November 18, 2013

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx

OK, finally coming to the end of our review of the small molecule, mostly oral, CLL drugs, highlighting a few impressive studies.

First, the Idelalisib plus Rituxan (Rtx) phase 3 results were posted to late-breaking abstracts (Abstract LBA6). The trial was run in high-risk rrCLL patients, comparing placebo/Rituxan to Idelalisib/Rituxan. The data are summarized here:

The trial was stopped early based on the impressive data, including doubling of survival at 24 weeks. Detailed results should be presented at ASH.

Back to the abstracts:

Karyopharm is presenting Phase 1 results of KPT-330 (Selinexor) in NHL/CLL patients (Abstract #90) and AML patients (Abstract #1440). KPT-330 is an inhibitor of the Exportin/Xpo1 protein, whose normal function is to export tumor suppressor proteins from the cell nucleus. Blocking export of tumor suppressor proteins keeps them active in the nucleus, and induces the death of tumor cells. Xpo1 is mutated in some lymphoma patients, and mutated Xpo1 is associated with poor patient outcome.

Patients with advanced NHL or rrCLL, having failed therapy with all available drug classes, were dosed with oral Selinexor. The cohorts include patients refractory to Ibrutinib therapy and refractory to Rituxan plus chemotherapy (R-CHOP). Patients were dosed between 3 – 30 mg/m2 for 8-10 doses per 4-week cycle (NCT01607892). Grade 3/4 AEs were common, including cytopenias. No MTD has been established and dose escalation is continuing. Remarkably, ORR = 80% for all patients that could be evaluated; 20% of patients had PD. These preliminary results in such a high-risk rrNHL/CLL patient population investigators are very encouraging and the investigators will present updated results at the meeting.

Vorinostat, the HDAC inhibitor from Merck, is worthy of notice. What we see in the Phase 1/2 trial is an approach similar to the one Merck used for the AKT inhibitor MK2206. In both cases, combination therapy is initiated very early in the clinical trial process. Abstract #4191 outlines a trial design in which previously untreated CLL/SLL patients are given Vorinostat plus fludarabine, cyclophosphamide and Rituxan (FCR) for 4-6 cycles of therapy, followed by treatment with Vorinostat plus Rituxan alone. Analysis of 22 patients that had completed the treatment cycle is presented. The ORR = 100%, with CR= 73%, PR = 22% and SD = 4.5%. AEs are generally cytopenias, and GI complications.

A second study (Abstract #3063) examines the effect of Vorinostat in the context of Rituxan and cladribine therapy. The investigators will update previous results of a 40 patient Phase 1 study in newly diagnosed MCL patients. The abstract details the impact of a cyclin D1 allele on response to therapy, which has been reported as an ORR = 100% and CR= 87%.

Vorinostat has been around for a long time (aka SAHA) and it is encouraging to see these applications. What is interesting about these studies is that intervention is early (i.e. these are previously untreated patients) and aggressive. In will be useful to look at the comparative data for FRC treatment alone in these patient populations, but the available (and preliminary) data suggest that the Vorinostat combinations are very effective.

Of interest will be data from studies in which more selective HDAC inhibitors are used in place of Vorinostat, and data from other classes of epigenetic modulators.

We will turn next to Biologics, coming up in Part 5.