Treatment with Ofatumumab and Bendamustine in patients with lymphoma resistant to previous therapies

Phase 1

• Conditions: on-Hodgkin's Follicular and Non-Follicular indolent lymphomas, relapsed/refractory; MedDRA version: 16.0Level: LLTClassification code 10051812Term: Small cell lymphocytic lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: PTClassification code 10003908Term: B-cell small lymphocytic lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: PTClassification code 10029460Term: Nodal marginal zone B-cell lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: PTClassification code 10025342Term: Lymphoplasmacytoid lymphoma/immunocytomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: PTClassification code 10065856Term: Non-Hodgkin's lymphoma unspecified histology indolentSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: PTClassification code 10047801Term: Waldenstrom's macroglobulinaemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2012-005338-13-IT
• Lead Sponsor: Istituto Clinico Humanitas - Humanitas Cancer Center

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2013-06-24
• Last Update Posted: 23 November 2020

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 73

Inclusion Criteria

1. Signed written informed consent obtained according to local guidelines
2. Histologically documented diagnosis of grade I-II-IIIa follicular lymphoma or defined according to WHO guidelines 2008. Re-biopsy suggested if transformation to aggressive subtype is suspected OR histologically documented indolent non follicular lymphoma: small lymphocytic lymphoma, lymphoplasmacytoid/lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, nodal marginal zone lymphoma
3. Relapsed or refractory disease after >=1 chemotherapy
lines, at least one rituximab-containing. Both patients with rituximab–sensitive and rituximab-refractory disease in any previous line are admitted.
Refractoriness to rituximab is defined as no objective response or documented progression within 6 months of a) receiving the first dose of a full-course single agent rituximab or b) completion of rituximab maintenance therapy or progression before the next rituximab dose or c) completion of a full course
rituximab in combination with chemotherapy . Previous high dose therapy and autologous stem cell transplantation (ASCT) is also admitted. Previous allogeneic transplantation is excluded.
4. Age >= 18 years
5. ECOG performance status 0-2
6. Locally available histological material
7. Clinical indication for treatment as determined by the investigator
8. No prior treatment with bendamustine and/or ofatumumab
9. Measurable disease by CT scan
10. Life expectancy of at least 3 months
11. Laboratory values:
· Absolute neutrophil count (ANC) = 1.5 x 109/L
unless due to marrow involvement by lymphoma -
In this case patient can be included upon
physicians’s decision
· Platelet count : = 100 x 109/L unless due to marrow
involvement by lymphoma. In this case patient can
be included upon physicians’s decision
· Serum creatinine within normal range
· Serum total bilirubin = 1.5 x ULN (or = 3.0 x ULN, if patient has Gilbert syndrome), unless due to lymphoma involvement of the liver. In case of liver
involvement, patient can be included upon
physicians’s decision.
· AST/SGOT and ALT/SGPT = 2.5 x upper limit of normal (ULN) or = 5.0 x ULN if the transaminase elevation is due to disease involvement of the liver
· alkaline phosphatase = 2.5 times ULN (unless due to disease involvement of the liver or bone). In case of liver or bone involvement, patient can be
included upon physicians’s decision
12. Adequate cardiac function : LVEF > 50% through
echocardiography or MUGA scan
13. Resolution of all acute toxic effects (excluding alopecia) of any prior therapy to NCI CTCAE (Version 4.03) Grade = 1
14. Not pregnant or nursing
15. Negative pregnancy test
16. Fertile patients must use effective contraception during the study and 3 months after the end of treatment.
17. Negative HIV test
18. No other prior malignancies except for adequately treated basal cell carcinoma, squamous cell carcinoma
of the skin, carcinoma in situ of the cervix, or other cancer from which the patient has been disease-free for
= 5 years unless approved by the Sponsor Principal Investigator
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 49
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 24

Exclusion Criteria

1. Diagnosis of mucosa associated marginal zone
lymphoma, splenic marginal lymphoma or chronic
lymphocytic leukaemia
2. Evidence of histological transformation to an
aggressive histological subtype
3. Previous allogeneic stem cell transplantation
4. Subjects who have current active hepatic or biliary
disease (with exception of patients with Gilbert's
syndrome, asymptomatic gallstones, liver
involvement by lymphoma or stable chronic liver
disease per investigator assessment)
5. Treatment with any known non-marketed drug
substance or experimental therapy within 5 terminal
half lives or 4 weeks prior to enrollment, whichever is
longer, or currently participating in any other
interventional clinical study.
6. Prior treatment with anti-CD20 monoclonal antibody or alemtuzumab within 1 month prior to start the
therapy
7. Chronic or current infectious disease requiring
systemic antibiotics, antifungal, or antiviral treatment
such as, but not limited to, chronic renal infection,
chronic chest infection with bronchiectasis,
tuberculosis and active Hepatitis C (see below).
8. History of significant cerebrovascular disease in the
past 6 months or ongoing event with active symptoms
or sequelae
9. Clinically significant cardiac disease including
unstable angina, acute myocardial infarction within
six months prior to randomization, congestive heart
failure (NYHA III-IV), and arrhythmia unless
controlled by therapy, with the exception of extra
systoles or minor conduction abnormalities.
10. Significant concurrent, uncontrolled medical
condition including, but not limited to, renal, hepatic,
gastrointestinal, endocrine, pulmonary, neurological,
cerebral or psychiatric disease which in the opinion of
the investigator may represent a risk for the patient.
11. Any concurrent medical condition requiring long term
use (> 1 month) of systemic corticosteroids
12. Any concurrent medical or psychiatric condition
which might impair administration of therapy or
preclude the ability to give informed consent
13. Known hypersensitivity to study drugs, mannitol, or
any excipients
14. Positive serology for Hepatitis B (HB) defined as a
positive test for HBsAg. In addition, if negative for
HBsAg but HBcAb positive (regardless of HBsAb status), a HBV DNA test will be performed and if positive the subject will be excluded. HBV DNA –negative cases can be included provided that HBV monitoring is performed during treatment and follow up period.
15. Positive serology for hepatitis C (HC) defined as a positive test for HCVAb, in which case reflexively perform a HCVRNA test to confirm the result. Cases with no signs of active chronic hepatitis (= HCV RNA NEG) are admitted.
16. Women of childbearing potential, including women whose last menstrual period was less than one year
prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception
is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence.
17. Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the efficacy of Ofatumumab in combination with Bendamustine<br>in previously treated (>=1 chemotherapy lines, at least one rituximab-containing) indolent<br>follicular and non follicular non Hodgkin’s lymphomas.;Secondary Objective: - To further characterize the efficacy profile of Ofatumumab-Bendamustine in combination (duration of response, time to next treatment, progression free survival and overall survival, minimal residual disease in follicular lymphoma subtypes).<br>- To evaluate safety;Primary end point(s): Overall response rate (CR+ PR) defined as per Cheson criteria.;Timepoint(s) of evaluation of this end point: Response will be evaluated during treatment, at the end of treatment and during follow up.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Toxicities as outlined in NCI-CTCAE<br>version 4.03, Duration of response defined for<br>patients in CR or PR, Time to Next Treatment,<br>progression free survival, overall survival,<br>MRD evaluation in FL patients only and<br>correlation with PFS and OS.;Timepoint(s) of evaluation of this end point: During treatment and follow up.