Cell Therapeutics, Inc. (CTI), a biopharmaceutical company committed to developing an integrated portfolio of oncology products aimed at making cancer more treatable, reported that the phase 1 study data of its highly selective oral JAK2 inhibitor pacritinib, or SB1518, showed encouraging anti-tumour activity and good tolerability in 34 patients with relapsed/refractory lymphoma. The results were published online in the Journal of Clinical Oncology in September, 2012.
Thirty-four patients received daily oral doses of pacritinib ranging from 100mg to 600mg. The maximal tolerated dose was not reached. Median time on study was 88 days (range of one to 574 days) with six patients on pacritinib for longer than six months. Seventeen of the 34 patients (50%) had measurable decreases in target tumour measurements ranging from 4% to 70% shrinkage. Partial remissions were noted in three patients (mantle cell (2), indolent lymphoma (1)) while 15 patients had stable disease. Median progression free and overall survival was 120 and 130 days, respectively. Gastrointestinal (GI) side effects were most frequent and mild to moderate (grade 1-2) with no patient reporting severe (grade 3-4) GI side effects even at the 600mg dose level. Cytopenias were infrequent and modest (less than 15% all grades).
"While it is becoming increasingly accepted that activating mutations in JAK2 and FLT3 play an important role in a majority of patients with acute myeloid leukaemia, this phase 1 study suggests the potential therapeutic value of targeting the JAK2 pathway in lymphomas with encouraging single agent activity demonstrated despite the extensive degree of prior therapy and refractory nature of the disease among the patients who were enrolled in this trial," noted Steven E. Benner, M.D., M.H.S., chief medical officer of CTI.
The primary objective was a dose finding, pharmacokinetic/ pharmacodynamics study of oral pacritinib in patients with relapsed lymphoma.
The study enrolled 35 patients with relapsed or refractory Hodgkin's or non-Hodgkin's lymphoma of any type except Burkitt's or CNS lymphoma. Patients had relapsed following a median of five prior therapies (range 2-15); 44% had failed prior stem cell transplant and 52% were rituximab refractory.
Thirty-four patients received daily doses of pacritinib for a 28-day each cycle of doses ranging from 100 to 600 mg/day. The maximum tolerated dose was not reached. Pacritinib inhibited JAK2 signalling at all dosing levels and FLT-3 inhibition were seen in most patients. The median time on study drug was 88 days (range of one to574) with six patients on pacritinib for longer than six months and 17 patients for longer than three months. There were three partial responses (greater than or equal to 300 mg/d) (2 mantle cell; 1 indolent NHL); 15 patients achieved stable disease. Seven of 13 patients with stable disease had tumour reductions ranging from 4% to 46% of baseline target lesions. Treatment was well tolerated, with mostly grade 1-2 toxicities. Gastrointestinal toxicities were the most frequent (32%) with no grade 3-4 side effects reported even among the 12 patients treated at the highest dose (600mg/d). Cytopenias were infrequent and modest supporting the lack of myelosupression with pacritinib therapy even among a patient population with poor baseline marrow reserve. The authors concluded, "collectively our data demonstrate that SB1518 is well tolerated in patients with relapsed lymphoma and has promising activity. The data warrant further efficacy studies of JAK/STAT pathway inhibitors either alone or in combination regimens."
The JAK family of enzymes are a central component in signal transduction pathways, which are critical to normal blood cell growth and development as well as inflammatory cytokine expression and immune responses. When dysregulated by activating mutations, uncontrolled blood cell growth can occur accompanied by inflammation and immune system activation contributing to disease manifestations in MPN. Autoimmune diseases such as psoriasis and rheumatoid arthritis also have activation of this pathway and JAK inhibitors are in development for these disorders.
Normal expression of FLT3 is restricted to haemopoietic progenitor cells in the bone marrow, thymus and lymph nodes, but is also found on other tissues such as placenta, brain, cerebellum and gonads. Aberrantly expressed FLT3 is observed at high levels in a spectrum of hematologic malignancies including 70% to 100% of AML (Acute Myelogenous Leukaemia), B-precursor cell ALL (Acute Lymphoblastic Leukaemia), a fraction of T-Cell ALL, and CML (Chronic Myelogenous Leukaemia).
Pacritinib is an oral, once a day, tyrosine kinase inhibitor (TKI) with dual activity against JAK2 and FLT3. Mutations in these kinases have been shown to be directly related to the development of a variety of blood related cancers including Myeloproliferative disorders ("MPD"), leukaemia and lymphoma. Pacritinib has demonstrated encouraging results in phase 1 and 2 studies for patients with myelofibrosis and a phase 3 study is planned in this disease.
FLT3 is a commonly mutated gene found in acute myeloid leukaemia ("AML") patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome suggesting a possible future role for treatment of AML.
Lymphoma is a cancer of the white blood cells, namely lymphocytes, which constitute the lymphatic system. Lymphoma occurs when lymphocytes grow abnormally. The two main types of lymphoma are Hodgkin lymphoma and non- Hodgkin lymphoma. Lymphoma is the most common blood cancer.