New investigational epigenetic therapy shows clinical activity against several blood cancers

April 8, 2014

Patients with a variety of hematological, or blood, cancers benefited from treatment with OTX015, a member of a new class of investigational epigenetic therapies that block the activity of bromodomain and extraterminal (BET)-bromodomain proteins, according to results of a phase I clinical trial presented here at the AACR Annual Meeting 2014, April 5-9.

BET-bromodomain proteins have an important role in controlling whether a gene is turned on or off. They work by attaching to special epigenetic flags on the genome. The positioning of many epigenetic flags is abnormal in many different types of cancer, and this can inappropriately turn genes on or off, helping drive these cancers.

"OTX015 is a potent, small-molecule inhibitor of the BET-bromodomain proteins BRD2, 3, and 4," said Esteban Cvitkovic, M.D., professor of oncology and founder of OncoEthix. "Preclinical data showed that it may be effective against a wide range of . This ongoing study is designed to determine the recommended dose and schedule of OTX015 to be given orally as a single agent to patients with hematologic malignancies.

"We have been excited to see that several leukemia and , having failed all available standard therapies, have durable, objective responses to monotherapy with oral OTX015 at doses that have little or no toxicity," added Cvitkovic. "As far as we know, this is the first clinical evidence that BET-bromodomain inhibitors, a new family of anticancer agents, may have a role in the treatment of human malignancies."

So far, Cvitkovic and colleagues have enrolled 42 patients in their clinical trial, 21 with acute leukemia—mainly (AML)—and 21 with other hematological malignancies, including diffuse large B-cell lymphoma (DLBCL) and multiple myeloma. These patients were assigned to a single dose of 10 mg, 20 mg, 40 mg, or 80 mg of OTX015 daily, or to two 40 mg doses of OTX015 daily. There were from three to six patients with and three to six patients with another hematological malignancy assigned to each dosing regimen.

Of the 38 patients for whom data are mature enough to allow evaluation, the researchers saw clinically meaningful activity in seven. Four of these seven patients received a single dose of 80 mg of OTX015 daily, one received 10 mg daily, and the other two received 40 mg daily. Treatment of three of these seven patients is ongoing, between two and six months from the start of treatment.

Among the patients who benefited clinically are four with AML. One is experiencing an ongoing complete response, which means the patient's bone marrow and blood returned entirely to normal. A second is experiencing a complete response with incomplete recovery, meaning there are no leukemia cells detectable in the bone marrow and blood but only partial recovery of normal blood cells. The researchers saw a significant decrease in the number of in and blood for the two other patients with AML. They also saw partial responses in two lymphoma patients, one with DLBCL and one with lymphoplasmacytic lymphoma. A patient with follicular lymphoma has an ongoing minor response with clinical symptom clearance.

No dose-limiting toxicities have been observed so far in patients with leukemia, according to Cvitkovic, while thrombocytopenia is emerging as a dose-limiting toxicity for patients with other hematological malignancies. Enrollment in the trial is continuing, with patients being assigned to single doses of 120 mg OTX015 daily.

Other sporadic adverse events reported so far have been increased blood glucose in previously diabetic , mild to moderate digestive symptoms, and fall of platelet counts. No cumulative toxicity has been observed.

"With dose escalation still ongoing, we have yet to determine the optimal dosing and schedule for monotherapy with OTX015," said Cvitkovic. "Given that, we are very pleased to have already seen clear evidence of antineoplastic activity."

Explore further: Cancer metabolism drug AG-221 shows clinical activity in advanced blood cancers

Related Stories

Cancer metabolism drug AG-221 shows clinical activity in advanced blood cancers

April 7, 2014
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 ...

High-dose cytarabine improves outcome in patients with AML in EORTC-GIMEMA AML-12 Trial

December 19, 2013
Results of the EORTC and GIMEMA (Gruppo Italiano Malattie Ematologiche dell' Adulto) AML-12 Trial appearing in the Journal of Clinical Oncology show that high-dose cytarabine in induction treatment improves outcome of adult ...

New antibody-drug conjugate shows early promise against all forms of melanoma

April 8, 2014
The investigational drug DEDN6526A, which is a new member of a class of drugs called antibody-drug conjugates, was safe, tolerable, and showed hints of activity against different forms of melanoma—cutaneous, mucosal, and ...

Eribulin shows early promise in pediatric sarcoma treatment

November 5, 2013
The drug eribulin, currently approved for the third-line treatment of breast cancer, may represent a new treatment option for pediatric patients with a type of cancer called sarcoma, according to results of preclinical studies ...

Weekly dose reduces targeted drug's side effects, but not its activity against ALL

December 11, 2012
A potent chemotherapy agent wrapped within a monoclonal antibody selectively destroys the malignant cells responsible for acute lymphocytic leukemia (ALL) in either weekly or monthly dosing, researchers report at the 54th ...

Ponatinib acts against the most resistant types of chronic myeloid leukemia

November 28, 2012
A previously invincible mutation in chronic myeloid leukemia (CML) has been thwarted by an investigational drug in a phase I clinical trial reported in the current edition of The New England Journal of Medicine.

Recommended for you

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

No dye: Cancer patients' gray hair darkened on immune drugs

July 21, 2017
Cancer patients' gray hair unexpectedly turned youthfully dark while taking novel drugs, and it has doctors scratching their heads.

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.