SU2C Partnership Results in New, Potent Epigenetic Drug for Myelodysplastic Syndromes, Leukemia

This abstract will be presented at an AACR press conference on Sunday April 1 at 1 p.m. CT in room CC10 A/B/C of the Hyatt McCormick Conference Center. Newswise — CHICAGO — As a result of collaboration between academic and pharmaceutical scientists, made possible by a Stand Up To Cancer research grant, researchers may have discovered a new, potent epigenetic drug that could safely alter the way cancer cells function within the body, according to data presented at the AACR Annual Meeting 2012, held here March 31 - April 4.

The epigenetic code studied can be thought of as small tags that decorate DNA and provide instruction for how the body uses DNA, according to Jean-Pierre Issa, M.D., professor of medicine and director of the Fels Institute for Cancer and Molecular Biology at Temple University in Philadelphia, Pa. In patients with cancer, this code has become abnormal. DNA methylation inhibitors are drugs that try to normalize these tags and the code of cancer cells.

“I compare it to war and diplomacy,” Issa said. Traditional cancer drugs declare war on cancer cells by killing them. In contrast, DNA methylation inhibitors use “diplomacy” and try to alter cancer cells.

“These drugs try to remind the cancer cell of its normal origin and proper behavior,” he said. “They remove these ‘tags’ and rewrite the instruction manual.”

Using Stand Up To Cancer’s grant model of collaborative research, Issa and colleagues worked with Astex Pharmaceuticals to develop SGI-110, a novel DNA methylation inhibitor that is a modified form of an existing epigenetic treatment, decitabine. According to Issa, decitabine currently has limited efficacy because it is quickly degraded in the body. SGI-110 has the potential to demonstrate prolonged drug exposure and improved efficacy through protection from degradation.

Issa and colleagues conducted a phase I trial to establish a biologically effective dose and tolerability of SGI-110 in patients with either myelodysplastic syndrome or leukemia — a novel approach that differs from traditional use of the maximum tolerated-dose trial design. In the first-in-human study, researchers randomly assigned patients with relapsed or refractory intermediate- or high-risk myelodysplastic syndrome or leukemia to subcutaneous daily injections of SGI-110 for five days or to weekly injections for three weeks.

To date, Issa and colleagues have recruited 66 patients. Results indicated that SGI-110 is well tolerated, with local injection site pain, neutropenia, thrombocytopenia and anemia as observed adverse effects.

In addition, data revealed that SGI-110 has an extended half-life and produces clinical response. At least two patients have had disease remission, with one complete response and one partial response. Issa presented complete safety and efficacy results during the meeting.

“There have been some remarkable results in patients who have no options left to them,” Issa said. A phase II study will soon be under way to further explore SGI-110 doses. In addition, Issa and colleagues are beginning to design studies exploring the use of the drug in other, more common solid tumors such as lung cancer and breast cancer.

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About the AACRFounded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR’s membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for patient benefit. The AACR actively communicates with legislators and policy makers about the value of cancer research and related biomedical science in saving lives from cancer.

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Presenter: Jean-Pierre Issa, M.D.

Abstract Number: LB-214

Title: Interim results from a randomized phase I-II first-in-human study of PK/PD guided escalating doses of SGI-110, a novel subcutaneous second generation hypomethylating agent in relapsed/refractory MDS and AML.

Author Block: Jean Pierre Issa1, Gail Roboz2, David Rizzieri3, Stefan Faderl4, Casey O'Connell5, Wendy Stock6, Raoul Tibes7, Elizabeth Griffiths8, Karen Yee9, Woonbok Chung1, Gavin Choy10, Aram Oganesian10, Pietro Taverna10, Mohammad Azab10, Hagop Kantarjian4. 1Fels Institute, Temple University, Philadelphia, PA; 2Weill Cornell Medical College, New York, NY; 3Duke University Medical Center, Raleigh, NC; 4UT M.D. Anderson Cancer Center, Houston, TX; 5University of Southern California, Los Angeles, CA; 6University of Chicago Medical Center, Chicago, IL; 7Mayo Clinic Arizona, Scottsdale, AZ; 8Roswell Park Cancer Institute, Buffalo, NY; 9Princess Margaret Hospital, Toronto, Ontario, Canada; 10Astex Pharmaceuticals, Dublin, CA.

Abstract: SGI-110 is a novel subcutaneous (SQ) second generation hypomethylating agent (HMA) designed as a dinucleotide of decitabine and guanosine, to prolong in vivo exposure and potentially improve efficacy of decitabine by protecting it from rapid deamination by cytidine deaminase. Preclinically, SGI-110 demonstrated potent activity in-vivo using different routes of administration.A randomized phase I-II first-in-human (FIH) PK/PD-guided, dose-escalation study is being conducted in subjects with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage of the study is to determine the safety and tolerability of SGI-110 and to establish the MTD and the biologically effective dose (BED). Subjects are randomized to one of two SQ regimens (daily x5 or once weekly x3, both given in 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation, and gene re-expression studies. The second stage of the study will be a randomized phase II dose expansion, once the BED and MTD have been determined.Currently, 5 dose-cohorts have been fully enrolled, (n= 55) at doses ranging from 3mg/m2 to 60 mg/m2 daily x5, and 6mg/m2 to 90mg/m2 weekly x3. PK guidance has allowed rapid dose escalation, and PD assessment of global hypomethylation has been correlated with increased dose and exposure levels. Apart from manageable local injection site pain, SGI-110 has been well tolerated. Other AE’s were neutropenia, thrombocytopenia, or anemia. There have been 2 remissions in relapsed AML subjects: 1 CR and 1 PR with weekly (60mg/m2) and daily (36mg/m2) regimens respectively. The PK profile showed efficient conversion of SGI-110 to decitabine and confirmation of a decitabine exposure profile as predicted from the SGI-110 rational design (i.e, longer decitabine apparent half life and lower Cmax as compared to historical data based on molar equivalent doses of IV decitabine). Dose-dependent hypomethylation induction in the first 4 cohorts was observed. The patient who achieved a CR had the highest degree of hypomethylation induction of all subjects tested to date, and also the highest decitabine AUC in the cohort. Updated efficacy, safety, PK, and PD data of both regimens will be presented. SGI-110 is safe and well tolerated to date; biologically effective and therapeutic dose levels have been achieved with little toxicity so far with both regimens. Preliminary efficacy (PR+CR) has been observed in relapsed AML subjects. The PK profile showed efficient conversion of SGI-110 to decitabine with longer apparent half life, and lower Cmax than predicted from equivalent decitabine doses given IV. Global Hypomethylating effects were observed at all dose levels, evaluated to date with both regimens. The results justify the progress of the study to the second dose-expansion phase II stage after establishing the BED and MTD.