Atherton, Pamela J.

TPS4593 Background: Bone metastases are prevalent in approximately 30% of pts with advanced RCC. Pts with bone metastases have a worse prognosis compared to pts without bone metastases and are at risk of symptomatic skeletal events (SSEs). Cabozantinib, a multitargeted inhibitor of multiple kinases, including vascular endothelial growth factor (VEGF) receptor and MET, has improved survival in pts with metastatic RCC and has enhanced activity in bone. Ra-223, an alpha-emitting radioisotope with natural bone-seeking proclivity, has been shown to prolong survival in men with castration-resistant prostate cancer. We previously conducted a pilot study of Ra-223 with VEGF inhibition and demonstrated safety and declines in markers of bone formation and resorption with the combination (McKay et al, CCR 2018). Given that decreasing rates of SSEs and improving outcomes for pts with RCC with bone metastases are unmet needs in pts with RCC, we designed a randomized phase 2 study through the National Clinical Trials Network (NCTN) investigating cabozantinib with or without Ra-223 in patients with RCC with bone metastases. Methods: This is an open-label multicenter study. Eligible pts have metastatic RCC of any histology with ≥2 metastatic bone lesions untreated with prior radiation therapy and no more than 2 prior lines of systemic therapy. Pts with non-clear cell RCC are eligible and will be capped at 20% of the total accrual goal. Pts must have a Karnofsky performance status of ≥60%, have symptomatic bone pain defined as a prior SSE or need of analgesics, and be on osteoclast-targeted therapy unless otherwise contraindicated. Pts are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) Ra-223. Starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade ≥3 toxicity. Ra-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, quality of life measures, and correlative analyses including liquid biopsy studies and tumor tissue analysis. The study has 90% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided α = 0.025 significance. To ensure 191 evaluable patients, target accrual is 210 pts. This design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events (72 SSE events) have been observed. Final data analysis will occur when 143 events have been observed. The study was activated in December 2019 and accrual is currently ongoing throughout the NCTN. Clinical trial information: NCT04071223.

Abstract Background: Debate continues as to the clinical relevance of subclassifying patients with the myeloproliferative disorder (MPD) MMM into the subgroups of agnogenic myeloid metaplasia (AMM), post-polycythemic myeloid metaplasia (PPMM), and post-thrombocythemic myeloid metaplasia (PTMM). We looked to validate previously described phenotypic variability amongst subtypes, and explore relevant and differences in constitutional symptoms. Methods: An detailed analysis of patients with MMM whom responded to an international web based survey of MPD patients which registered responses regarding diagnosis, disease course, complete blood counts, co-morbidities (Charlson Co-morbidity index), symptoms, and fatigue (Fact-An and Brief Fatigue Inventory (BFI)). Results: A total of 456 patients self described as MMM responded of which 32.3% had AMM (n = 148), 38.0% % had PPMM (n = 174), and 29.7% had PTMM (n = 136). Detailed breakdown of differences in demographics, clinical course, current laboratory studies, treatment history, and current symptoms are outlined in the table below. Phenotypic Variability Amongst 458 MMM Patients Category AMM (N=148; 32.3%) PPMM (N=174; 38.0%) PTMM (N=136; 29.7%) MMM Total (N=458) Δ between groups (p = ) Hb = Hemoglobin; SCT = Stem Cell Transplant Age (Median) 61 57 57 58 0.09 Sex (% Males) 60% 49% 30% 47% <0.01 Yrs from MPD Dx 5 6 8 6 <0.01 Labs/ Prior History Hb (g/dL) 11.0 13.7 11.6 12.1 <0.01 % with RBC Tx 43% 6% 11% 20% <0.01 Leukocytes (×10(9)/L) 8.0 7.6 7.2 7.7 0.64 Platelets (×10(9))/L) 200 352 396 321 <0.01 % with Splenomegaly 76% 49% 41% 54% <0.01 % with Prior Thrombosis 10% 22% 31% 21% <0.01 % with Prior Bleed 16% 20% 31% 22% 0.01 Treatment History for the MMM % with Prior Tx for MPD 64% 88% 77% 77% <0.01 % Medical Therapy 57% 70% 75% 67% <0.01 # Meds (Median (Range)) 1 (0–8) 2 (0–6) 2 (0–6) 2 (0–8) <0.01 % with Splenectomy 8% 5% 6% 6% 0.48 % with SCT 6% 1% 1% 3% <0.01 MMM Associated Constitutional Symptoms % with Fatigue 85% 81% 85% 84% 0.56 % with Bone Pain 51% 46% 44% 47% 0.51 % with Fevers 19% 17% 18% 18% 0.87 % with Pruritus 39% 69% 39% 50% <0.01 % with Night Sweats 55% 58% 53% 56% 0.67 % with Weight Loss 30% 15% 16% 20% <0.01 Overall the data suggests patients with AMM are more likely male, with greater burdens of anemia, splenomegaly, and weight loss. However they are less likely to have experienced thrombohemorrhagic complications and have received fewer MPD medications. In contrast PPMM patients (not unsurprisingly) have little trouble from anemia, but have the most pruritus. Patients with PTMM are most likely female, with the highest platelet counts, and the greatest likelihood of thrombohemorrhagic complications. Additionally, all three subgroups of MMM had significant fatigue compared to published controls for both fatigue instruments (P<0.0001) yet there was no difference between MMM subtypes for the severity of fatigue. Conclusions: A large unselected series of MMM patients supports that although constitutional symptoms are significant and similar amongst MMM subgroups, these patients have variable burdens of other MPD manifestations.

Abstract Background: Scant data exists regarding the burden of fatigue and constitutional symptoms in patients with myeloproliferative disorders (MPDs) (essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis with myeloid metaplasia (MMM)). Methods: An Internet based survey of MPD patients regarding clinical course, blood counts, constitutional symptoms, and fatigue (FACT-AN and Brief Fatigue Inventory (BFI)). Results: Patient Demographics: A total of 1179 MPD patients (median age 56; 41.4% male) internationally (76% USA: 50 states, 30 countries, 6 continents) responded to the survey. Self reported diagnoses were PV (35%), ET (26%), or MMM (39%). Clinical History: 1025 patients (87%) had undergone MPD therapy (drugs 70.5%, phlebotomy 44.1%, other 16%). Thrombosis (n=261, 22%), hemorrhage (N=272; 23%), and splenomegaly (N=478 (43%) were frequently reported. Blood tests (available in 917) showed 39% were anemic, 7% transfusion dependent. Symptoms: Fatigue, pruritus, night sweats and bone pain were present across the majority of MPD patients (see table). Additionally it was observed that these symptoms appeared with nearly equal frequency in PV as in MMM patients. However MMM patients displayed more advanced features (fevers, night sweats and weight loss). MPD Associated Constitutional Symptoms in 1179 Patients SYMPTOM PV (N=405) ET (N=304) MMM (N=456) MISSING (N=14) TOTAL (N=1179) P VALUE Fatigue 344 (84.9%) 220 (72.4%) 381 (83.6%) 7 945 (81.1%) <0.0001 Pruritus 265 (65.4%) 120 (39.5%) 228 (50.0%) 3 613 (52.6%) <0.0001 Night Sweats 199 (49.1%) 123 (40.5%) 254 (55.7%) 4 576 (49.4%) 0.0002 Bone Pain 174 (43.0%) 125 (41.1%) 214 (46.9%) 4 513 (44%) 0.2480 Fevers 53 (13.1%) 26 (8.6%) 81 (17.8%) 2 160 (13.7%) 0.0013 Weight Loss 39 (9.6%) 22 (7.2%) 93 (20.4%) 0 154 (13.2%) <0.0001 Spleen Pain 17 (4.2%) 27 (8.9%) 30 (6.6%) 4 74 (6.3%) <0.0001 Fatigue (82% MPD linked) was significantly increased across all MPD subtypes compared to published controls for both the BFI (P<0.0001) and Fact-An (P<0.0001). Additionally 69% curtail social activity because of fatigue, 35% need assistance with activities of daily living, and 11% reported MPD associated medical disability. Fatigue strongly correlated with multiple MPD disease features including: anemia, bone pain, constitutional symptoms, pruritus, splenic pain, smoking, thrombosis, and hemorrhagic events (all p<0.0001). Interestingly, even in “asymptomatic” MPD patients (those without anemia, splenomegaly, or thrombohemorrhagic complications) (n=279)) 24% (41% PV, 31% ET, 28% MMM) described significant fatigue worse than published controls. Conclusions: Fatigue and other constitutional symptoms are a significant burden to MPD patients, despite current therapies employed. Additionally fatigue is also a significant problem even in MPD patients lacking other advanced disease features. Clearly, direct attempts to improve fatigue (through pharmacologic and non-pharmacologic interventions) are necessary.

3501 Background: Cumulative neurotoxicity commonly leads to early discontinuation of oxaliplatin-based therapy. In a relatively small, prematurely-discontinued, randomized study, IV CaMg was associated with reduced oxaliplatin-induced sNT (Grothey, JCO, 2011). N08CB was designed to definitively test whether IV CaMg significantly decreases cumulative oxaliplatin-related sNT. Methods: 353 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to 3 arms: IV CaMg (1g calcium gluconate, 1g magnesium sulfate) before and after oxaliplatin vs PL before and after vs CaMg before and PL after. The primary endpoint was cumulative sNT repeatedly measured by the sensory subscale of the EORTC QLQ-CIPN20. Secondary endpoints, using CTCAE 4.0 and an oxaliplatin specific neurotoxicity scale, were also assessed. Acute neuropathy data were also collected for 5 days following each oxaliplatin dose. The area under the curve (AUC) of the sensory subscale during the treatment cycles was used as summary measures for comparison. The Wilcoxon rank-sum tests were conducted for each treatment versus placebo arm, at 2.5%, adjusting for multiplicity using Bonferroni’s approach. Results: CaMg did not reduce cumulative sNT. Primary and secondary analyses data are summarized in the Table. In addition, there were no significant differences between arms regarding oxaliplatin administered doses or chemotherapy discontinuation rates. Also, there were no substantial differences in acute neuropathy scores or side-effects between study arms. Conclusions: This study does not demonstrate any activity of IV CaMg as a neuroprotectant against oxaliplatin-induced neurotoxicity. Clinical trial information: NCT01099449. [Table: see text]

2596 Background: Docetaxel (D) is an anti-mitotic drug metabolized by the cytochrome P450 (CYP) 3A4 enzyme. While case reports have demonstrated a potential association of CYP3A inhibitor use with severe toxicity in D treated patients (pts), there are no data whether co-administration of CYP3A inhibitors with D increases the rate of hospitalization and/or death. Methods: A retrospective cohort of pts treated with D at the Mayo Clinic Rochester from 1/1/09-10/1/11 was identified. Information regarding D and concomitant chemotherapy (starting dose and dose reductions), type of CYP3A inhibitor, growth factor use, hospitalizations and deaths was abstracted. Time to event analyses (either hospitalization or death) were conducted using Kaplan-Meier estimates and proportional hazards modeling. Results: 384 pts (median age 63, range 20-93) received D as monotherapy (48%) or as multi-agent chemotherapy (52%) for a median of 4 cycles. 56 pts were co-administered CYP3A inhibitors (45 moderate, 11 strong). 90 pts were hospitalized during D chemotherapy and 15 died. The mean time to hospitalization was significantly shorter in pts treated with a mod/strong CYP3A inhibitor (186 days) vs not treated (408 days) (p=0.02) . While time to death was not significantly different based on inhibitor use (111 vs. 177 days, p=0.49), time to first event (hospitalization or death) varied significantly according to those on inhibitors (187 days) versus not (397 days) (HR: 1.78, p=0.02). Time dependent analyses indicated that use of multiage chemotherapy (combination vs D monotherapy; HR 1.96, p= 0.002) and chemotherapy dose reduction of either D (HR 0.54, p<0.01) or other chemotherapy (HR 0.61, p=0.02) were significantly associated with the risk of an event. In a multivariate analysis, moderate/strong CYP3A inhibitor use was associated with a higher risk of any event (HR 1.79, p<0.02), independent of the use or dose of either multi-agent chemotherapy or D dose. Conclusions: These are the first data to demonstrate that co-administration of CYP3A inhibitors with D increases the risk of hospitalization and/or death. Oncologists should reconcile medications prior to D administration and mod/strong CYP3A inhibitors should be avoided or used with caution.

6133 Background: Patient (pt) trial experience may give insight to quality of life (QOL) factors affecting accrual, retention and outcome. While pts are vital to clinical trial success, we know little about their post-trial opinions. This trial examined pt opinion of their trial and treatment decision making (TDM). Methods: Pts enrolled on designated North Central Cancer Treatment Group (NCCTG) phase II or III treatment trials completed the TDM Control Preferences Scale at baseline and the Was It Worth It (WIWI) satisfaction assessment at the ends of cycle 1 and active protocol treatment. The primary endpoint was the proportion of pts reporting worthwhile participation. Fisher Exact tests compared pt opinion across subgroups. Results: As of 01/15/2012, 264 pts were enrolled on 25 protocols and treated at 79 sites. 86% of pts were in phase II studies and 89% had stage IV disease. At the end of cycle 1, pts felt the trial was worthwhile (74%), would do it again (85%), and would recommend it to others (82%). 85% of pts reported undiminished QOL and only 7% rated the trial worse than expected. End of treatment responses were similar. Satisfaction rates varied by tumor site (p=0.04). 11% of pts having tumor response rated the trial as not worthwhile, and 66% of pts with progressive disease rated it worthwhile (see table). Pts with concordant preferred and actual TDM roles rated participation higher than pts with discordant TDM roles (see table). Conclusions: Most pts endorsed their clinical trial experience. Contrary to popular beliefs, treatment outcome did not have an overwhelming impact on pt satisfaction, and was just one of many factors such as TDM role discordance. Assessing pt satisfaction will inform future study design that can potentially improve pt accrual and retention. [Table: see text]

e16572 Background: The Bowel Function Questionnaire (BFQ) has been used in clinical trials to document patient-reported symptoms following pelvic radiation therapy (RT). This study evaluated the importance patients placed on the symptoms included in the BFQ as measured by a Content Validity Questionnaire (CVQ). Methods: Patients treated with pelvic RT assessed symptoms and importance at baseline, after completion of RT (4 weeks), and 12 and 24 months. BFQ measured quality of life (QOL) and symptoms of: nocturnal bowel movements, incontinence, greater than one bowel movement in 30 minutes, need for protective clothing, inability to differentiate stool and gas, liquid bowel movements, urgency, cramping, and bleeding. Bowel movement frequency was also assessed. Symptoms were rated via the CVQ as “not very important,” “moderately unimportant,” “neutral,” “moderately important,” or “very important." Summary statistics were compiled. Fisher Exact, Chi-Square and Wilcoxon methodology compared BFQ and CVQ results. Results: 125 patients participated. All symptoms were rated as moderately important or very important by most patients.Measures of bowel function of greatest importance (moderately or very important) at baseline were ability to control bowel movements (94%), not having to wear protective clothing (90%), and not having rectal bleeding (93%). In general, patients gave similar ratings of symptom importance at all time points in the study and ratings were independent of whether the symptom was experienced. With the exception of the need for protective clothing, the presence of a symptom at 4 weeks was associated with significantly worse QOL (p-values < 0.001 to 0.005). Conclusions: The BFQ has excellent content validity. Patients rated most symptoms measured by the BFQ as moderately important or very important, indicating the BFQ is an appropriate tool for symptom assessment during and after pelvic RT. With the exception of the need for protective clothing, the presence of every symptom measured by the BFQ was associated with worse QOL. These criteria make them appropriate targets for future research to mitigate radiation-related bowel dysfunction.

Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature aggressive T-cell non-Hodgkin lymphomas. They carry a worse prognosis for most subtypes compared with their B-cell counterparts. Despite the recent approval of newer therapies, the response rate and duration of clinical benefit is short and the outlook for patients with relapsed/refractory (RR) PTCL remains poor. There is therefore a need for novel effective therapies in PTCL. Targeting the profoundly immunosuppressive tumor microenvironment (TME) in PTCL is one such approach. Preclinical data show that malignant cells in PTCL overexpress programmed death ligand 1 (PD-L1), which signals via programmed death-1 (PD-1) receptor, and provides an inhibitory signal further suppressing antitumor immunity. PD-1/PD-L1/2 interactions in PTCL are particularly complicated as both the receptor and ligands can be expressed on the malignant T-cell. While the use of anti-PD-1 blocking antibodies has shown remarkable efficacy particularly in relapsed Hodgkin lymphoma, only a small number of patients with PTCL have been treated with checkpoint blockade. We conducted an investigator-initiated phase 2 prospective study of single-agent nivolumab for RR PTCL. We report here the results of the prespecified interim analysis. Study design and patient selection: Nivolumab was given at a flat dose of 240 mg intravenously (IV) every 2 weeks for 8 cycles then 480 mg IV every 4 weeks starting cycle 9. The primary objective was to assess the overall response rate (ORR) defined as proportion of subjects achieving either a partial response (PR) or complete response (CR) within 12 cycles of treatment. Secondary objectives were to assess safety and tolerability of nivolumab in PTCL and to assess progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Pre-planned sample size was 39, assuming that an ORR of 10% or less would be considered negative and an ORR of 30% or greater would warrant further study. We used a one-stage design with an interim analysis (upon enrolling 12 subjects) based on a Simon optimal design to assess efficacy. This design had a 90% power with a 1-sided 10% level test. The Duffy and Santner method was utilized to determine confidence intervals for the ORR. Kaplan-Meier methods were used to assess PFS, OS, and DOR. This study was sponsored by Bristol-Myers Squibb (NCT03075553). Results: Twelve patients who received at least one cycle of nivolumab were included in this interim analysis. Patient characteristics are illustrated in table 1. Half (6/12) of the patients had angioimmunoblastic T-cell lymphoma (AITL), 3/12 had PTCL, not otherwise specified (NOS), one had ALK negative anaplastic large cell lymphoma (ALK- ALCL). Most (11/12) were advanced stage (stage 4), had extranodal disease and half of the patients had received a prior autologous transplant. The ORR was 33% (4/12) (95% CI: 12.3 - 63.7%): 1 CR seen in ALK-ALCL; 2 PR, 1 in PTCL, NOS and 1 in enteropathy associated T-cell lymphoma; 1 CR in AITL. The median DOR was 3.6 months (95% CI: 1.9-6.9). The median PFS for all 12 patients was short at 1.9 months (95% CI: 1.5-8.7); median OS was 7.9 months (95% CI: 3.4-10.8) (Panel A). Hyperprogressive disease (defined as dramatic progression within 1 cycle of treatment) occurred in 4 patients. Observed grade 3 and higher adverse events (AEs) were as follows: non-hematologic AEs in 5/12 (41.7%), while hematologic AEs were seen in 3/12 (25%) patients. Conclusions: Nivolumab had modest clinical activity in patients with R/R PTCL and the study met the criteria at interim analysis to continue accrual. However, due to the high number of patients with hyperprogressive disease, the moderate activity of the drug, and short DOR, a decision was made to halt the study. These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases. Further studies are indicated using nivolumab in combination (rather than a single-agent) and use of biomarkers to better predict the responders. Disclosures Bennani: Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding. Ansell:Merck: Other: research funding for clinical trials; Seattle Genetics: Other: research funding for clinical trials; Takeda: Other: research funding for clinical trials; Bristol Myers Squibb: Other: research funding for clinical trials; Regeneron: Other: research funding for clinical trials; Affimed: Other: research funding for clinical trials; Pfizer: Other: research funding for clinical trials; AI Therapeutics: Other: research funding for clinical trials.

Abstract Background: Acute myeloid leukemia (AML) is an aggressive blood cancer with a wide range of response and relapse rates using standard chemotherapy combining anthracycline plus cytarabine (7+3). The stem cell receptor tyrosine kinase KIT is expressed on more than 10% of blasts in 95% of relapsed AML cases and mediates leukemic proliferation and has anti-apoptotic effects (Domen and Weissman 2000). AML with high KIT expression is associated with poorer outcome (Del Poeta, Venditti et al 2003). Goals: To study the efficacy and safety of combination 7+3 and nilotinib in patients (pts) with AML and KIT expression. Primary goal is to determine the complete response (CR) rate; while secondary goals include 2-year overall survival (OS) and disease free survival (DFS) in addition to safety. Methods: A single arm, Phase II study, enrolled pts at Mayo Clinic (MN and AZ). Appropriate IRB was obtained and study was registered (NCT 01806571). Pts were enrolled if they were newly diagnosed with AML with KIT (CD117) expression of ≥ 20% on myeloblasts by flow cytometry. KIT mutations were allowed. Nilotinib 300 mg twice daily was given on days 4-14 of induction and consolidation; and continuous daily maintenance therapy for up to 2 years. Cytarabine 100 mg/m2/day continuous IV x7 days plus daunorubicin 60 mg/m2 IV daily x3 days were used for induction, while consolidation used standard cytarabine 3 gm/m2 twice daily days 1, 3, 5 for a total of 4 cycles. This is a Simon 1-stage design with a safety analysis after enrolling 12 pts, and an interim analysis after enrolling 18 out of 43 pts (Al-Kali, ASH 2015) recommended to continue study accrual. Results: i)- Demographics: Thirty four pts were enrolled from July 2013 to June 2017. Median age was 59 years (range 24-69) with 71% being male. Median laboratory findings include hemoglobin of 8.8 gm/dL, platelets of 56 x109/L, white blood count of 3.3 x109/L (0.4-125), and peripheral blood blasts 17 %(0-94%). Cytogenetics were normal in 43% of the pts and favorable cytogenetics were seen in 6%(inv 16). FLT3 gene testing was done on 26 pts and was positive in 13%. KIT gene sequencing (exon 8, 9, 10, 11, 17) revealed pathogenic mutation in 1/28 cases (4%). ii)- Clinical outcome Out of all 34 pts enrolled on the study, 18 (53%) achieved CR (or CR with incomplete platelet recovery) with a median CR duration of 21.8 months. Of 26 evaluable pts, the overall CR rate was 69%. 4 of the 18 pts (22%) who achieved remission needed a second induction. One pt died due to liver failure (had only one dose of nilotinib and toxicity was attributed to daunorubicin). 13 (38%) pts proceeded to allogeneic stem cell transplant (HSCT), 12 of whom are alive and none were able to initiate nilotinib maintenance. Only 6 (1 had HSCT) out of 34 (18%) pts relapsed after achieving CR. Median DFS was 45.8 months, while median OS was 42.4 months. 2-year DFS and OS were 58% and 72%, respectively. iii)- Safety Thirty four pts were evaluated for adverse events (AE). Fourteen pts had G4 non-hematological AEs, including fourteen G4 AEs related to infection, 2 with electrolyte imbalances, 1 heart failure, 1 elevated bilirubin, 1 elevated lipase, and 1 jejunal hemorrhage. One patient had G5 liver failure. Most common (>20%) G3 non-hematological AEs were febrile neutropenia (56%), hypophosphatemia (21%), elevated ALT (21%) and hypertension (21%). Conclusion: Combination daunorubicin and cytarabine with nilotinib (DATA) appears to be safe and effective. Final results show an acceptable safety profile with most common AE being infection. Thirty day mortality was low (3%). DATA regimen has comparable CR rates of 53% (intent to treat) and 69% in evaluable pts. Relapse rates were very low at 18% with durable responses and encouraging survival rates. Figure. Figure. Disclosures Al-Kali: Novartis: Research Funding. Tibes:Novartis: Research Funding. Palmer:Novartis: Research Funding.

Abstract Background: Acute myeloid leukemia (AML) is an aggressive form of blood cancers with a wide range of response and relapse rates using standard chemotherapy regimen (commonly known as 7+3). Several genes (FLT3, IDH1, RAS) have been targeted using small molecule tyrosine kinase inhibitors with encouraging results. The stem cell receptor tyrosine kinase KIT is expressed more than 10% in the blasts in 95% of relapsed AML cases and mediates leukemic proliferation and has anti-apoptotic effects (Domen and Weissman 2000). AML with high KIT expression is associated with poorer outcome (Del Poeta, Venditti et al 2003). Goals: To study the efficacy and safety of combination 7+3 and nilotinib in patients (pts) with AML and KIT expression. Primary goal is to determine the complete response (CR) rate; while secondary goals include 2-year overall survival (OS) and disease free survival (DFS) in addition to safety of DATA regimen. Methods: A single arm, Phase II study, enrolled pts at Mayo Clinic (MN and AZ). Appropriate IRB was obtained and study was registered (NCT 01806571). Pts were enrolled if they were newly diagnosed with AML with KIT (CD117) expression of 20% or higher on myeloblasts by flow cytometry. KIT mutations were allowed if present. Nilotinib 300 mg twice daily was given on days 4-14 of induction and consolidation; and continuous daily maintenance therapy for up to 2 years. Cytarabine 100 mg/m2/day continuous IV x7 days plus daunorubicin 60 mg/m2 IV daily x3 days were used for induction , while consolidation used standard cytarabine 3 gm/m2 twice daily days 1, 3, 5 for a total of 4 cycles. This is a Simon 1-stage design with a safety analysis after enrolling 12 pts, and an interim analysis after enrolling 18 out of 43 pts. If 11 or fewer pts achieve complete remission, the regimen will be considered ineffective. Results: Eighteen pts have been enrolled between July 2013 and July 2015, 17 of which have baseline data. Median age was 58 years (range 24-65) with 76.5% being male. Median laboratory findings include hemoglobin of 9.3 gm/dL, platelets of 52 x109, and white blood count of 7.0 (0.5-125). Cytogenetics were normal in 41% of the pts. Favorable cytogenetics were seen in 2 pts (inv 16). FLT3 testing was done on 15 pts and was positive in 27%. KIT gene sequencing (exon 8, 9, 10, 11, 17) revealed no pathogenic mutation. Median number of cycles was 3 (range 1-7). Six pts had treatment delays, with 2/13 (15%) delays being due to non-hematologic toxicities. No delays or missed doses affected cytarabine and daunorubicin administration. Out of 15 pts evaluable for response, 12 (80%) achieved CR (or CR with incomplete platelet recovery). Six of the 12 pts (50%) who achieved remission needed a second induction on protocol. Two out of 15 did not respond (did not get re-induction on protocol). One pt died before disease assessment due to liver failure (G5, had only one dose of nilotinib and toxicity was attributed to daunorubicin). Of the 14 pts having at least 1 bone marrow biopsy, the overall CR rate was 86%. Five (33%) pts proceeded to allogeneic stem cell transplant, all are alive and none were able to initiate protocol nilotinib maintenance therapy. Only 2 out of 12 (17%) pts relapsed after achieving CR, one was secondary AML from myelodysplastic syndrome with complex karyotype and the other was therapy-related AML with t(9;11). Only 2 (11%) pts died at time of report. Thirteen pts were evaluated for adverse events (AE). Six pts had G4 non-hematological AEs. Five of 12 G4 AEs were related to infection, 2 were electrolyte imbalances, and 2 were heart failures. Most common G3 non-hematological AEs were febrile neutropenia (53%), hypophosphatemia (23%), hyperglycemia (23%), and hypertension (23%). In agreement with the favorable outcomes, the molecular target validation revealed that nilotinib treatment down-regulates the expression of KIT, Sp1, DNA methyltransferase (DNMT) 1, DNMT3a and DNMT3b. Conclusion: Combination daunorubicin and cytarabine with nilotinib (DATA) appears to be safe and effective. Interim results show an acceptable safety profile in the first 12 evaluable pts with most common AE being infection as expected. Thirty day mortality is acceptable (7%). DATA regimen has encouraging CR rates of 80% (intent to treat) and 86% in assessed pts, with half of the pts who achieved remission requiring 2 cycles of induction. Relapse rate seems to be low at 17%. We will continue accrual until all pts accrued for final results. Disclosures Al-Kali: Celgene: Research Funding. Off Label Use: This is a Phase II study of combination nilotinib to standard chemotherapy in patients diagnosed with AML.. Tibes:TetraLogic Pharmaceuticals: Research Funding.