E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed chronic lymphocytic leukemia |
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E.1.1.1 | Medical condition in easily understood language |
Chronic lymphocytic leukemia which has been previously treated and disease has returned. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008958 |
E.1.2 | Term | Chronic lymphocytic leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | 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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E.2.2 | Secondary objectives of the trial |
To determine the effect of NOX-A12 alone and combined with BR on the mobilization of peripheral blood CD34+ cells and CLL cells
To determine the overall response rate (ORR=CR + PR)
To determine time to event endpoints such as progression free survival (PFS), event free survival (EFS), time to progression (TTP), duration of response (DOR) and overall survival (OS) after treatment with NOX-A12 in combination with BR
To determine the plasma concentration of SDF-1 after treatment with NOX-A12 alone (pilot group only) and in combination with BR
To determine the pharmacokinetics of NOX-A12 alone (pilot group only) and in combination with BR |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male of female, age ≥ 18
2. Diagnosis of B cell CLL
3. Relapsed, bendamustine-sensitive (at least partial response with a duration of at least six months) or bendamustine-naive patients after at least one but not more than 3 prior treatments of their disease.
4. CLL in need of treatment (Binet C or A/B with active disease) according to the IWCLL guidelines
5. Subject must have measurable disease according to IWCLL guidelines
6. Pre-study WHO performance status of ≤ 2 and modified cumulative illness rating scale (CIRS) of less than 7
7. Signed and dated, written informed consent
8. Men and women of reproductive potential must agree to follow accepted birth control methods during treatment and for 3 months after completion of treatment. Medically acceptable methods of birth control are methods with a low failure rate of less than 1% per year; e.g. hormonal contraceptives for at least the 7 days before trial enrolment or an interuterine device, or double barrier method (male or female condom or diaphragm, in combination with a spermicidal gel). All women, including those with tubal ligation, are considered to be of childbearing potential unless they have been postmenopausal for at least 2 years. Hysterectomized women are considered surgically sterile and are not required to use any contraception.
9. Acceptable liver function at screening: bilirubin ≤1.5 x ULN, AST and/or ALT ≤ 2.5 x ULN
10. Acceptable heamatological status: platelet count ≥ 75 x10 9/L, ANC > 0.75 x 10 9/L
11. Acceptable renal function: serum creatinine ≤1.5 ULN and/or creatinine clearance ≥ 50 ml/min (Cockcroft Gault formula)
12. No clinical significant abnormalities of liver volume, liver heamodynamics or elasticity, measured by abdominal ultrasound. |
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E.4 | Principal exclusion criteria |
1. Relapse of B-cell CLL within 6 months after last chemotherapy
2. Subjects who have progressed to more aggressive B-cell cancers such as Richter's syndrome
3. CLL with either deletion of the short arm of chromosome 17 (17p-) or mutations associated with the loss of p53
4. The subject has a history of or is clinically suspicious of cancer related CNS disease
5. Patients at risk of hemostasis or spleen rupture
6. Autoimmune hemolytic anemia
7. Prior allogeneic stem cell transplant or patients who are considered to be candidates for allo SCT as assessed by their treating physician
8. Patient has a history of other active malignancies within three years prior to study entry, with the exception of: adequately treated in situ carcinoma of the cervix uteri; basal or squamous cell carcinoma of the skin; in situ carcinoma of the bladder; previous malignancy confirmed and surgically resected with curative intent.
9. The patient exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to: uncontrolled systemic infection (viral, bacterial or fungal); diagnosis of fever and neutropenia within 1 week prior to study drug administration
10. Female subject is pregnant or breast feeding
11. Known infection with HIV, active Hepatitis B or Hepatitis C
12. The patient has a history of prior toxicity from bendamustine or rituximab that resulted in permanent discontinuation of treatments.
13. Treatment with other investigational drugs, or participation in another clinical trial within 30 days prior to study drug administration
14. Uncontrolled hypertension (defined as systolic blood pressure (BP) > 160 mmHg or diastolic BP >100mmHg)
15. Myocardial infarction or unstable angina within the past 6 months prior to study drug administration. Heart failure of New York Heart Association functional Class III or IV prior to study drug administration.
16. Systemic illnesses or other severe concurrent disease including alcoholism which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and efficacy of the investigational treatment
17. Known or suspected of not being able to comply with the trial protocol
18. Having previously enrolled in this clinical trial
19. Known hypersensitivity to rituximab or to any of the excipients or to murine proteins
20. History of recurring or chronic infections or underlying conditions which may further predispose patients to serious infection
21. Known hypersensitivity to bendamustine or to mannitol
22. Invasive surgery within 30 days prior to study drug administration |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety
the safety evaluation will be based on the following assessments:
- adverse events
- vital signs
- 12 lead ECG
- laboratory parameters (CBC, platelets, differential WBC count, serum chemistry, coagulation parameters, urinalysis)
- immunogenicity
- physical examinations
Remission Rates
Assessment of overall tumour response - as measured by lymphadenopathy, splenamegaly, hepatomegaly, bone marrow cell counts, peripheral platelet and neutophil counts and heamoglobin measurements. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety - throughout the treatment period and for 30 days post last dose
Efficacy - at the end of Cycle 3 and Cycle 6 of treatment |
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E.5.2 | Secondary end point(s) |
- mobilization of CD34+ and CLL cells
- immunophenotyping and cell surface antigens of CD34+ and CLL cells
- disease assessment, as per the primary endpoint
- survival free of disease
- death
- pharmacokinetic analysis of SDF-1 in plasma
- pharmacokinetic analysis of NOX-A12 in plasma |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Characterisation of circulating blood cells - Pilot group only - Day 1,2 and 4 post first dose. All patients - Day 1 and 2, Cycle 1 and 4
Pharmacokinetic analysis - Pilot group only - Day 1, 2 and 4 post first dose. All patients - Day 1 Cycle 1 and 4
Progression - 12 weekly intervals for 30 months post end of treatment |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial will be the date of the last patient last contact in the expansion phase of the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |