NOX-A12 in Combination With Bendamustine and Rituximab in Relapsed Chronic Lymphocytic Leukemia (CLL)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of NOX A12 in combination with a background therapy of bendamustine and rituximab (BR) chemotherapy in previously treated patients with chronic lymphocytic leukemia (CLL).

Detailed Description
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CLL cells express high levels of CXCR4 chemokine receptors, which cause leukemia cell migration and adhesion to stromal cells secreting the CXCR4 ligand, CXCL12 (or stromal-derived-factor 1, SDF-1). NOX A12 is a specific CXCL12 antagonist and may improve BR therapy by disrupting CXCR4-CXCL12 interactions, thereby mobilizing CLL cells from protective tissue microenvironments to the blood. Furthermore, SDF-1 inhibition may alter the activation status of CLL cells, thereby triggering apoptosis or sensitization of CLL cells towards chemotherapy.

Official Title
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A Multi-center, 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)

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: NOX-A12


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of B-cell CLL 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. CLL in need of treatment (Binet C or A/B with active disease) according to Hallek et al. 2008 Subject must have measurable disease according to NCI-WG criteria (for details see Hallek M, Blood 2008; 111: 5446-5456). Pre-study WHO performance status ≤ 2 and modified cumulative illness rating score (CIRS) of less than 7. Signed, written informed consent. Men and women of reproductive potential must agree to follow accepted birth control methods during treatment and for 3 months after completion of treatment. Acceptable liver function: Bilirubin ≤ 1.5 x upper limit of normal (ULN) at screening, AST (SGOT) and/or ALT (SGPT) ≤ 2.5 x ULN. Acceptable hematologic status: Platelet count ≥ 75 x 109/L, ANC > 0.75x109/L. Acceptable renal function: Serum creatinine ≤1.5 ULN and/or calculated creatinine clearance (Cockroft-Gault Formula) ≥ 50 mL/min Male or female, age ≥ 18 No clinically significant abnormalities of liver volume, liver hemodynamics or elasticity, measured by abdominal ultrasound. Exclusion Criteria: Relapse of B-cell CLL within 12 months after last chemotherapy. Subjects who have progressed to more aggressive B-cell cancers such as Richter's syndrome. CLL with documented loss of the short arm of chromosome 17 (17p-) associated with the loss of p53. The subject has a history of or is clinically suspicious for cancer-related Central Nervous System disease. Patients at risk of hemostasis or spleen rupture. Autoimmune hemolytic anemia. Prior allogeneic stem cell transplant (alloSCT) or patients who are considered to be candidates for allo SCT as assessed by their treating physician 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 confined and surgically resected with curative intent. 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. Female subject is pregnant or breast-feeding. Known infection with HIV, active Hepatitis B or Hepatitis C. The patient has a history of prior toxicity from bendamustine or rituximab that resulted in permanent discontinuation of treatments. Treatment with other investigational drugs, or participation in another clinical trial within 30 days prior to study drug administration. Uncontrolled hypertension (defined as systolic blood pressure (BP) > 160 mm Hg or diastolic BP > 100 mm Hg). Myocardial infarction or unstable angina within the past 6 months prior to study drug administration. 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 treatments. Known or suspected of not being able to comply with the trial protocol. Having been previously enrolled in this clinical trial. Known hypersensitivity to rituximab or to any of the excipients or to murine proteins History of recurring or chronic infections or underlying conditions which may further predispose patients to serious infection. Known hypersensitivity to bendamustine or to mannitol. Invasive surgery within 30 days prior to study drug administration.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NOX-A12<br> | Drug: NOX-A12<br>* Pilot Group (NOX-A12 single agent, and combined with BR): 3 cohorts of 3 patients will receive treatment with NOX-A12 alone at a single dose of 1, 2 or 4 mg/kg i.v. 2 weeks before the combination treatment of NOX-A12 and BR begins.The combination of NOX-A12 and BR will follow a dose titration design beginning at 1 mg/kg NOX-A12 (cycle 1), proceeding to dose levels of 2 mg/kg (cycle 2) and 4 mg/kg (cycle 3) NOX-A12 in combination with BR. This is followed by consolidation in cycles 4-6 when NOX-A12 will be kept at the highest individually titrated dose. Expansion Group (NOX-A12 in combination with BR): Expansion patients will not receive single agent NOX-A12, but will receive combination treatment as for the pilot group.<br>* Other names: olaptesed pegol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of NOX A12 alone and in combination with BR. | The safety evaluation will be based on the following assessments: adverse events vital signs 12 lead ECGs laboratory parameters immunogenicity | 30 months | 
| Complete remission (CR) rate | Assessment of the complete remission rate after cycle 3 and 6 will be the primary efficacy endpoint. The 1996 NCI-WG criteria which have been updated in 2008 will be applied. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamics of NOX-A12 alone and in combination with BR | The pharmacodynamics evaluation will be based on the following assessments: mobilization of peripheral blood CD34+ cells and CLL cells plasma concentration of SDF-1/CXCL12 | 6 months | 
| Overall response rate (ORR = CR + PR) |  | 6 months | 
| Progression free survival (PFS) |  | 30 months | 
| Pharmacokinetics of NOX-A12 alone and in combination with BR | The pharmacokinetics evaluation will be based on the following assessments: plasma concentration of NOX-A12 24-hour urine excretion of NOX-A12 | 10 time points over 6 months | 
| Event free survival (EFS) |  | 30 months | 
| Time to progression (TTP) |  | 30 months | 
| Duration of response (DOR) |  | 30 months | 
| Overall survival (OS) |  | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed Chronic Lymphocytic Leukemia (CLL), NOX-A12, Bendamustine, Rituximab, Spiegelmer, Chemosensitization, Stromal cell-derived factor-1 (SDF-1), CXCL12