Inclusion Criteria:
- - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 70%)
within a 14-day window prior to randomization.
- - Patients must have histologically confirmed glioblastoma (or gliosarcoma) at first
or second recurrence after initial standard, control or experimental, therapy that
includes at least radiation therapy (RT) and temozolomide (TMZ)
- Evidence of progressive disease (PD) by modified response assessment in
neuro-oncology criteria (using the post-chemoradiation time point as baseline),
defined by any of the following:
- >= 25% increase in sum of products of perpendicular diameters of measurable
enhancing lesions, compared with the smallest tumor measurement obtained either
at the post-chemoradiation baseline (if no decrease) or best response (on
stable or increasing steroid dose).
- - Any new measurable (> 1 x 1 cm) enhancing lesions after the post-chemoradiation
scan.
- - A total of at least 2 serial magnetic resonance imaging (MRI) scans documented at
Screening including: 1) a scan at the time of suspected tumor progression; and 2) a
scan prior to the time of progression.
Patients must have progressed after standard
of care treatment (it typically includes surgery, radiation and temozolomide).
Pseudoprogression or radiation necrosis has been ruled out.
- - Hemoglobin >= 9.0 g/dl (no transfusions allowed within 7 days of cycle 1 day 1 to
meet entry criteria) (within 14 days of starting treatment)
- Absolute neutrophil count (ANC) >= 1,500/mcL (after at least 7 days without growth
factor support or transfusion) (within 14 days of starting treatment)
- Platelets >= 100,000/mcL (no transfusions allowed within 7 days of cycle 1 day 1 to
meet entry criteria) (within 14 days of starting treatment)
- International normalized ratio (INR) =< 1.5 (within 14 days of starting treatment)
- Partial thromboplastin time (PTT) < 1.5 x upper limits of normal (ULN) (within 14
days of starting treatment)
- Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) (within
14 days of starting treatment)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.0 times the ULN
(within 14 days of starting treatment)
- High amylase or lipase above upper normal limit (UNL) (within 14 days of starting
treatment)
- Serum creatinine =< 1.5 x ULN or creatinine clearance >= 60 mL/min/1.73 m^2 for
patients with creatinine levels > 1.5 x ULN.
Creatinine clearance should be
calculated per institutional standard (within 14 days of starting treatment)
- - Electrocardiogram corrected QT interval by Fridericia's formula (QTcF) < 450 ms
(within 14 days of starting treatment)
- Clinically significant toxic effect(s) of the most recent prior anti-cancer therapy
must be grade 1 or resolved (except alopecia)
- A minimum time of 28 days elapsed from the administration of any prior cytotoxic
agents.
- - Have undergone recent surgery for recurrent or progressive brain tumor are eligible
provided that:
- Prior to surgery there was imaging evidence of measurable progressive disease
(PD) as described above.
- - Craniotomy or intracranial biopsy site must be adequately healed and free of
drainage or cellulitis, and the underlying cranioplasty must appear intact at
the time of randomization.
- - Initiation of study treatment is at least 14 days from prior surgery/biopsy.
- - Availability of tumor tissue representative of glioblastoma (GBM) from initial
definitive surgery and/or, recurrent surgery, if performed.
- - Female of child-bearing potential (FCBP) must have a negative serum or urine
pregnancy test prior to starting therapy.
- - FCBP and men must agree to use adequate contraception (hormonal or barrier method of
birth control; abstinence) prior to study entry and for the duration of study
participation.
Should a woman become pregnant or suspect she is pregnant while she
or her partner is participating in this study, she should inform her treating
physician immediately. Men treated or enrolled on this protocol must also agree to
use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of study administration. A female of
childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal
for at least 24 consecutive months (i.e., has had menses at any time in the
preceding 24 consecutive months)
- - Willingness and ability of the subject to comply with scheduled visits, drug
administration plan, protocol-specified laboratory tests, other study procedures,
and study restrictions.
Evidence of a personally signed informed consent indicating
that the subject is aware of the neoplastic nature of the disease and has been
informed of the procedures to be followed, the experimental nature of the therapy,
alternatives, potential risks and discomforts, potential benefits, and other
pertinent aspects of study participation.
Exclusion Criteria:
- - Patients who received temozolomide within 28 days prior to starting first cycle
under this study.
- - Optune device is not allowed.
- - Patients who received prior lomustine, carmustine wafers, bevacizumab or any other
anti-angiogenic agent.
- - Dexamethasone at time of study entry is not allowed.
After a stable dose of
methimazole and T3 is reached, dexamethasone can be used with a dose determined by
treating physician.
- - Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance
with study requirements.
- - Computed tomography (CT) scan with contrast within 6 weeks from enrollment as it may
influence thyroid tests due to the iodine content.
- - History of cardiac arrhythmias (in particular, sinus bradycardia, atrial
fibrillation or flutter, atrioventricular [AV] block, prolonged QTc, ventricular
arrythmias, pacemaker, or implantable cardiac defibrillator).
). Significant
cardiovascular disease (eg, myocardial infarction, arterial thromboembolism,
cerebrovascular thromboembolism) within 6 months prior to start of study therapy;
angina requiring therapy; symptomatic peripheral vascular disease; left ventricular
ejection fraction less than or equal to 35%;New York Heart Association class 3 or 4
congestive heart failure; or uncontrolled grade >= 3 hypertension (diastolic blood
pressure >= 100 mmHg or systolic blood pressure >= 160 mmHg) despite
antihypertensive therapy, or use of amiodarone within the last 6 months.
- - Uncontrolled type 2 diabetes mellitus (T2DM) (HbA1C greater than 8%) or a history of
frequent hypoglycemia, or significantly uncontrolled hyperglycemia.
- - Pregnant women are excluded from this study because of the potential for teratogenic
or abortifacient effects of the study drugs.
Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with study drugs breastfeeding should be discontinued if the mother will be
on treatment.
- - Early disease progression prior to 3 months (12 weeks) from the completion of
RT-TMZ, unless histologically proven to be recurrent GBM.
- - Had more than 2 prior lines for chemotherapy administration.
NOTE: In the 1st line
adjuvant setting, combination of TMZ with an experimental agent, is considered one
line of chemotherapy.
- - Any prior treatment with an intracerebral agent.
- - Receiving additional, concurrent, active therapy for GBM outside of the trial.
- - Extensive leptomeningeal disease and defined by the principal investigator (PI)
- History of allergy or hypersensitivity to any of the study treatments or any of
their excipient.
- - Unable or unwilling to undergo brain MRI scans with gadolinium.
- - History of another malignancy in the previous 2 years, with a disease-free interval
of < 2 years.
Participant with prior history of in situ cancer or basal or squamous
cell skin cancer are eligible.
- - Serious, non-healing wound, ulcer, bone fracture, or abscess.
- - Any cerebrovascular accident (including transient ischemic attacks) within the last
6 months prior to initiation of study treatment.
- - Any hemorrhage or bleeding event that is >= grade 3 based on National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), grade 2
intracranial hemorrhage, or persistent thrombotic/embolic event within 4 weeks prior
to the start of study medication.
- - History of interstitial lung disease, history of slowly progressive dyspnea and
unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary
hypersensitivity pneumonitis, or symptomatic pleural effusion.
- - Active, known or systemic suspected autoimmune disease, including systemic lupus
erythematosus, scleroderma, polyarteritis nodose, or auto-immune hepatitis.
- - Known history of hepatitis B, human immunodeficiency virus (HIV), or active
hepatitis C infection requiring treatment with antiviral therapy.
- - History of bleeding diathesis (irrespective of severity)
- History of agranulocytosis.
- - History of pancreatitis.
- - Uncontrolled psychiatric illness or any condition that could make the subject
noncompliant with the study procedures and/or study requirements.
- Participant has not been on a stable dose of anticoagulants for at least 2 weeks
before randomization
