Clinical trial NCT00453427: Alemtuzumab and CHOP Chemotherapy for Aggressive Histological Peripheral T-Cell Lymphomas
Official title: Alemtuzumab and CHOP Chemotherapy for Aggressive Histological Peripheral T-Cell Lymphomas: A Multi-centre Phase I and II Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Peripheral T-cell Lymphomas
Keywords: PTL NOS
AILD
NHL
CHOP
Lead sponsor: Ontario Clinical Oncology Group (OCOG)
Sponsor class: OTHER
Collaborators: name: Sunnybrook Health Sciences Centre
name: Genzyme, a Sanofi Company
First posted: 2007-03-29
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary objectives of this study are to:

1. establish the safety and dose limiting toxicities of combining alemtuzumab with CHOP chemotherapy for patients with newly diagnosed aggressive T-cell lymphomas; and
2. to measure the pharmacokinetics of alemtuzumab used in different subcutaneous doses and schedules.

This will then determine the dose with the highest achievable drug levels with acceptable toxicities worthy of further investigation.

The secondary objectives are to:

1. establish the efficacy of combination alemtuzumab with CHOP chemotherapy; and
2. to measure the effects of combination alemtuzumab with CHOP chemotherapy on T-cell reconstitution and cytomegalovirus (CMV) reactivation.

Detailed description: Aggressive peripheral T-cell lymphomas account for 10 - 15% of all Non-Hodgkin's Lymphoma (NHL) and present with more adverse prognostic features than aggressive histology B-cell NHL . Correspondingly, they have an overall poorer prognosis than B-cell lymphomas, achieving lower complete response rates, freedom from progression and overall survival with conventional anthracycline-based CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. Fewer than 30% of patients are cured with therapy. New treatments that replicate the improved survivals with chemo-immunotherapy for B-cell lymphomas are needed. Alemtuzumab is a humanized murine antibody that binds to a ubiquitous lymphoid marker CD52 and is efficacious (as monotherapy) in related lymphoproliferative diseases. Combining alemtuzumab with CHOP chemotherapy may improve the response rates and outcomes of patients with this sub-type of NHL. The combination must be first tested in a dose escalation fashion to establish the dosage of the doublet because of the potential for overlapping or exaggerated toxicities.

This prospective, multi-center, open label Phase I-II study will enroll 22-84 patients with newly diagnosed previously untreated aggressive histology peripheral T-cell lymphomas. In the Phase I component, patients will be sequentially enrolled in cohorts of three patients and treated with increasing doses of alemtuzumab administered in combination with standard CHOP chemotherapy. When the maximal tolerated dose is determined, this dose and schedule will then be tested in up to 46 patients using a Simon two stage Phase II design.

Eligibility criteria: Inclusion Criteria:

* Patients aged 18 years of age or older at time of enrollment,
* Histologically proven and centrally reviewed CD52+ T-cell NHL Stages 2-4 including the following nodal and extranodal subtypes:

Nodal:

* Peripheral T-cell lymphoma not otherwise specified (PTL NOS)
* Angioimmunoblastic lymphadenopathy (AILD)
* ALK 1 negative anaplastic large cell NHL

Extranodal:

* Hepatosplenic
* Enteropathy-associated
* Panniculitic

Exclusion Criteria:

* Previous treatment with chemotherapy or radiation with the exception of up to 1 cycle of CHOP chemotherapy.
* Expected survival \< 4 months.
* ECOG performance status \> 3.
* Inadequate haematologic function (Hb \< 85g/L, ANC \< 1000/mm3, or platelet count \< 75,000/mm3) unless directly attributable to the NHL.
* Inadequate hepatic function (total bilirubin \> 35μmol/L, alkaline phosphatase \> 2x UL normal, AST/ALT \> 2x UL normal)
* Inadequate renal function (serum creatinine \> 130μmol/L), unless directly attributable to the NHL.
* Non-measurable or non-evaluable disease, according to criteria of Cheson et al49.
* Geographically inaccessible for follow-up
* Known hypersensitivity to study drugs
* Serious illnesses that may interfere with subject compliance, determination of causality of adverse events or would compromise other protocol objectives.
* Known HIV positivity or other pre-existing immunodeficiency (e.g., post-organ transplant).
* Known CNS involvement with lymphoma (tests to investigate CNS involvement are required only if clinically indicated).
* Pregnant or lactating women.
* Women who are of childbearing potential but are not using effective contraception. Men with reproductive potential who are not using effective contraception.
* Previous malignancy within the last 5 years with the exception of cervical carcinoma in situ or non melanoma skin cancer.
* Nasal natural killer (NK) T-cell NHL

Primary outcomes:
measure: toxicity
timeFrame: 8 cycles of treatment
Secondary outcomes:
measure: efficacy
timeFrame: Post cycle 3 and Post cycle 8
measure: tumour response
timeFrame: Post Cycle 3 and Post Cycle 8 Q 6 months in Followup
measure: pharmacokinetic analysis
timeFrame: Day 1 of 8 Cycles of treatment and Post Last Dose on Day 3,6,10,13
measure: immunological monitoring
timeFrame: Baseline Day 1 On Treatment Day 1 Cycle 4 and Cycle 8 and 6 months Follow-up
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre, Odette Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
Study officials:
affiliation: Sunnybrook Health Sciences Centre, Odette Cancer Centre
name: Rena Buckstein, MD
role: PRINCIPAL_INVESTIGATOR
References: