CLL-Irl Study. CTRIAL-IE (ICORG) 07-01, V7

OBJECTIVES:

Primary

* Evaluate the efficacy, in terms of complete remission rate, of fludarabine phosphate, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia.

Secondary

* Determine the time to treatment failure (TTF) in these patients.
* Determine the overall survival of these patients until 10th January 2019.
* Assess the predictive value of immunophenotype, hypermutation analysis, and FISH in determining TTF and OS in these patients.
* Determine the safety profile of this regimen.

OUTLINE: This is a multicenter study.

Patients receive fludarabine IV over 30 minutes or orally and cyclophosphamide IV or orally on days 1-3 and pegfilgrastim subcutaneously on day 4. Starting on course 2, patients receive rituximab IV on day 1. Treatment repeats every 28 days for up to 6* courses in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients achieving negative minimal residual disease receive 4 courses of treatment.

Blood samples are collected periodically for biomarker analysis. Samples are analyzed for protein expression (i.e., CD38, CD20, and ZAP70) by flow cytometry; quantitative immunoglobulins, β2-microglobulin, and T-cell subsets by electrophoresis; IgVH mutation status; and cytogenetics (i.e., +12, del 13q, del 11q, and del 17p) by FISH.

After completion of study therapy, patients are followed every 6 months for 5 years and then annually until 10th January 2019.

• pegfilgrastim (Biological)
• rituximab (Biological)
• cyclophosphamide (Drug)
• fludarabine phosphate (Drug)
• cytogenetic analysis (Genetic)
• fluorescence in situ hybridization (Genetic)
• gene expression analysis (Genetic)
• mutation analysis (Genetic)
• protein expression analysis (Genetic)
• flow cytometry (Other)
• laboratory biomarker analysis (Other)

Primary outcomes

• Complete remission rate by NCI response criteria and minimal residual disease (MRD) analysis [A formal assessment of response by NCI Criteria (Appendix 3) with the addition of assessment of minimal residual disease in the marrow and if relevant assessment of bulky disease by CT scanning will be made after 4 +/-6 courses of therapy.]

Secondary outcomes

• Time to treatment failure (TFF) [A clinical assessment of response will be made after 4 courses of therapy, Patients with evidence of progressive disease will stop therapy and will be deemed to have failed treatment.]
• Overall survival [Until 10th January 2019]
• Predictive value of immunophenotype, FISH, and hypermutation analysis in determining TTF and OS [See description]: Timing and type of response assessment During chemotherapy. A clinical assessment of response will be made after 4 courses of therapy. Patients with evidence of progressive disease will stop therapy and will be deemed to have failed treatment. A formal assessment of response by NCI Criteria (Appendix 3) with the addition of assessment of minimal residual disease in the marrow and if relevant assessment of bulky disease by CT scanning will be made after 4 +/-6 courses of therapy. Following chemotherapy. Disease assessment after the end of therapy will involve a history(recording B-symptoms), complete physical examination, full blood count and blood MRD analysis every 6 months for 5 years and then annually until 10th of January 2019 or until disease progression.
• Acute and chronic toxicity as assessed by NCI criteria [A formal assessment of response by NCI Criteria (Appendix 3) with the addition of assessment of minimal residual disease in the marrow and if relevant assessment of bulky disease by CT scanning will be made after 4 +/-6 courses of therapy.]

Sex: All, ages: 0 Years to 64 Years

DISEASE CHARACTERISTICS:

* Diagnosis of chronic lymphocytic leukemia

  * Stage I-IV disease (Binet stage progressive A, B, C)
  * CD5 and CD23 positive
  * Untreated OR relapsed/resistant disease after combination chemotherapy or rituximab
  * No 17p deletion

PATIENT CHARACTERISTICS:

* WHO performance status 0-2
* Life expectancy > 1 year
* Creatinine clearance ≥ 50 mL/min
* HIV negative
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No other concurrent malignancy except for noninvasive cervical cancer or localized nonmelanomatous skin cancer
* No history of anaphylaxis to mouse-derived humanized monoclonal antibody
* No other severe concurrent (e.g., cardiac or pulmonary) diseases or mental disorders that could interfere with ability to participate in the study

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics

• Results publication: Appleby N, O'Brien D, Quinn FM, Smyth L, Kelly J, Parker I, Scott K, Cahill MR, Crotty G, Enright H, Hennessy B, Hodgson A, Leahy M, O'Leary H, O'Dwyer M, Hayat A, Vandenberghe EA. Risk adjusted therapy in chronic lymphocytic leukemia: a phase II cancer trials Ireland (CTRIAL-IE [ICORG 07-01]) study of fludarabine, cyclophosphamide, and rituximab therapy evaluating response adapted, abbreviated frontline therapy with FCR in non-del(17p) CLL. Leuk Lymphoma. 2018 Jun;59(6):1338-1347. doi: 10.1080/10428194.2017.1376746. Epub 2017 Sep 19. PMID 28925785

• Elisabeth Vandenberghe, MD, Principal investigator, St. James's Hospital, Ireland

NIH grants: 2008