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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
NOXXON Pharma AG
ClinicalTrials.gov Identifier:
NCT01486797
First received: December 1, 2011
Last updated: June 25, 2014
Last verified: June 2014
  Purpose

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 Intervention Phase
Chronic Lymphocytic Leukemia
Drug: NOX-A12
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by NOXXON Pharma AG:

Primary Outcome Measures:
  • Safety and tolerability of NOX A12 alone and in combination with BR. [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]

    The safety evaluation will be based on the following assessments:

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

  • Complete remission (CR) rate [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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:
  • Pharmacodynamics of NOX-A12 alone and in combination with BR [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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

  • Overall response rate (ORR = CR + PR) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Progression free survival (PFS) [ Time Frame: 30 months ] [ Designated as safety issue: No ]
  • Pharmacokinetics of NOX-A12 alone and in combination with BR [ Time Frame: 10 time points over 6 months ] [ Designated as safety issue: No ]

    The pharmacokinetics evaluation will be based on the following assessments:

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

  • Event free survival (EFS) [ Time Frame: 30 months ] [ Designated as safety issue: No ]
  • Time to progression (TTP) [ Time Frame: 30 months ] [ Designated as safety issue: No ]
  • Duration of response (DOR) [ Time Frame: 30 months ] [ Designated as safety issue: No ]
  • Overall survival (OS) [ Time Frame: 30 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 33
Study Start Date: March 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01486797

Locations
Austria
Medical University Innsbruck, Division of Hematology and Oncology
Innsbruck, Austria
University Hospital Salzburg, Department of Medicine III, Center of Oncology and Hematology
Salzburg, Austria
Landeskrankenhaus Steyr, Department of Internal Medicine II (Hematology and Oncology)
Steyr, Austria
Hospital Wels-Grieskrichen, Department of Internal Medicine IV (Hematology and Oncology)
Wels, Austria
Belgium
Institute Jules Bordet, Department of Hematology
Brussels, Belgium
Cliniques universitaires Saint-Luc
Brussels, Belgium
University Hospital Gasthuisberg, Department of Hematology
Leuven, Belgium
France
Centre Hospitalier Universitaire Clémenceau, Department of Hematology
Caen, France
Hospices Civils, Department of Hematology
Lyon, France
Centre Hospitalier Universitaire de la Milétrie, Department of Hematology
Poitiers, France
Italy
University Hospital, Institute of Hematology and Oncology
Bologna, Italy
Azienda Sanitaria Locale 8, Department of Oncology
Cagliari, Italy
University Hospital San Martino, Department of Hematology and Oncology
Genova, Italy
University Scientific Research Institute San Raffaele
Milano, Italy
Niguarda Ca'Granda Hospital
Milano, Italy
University School of Medicine, Department of Hematology
Padova, Italy
University La Sapienza, Department of Cellular Biotechnologies and Hematology
Rome, Italy
Sponsors and Collaborators
NOXXON Pharma AG
Investigators
Study Director: Kai Riecke, MD NOXXON Pharma AG
  More Information

No publications provided

Responsible Party: NOXXON Pharma AG
ClinicalTrials.gov Identifier: NCT01486797     History of Changes
Other Study ID Numbers: SNOXA12C201, 2011-004672-11
Study First Received: December 1, 2011
Last Updated: June 25, 2014
Health Authority: Italy: The Italian Medicines Agency
Belgium: Federal Agency for Medicinal Products and Health Products
Austria: Federal Office for Safety in Health Care
France: Agence Nationale de Sécurité du Médicament et des produits de santé

Keywords provided by NOXXON Pharma AG:
Relapsed Chronic Lymphocytic Leukemia (CLL)
NOX-A12
Bendamustine
Rituximab
Spiegelmer
Chemosensitization
Stromal cell-derived factor-1 (SDF-1)
CXCL12

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Immune System Diseases
Immunoproliferative Disorders
Leukemia, B-Cell
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Bendamustine
Rituximab
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014