Clinical trial NCT01294579: Ofatumumab and Bendamustine Followed by Maintenance Ofatumumab for Rituximab Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (B-NHL)
Official title: A Phase II Open-Label Study of Ofatumumab and Bendamustine Followed by Maintenance Ofatumumab for Indolent B-cell Non-Hodgkin's Lymphoma (B-NHL) Which Has Relapsed After Rituximab or a Rituximab Containing Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lymphoma, Non-Hodgkin
Keywords: Non-Hodgkin's Lymphoma
Ofatumumab
Relapsed
Rituximab
Bendamustine
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-02-11
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: The purpose of this phase II open label study was is to evaluate the safety and efficacy of ofatumumab and bendamustine followed by maintenance ofatumumab in subjects with indolent B-NHL who had relapsed after Rituximab treatment. A maximum of 53 subjects at least 18 years old with Small lymphocytic, lymphoplasmacytic, marginal zone lymphoma, or follicular lymphoma; Grades 1, 2 and 3a, would have been enrolled (34 in Stage 1 and 19 in Stage 2). Subjects should have had Rituximab-sensitive disease, defined as a Partial Remission (PR) or Complete Remission (CR) to the last rituximab-containing therapy lasting at least 6 months following completion of therapy or subjects should have relapsed or have had disease progression following response to prior rituximab-based therapy a Eastern Cooperative Oncology Group (ECOG) Performance status of 0 1 or 2. During the induction phase, ofatumumab 1000 mg IV on day 1 of each cycle (cycles 1-6) were followed by Bendamustine 90 mg/m2 IV on days 1, 2 of each cycle (cycles 1-6).During the maintenance phase, subjects with a PR or CR after the induction phase received ofatumumab 1000 mg IV every 2 months for 2 years.


Eligibility criteria: Inclusion Criteria:

* Signed written informed consent
* Small lymphocytic, lymphoplasmacytic, marginal zone lymphoma, and follicular lymphoma; Grades 1, 2 and 3a, defined according to World Health organization (WHO) guidelines. \[Tefferi, 2008\]
* Tumor was verified to be CD20+ (based on local evaluation), from a current or previous tissue biopsy. Tissue biopsy should be repeated if no report or specimen is available, CD20 staining was not previously performed, or there is clinical suspicion that the indolent lymphoma has transformed to aggressive lymphoma/higher malignancy grade.
* Rituximab-sensitive disease, defined as a Partial Remission (PR) or Complete Remission (CR) to the last rituximab-containing therapy lasting at least 6 months following completion of therapy. Last rituximab-containing therapy is defined as the last therapy regimen containing at least one full dose of rituximab.
* Relapse or disease progression following response to prior rituximab-based therapy, that requiried treatment by 2007 Revised Response Criteria for Malignant Lymphoma (RRCML) guidelines.
* CT imaging in screening (based on local evaluation) showing 2 or more clearly demarcated lesions with a largest diameter \> 1.5 cm, or 1 clearly demarcated lesion with a largest diameter \> 2.0 cm.
* ECOG Performance Status of 0, 1, or 2.
* Age ≥ 18 years.
* Life expectancy of at least 6 months in the opinion of the investigator.
* Women of childbearing potential must have had a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception during the study and for one year following the last dose of study drug.
* Men with a female partner of childbearing potential must have had either had a prior vasectomy or agree to use effective contraception from 2 weeks prior to administration of the first dose of study treatment until one year after the last dose of study treatment.
* Must not have been on any prohibited medications.
* Subjects who had received prior bendamustine were eligible if they had achieved a response (CR/PR) which lasted \> 6 months after the end of bendamustine containing treatment.

Exclusion Criteria:

* Lactating women
* CLL, Grade 3b follicular lymphoma or evidence that the indolent lymphoma had transformed to aggressive lymphoma. Subjects suspicious for transformation should have undergone a biopsy to exclude the possibility of transformation. Subjects with a previous diagnosis of small lymphocytic leukemia (SLL) and a screening monoclonal B-lymphocyte count of ≥ 5000/µl are defined by 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria to have CLL; such patients were NOT eligible for this study.
* Rituximab-refractory disease, defined as failure to have responded to or progression within 6 months of completing rituximab or rituximab-containing combination therapy.
* Previous treatment with ofatumumab.
* Previous radioimmunotherapy (RIT) within 6 months of study entry. Subjects who have received RIT must have attained a PR or CR lasting at least 6 months, and must have recovered from any hematologic or other toxicity.
* Previous allogeneic stem cell transplantation at any time OR autologous stem cell transplantation within 6 months of study entry.
* Prior use of monoclonal antibody (other than anti CD20) within 3 months prior to randomization. Chemotherapy or other systemic lymphoma therapy within 4 weeks of study entry.
* Received treatment with an investigational agent within 4 weeks of study entry, or was actively participating in another interventional clinical study.
* Known Central Nervous System (CNS) involvement by lymphoma.
* Current or previous other malignancy within 2 years of study entry. Exception: Subjects who have been disease-free for 2 years or more, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
* Chronic or currently active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment including, but not limited to: chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, active Hepatitis C, and known HIV disease. All Human Immunodeficient virus (HIV)-positive subjects are excluded from this study, regardless of whether they have an Acquired Immunodeficiency Syndrome (AIDS) defining disease and/or are on antiviral therapy.
* Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months of study entry, uncontrolled congestive heart failure, and uncontrolled arrhythmia. Subjects with congestive heart disease or arrhythmia such as atrial fibrillation whose cardiac disease is well controlled on a stable medical regimen are eligible.
* Other significant concurrent, uncontrolled medical conditions including, but not limited to, renal, hepatic, autoimmune, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which, in the Investigator's opinion, will impact study participation.
* Positive serology for Hepatitis B (HB) defined as a positive test for Hepatitis B surface antigen (HBsAg). In addition, if negative for HBsAg but (Hepatitis B core antibody (HBcAb) positive (regardless of Hepatitis B surface antibody \[HBsAb\] status), a HB DNA test had to have been performed and if positive the subject will be excluded. If HBV DNA is negative, subject may be included but must have undergone HBV DNA monitoring. Prophylactic antiviral therapy may have been initiated at the discretion of the investigator.
* Current active liver or biliary disease. Exception: Subjects with Gilbert's syndrome or asymptomatic gallstones, liver metastases related to indolent NHL or otherwise stable chronic liver disease per investigator assessment, are eligible.
* Screening laboratory values:

Neutrophils \< 1.5 x 109/L (unless due to NHL involvement of the bone marrow). Platelets \< 100 x 109/L (unless due to NHL involvement of the bone marrow). Serum creatinine ≥2.0 mg/dL; subjects with serum creatinine ≥2.0 mg/dL were are eligible if the creatinine clearance (Cockcroft Gault equation \[Cockcroft, 1976\]) is ≥40 mL/min.

Total bilirubin \> 1.5 times ULN \[upper normal limit\] (unless due to liver involvement by NHL or Gilbert's disease).

Transaminases \> 3 times ULN (unless due to NHL involvement).

* Known or suspected inability to fully comply with study protocol.
* Known or suspected hypersensitivity to ofatumumab, bendamustine or mannitol.

Primary outcomes:
measure: Complete Remission (CR) Rate of Induction Therapy After Cycle 6 (28 Days) (FAS)
timeFrame: Baseline up to 24 weeks
Secondary outcomes:
measure: Overall Response Rate (ORR) During Induction Phase After Cycle 6 (FAS)
timeFrame: Baseline up to 24 weeks
measure: Conversion Rate of Partial Response in Induction Phase to Complete Response With Maintenance Ofatumumab (FAS)
timeFrame: Partial response in induction phase up to 24 weeks
measure: Percentage of Participants With Progression Free Survival (PFS) up to 30 Months (FAS)
timeFrame: Baseline up to approximately 30 months
measure: Kaplan-Meier Estimates of Progression Free Survival up to 30 Months (FAS)
timeFrame: Baseline up to approximately 30 months
measure: Pharmacokinetic Profile Which Includes Measuring Blood Levels of Ofatumumab and Bendamustine in Combination and Ofatumumab Alone During Maintenance Treatment and Measuring Blood Levels of Circulating B Cell
timeFrame: up to 30 months
measure: All Deaths by Preferred Term (Safety Set) up to Approximately 30 Months
timeFrame: Baseline up to approximately 30 months
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Burbank
country: United States
facility: Novartis Investigative Site
state: California
city: Fresno
country: United States
facility: Novartis Investigative Site
state: California
city: Oxnard
country: United States
facility: Novartis Investigative Site
state: California
city: Aurora
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Orange Park
country: United States
facility: Novartis Investigative Site
state: Florida
city: Burlington
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Omaha
country: United States
facility: Novartis Investigative Site
state: Nebraska
city: Las Vegas
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Cary
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Charlotte
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Raleigh
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Kettering
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Eugene
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Charleston
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Greenville
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: San Antonio
country: United States
facility: Novartis Investigative Site
state: Texas
city: Sherman
country: United States
facility: Novartis Investigative Site
state: Texas
city: Tyler
country: United States
facility: Novartis Investigative Site
state: Texas
city: Waco
country: United States
facility: Novartis Investigative Site
state: Texas
city: Vancouver
country: United States
facility: Novartis Investigative Site
state: Washington
city: Yakima
country: United States
facility: Novartis Investigative Site
state: Washington
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Lyons RM, Shtivelband M, Kingsley E, Moezi M, Richards D, Sharman J, Feng X, Cannan M, Fellague-Chebra R, Boyd TE. Efficacy and safety of ofatumumab and bendamustine followed by ofatumumab maintenance in patients with relapsed indolent non-Hodgkin lymphoma after prior rituximab. Leuk Lymphoma. 2021 Jun;62(6):1353-1360. doi: 10.1080/10428194.2020.1869957. Epub 2021 Jan 15.