Chronic lymphocytic leukaemia Cancer Lymphoid leukaemia
Conditions
Interventions
Phase I:
Dose escalation study (cumulative 3 + 3 design) of the PARP inhibitor, olaparib (previously known as AZD2281 and KU-0059436). Two cohorts: 200 mg twice daily (bd) and 400 mg b
Sponsors
University of Birmingham (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Relapsed or refractory chronic lymphocytic leukaemia (CLL), mantle cell lymphoma or T-prolymphocytic leukaemia (T-PLL) patients (World Health Organization [WHO] Classification of Haematopoietic and Lymphoid Tissues, Fourth Edition) who are not considered to be appropriate for further conventional treatment 2. CLL patients only: confirmation of chromosome 11q deletion by fluorescent in situ hybridisation (FISH) or an ATM mutation (ATM mutation requires the presence of both a predicted ATM mutation and demonstration of reduced ATM dependent phosphorylation)* 3. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2 4. Aged 18 years or older, either sex 5. Written informed consent 6. Not known to be positive for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen and hepatitis C antibody 7. Estimated life expectancy of greater than 16 weeks *Please note that confirmation of 11q deletion or an ATM mutation prior to registration is not required for CLL patients taking part in phase 1 (dose escalation phase). All other eligibility criteria apply to both phase 1 and phase 2.
Exclusion criteria
Exclusion criteria: 1. Receiving treatment for CLL, mantle cell lymphoma or T-PLL including corticosteroids (greater than 10 mg prednisone/day or equivalent) or have received treatment for CLL, mantle cell lymphoma or T-PLL for the 4 weeks prior to study entry 2. Receiving corticosteroids (at a dose greater than 10 mg prednisone/day or equivalent) for other medical conditions 3. Previous treatment with a PARP-inhibitor, including olaparib 4. A known hypersensitivity to olaparib or any excipient of the product 5. Treatment with any investigational product within 28 days of registration 6. Receiving or have received the following inhibitors of CYP34A: 6.1. Azole antifungals 6.2. Macrolide antibiotics 6.3. Protease inhibitors 7. Impaired hepatic or renal function as defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2.5 x upper limit of normal (ULN), bilirubin greater than 2 x ULN, serum creatinine greater than 2 x ULN 8. Persisting (greater than 8 weeks) severe pancytopenia due to previous therapy rather than disease (neutrophils less than 0.5 x 10^9/L or platelets less than 50 x 10^9/L) 9. Central nervous system (CNS) involvement with CLL 10. Cardiac dysfunction as defined as: myocardial infarction within 6 months of study entry, New York Heart Association (NYHA) class III/IV heart failure, unstable angina, unstable cardiac arrhythmias 11. Any other malignancy which has been active or treated within the past 3 years, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions or endometrial carcinoma stage 1A grade 1 12. Unable to swallow orally administered medications 13. Patients with uncontrolled seizures 14. Active infection requiring systemic antibiotics, antifungal or antiviral drugs 15. Concurrent severe and/or uncontrolled medical condition (e.g. severe chronic obstructive pulmonary disease [COPD], severe Parkinsons's disease) or psychiatric condition 16. Women of child-bearing potential and men who have partners of child-bearing potential who are not willing to practise effective contraception for the duration of the study and for three months after the last study drug administration 17. Pregnancy or lactating women. Pre-menopausal women of child bearing potential must have a negative urine or serum pregnancy test within 7 days prior to registration.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Demonstration of sufficient efficacy in patients with ATM deficient, relapsed and refractory CLL to warrant further investigation in a phase III trial. Sufficient efficacy is defined as at least 20% of patients showing a clinical response (defined as either a complete remission or partial remission) after 16 weeks of therapy with olaparib. For CLL patients, clinical response will be defined according to guidelines from the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL). Response for mantle cell lymphoma patients is classified according to the definitions recommended by the International Workshop to Standardise Response Criteria for non-Hodgkin's lymphomas. There are no published response criteria for T-PLL and response is defined as for CLL. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. To investigate whether there is evidence of efficacy within relapsed/refractory CLL, mantle cell lymphoma and T-PLL patients dependent on the ATM status of the remaining ATM allele 2. To measure the progression free survival and overall survival of patients treated with olaparib 3. In all patients with CLL, MCL and T-PLL a secondary outcome will be to determine the safety, tolerability and toxicity of this treatment (graded according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v4.0) All measured after the last patient has received at least 16 weeks of treatment. | — |
Countries
England, United Kingdom
Outcome results
None listed