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93 Background: Fruquintinib (F) is a highly selective, novel, oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3. The phase (Ph) 3 FRESCO study (NCT02314819) that investigated F (5mg daily, 3 weeks (wks) on 1 wk off) showed improved median overall survival in patients (pts) with metastatic colorectal cancer (mCRC) in third line and beyond when compared to placebo (9.3 vs. 6.6 months); hazard ratio 0.65 (P < 0.001) and led to its approval in China. Methods: This is an ongoing Ph 1/1b open-label, dose escalation/expansion study conducted in the US. Here we present the preliminary safety and antitumor efficacy data from pts with refractory mCRC in Cohort (Coh) B (progressed on all standard therapies including TAS-102 [TAS] and/or regorafenib [R]) and in Coh C (did not receive TAS or R). Results: As of data cutoff on 27 July 2021, 81 mCRC pts had been treated (41 in Coh B and 40 in Coh C); median age of 57 years (range: 34─77), Caucasian (81.5%), female (44.4%), and ECOG PS 1 (59.3%). In Coh B, the median number of prior therapies was 5 (range: 3-9), 8 pts (19.5%) received R, 19 (46.3%) received TAS and 14 (34.1%) received both R and TAS. In Coh C, the median number of prior therapies was 4 (range: 1-10). Five pts remain on treatment; reasons for treatment discontinuation included: 56 pts (69.1%) due to progressive disease or death, 8 pts (9.9%) due to adverse events (AE), and 12 pts (14.8%) due to withdrawal of consent or physician decision. The median duration of F treatment was 4.4 months (range: 0.7– 20.0) in Coh B and 3.7 months (range: 0.02-14.3) in Coh C. The most frequently reported AEs of any grade in Coh B were fatigue (53.7%), proteinuria (51.2%), and hypertension (HTN; 48.8%). In Coh C the most frequently reported AEs of any grade were HTN (75.0%), proteinuria (40.0%), and myalgia (32.5%). Hand-foot syndrome (HFS) was reported in 29.3% of Coh B pts and 22.5% of Coh C pts. The disease control rate [DCR] was 68.3% in Coh B (1 partial response [PR] and 27 stable disease [SD]) and 59.5% for the 37 patients with at least one post-baseline tumor assessment in Coh C (2 PRs and 20 SDs). Conclusions: F is generally well-tolerated in heavily-pretreated pts with refractory mCRC. Evidence of antitumor activity was observed in cohorts B and C. The multi-cohort dose expansion is ongoing. F is being further investigated in refractory mCRC in a global Ph 3 study (NCT04322539). Clinical trial information: NCT03251378.

CC‐486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC‐486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC‐486 300 mg once‐daily for 21 days of repeated 28‐day cycles. Median age was 71 years (range: 53‐93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC‐486 treatment cycles was 4 (range: 1‐32). The most common treatment‐emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3‐4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC‐486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on‐study. No baseline gene mutation was predictive of response/nonresponse. CC‐486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics. KEY POINTS The safety profile of oral CC‐486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal. Extended (21‐day/cycle) CC‐486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.

Thrombocytopenia is among the strongest predictors of decreased survival for patients with myelodysplastic syndromes (MDS) across all prognostic risk groups. The safety and efficacy of CC-486 (oral azacitidine) was investigated in early-phase studies; we assessed clinical outcomes among subgroups of MDS patients from these studies, defined by presence or lack of pretreatment thrombocytopenia (≤75 × 109/L platelet count). Patients received CC-486 300 mg once-daily for 14 or 21 days of repeated 28-day cycles. Overall, 81 patients with MDS, median age 72 years, comprised the Low Platelets (n = 45) and High Platelets (n = 36) cohorts. Pretreatment median platelet counts were 34 × 109/L and 198 × 109/L, respectively. Grade 3–4 bleeding events occurred in 2 patients in the Low Platelets and 1 patient in the High Platelets groups; events resolved without sequelae. Treatment-related mortality was reported for 7 patients, 5 of whom had pretreatment platelet values

Background: When administered subcutaneously (SC), the epigenetic modifier, azacitidine (AZA) is shown to improve overall survival in patients (pts) with AML compared with conventional care regimens (Fenaux, JCO, 2010; Dombret, Blood, 2015). CC-486, the oral formulation of AZA, is in clinical development for use in hematologic malignancies. An early dose-finding study of CC-486 administered on a 7-day schedule showed it to be safe and clinically active in pts with AML (Garcia-Manero, JCO, 2011; Gore, Blood, 2011). Extending CC-486 dosing for more than 7 days may increase AZA exposure to leukemic cells over the treatment (Tx) cycle to improve response. Objective: Evaluate the safety and efficacy of CC-486 administered in extended dosing schedules (14 days or 21 days per 28-day cycle) in pts with AML. Methods: Pts with AML from two phase I/II studies were sequentially assigned to receive CC-486 in 1 of 4 extended dosing regimens: 300mg QD x14 days (d)/28d (14-QD), 300mg QD x21d/28d (21-QD), 200mg BID x14d/28d (14-BID), or 200mg BID x21d/28d (21-BID). Hematologic responses (complete remission [CR], partial remission [PR], CR with incomplete hematologic recovery [CRi], marrow CR [mCR]), were assessed using IWG criteria for AML (Cheson, J Clin Oncol, 2003), and hematologic improvement (HI) and transfusion independence (TI) were assessed using IWG criteria for MDS (Cheson, Blood, 2006). Tx-emergent adverse events (TEAEs) were graded by NCI-CTCAE v3.1 or v4.0. Results: In all, 23 pts with AML participated in the studies: 14-QD n=4, 21-QD n=12, 14-BID n=4, 21-BID n=3. Median age was 68 years (range 44 - 93), 48% were male, 22% and 78% had ECOG performance status scores of 0-1 or 2, respectively, median % bone marrow blasts was 25%, and median baseline hematology counts were: Hgb 9.1 g/dL (7.4 - 11.7), platelets 33 x 109/L (3 - 435), and ANC 0.3 x 109/L (0 - 6.4). Median time from diagnosis was 1.1 month (range -0.2 - 82.1). Eleven pts (52%) had prior MDS and 13 pts (57%) had received prior Tx for MDS (n=5) or AML (n=8), including 5 pts (38%) who had received hypomethylating agents (HMAs). The median number of CC-486 Tx cycles for all pts was 4 (1 - 9) (Figure). Overall response (CR, PR, CRi, mCR, HI or TI) rate was 48% (11/23), with generally comparable responses and response rates across the 4 dosing regimens (Table 1). Responses were observed in 4 pts (50%) who were relapsed/refractory to prior AML Tx. Two pts (40%) who had received prior HMA Tx responded, 1 of whom attained CR. HI was achieved by 32% (7/22) of pts, and 20% (3/15) of RBC transfusion-dependent pts attained RBC TI. Six pts with prior MDS (55%) responded during Tx. One pt proceeded to transplant. Febrile neutropenia (30%) and anemia (22%) were the most common grade 3-4 TEAEs (Table 2). Incidences of grade 3-4 TEAEs were generally similar across the 4 CC-486 dosing regimens. Conclusions: CC-486 administered in extended 14- or 21-day per cycle schedules was well tolerated. One-half of these older pts with AML had a hematologic response, including pts who had prior MDS, or AML that failed or lost response to prior Tx. Interestingly, pts who previously received injectable HMA Tx had hematologic responses (including CR) with CC-486, likely due to the alternative methylation pattern obtained with prolonged oral administration (Laille, Plos One, in press). Ease of administration of CC-486 can facilitate long-term Tx for sustained disease modification, provide an additional option for failure of IV/SQ HMA therapy, and may improve outcomes in combination Tx regimens, which warrant investigation. Disclosures Savona: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gore:Celgene: Consultancy, Honoraria, Research Funding. Kolibaba:Janssen: Research Funding; Acerta: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; Cell therapeutics: Research Funding; GSK: Research Funding; Novartis: Research Funding; Genentech, Inc.: Research Funding; Seattle Genetics: Research Funding. Ukrainskyj:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Dong:Celgene Corporation: Employment, Equity Ownership. Hetzer:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment, Equity Ownership.

Background: CC-486 is an oral formulation of the epigenetic modifier, azacitidine, in clinical development for treatment (Tx) of hematological cancers. Part 1 of this phase I, multicenter study showed no effect on pharmacokinetics (PK) of CC-486 when taken with food or with a proton-pump inhibitor (Laille, 2014). A prospective extension phase of this study is ongoing to assess the safety and efficacy of CC-486. Objectives: To assess safety, tolerability, and hematological response associated with an extended CC-486 dosing schedule in patients (pts) with MDS, AML, or CMML. Methods: Eligible pts were age ≥18 years, had confirmed WHO-defined MDS, CMML, or AML based on bone marrow (BM) aspirate and biopsy, and an ECOG performance status score 0-2. In the PK phase, pts received 2 to 3 single CC-486 doses and in the extension phase, pts received CC-486 300 mg QD for the first 21 days of repeated 28-day cycles. Tx-emergent adverse events (TEAEs) were coded by MedDRA v15.0 and graded using NCI-CTCAE v4.0. In addition to TEAEs for all pts, because PK-phase exposure was quite limited, TEAEs of interest are reported for the subset of pts who entered the extension phase (21-day dosing). Responses (complete or partial remission [CR, PR], CR with incomplete blood count recovery [CRi], marrow CR [mCR], hematologic improvement [HI], and transfusion independence [TI]) were defined by IWG 2006 (MDS) or IWG 2003 (AML) criteria. Baseline transfusion dependence (TD) was defined as ≥4 red blood cell (RBC) units or ≥2 platelet transfusions, in the 56 days before first dose. TI was defined as no transfusion for 56 consecutive days. The safety-evaluable cohort included all pts who received ≥1 CC-486 dose. Efficacy-evaluable pts had ≥1 post-baseline efficacy measurement during the extension phase as of data cut-off (June 6, 2014). Efficacy results are reported for the combined MDS and CMML pt population and separately for pts with AML. Results: A total of 32 pts (MDS n=19 [59%], CMML n=4 [13%], and AML n=9 [28%]) received ≥1 CC-486 dose and are evaluated for safety. Median (range) age of all pts was 72 (53-93) years, with 44% of pts age ≥75 years. Most pts were male (69%) and all were Caucasian. Median number of CC-486 Tx cycles for all pts was 4 (range 1-18), and within the MDS, CMML, and AML groups was 5 (1-18), 4 (2-17), and 1 (1-9), respectively. The mean ±SD Tx cycle length was 30 ±9.0 days overall (by group: 33 ±8.3 days in MDS, 25 ±5.4 in CMML, and 27 ±10.7 in AML pts). The most frequent types of TEAE were gastrointestinal (GI) and hematological (Table 1). CC-486 dose was adjusted due to GI TEAEs for 5 pts (16%), and due to hematological TEAEs for 8 pts (25%). Of all 32 pts, 30 pts (94%) entered the 21-day dosing extension phase. Of these pts, GI TEAEs (grade ≥2) were reported for 23 pts (77%). Of these, only 4 grade 3 (vomiting and diarrhea, 2 each) and no grade 4 TEAEs were observed. Hematological TEAEs (grade ≥3) were reported for 19 pts (63%). Neutropenic grade ≥2 TEAEs occurred in 12 (40%) of 30 pts, of which 29% were grade 2, 38% grade 3, and 32% grade 4. Febrile neutropenia occurred in 3 pts and grade 4 thrombocytopenia in 3. Most TEAEs occurred during the first 2 Tx cycles: GI, 73% and hematological, 55%. The efficacy-evaluable population at data cut-off included 27 pts (84%): 20 pts with MDS or CMML, and 7 pts with AML (Table 2). One pt with MDS achieved CR, 1 pt with AML achieved CRi, and 1 pt with AML achieved PR (pt was to proceed to transplant). Of HI-evaluable pts in the MDS+CMML and AML groups, respectively, 6/18 (33%) and 2/7 (29%) attained an HI response. Few pts were TD at baseline. Of pts who were RBC TD at baseline, 1/5 pts (20%) in the MDS+CMML group and 1/5 pts (20%) in the AML group attained RBC TI. Of 3 pts who were platelet TD at baseline, 1 pt with AML attained platelet TI. Conclusions: CC-486 can provide the flexibility to adjust dose or dosing regimen to improve tolerability or efficacy as needed. The safety and tolerability of CC-486 300 mg QD taken for the first 21 days of repeated 28-day cycles were consistent with the known safety profile of injectable azacitidine in these pts with MDS, CMML, and AML. Grade 3-4 gastrointestinal TEAEs were infrequent ( Disclosures Savona: Karyopharm: Consultancy, Equity Ownership; Celgene: Consultancy; Gilead: Consultancy; Incyte: Consultancy. Kolibaba:Celgene: Research Funding. Conkling:Celgene: Research Funding. Rifkin:Celgene: Scientific Advisory Board Other; Millennium/Takeda: Scientific Advisory Board, Scientific Advisory Board Other; Onyx/Amgen: Scientific Advisory Board, Scientific Advisory Board Other. Laille:Celgene: Employment, Equity Ownership. Kellerman:Celgene: Employment. Ukrainskyj:Celgene: Employment, Equity Ownership. Dong:Celgene: Employment. Skikne:Celgene: Employment, Equity Ownership.