A Phase II study in adult patients with newly-diagnosed chronic myeloid leukaemia of initial intensified Glivec® therapy, and sequential combination therapy for non-responders, in order to assess response and survival (CML06)

Funding

Commercial sector/Industry,Novartis Australia

Scientific enquiries

A/Prof Timothy Hughes

Brief Summary

We conducted a trial in 103 de-novo chronic phase CML patients using imatinib 600 mg/day initially, increasing to 800 mg for suboptimal response. Ten patients not achieving major cytogenetic response (MCR) at 6 months and 13 with no complete cytogenetic response (CCR) at 9 months were eligible for dose increase, but this was only possible in 7/23 patients due mainly to non-hematologic toxicities. CCR was achieved in 90% and 95% of patients by 12 and 24 months, compared to rates of 69% and 80% in .... We conducted a trial in 103 de-novo chronic phase CML patients using imatinib 600 mg/day initially, increasing to 800 mg for suboptimal response. Ten patients not achieving major cytogenetic response (MCR) at 6 months and 13 with no complete cytogenetic response (CCR) at 9 months were eligible for dose increase, but this was only possible in 7/23 patients due mainly to non-hematologic toxicities. CCR was achieved in 90% and 95% of patients by 12 and 24 months, compared to rates of 69% and 80% in the IRIS trial. Major molecular response (MMR) was achieved in 47% and 72% of patients by 12 and 24 months compared to estimated frequencies of 40% and 55% in the IRIS trial. In the group averaging 600 mg throughout the first 12 months (n=51) 89% achieved MMR by 24 months compared to 50% in those averaging 500-599 mg in the first 6 months and 600mg in the second (n=18) (p=0.009). The superior molecular responses achieved in imatinib-treated patients who averaged 600 mg/day, compared to patients who were dose modified, suggest that early dose intensity of imatinib therapy may be critical to optimise response in CML.
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Key Inclusion Criteria

1.Male or female patients between 16 and 75 years of age inclusive. Patients must have all of the following: 2.i.be enrolled within 6 months of initial diagnosis of CML-CP ii.be previously untreated for CML with the exception of hydroxyurea and/or anagrelide, iii.cytogenetic confirmation of Philadelphia chromosome or variants of (9;22) translocations; OR molecular (PCR) confirmation of bcr-abl gene rearrangement(s); iv.(a) < 15% blasts in peripheral blood and bone marrow; (b) < 30% blasts plus p .... 1.Male or female patients between 16 and 75 years of age inclusive. Patients must have all of the following: 2.i.be enrolled within 6 months of initial diagnosis of CML-CP ii.be previously untreated for CML with the exception of hydroxyurea and/or anagrelide, iii.cytogenetic confirmation of Philadelphia chromosome or variants of (9;22) translocations; OR molecular (PCR) confirmation of bcr-abl gene rearrangement(s); iv.(a) < 15% blasts in peripheral blood and bone marrow; (b) < 30% blasts plus promyelocytes in peripheral blood and bone marrow; (c) < 20% basophils in peripheral blood, (d) > 100 x 109/L platelets v.no evidence of extramedullary leukemic involvement, with the exception of the spleen and liver, 3.Written voluntary informed consent. 4.Patients with an Eastern Cooperative Oncology Group performance status score of 2 or less. 5.Patients with serum bilirubin, Serum glutamic oxaloacetic transaminase, Serum glutamic pyruvic transaminase and creatinine concentrations <1.5x the institutional upper limits of normal (ULN). 6.Patients with a coagulation international normalised ratio (INR) and a partial thromboplastin time (PTT) <1.5x the institutional ULN, with the exception of allowing inclusion of patients on oral anticoagulant therapy.
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Key Exclusion Criteria

1.Patients who have received other investigational agents. 2.Patients with secondary chromosomal abnormalities in their CML cells. 3.Patients who received prior chemotherapy. Previous treatment with hydroxyurea is allowed. 4.Patients with uncontrolled medical disease 5.Patients with a positive test for human immunodeficiency virus 6.Patients who have undergone major surgery within 4 weeks of Study Day 1, or who have not recovered from prior major surgery. 7.Patients who are: (a) pregnant, (b) br .... 1.Patients who have received other investigational agents. 2.Patients with secondary chromosomal abnormalities in their CML cells. 3.Patients who received prior chemotherapy. Previous treatment with hydroxyurea is allowed. 4.Patients with uncontrolled medical disease 5.Patients with a positive test for human immunodeficiency virus 6.Patients who have undergone major surgery within 4 weeks of Study Day 1, or who have not recovered from prior major surgery. 7.Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to Study Day 1, and (d) male or female of childbearing potential unwilling to use barrier contraceptive precautions throughout the trial (postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential). 8.Patients with a history of another malignancy within the past five years, with the exception of adequately-treated basal or squamous cell skin carcinoma or cervical carcinoma in situ. 9.Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable.
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