The primary objective of this study is to demonstrate superiority in overall survival (OS) and comparable safety when eflornithineis added to lomustine compared to lomustine alone in patients with anaplastic astrocytoma (AA) that progress/recur…
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Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy: The primary efficacy endpoint is the duration of OS as measured from
the date of randomization to the date of death due to any cause.
Safety:Adverse events, vital signs and clinical laboratory tests
Pharmacokinetics (PK): Plasma drug concentrations will be analyzed to evaluate
PK of eflornithine in a subset of patients (n=approximately 20) on
Treatment Arm A only
The primary efficacy analysis will be performed in accordance with the
intention-to-treat (ITT) principle. All randomized patients will be included in
the primary efficacy analysis according to their randomly assigned study
treatment, irrespective of the actual receipt of such treatment.
OS and PFS will be summarized descriptively using the Kaplan-Meier method. For
both endpoints, the primary inferential comparison between treatment arms will
be performed using the log-rank test stratified by the randomization
stratification factors for age, region, IDH-1 status, and number of prior
surgeries.
Estimation of the hazard ratio (HR) for treatment arm will be determined using
a stratified Cox proportional hazards model, without any other covariate. For
PFS, disease progression will be assessed using criteria described in Appendix
5. The disease progression date and censoring date for PFS will be based on
published conventions (FDA 2007). Sensitivity analyses will be performed to
identify asymmetry between treatment arms for the frequency of missed disease
assessments, deviations of the actual disease assessment times from the planned
assessment times, and
alternative censoring conventions.
ORR will be estimated based on the proportion of patients in each treatment arm
whose best overall response during the course of study treatment is CR or PR.
Tumor response will be assessed using criteria described in Appendix 5.
Approximate 95% confidence intervals will be calculated by treatment arm for
the true ORR. The inferential comparison of the observed ORRs will be made
using the Cochran-Mantel-Haenszel chi-square test, stratified by the
aforementioned randomization stratification factors.
The overall type I error rate for the study is set at 0.05 (two-sided). With
the exception of OS, all hypothesis testing will be assessed using a two-sided
significance level of 0.05. The O*Brien-Fleming group sequential procedure will
be used to control the overall type I error for multiple testing of OS (see
below). If superiority of OS is demonstrated at either the interim or primary
analysis, formal inferential comparisons between treatment arms are planned for
the secondary endpoints PFS and ORR. The tests will be performed in a
sequential hierarchical manner based on a
closed testing procedure (CTP). The CTP will be employed to maintain control of
the overall type I error rate to account for hypothesis testing of multiple
secondary endpoints. The sequential hierarchical order in which the secondary
efficacy endpoints will be tested is described in Section 8.6.1.
The sample size was calculated by assuming true median OS of 12 months for the
treatment arm receiving lomustine monotherapy (control arm). It is hypothesized
true median OS will be 18 months or longer for the treatment arm receiving
eflornithine plus lomustine (investigational arm). Under the assumption that OS
follows an exponential probability distribution for each treatment arm, such an
improvement represents a true hazard ratio
of 0.667 (investigational arm/control arm). Inferential comparisons of OS will
be performed using a stratified log-rank test, stratifying on the randomization
stratification factors. Total accrual of approximately 340 patients (170 per
treatment arm) and total information of 261 deaths is estimated to provide 90%
power to detect a 33% reduction in the OS failure hazard rate, based on a
two-sided overall type I error of 5% with adjustment for one interim analysis
for superiority at 67% of total deaths (SEQDESIGN procedure, SAS version 9.2).
The primary analysis
for the OS comparison is expected to occur approximately 36 months (18 months
of accrual plus 18 months of follow-up) after the first patient is randomized.
It is projected that an observed hazard ratio of 0.78 or less, which
corresponds to a 3.44 month or greater observed improvement in median OS (12
vs. 15.4 months), would result in a statistically significant improvement for
the primary analysis of OS in favor of the arm receiving the investigational
treatment.
One formal interim analysis of OS for futility is planned after 130 deaths (50%
of total deaths) have been observed, which is projected to occur approximately
18 months after the date the first patient is randomized. The objective of the
futility analysis is to terminate the study early if there is evidence the
investigational treatment is not offering an improvement over the control
treatment. Based on a nonbinding version of the futility stopping rule
originally described by Ellenberg and Eisenberger, the study may be terminated
early if the estimated hazard ratio for treatment
(investigational arm/control arm) is greater than or equal to one. Such a
futility stopping rule, when based on 50% of the planned events, results in
loss of power of no more than 2-3%.
One formal interim analysis of OS for superiority is planned after 174 deaths
(67% of total deaths) have been observed, which is projected to occur
approximately 24 months after the date the first patient is randomized. This
formal comparison of OS will allow for early stopping for superiority. The
boundary for declaring superiority will be derived based on the actual number
of deaths using the Lan-DeMets alpha spending function with an O*Brien-Fleming
type boundary.
An independent data monitoring committee (IDMC) will review the results of the
interim efficacy analyses. Additionally, the IDMC will review safety data on a
periodic basis, but not less frequently than approximately every 6 months.
Unplanned safety review meetings of the IDMC may be called at any time. The
first safety review meeting will be held after the first 20 patients are
randomized (approximately 10 per treatment arm) and have
completed at least 4 weeks of follow-up after the initiation of study treatment
or terminated therapy at an earlier time point due to toxicity. The second
safety review meeting will be held after an additional 20 patients are
randomized (approximately 10 additional patients per treatment arm; providing a
cumulative 40 patients) and have completed at least 4 weeks of follow-up after
the initiation of study treatment or terminated therapy at an earlier time
point due to toxicity. The third safety review meeting will be held after an
additional 20 patients are randomized (approximately
10 additional patients per treatment arm; providing a cumulative 60 patients)
and have completed at least 4 weeks of follow-up after the initiation of study
treatment or terminated therapy at an earlier time point due to toxicity.
Enrollment may continue while the IDMC conducts their initial review unless
otherwise recommended by the IDMC. The IDMC*s assessment for this and
subsequent safety reviews will focus on deaths (due to any cause), treatment
modifications, treatment discontinuations, and serious adverse events. The
safety monitoring plan will also provide for
prompt notification of the IDMC and/or study accrual to be temporarily
suspended to allow for full review of the safety data by the IDMC under certain
conditions (see Section 8.4.1). The IDMC chair will be notified promptly after
each Grade 4 treatment-related adverse event is reported and within 48 hours of
the occurrence of any treatment-related death. In the event of a
treatment-related death, study accrual will be temporarily
suspended to allow for full review of the safety data by the IDMC. Depending on
the outcome of the review, the IDMC may recommend continuation, termination, or
modification of the stu
Secondary outcome
The secondary efficacy endpoints are PFS, ORR, OS for the IDH-1 mutant patients
and OS for the IDH-1 wild type patients
Background summary
The purpose of this study is to measure how well and how safe eflornithine is
in combination with lomustine, compared to lomustine taken alone, in treating
patients whose anaplastic astrocytoma has come back after radiation and
chemotherapy. Safety and how well you can tolerate the drug will be determined
on the basis of physical exams, laboratory tests, and questions about any
problems you might experience during the study.
Anaplastic astrocytoma (AA) is a World Health Organization (WHO) grade 3
primary glioma tumor with an incidence of at least 0.4/100,000 patient-years
and about 5,600 newly diagnosed patients in the U.S. yearly, based on the 2006-
2010 data. Most WHO grade 3 tumors respond to cytotoxic chemotherapy to a
variable extent. These tumors infiltrate (invade) adjacent brain. Since
chemotherapy agents vary in their ability to
cross normal cerebral vasculature (blood-brain-barrier) as well as tumor
capillary beds (blood-tumor barrier), many drugs tested over the years have
failed to produce meaningful antitumor efficacy, because they were unable to
reach invading tumor cells in sufficient dose and for sufficient time. All
alkylating agents considered to be *active* against high-grade gliomas have
demonstrated an ability to traverse the normal brain vasculature as well as
tumor capillary beds to achieve therapeutic levels in and surrounding
infiltrating tumor cells. These active agents are the lipophilic drugs BCNU
(carmustine), CCNU (lomustine), procarbazine (Matulane®), and temozolomide
(Temodar®).
Over the past several decades, there has been much progress in the treatment of
AA, with the median survival time in the 1980s being 13 to 19 months in
patients treated with surgery and irradiation. Nonetheless, curative treatments
with reduced regional and systemic toxicity are still very much needed for AA
tumors, given the high rate of transformation of AA tumors into glioblastoma
multiforme (GBM) if they are not cured while phenotypically AA. A Phase 3
randomized study of post-radiotherapy adjuvant chemotherapy with the
combination therapy of procarbazine, lomustine, and vincristine (PCV) in 228
evaluable patients with anaplastic glioma (AG) showed that addition of
eflornithine improved overall
survival (OS) from a median of 61.1 months to 75.8 months from randomization.
Study objective
The primary objective of this study is to demonstrate superiority in overall
survival (OS) and comparable safety when eflornithine
is added to lomustine compared to lomustine alone in patients with anaplastic
astrocytoma (AA) that progress/recur after irradiation and adjuvant
temozolomide chemotherapy.
The secondary objectives of this study are to determine:
• Progression-free survival (PFS)
• The objective response rate (ORR)
• OS for IDH-1 mutant patients
• OS for the IDH-1 wild type patients
The exploratory objectives of this study are to determine:
• Clinical benefit response (CBR) based on magnetic resonance imaging (MRI)
criteria
• OS rate at 18 months (OS-18)
• Relevance of OS, PFS, ORR, and CBR to commonly used molecular/genetic
biomarkers obtained from most recent prestudy tumor samples (i.e., p53
mutation, deletion of chromosomes 1p and 19q, IDH1 mutations, ATRX mutation,
Mib-1 labeling index, MGMT promoter methylation)
• Steady-state plasma pharmacokinetics (PK) for eflornithine in patients within
2 weeks of initial dosing
Study design
This is a randomized, open-label, multicenter, active-controlled study to
evaluate the efficacy and safety of eflornithine with lomustine compared to
lomustine alone in patients with AA that progress/recur after irradiation and
adjuvant temozolomide chemotherapy.
Patients who provide written consent and meet all eligibility criteria will be
randomized in a 1:1 ratio to one of the following two treatment arms:
Treatment Arm A: Eflornithine administered on a 2 week on,1 week off schedule +
Lomustine administered every 6 weeks (n=170)
Treatment Arm B: Lomustine administered every 6 weeks (n=170)
Note: Refer to Section 3.2 of the protocol for additional dosing information.
Randomization will be stratified by:
• Age <= 45 years or > 45 years at study randomization
• Region (US vs Ex-US) at study randomization
• IDH-1 status (wild type vs mutant) at study randomization
• Number of prior surgeries (biopsy only vs (1 or 2 surgical resections [e.g.,
surgical resection at primary diagnosis and secondary surgical resection after
first progression/recurrence])) at study randomization
Intervention
Eflornithine 2.8 g/m2 administered orally every 8 hours on a 2 week on, 1 week
off schedule, without regard to food
Lomustine 90 or 110 mg/m2 administered orally once every 6 weeks, without
regard to food
Study burden and risks
Eflornithine
The possible discomforts, side effects and risks related to eflornithine
treatment are not all known. Most side effects are not serious. Some may be
serious and may require treatment or additional testing. This section
describes how frequently side effects occurred in patients who have been
treated with eflornithine.
Very common (more than or equal to 10%):
• changes in white blood cell counts
• diarrhea
Common (>= 1% and < 10%):
• changes in red blood cell count
• changes in platelets (blood cells that help blood clot)
• hearing loss or other problems related to ears
• nausea/vomiting
• flatulence (gas)
• feeling general discomfort
• feeling tired
• headache
• dizziness
• seizure or convulsion
• skin rash
• appearance of protein in urine
• alter or change of sense of taste
Lomustine
The following adverse reactions to treatment with lomustine have been
identified:
Very common (more than or equal to 10%):
• changes in your white blood cell count
• changes in your red blood cell count
• changes in platelets (blood cells that help blood clots)
• changes in your liver
• feeling confused and tired
• poor appetite
• loss of ability to conceive or father a child
Common (more than or equal to 1% and less than 10%):
• nausea and vomiting
• mouth sores
• diarrhea
• hair loss
Uncommon (more than or equal to 0.1% and less than 1%):
• blurred vision
• speech problems
• losing control of your body movement
• get a second cancer or leukemia some years after lomustine treatment
• changes in your lung or kidney functions
UKNOWN/UNEXPECTED RISKS AND DISCOMFORTS
In addition to the risks listed above, there are risks that are not known or do
not happen often when patients take these study drugs, including severe or
life-threatening allergic reactions, interactions between study drugs or
interactions with another medication. You will be informed in a timely manner,
both verbally and in writing of any new information, findings or changes to the
way the research will be done that might influence your willingness to continue
to take part in this study.
PREGNANCY AND BREAST-FEEDING
The effects of eflornithine and lomustine have not been evaluated on the
developing human fetus. However, based on animal studies (e.g. rats, dogs)
eflornithine and lomustine are considered to be embryotoxic, meaning it can
harm the developing fetus. It is very important while you are in this study
that you do not become pregnant if you are a female, or do not cause others to
become pregnant if you are a male.
If you are a sexually active female, it is required that you use an acceptable
method of birth control from the screening visit throughout the study and for
30 days following the last dose of study drug. Not having sex is the only
certain way to prevent pregnancy. Otherwise, the following methods of birth
control is accepted: birth control pills, intrauterine device (IUD or coil),
intrauterine system (IUS - small, plastic device which sits inside the womb),
tubal sterilization, Essure micro-insert system, or vasectomy in the male
partner. Please speak with your study doctor to determine the best method of
birth control for you to use during this study.
Even if you use an acceptable method of birth control, you could still become
pregnant. There is a slight chance that a pregnancy test could be wrong. If the
pregnancy test is wrong, and you receive the study drug while pregnant, the
study drug may harm an unborn baby.
If you are female and become pregnant or suspect that you have become pregnant
while in the study and within 30 days of last dose of study drug, you will be
required to stop taking all the study drugs and to notify your study doctor
immediately. You will be discontinued from the study. The study doctor will
request to track your pregnancy and will report the pregnancy and outcome to
the sponsor.
Other not yet identified side effects could occur to you, your embryo or fetus
should you become pregnant during the time you participate in the study or
after you have completed the study.
ALLERGIC REACTION RISKS
Although allergic reactions have not been seen previously in patients who have
received eflornithine by mouth in prior oncology studies, as with taking any
drug, there is a potential risk of an allergic reaction. Allergic reaction
symptoms can range from mild (example, mild itching) to very severe reactions.
If you have a very serious allergic reaction, you may be at risk of death.
Some symptoms of allergic reactions are:
• Rash
• Itching
• Difficulty breathing
• Wheezing
• Sudden drop in blood pressure
• Swelling around the mouth, throat or eyes
• A fast pulse
• Sweating
Please seek treatment and alert the study doctor and study staff immediately if
you have any of these symptoms, or any other side effects, during the study.
RISKS OF ADDITIONAL STUDY PROCEDURES:
Blood Draws
Drawing blood from a vein may cause local pain, bruising, occasional
lightheadedness, fainting, and very rarely, infection at the site of the blood
draw.
Electrocardiogram (ECG)
After you have an ECG, you may have mild irritation, slight redness, and
itching at the places on your skin where the recording patches are placed.
You may have to have your chest shaved for this procedure.
Magnetic Resonance Imaging (MRI)
An MRI scan is a type of scan that uses a magnetic field and pulses of radio
wave energy to produce detailed images of your brain. The risk for taking an
MRI is minimal.
Hearing Test and Lung Function Test
These tests are not invasive and the risks are minimal.
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Listed location countries
Age
Inclusion criteria
Patients must meet all of the following inclusion criteria to be
eligible for participation in this study:
1. The ability to understand and sign a written informed consent form, which
must be obtained prior to initiation of study procedures.
2. Age >= 18 years.
3. Surgical or biopsy-proven diagnosis of WHO grade 3 AA.
4. Received EBRT and temozolomide chemotherapy prior to first tumor progression
or recurrence of WHO Grade 3 AA.
5. First AA tumor progression or recurrence <= 6 months prior to randomization
based on MRI using T2 hyperintensity, gadolinium (Gd)-contrast enhancement, or
both. To avoid enrollment of patients with glioblastoma, patients with
Gd-contrast enhancing tumors will be eligible if there is no necrosis seen on
MRI and any of the following criteria is true:
a. Gd-contrast lesion margins are not clearly defined,
b. Gd-contrast lesions are only measurable in one dimension,
c. Gd- contrast lesion has two perpendicular diameters less than 10 mm [1],
d. Gd-contrast lesion has two perpendicular diameters greater than 10 mm but
less than 20 mm and lesion does not demonstrate central necrosis,
e. Recent histopathological confirmation of WHO grade 3 AA
6. Completion of EBRT >= 6 months prior to randomization.
7. Stained, unstained slides or tumor tissue block(s) are available from their
most recent tumor surgery for central histological confirmation.
8. A patient whose AA tumor has progressed or recurred and has had another
surgical resection prior to randomization will be eligible if a) pathology
review confirms AA, and b) postsurgical
MRI demonstrates measurable tumor on T2 FLAIR.
9. If taking corticosteroids, must be on a stable or decreasing dose for at
least 5 days prior to the screening MRI.
10. Karnofsky Performance Status score of > 70.
11. Off anticancer therapy for at least 4 weeks and recovered from any
significant treatment-related toxicities to Grade <= 1 prior to randomization.
12. Adequate recovery from any major surgery is required; at least 4 weeks must
have elapsed from the time of any major surgery and must have recovered from
all surgery-related toxicities to
Grade <= 1 prior to randomization.
13. Adequate hematologic function (ANC >= 1,500/µL, platelet count >= 100,000/µL,
and hemoglobin >= 10.5 gm/dL) within 14 days prior to randomization.
14. Total bilirubin <= 1.5x upper limit of normal (ULN) within 14 days prior to
randomization.
15. Hepatic transaminases (AST and ALT) <= 2x ULN within 14 days prior to
randomization.
16. Adequate renal function (serum creatinine <= 1.5x ULN) within 14 days prior
to randomization.
17. Life expectancy >= 6 months.
18. Female patients of childbearing potential must agree to utilize acceptable
contraceptive methods from screening throughout the duration of the study
period, and for 30 days following the
last dose of study drug. Abstinence is an acceptable method of contraception.
Otherwise, consistent and current use of 1 of the following methods of birth
control is accepted: oral
contraceptive, intrauterine device (IUD), intrauterine hormone-releasing system
(IUS), tubal sterilization, Essure micro-insert system, or vasectomy in the
male partner. Female
patients must also refrain from egg donation and in vitro fertilization during
treatment and until at least 30 days from the last dose of study drug.
19. Male patients must agree to abstain from sexual intercourse or use an
acceptable contraceptive method (e.g. condoms) from screening throughout the
duration of the study period, and for
90 days following the last dose of study drug. Male patients must also refrain
from sperm donation during treatment and until at least 90 days from the last
dose of study drug.
Exclusion criteria
Patients who meet any of the following exclusion criteria are not
eligible for study participation:
1. MRI defining progression is consistent with a diagnosis of glioblastoma or
radiation necrosis.
2. Patients who are considered to be refractory to EBRT and temozolomide but
who have not progressed.
3. Prior systemic therapy for recurrence of AA.
4. Presence of extracranial or leptomeningeal disease.
5. Prior lomustine use.
6. History of other invasive malignancy, unless adequately treated with
curative intent and with no known active disease present within 2 years prior
to randomization. Patients with
non-melanoma skin cancer, carcinoma in situ (including superficial bladder
cancer), cervical intraepithelial neoplasia and organ-confined prostate cancer
deemed by the Investigator to be at low risk of recurrence are not excluded.
7. Active infection or serious intercurrent medical illness.
8. Known to be HIV positive or to have an AIDS-related illness, active
Hepatitis B Virus (HBV), or active Hepatitis C Virus (HCV).
9. Poorly controlled seizures.
10. Unable to undergo an MRI with contrast.
11. Uncontrolled or severe cardiovascular disease, including myocardial
infarction or unstable angina within 6 months prior to randomization, New York
Heart Association (NYHA) Class
III or IV congestive heart failure, serious arrhythmias requiring medication
for treatment, clinically significant pericardial disease, or cardiac
amyloidosis.
12. Malabsorption syndrome, history of resection of the stomach or small bowel,
active ulcerative colitis or Crohn*s disease, partial or complete bowel
obstruction or other conditions that
would be expected to alter the absorption or pharmacokinetics of study drugs.
13. Receipt of any other anticancer therapy while receiving protocol-defined
therapy.
14. Concurrent use of any other investigational agent during the study or
within 30 days prior to randomization.
15. Any other clinical condition or prior therapy that, in the opinion of the
Investigator, would make the patient unsuitable for the study.
16. Pregnant or breastfeeding.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-000089-45-NL |
| ClinicalTrials.gov | NCT02796261 |
| CCMO | NL61119.078.17 |