Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT03096821 |
Other study ID # |
EXALT1.1 |
Secondary ID |
1830/2015 |
Status |
Completed |
Phase |
|
First received |
|
Last updated |
|
Start date |
September 2015 |
Est. completion date |
January 30, 2020 |
Study information
Verified date |
February 2021 |
Source |
Medical University of Vienna |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Observational
|
Clinical Trial Summary
Patients with relapsed/ refractory acute leukemia and relapsed/ refractory aggressive
lymphoma harboring an activating genetic alteration (gene mutation, gene fusion) or drug-able
biomarker / activated signal transduction pathway and resistant to any approved treatment
modality will be eligible for this study.
The investigators aim to combine DNA sequencing-based molecular profiling with an ex vivo
high-throughput drug screening strategy. For the latter method, viable cells are obtained
from the individual patient's lymphoma or leukemia in order to determine i)the expression of
relevant therapeutic target molecules and ii)the ex vivo response of the patient's cancer
cells to a panel of agents with anticancer activity. In addition, analysis of tumor stroma
cells will provide information about the differential target expression and cellular
sensitivity aiming at the evaluation of a therapeutic safety window. Thereby, biological
material will have to be accessed within 4 weeks before onset of individualized treatment
(real-time biopsy). Bioinformatic data-management based on a Bayesian statistical approach
will support individualized treatment decisions in this controlled clinical approach.
Description:
Background and rationale for the trial Etiological concepts on cancer development, malignant
growth and tumor propagation have led to the discovery of various molecular driver
mechanisms. Based on these advances, medical oncology has started to enter an era of
individualized medicine where treatment selection is becoming tailored to drug-able molecular
pathways. This individualized treatment concept is mainly based on molecular and genetic
characterization of the tumors including biomarker technology, which allow us to align the
most appropriate treatment according to the patient's disease. Although there is a general
acceptance towards such individualized approach thereby stratifying and subgrouping patients
to improve the quality of clinical care in oncology, molecular profiling has just started to
assist prediction of the drug's clinical benefit by identifying the most responsive patient
subgroup. Recently, excellent demonstrations of the utility of prognostic and/or predictive
biomarkers have emerged. Von Hoff and co-workers have recently demonstrated that molecular
profiling of patients' tumors is an efficient approach to identify potential targets and
select treatments for their treatment-refractory cancers(Von Hoff, Stephenson et al. 2010).
Such a tailored treatment strategy revealed to be an effective approach to increase
progression free survival (PFS), when compared to the patients' most recent standard
treatment regimen. Another example for individualized treatment of patients is given by the
recently published BATTLE trial (Biomarker-integrated Approaches of Targeted Therapy for Lung
Cancer Elimination), a prospective biomarker and biopsy driven trial in pretreated non-small
cell lung cancer (NSCLC) patients (Kim, Herbst et al. 2011). By this Bayesian approach, the
authors demonstrated that targeting individually analyzed molecules of the patient's tumor
might represent an efficient therapeutic approach in the treatment of an incurable disease.
While these examples suggest a benefit for individual tumor characterization for selection of
a tailored treatment concept, currently novel targeted agents in the treatment of cancer are
rather approved for a certain subtype of cancer, but not for patients based on the expression
or activity of respective target lesions. Therefore, the need of an extension of clinical
protocols focusing on molecular profile-based treatment decisions, rather than on anatomic
cancer-subtypes is mandatory. Based on this concept the current protocol was designed. The
investigators hypothesize that molecular profiling of a patient's tumor might not only
predict treatment response, but also leads to an individualized treatment protocol resulting
in clinical benefit for the individual patient. Therefore, this project aims to assess the
feasibility of an individualized treatment concept for pre-defined patient's benefit.
Design, methodology, statistical considerations and organization The Medical University of
Vienna will be clinical sponsor and clinical center of this investigator-initiated open-label
single center single-arm, exploratory phase II study. The individualized treatment concept is
determined to be biopsy-mandated and biomarker-based. Bio-data analysis will be supported by
a software, which is generated by the Center of Medical Statistics, Informatics and
Intelligent Systems.
Study design and methodology Patients with relapsed/ refractory acute leukemia and relapsed/
refractory aggressive lymphoma harboring an activating genetic alteration (gene mutation,
gene fusion) or drug-able biomarker / activated signal transduction pathway and resistant to
any approved treatment modality will be eligible for this study.
The investigators aim to combine DNA sequencing-based molecular profiling with an ex vivo
high-throughput drug screening strategy. For the latter method, viable cells are obtained
from the individual patient's lymphoma or leukemia in order to determine i)the expression of
relevant therapeutic target molecules and ii)the ex vivo response of the patient's cancer
cells to a panel of agents with anticancer activity. In addition, analysis of tumor stroma
cells will provide information about the differential target expression and cellular
sensitivity aiming at the evaluation of a therapeutic safety window. Thereby, biological
material will have to be accessed within 4 weeks before onset of individualized treatment
(real-time biopsy). Bioinformatic data-management based on a Bayesian statistical approach
will support individualized treatment decisions in this controlled clinical approach.
Number of patients. A sample size of 49 patients achieves ≥ 80% power to detect a difference
of 15% between the null hypothesis proportion P0 (PFS ratio ≥ 1.3) = 10% and the alternative
proportion P1(PFS ratio ≥ 1.3) = 25% using a one-sided exact binomial test at a significance
level of 0.0250. The null hypothesis can be rejected, if at least 10 out of 50 patients
treated show a PFS ratio ≥ 1.3. The investigators therefore aim to enroll 49 leukemia
patients and 49 lymphoma patients.
Target population. Patients with relapsed/ refractory acute leukemia and relapsed/ refractory
aggressive lymphoma after standard treatment. Standard treatment is defined according to
actual National Comprehensive Cancer Network (NCCN)
(http://www.nccn.org/professionals/physician_gls/f_guidelines.asp) and/or local guidelines.
49 acute leukemia subjects and 49 lymphoma subjects will be screened for enrolment in the
trial. Deviations from inclusion criteria are not allowed because they can potentially
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.
Therefore, adherence to the criteria as specified in the protocol is essential. Inclusion
criteria as well as exclusion criteria must be respected.