The primary objective of this study is to compare overall survival (OS) in patients receiving Marizomib in combination with standard treatment (TMZ with concomitant RT, followed by TMZ maintenance therapy: TMZ/RT*TMZ) with patients receiving…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to compare overall survival in patients
receiving Marizomib in combination with standard treatment (TMZ with
concomitant RT, followed by TMZ maintenance therapy: TMZ/RT*TMZ) with patients
receiving standard treatment only (TMZ/RT*TMZ). The testing strategy is defined
to assess this objective in both the whole population and the subgroup of
unmethylated MGMT patients with adequate statistical power.
The median OS is 16 months in the standard treatment alone, the median OS is
21.6 months for standard treatment plus marizomib. Lenght is FU will be
accordingly.
Secondary outcome
Secondary objective is to compare PFS in the two treatment arms in the whole
population.
Further secondary objectives are:
-To assess the safety and tolerability of marizomib combined with TMZ/RT*TMZ.
-To assess the neurocognitive function and quality of life of patients treated
with this approach.
-Descriptive and correlative translational research
-To evaluate pharmacokinetics in the MRZ arm
Background summary
TGlioblastoma, a grade IV glioma, is not only the most malignant but also the
most common primary brain tumor in adults. The median survival of glioblastoma
patients is in the range of one year in population-based studies (Gramatzki D,
Dehler S, Rushing EJ, Zaugg K, Hofer S, Yonekawa Y, et al. Glioblastoma in the
Canton of Zurich, Switzerland revisited: 2005 to 2009. Cancer 2016; 122(14):
2206-15) and is in the range of 15-16 months in clinical trial populations
(Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al.
Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N
Engl J Med 2014; 370(8): 709-22; Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS,
Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly
diagnosed glioblastoma. N Engl J Med 2014; 370(8): 699-708). Since 2005,
patients with newly diagnosed glioblastoma aged 70 years or younger are treated
with maximal safe surgery followed by involved-field radiotherapy (RT) with
concomitant temozolomide (TMZ) therapy followed by up to 6 cycles of
maintenance temozolomide therapy (TMZ/RT*TMZ) according to results of the EORTC
26981/22981-NCIC CE3 trial (Stupp R, Mason WP, van den Bent MJ, Weller M,
Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant
temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987-96; Weller M,
van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, et al. EANO guideline
for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet
Oncol 2014; 15(9): e395-403).
The proteasome is a central cellular structure for the turnover of proteins.
Its activity is constituted by multiple proteases assembled in a large
multi-protein complex. Cancer cells often exhibit enhanced proteasome activity
and inhibition of proteasome activity may preferentially affect the viability
of cancer cells, including glioblastoma cells (Wagenknecht B, Hermisson M,
Eitel K, Weller M. Proteasome inhibitors induce p53/p21-independent apoptosis
in human glioma cells. Cell Physiol Biochem 1999; 9(3): 117-25; Wagenknecht B,
Hermisson M, Groscurth P, Liston P, Krammer PH, Weller M. Proteasome
inhibitor-induced apoptosis of glioma cells involves the processing of multiple
caspases and cytochrome c release. J Neurochem 2000; 75(6): 2288-97; Scoccianti
S, Detti B, Gadda D, et al. Organs at risk in the brain and their
dose-constraints in adults and in children: a radiation oncologist's guide for
delineation in everyday practice. Radiother Oncol 2015; 114(2): 230-8).
Marizomib displays a unique pharmacologic profile among proteasome inhibitors
characterized by high potency and irreversible pan-proteasome inhibition.
Preclinically, marizomib has been shown to induce apoptotic cell death in
stable human glioma tumor cell lines and in glioma stem cells, as well as in
intracranial glioblastoma models in vivo (Manton CA, Johnson B, Singh M, Bailey
CP, Bouchier-Hayes L, Chandra J. Induction of cell death by the novel
proteasome inhibitor marizomib in glioblastoma in vitro and in vivo. Sci Rep
2016; 6: 18953; Di K, Lloyd GK, Abraham V, MacLaren A, Burrows FJ, Desjardins
A, et al. Marizomib activity as a single agent in malignant gliomas: ability to
cross the blood-brain barrier. Neuro Oncol 2016; 18(6): 840-8; Bota AA,
Alexandru D, Keir ST, Bigner D, Vredenburgh J, Friedman HS. Proteasome
inhibition with bortezomib induces cell death in GBM stem-like cells and
temozolomide-resistant glioma cell lines, but stimulates GBM stem-like cells*
VEGF production and angiogenesis. J Neurosurg 2013; 119(6): 1415-23.).
Preclinical data strongly support the conclusion that marizomib is brain
penetrant.
As of the data cut date of 08 Sep 2017, marizomib has been tested in 139
patients with newly diagnosed and recurrent glioblastoma in phase Ib and phase
I/II studies, respectively.
Single agent MRZ activity was clearly observed but was limited: 1 confirmed PR
(per RANO) lasted for 10 months and 3 additional patients had long disease
stabilization lasting for 11, 8, and 8+ months. As of 08 Sep 2017, 1 of 30
patients is still on study following 9 cycles of treatment. Although the
overall survival (OS) data for the study are not yet mature (16 patients
censored), the median is 11.4 months, with a median follow-up for all surviving
patients of 7.0 months. A phase Ib trial of marizomib in combination with
standard doses and schedules of TMZ/RT*TMZ in newly diagnosed glioblastoma has
been ongoing and the dose level of 0.8 mg/m2 was selected for further clinical
evaluation.
Study objective
The primary objective of this study is to compare overall survival (OS) in
patients receiving Marizomib in combination with standard treatment (TMZ with
concomitant RT, followed by TMZ maintenance therapy: TMZ/RT*TMZ) with patients
receiving standard treatment only (TMZ/RT*TMZ). The testing strategy is defined
to assess this objective in both the whole population and the subgroup of
unmethylated MGMT patients with adequate statistical power.
Secondary objective is to compare PFS in the two treatment arms in the whole
population.
Further secondary objectives are:
- To assess the safety and tolerability of marizomib combined with TMZ/RT and
TMZ.
- To assess the neurocognitive function and quality of life of patients treated
with this approach.
- Descriptive and correlative translational research
-To evaluate pharmacokinetics in the MRZ arm
Study design
This is a multicenter, randomized, controlled, open label phase III superiority
trial with an early stopping rule for futility.
After signing the informed consent form and upon confirmation of the patient
eligibility, patients will be randomized 1:1 to the experimental arm (addition
of marizomib to the standard treatment) or the standard arm.
Experimental arm: Standard radiotherapy (60 Gy in 30 fractions over 6 weeks) +
TMZ 75 mg/m2 p.o. daily for 6 weeks (during radiotherapy) and marizomib (MRZ)
dose 0.8 mg/m2 IV at days 1, 8, 15, 29 and 36.
This is followed, after 4-week break, by up to 6 cycles of maintenance TMZ
150-200 mg/m2 p.o. on days 1-5 of a 28-day cycle and up to 18 cycles of
maintenance MRZ treatment (0.8 mg/m2 IV) at days 1, 8, 15 of a 28-day cycle
until disease progression, unacceptable toxicity or withdrawal of consent.
Continuation of maintenance temozolomide beyond 6 cycles is not encouraged, but
will not constitute a protocol violation as long as it does not exceed 12
cycles in total.
Standard arm: Standard radiotherapy (60 Gy in 30 fractions over 6 weeks) + TMZ
75 mg/m2 p.o. daily for 6 weeks (during radiotherapy) then (after 4-week break)
up to 6 cycles of maintenance TMZ 150-200 mg/m2 p.o. on days 1-5 of a 28-day
cycle.
Continuation of maintenance TMZ beyond 6 cycles is not encouraged, but will not
constitute a protocol violation as long as it does not exceed 12 cycles in
total.
Intervention
Experimental arm: Standard radiotherapy (RT) (60 Gy in 30 fractions over 6
weeks) + TMZ 75 mg/m2 p.o. daily for 6 weeks (during radiotherapy) and
marizomib (MRZ) dose 0.8 mg/m2 IV at days 1, 8, 15, 29 and 36.
This is followed, after 4-week break, by up to 6 cycles of maintenance TMZ
150-200 mg/m2 p.o. on days 1-5 of a 28-day cycle and up to 18 cycles of
maintenance MRZ treatment (0.8 mg/m2 IV) at days 1, 8, 15 of a 28-day cycle
until disease progression, unacceptable toxicity or withdrawal of consent.
Continuation of maintenance temozolomide beyond 6 cycles is not encouraged, but
will not constitute a protocol violation as long as it does not exceed 12
cycles in total.
Standard arm: Standard radiotherapy (RT) (60 Gy in 30 fractions over 6 weeks) +
TMZ 75 mg/m2 p.o. daily for 6 weeks (during radiotherapy) then (after 4-week
break) up to 6 cycles of maintenance TMZ 150-200 mg/m2 p.o. on days 1-5 of a
28-day cycle.
Continuation of maintenance TMZ beyond 6 cycles is not encouraged, but will not
constitute a protocol violation as long as it does not exceed 12 cycles in
total.
Study burden and risks
The subjects participating in the studywill have a higher burden because of
participation in the trial. This burden consists of extra visits to the site, ,
additional blood draws besides the standard safety labs. Next to this the
subjects will complete questionnaires. Furthermore every 8 weeks an MRI will be
performed.
Avenue E. Mounier 83/11
Brussels 1200
BE
Avenue E. Mounier 83/11
Brussels 1200
BE
Listed location countries
Age
Inclusion criteria
Histologically confirmed newly diagnosed glioblastoma (WHO grade IV)
• Tumor resection (gross total or partial), or open biopsy only (No
stereotactic biopsy)
• Availability of FFPE tumor block or 24 unstained slides for MGMT analysis
• Patient must be eligible for standard TMZ/RT*TMZ
• Karnofsky performance score (KPS) >= 70
• Recovered from effects of surgery, postoperative infection and other
complications of surgery
(if any)
• The patient is at least 18 years of age on day of signing informed consent
• Stable or decreasing dose of steroids for at least 1 week prior to inclusion
• The patient has a life expectancy of at least 3 months
• Patient has undergone a brain MRI within 14 days of randomization but after
intervention
(resection or biopsy)
• Women of child bearing potential (WOCBP) must have a negative urine or
serum pregnancy test within 7 days prior to randomization.
• Patients of childbearing / reproductive potential must agree to use
adequate birth control
measures, as defined by the investigator, during the study treatment period and
for at least 6
months after the last study treatment. A highly effective method of birth
control is defined as
those which result in low failure rate (i.e. less than 1% per year) when used
consistently and correctly. Patients must also agree not to donate sperm during
the study and for 6 months after receiving the last dose of study medication.
• Women who are breast feeding must agree to discontinue nursing prior to the
first dose of study
treatment and until 6 months after the last study treatment.
• Ability to understand the requirements of the study, ability to provide
written informed consent and authorization of use and disclosure of protected
health information, and agree to abide by the
study restrictions and return for the required assessments.
• Before patient registration/randomization, written informed consent must be
given according to
ICH/GCP, and national/local regulations.
Exclusion criteria
• Patients with known IDH mutation (IDH mutation testing should be
conducted for younger patients (<55 years old), for patients with tumors with
atypical features and for patients with history of present concurrent lower
grade gliomas).
• Prior treatment for glioblastoma other than surgery; prior RT to brain
and/or prior
chemotherapy for lower grade glioma. Placement of BCNU
wafer during surgery is not allowed
• Known hypersensitivity to the active substance or any of the excipients in
the IV formulation
• History of thrombotic or hemorrhagic stroke or myocardial infarction in
past 6 months
• Congestive heart failure (New York Heart Association Class III to IV),
symptomatic ischemia,
conduction abnormalities uncontrolled by conventional intervention, and
myocardial infarction
within 6 months prior to first dose
• Concurrent severe or uncontrolled medical disease (e.g., active systemic
infection, diabetes,
hypertension, coronary artery disease, psychiatric
disorder) that, in the opinion of the investigator, would compromise the safety
of the patient or
compromise the ability of the patient to complete the study
• Known history of current evidence of active Hepatitis B (e.g., positive HBV
surface antigen) or C (e.g., HCV RNA [qualitative] is detected).
• Known or current evidence of Human Immunodeficiency Virus (HIV) (positive
HIV-1/2 antibodies)
• Prior or second invasive malignancy, except non-melanoma skin cancer,
completely resected cervical carcinoma in situ, low risk prostate cancer
(cT1-2a N0 and Gleason score <= 6 and PSA < 10 ng/mL), either totally resected
or irradiated with curative intent (with PSA of less than or equal to 0.1
ng/mL) or under active surveillance as per ESMO guidelines. Other cancers for
which the subject has completed potentially curative treatment more than 3
years prior to study entry are allowed.
• Presence of any psychological, familial, sociological or geographical
condition potentially
hampering compliance with the study protocol and follow-up schedule; those
conditions should be discussed with the patient before registration in the
trial.
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 | EUCTR2017-003908-50-NL |
| ClinicalTrials.gov | NCT03345095 |
| CCMO | NL64398.041.18 |