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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01486797
Recruitment Status : Completed
First Posted : December 7, 2011
Last Update Posted : May 22, 2017
Information provided by (Responsible Party):

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: NOX-A12 Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 28 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Study Start Date : March 2012
Actual Primary Completion Date : November 2014
Actual Study Completion Date : April 2017

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: NOX-A12 Drug: NOX-A12

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.
Other Name: olaptesed pegol

Primary Outcome Measures :
  1. Safety and tolerability of NOX A12 alone and in combination with BR. [ Time Frame: 30 months ]

    The safety evaluation will be based on the following assessments:

    • adverse events
    • vital signs
    • 12 lead ECGs
    • laboratory parameters
    • immunogenicity

  2. Complete remission (CR) rate [ Time Frame: 6 months ]
    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.

Secondary Outcome Measures :
  1. Pharmacodynamics of NOX-A12 alone and in combination with BR [ Time Frame: 6 months ]

    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

  2. Overall response rate (ORR = CR + PR) [ Time Frame: 6 months ]
  3. Progression free survival (PFS) [ Time Frame: 30 months ]
  4. Pharmacokinetics of NOX-A12 alone and in combination with BR [ Time Frame: 10 time points over 6 months ]

    The pharmacokinetics evaluation will be based on the following assessments:

    • plasma concentration of NOX-A12
    • 24-hour urine excretion of NOX-A12

  5. Event free survival (EFS) [ Time Frame: 30 months ]
  6. Time to progression (TTP) [ Time Frame: 30 months ]
  7. Duration of response (DOR) [ Time Frame: 30 months ]
  8. Overall survival (OS) [ Time Frame: 30 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Diagnosis of B-cell CLL
  2. 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.
  3. CLL in need of treatment (Binet C or A/B with active disease) according to Hallek et al. 2008
  4. Subject must have measurable disease according to NCI-WG criteria (for details see Hallek M, Blood 2008; 111: 5446-5456).
  5. Pre-study WHO performance status ≤ 2 and modified cumulative illness rating score (CIRS) of less than 7.
  6. Signed, written informed consent.
  7. Men and women of reproductive potential must agree to follow accepted birth control methods during treatment and for 3 months after completion of treatment.
  8. Acceptable liver function: Bilirubin ≤ 1.5 x upper limit of normal (ULN) at screening, AST (SGOT) and/or ALT (SGPT) ≤ 2.5 x ULN.
  9. Acceptable hematologic status: Platelet count ≥ 75 x 109/L, ANC > 0.75x109/L.
  10. Acceptable renal function: Serum creatinine ≤1.5 ULN and/or calculated creatinine clearance (Cockroft-Gault Formula) ≥ 50 mL/min
  11. Male or female, age ≥ 18
  12. No clinically significant abnormalities of liver volume, liver hemodynamics or elasticity, measured by abdominal ultrasound.

Exclusion Criteria:

  1. Relapse of B-cell CLL within 12 months after last chemotherapy.
  2. Subjects who have progressed to more aggressive B-cell cancers such as Richter's syndrome.
  3. CLL with documented loss of the short arm of chromosome 17 (17p-) associated with the loss of p53.
  4. The subject has a history of or is clinically suspicious for cancer-related Central Nervous System disease.
  5. Patients at risk of hemostasis or spleen rupture.
  6. Autoimmune hemolytic anemia.
  7. Prior allogeneic stem cell transplant (alloSCT) 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 confined 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 mm Hg or diastolic BP > 100 mm Hg).
  15. Myocardial infarction or unstable angina within the past 6 months 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 treatments.
  17. Known or suspected of not being able to comply with the trial protocol.
  18. Having been 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01486797

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Sponsors and Collaborators
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Study Director: Kai Riecke, MD NOXXON Pharma AG
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: NOXXON Pharma AG Identifier: NCT01486797    
Other Study ID Numbers: SNOXA12C201
2011-004672-11 ( EudraCT Number )
First Posted: December 7, 2011    Key Record Dates
Last Update Posted: May 22, 2017
Last Verified: May 2017
Keywords provided by NOXXON Pharma AG:
Relapsed Chronic Lymphocytic Leukemia (CLL)
Stromal cell-derived factor-1 (SDF-1)
Additional relevant MeSH terms:
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Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell