Hematologic Drug Pipeline Boasts Novel Approaches

Wayne Kuznar

February 2014, Vol 5, No 1 - Emerging Therapies


New Orleans, LA—Novel options for the treatment of patients with hematologic conditions are in the pharmaceutical pipeline, with many drugs showing promising results. Here is a look at key studies presented at the 2013 American Society of Hematology annual meeting.

Chronic Lymphocytic Leukemia
Phase 3 studies of idelalisib demonstrated impressive progression-free survival (PFS) in previously treated patients with chronic lymphocytic leukemia (CLL).

An orally bioavailable selective inhibitor of the Bcl-2 protein, known as ABT-199, induced remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma in an early-phase, open-label dose-escalation trial. Overall, 88% of patients had at least a 50% reduction in their nodal masses, and 89% of patients had at least a 50% reduction in bone marrow infiltrate at week 25.

The small molecule inhibitor IPI-145, which blocks the activity of the enzyme phosphoinositide-3-kinase (that is responsible for CLL signaling), was investigated in an early-phase trial of 193 patients, including 52 patients with relapsed or treatment-resistant CLL and 15 patients with untreated CLL. IPI-145 demonstrated activity in approximately 50% of the patients with a p53 mutation. A 25-mg twice-daily dose of IPI-145 will be further evaluated in a randomized phase 3 clinical trial.

A phase 2 clinical trial of patients with relapsed CLL who received otlertuzumab in combination with bendamustine (Treanda) showed superior response rates compared with bendamustine alone. Among 65 patients with relapsed CLL who had received 1 to 3 previous regimens had overall response rates (ORRs) of 68% (International Workshop on CLL criteria) and 81% (National Cancer Institute Working Group response criteria) in the group receiving otlertuz­umab plus bendamustine versus 32% and 64%, respectively, with bendamustine alone.

Myelodysplastic Syndromes
In patients with myelodysplastic syndrome (MDS) refractory to hypomethylating agents, sapacitabine was associated with a 1-year survival rate of up to 38%. Sapacitabine is an oral nucleoside analog prodrug that interferes with DNA synthesis by introducing single-strand DNA leading to the arrest of the cell division cycle at G2 phase. In a phase 2 clinical study, 63 patients with MDS refractory to azacitidine and/or decitabine were randomized to 1 of 3 dosage arms of sapacitabine. The 1-year overall survival (OS) rate was 32%, with greater survival seen in the 2 higher-dosage arms. Of the 63 patients in the study, 23 had stable disease at ≥16 weeks.

Oral rigosertib (Estybon) induced responses and transfusion independence in lower-risk patients with MDS in a phase 2 clinical trial. Rigosertib inhibits the cellular-signaling pathways PI3K and PLK. A combined response rate of 53% (International Working Group criteria) was observed in 36 evaluable patients receiving an intermittent dosing schedule. Overall, transfusion independence was seen in 39% of patients who received ≥8 weeks of intermittent rigosertib.

Non-Hodgkin Lymphoma
Monotherapy with the selective oral PI3K-delta inhibitor idelalisib produced a high response rate in patients with indolent B-cell non-Hodg­kin lymphoma (NHL) refractory to rituximab (Rituxan) and an alkylating agent, with responses persisting for 1 year in the average patient. Idelalisib was well tolerated, with the primary adverse event (AE) being diarrhea (13% grade ≥3).

After a median of 3 treatment cycles, copanlisib showed significant activity, including many complete responses (CRs), with weekly infusions of copanlisib in 67 patients with relapsed or refractory lymphoma. The ORRs were high in patients with follicular lymphoma (40%), chronic lymphocytic leukemia (43%), mantle-cell lymphoma (71%), peripheral T-cell lymphoma (50%), and diffuse large B-cell lymphoma (13%).

SAR245409 is a potent oral pan-inhibitor of PI3K that also inhibits mTORC1 and mTORC2. The multicenter phase 2 ARD12130 study evaluated the efficacy of SAR245409, given continuously as a single agent, in 28 patients with follicular lymphoma who had received a median of 3 previous regimens. In 27 efficacy-evaluable patients, the ORR was 44%, including CRs in 15%. All but 4 patients had a reduction in target lesions, which exceeded 50% in more than half of the patients. AEs were observed in 57% of patients and were most frequently diarrhea, although this was grade ≥3 in only 2 (7%) patients.

PNT2258 is a DNA “interference” molecule targeting the Bcl2 gene, which is in very early development. A total of 12 patients with various NHL subtypes and relapsed/refractory disease received PNT2258 intravenously for 5 days every 3 weeks for 6 cycles. PNT2258 exhibited antitumor effects, and 9 of 11 evaluable patients derived clinical benefit, including CRs in 2 patients and a partial response (PR) in 1 patient.

Multiple Myeloma
In newly diagnosed patients with multiple myeloma (MM), the oral proteasome inhibitor ixazomib led to high response rates and increased depth of response with extended treatment duration when combined with lenalidomide (Revlimid) and dexamethasone. A study of treatment-naïve patients included 14 patients in the dose-finding phase 1 trial and 57 patients in the phase 2 study who received ixazomib 3 mg every 21 days for up to 16 cycles. The ORR was 94%, and CRs plus very good PRs (VGPRs) were achieved by 76% of patients. Drug-related serious AEs were seen in 28% of patients; grade 3 drug-related AEs were reported in 58%, and there were no grade 4 events.

In another phase 2 study of ixazomib, 69 patients with relapsed MM who had not received bortezomib or who received <6 cycles of bortezomib had a PR or better without progression. Patients who progressed or who had an inadequate response also received dexamethasone. For the 32 patients remaining on study, the ORR was 34%. At 12 months, 77.5% of the surviving patients have not progressed and 59% are alive without progression.

The oral proteasome inhibitor, oproz­omib, is also demonstrating promising activity. In an ongoing dose-finding study of 42 relapsed patients, approximately 1 of 4 patients is responding.

In the phase 2 PANORAMA 2 trial, which evaluated the oral HDAC inhibitor panobinostat paired with bortezomib (Velcade) and dexamethasone in 55 patients with relapsed and bortezomib-refractory disease, patients received up to 8 cycles (21 days per cycle) of the combination. The ORR was 35%, the median PFS was 5.4 months, the median OS was 17.5 months, and the drug’s safety profile was manageable.

Another multicenter phase 2 study evaluated panobinostat in combination with carfilzomib (Kyprolis) in 44 patients with relapsed/refractory MM. The median PFS was 6.8 months, and the 12-month PFS rate was 41%.

There are more than 10 potential monoclonal antibodies in various stages of development for MM. In an evaluation of 11 patients who received dar­atumumab, 8 patients achieved a PR or better after single-agent treatment (up to 16 mg/kg), including CRs in 3 patients, VGPRs in 2 patients, and PRs in 3 patients. Two patients achieved a minimal response, and 1 had stable disease; no patients progressed. The drug was generally well tolerated.

SAR650984 is another monoclonal antibody on the radar, although it is further behind in development.

In a phase 2 trial in heavily pretreated patients, the response rates were 16% for single-agent filanesib (ARRY-520), a highly selective, targeted kinesin spindle protein inhibitor, and 15% for patients who were dual refractory to bortezomib and lenalidomide and also received dexamethasone. In addition, the retrospective use of acute-phase protein alpha-1-acidic glycoprotein (AAG) levels as a biomarker improved response rates and OS. In AAG-low patients, the response rate was 24% with filanesib alone and 19% with filanesib plus dexamethasone. The incidence of nonhematologic AEs was low, including an absence of peripheral neuropathy.

Indatuximab ravtansine is a combination antibody and chemotherapy that helps deliver the drug to myeloma cells and other cancer cells. Among the 9 patients who are currently available for response, the ORR was 78%.

ImMucin is a myeloma vaccine in development that is based on the protein MUC1, which is found on the surface of cancer cells. A total of 15 patients with myeloma who had received a median of 2 previous lines of therapy and who had residual or progressive disease after stem-cell transplantation received 6 or 12 biweekly ImMucin injections plus growth factors. Most patients achieved vaccine-specific immune responses and significant reductions in MUC1 levels, and had stable disease lasting up to 29 months after study completion.