1. Overall survival (primary efficacy endpoint)2a. Efficacy: progression-free survival (PFS), overall response rate (ORR = CR + PR), and a clincal benefit rate (CBR) will be evaluated as CR + PR + SD for at least 3 months.2b. Safety: adverse events…
ID
Source
Brief title
Condition
- Cervix disorders (excl infections and inflammations)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy variable will be overall survival (OS)
The primary analysis of the primary efficacy variable will be based on the ITT
population. The final OS analysis, which is event-based, will be conducted
after approximately 384 randomized patients have died. In the primary analysis,
a log-rank test with an overall two-sided Type I error rate of 0.05 after
taking the interim analyses into account will be used to compare OS between the
two treatment arms via a SAS lifetest procedure. Kaplan-Meier estimates will be
used to calculate median OS and the 95% confidence interval of the median OS.
The proportion of patients alive at six and 12 months (from randomization date)
and the 95% confidence intervals for these estimated proportions, if
appropriate, will be presented.
Secondary outcome
Approximately 384 events of deaths will be required to achieve 80 % power to
detect a treatment difference at the two-sided 0.05 significance level. It is
expected that approximately 500 patients will be enrolled during an estimated
24-month recruitment period and will then be followed for 12 months to observe
a total of approximately 384 death events. In the sample size calculation, it
is assumed that the median OS is 12 months for AEZS-108 and 9 months for
doxorubicin. The sample size calculation has taken two planned interim looks
into account, the first being a futility analysis only.
Background summary
AEZS-108 is an experimental drug
. AEZS-108 is composed of two parts: one part is doxorubicin (an approved
chemotherapy drug) and the other part is a kind of hormone that helps
doxorubicin to stick and to enter tumors with docking sites for this hormone
(so called LHRH receptors). The first research studies with AEZS-108 in humans
were completed in 2006. In 2010, other studies in Europe were completed in
women with endometrial and ovarian cancers. There are ongoing studies in
patients with prostate cancer, bladder cancer, and breast cancer.
Study objective
1. Overall survival (primary efficacy endpoint)
2a. Efficacy: progression-free survival (PFS), overall response rate (ORR = CR
+ PR), and a clincal benefit rate (CBR) will be evaluated as CR + PR + SD for
at least 3 months.
2b. Safety: adverse events, clinical laboratory, ECG and LVEF
2c. Quality of Life: EORTC QLQ30 + QLQ-EN24 questionnaires.
3. Pharmacokinetic and electrocardiographic parameters of the PK sub-study
Study design
Open-label, randomized, active-controlled, two-arm Phase III study to compare
the efficacy and safety of AEZS-108 and doxorubicin. The study will include
about 500 patients with endometrial cancer resistant to platinum and
taxane-based chemotherapy
Intervention
Patients will be centrally randomized in a 1:1 ratio to receive treatment with
either AEZS 108 (Arm A) or doxorubicin (Arm B).
During ongoing treatment, response will be evaluated every 3 cycles; earlier
reassess-ments should be scheduled to verify a response (at least 4 weeks after
first observation of the response) or in case of suspected progression.
Patients, who have gone off-treatment for reasons other than progression, will
be reassessed every 12 weeks until progression. All patients will be
followed-up for survival.
On a regular basis, at intervals no longer than 6 months, results from safety
analyses will be submitted to an independent Data and Safety Monitoring Board
(DSMB) that will advise the Sponsor of potentially critical findings.
The final analysis will be performed after about 384 deaths have been observed.
There will be two planned interim analyses; the first will be for futility
only, the second will be for safety and efficacy.
Based on the availability of the assay for LHRH receptor expression in tumor
specimens, subgroup analyses stratified for extent of LHRH receptor expression
will assess the predictive value of the LHRH receptor assay.
Study burden and risks
No standard of care or approved drugs are available for patients with
endometrial cancer failing on or after first line chemotherapy for
advanced/recurrent disease if this comprised platinum/taxane-based combination
chemotherapy. In prior studies, it has been shown that, patients with
endometrial and ovarian cancer who failed after or were resistant to
platinum/taxane-based chemotherapy, including combinations, still responded to
AEZS 108.
Although the investigational drug AEZS-108 is a targeted drug that is expected
to enter cells bearing preferentially LHRH receptors, the study is being
conducted in patients who will not be selected for expression of this specific
target. Ultimately, a patient whose tumor cells do not express LHRH receptors
could have a higher uptake of doxorubicin if it was administered as free
doxorubicin, not coupled to the LHRH analog. In the Phase II study of AEZS-108,
92.8% of the endometrial cancer specimens analyzed during prescreening had been
classified as receptor positive, so that only about 7% of the patients who
might have entered the study if the receptor assay had been omitted. No
correlation of the degree of receptor expression and the tumor response was
noted in this earlier study. Accordingly, even patients with tumors classified
as LHRH receptor negative * with the former assay - could have a chance to
benefit from treatment with AEZS-108. Ultimately, since doxorubicin is being
gradually released during and after the infusion of AEZS-108, a patient with an
LHRH receptor negative tumor has the chance to benefit from the uptake of
hydrolytically released doxorubicin by the tumor
Weismüllerstrasse 50
Frankfurt am Main D-60314
DE
Weismüllerstrasse 50
Frankfurt am Main D-60314
DE
Listed location countries
Age
Inclusion criteria
1. Woman * 18 years of age
2. Histologically confirmed endometrial adenocarcinoma of any subtype
a) Endometrioid carcinoma
i. variant with squamous differentiations
ii. Villoglandular variant
iii. Secretory variant
iv. Ciliated cell variant
b) Mucinous adenocarcinoma
c) Serous adenocarcinoma
d) Clear cell adenocarcinoma
e) Mixed cell adenocarcinoma
f) Squamous cell carcinoma
g) Transitional cell carcinoma
h) Small cell carcinoma
i) Undifferentiated carcinoma;3. Advanced (FIGO stage III or IV), recurrent or metastatic disease.;4. Measurable or non-measurable disease that has progressed since last treatment.;5. Patients with advanced, recurrent or metastatic endometrial cancer who have received one chemotherapeutic regiment with platinum and taxane (either as adjuvant or as first line treatment) and who have progressed.;6. Availability of fresh or archival FFPE tumor specimens for analysis of LHRH receptor expression.
Exclusion criteria
1. Eastern Cooperative Oncology Group (ECOG) performance status > 2
2. Inadequate hematologic, hepatic or renal function
- thromobocyte count: < 100 x 109/L;
- absolute neutrophil count (ANC): < 1.5 x 109/L;
- hemoglobin: < 5.6 mmol/L (< 9 g/dL);
- ASAT, ALAT, AP: > 2.5 times upper limit of normal range (ULN) (> 5x ULN if clearly related to liver metastases)
- creatinine, bilirubin: > 1.5x ULN
3. Red blood cell transfusion within 2 weeks prior to anticipated start of study treatment.
4. History of myocardial infarction, acute inflammatory heart disease,unstable angina, or uncontrolled arrhythmia within the past 6 months.
5. Impaired cardiac function defined as left ventricular ejection fraction (LVEF) < 50 % (or below the study site*s lower limit of normal) as measured by MUGA or ECHO.
6. Concomitant use of prohibited therapy (as specified in Section 6.3.2).
7. Chemo-, immune- or hormonetherapy within 5 elimination half life times or 4 weeks prior to randomization, whichever is the shorter. Radiotherapy (including pre- or post- operative brachytherapy) within 4 weeks prior to randomization.
8. Previous anthracycline-based chemotherapy (daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone and valrubicin) in any formulation.
9. Anticipated ongoing concomitant anticancer therapy during the study.
10. History of serious co-morbidity or uncontrolled illness that would preclude study therapy, such as active tuberculosis or any other active infection.
11. Brain metastasis, leptomeningeal disease.
12. Pregnant or lactating female or female of child-bearing potential not employing adequate contraception. Women of childbearing potential must agree to employ adequate contraception until 6 months after the last dose of study drug, defined as
- complete abstinence (Note: acceptable only as *true abstinence*, i.e. when this is
in line with the preferred and usual lifestyle of the subject. Periodic abstinence, (e.g.,
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception).;
- any intrauterine device (IUD) with published data showing that the lowest expected failure rate is < 1 % per year; or
- any other methods with published data showing that the lowest expected failure rate is less than 1 % per year.
13. Subjects with known hypersensitivity to peptide drugs, including
LHRH agonists.
Lack of suitability for the trial:
22. Malignancies arising from the uterine Cervix.
23. Uterine sarcomas or mixed epithelial and mesenchymal tumors including carcinosarcoma, adenosarcoma, or carcinofibroma.
14. Receipt of 2 or more prior cytotoxic chemotherapy regimens for advanced, recurrent, or metastatic endometrial cancer.
15. Prior treatment with AEZS-108.
16. Use of LHRH agonist or antagonist treatment within 6 months prior to randomization.
17. Malignancy within last 5 years except non-melanoma skin cancer.
18. Any concomitant disease or condition which would interfere with the subjects* proper completion of the protocol assignment.
19. Concomitant or recent treatment with other investigational drug (within 4 weeks or 5 elimination half life times prior to anticipated start of study treatment).
Administrative reasons:
20. Lack of availability for willingness to give informed consent.
21. Anticipated non-availability for study visits/procedures.
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 | EUCTR2012-005546-38-NL |
| ClinicalTrials.gov | NCT01767155 |
| CCMO | NL45515.018.13 |