease progression (confirmed progression) or unacceptable toxicity.
ARM II: Patients receive temozolomide as in Arm I and placebo PO BID on days 1-7. Treatment
repeats every 28 days for 6 courses in the absence of disease progression (confirmed
progression) or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 3 years,
every 6 months for 2 years.
A Phase 3 Randomized Double-blind, Controlled Study of ICT-107 With Maintenance Temozolomide (TMZ) in Newly Diagnosed Glioblastoma Following Resection and Concomitant TMZ Chemoradiotherapy
This is a double blind Phase III study where eligible subjects are randomized into two
treatment arms following the SOC primary treatment with chemoradiation: Arm 1 will receive
ICT-107 in combination with the standard of care, temozolomide (TMZ), Arm 2 will receive TMZ
with a blinded control. A 1:1 randomization will be employed, where ARM 1 will receive
ICT-107 and Arm 2 will receive placebo control. All subjects must be HLA-A2+. All subjects
must have glioblastoma tissue that has tumor assessment for MGMT methylation status prior to
randomization (for stratification). Subjects will have had tumor resection and magnetic
resonance imaging (MRI) prior to enrollment into the study. After signing of written informed
consent and any required privacy compliance forms and screening, enrolled subjects will
undergo large volume apheresis at the study site for collection of PBMCs. Apheresis product
will be sent to the manufacturing site where both active therapy (ICT-107) and control will
be prepared for each subject prior to randomization The study period consists of 4 time
periods; a 6-week Post-Surgery Standard of Care Treatment Phase where subjects receive
radiotherapy and TMZ; TMZ and radiation to be initiated no more than 8 weeks after surgical
resection of glioblastoma; a Rest Period of no more than 14 days where subjects are
reassessed for eligibility, and then randomized; a 4 week Induction Phase where study therapy
(ICT-107 or Control) is given weekly; followed by a Maintenance Phase where study therapy is
given monthly for 11 months, and then every 6 months until either progression, withdrawal
from the study, death, or the supply of autologous study therapy is exhausted. Randomized
subjects will receive 4 weekly administrations of subject-specific study therapy (ICT-107 or
Control) during the Induction Phase. No TMZ will be given during the 4 week Induction Phase.
Each study therapy injection will be delivered intradermally (axilla).
The Maintenance Phase will consist of administration of subject-specific study therapy
monthly for 11 months after the Induction Phase (for a total of 15 injections over 12 months
during the Induction and Maintenance Phases), and then every 6 mos. thereafter until
depletion or confirmation of progressive disease (PD). During the Maintenance Phase (where
ICT-107 or control are given monthly), the administration of TMZ and subject specific study
therapy or control will be separated in time by approximately 2 weeks (see Section 9.1.4).
Pre-treatment, treatment and assessment schedules will be the same for all subjects.
A Prospective, Non-randomized, Concurrent Control, Open Label, Post-approval Study of NovoTTF-100A in Recurrent GBM Patient
PAST CLINICAL EXPERIENCE:
The effect of the electric fields generated by the NovoTTF-100A device (TTFields, TTF) has
been tested in a large prospective, randomized trial, in 237 recurrent GBM patients. The
outcome of subjects treated with the NovoTTF-100A device was compared to those treated with
an effective best standard of care chemotherapy (including bevacizumab). NovoTTF-100A
subjects had comparable overall survival to subjects receiving the best available
chemotherapy in the US today. Similar results showing comparability of NovoTTF-100A to BSC
chemotherapy were seen in all secondary endpoints.
Recurrent GBM patients treated with the NovoTTF-100A device in this trial experienced fewer
side effects in general, significantly fewer treatment related side effects, and
significantly lower gastrointestinal, hematological and infectious adverse events compared to
controls. The only device-related adverse events seen were a mild to moderate skin irritation
beneath the device electrodes. Finally, quality of life measures were better in NovoTTF-100A
subjects as a group when compared to subjects receiving effective best standard of care
DESCRIPTION OF THE TRIAL:
Patients with GBM whose disease has first recurred despite standard treatment (Surgery,
radiation therapy, Temozolomide treatment) and meet all of the requirements for participation
in the study will be recruited to one of two groups based on patient preference alone:
1. Treatment with the NovoTTF-100A device, or
2. Treatment with the best standard of care practiced at each of the participating centers.
If recruited to the best standard of care group, patients will receive a chemotherapeutic
agent chosen based on their prior treatments and the standard of care practiced at each
If recruited to the NovoTTF-100A group, the patients will be treated continuously until tumor
progression. NovoTTF-100A treatment will consist of wearing four electrically insulated
electrodes on the head. Electrode placement will require shaving of the scalp before
treatment. Patients will continue treatment at home where they can maintain their regular
During the trial, regardless of whether assigned to the NovoTTF-100A treatment group or the
best standard of care group, patients will need to return once every month the hospital
outpatient clinics where they will be examined by a physician. These routine visits will
continue for as long as the patient's disease is not progressing.
During the visits to the clinic patients will be examined physically and neurologically, as
well as fill in neuro-cognitive questionnaires. Adverse events data will be collected from
all patients.. After this follow up plan, patients will be contacted once per month by
telephone to answer basic questions about their health status.
TTFields are alternating electric fields of low intensity. This means that they change their
direction repetitively many times a second. Since they change direction very rapidly (200
thousand times a second), they do not cause muscles to twitch, nor do they have any effects
on other electrically activated tissues in the body (brain, nerves and heart). Since the
intensities of TTFields in the body are very low, they do not cause heating.
The breakthrough finding made by NovoCure was that finely tuned alternating fields of very
low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in
the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are
multiplying, TTFields cause the building blocks of these cells to move and pile up in such a
way that the cells physically explode. In addition, cancer cells also contain miniature
building blocks which act as tiny motors in moving essential parts of the cells from place to
place. TTFields cause these tiny motors to fall apart since they have a special type of
As a result of these two effects, cancer tumor growth is slowed and can even reverse after
continuous exposure to TTFields.
Other cells in the body (normal healthy tissues) are affected much less than cancer cells
since they multiply at a much slower rate if at all. In addition TTFields can be directed to
a certain part of the body, leaving sensitive areas out of their reach.
In conclusion, TTField hold the promise of serving as a brand new cancer treatment with very
few side effects and promising affectivity in slowing or reversing this disease.