Dexamethasone, Ofatumumab and Bendamustine (DOT) First-line in Mantle-cell Lymphoma(MCL)

Phase 1

• Conditions: Lymphoma, Mantle-Cell
• Interventions: Drug: Combination of dexamethasone, ofatumumab and bendamustine

• Registration Number: NCT01221103
• Lead Sponsor: Southern Europe New Drug Organization

Brief Summary

The rationale for this study design is based on the fact that the maximum tolerated dose (MTD) of single-agent ofatumumab and bendamustine have been previously determined. The choice of the doses for the combination is based on the investigators unpublished clinical experience, as well as inferred from extensive experimental data on the use of other monoclonal antibodies in combination chemotherapy in lymphoma patients. The starting dose of the 2 main component drugs is the MTD of each drug as single agent.

Detailed Description

Not available

Study Timeline

• Study Start: 2010-04
• Study First Submitted: 2010-10-13
• Study First Submitted QC: 2010-10-13
• Study First Posted: 2010-10-14
• Status Verified: 2011-09
• Last Update Submitted: 2011-09-12
• Last Update Posted: 2011-09-13
• Primary Completion: 2012-04
• Study Completion: 2012-06

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

1. Age ≥ 60 years.

2. ECOG Performance Status 0-1.

3. Life expectancy of at least 6 months.

4. Histological diagnosis of MCL (morphology, CD5+/CD20+ /CD23-, t(11:14) and/or cyclin D1 overexpression).

5. Disease requiring treatment (patients with bone marrow only disease, who are candidates for a watch-and-wait approach, will be excluded)

6. Adequate bone marrow, liver and renal function, unless the abnormality is related to the tumor and is unlikely to affect the safety of bendamustine and ofatumumab use. Adequate marrow and organ function will be assessed by the following laboratory requirements to be conducted within 7 days prior to screening:

   • Hemoglobin ≥ 9.0 g/dL
   • Absolute neutrophil count (ANC) ≥ 1000/µl
   • Platelet count ≥ 75000/µl
   • Total bilirubin ≤ 1.5 times the ULN
   • AST and ALT ≤ 2.5 x ULN
   • Alkaline phosphatase ≤ 4 x ULN
   • Serum creatinine ≤ 2.5 x ULN

7. PT-INR/PTT < 1.5 x ULN [Patients who are being therapeutically anticoagulated with agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists]

8. Written informed consent.

Exclusion Criteria

1. Previous treatment for mantle-cell lymphoma (MCL)
2. 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.
3. Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
4. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to Visit 1, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities
5. History of significant cerebrovascular disease or event with significant symptoms or sequelae
6. Glucocorticoid use, unless given in doses ≤ 100 mg/day hydrocortisone (or equivalent dose of other glucocorticoid) for <7 days for exacerbations other than CLL (e.g., asthma)
7. Known HIV positive
8. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
9. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive and HBsAb negative, a HB DNA test will be performed and if positive the subject will be excluded. Note: If HBcAb positive and HBsAb positive, which is indicative of a past infection, the subject can be included.
10. Positive serology for hepatitis C (HC) defined by positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result.
11. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to Visit 1, whichever is longer or currently participating in any other interventional clinical study
12. Known or suspected inability to comply with study protocol
13. History of organ allograft
14. Patients with evidence or history of bleeding diathesis.
15. Patients undergoing renal dialysis.
16. Substance abuse, medical psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
17. Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
DOT	Combination of dexamethasone, ofatumumab and bendamustine	Combination of dexamethasone, ofatumumab and bendamustine

Primary Outcome Measures

Name	Time	Method
Adverse events (Phase I)	60 days after last dose of investigational drug	Incidence, severity, and attribution of treatment-emergent AEs
Complete Response rate (Phase II)	24 months	Response determined according to the revised response criteria for malignant lymphoma (Cheson, JCO 2008)

Secondary Outcome Measures

Name	Time	Method
Molecular analysis of CD34+ cells	cycle 4 (12 weeks) or cycle 6 (18 weeks for inadequate harvests after cycle 4)
Duration of response (Phase II)	At the screening, cycle 4 (12 weeks) , cycle 6 (18 weeks), 1 year Follow-up	Duration estimated from the first confirmed tumor regression to the disease progression.
Serial peripheral blood CD34+ cell counts	Cycles 1 (3 weeks), 4 (12 weeks) and 6 (18 weeks)
Serial molecular analysis of peripheral blood cells	Cycles 1 (3 weeks), 4 (12 weeks) and 6 (18 weeks)	Serial molecular analysis by PCR
Ability to harvest ≥ 7 x106 CD34+ cells/kg	Cycle 4 (12 weeks) or cycle 6 (18 weeks for inadequate harvests after cycle 4)
Presence of tumor cells in the peripheral blood	Cycle 1 (3 weeks), 4 (12 weeks) and 6 (18 weeks)	Monitored by morphology, immunophenotype and PCR

Trial Locations

Locations (2)

Fondazione IRCCS Istituto Nazionale Tumori; 🇮🇹 Milano, Italy

Ospedali Bianchi - Melacrino - Morelli; 🇮🇹 Reggio Di Calabria, Italy