New Ways to Treat Solid Tumours

Editor’s note: Recent research has uncovered a potential new way to fight some cancer types. The key is a protein called Eph3A, which is made by the cells of blood cancers and solid tumors. Researchers made a new drug called KB004 to target and kill cells with Eph3A. The drug is currently being tested in a clinical trial with volunteer leukemia patients.

“An international team of scientists has shown that an antibody against the protein EphA3, found in the micro-environment of solid cancers, has anti-tumour effects.

“As EphA3 is present in normal organs only during embryonic development but is expressed in blood cancers and in solid tumours, this antibody-based approach may be a suitable candidate treatment for solid tumours…

“Currently, KaloBios Pharmaceuticals is testing the anti-EphA3 antibody KB004 in a multi-centre Phase I/II clinical trial in Melbourne and the US in patients with EphA3 expressing blood malignancies: AML, MDS and myelofibrosis.”

Agios Gets FDA Fast-Track Designation for its Experimental Leukemia Drug

Editor’s note: The U.S. Food and Drug Administration (FDA) has granted a “Fast-Track” designation to a new drug for certain patients with acute myelogenous leukemia (AML). The drug, called AG-221, is a targeted therapy that is meant to treat people with AML whose tumors have mutations in the isocitrate dehydrogenase-2 protein (IDH2), as detected by molecular testing. The Fast-Track designation means that the FDA will facilitate a faster approval process so that the drug can soon be prescribed by oncologists in the U.S.

“Agios Pharmaceuticals Inc., a Cambridge company seeking to develop new treatments for cancer, said Wednesday that the US Food and Drug Administration has granted a so-called “Fast Track” designation to its experimental treatment for a type of acute myelogenous leukemia, or AML.

“The FDA’s fast track program is designed to facilitate frequent interactions with the FDA review team to expedite clinical development and submission of a New Drug Application, or NDA. The designation is given to medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs. The program provides the opportunity to submit sections of a new drug application on a rolling basis as data become available. This permits the FDA to review portions of the new drug application as they are received instead of waiting for the entire application submission.

“Agios currently calls its drug candidate AG-221, and it is designed to the treat patients with AML who harbor an isocitrate dehydrogenase-2 mutation.”

Volasertib plus Cytarabine Extended Survival in AML

The gist: Researchers have been conducting a clinical trial with volunteer patients to test a new acute myeloid leukemia (AML) drug called volasertib. The researchers have found promising results for patients treated with a combination of volasertib and the drug cytarabine.

“The addition of the investigational agent volasertib to low-dose cytarabine improved response and extended survival in patients with acute myeloid leukemia, according to results of a randomized phase 2 trial.

“Researchers observed the combination’s activity across AML subgroups, and the regimen also demonstrated a manageable toxicity profile, researchers said.

“The analysis included 86 patients (median age, 75 years) with AML who were ineligible for intensive induction therapy. Patients underwent one of two treatment regimens in 4-week cycles.”

Synta Announces Advancement of Ganetespib into Phase 3 Extension of AML LI-1 Study for Patients with AML and High-Risk MDS

The gist: Researchers are conducting a clinical trial with volunteer patients to test new treatments for newly diagnosed elderly patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) who, for whatever reason, cannot undergo intensive chemotherapy. One of the treatments being tested combines the drugs ganetespib and cytarabine. Based on promising results for patients from phase 2 of the trial, the combination treatment is advancing to phase 3, in which it will be tested in even more patients.

“Synta Pharmaceuticals Corp. SNTA +2.46% today announced the advancement of ganetespib into the Phase 3 extension of the AML LI-1 (less intensive) trial. AML LI-1 is a multicenter, randomized Phase 2/3 clinical study evaluating several novel treatment regimens, including the combination of ganetespib with low dose cytarabine (Ara-C), in newly diagnosed elderly patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) who are not eligible for intensive chemotherapy. Ganetespib is a next-generation inhibitor of the chaperone protein Hsp90, which is critical for the activation and stability of numerous proteins that drive cancer growth and proliferation. Ganetespib has been studied in over 1000 patients to date.

“Advancement into the Phase 3 extension follows an interim analysis of results from 50 patients who received the ganetespib-cytarabine combination in the Phase 2 portion of the trial. The primary efficacy outcome in Phase 2 was rate of complete response. Per protocol, the Phase 3 extension will include an interim futility analysis and enroll approximately 200 patients in the ganetespib-cytarabine and the cytarabine alone arms, for a total of approximately 400 patients. The primary efficacy endpoint for the Phase 3 extension will include overall survival. The Company is currently in discussion with study investigators, and anticipates providing additional details, including the timing of study milestones, as they become formalized.”

Gemtuzumab Ozogamicin Plus Chemotherapy Extended OS in AML

Editor’s note: New research shows that some adults with acute myeloid leukemia (AML) might benefit from adding the drug gemtuzumab ozogamicin to their initial chemotherapy treatment. The combination was found to be beneficial specifically for patients with favorable or intermediate “cytogenic characteristics,” according to a scale sometimes used to classify patients.

“The addition of gemtuzumab ozogamicin to induction chemotherapy significantly extended survival in adults with acute myeloid leukemia who did not have adverse cytogenetic characteristics, according to results of a meta-analysis.

“Gemtuzumab ozogamicin (Mylotarg, Pfizer) was approved as the first antibody-directed chemotherapy for cancer treatment in 2000. However, it was withdrawn from the US market in 2010 due to the early termination of the SWOG S0106 trial, which showed excess early mortality among patients assigned gemtuzumab ozogamicin in 6-mg/m2 doses, according to background information provided by the researchers.

“Robert K. Hills, MD, of the School of Medicine at Cardiff University in the United Kingdom, and colleagues identified five randomized controlled trials published through 2013 that compared gemtuzumab ozogamicin plus induction chemotherapy vs. chemotherapy alone.”

Elacytarabine Failed to Improve Outcomes in Relapsed/Refractory AML

Editor’s note: This article covers recent research that hoped to identify good treatments for people with acute myeloid leukemia that has relapsed (returned after initial treatment) or is refractory (resistant to initial treatment). Unfortunately, neither a new drug called elacytarabine nor seven other treatments showed any benefits for the patients involved in the study. One of the researchers said that patients with relapsed/refractory acute myeloid leukemia should be treated in clinical trials whenever possible. Clinical trials are studies with volunteer patients to test promising new treatments. They have risks and advantages, but they can let patients receive cutting-edge drugs they might not otherwise be able to take.


“Neither the novel agent elacytarabine nor seven other commonly used salvage regimens provided clinically meaningful benefit to patients with relapsed/refractory acute myeloid leukemia, according to results of a phase 3 study.

“ ‘The data from our work sadly reaffirm, on a global basis, the dismal prognosis of patients with relapsed/refractory AML,’ Gail J. Roboz, MD, director of the leukemia program and associate professor of medicine at Weill Cornell Medical College and New York-Presbyterian Hospital, and colleagues wrote. ‘There is no effective standard of care, and patients with this disease should be treated on clinical trials whenever feasible. ‘”

Karyopharm Initiates Registration-Directed, Randomized Study Of Selinexor (KPT-330) In Older Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML)

“Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company focused on the discovery and development of novel first-in-class drugs directed against nuclear transport targets for the treatment of cancer and other major diseases, today announced the initiation of its Phase 2 study of Selinexor (KPT-330) in patients 60 years of age or older with relapsed or refractory acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy and/or transplantation. This S elinexor in O lder P atients with R elapsed/Refractory A ML (SOPRA) study is a randomized trial of Selinexor, the company’s novel oral Selective Inhibitor of Nuclear Export (SINE) compound, versus physician’s choice, and will be conducted at approximately 40 sites worldwide including sites in the United States, Canada, Europe and Israel.”

Editor’s note: This story is about a clinical trial to test a potential new treatment for relapsed or refractory acute myelod leukemia (AML) in volunteer patients. The trial is testing whether a drug called Selinexor (aka KPT-330) is effective for patients 60 years of age or older who, for whatever reason, cannot be treated with intensive chemotherapy and/or transplantation. 2/3 of the participating patients will take Selinexor, and for comparison, 1/3 will receive a different standard treatment. The trial is randomized, meaning that patients cannot choose which treatment they receive.

Cancer Metabolism Drug AG-221 Shows Clinical Activity in Advanced Blood Cancers

“AG-221, a novel inhibitor of isocitrate dehydrogenase (IDH) 2-mutant metabolic enzyme, was well tolerated and showed early promise in patients with advanced and refractory blood cancers harboring IDH2 mutations, according to the initial results of a phase I study presented here at the AACR Annual Meeting 2014, April 5-9.

” ‘Mutations in the genes for the metabolic enzymes IDH1 and IDH2 are thought to be the drivers of distinct subsets of acute myeloid leukemias (AML),’ said Eytan M. Stein, M.D., assistant attending physician in the Leukemia Service at Memorial Sloan Kettering Cancer Center in New York. ‘They lead to the production of increased levels of an oncometabolite called 2-hydroxyglutarate (2-HG), which is hypothesized to prevent normal healthy bone marrow cells from maturing, leading to cancer.’ ”

Editor’s note: AG-221 is a targeted therapy drug. The goal of this phase I clinical trial was to test the safety of AG-221 for patients. The trial found that AG-221 is safe and shows real promise as a cancer-fighting treatment for patients whose blood cancers have mutations in the IDH2 gene, as detected by molecular testing.

Transcription Factor SALL4 Is New Kind of Target for Cancer Treatment

Researchers at the Harvard Stem Cell Institute (HSCI) are pursuing a gene called SALL4 as a potential new target for cancer treatment. SALL4 encodes a transcription factor, a type of protein modifies when and how much other genes get expressed. Until now, cancer therapies have not focused on transcription factors; instead, most cancer drugs act on kinases—protiens that modify other proteins. SALL4 is normally only expressed in embryos. However, it can become active again in adults and promote tumor formation. Active SALL4 is found in almost all cases of acute myeloid leukemia (AML), a type of blood cancer, as well as in many patients with other types of cancer, including lung cancer. In two studies, HSCI researchers found that blocking either the SALL4 gene itself or its protein product suppressed cancer cells and improved survival in mouse models of AML and liver cancer. The scientists are now hoping to develop cancer treatments that target SALL4.