Potent Hypomethylating Agent Is Tested in 2 Hematologic Malignancy Trials

Ariela Katz
Published: Monday, Jun 11, 2018
Guillermo Garcia-Manero, MD

Guillermo Garcia-Manero, MD

Patients with relapsed/refractory acute myeloid leukemia (AML) have limited options for treatment, especially if they are not candidates for hematopoietic cell transplant or do not have targetable genetic mutations. Individuals with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) face a similar challenge. Their treatment often includes hypomethylating agents, but many patients relapse after receiving this therapy.

Two randomized phase III clinical trials, ASTRAL-2 (NCT02920008) and ASTRAL-3 (NCT02907359), are designed to determine whether guadecitabine (SGI-110), a potent second-generation hypomethylating agent, could answer the unmet medical needs for these patient populations. Most patients with MDS or CMML do not respond to highdose chemotherapy, which is the first line of therapy, said Guillermo Garcia-Manero, MD, deputy chair of translational research in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “Genetic screening for these patients has helped to find actionable mutations for targeted therapies, but there are a large number of patients who don’t have targetable mutations, and in that context, that’s where [guadecitabine] will be important.”

In ASTRAL-2, outcomes with guadecitabine are being compared with physician’s choice of therapy (Figure 1): cytarabine in various doses and combinations; low-dose cytarabine or a hypomethylating agent different from guadecitabine; or best supportive care. Patients who are eligible must have AML previously treated with initial induction therapy using a standard intensive chemotherapy regimen, including cytarabine and an anthracycline, and must be refractory to initial induction (primary refractory) or in relapse after initial induction.

In ASTRAL-3, guadecitabine also is being compared with physician’s choice of therapy, but is using different regimens than ASTRAL-2, including a chemotherapy option and no hypomethylating agents other than the study drug (Figure 2). The therapies are more appropriate for patients with MDS and CMML: low-dose cytarabine, standard intensive chemotherapy of a 7+3 regimen, or best supportive care. ASTRAL-3 is enrolling patients with MDS or CMML who were previously treated with at least 1 hypomethylating agent. The primary endpoint for both trials is overall survival (OS).

“The prognosis of this group of patients [with MDS and CMML] is very poor, there is usually no cure, and because most of these patients are older, they generally are not candidates for allogeneic stem cell transplant,” said Garcia- Manero, principal investigator for ASTRAL-3 and a site investigator for ASTRAL-2.

“The question then is, why would you treat patients with hypomethylation failure with a hypomethylating agent?” Garcia-Manero said. “That in itself seems counterintuitive. But there [are] data that some of these second-generation hypomethylating agents may in part overcome the resistance to [hypomethylating] drugs like azacitidine or decitabine.”

Figure 1. Guadecitabine in Relapsed/Refractory AML

Novel Mechanism of Action

Guadecitabine is a next-generation hypomethylating agent resistant to degradation by cytidine deaminase, an enzyme that can inactivate hypomethylating agents. The drug is a dinucleotide of decitabine bonded to guanosine. In this form, decitabine is not inactivated by cytidine deaminase, which results in prolonged in vivo exposure to the active metabolite decitabine, making guadecitabine more potent than other hypomethylating agents.1 Guadecitabine inhibits DNA methyltransferase, a family of enzymes that catalyze DNA methylation and regulate many normal cellular processes.

Aberrant DNA methylation is one of the mechanisms that results in inactivation of tumor suppressor genes, leading to genomic instability, increased cellular proliferation, decreased apoptosis, and increased metastasis. One effect of guadecitabine reversing the aberrant hypomethylation is the upregulation of tumor associated antigens. It can also sensitize tumor cells to other anticancer agents or resensitize resistant cancer cells to chemotherapeutics.2

“This hypomethylation can activate an immune response, directly kill cells, or lead to cellular differentiation, so there are downstream effects of the primary mechanism of action,” said Jean-Pierre Issa, MD, professor of medicine and director of the Fels Institute for Cancer Research and Molecular Biology at Temple University in Philadelphia, Pennsylvania, and chair of the steering committee for the ASTRAL-1 clinical trial, which is also investigating guadecitabine in patients with treatment-naïve AML.

Prior research has demonstrated that guadecitabine is safe and well-tolerated in patients with AML (both treatment naïve and relapsed/refractory) or MDS. Results from a randomized phase I/II trial (NCT01261312) assessed 3 doses/schedules of guadecitabine: 60 mg/m2 or 90 mg/m2 on the first 5 days of a 28-day cycle or 60 mg/m2 on days 1 to 5 and 8 to 12 of a 28-day cycle. All patients were evaluable for response, and there was no statistically significant difference in the complete response (CR) rate for the 3 cohorts (38%, 41%, and 33%, respectively). Median OS was similar for the 5-day cohorts (316 days; 95% CI, 160-420; 44 patients died) and the 10-day cohort (284 days; 95% CI, 140-478; 42 patients died).3

Figure 2. Guadecitabine in Relapsed/Refractory MDS or CMML

The 60-mg/m2 dose on the 5-day schedule was determined to be the recommended guadecitabine regimen for patients with treatment- naïve and relapsed/refractory AML and is the dosage being used in the phase III trials.3

The most frequent (≥25%) grade 1/2 adverse events (AEs) seen in 5-day schedule cohorts included constipation, diarrhea, nausea, fatigue, decreased appetite, dyspnea, hypokalemia, hypomagnesemia, cough, peripheral edema, dizziness, and stomatitis. The most frequent (≥25%) grade 3/4 AEs were febrile neutropenia, thrombocytopenia, and neutropenia.3

“The drug is very well tolerated in AML and MDS; hypomethylating agents result in cytopenia, that’s an expected adverse effect. In my experience, this doesn’t seem to be more frequent or more severe than what you would see in any other hypomethylating agent,” Garcia-Manero commented.

Investigators are also looking into prognostic factors to determine which patients with AML could have the best response to guadecitabine. Results presented at the 2017 American Society of Hematology Annual Meeting in Atlanta, Georgia, showed that in a prospective phase II study of 206 patients with AML treated with guadecitabine, better ECOG performance status and lower baseline peripheral blood blasts ≤30% were associated with a significantly higher likelihood of response and a longer OS.1

Additionally, patients with treatment-naïve AML had a 5-fold higher likelihood of response to guadecitabine than patients with relapsed/ refractory disease (OR, 0.22; P <.004). However, this was not a significant factor for predicting OS when other factors were present in the model, such as ECOG performance status, cytogenetics risk, and peripheral blood blasts.1

Doses Compare

In a presentation given at the 14th International Symposium on Myelodysplastic Syndromes in Valencia, Spain, investigators compared the 60-mg/m2 dose with the 90-mg/m2 dose in patients with higher-risk MDS or CMML and no prior treatment with hypomethylating agents. They concluded that both doses were clinically active in patients with hypomethylating agent–naïve MDS or CMML, with a 22% CR rate and an overall response rate of 51%.

In all patients, the OS was almost 2 years. The 60-mg/m2 dose cohort had a longer OS (25.7 vs 18.6 months), but this was not a statistically significant difference. The toxicity profile was consistent with prior studies, with the most common AEs including thrombocytopenia, anemia, neutropenia, and febrile neutropenia.4

There is also the phase III ASTRAL-1 clinical trial (NCT02348489), which is now fully enrolled with 815 participants. This trial is comparing guadecitabine with investigator’s choice of cytarabine, decitabine, or azacitidine in patients with untreated AML who are not candidates for intensive remission induction therapy.

“There is no real standard of care for patients with AML who are not fit for intensive chemotherapy induction; informally, people use hypomethylating drugs in this group of patients, and this trial is trying to establish a new standard of care,” Issa said.

According to Issa, a presentation of the results of the ASTRAL-1 clinical trial is expected in the second half of 2018. 

Guadecitabine is being developed by Astex Pharmaceuticals, based in Pleasanton, California.

References

  1. Kantarjian HM, Roboz GJ, Kropf PL, et al. Predictors of response and survival in 206 AML patients treated with guadecitabine in a phase 2 study. Abstract presented at: 2017 American Society of Hematology Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 3854. bloodjournal.org/content/130/Suppl_1/3854.
  2. Clinical pipeline. Astex pharmaceuticals website. astx.com/ research-development/clinical-pipeline/guadecitabine-sgi-110-dnmt- inhibitor-treatment-naive-aml/. Accessed May 1, 2018.
  3. Kantarjian HM, Roboz GJ, Kropf PL, et al. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet Oncol. 2017;18(10):1317-1326. doi: 10.1016/S1470-2045(17)30576-4.
  4. Savona M, Garcia-Manera G, Roboz GJ, et al. Randomized phase 2 study of guadecitabine in patients with MHA-naïve risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). Poster presented at: 14th International Symposium on Myelodysplastic Syndromes; May 3-6, 2017; Valencia, Spain. Abstract 013. astx.com/wp-content/uploads/2017/05/2017_SGI- 110_Poster_MDS_abst_MDS17-013_Savona_final.pdf.



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