Oral Azacitidine (CC-486) Plus R-CHOP in Patients with High-Risk or Previously Untreated Diffuse Large B-Cell Lymphoma, Grade 3B Follicular Lymphoma, or Transformed Lymphoma (AFT-08)
Authors: Martin Peter , Bartlett Nancy L. , Chavez Julio C. , Reagan John L. , Smith Sonali M. , LaCasce Ann S. , Jones Jeffrey A. , Drew James , Wu Chengqing , Cerchietti Leandro , Leonard John P. 
Published: October 2019

Abstract
Background: For patients with diffuse large B-cell lymphoma (DLBCL), resistance to standard R-CHOP immunochemotherapy remains an urgent and unmet clinical challenge. Aberrant DNA methylation likely contributes to chemoresistance and may represent a therapeutic target.In a phase I study of R-CHOP plus subcutaneous azacitidine, a DNA methyltransferase inhibitor, complete responses (CRs) were achieved in 10/11 high-risk DLBCL patients (Clozel et al. Cancer Discovery 2013), providing the rationale for this study of oral azacytidine (CC-486) plus R-CHOP. Previously reported data from the dose escalation phase of this study demonstrated promising response rates in patients with high-risk DLBCL (Martin et al. Blood 2017). Here, we present results from both the dose escalation and expansion phases after substantially longer follow-up.
Methods: CC-486-DLBCL-001 (NCT02343536) is a phase I, open-label, multicenter study of CC-486 plus standard R-CHOP in patients with previously untreated DLBCL, grade 3B follicular lymphoma (FL), or transformed FL. Eligible patients were aged ≥18-80 years with no active viral hepatitis, had an International Prognostic Index (IPI) score ≥2 or DLBCL double-positive for BCL2 and c-MYC, an Eastern Cooperative Oncology Group performance status ≤2, and Ann Arbor stage II-IV disease. Patients in the dose escalation phase were enrolled sequentially into 4 dose cohorts of CC-486 (100, 150, 200, and 300 mg) using the time-to-event continual reassessment method. Additional patients were enrolled in the expansion phase to evaluate preliminary efficacy. Patients received up to six 21-day cycles. CC-486 was administered for 7 days before initiation of R-CHOP and on days 8-21 of cycles 1-5. Granulocyte-colony stimulating factor was mandated by protocol and anti-emetics were standard treatment. The primary objectives were to determine safety (per NCI CTCAE v4.03) and the recommended phase 2 dose (RP2D) of CC-486 in combination with standard R-CHOP. Secondary endpoints included pharmacokinetics and preliminary efficacy per the International Working Group criteria (Cheson et al.J Clin Oncol 2014).
Results: Fifty-nine patients were enrolled as of May 31, 2018, including 40 treated at the RP2D of CC-486 300 mg. The median age in the overall population was 66 years (range, 25-80), 76% were aged >60 years, 59% were male, and 59% had an IPI score ≥3. Fifty-four patients (92%) completed all 6 planned cycles of study treatment. Thirteen patients (22%) had CC-486 dose reductions because of adverse events (AEs). Two patients discontinued CC-486 due to AEs: febrile neutropenia (n=1; 150 mg) and sepsis (n=1; 300 mg). The most common AEs were gastrointestinal, which were mainly grade 1/2; hematologic AEs were the most common grade 3/4 toxicity (Table 1). Grade 3/4 AEs related to CC-486 occurred in 36 (61%) patients, most commonly neutropenia (41%) and febrile neutropenia (20%). Febrile neutropenia was more common among older patients (9/15 patients with this AE were aged >70 years) and those with IPI scores ≥3 versus ≤2 (31% vs 17%) but was not correlated with CC-486 dose. One patient died during the study (acute respiratory failure possibly related to study treatment). All patients were evaluable for response. The overall response rate was 95%, with 52 patients (88%) achieving a CR; response rates were generally similar in patients with IPI scores ≥3 and ≤2 and in patients treated at the RP2D (Table 2). Median progression-free survival (PFS) was not reached (median follow-up of 12 months); estimated 1-year PFS rates were similar in the overall population (86%) and in patients with IPI scores ≥3 (84%) and ≤2 (89%).
Conclusions: Epigenetic priming with CC-486 before R-CHOP demonstrated promising clinical activity in patients with high-risk, previously untreated DLBCL, transformed FL, or grade 3B FL. AEs were generally consistent with the known safety profile of azacitidine and toxicities associated with R-CHOP. These results support further investigation of oral azacitidine (CC-486) in combination with R-CHOP, including patients with high-risk disease.

Disclosures
Martin: Gilead: Consultancy; Janssen: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy. Bartlett:Astra Zeneca: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; ImaginAB: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Pharmacyclics: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Research Funding; Immune Design: Research Funding. Chavez:Merck: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Humanigen: Consultancy. Reagan:Alexion: Honoraria; Takeda Oncology: Research Funding; Pfizer: Research Funding. Smith:Portola: Honoraria; BMS: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau. Jones:Celgene: Employment, Equity Ownership. Drew:Celgene Corp.: Employment. Wu:Celgene: Employment, Equity Ownership. Cerchietti:Celgene: Research Funding; Weill Cornell Medicine: Employment. Leonard:ADC Therapeutics: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy; BMS: Consultancy; Juno: Consultancy; Celgene: Consultancy; Biotest: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Sutro: Consultancy; United Therapeutics: Consultancy.