IND.216: a phase II study of buparlisib and associated biomarkers, raptor and p70S6K, in patients with relapsed and refractory chronic lymphocytic leukemia.

Buparlisib is an orally available pan-Class I PI3K inhibitor, that is more potent than idelalisib in vitro. Its distinct toxicities include hyperglycemia, hypertension, and mood disturbance. IND216 is a single arm phase II trial of buparlisib in Relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Fourteen patients were enrolled, 13 were evaluable for response and toxicity. Six of 13 patients had a partial response (46%) with a median duration of response of 15.5 months, all 11 patients with tumor assessment experienced tumor shrinkage. The most common adverse events (≥15%) were hyperglycemia, fatigue, anxiety, and gastrointestinal toxicities; all were < grade 3 except for fatigue. Three patients stopped therapy for alterations in mood. Lower levels of raptor were significantly associated with greater tumor shrinkage, suggesting that raptor could be a biomarker for response. This requires further validation in a larger CLL patient cohort. The clinical activity of buparlisib is comparable to other phosphatidylinositol-3-kinase inhibitors, with a different toxicity profile.Novelty and impactBuparlisib, an oral, pan PI3 kinase inhibitor, is associated with a 46% partial response rate among patients with relapse chronic lymphocytic leukemia (CLL). This is a similar clinical activity to other phosphatidylinositol-3-kinase inhibitors tested. However, buparlisib has a distinct toxicity profile, characterized by hyperglycemia, hypertension, and mood alteration. In agreement with our previous preclinical study, our results suggest that basal raptor expression in CLL correlates with clinical response to buparlisib.

A phase I study of romidepsin, gemcitabine, dexamethasone and cisplatin combination therapy in the treatment of peripheral T-cell and diffuse large B-cell lymphoma; the Canadian cancer trials group LY.15 study†.

We investigated GDP (gemcitabine, 1000 mg/m2 IV d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m2 IV d1) combined with romidepsin on days 1 and 8 every 21 days to a maximum of six cycles in a standard 3 + 3, phase I dose escalation trial for patients with relapsed/refractory peripheral T-cell (PTCL) or diffuse large B-cell (DLBCL) lymphoma (NCT01846390). After treating four patients, gemcitabine and romidepsin were given on days 1 and 15 every 28 days. On the 21-day schedule at 6 mg/m2 romidepsin, there were three dose-limiting toxicities (DLTs) among four patients. On the 28-day schedule, there were no DLTs at the 6, 8, or 10 mg/m2 dose. At 12 mg/m2, there were four observed grade 3 DLTs among six evaluable patients. Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m2 if given on a day 1, 15 every 28 days schedule.

Salvage chemotherapy and autologous stem cell transplantation for peripheral T-cell lymphoma: a subset analysis of the Canadian Cancer Trials Group LY.12 randomized phase 3 study.

Peripheral T-cell lymphoma (PTCL) is a rare, heterogeneous malignancy. Of the 619 patients with relapsed and refractory (R/R) aggressive lymphoma enrolled in the Canadian Cancer Trials Group LY.12 phase 3 trial, 59 (9.5%) had PTCL. Among these, 81% had advanced stage disease, 41% had an International Prognostic Score ≥3, and 41% were refractory to primary therapy. Within the PTCL cohort, the overall response rate after two cycles of salvage chemotherapy was 36%; no difference was observed between dexamethasone, cytarabine, cisplatin (10/30, 33%), and gemcitabine, cisplatin, dexamethasone (11/29, 38%) therapy. At one year, event-free survival (EFS) was 16% and overall survival (OS) was 28%. For PTCL patients, who received autologous stem cell transplant, two-year EFS and OS were 21% and 42%, respectively. Patients with PTCL had inferior OS (HR 0.49, p < .0001) and EFS (HR 0.53, p < .0001) compared to B-cell lymphoma. Outcomes for patients with R/R PTCL are poor with currently available therapies.

Radiological and pathological response following pre-operative radiotherapy for soft-tissue sarcoma.

PURPOSE: To report radiological and pathological response to neo-adjuvant radiotherapy for extremity and trunk soft-tissue sarcomas. MATERIALS/METHODS: Fifty patients were identified retrospectively. All patients had MRI imaging pre and post neo-adjuvant external beam radiotherapy. Tumor volumes were measured in 3D on T1 Gadolinium enhanced sequences. Pathological treatment response was quantified in terms of percentage of treatment-related necrosis for each case. RESULTS: Histopathologic responses to treatment varied from 0% to 100%. The median pathological treatment response was 67.5% for low-grade sarcomas and 50% for high-grade sarcomas. The median decrease in tumor volume was 13.8% for non-myxoid low-grade sarcomas, 82.1% for myxoid liposarcomas and <1% for high-grade sarcomas. A partial response on MRI (volume reduction ≥50%) was highly predictive of a good pathological response (p<0.001). Patients with stable disease on imaging or volumetric progression had wide ranging pathological responses. CONCLUSIONS: Soft-tissue sarcomas show significant pathological treatment responses in the form of hyaline fibrosis, necrosis and granulation tissue. Despite this, there is minimal early volumetric response to radiation, especially for high-grade tumors. Although radiological partial response was predictive of pathological response, the significance of radiological progression was unclear. Myxoid liposarcoma tumor type was predictive of both pathological and radiological tumor response.