Safety Expansion Cohort Research Articles

Tocilizumab Prophylaxis Following Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Most patients treated with axi-cel experience cytokine release syndrome (CRS) and/or adverse neurologic events (NEs). To explore potential approaches for reducing CAR T-cell-related toxicities with axi-cel, several safety expansion cohorts were added to the pivotal ZUMA-1 trial. ZUMA-1 Cohort 3 was an exploratory safety cohort that investigated the use of the IL-6 receptor-blocking antibody tocilizumab and anticonvulsant levetiracetam as prophylaxis against CRS and NEs in patients treated with axi-cel. Patients with R/R LBCL were enrolled in Cohort 3 and received conditioning chemotherapy on d -5 through -3 followed by a single infusion of axi-cel (2 × 106 cells/kg) on d 0. Prophylactic tocilizumab (8 mg/kg) was administered 48 h after axi-cel infusion. Primary endpoints were incidence and severity of CRS and NEs. Key secondary endpoints included the incidence of adverse events, objective response rate (ORR), duration of response, progression-free survival, overall survival (OS), and biomarker analyses (eg, circulating CAR T cells, cytokines, chemokines). Forty-two patients were enrolled in Cohort 3, 38 of whom received axi-cel. In the 24-month analysis, any-grade CRS and NEs occurred in 92% and 87% of patients, and Grade ≥3 CRS and NEs occurred in 3% and 42% of patients, respectively. One Grade 5 NE (cerebral edema) occurred. With 24-mo minimum follow-up, the ORR was 63%, and 39.5% of patients had ongoing response. With 48-month follow-up, median OS was 34.8 mo (95% CI, 5.4-not estimable). CAR T-cell expansion in ZUMA-1 Cohort 3 was comparable with pivotal Cohorts 1 and 2. Consistent with tocilizumab-mediated inhibition of IL-6R, serum IL-6 levels were increased relative to Cohorts 1 and 2. Grade ≥3 NEs were associated with elevated IL-6 levels, proinflammatory cytokines, and myeloid cells in the cerebrospinal fluid. Based on these findings, prophylactic tocilizumab is not recommended to prevent CAR T-cell-related adverse events, and beneficial effects of prophylactic levetiracetam remain uncertain in patients with R/R LBCL.

Impact of debulking therapy on the clinical outcomes of axicabtagene ciloleucel in the treatment of relapsed or refractory large B-cell lymphoma.

Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, was approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) based on the results from pivotal Cohorts 1+2 of ZUMA-1 (NCT02348216). ZUMA-1 was expanded to investigate safety management strategies aimed at reducing the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs). Prospective safety expansion Cohort 5 evaluated the impact of debulking therapy, including rituximab-containing immunochemotherapy regimens and radiotherapy, in axi-cel-treated patients; the CRS and NE management strategy paralleled those in Cohorts 1+2. Among the 50 patients in Cohort 5 who received axi-cel, 40% received ≥3 prior lines of chemotherapy, and 40% had disease that progressed while on the most recent chemotherapy. Forty-eight patients (96%) received debulking therapy, 14 (28%) radiotherapy only, and 34 (71%) systemic immunochemotherapy. Median decrease in tumor burden (per sum of product of diameters of target lesions) relative to screening was 17.4% with R-ICE/R-GDP, 4.3% with other debulking chemotherapies, and 6.3% with radiotherapy only. All patients were followed for ≥8 months. CRS was reported in 43 patients (86%), with 1 patient (2%) experiencing grade ≥3. NEs were reported in 28 patients (56%), with 6 (12%) experiencing grade ≥3. Cytopenias were the most frequent grade ≥3 adverse event (AE); 19 (38%) and 18 (36%) treated patients had any and grade ≥3 prolonged thrombocytopenia, respectively, and 25 (50%) and 24 (48%) patients had any and grade ≥3 prolonged neutropenia, respectively. Overall, patients who received debulking chemotherapy had higher incidences of serious treatment-emergent AEs than those who received radiotherapy only. At the 24-month analysis, objective response rate was 72%, and complete response rate was 56%. Median duration of response, progression-free survival, and overall survival were 25.8, 3.1, and 20.6 months, respectively. These results from exploratory Cohort 5 demonstrate the feasibility of debulking prior to axi-cel, and together with current real-world evidence, suggest that debulking regimens may help minimize the frequency and severity of CRS and NEs in patients with R/R LBCL. The incidence of other AEs observed in Cohort 5 suggest the risk/benefit profile was not improved via the debulking regimens studied here.

AZURE: A Phase 1/2 Study of Blu-263 As Monotherapy and in Combination with Azacitidine in Patients with Advanced Systemic Mastocytosis

Background: Systemic mastocytosis (SM) is a clonal hematologic neoplasm, which leads to proliferation and accumulation of mast cells (MCs) in multiple body organs (the skin, bone marrow [BM], spleen, liver, and gastrointestinal tract) causing end organ damage. The KIT D816V mutation is identified in up to 95% of patients and is therefore a major therapeutic target in advanced SM (AdvSM) which consists of aggressive SM, mast cell leukemia, and SM with an associated hematologic neoplasm (SM-AHN). SM-AHN is associated with a high degree of genetic heterogeneity and some patients with high risk AHNs require the use of AHN-directed therapy, such as hypomethylating agents (HMAs). The combination of a highly selective KIT D816V inhibitor with an HMA represents an opportunity to improve response by inhibiting both MC and AHN clones in high-risk patients. AZURE, an international phase 1/2, open-label, 2-arm study, will evaluate the safety and efficacy of BLU-263, an orally administered and selective inhibitor of KIT D816V in patients with AdvSM, both as monotherapy as well as in combination with azacitidine. Study design and methods: Approximately 18 patients will initially be treated with escalating BLU-263 monotherapy doses to determine the recommended dose (RD) of BLU-263 (RDmono). This will be followed by dose expansion with an additional 13 patients to further characterize the safety and preliminary efficacy of BLU-263 in AdvSM. Once an initial BLU-263 monotherapy dose has been demonstrated to be safe, patients may begin enrollment in the combination arm, where approximately 18 patients will receive standard azacitidine at doses of 75 mg/m2/day on days 1-7 of each 28-day cycle, and BLU-263 starting at 50% of the monotherapy dose to determine the RDcombo. After RDcombo determination, approximately 10 additional patients will be enrolled into a safety expansion cohort. Dose escalation of monotherapy and combination therapy will follow the rules of Bayesian optimal interval design. Key eligibility criteria include age ≥18 years and Eastern Cooperative Oncology Group performance status 0-3. Eligible patients must have a centrally confirmed pathologic diagnosis of AdvSM per World Health Organization criteria. Patients eligible for the combination therapy include those with chronic myelomonocytic leukemia-2; high- or very high-risk myelodysplastic syndrome (MDS) per International Prognostic Scoring System for Myelodysplastic Syndromes-Revised (IPSS-R); accelerated phase myeloproliferative neoplasm; MDS with excessive blasts-2; complex karyotype/mutational profile; or patients with a hematologic neoplasm and strong rationale for combination treatment following consultation with the sponsor and response assessment committee where needed. Primary endpoints include determination of the RD and safety profile of BLU-263 monotherapy and BLU-263 + azacitidine combination therapy, as well as efficacy according to established response criteria in AdvSM. Secondary endpoints include pharmacokinetic parameters of BLU-263 and BLU-263 + azacitidine, overall response rate, time to response, duration of response, progression-free survival, and the proportion of patients pursuing allogeneic hematopoietic stem cell transplantation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P561: VIALE-T: A RANDOMIZED, OPEN-LABEL, PHASE 3 STUDY OF VENETOCLAX IN COMBINATION WITH AZACITIDINE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA

Background: Acute myeloid leukemia (AML) is an aggressive malignancy and is the most common and second most common form of acute leukemia in adults and children, respectively. The combination of the highly selective BCL-2 inhibitor venetoclax and the hypomethylating agent azacitidine was shown to be safe and effective in clinical trials (DiNardo et al. Blood. 2019;133:7-17; DiNardo et al. N Engl J Med. 2020;383:617-629) and is approved by the United States Food and Drug Administration and European Medicines Agency for the treatment of patients with AML who are not eligible to receive intensive chemotherapy. Following allogeneic stem cell transplantation (alloSCT), most patients do not receive antileukemic therapy; however, an unmet need remains as disease relapse and graft-versus-host disease (GvHD) commonly occur posttransplant. In addition to the antileukemic effect of venetoclax shown in clinical studies, preclinical studies suggest venetoclax may mitigate the risk of GvHD. VIALE-T is a Phase 3, randomized, open-label trial in progress (NCT04161885) evaluating the safety and efficacy of venetoclax in combination with azacitidine versus best supportive care (BSC) as maintenance therapy following alloSCT in patients with AML. Aims: N/A Methods: This Phase 3 study consists of 2 parts (Figure). Key inclusion criteria include diagnosis of AML; plans to receive alloSCT or have received alloSCT within the past 30 days; bone marrow blasts <10% before pretransplant conditioning and <5% posttransplant; have received myeloablative, or reduced intensity, or nonmyeloablative pretransplant conditioning protocols. Grafts are allowed from various sources (bone marrow, peripheral blood stem cells, cord blood cells). Patients must be ≥18 years old for Part 1 and ≥12 years old for Part 2. Additionally, patients must meet key laboratory values for absolute neutrophil count (Part 1, ≥1500/µL; Part 2, ≥1000/µL), platelet count (Part 1, ≥80,000/µL; Part 2, ≥50,000/µL), bilirubin ≤3 times the upper limit of normal, and creatinine clearance >30 mL/min. Patients who have received venetoclax and had no history of disease progression while receiving venetoclax are eligible. Part 1 evaluates dose levels of venetoclax combined with azacitidine to determine the recommended Phase 3 dose (RP3D), which will be confirmed in approximately 12 additional patients enrolled in the Safety Expansion Cohort. Part 2 will be a randomized, open-label evaluation of the RP3D of venetoclax combined with azacitidine and BSC versus BSC only in adults and children aged 12 years or older. All venetoclax-treated patients will receive antibiotic prophylaxis during Cycle 1. The primary endpoint for Part 1 is the frequency of dose-limiting toxicities. The primary endpoint for Part 2 is relapse-free survival as assessed by an independent review committee. Key secondary endpoints for Part 2 include overall survival, GvHD-free relapse-free survival, and the rate of patients without higher grade GvHD at 90 days after randomization. Enrollment into the Safety Expansion Cohort will be completed in 2021. Part 2 will enroll approximately 400 patients across approximately 175 participating study sites in 17 countries, with recruitment beginning in 2022. Results: N/A Image:Summary/Conclusion: N/A

S146: VENETOCLAX IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA WITH 17P DELETION: 6-YEAR FOLLOW-UP AND GENOMIC ANALYSES IN A PIVOTAL PHASE 2 TRIAL

Background: Patients (pts) with chronic lymphocytic leukemia (CLL) with del(17p) and/or mutated TP53 have adverse prognosis and are a population of interest for improving outcomes. In a pivotal Phase 2 study (NCT01889186) evaluating venetoclax (Ven; a selective oral BCL2 inhibitor) monotherapy in del(17p) CLL (N=158), overall response rate (ORR) was 77% (median time on study, 26.6 mo; Stilgenbauer. J Clin Oncol. 2018;17:1973). Aims: To report final analyses after 5 y from last pt enrolled, including post-hoc subgroup analyses of prognostic markers. Methods: Adults with R/R or previously untreated del(17p) CLL received Ven 400 mg (via ramp-up) orally daily until progressive disease (PD) or intolerance. Main cohort comprised pts with R/R CLL; safety expansion cohort included pts with R/R or untreated CLL. Primary endpoints were ORR (main) and safety (safety expansion). Peripheral blood (PB) and bone marrow (BM) were analyzed pre-Ven for somatic mutations via targeted next-generation sequencing (NGS). Minimal residual disease (MRD) was assessed by flow cytometry, ASO-PCR, and/or clonoSEQ NGS; undetectable MRD (uMRD) is reported at <10−4. Results: In all, 158 pts received Ven (main, n=107; safety expansion, n=51). Data cutoff was 15 December 2020. Pts had median 2 (range, 0−10) prior lines of therapy (LOT); 5 had untreated CLL (first-line [1L]). Common mutations (n/N) were TP53 (113/138 [82%]; 35/113 [31%] had >1), SF3B1 (28/137 [20%]) NOTCH1 (22/137 [16%]), ATM (11/120 [9%]), and BIRC3 (6/120 [5%]); 93/115 (81%) had unmutated IGHV and 118/158 (75%) had ≥20% del(17p). Median time on Ven was 27.4 (range, 0–79.3) mo. At study close, 77 pts were alive; 26 remained on Ven. No new safety signals were observed. With 70 mo median follow-up (f/u), investigator-assessed ORR was 77% (95% CI, 70−84); 21% achieved complete remission (CR)/CR with incomplete blood count recovery (CRi). Median duration of response was 39.3 mo (95% CI, 31.1−50.5); 28% had ongoing response at 60 mo. Of 61 evaluable pts with a PB MRD assessment, 25% had uMRD at ~2 y (24−30 mo). Median progression-free survival (mPFS) was 28.2 mo (95% CI, 23.4−37.6; Figure). Median overall survival (mOS) was 62.5 mo (95% CI, 51.7−NR; 5-y PFS and OS rates, 24% and 52%). Of 5 1L pts, 4 were alive and progression-free. In pts with CR/CRi (n=37), mPFS was 62.2 mo (95% CI, 53.1−NR); in pts with partial remission (PR)/nodular PR (n=85), mPFS was 27.6 mo (95% CI, 22.8−38.0). Overall, 98/158 (62%) pts had PD, including 24/158 (15%) with Richter transformation. Of pts with PD (n=98) or whose disease was refractory to Ven (n=11), 73 received another LOT, most commonly ibrutinib (n=41); mOS from ibrutinib initiation was 28.0 mo. In pts with both del(17p) and TP53 mutation (n=111) vs those with either (n=19), ORR was 75% vs 79%; mPFS was 27.4 vs 22.8 mo (P=.8). In pts with mutated (n=22) vs unmutated IGHV (n=93), mPFS was 40.4 vs 26.9 mo (P=.11). No significant difference in ORR, PFS, or OS was observed in pts with vs without ≥20% del(17p), >1 TP53 mutation, NOTCH1, ATM, or BIRC3 mutations; mPFS was shorter in pts with mutated SF3B1 (n=28) vs without (n=109; 16.4 vs 30.2 mo [P=.0071]). Multivariate analysis is ongoing. Image:Summary/Conclusion: At end of study (median f/u, 70 mo), 48% of pts were alive, 24% were progression-free, and 16% remained on Ven, confirming the long-term activity of Ven in this high-risk population with del(17p) CLL and median 2 prior LOT. Except SF3B1 mutation, other adverse features (eg, >1 TP53 mutation, NOTCH1 mutations, unmutated IGHV) did not influence outcomes with Ven treatment in this cohort.

NRG-DT001 phase Ib trial of neoadjuvant navtemadlin (previously AMG232 and KRT232) concurrent with preoperative radiotherapy in wild-type p53 soft tissue sarcoma of the extremity and body wall.

11521 Background: NRG-DT001 is a phase Ib trial evaluating neoadjuvant navtemadlin with preoperative radiation therapy (RT) in patients (pts) with wild-type (WT) p53 soft tissue sarcoma (STS). The primary objective is to evaluate the safety and tolerability of the MDM2 inhibitor navtemadlin in combination with standard-dose RT in STS in two cohorts (A, extremity or body wall; B, abdomen/pelvis/retroperitoneum) to determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of navtemadlin in combination with RT. This report contains the results for cohort A. Methods: Eligible pts had grade 2-3 STS ≥ 5 cm, age ≥ 18, and Zubrod performance status 0-1. Dose levels were 120 mg 2x/week (DL-1), 120 mg 3x/week (DL1), 4x/week (DL2), and 5x/week (DL3) 1 week prior to and during RT (50Gy/5 weeks). Surgery was 5-8 weeks after RT. A 3+3 design was used to make dose escalation/de-escalation decisions at each dose level. Five additional pts were enrolled to the MTD to ensure safety (expansion cohort) with a dose limiting toxicity (DLT) rate of ≤ 1/5 considered safe. The DLT observation period was from the start of navtemadlin until 4 weeks after completion of drug+RT. Tumor Tp53 mutation status was determined by NGS sequencing. All eligible and treated p53 WT pts who experienced DLT or completed the observation period were considered DLT-evaluable. DLT included all grade 4-5 AE definitely, probably, or possibly related to navtemadlin. Any grade 3 AE definitely, probably, or possibly related to navtemadlin was also considered DLT if any of the 2 following situations occurred: a delay of treatment &gt; 2 weeks or ≥ 2 dose reductions due to the grade 3 AE. The decision to escalate or de-escalate was made by consensus of the study team in accordance with the protocol. Results: Between 11/3/2017 and 9/10/2021, 4 (3 WT), 7 (4 WT) and 7 (4 WT) pts were enrolled at DL1, DL2, and DL3 respectively. An additional 9 (5 WT) pts were enrolled on DL3 expansion cohort. Preoperative RT was completed for all except 1 pt (pt refusal/DL3). On DL1 and DL2, 100% of pts completed navtemadlin. On DL3 (including expansion cohort), 78% (7/9) completed navtemadlin (1 AE, 1 pt refusal). On DL1, DL2, and DL3, 3/3, 3/4 (1 disease progression), and 5/6 (1 consent withdrawal; 3 pending) completed surgery. There were no DLTs in any dose level (DL1 0/3, DL2 0/4, DL3 0/9), establishing DL3 as the MTD/RP2D. Tumor necrosis rates will be reported at the time of presentation. Conclusions: Neoadjuvant navtemadlin concurrent with standard dose preoperative RT is well tolerated in patients with WT p53 STS at extremity or body wall, and the 120 mg PO daily of navtemadlin, 5 days per week dose should be used to design future trials of RT with extremity STS. Incorporating NGS sequencing results as an integral biomarker in a clinical trial of neoadjuvant radiotherapy and a radiosensitizer is feasible. Clinical trial information: NRG-DT001 NCT03217266.

Comparison of dose modification strategies to address expected hematologic toxicities in treatment-naïve higher-risk (HR) MDS patients treated with venetoclax + azacitidine.

7041 Background: Venetoclax (Ven) is a selective, potent BCL-2 inhibitor. Ven + azacitidine (Aza) were associated with a combined complete remission (CR)/marrow CR (mCR) rate of 79% in a phase 1b study of patients (pts) with HR-MDS. Here we compared two different dose modification strategies to manage expected hematologic toxicities in two safety expansion cohorts with similar follow-up periods. Methods: Pts ≥18y diagnosed with treatment-naïve IPSS intermediate-2 or high-risk MDS with ECOG ≤2 were enrolled. Aza 75 mg/m2 (iv or subQ daily) was administered for 7 days (d) and Ven was administered at 400 mg for 14d in each 28d cycle. In both cohorts, dose modification during Cycle 1 was not recommended; dose modifications in subsequent cycles were prescribed for AEs. In Safety Expansion Cohort 1 (SE1), either Aza or Ven were initially reduced according to investigator’s choice for significant neutrophil or platelet toxicity. Dose reductions per protocol were 33% for Aza and 50% for Ven (for 14d each cycle). In subsequent cycles, Ven duration could be shortened to 9d of each cycle. In Safety Expansion Cohort 2 (SE2), dose modification guidelines recommended stepwise reductions, first in Aza dose (first to 50 mg/m2, then 36 mg/m2) and subsequently in Ven duration to 7d of each cycle (Ven 400 mg). The impact of each dose modification strategy on safety and efficacy in SE1 vs SE2 was compared. Worsening of treatment-emergent adverse events (TEAE) grades from baseline (BL) was analyzed by cycle. Responses were evaluated using IWG 2006 criteria. Analyses included all pts who received ≥1 dose of study drug. Results: We compared 22 pts in SE1 and 21 pts in SE2 with median (range) follow-up of 7.5 (1.0–8.9) and 7.9 (1.8–10.1) mos, respectively. A similar frequency of ≥ G3 hematologic TEAEs (approx %) were reported in SE1 and SE2, respectively, including anemia (14% and 33%), febrile neutropenia (46% and 48%), leukopenia (36% and 19%), neutropenia (55% and 48%) and thrombocytopenia (32% and 38%). Infections (59% and 38%) were more frequent in SE1 than SE2. In a longitudinal analysis, there were more TEAE grade increases from BL to Cycle 1 in SE2 vs SE1. This could be accounted by pts in SE1 and SE2 having unbalanced susceptibility to AEs at BL, as SE1 and SE2 pts received identical Aza + Ven doses in Cycle 1. Response rates were identical: 86% of pts in both SE1 and SE2 had CR or mCR. For pts with mCR, hematologic improvement occurred in 50% of SE1 and 46% of SE2 pts. Conclusions: No obvious hematologic differences were observed when reducing Aza before Ven (SE2) in MDS compared to investigator’s choice (SE1). Both approaches had a similar acceptable safety profile without compromising efficacy for pts with HR-MDS. Clinical trial information: NCT02942290. [Table: see text]

NBE-002: A novel anthracycline-based antibody-drug conjugate (ADC) targeting ROR1 for the treatment of advanced solid tumors—A phase 1/2 clinical trial.

TPS1108 Background: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly expressed during embryonic development, but is minimally present or absent on post-partum healthy tissues. ROR1 is expressed in a variety of hematological and solid tumors and is associated with aggressive cancer phenotype and poor clinical outcomes. NBE-002 is an ADC targeting ROR1, obtained by site-specific, enzymatic conjugation of the anthracycline-derivative PNU-159682, modified with a non-cleavable linker to a humanized recombinant IgG1 monoclonal antibody, based on a novel anti-human ROR1 monoclonal antibody XBR1-402 (Peng et al. (2017) J. Mol. Biol. 429: 2954-73). Direct anti-tumor activity of NBE-002 was evaluated in immunodeficient, ROR1 expression-low/-intermediate/-high PDX models of several carcinoma and sarcoma subtypes. The most pronounced anti-tumor effect was achieved in triple-negative breast cancer (TNBC), at doses as low as 0.033 mg/kg, suggesting a best-in-class therapeutic index in light of the high tolerability in preclinical toxicology models. Administration in a fully immune competent setting (EMT6/ROR1 orthotopic breast cancer model) led to a strong anti-tumor response and a long-lasting anti-tumor immune protection dependent on CD8 T cells. Methods: NBE-002-01 (NCT04441099) is a first-in-human, open-label, multi-center, phase (Ph) 1/2 study of NBE-002 in adult patients with advanced solid tumors. Ph 1 of the study consists of a Dose Escalation Cohort (DEC), utilizing an accelerated titration design, followed by a traditional 3+3 design, and an optional Safety Expansion Cohort (SEC). Ph 2 will include two parallel Expansion Cohorts (EC), enrolling patients with advanced TNBC (EC1) or other solid tumors (EC2), with Simon’s two-stage design. Key eligibility criteria include Eastern Cooperative Oncology Group performance status of 0-2 (Ph 1) or 0-1 (Ph 2), adequate organ function defined as: hemoglobin ≥9.0 g/dL, neutrophils ≥1500 /µL, platelets ≥100000/µL, aspartate and alanine aminotransferases ≤2.5x the upper limit of normal (ULN), total bilirubin ≤1.5x ULN, creatinine ≤1.5x ULN, left ventricular ejection fraction ≥50%. The primary objectives are to assess safety and tolerability and to establish the recommended dose for further development (Ph 1), and to evaluate anti-tumor activity of (Ph 2). Secondary and exploratory objectives include characterization of immunogenicity as well as pharmacokinetic and pharmacodynamic profiles. NBE-002 is given intravenously once every three weeks until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-specific criteria are met. Ph 1 dose escalation was initiated on 17 JULY 2020 and is still recruiting in the US. Ph 2 is planned to be initiated in 2022. Clinical trial information: NCT04441099 .

Venetoclax and Navitoclax in Pediatric Patients with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Venetoclax and Navitoclax in Pediatric Patients with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non–Small Cell Lung Cancer

Consolidative programmed death ligand-1 (PD-L) inhibition after chemoradiotherapy improves overall survival and progression-free survival (PFS) for stage III non-small cell lung cancer (NSCLC) and requires safety evaluation for incorporation of programmed cell death 1 (PD-1) inhibition at the onset of chemoradiotherapy. To determine the safety and tolerability of PD-1 inhibition concurrently with definitive chemoradiotherapy for NSCLC. This phase 1 prospective multicenter nonrandomized controlled trial using a 3 plus 3 design was performed from August 30, 2016, to October 24, 2018, with a median follow-up of 16.0 (95% CI, 12.0-22.6) months and data locked on July 25, 2019. Twenty-one participants had locally advanced, unresectable, stage III NSCLC as determined by multidisciplinary review, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function. Data were analyzed from October 17, 2016, to July 19, 2019. Pembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Dose cohorts evaluated included full-dose pembrolizumab (200 mg intravenously every 3 weeks) 2 to 6 weeks after chemoradiotherapy (cohort 1); reduced-dose pembrolizumab (100 mg intravenously every 3 weeks) starting day 29 of chemoradiotherapy (cohort 2); full-dose pembrolizumab starting day 29 of chemoradiotherapy (cohort 3); reduced-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 4); and full-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 5). A safety expansion cohort of 6 patients was planned based on the maximum tolerated dose of pembrolizumab. Dose-limiting toxic effects were defined as pneumonitis of at least grade 4 within cycle 1 of pembrolizumab treatment. Safety and tolerability of PD-1 inhibition with chemoradiotherapy for NSCLC. Secondary outcomes included PFS and pneumonitis rates. Among the 21 patients included in the analysis (11 female [52%]; median age, 69.5 [range, 53.0-85.0] years), no dose-limiting toxic effects in any cohort were observed. One case of grade 5 pneumonitis occurred in the safety expansion cohort with the cohort 5 regimen. Immune-related adverse events of at least grade 3 occurred in 4 patients (18%). Median PFS for patients who received at least 1 dose of pembrolizumab (n = 21) was 18.7 (95% CI, 11.8-29.4) months, and 6- and 12-month PFS were 81.0% (95% CI, 64.1%-97.7%) and 69.7% (95% CI, 49.3%-90.2%), respectively. Median PFS for patients who received at least 2 doses of pembrolizumab (n = 19) was 21.0 (95% CI, 15.3 to infinity) months. These findings suggest that combined treatment with PD-1 inhibitors and chemoradiotherapy for stage III NSCLC is tolerable, with promising PFS of 69.7% at 12 months, and requires further study. ClinicalTrials.gov Identifier: NCT02621398.

Atezolizumab + intravesical BCG (Bacillus Calmette-Guerin) in high-risk non-muscle invasive bladder cancer (NMIBC) patients: Institutional clinical and translational study (BladderGATE).

TPS598 Background: Intravesical Bacillus Calmette-Guerin (BCG) induction + BCG maintenance after transurethral resection (TURBT) is the current standard of care for patients (pt) with high-risk non-muscle invasive bladder cancer (NMIBC). Recurrence rate at 2 years is around 30%, which is clearly unsatisfactory. Programmed death ligand 1 (PD-L1) is a surface glycoprotein that functions as an inhibitor of T-cells and plays a crucial role in suppression of cellular immune response. Atezolizumab is a humanized IgG1 monoclonal antibody targeting PD-L1 and is associated with long-term durable remissions in pts with metastatic urothelial cancer (Powles T. Lancet. 2018). Atezolizumab in combination with standard BCG could be beneficial in pts with NMIBC. BladderGATE (NCT04134000) is a phase Ib-II study aims to evaluate the clinical impact and safety of the combination of Atezolizumab + intravesical BGC (medac strain), including a translational study (microbioma and urobioma) in pts with NMIBC. Methods: Eligible pt have confirmed histopathology of NMIBC, BCG naïve or stopped &gt;3 years ago, WHO PS 0-1, no prior radiation to bladder and adequate hematologic and end-organ function. We propose a de-escalation design to enroll patients to identify DLT and MTD proposed to safety and efficacy expansion cohort. Pt will receive induction BCG, 1 instillation every week (qw) (dose level 0) or BCG, 1/2 instillation qw (dose level -1) + intravenously atezolizumab 1200 mg every 3 w (q3w), during 6 w. After induction, BCG will be administered as maintenance treatment at weeks 12, 24 and 48 and atezolizumab 1200 mg q3w up to 1 year. Pt will be accrued to each dose level in cohorts of 10 pt until the MTD is achieved (the highest dose at which &lt;4 out of 10 pt experience DLT). DLT will be evaluated during induction treatment. Additional pt will be included in the expansion cohort up to 40 pt. DLT and safety profile will be evaluated according to NCI-CTCAE v 5.0 criteria. Recurrence-free survival will be assessed per RECIST 1.1. Tissue, plasma and urine sample will be collected for translational study. Clinical trial information: NCT04134000.

Earlier Steroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Large B Cell Lymphoma (R/R LBCL)

Background Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment (Tx) of patients (pts) with R/R LBCL with ≥ 2 prior systemic therapies. In Cohorts 1+2 (C1+2) of the ZUMA-1 study, Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 11% and 32% of pts, respectively (Locke FL et al, Lancet Oncol 2019). A nonrandomized safety expansion cohort (Cohort 4 [C4]) evaluated the impact of earlier steroid use on CRS and NE rates. Here we present the primary analysis of ZUMA-1 C4 with a greater number of pts and longer follow-up (F/U). Methods Eligible pts were leukapheresed, could receive optional bridging chemotherapy (not allowed in C1+2), and received conditioning chemotherapy before axi-cel infusion at a targeted 2 × 106 anti-CD19 CAR T cells/kg. C4 pts received early steroid intervention at Grade 1 NE and at Grade 1 CRS after 3 days of supportive care. Primary endpoints were incidence and severity of CRS and NEs. ORR and CAR T cell levels were compared across quartiles of tumor burden (TB). Results As of May 6, 2019, 41 pts had received axi-cel, with a median F/U of 8.7 mo. Pts who received bridging therapy prior to axi-cel (68%) all had evidence of disease after bridging, documented by a new baseline PET/CT scan. The median age was 61 y (range, 19 – 77 y; 32% ≥ 65 y). The majority of pts (63%) had DLBCL; 49% had an ECOG 1; 70% had disease stage III/IV; 68% were refractory to ≥ 2nd-line therapy; 63% had ≥ 3 prior lines of therapy; and 20% had relapsed after ASCT. C4 pts had a lower median TB by sum of product diameters (SPD; C4: 2100 mm2; C1+2: 3723 mm2) and lower pre-Tx serum LDH level than C1+2 pts. A greater proportion of C4 pts received steroids and tocilizumab vs C1+2 (73% and 76% vs 27% and 43%). Fewer C4 pts experienced Grade ≥ 3 CRS (2%) and NE (17%) than C1+2 pts. The ORR in C4 was 73% with a CR rate of 51%. Response was ongoing in C4 54% of pts with ≥ 6 mo F/U vs the 44% ongoing response rate at the primary analysis of C1+2 (also ≥ 6 mo F/U). Although most pts in C4 had lower SPDs than those in C1+2, responses were comparable when evaluated by TB. Median DOR was 8.9 mo, consistent with that observed for C1+2 (8.1 mo; Locke, AACR 2017; Figure). Median PFS was 11.7 mo; median OS was not reached. Peak CAR T cell levels were 42 cells/µL blood in C1+2 vs 59 cells/µL in C4. C1+2 had a median CAR AUC of 462 cells/µL × days vs 512 cells/µL in C4. CAR T cell expansion was comparable between cohorts when adjusted by TB. Levels of key NE-associated biomarkers including ferritin (pre- and post-Tx) and IL-2 (post-Tx) appeared lower in C4 than in C1+2. Conclusions Earlier steroid use may reduce the rates of CAR T cell Tx-related CRS and NEs without affecting efficacy. Conclusions are limited by the nonrandomized study design and differences in population sizes and baseline characteristics between cohorts. Optimizing AE management is important to improve the benefit–risk profile of CAR T cell therapy.

Earlier Steroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Large B Cell Lymphoma

Earlier Steroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Large B Cell Lymphoma

Phase I Dose Escalation Study with Expansion Cohort of the Addition of Nab-Paclitaxel to Capecitabine and Oxaliplatin (CapOx) as First-Line Treatment of Metastatic Esophagogastric Adenocarcinoma (ACTION Study).

First-line triplet chemotherapy including a taxane may prolong survival in patients with metastatic esophagogastric cancer. The added toxicity of the taxane might be minimized by using nab-paclitaxel. The aim of this phase I study was to determine the feasibility of combining nab-paclitaxel with the standard of care in the Netherlands, capecitabine and oxaliplatin (CapOx). Patients with metastatic esophagogastric adenocarcinoma received oxaliplatin 65 mg/m2 on days 1 and 8, and capecitabine 1000 mg/m2 bid on days 1–14 in a 21-day cycle, with nab-paclitaxel on days 1 and 8 at four dose levels (60, 80, 100, and 120 mg/m2, respectively), using a standard 3 + 3 dose escalation phase, followed by a safety expansion cohort. Baseline tissue and serum markers for activated tumor stroma were assessed as biomarkers for response and survival. Twenty-six patients were included. The first two dose-limiting toxicities (i.e., diarrhea and dehydration) occurred at dose level 3. The resulting maximum tolerable dose (MTD) of 80 mg/m2 was used in the expansion cohort, but was reduced to 60 mg/m2 after three out of eight patients experienced diarrhea grade 3. The objective response rate was 54%. The median progression-free (PFS) and overall survival were 8.0 and 12.8 months, respectively. High baseline serum ADAM12 was associated with a significantly shorter PFS (p = 0.011). In conclusion, albeit that the addition of nab-paclitaxel 60 mg/m2 to CapOx may be better tolerated than other taxane triplets, relevant toxicity was observed. There is a rationale for preserving taxanes for later-line treatment. ADAM12 is a potential biomarker to predict survival, and warrants further investigation.

PS1067 AXICABTAGENE CILOLEUCEL (AXI‐CEL) IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B CELL LYMPHOMA: PRELIMINARY RESULTS OF EARLIER STEROID USE

Background:Axicabtagene ciloleucel (axi‐cel) is an autologous anti‐CD19 chimeric antigen receptor (CAR) T cell therapy approved in the European Union and United States for patients with relapsed/refractory large B cell lymphoma with ≥ 2 prior systemic therapies. In the 2‐year follow‐up of ZUMA‐1, the objective response rate was 83% with a complete response rate of 58%. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 11% and 32% of patients, respectively; 26% of patients received steroids, and 43% received tocilizumab (Locke et al. Lancet Oncol. 2019). A safety expansion cohort was added to evaluate the effect of earlier steroid use on the rates of these adverse events (AEs).Aims:To assess the impact of early steroid use on outcomes in patients treated with axi‐cel.Methods:Eligible patients with relapsed/refractory large B cell lymphoma were leukapheresed and received conditioning chemotherapy followed by a target dose of 2 × 106 anti‐CD19 CAR T cells/kg. Patients in this cohort received early steroid intervention starting at Grade 1 NE and at Grade 1 CRS when no improvement was observed after 3 days of supportive care. The primary endpoint for this cohort was incidence and severity of CRS and NE.Results:As of September 14, 2018, 21 of 40 planned patients received axi‐cel with a minimum follow‐up of 1 month (median, 2.6 months). The median age was 63 years (range, 36 – 73), 67% were male, 81% had disease stage III‐IV, 76% were relapsed/refractory to ≥ second‐line therapy, and 10% had relapsed post‐autologous stem cell transplantation. Seventy‐six percent of patients received steroids and 81% received tocilizumab. Most patients (81%) had Grade ≥ 3 AEs, most commonly neutrophil count decreased (33%), anemia (29%), and pyrexia (24%). Grade ≥ 3 NE occurred in 10% of patients; the most common symptoms were somnolence (10%) and confusional state (10%). Grade 1 and 2 NE occurred in 38% and 5% of patients, respectively. No patient had Grade ≥ 3 CRS; 33% of patients had Grade 1 CRS and 67% had Grade 2. There were no deaths due to AEs; 1 patient died due to disease progression. The objective response rate per investigator assessment was 76% with 48% of patients achieving a complete response. Pharmacokinetic data will be presented.Summary/Conclusion:Early use of steroids may help in managing severe CRS and NE by potentially reducing their incidence in patients treated with CAR T cell therapy without affecting response rates. Optimizing AE management may help to further improve the benefit:risk profile of CAR T cell therapy.

Preliminary results of earlier steroid use with axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL).

7558 Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved in the EU and US for patients (pts) with R/R LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 11% and 32% of pts, respectively; 26% of pts received steroids, and 43% received tocilizumab (Locke et al. Lancet Oncol. 2019). A safety expansion cohort was added to evaluate the effect of earlier steroid use on the rates of these adverse events (AEs). Methods: Eligible pts with R/R LBCL were leukapheresed and received conditioning chemotherapy followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. Pts in this cohort received early steroid intervention starting at Grade 1 NE and at Grade 1 CRS when no improvement was observed after 3 days of supportive care. The primary endpoint for this cohort was incidence and severity of CRS and NE. Results: As of 9/14/2018, 21 of 40 planned pts received axi-cel with a minimum follow-up of 1 mo (median, 2.6 mo). The median age was 63 y (range, 36 – 73), 67% were male, 81% had disease stage III-IV, 76% were R/R to ≥ second-line therapy, and 10% had relapsed post-autologous stem cell transplantation. Seventy-six percent of pts received steroids and 81% received tocilizumab. Most pts (81%) had Grade ≥ 3 AEs, most commonly neutrophil count decreased (33%), anemia (29%), and pyrexia (24%). Grade ≥ 3 NE occurred in 10% of pts; the most common symptoms were somnolence (10%) and confusional state (10%). Grade 1 and 2 NE occurred in 38% and 5% of pts, respectively. No pt had Grade ≥ 3 CRS; 33% of pts had Grade 1 CRS and 67% had Grade 2. There were no deaths due to AEs; 1 pt died due to disease progression. The ORR per investigator assessment was 76% with 48% of pts achieving a CR. Pharmacokinetic data will be presented. Conclusions: Early use of steroids may help in managing severe CRS and NE by potentially reducing their incidence in pts treated with CAR T cell therapy without affecting response rates. Optimizing AE management may help to further improve the benefit:risk profile of CAR T cell therapy. Clinical trial information: NCT02348216.

Abstract P1-19-03: A phase I trial of sorafenib with whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases and a correlative study of FLT-PET brain imaging in patients receiving WBRT with or without sorafenib

Abstract Background: WBRT is a standard therapy for metastatic breast cancer (MBC) patients (pts) with brain metastases (BM), but disease progression in the brain is common. Sorafenib, a tyrosine kinase inhibitor with anti-VEGF activity, has demonstrated anti-tumor efficacy in MBC and radiosensitizing activity preclinically. [18F] 3'deoxy-3'-fluorothymidine (FLT) is a new PET tracer which correlates with cellular proliferation and may improve response assessment in the brain. Methods: A phase I trial of sorafenib with WBRT in MBC pts with BM was conducted using a 3+3 design. Sorafenib was given orally daily at the start of WBRT for a total of 21 days with 3 doses levels: 200mg, 400mg, and 600mg. The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was central nervous system progression-free survival (CNS-PFS). Macdonald Criteria were used for response assessment with serial MRI brain imaging. Key eligibility criteria include MBC with new or progressive ≥ 1cm BM, ECOG PS 0-2, non-escalating corticosteroid dose, and no other concurrent anti-tumor therapy except trastuzumab. In parallel, we conducted a correlative FLT-PET imaging study (baseline, 7-10 days (FU1), and 10-12 weeks (FU2) after the WBRT) to assess radiographic changes among pts receiving WBRT + sorafenib and in a separate WBRT only cohort. FLT standard uptake value (SUV) and kinetic parameter data were obtained. Results: 13 pts were treated in the dose escalation phase and evaluable for dose-limiting toxicity (DLT). The median age was 56 years (range: 43-77). There were 4 HER2 positive (31%) and 3 triple negative (23%) pts. 2 pts had prior stereotactic radiosurgery. DLTs were: Grade (G) 4 increased lipase at 200mg (1 pt) and G3 rash at 400mg (3 pts) level. MTD was determined to be 200mg. 10 pts were evaluable for response (at least 1 follow up brain imaging). The overall response rate was 70%: 4 complete responses (CR) + 3 partial responses. All 13 pts were evaluated for CNS PFS with a median follow up of 29.7 months (min 19.6, max 57.4mo). Median CNS-PFS was 8.2 months (95%CI: 3.4-31.8). Median OS was 15.4 months (95% CI: 3.4-NR). A total of 10 pts with WBRT and sorafenib and 5 pts with WBRT only were enrolled in the FLT-PET study: all 15 pts had baseline FLT PET, 14 with FU1, and 9 with FU2. 55 baseline lesions, 38 at FU1 and 15 at FU2 were observed and analyzed. All lesions with FLT uptake had MRI correlates. Decline in average SUVmax of ≥25% was seen in 9/10 (90%) of WBRT+sorafenib and 2/4(50%) of WBRT only pts at FU1. A complete disappearance of FLT uptake was noted in 1 pt at FU1 and 2 more pts at FU2. Conclusions: Concurrent WBRT with sorafenib appears safe at 200mg daily dose with a higher rate of CR compared to historical WBRT data. We are currently enrolling patients in the safety-expansion cohort. This combination should be considered for further efficacy evaluation. Additional analysis of FLT-PET as a complementary imaging modality to MRI is currently ongoing. Clinical trial registry: NCT01724606 and NCT01621906. Support: Bayer, Susan G Komen, ASCO Gianni Bonadonna Breast Cancer Award Citation Format: Morikawa A, Jhaveri K, Grkovski M, Tang K, Humm JL, Holodny A, Beal K, Schoder H, Seidman AD. A phase I trial of sorafenib with whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases and a correlative study of FLT-PET brain imaging in patients receiving WBRT with or without sorafenib [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-19-03.

A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumours

BackgroundVeliparib is a potent poly(ADP-ribose) polymerase inhibitor. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib combined with various FOLFIRI regimens in patients with solid tumours.MethodsPatients received veliparib (10–270 mg BID, days 1–5, 15–19) and FOLFIRI (days 1–3, 15–17) in three regimens containing 5-fluorouracil 2,400 mg/m2: irinotecan 150 mg/m2 and folinic acid 400 mg/m2 (part 1); irinotecan 180 mg/m2, folinic acid 400 mg/m2, and 5-fluorouracil 400 mg/m2 bolus (part 2), or irinotecan 180 mg/m2 (part 3). The RP2D was further evaluated in safety expansion cohorts. Preliminary antitumour activity was also assessed.ResultsNinety-two patients received ≥1 veliparib dose. MTD was not reached; RP2D was set at 200 mg BID veliparib plus FOLFIRI (without 5-fluorouracil bolus). Most common treatment-emergent adverse events were neutropenia (66.3%), diarrhoea, and nausea (60.9% each). Dose-limiting toxicities (n = 4) were grade 3 gastritis and grade 4 neutropenia and febrile neutropenia. Veliparib exposure was dose-proportional, with no effects on the pharmacokinetics of FOLFIRI components. Fifteen patients had a partial response (objective response rate, 17.6%).ConclusionsThe acceptable safety profile and preliminary antitumour activity of veliparib plus FOLFIRI support further evaluation of this combination.

Abstract B079: Single agent AZD 1775, a Wee1 inhibitor, shows activity in BRCA deficient patients

Abstract Background: Modulation of BRCA1 and ATR has been postulated as an activation mechanism of checkpoint 1 (Chk1), which in turn triggers homologous recombination repair through modulation of BRCA2-Rad51, and the initiation of cell cycle checkpoints through phosphorylation and activation of Wee1. Wee1 is a tyrosine kinase implicated in the inhibitory phosphorylation of cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest in response to DNA damage. AZD1775 is a first-in-class selective inhibitor of Wee1 kinase that directly prevents phosphorylation of CDC2 at Tyr15. Model data show single-agent antitumor activity in multiple cancer cell lines across the NCI-60 and in both p53 intact and deficient tumor xenografts. We are conducting a phase I trial of AZD1775 in patients (pts) with refractory solid tumors, both with and without germline BRCA1/2 mutations (BRCA+), evaluating two different dosing schedules. We have previously reported on initial antitumor activity and proof-of-mechanism (Do et al, J Clin Oncol. 2015). This abstract reports the efficacy seen in the BRCA+ population. Methods: AZD1775 was administered orally twice daily (BID) for 5 doses [D1-3 and 8-10, Cohort A (A)] or once daily for 5 days [D1-5 and 8-12, Cohort B (B)] during weeks 1 and 2 of a 21-day cycle; 3+3 design. Primary objectives: establish safety, tolerability and PK of AZD1775. Secondary objectives: determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor tissue/circulating tumor cells, and antitumor activity. Dose-limiting toxicity (DLT) was determined during Cycle 1. Response defined by RECIST 1.1 on CT. Results: A total of 17 BRCA+ pts have enrolled; 9 pts on A (one pt withdrew for other therapy), and 8 pts on B. Nine pts with BRCA1, 7 pts with BRCA2: ovarian (9 pts), breast (2), pancreas (1), prostate (1), Fallopian tube (1), and peritoneal (1) cancer. Partial responses (PR) were confirmed on 2/8 pts (25%) in A with BRCA1 papillary serous ovarian cancer and squamous cell carcinoma of tongue. Two additional PRs (25%) were confirmed in BRCA1 serous ovarian cancer pts in B. Two further BRCA1 ovarian pts trended near PR. All 4 responders received prior platinum therapy; 3/3 ovarian cancer pts received and responded to prior PARP inhibitor therapy. No differences were noted in severity or rate of toxicity in pts with/without BRCA+: common grade 3/4 toxicities include anemia (6 pts, 37%), lymphopenia (5, 31%), neutropenia (4, 25%), and thrombocytopenia (3, 18%), occurring in responders and nonresponders. Conclusions: AZD1775 has single-agent antitumor activity in a BRCA deficient population, especially BRCA1. Responses were observed in pts with prior exposure to platinum and a PARP inhibitor. Additional accrual on a safety expansion cohort is ongoing, and assessment of PD biomarkers is planned for paired biopsies (NCT01748825). Citation Format: Geraldine OSullivan Coyne, Shivaani Kummar, Naoko Takebe, Khanh Tu Do, Robert Meehan, Richard Piekarz, Jennifer Zlott, Lamin Juwara, Mary Quinn, Elad Sharon, Howard Streicher, Lawrence Rubinstein, Chana Levine, James H. Doroshow, Alice P. Chen. Single agent AZD 1775, a Wee1 inhibitor, shows activity in BRCA deficient patients [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B079.

Preliminary Results of Prophylactic Tocilizumab after Axicabtageneciloleucel (axi-cel; KTE-C19) Treatment for Patients with Refractory,Aggressive Non-Hodgkin Lymphoma (NHL)

▪Background: ZUMA-1 is a pivotal, multicenter trial of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, for the treatment of patients with refractory, aggressive NHL. The objective response rate (ORR) was 82% with a 54% rate of complete response and 44% of responses were ongoing at the time of the primary analysis (Locke et al. AACR 2017. #9986). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 13% and 28% of patients, respectively. A safety expansion cohort was added to further characterize mechanisms underlying CRS and NE associated with CAR T cell therapy and to evaluate the impact of prophylactic use of tocilizumab and levetiracetam on the rates of these adverse events (AEs).Methods: Patients (≥ 18 years) must have had an Eastern Cooperative Oncology Group performance status of 0-1 and refractory or relapsed transplant ineligible disease. Patients received low-dose conditioning of 500 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine for 3 days followed by axi-cel at a target dose of 2 × 106 CAR T cells/kg. Patients also received prophylactic treatment with 750 mg of levetiracetam twice a day on day 0 and 8 mg/kg of tocilizumab on day 2 post axi-cel infusion. To evaluate the mechanisms of NE, paired serum and cerebrospinal fluid (CSF) were obtained for all patients prior to conditioning chemotherapy and after axi-cel infusion (day 5).Results: As of April 26, 2017, 31 patients received axi-cel. Median age was 51 years (range, 21-74), 52% were male, 65% had stage III-IV disease, 74% were refractory to ≥ second-line therapy, and 19% relapsed ≤ 12 months after autologous stem cell transplant. Most patients (97%) experienced at least 1 grade ≥ 3 AE. The most common grade ≥ 3 AEs were neutropenia/neutrophil count decreased (71%), anemia (55%), thrombocytopenia/platelet count decreased (52%), leukopenia/white blood cell count decreased (35%), febrile neutropenia (29%), encephalopathy (23%), and hypotension (23%). One patient (3%) experienced a grade ≥ 3 (grade 4) CRS. Grade 3 and 4 NE occurred in 29% and 6% of patients, respectively. One patient died of cerebral edema; there were no other deaths due to AE.Updated efficacy, safety, subgroups, and paired blood/serum/CSF biomarker associative analyses will be presented.Conclusions: Early use of tocilizumab may reduce the incidence of severe CRS but not NE in patients treated with CAR T cell therapy. These data provide evidence that the underlying pathophysiology of NE may differ from that of CRS. Understanding the mechanisms of NE may help to further improve the benefit:risk profile for CAR T cell therapy.Drs Locke and Neelapu contributed equally to this work. DisclosuresLocke:Kite Pharma: Consultancy; Cellular Biomedicine Group Inc: Consultancy. Neelapu:Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jacobson:Pharmacyclics, LLC: Consultancy; Kite Pharma: Consultancy. Braunschweig:Kite Pharma: Equity Ownership. Oluwole:Kite Pharma: Consultancy. Siddiqi:Seattle Genetics: Speakers Bureau; Juno: Other: Steering committee for JCAR017; Pharmacyclics, an AbbVie Company: Other: Steering committee for ibrutinib, Speakers Bureau. Timmerman:Celgene: Consultancy; Seattle Genetics: Consultancy; Kite Pharma: Research Funding; ImmuneGene: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genmab: Consultancy, Equity Ownership. Reagan:Seattle Genetics: Research Funding. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Sherman:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Elias:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership. Miklos:Pharmacyclics, LLC: Consultancy, Other: Travel expenses, Patents & Royalties, Research Funding; Kite Pharma: Consultancy, Other: Travel expenses, Research Funding; Adaptive Biotechnologies: Consultancy, Other: Travel expenses; Roche: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel expenses; Sanofi: Honoraria.