ALBERT

Description: Treatment of cancer cells with Hsp90 inhibitors/antagonists results in cell cycle arrest, destabilisation and apoptosis. This ability of Hsp90 antagonists to modulate tumour microenvironments and initiate the selective degradation of various factors needed for cell proliferation and survival make them potential candidates for the treatment of B-cell malignancies such as multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin’s lymphoma (NHL). KW-2478 is a novel non-ansamycin, non-purine analogue antagonist for Hsp90. This study investigated KW-2478 in patients (aged ≥18 y) with relapsed/refractory MM, CLL or NHL. Fifteen patients (5 cohorts of 3) received escalating doses of KW-2478 at 14, 28, 47, 71, 99 mg/m2, IV over 60 min, once daily on Days 1 to 5 of a 14-day cycle. Patients could receive further cycles for up to one year, with a dose escalation option. Study objectives were to determine safety, tolerability, pharmacokinetic and pharmacodynamic profiles of KW-2478. Safety was assessed throughout the study (AEs, dose-limiting toxicities [DLTs], vital signs, ECG, physical examination, safety laboratory tests and visual ophthalmological examination with electroretinogram [ERG]). DLT was defined as an event during the first cycle which was considered related to KW-2478 and either led to treatment delay, persisted beyond Day 14, was a clinically significant ERG change, was a grade 4 or clinically significant grade 3 non-hematological event, or was a grade 4 hematological toxicity not related to primary disease that had not recovered to ≤ grade 3 by Day 14. On Days 1 and 5 (first cycle), blood samples were collected at pre-dose, 50 min post start of infusion and 10 and 30 min, and 1, 2, 4 and 8 h post infusion for KW-2478 pharmacokinetic analysis. Blood was sampled for pharmacodynamic analysis at pre-dose and 8 h on Days 1 and 5. Hsp70 expression in PBMCs was analyzed by Western blot. Results showed good tolerability with no DLTs between KW-2478 doses of 14 and 99 mg/m2. Patients received a median of three treatment cycles though one MM patient underwent 19 treatment cycles and had two dose escalations with no toxicity. Overall, six patients (40%) had KW-2478 related toxicities (seven grade 1, seven grade 2 and two grade 3) and there were three grade 4 toxicities, not related to KW-2478. There were no trends noted for any specific toxicities associated with KW-2478, though one grade 1 and one grade 2 KW-2478 related episodes of hypertension were observed in a single patient, leading to hospitalization overnight. Two grade 3 related episodes of QTc interval prolongation were reported in one patient. Overall, KW-2478 related toxicities led to dose interruption (6%) or withdrawal from the study (13%). Two patients died from disease progression and no patients died from treatment related causes. Peak plasma concentrations were observed at the end of the infusion, after which KW-2478 plasma concentrations decayed in a biphasic manner with a dose-independent half-life of approximately 6 h. For Day 1, maximum plasma concentration (Cmax) and area under the KW-2478 concentration-time curve from time zero to infinity (AUC0–∞) values increased in a dose-dependent manner at all doses. Repeated 5-day administration had no effect on plasma concentration at all doses. Mean [range] Day 5 KW-2478 Cmax varied from 656 [482–1050] ng/mL at the 14 mg/m2 dose to 2977 [2440–3640] ng/mL at 99 mg/m2. Mean [range] Day 5 KW-2478 AUC to last measurable concentration (AUC0-t) varied from 836 [532–1336] ng/mL at the 14 mg/m2 dose to 3465 [2997–4318] ng/mL at 99 mg/m2. Pharmacodynamic data were variable but there was a trend toward increased Hsp70 expression with increasing doses of KW-2478. This trend was most evident at 71 and 99 mg/m2, at 8 h post dose on Day 5. Once-daily infusions at doses of up to 99 mg/m2 achieved exposure levels similar to those that showed anti-tumor activity in pre-clinical models including models of human MM. Hsp70 induction data suggested that these exposure levels may be sufficient to affect function of Hsp90 in B-cell malignancies. Overall, KW-2478 was well tolerated with no DLTs at doses up to 99 mg/m2 and demonstrated a predictable pharmacokinetic profile in its target population. The study is proceeding with a KW-2478 dose of 132 mg/m2; further dose escalation is planned.

Description: Despite impressive primary response rates relatively few patients with multiply relapsed or refractory Hodgkin lymphoma (HL) are ultimately cured with conventional chemotherapy. The application of allogeneic stem cell transplantation has historically been limited in this group by high transplant related mortality (TRM) rates, and evidence for a clinically relevant graft-versus-lymphoma (GvL) effect has been limited. Reduced intensity transplantation (RIT) approaches enable durable engraftment of allogeneic stem cells with a low spectrum of toxicity, but graft-versus-host disease (GvHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion (TCD), using alemtuzumab, has been shown to reduce the incidence of GvHD. However, this approach potentially adversely impacts on disease response by abrogating GvL activity. To explore the impact of TCD in HL we have compared the results in 89 recipients of a RIT enrolled in 2 prospective studies based on conditioning with the same combination of fludarabine (30mg/m2 x 5) and melphalan (140 mg/m2). The studies differed in GvHD prophylaxis. The United Kingdom regimen (MF-A, n=49) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (MF, n=40) used cyclosporin A plus methotrexate. There were no significant differences in age (median 32 versus 35 years), sex or histological subtype (nodular sclerosis in 86% versus 88%). Median follow-up in surviving patients is 826 (MF-A) versus 376 (MF) days. In those with matched sibling donors use of alemtuzumab resulted in a trend towards a lower incidence of acute GvHD (29% versus 46% at day 180, P=0.09) and significantly less chronic GvHD (10% versus 57%, P=0.0003). This was associated with a trend towards lower TRM in the MF-A group (actuarial 2 year TRM 17% versus 33% for MF, P=0.06), but no apparent excess of relapse/progression (actuarial 2 year relapse risk 49% for MF-A versus 68% for MF, P=0.16). In this sibling transplant cohort both overall and event-free survival were superior in the MF-A group (actuarial 2 year OS 72% versus 48%, P=0.04; EFS 47% versus 19%, P=0.009). Sixteen patients in the MF-A group and 10 in the MF group received donor lymphocyte infusions (DLIs) to achieve disease control. Nine (8CR, 1PR) of the former, and 6 (3CR, 3PR) of the latter achieved a response. On univariate analysis of the entire cohort chemo-sensitivity significantly influenced relapse risk (p=0.01), OS (P=0.01) and EFS (P=0.003). TCD significantly improved EFS (P=0.01) despite an excess of unrelated/mismatched donors (18 versus 3, P=0.001) and patients who had failed a prior autograft in the MF-A cohort (44 versus 29, P=0.03). Prior autograft or donor source had no significant influence on TRM, relapse, OS or EFS. More patients were chemo-sensitive prior to RIT in the MF-A group (36 versus 20, P=0.03) but TCD retained independent positive prognostic significance for EFS in multivariate analysis (P=0.02; Hazard ratio 0.69(0.51–0.93)), as did chemo-sensitivity (P=0.01). In conclusion, alemtuzumab significantly reduced GvHD without resulting in an apparent impact on disease relapse. Both groups often required DLIs to achieve tumor control and the response rates support a significant GvL activity.

Description: Background: CHIR-258 is an orally active small molecule receptor tyrosine kinase (RTK) inhibitor which exhibits potent single digit nanomolar inhibitory activity against multiple RTKs involved in tumor growth and angiogenesis (IC50