Clinical trial NCT01486797: NOX-A12 in Combination With Bendamustine and Rituximab in Relapsed Chronic Lymphocytic Leukemia (CLL)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
Keywords: Relapsed Chronic Lymphocytic Leukemia (CLL)
NOX-A12
Bendamustine
Rituximab
Spiegelmer
Chemosensitization
Stromal cell-derived factor-1 (SDF-1)
CXCL12
Lead sponsor: TME Pharma AG
Sponsor class: INDUSTRY
First posted: 2011-12-07
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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 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.

Primary outcomes:
measure: Safety and tolerability of NOX A12 alone and in combination with BR.
timeFrame: 30 months
measure: Complete remission (CR) rate
timeFrame: 6 months
Secondary outcomes:
measure: Pharmacodynamics of NOX-A12 alone and in combination with BR
timeFrame: 6 months
measure: Overall response rate (ORR = CR + PR)
timeFrame: 6 months
measure: Progression free survival (PFS)
timeFrame: 30 months
measure: Pharmacokinetics of NOX-A12 alone and in combination with BR
timeFrame: 10 time points over 6 months
measure: Event free survival (EFS)
timeFrame: 30 months
measure: Time to progression (TTP)
timeFrame: 30 months
measure: Duration of response (DOR)
timeFrame: 30 months
measure: Overall survival (OS)
timeFrame: 30 months
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Medical University Innsbruck, Division of Hematology and Oncology
city: Salzburg
country: Austria
facility: University Hospital Salzburg, Department of Medicine III, Center of Oncology and Hematology
city: Steyr
country: Austria
facility: Landeskrankenhaus Steyr, Department of Internal Medicine II (Hematology and Oncology)
city: Wels
country: Austria
facility: Hospital Wels-Grieskrichen, Department of Internal Medicine IV (Hematology and Oncology)
city: Brussels
country: Belgium
facility: Cliniques universitaires Saint-Luc
city: Brussels
country: Belgium
facility: Institute Jules Bordet, Department of Hematology
city: Leuven
country: Belgium
facility: University Hospital Gasthuisberg, Department of Hematology
city: Caen
country: France
facility: Centre Hospitalier Universitaire Clémenceau, Department of Hematology
city: Lyon
country: France
facility: Hospices Civils, Department of Hematology
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire de la Milétrie, Department of Hematology
city: Bologna
country: Italy
facility: University Hospital, Institute of Hematology and Oncology
city: Cagliari
country: Italy
facility: Azienda Sanitaria Locale 8, Department of Oncology
city: Genova
country: Italy
facility: University Hospital San Martino, Department of Hematology and Oncology
city: Milano
country: Italy
facility: Niguarda Ca'Granda Hospital
city: Milano
country: Italy
facility: University Scientific Research Institute San Raffaele
city: Padova
country: Italy
facility: University School of Medicine, Department of Hematology
city: Rome
country: Italy
facility: University La Sapienza, Department of Cellular Biotechnologies and Hematology
Study officials:
affiliation: TME Pharma AG
name: Kai Riecke, MD
role: STUDY_DIRECTOR
References:
citation: Steurer M, Montillo M, Scarfo L, Mauro FR, Andel J, Wildner S, Trentin L, Janssens A, Burgstaller S, Fromming A, Dummler T, Riecke K, Baumann M, Beyer D, Vauleon S, Ghia P, Foa R, Caligaris-Cappio F, Gobbi M. Olaptesed pegol (NOX-A12) with bendamustine and rituximab: a phase IIa study in patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica. 2019 Oct;104(10):2053-2060. doi: 10.3324/haematol.2018.205930. Epub 2019 May 16.
citation: Park EJ, Choi J, Lee KC, Na DH. Emerging PEGylated non-biologic drugs. Expert Opin Emerg Drugs. 2019 Jun;24(2):107-119. doi: 10.1080/14728214.2019.1604684. Epub 2019 Apr 19.