Category Archives: HDAC


 by Paul D Rennert, February 11, 2014

In looking at Acute Myeloid Leukemia (AML) we see a cancer field right on the cusp of change in clinical practice. Standard of care chemotherapy regimens and stem cell transplantation protocols have proven to be of limited utility, especially in older patients. However, potentially big advances in care are being made, with exciting news coming out regularly. As we move toward the spring Medical Conference season, we felt an overview of this rapidly evolving area of oncology would be timely.

AML is a rapidly growing cancer of myeloid lineage cells that proliferate in the bone marrow and interfere with normal hematopoiesis. AML typically arises in the context of defined genetic mutations. For example, translocations of chromosome 16 disrupt RUNX1 gene activity and are one of the several underlying causes of Core Binding Factor AML. CBF-AML). Since RUNX1 regulates the transcription of many genes, the effect of its disruption is complex. CBF-AML patients are generally responsive to chemotherapy initially, although up to half of these patients will relapse over time due to additional genetic mutations.

Mutation of the FLT3 protein is the most common genetic abnormality in AML, found in about 30% of patients. This is a genetic characteristic associated with poor prognosis. The most common FLT3 mutation, FLT3-ILD, is caused by an tandem duplication within the coding region of the gene. The resulting protein drives hyper-signaling and oncogenic cell responses. Mutations that change the active site of the protein, causing unregulated phosphorylation, have also been described. Mutations in the receptor tyrosine kinase c-Kit are also associated with oncogenic signaling in AML. Both of these pathways cause mutiple downstream effector pathways to be activated. The JAK2 mutations, commonly see in myelofibrosis and other myeloproliferative disorders, are rare in AML but when characterized can potentially be treated with Jak2 inhibitors.

According to a recent market research analysis                           ( a total of 62,226 new cases of Acute Myeloid Leukemia (AML) were recorded in 2010, with 95,000 predicted new cases for 2015 and nearly 130,000 predicted new cases in 2020. Note that as of February 2014 approved agents for AML remain limited to chemotherapeutics ( Despite the lack of new targeted drugs, the AML therapeutics market was nearly 240 MM USD in 2011. At the current rate of growth the AML market could reach over 700 MM USD by 2018. These numbers are based on the analysis of future AML drugs growing at a 17% compound annual growth rate from through 2018.

Numbers like these are continuing to drive intensive research into effective, novel therapies for AML. It only helps that in many cases such therapeutics find use in other hematopoietic diseases such as Chronic Myeloid Leukemia (CML) and in the B cell lymphomas, including Hodgkin’s Lymphoma and the non-Hodgkin’s Lymphomas (NHL).

 There is obvious unmet medical need for effective therapies in AML since this is a disease characterized by quick relapse after therapy with grim survival statistics. In some older patients, survival is as little as 1-1.5 years despite first and second line treatment regimens.

What’s exciting from the drug development and biotech investment perspectives is that the AML treatment landscape is advancing simultaneously across therapeutic modalities. This rapidly changing landscape give us a chance to look at targeted small molecule drugs, monoclonal antibodies (naked, bi-specific, radiolabelled, immunotherapeutic, ADC), targeted T cells and other novel technologies.

 We can then ask ourselves: who will the winners be in 5 years?

 A) Targeted small molecule drugs.

Lets just be clear upfront that the goal of these targeted therapies is to get patients who have relapsed, or are refractory to chemotherapy, to a complete response (CR) with minimal residual disease (MRD) so they can qualify for an allogeneic stem cell transplant (SCT). That’s a lot of acronyms but what this is really saying is that for most patients the goal is a modest one – we are not asking for a durable remission, at least not yet.

 A variety of established drugs are being tested in AML. Also, the identification of oncogenic mutations in FLT3 and cKIT has driven interest in developing new tyrosine kinases inhibitors (TKIs) for AML.

 Sorafenib (NexavarTM; Bayer and Onyx) is a dual targeting drug that blocks RAF signaling (and therefore the MEK>ERK signaling) and also the growth factor receptor tyrosine kinases VEGFR and PDGFR. The NCI is running a large phase 3 trial enrolling new onset pediatric AML patients (NCT01371981) with sorafenib being given in combination with various chemo regimens.  Bayer and Onyx are running several earlier phase AML trials. An interesting phase 1 trial in patients 18 or older combines sorafenib with plerixafor and G-CSF (NCT00943943). The idea here is to have the CXCR4 blocker (plerixafor) and the growth factor (G-CSF) flush tumor cells, and also tumor stem cells, from the bone marrow and lymph nodes so that they are more sensitive to sorafenib treatment. This trial is co-sponsored by Genzyme/Sanofi, which owns plerixafor.

Another interesting trial is the Phase 1/2 study of the combination of sorafenib, with vorinostat, and bortezomib (NCT01534260). Here we have a proteasome inhibitor and an HDAC inhibitor added to growth factor and signaling inhibition provided by sorafenib. This potent combination is being used in patients with a poor genetic risk profile, including FLT3-ILD positive tumors. This study is co-sponsored by Bayer/Onyx, Millennium/Takeda and Merck Sharp & Dohme Corp.

Bristol Myers Squibb is running an interesting trial (NCT01620216) in which AML and acute lymphocytic leukemia (ALL) patient samples are analyzed for sensitivity to drug treatment ex vivo, after a period on drug in the trial, as follows:

“An in vitro kinase inhibitor assay will be used to determine the sensitivity of primary leukemic cells to four kinase inhibitors/drugs:

Drug: Sunitinib, 50 milligrams (mg) qd, with or without food, for 4 weeks

Drug: Dasatinib, 100 mg qd…possible escalation to 140 mg qd for 28 days

Drug: Nilotinib, 400 mg twice daily for 28 days

Drug: Sorafenib, 400 mg (2 tablets) orally twice daily without food for 28 days

Drug: Ponatinib, 45 mg dose once per day

Sunitinib (Sutenttm; Pfizer) makes sense as a pan-growth factor receptor inhibitor; dasatinib (Spryceltm; Bristol Myers Squibb) is a Src and c-Kit inhibitor and is a reasonable choice for AML; nilotinib (Tasignatm; Novartis) is a pretty specific Bcr-Abl kinase inhibitor and is probably only being used for the ALL population – and even there only 25% of ALL patients carry this translocation; sorafenib we discussed earlier; ponatinib (Iclusigtm; Ariad) has a grab bag reactivity profile, hitting the BCL-ABL kinase, FLT3, RET, c-KIT and the FGFR, PDGFR and VEGFR growth factor receptor kinases. This is a dangerous drug, with a very narrow FDA approval in CML, and I suspect enrollment in this little exploratory trial will be stopped if possible.

If I had to guess I would say that this rather odd trial design has several goals. One is to look for signs of efficacy, although a month is pretty short duration. One might also look for patterns of resistance to therapy, which would be very interesting. Since this is BMY, I’d be surprised if they weren’t also looking at cell surface markers for possible immunotherapy treatment – more on this subject later.

Results from a dasatinib trial in CBF-AML were recently presented at the American Society of Hematology (ASH) conference (Abstract #357). Dasatinib was added to induction and consolidation chemotherapy in newly diagnosed AML patients. Unlike the rrAML population, the CBF-AML population can experience sustained periods of remission prior to relapsing, especially in younger patients. Since some of the relapses are driven by gain of function mutations in c-Kit, dasatinib should prevent at least those clones from becoming established. Early results looked good but longer term data are needed to see if this regimen will remain effective.

Imatinib (Gleevectm; Novartis) another Bcr-Abl, c-Kit and PDGF-R inhibitor, has been tested in multiple AML trials, but the results have not led to approval for use in AML. An interesting trial of the cytotoxic/immunomodulatory agent lenolidomide (Revlimidtm; Celgene) plus chemotherapy is being run by the NCI (NCT01246622). Lenolidomide has been approved for the treatment of a different bone marrow resident cancer, multiple myeloma (MM).

Anyway there is a lot of similar clinical trial work being done – using approved drugs in this new indication and looking for efficacy. This is ultimately good both for patients and the drug development companies.

Lets move on to some newer drugs in the pipeline. The FLT3 inhibitors give us a sense of the difficulty here, with low response rates as monotherapies.

Quizartinib (Ambit Biosciences; AMBI) remains stuck between phase 2 and 3 for relapsed/refractory (rr) AML. This drug is a FLT3 inhibitor with a somewhat tortured history, having been partnered for a time with Astellas, then returned, then running nicely in the clinic before running into disagreement with the FDA over approvable endpoints and safe dosage. In early December the company announced it would have to run a phase 3, likely with lower starting doses, in order to obtain FDA approval. Investors were hoping the company could file on its phase 2 trials. Notably, later in December Ambit showcased its’ quizartinib data from the FLT3-ILD rrAML trial, in which a 50% response rate (50% or greater reduction in leukemic blast cells) was reported with relatively low doses of drug. Unfortunately, it will be a while yet before more news becomes available about this drug.

In the meantime heavy hitter Novartis is already in phase 3 with its’ FLT3 and Protein Kinase C inhibitor midostaurin. The phase 3 in newly diagnosed patients is being run by the NCI (our tax dollars at work), along with The Alliance for Clinical Trials in Oncology and the Cancer and Leukemia Group (NCT00651261). A trial of midostaurin administered with or without bortezomib in adult rrAML patients is being run by Novartis and Millennium/Takeda (NCT01174888). Preliminary results were presented at ASH (abstract #3966). While response rates were impressive the toxicity was extreme, and this seemed to be due to the bortezomib dose, which was adjusted. Phase 2 trials in adult patients who carry c-KIt, FLT3-ILD, and various other mutation or cytogenetic markers are also underway (NCT01830361, NCT01846624). A phase 2b midostaurin  monotherapy study published several years ago showed modest improvement in AML patients with mutated FLT3; this study recognized the need for combination therapy to improve the clinical response (

Another FLT3 inhibitor, lestaurtinib, is the subject of 2 NCI sponsored trials in pediatric ALL/AML but drug development of this agent seems to have stalled when Teva bought Cephalon. Another FLT3 inhibitor is PLX3397 (Plexxikon) which has activity against  KIT, CSF1R and FLT3. This drug is in a phase 1/2 trial in adult rrAML (NCT01349049).

One of the major challenges for FLT3 inhibitors is breadth of action. These inhibitors work best on patients who have mutated FLT3 and are less effective in patients with normal FLT3. Also, secondary mutations have already been discovered in response to FLT3 inhibition. Specifically, in those patients who have mutations in the active site of the kinase, so-called gatekeeper mutations arise, conferring resistance to the drug.

A dominant theme in recent drug development for AML has been built on the observation that proteasome inhibitors can impact cancers of the bone marrow. Disruption of proteasome activity blocks a wide spectrum of cellular activities, and is particularly effective against rapidly dividing cells (like leukemic blasts) but also relatively quiescent tumor stem cells, that require specific proteasome-dependent signaling pathways (e.g. NK-kB). Bortezomib (Velcadetm, Millennium/Takeda) has shown activity in older patients when combined with chemotherapy. A phase 3 combination trial with sorafenib in newly diagnosed AML patients is underway, sponsored by the NCI (NCT01371981).

Carfilzomib (Onyx Pharmaceuticals) is in an early stage trial for AML, along with extensive trials in MM, B cell lymphomas, etc. The drug is furthest along in MM, now in phase 3 (NCT01568866). Early reports so far have suggested that this drug has an activity profile similar to bortezomib, but may have a better safety profile. This is an interesting drug (and company) to watch. They have a second generation oral version of carfilizomib, oprozomib, in phase 1 MM trials. Millennium/Takeda are developing ixazomib in MM and lymphomas. An AML trial is listed but not yet recruiting.

A third theme that we can follow in AML therapeutic drug development is the use of drugs that impact epigenetic gene regulation. Because AML is driven by genetic translocations, gene regulation at the level of chromatin structure is disrupted. There are two processes at work here that can be targeted. One is the aberrant methylation of CpG islands in gene promoter regions, which can be targeted by DNA methyltransferase inhibitors. The second is changes in the conformation of chromatin caused by dysregulated histone acetylation. This process can be therapeutically targeted using histone deacetylase [HDAC] inhibitors.

The HDAC inhibitor vorinostat (Zolinzatm, Merck) has been extensively studied in AML, and is currently in a phase 3 trial with chemotherapy for young patients with newly diagnosed disease (NCI; NCT01802333). Vorinostat monotherapy was generally ineffective, but combination with chemo agents proved much more potent. As detailed at ASH in December (Abstract #2684), newly diagnosed and rrAML patients were enrolled in a phase 2 expansion study. Of 75 patients, 57 patients achieved CR, and 7 achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 85 percent. Median overall survival was 82 weeks and median event free survival was 47 weeks. For patients with the high-risk Flt-3 ITD mutation the 10/11 achieved CR and 1/11 CRp. The ORR = 100% in these patients. Their median overall survival was 91 weeks and median event free survival was 66 weeks. About 25% of the total patients in CR received SCT.

Other combination trials include the sorafenib trial mentioned above, and a trial in combination with antibody therapy (gemtuzumab ozogamicin) for rrAML (NCI; NCT00895934). This trial reported early results at ASH (Abstract #3936). The response rates ere encouraging and about 20% of patients obtained durable remission. There were significant toxicity issues. This drug is very likely to play a critical role in the evolution of combination therapy for AML. We’ll discuss antibody therapies further in Part 2.

Other important HDAC inhibitors in development for AML is panobinostat (Novartis). What’s interesting about the development campaign with this drug is the pairing in multiple trials with 5-azacitidine, a DNA methytransferase inhibitor. In such settings two modes of epigenetic regulation are being targeted simultaneously. One of these studies published findings last month                                 ( and demonstrated good tolerability and reasonable response rates. Clearly, this combination should move forward in the context of chemotherapy or other drugs. Of note the DNA methyltransferase inhibitor decitabine (Dacogentm, MGI Pharma) is already approved for AML. There was also a presentation on the HDAC inhibitor entinostat (Syndax Inc) with 5-azacitidine in myeloid neoplasia (Abstract #2777), and there are several clinical trials listed for AML, however this drug is mainly being used in solid tumor trials.

Other interesting drugs in this area include alisertib, an Aurora A kinase inhibitor (Millennium/Takeda) being tested extensively in B and T cell lymphomas and in solid tumors. There are several AML trials including a phase 2 trial completed by MLMN (NCT00830518). Selinexor, (Karyopharm) a selective inhibitor of nuclear export, in in phase 1 trial for advanced AML. Abbvie’s Bcl2 inhibitor ABT-199 is also in an AML trial.

If we take a step back we can appreciate that in small molecule development Novartis, Merck and Onyx are placing big bets in this therapeutic area. We’ll sort out the best looking therapeutics as we dig in a little deeper.

In Part 2 we’ll take a look at the biologics landscape, and begin to draw the bigger picture.

Snapshots, 2013 American Society of Hematology Abstracts – New & Noteworthy

Part 4. Novel and exciting new pathways, drugs and combinations.

November 18, 2013

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at

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.