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

Lymphoma, Mantle-Cell Clinical Trial

Official title:

Phase I/II Trial of Dexamethasone, Ofatumumab and Bendamustine [Treanda] (DOT) as First-line Treatment of Mantle-cell Lymphoma (MCL) in the Elderly

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01221103
• Other study ID #: INT5909
• Status: Recruiting
• Phase: Phase 1/Phase 2
• First received: October 13, 2010
• Last updated: September 12, 2011
• Start date: April 2010
• Est. completion date: June 2012

Study information

• Verified date: September 2011
• Source: Southern Europe New Drug Organization
• Contact: Michele Magni, MD
• Email: michele.magni[@]istitutotumori.mi.it
• Is FDA regulated: No
• Health authority: Italy: Competent Authority
• Study type: Interventional

Clinical Trial 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 The choice of the doses for the combination is based on the investigators unpublished clinical experience, as well as inferred from extensive experimental data on the use of other monoclonal antibodies in combination chemotherapy in lymphoma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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: June 2012
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 60 Years and older

Eligibility

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

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Mantle-Cell

Intervention

Drug:
• Combination of dexamethasone, ofatumumab and bendamustine
Ofatumumab (liquid concentrate for infusion in glass vials) infused iv on day 1 at 300 mg during the first cycle, followed by infusions of 1000 mg on day 1 of each subsequent cycle Bendamustine (powder dissolved in sterile water) infused iv over 30-60 minutes at the dose of 120 mg/m2 (days 2,3 every 21 days) or 120 mg/m2(days 2,3 every 28) or 90 mg/m2 (days 2,3 every 28 days) depending on toxicity Dexamethasone administered i.v. at 40 mg (days 1,2,3,4)

Locations

Country	Name	City	State
Italy	Fondazione IRCCS Istituto Nazionale Tumori	Milano
Italy	Ospedali Bianchi - Melacrino - Morelli	Reggio Di Calabria

Sponsors (2)

Lead Sponsor	Collaborator
Southern Europe New Drug Organization	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events (Phase I)	Incidence, severity, and attribution of treatment-emergent AEs	60 days after last dose of investigational drug	Yes
Primary	Complete Response rate (Phase II)	Response determined according to the revised response criteria for malignant lymphoma (Cheson, JCO 2008)	24 months	No
Secondary	Duration of response (Phase II)	Duration estimated from the first confirmed tumor regression to the disease progression.	At the screening, cycle 4 (12 weeks) , cycle 6 (18 weeks), 1 year Follow-up	No
Secondary	Serial peripheral blood CD34+ cell counts		Cycles 1 (3 weeks), 4 (12 weeks) and 6 (18 weeks)	No
Secondary	Molecular analysis of CD34+ cells		cycle 4 (12 weeks) or cycle 6 (18 weeks for inadequate harvests after cycle 4)	No
Secondary	Serial molecular analysis of peripheral blood cells	Serial molecular analysis by PCR	Cycles 1 (3 weeks), 4 (12 weeks) and 6 (18 weeks)	No
Secondary	Ability to harvest = 7 x106 CD34+ cells/kg		Cycle 4 (12 weeks) or cycle 6 (18 weeks for inadequate harvests after cycle 4)	No
Secondary	Presence of tumor cells in the peripheral blood	Monitored by morphology, immunophenotype and PCR	Cycle 1 (3 weeks), 4 (12 weeks) and 6 (18 weeks)	No