Clinical Trial Results:
A multi-centre, open label, uncontrolled, Phase IIa clinical trial evaluating the safety and efficacy of NOX-A12 in combination with a background therapy of bendamustine and rituximab (BR) in previously treated patients with chronic lymphocytic leukemia (CLL)
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Summary
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EudraCT number |
2011-004672-11 |
Trial protocol |
DE BE IT AT |
Global end of trial date |
24 Apr 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Dec 2017
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First version publication date |
24 Dec 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
14SNOXA12C201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01486797 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
NOXXON Pharma AG
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Sponsor organisation address |
Max-Dohrn-Strasse 8-10, Berlin, Germany, 10589
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Public contact |
Clinical Trial Disclosure Desk NOXXON, NOXXON Pharma AG, clinicaltrialdisclosuredesk@noxxon.com
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Scientific contact |
Clinical Trial Disclosure Desk NOXXON, NOXXON Pharma AG, clinicaltrialdisclosuredesk@noxxon.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Jul 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
24 Apr 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Apr 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the safety and tolerability of NOX-A12 alone (pilot group only) and in combination with BR.
To determine the complete remission (CR) rate.
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Protection of trial subjects |
This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, 2005/28/EC, and 2003/63/EC and relevant national and local legislations, and with the ethical principles that have their origin in the Declaration of Helsinki. Only subjects that met all the study inclusion and none of the exclusion criteria were randomized. Study drug administrations were performed by qualified and trained study personnel. Patient who received treatment were closely followed by means of adverse event reporting and vital signs. In the event of a study related adverse event, patients were monitored to determine the outcome. The clinical course of the AE was followed up according to accepted standards of medical practice, even after the end of the period of observation, until a satisfactory explanation is found or the Investigator considered it medically justifiable to terminate follow-up.
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Background therapy |
bendamustine and rituximab | ||
Evidence for comparator |
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Actual start date of recruitment |
21 May 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 13
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Country: Number of subjects enrolled |
Belgium: 1
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Country: Number of subjects enrolled |
Italy: 14
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Worldwide total number of subjects |
28
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EEA total number of subjects |
28
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
8
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From 65 to 84 years |
20
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||
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Pre-assignment
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Screening details |
32 patients with diagnosis of relapsed/refractory CLL for which bendamustine / rituximab would be given as standard of care were screened; 4 patients were screening failure. After a screening period of 2 weeks 28 patients were enrolled. | ||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||
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Arms
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Arm title
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Olaptesed pegol + BR | ||||||||||||||||
Arm description |
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Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Olaptesed pegol
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Investigational medicinal product code |
NOX-A12
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Pilot group: 1, 2, or 4 mg/kg body weight olaptesed pegol given as single i.v. injections on Day -14. If no DLT occurred, doses given on Day 1 of each 28-day cycle were 1 mg/kg for Cycle 1, 2 mg/kg for Cycle 2 and 4 mg/kg for Cycle 3 and the highest individually titrated doses through cycles 4 to 6.
Expansion group: i.v. injections of 1 mg/kg body weight olaptesed pegol for Cycle 1, 2 mg/kg for Cycle 2 and 4 mg/kg for Cycle 3 given on Day 1 of each 28-day cycle and the highest individually titrated doses through cycles 4 - 6.
Doses were calculated according to screening body weight. In case body weight changed by more than 10%, the dose was re-calculated.
Single-use, preservative-free, sterile solution of olaptesed pegol in an aqueous glucose solution for adjustment of tonicity to physiological levels.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial (overall period)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Olaptesed pegol + BR
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Reporting group description |
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End point title |
Complete remission rate [1] | ||||||||
End point description |
The primary efficacy variable was to determine the complete remission rate according to IWCLL guidelines.
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End point type |
Primary
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End point timeframe |
Six (6) 28-day cycles of treatment
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: It was planned to test for a higher CR than the historical control of 15%, based on published CLL data after treatment with BR alone ranging from 9% (Fischer 2011) to 19% (Waldthaler 2011). Recent data with novel drugs inducing lymphocytosis by mechanisms that interfere with the CXCL12/CXCR4 axis (e.g. ibrutinib, idelalisib) cast doubt whether this is a valid assumption. Results suggest that ORR is a more appropriate end-point regarding the MoA of olaptesed. ORR at the end of treatment was 86%. |
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| Notes [2] - One patient was without disease assessment and thus excluded from analysis. |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From time the patient gives informed consent until 30 days after the last NOX-A12 administration
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
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Reporting groups
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Reporting group title |
Olaptesed pegol + BR
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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13 Apr 2012 |
IC8: permissible forms of reliable contraceptive methods are included in the IC, as per ‘Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals’ (CPMP/ICJ/286/95, amendment)
EC5: initial EC5 appears to be in conflict with IC5: "Subject must have measurable disease according to IWCLL criteria (Hallek et al.)." With respect to the WBC, the guideline states: Progr. lymphocytosis with an increase of more than 50% over a 2-mth period or lymphocyte doubling time (LDT) of less than 6 months. LDT can be obtained by lin. reg. extrapolation of abs. lymphocyte counts obtained at intervals of 2 wks over an observation period of 2-3 mths. In pts with initial blood lymphocyte counts of <30,000/μL, LDT should not be used as a single parameter to define a treatment indication. Pts with CLL may present with a markedly elevated leukocyte count; however, the symptoms associated with leukocyte aggregates that develop in pts with acute leukemia rarely occur in pts with CLL. Therefore, the absolute lymphocyte count should not be used as the sole indicator for treatment. In CLL pts, symptoms of leukostasis are rare unless the WBC count exceeds 400,000/μL. This is mainly due to the fact that malignant B cells are much smaller than, for example, malignant cells of the myeloid lineage seen in AML and CML
EC15: add. safety measure, pts with concomitant diseases; e.g. heart diseases; will be excluded from the study
Add. safety measure: pts with contraindications noted in the rituximab and bendamustine SPCs will be excluded from the study
Add. PK/SDF-1 samples to allow assessment of plasma clearance and half-life of NOX-A12 in combination with BR
Clarification: ECGs, vitals, samples for PK/SDF-1 & CD34+ & CLL cell analysis are taken 1 h after NOX-A12, and before BR
Add. safety measure and clarification: investigators will assess event relationship to NOX-A12, rituximab and bendamustine and will be included in listings and tables
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10 Jul 2012 |
In accordance with ANSM request, contraception prolonged to duration specified in SmPC for background therapies.
In accordance with ANSM request, additional pregnancy tests each cycle to ensure continued maintenance of contraception during treatment.
In accordance with ANSM request, contraception prolonged to duration specified in SmPC for background therapies. In compliance with bendamustine SmPC, discussion with men of reproductive age regarding infertility risk.
In accordance with ANSM request, additional pregnancy tests each cycle to ensure continued maintenance of contraception during treatment.
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19 Sep 2012 |
Additional samples required in Cycle 4 to show the profile of CD34+ cells and CLL cell counts following repeat dosing of NOX-A12 in combination with chemotherapy |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
