PICLLe

• Research type

  Research Study

• Full title

  Phase I/II clinical trial to assess the efficacy and safety of olaparib, a PARP-inhibitor, in relapsed and refractory Chronic Lymphocytic Leukaemia patients with an 11q deletion or ATM mutation and relapsed/refractory patients with T-Prolymphocytic Leukaemia and Mantle Cell Lymphoma.

• IRAS ID

  16539

• Contact name

  Guy Pratt

• Sponsor organisation

  University of Birmingham

• Eudract number

  2009-015081-61

• ISRCTN Number

  N/A

• Research summary

  The therapeutic options for relapsed Chronic lymphocytic leukaemia (CLL), T-prolymphocytic leukaemia (T-PLL) and Mantle cell lymphoma (MCL) are limited. Mutations in a gene called ATM are the commonest genetic alteration in CLL and lead to resistance to chemotherapy. ATM mutant cells are defective in repairing DNA damage using a repair pathway called homologous recombination DNA repair. All cells including cancer cells need to be able to repair DNA and there are two major pathways for repairing DNA. The drug Olaparib inhibits DNA repair by a different mechanism by inhibiting the enzyme PARP-1 and cancer cells already defective in ATM when treated with olaparib would no longer be able to repair DNA damage leading to the accumulation of unrepaired DNA ultimately resulting in the death of the cancer cell. Olaparib is safe and effective in solid tumour patients with a BRCA mutation, similar to ATM, and our laboratory studies show efficacy in CLL samples hence the need for a clinical study. This study is in two phases. The aim of phase I is to determine whether the dose to use (so called maximum tolerated dose MTD) in patients with haematological malignancies is the same as for solid tumours (400mg bd). Phase I is a conventional dose escalation study (cumulative 3 design) in which 3-18 patients will participate. The aim of phase II is to assess the efficacy of olaparib as treatment for ATM deficient, relapsed and refractory CLL, T-PLL and MCL. 58 patients will receive olaparib at the MTD established in phase I until disease progression or unacceptable toxicity. Response to treatment will be assessed at week 16 using the International Workshop on CLL (IWCLL) criteria (CLL and T-PLL) and the definitions recommended by the International Workshop to Standardise Response Criteria for on-Hodgkins Lymphoma (MCL). All patients will be followed by indefinitely.

• REC name

  West Midlands - Coventry & Warwickshire Research Ethics Committee

• REC reference

  10/H1211/8

• Date of REC Opinion

  20 May 2010

• REC opinion

  Further Information Favourable Opinion