The primary objective of this Phase II study is to evaluate the clinical efficacy in terms of Disease Free Survival of recMAGE-A3 + AS 15 ASCIversus placebo in the overall population.Secondary objectives are:• To evaluate overall survival in the…
ID
Source
Brief title
Condition
- Bladder and bladder neck disorders (excl calculi)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint is Disease-free Survival (DFS):
Defined as the time from randomization to either the date of first recurrence
of the disease or the date of death (whatever the cause), whichever occurs
first.
· Types of recurrence to be considered as an event include loco-regional and
distant metastases.
· In addition, any death occurring without prior documentation of tumor
recurrence will be considered as an event (and will not be censored in the
statistical analysis) as this approach is less prone to introduce bias.
· If no event has occurred by the time of the analysis, then the time to event
will be censored at the date of the last assessment of the patient in question.
· Any new primary cancer at another site, including transitional carcinoma of
the upper urinary tract, will not be considered as recurrence and should be
reported as a SAE.
Protocol Amendment 4: The primary and secondary objectives will not be assessed
as planned. All clinical data collected in the study will be analysed
descriptively.The immune response will not be evaluated anymore as the immune
response to IP administration was confirmed in other ASCI trials, but did not
show any correlation with the potential efficacy.
Secondary outcome
Secondary endpoints are:
· Overall Survival: Defined as the interval from randomization to the date of
death, irrespective of the cause of death; patients still alive will be
censored at the date of the last assessment.
· Disease-free specific survival (DFSS): Defined as the interval from
randomization to the date of first recurrence of disease or date
of death due to bladder carcinoma, whichever occurs first. Patients without
recurrence or death are censored at the date of last assessment. Patients
without recurrence who die from another cause are censored at the date of death.
· Distant metastasis-free survival (DMFS): Defined as the interval from
randomization to the date of first distant metastasis or date of
death, whichever occurs first. Patients alive and without distant metastasis
are censored at the date of last assessment.
· (Serious) Adverse events.
· To evaluate impact of predictive gene signature on efficacy of
treatment in terms of DFS and overall survival.
· To evaluate the immune response to the AS15 ASCI.
· To evaluate Gene expression profiles of the primary tumor by microarray.
Protocol Amendment 4: The primary and secondary objectives will not be assessed
as planned. All clinical data collected in the study will be analysed
descriptively.The immune response will not be evaluated anymore as the immune
response to IP administration was confirmed in other ASCI trials, but did not
show any correlation with the potential efficacy.
Background summary
Currently, the standard treatment for localized muscle invasive bladder cancer
is radical cystectomy.
· Many patients with muscle invasive bladder cancer will relapse after
cystectomy
The 10-year disease-specific and overall survival of patients with organ
confined (defined as < pT3a) is 72.9% and 49.1%, rapidly decreasing to
33.3% and 22.8% for non-organ confined disease (13). There is thus a clear
medical need for an additional anti-tumoral treatment in this population.
· There is not enough evidence in favour of the routine use of adjuvant
chemotherapy
From scientific evidence so far available, it is unclear whether immediate
adjuvant chemotherapy or chemotherapy at the time of relapse is superior or if
the two approaches are equivalent with respect to the end-point overall
survival.
· MAGE-A3 is a factor of poor prognosis
The interest in recMAGE-A3 ASCI treatment is further reinforced by the possible
link between MAGE-A3 expression and shorter survival (34)
· MAGE-A3 is tumor-specific, recMAGE-A3 ASCI treatment highly tolerated and
shows promising Phase II results
Taking into account the tumor-specificity of MAGE-A3, the high tolerability of
recMAGE-A3 + AS15 and the promising results from the Phase II clinical trials
in melanoma and lung cancer, EAU RF proposes to initiate a randomized,
placebo-controlled clinical Phase II trial with recombinant MAGE-A3
(recMAGE-A3) combined with the AS15 adjuvant in patients with muscle invasive
bladder cancer with MAGE-A3 expression after cystectomy.
This trial will assess whether adjuvant treatment with recMAGE-A3 + AS 15 ASCI
after cystectomy is safe and effective and improves outcome of
MAGE-A3 positive patients after cystectomy.
Study objective
The primary objective of this Phase II study is to evaluate the clinical
efficacy in terms of Disease Free Survival of recMAGE-A3 + AS 15 ASCI
versus placebo in the overall population.
Secondary objectives are:
• To evaluate overall survival in the overall study population, in the
subpopulations with and without use of neo-adjuvant chemotherapy and in the
subpopulations with and without use of adjuvant chemotherapy
• To evaluate Disease-free (DFS) in the subpopulations with and without use of
neo-adjuvant chemotherapy and in the subpopulations with and without use of
adjuvant chemotherapy.
• To evaluate Disease-free specific survival (DFSS) in the overall study
population, in the subpopulations with and without use of neo-adjuvant
chemotherapy and in the subpopulations with and without use of adjuvant
chemotherapy.
• To evaluate Distant metastasis-free survival (DMFS) in the overall study
population, in the subpopulations with and without use of neo-adjuvant
chemotherapy and in the subpopulations with and without use of adjuvant
chemotherapy.
• To evaluate the safety of recMAGE-A3 + AS15 ASCI in the overall study
population, in the subpopulations with and without use of neo-adjuvant
chemotherapy and in the subpopulations with and without use of adjuvant
chemotherapy.
• To evaluate the immune response to recMAGE-A3 + AS15 ASCI in the overall
study population and in the subpopulations with and without use of neo-adjuvant
chemotherapy and in the subpopulations with and without use of adjuvant
chemotherapy.
• Translational research:
i) To identify a gene signature predictive to recMAGE-A3+AS15 ASCI in MIBC.
ii) To evaluate on exploratory basis a possible correlation between gene
expression profile of the primary tumor and clinical efficacy of recMAGE-A3 +
AS15 ASCI compared to placebo in terms of:
1. Disease-free Survival (DFS)
2. Overall survival
iii) To evaluate expression of genes in a previously identified gene signature
and evaluate their correlation with clinical efficacy of recMAGE-A3 + AS15 ASCI
compared to placebo in terms of:
1. Disease-free Survival (DFS).
2. Overall survival.
3. Disease-free specific survival (DFSS)
4. Distant metastasis-free survival (DMFS).
iv) To characterize the tumor microenvironment and lymphocyte infiltration in
the primary tumor and its recurrence lesions
Protocol Amendment 4: The analysis of MAGRIT study results confirmed the
absence of treatment effect in any of the primary, secondary, or exploratory
analyses. Consequently, GSK Biologicals has decided to stop further development
of recMAGE-A3 + AS15 as a standalone treatment for cancer patients. As of
Protocol Amendment 4.0, the recruitment will be stopped and the study
population will be unblinded.
For patients randomized to the placebo group, no further protocol visits will
be performed except for the concluding visit and no further doses will be
administered. As it cannot be excluded that one or more patients may benefit
from this treatment on an individual basis, patients receiving active
treatment will be offered the option to continue the administration of the
study treatment. Treatment will not be possible anymore after
30 November 2016.
Study design
This is a multicentre, prospective, randomized, placebo-controlled, parallel
group, double-blind, trial to compare the efficacy and safety of recMAGEA3 +
AS15 ASCI intramuscular injections with Placebo intramuscular injections.
The target will be to enrol 273 patients to be randomly assigned to 2 treatment
schedules in a 2:1 ratio, 2 patients randomized for recMAGE-A3 +
AS15 ASCI versus 1 patient randomized for placebo.
The treatment scheme consists of 5 doses administered at 3-week intervals
followed by 8 doses administered at 3-month intervals for a total maximum
duration of study treatment administration of 27 months. Data collection will
be organised by Remote Date Entry on Electronic Case
Report Forms (eCRF).
A total of 8-10 European countries will participate with an anticipated average
of 6-8 centres each. Sites should be able to contribute at least 10-15 screened
patients per year. Enrolment in this study is competitive.
Protocol Amendment 4: The analysis of MAGRIT study results confirmed the
absence of treatment effect in any of the primary, secondary, or exploratory
analyses. Consequently, GSK Biologicals has decided to stop further development
of recMAGE-A3 + AS15 as a standalone treatment for cancer patients. As of
Protocol Amendment 4.0, the recruitment will be stopped and the study
population will be unblinded.
For patients randomized to the placebo group, no further protocol visits will
be performed except for the concluding visit and no further doses will be
administered. As it cannot be excluded that one or more patients may benefit
from this treatment on an individual basis, patients receiving active
treatment will be offered the option to continue the administration of the
study treatment. Treatment will not be possible anymore after
30 November 2016.
Intervention
Please refer to the section of study design.
Study burden and risks
Protocol: Given the situation of the patient who needs a cystectomy, the extra
burdenand risks associated with participation in the study is considered
minimal and acceptable. During the first 3 months in the study, the number of
patient visits is higher. This is due to the need for administration of
treatment every 3 weeks. Hereafter, the number of visits and treatments is
equal to what patients with these criteria is offered when they are treated in
the standard way, which is watchful waiting after cystectomy. Possible extra
procedures in this study depend on local routine practices.
For example 3-monthly CT scans /MRI*s can be extra if 6-monthly imaging
procedures are considered standard routine practice (during treatment phase
only). Also laboratory assessments and the questionnaire on smoking habits can
be considered as
extra.
Explanation: As described above 3-monthly scans can be extra if 6-monthly
imaging procedure are considered standard routine which means that there will
be 5 extra scans (compared to the guideline given by EAU). It also has to be
taken into account that the standard of care concerning the frequency of scans
varies from country to country as for example in Germany 3 monthly scans is
standard of care. The treatment injections, laboratory assessments and the
questionnaire on smoking habits can be considered as extra. We refer to the
flowchart in the reply to question C1.4 of the CCMO, with indication of the 6
monthly scans as only standard routine practice, all other assessments are
trial specific.
The risks related to the expected treatment outcome, quality and quantity of
side effects of the study medication can be considered as
acceptable (see Section 2.5.3). Benefit for the patient is that the patient is
followed according to the latest standards and guidelines of treatment of MIBC
and the patient has a chance on early detection of recurrence of disease.
Mr. E.N. van Kleffensstraat 5
AA Arnhem 6803
NL
Mr. E.N. van Kleffensstraat 5
AA Arnhem 6803
NL
Listed location countries
Age
Inclusion criteria
1. Aged greater than or equal to 18 years at the time ICF is signed, either sex.;2. Histologically confirmed (after cystectomy or if needed transurethral resection) urothelial carcinoma of the bladder which is MAGE-A3 positive.;3. Written informed consent for tissue and (optional) urine sampling, MAGE-A3 expression analysis and gene profiling and optional translational research has been obtained from the patient prior to cystectomy, and written informed consent for the complete study has been obtained prior to the performance of any other protocol-specific procedure.;4. TNM classification at pathological examination of surgically removed specimen: Stage T2,3 N0 or N1 or N2 and M0 disease or Stage T4 N0 M0 disease. ;5. The patient is free of residual disease and free of metastasis, as confirmed by a negative baseline Computer Tomogram (CT scan) or Magnetic Resonance Imaging (MRI) of the pelvis, abdomen and chest no more than 13 weeks prior to randomization. Other examinations should be performed as clinically indicated.;6. Patient is fully recovered from surgery within 13 weeks following cystectomy. For patients who receive adjuvant chemotherapy, the patient is fully recovered within 3-6 weeks following chemotherapy.;7. The patient must have adequate bone-marrow reserve, defined as an absolute neutrophil count >= 1.0 x 109/L, and a platelet count >= 75 x 109/L, adequate renal function, defined as a serum creatinine <= 1.5 times the Upper Limit of Normal (ULN), and adequate hepatic function, defined as a Total bilirubin <= 1.5 times the ULN, and a Alanine transaminase (ALAT) and Aspartate Transaminase (ASAT) <= 2.5 times the ULN as assessed by standard laboratory criteria.;8. World Health Organization (WHO) performance status 0 - 1 at the time of randomization.;9. If the patient is female, she must be of non-childbearing potential, i.e. have a current tubal ligation, hysterectomy, ovariectomy or be post menopausal, or if she is of childbearing potential, she must practice adequate contraception for 30 days prior to administration of study treatment, have a negative pregnancy test and continue such precautions during all study treatment period and for 2 months after completion of the injection series.
Exclusion criteria
1. The patient has previous or concomitant malignancies at other sites except effectively treated non-melanoma skin cancer, cervical carcinoma in situ, incidental localised prostatic carcinoma or effectively treated malignancy that has been in remission for over 5 years.;2. The patient has received any anti cancer systemic treatment, including immunotherapy(local intravesical BCG is allowed), chemotherapy, except:;* For the treatment of previous malignancies as allowed by the protocol (i.e., nonmelanoma skin cancer, cervical carcinoma in situ, incidental localised prostatic carcinoma or effectively treated malignancy that has been in remission for over 5 years).
* For the treatment with neo-adjuvant chemotherapy for their muscle invasive bladder cancer
* For the treatment with adjuvant cisplatinum-based chemotherapy for their muscle invasive bladder cancer;3. The patient has received radiotherapy of the abdominal or pelvic region, within 6 months prior to randomization.;4. Women who are pregnant or breast feeding.;5. The patient has a known infection with human immunodeficiency virus (HIV) or chronic hepatitis B or C.;6. The patient has a history of allergic disease or reactions likely to be exacerbated by any component of the study investigational product.;7. The patient has any confirmed or suspected immunosuppressive or immunodeficient condition or potential immune-mediated diseases. Patients with vitiligo are not excluded to participate in the trial.;8. Patient has received a major organ allograft.;9. The patient requires concomitant treatment with systemic corticosteroids, or any other immunosuppressive agents. Note: the use of prednisone, or equivalent, < 0,125 mg/kg/day (absolute maximum 10 mg/day), or inhaled corticosteroids or topical steroids is permitted.;10. The patient has received any investigational or non-registered medicinal product other than the study medication within the 30 days preceding the first dose of study medication, or plans to receive such a drug during the study.;11. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures.;12. The patient has other concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk. For example, but not limited to: uncontrolled congestive heart failure or uncontrolled hypertension, unstable heart disease (coronary heart disease or myocardial infarction) or uncontrolled arrhythmia.;13. The patient uses alternative treatments eg. plantextracts.
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 | EUCTR2010-024355-85-NL |
| CCMO | NL35466.000.11 |