G3 Mucositis Research Articles

Safety and efficacy of intensified preoperative management of locally advanced gastrorsophageal junction cancer (INPROVE).

e16110 Background: The optimal management of locally advanced gastroesophageal junction adenocarcinoma (LAGEJad) is not fully established yet. Both neoadjuvant chemoradiotherapy (CRT) and perioperative taxane-based triplet chemotherapy (CT) are acknowledged treatment options for Siewert I and II cancers. In this retrospective study, we aimed to assess the safety and outcomes of an intensified preoperative regimen combining taxane-based triplet CT and CRT. Methods: We conducted a retrospective analysis of a cohort comprising 16 consecutive HER2 negative patients (pts) with LAGEJad treated at the Centro di Riferimento Oncologico of Aviano between 2019 and 2022. All pts received induction CT (iCT) consisting of fluoropyrimidine, oxaliplatin and docetaxel, followed by CRT (45Gy/25Fr) with simultaneous boost and concomitant CT. Surgery (Ivor-Lewis or McKeown) was performed 8 weeks post-CRT. Clinico-pathological (CP) and treatment features were analyzed using logistic regression to assess their association with response to iCT-CRT. The association of iCT-CRT with survival outcomes was investigated using the Kaplan-Meier method. Results: Key CP data are summarized in Table 1. Median age was 59 years, all pts were male. At diagnosis, 81.2% of pts exhibited cT3+ and cN+ disease. All pts received iCT and CRT. The rate of partial responses was 50% after iCT and 68.8% after CRT. Overall, 12 pts underwent surgery, all achieving R0 resections within a median timeframe of 9 [8.5;11] weeks post-CRT. Among them, 25% had a pathologic complete response, while 62.5% attained a Mandard tumor regression grade (TRG) of 1-2. No new safety signals emerged from iCT (only 2 pts had ≥G3 diarrhea) or CRT (≥G3 mucositis occurred in 6.2% and anemia in 6.2% of pts). No significant surgical delays were observed, although 5 pts experienced post-operative complications (4 grade I, 1 grade IIa). There were no statistically significant associations between CP variables and response to the iCT-CRT. Relapses were seen in 8 pts (2 locoregionally); 3-year survival was 46%. Median event-free survival was 5 [5;11] months, while median overall survival 34 [14;NR] months. Conclusions: The intensification of preoperative treatment in pts with LAGEJad is active and safe: the surgical schedule was not significantly delayed, and the safety profile remained comparable to standard regimens, with no major complications reported. Randomized clinical trials are ongoing to assess the clinical benefits of this approach. [Table: see text]

Abstract CT042: NCI10217: Phase Ib biomarker-driven tumor-agnostic combination (Combo) trial of copanlisib (Copa) and olaparib (Ola) in molecularly-selected patients (pts) with advanced cancers with PIK3CA hotspot, PTEN and DNA damage response (DDR) mutations

Abstract Background: Preclinically, PI3K and PARP inhibition synergize in cancers with DDR and PI3K pathway alterations. NCI10217 assessed the combo of Copa (pan-PI3K inhibitor) and Ola (PARP inhibitor) in tumors harboring mutations in PI3K/AKT or DDR pathways. Materials and Methods: Eligible pts had tumors with pathogenic PIK3CA hotspot, PTEN and DDR mutations. Copa was administered at 45 mg to 60 mg IV on Days (D) 1 and 15 or 1, 8 and 15 with Ola at 200 mg to 300 mg twice daily (BID) orally in 28-days cycles. Prior PARP and PI3K inhibitors were permitted. Fresh tumor biopsies and ctDNA were mandated at baseline and C1D15 and optional at the end of trial. Study objectives were safety, RP2D, pharmacokinetics, antitumor activity and translational analyses of serial tumor (WES; RNA-Seq; RPPA) and ctDNA samples. Results: 28 pts (M:F 8:20; ECOG PS 0:1 9:19; mean age 58y (28-76y) with breast (n=6), colorectal (n=5), prostate (n=4), endometrial (n=2), gastric (n=2), vaginal (n=2), appendix, cervix, head and neck, leiomyosarcoma, ovarian, peritoneal, and renal (n=1) cancers were enrolled. Pts with BRCA1/2 (n=12), PTEN (n=10), PIK3CA hotspot (n=6), ARID1A (n=4), CHEK2 (n=3), PALB2 (n=3), ATM (n=2), CDK12, CHEK1, MRE11A, RAD51C (n=1 each) mutations were enrolled. 10 pt tumors harbored >1 qualifying mutation. 17 (61%)/28 pts had ≥3 prior lines of therapy; 2 (7%)/28 had prior PARP inhibitors and 1 (4%)/28 had prior PI3K inhibitor. Common treatment-related toxicities included G1/2 mucositis (43%), nausea (43%), diarrhea (36%), anorexia (29%), fatigue (29%), maculo-papular rash (29%), hyperglycemia (25%), vomiting (25%); G3 transient hypertension (29%). Dose-limiting toxicities occurred in 3 (11%)/28 pts: 1 pt (G3 elevated transaminases) at Copa 45 mg (D1, D8 and D15) + Ola 200 mg BID, and 2 pts (G2 mucositis and maculo-papular rash, and G4 hyperglycemia) at Copa 60 mg (D1, D8, and D15) + Ola 300 mg BID. Of 22 pts evaluable for RECISTv1.1 criteria, 6 (27%)/22 pts achieved RECISTv1.1 partial responses (PR): 2 pts with BRCA1 mutation breast cancer; 1 pt with PIK3CA + PTEN + ARID1A mutation breast cancer; 1 pt with PTEN + PALB2 mutation breast cancer and prior PARP inhibitor exposure; 1 pt with BRCA2 mutation prostate cancer; 1 pt with BRCA2 + PTEN mutation prostate cancer. 8 (36%)/22 pts achieved RECISTv1.1 stable disease (SD); 2 (25%)/8 pts had SD≥6 months, including a pt with CA125 response (>50% reduction). Clinical benefit rate (SD≥6 months + PR) was 36%. Responses were deep (up to -100%) and durable (up to 37+ months). Based on these data, the RP2D was established at Copa 60 mg D1 and D15 + Ola 300 mg BID. Conclusion: Copa + Ola was safe and well-tolerated with clinical benefit observed in 36% of pts with advanced cancers with PIK3CA hotspot, PTEN and/or DDR mutations. Translational analyses are ongoing. Citation Format: Timothy A. Yap, Ecaterina E. Dumbrava, Jordi Rodon Ahnert, Apostolia M. Tsimberidou, David Hong, Sarina A. Piha-Paul, Daniel D. Karp, Siqing Fu, Aung Naing, Paula Pohlmann, Jessica R. Rhudy, Sheila B. Berenji-Jalaei, Ashley A. Cole, Christian Valladolid, Desirae Dufner, Bruno B. Bockorny, Andrea Bullock, Daniel Fein, Elizabeth Buchbinder, Atish Choudhury, Candace Haddox, Elizabeth Lee, Gerburg Wulf, Percy Ivy, Rabih Said, Geoffrey Shapiro, Funda Meric-Bernstam. NCI10217: Phase Ib biomarker-driven tumor-agnostic combination (Combo) trial of copanlisib (Copa) and olaparib (Ola) in molecularly-selected patients (pts) with advanced cancers with PIK3CA hotspot, PTEN and DNA damage response (DDR) mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT042.

Preliminary Analysis of an Ongoing Phase II Study of Response-Adapted Therapy with Copanlisib and Rituximab for Untreated Follicular Lymphoma

Introduction Frontline therapy for pts with follicular lymphoma (FL) is not based on the molecular profile of the tumor. The PI3K pathway is central to FL biology, but the molecular profile of tumors most sensitive to PI3K inhibition (PI3Ki) is unknown. Copanlisib inhibits both PI3Kα and δ isoforms, and we hypothesized that most pts with treatment naïve FL will have PI3Ki-sensitive tumors and durable complete responses (CRs) may be achievable with short durations of targeted therapy. A gene expression profiling (GEP) predictor utilizes a combination of the expression of 45 selected informative genes and an additional 19 housekeeping genes to identify FL pts at high-risk for early progression within 24 months (Wright et al. ASH Annual Meeting2022). We also hypothesized that copanlisib would induce durable CRs in high-risk pts by the GEP assay. Here, we report a preliminary analysis of an ongoing “window of opportunity” study of copanlisib followed by response-adapted copanlisib and rituximab in treatment-naïve pts with FL (NCT03789240). Methods Pts with untreated grade 1-2, 3A FL, ≥stage 2 are eligible if systemic therapy is indicated: symptoms, progressive lymphadenopathy, or organ compromise. Prior radiation is permitted. Eligibility includes age ≥18 and adequate organ function unless due to lymphoma. HIV, CMV, Hep B or C, and autoimmune conditions are excluded. Pts first receive copanlisib 60mg on days 1, 8, and 15 of a 28-day “window of opportunity” to explore the activity of copanlisib. Following the window, pts receive 6 cycles of copanlisib 60mg on days 1, 8, and 15 of a 28-day cycle along with rituximab 375mg weekly x 4 then on day 1 of each cycle and response is assessed with FDG-PET and CT scans. Pts without response after C6 are taken off study and those with a partial response (PR) can continue for an additional 6 cycles and then stop therapy. Pts who achieve a CR after 6 cycles stop therapy. No maintenance is given. Supportive care includesPCP prophylaxis. The primary endpoint is the CR rate with secondary endpoints of safety, duration of CR, and PFS. Exploratory objectives include identification of a predictive signature of PI3Ki response and the response rate in high-risk pts identified by the GEP assay. Results Twenty-eight pts have enrolled. Median age was 56y (range, 24-80). Seventeen (61%) and 12 (43%) pts had high-risk FLIPI and FLIPI-2 scores ≥3, respectively; 6 (21%) pts had Grade 3A FL, and 17 (61%) pts met two or more GELF criteria. After copanlisib monotherapy in the window, 27 (96%) pts had tumor reductions by CT with a median change of -38% (-62% to +16%) (Figure 1). Among 22 pts who completed 6 cycles, 21 (96%) responded, including 9 (41%) pts with PR and 12 (55%) pts with CR. Of 9 pts with PR who received an additional 6 cycles of therapy, only 1 (11%) converted to a CR bringing the overall CR rate to 59% (13/22 pts). After a median follow-up of 25.8 months, the 2-year PFS was 43.2% (95% CI, 20.7-64.0%). The median duration of CR was 29.7 months (95% CI, 6.3 months - not estimable) with 8 (62%) CRs ongoing (Figure 2). Toxicity was evaluated in 28 pts across 220 cycles. Most common were rash (64%), mucositis (50%), and nausea/vomiting (50%), all G1-2 except 1 (4%) pt with G3 mucositis. The most common ≥G3 toxicities were neutropenia and infections in 5 (18%) pts each. ≥G3 neutropenia occurred in 10 (5%) cycles, responded to therapy interruption and/or growth factors, and did not require dose reduction. Two (8%) pts had copanlisib dose reduced, 1 (4%) each due to rash and mucositis. Therapy was prematurely discontinued in 5 pts: 3 due to COVID-19, 1 for hepatotoxicity that resolved, and 1 due to infusion reaction to rituximab. Nine of 24 (38%) pts were poor risk by the GEP assay. Complete responses were observed in 71%, 67%, and 57% of pts categorized as high-risk by FLIPI, FLIPI-2, and GEP assay, respectively. The CR rate was not affected by bulky disease (any LN >7cm; p=1.00), high-risk FLIPI (p=0.19), high-risk FLIPI-2 (p=0.67), poor-risk GEP (p=1.00), or metabolic tumor volume (p=0.33). Conclusion Nearly all pts with treatment naïve FL have PI3Ki-responsive tumors, and the combination of copanlisib with rituximab achieved a CR rate of 59% at the end of induction therapy. The median duration of CR is nearly 30 months, including ongoing remissions without maintenance. CRs were observed in pts deemed high-risk by the GEP assay and FLIPI score. The safety profile is excellent, with mostly G1-2 toxicities manageable with supportive care.

An Update of Stereotactic Body Radiotherapy (SBRT) for the Palliation of Unirradiated Mucosal Head and Neck Squamous Cell Carcinoma (SCC)

We report the treatment outcomes of palliative Stereotactic Body Radiation Therapy (SBRT) in patients with primary mucosal head and neck cancer (HNC) who were not eligible to receive conventional radiation therapy (RT). This is a retrospective study that reviewed the medical records of patients with primary SCC mucosal HNC who were treated with SBRT between 2011 and 2022. Patients with other histologies, skin cancer, parotid tumors, or recurrent previously irradiated tumors were excluded from the study. A total of 74 patients and 77 tumors were treated with SBRT in this cohort. The median age in the study was 81 (52-97) years and the median follow-up was 7.2 months. The most common site of HNC was the oral cavity (62%), followed by the oropharynx (18%), hypopharynx (8%), larynx (5%), nasal cavity/sinonasal cancer (3%), and unknown primary (1%). T3-4 lesions were found in most patients (76%). SBRT doses ranged from 35-50 Gy in 5 fractions, and the most common prescription dose was ≥45 Gy in 5 fractions (60%) for the GTV prescription. An elective nodal volume of 25 Gy in 5 fractions was infrequently (17%) used. Most patients (81%) who were treated twice a week completed in ≤14 days. The predominant symptoms at presentation were: pain (41%), mass effect (39%), dysphagia/odynophagia (14%), headache/nasal obstruction (1.4%), bleeding (1.4%), stridor (1.4%), asymptomatic (1.4%), and unknown (1.4%). 84% of patients had symptomatic response to treatment with 24% of them having complete symptom response. Cumulative incidence of local failure (LF) was 6.7% and at 6 months and 17.9% at 12 months, respectively. Cumulative incidence of distant metastasis was 7.3% and 10.5% at 6 and 12 months. Cancer was the most common cause of death in 29 patients (51%). The median overall survival (OS) was 8 months with 6 and 12-month OS rates of 67% and 36%, respectively. 39% of patients developed acute G3 toxicity, including 30% with G3 mucositis, 5% with G3 dysphagia, and 4% with G3 dermatitis. A crude rate of late G ≥3 toxicity was observed in 11% of patients including (5%, n = 4) with osteoradionecrosis, and a single case of dysphagia, soft tissue necrosis, supraglottic ulceration, and mucosal necrosis. This study highlights the feasibility of SBRT as a treatment option for primary mucosal head and neck cancer patients who are not eligible for conventional radiation therapy. The results indicate that SBRT was effective in achieving local control and symptom relief, but larger prospective studies are needed to confirm the findings. The Canadian Cancer Trials Group has endorsed HN-13, a randomized control trial comparing HN SBRT to palliative RT.

A Multicenter Study of Clinician and Patient Reported Acute and Late Toxicity after Radical (Chemo)Radiotherapy for Non-Endemic Nasopharyngeal Cancer

Curative (chemo)radiotherapy ((CT)RT) for Nasopharyngeal cancers (NPC) achieves excellent disease control but is associated with significant late toxicities despite modern treatment delivery. Contemporary late toxicity data, including patient reported outcomes (PROs), is limited in the non-endemic population; we present a large contemporary series of toxicity outcomes and late PROs following treatment of non-endemic NPC. Adult patients completing radical (CT)RT for primary NPC between February 2016 and 2020 at 7 large UK cancer centers were identified on institutional databases. Patients were excluded if they had prior head and neck cancer or prior therapeutic head and neck surgery (except neck dissection). Patients with an active other cancer were excluded from PRO assessment. Demographic, treatment, acute toxicity and outcome data were collected retrospectively from patient records. Disease-free patients were invited to complete an M.D. Anderson Dysphagia Index (MDADI) and University of Washington (UoW) Quality of Life (QoL) PROs questionnaires. A total of 180 eligible patients were identified: 68% male, median age 54 years, 11% ≥70 years. EBV status was positive in 61% (unknown 12%). Patients had stage I (5%), II (22%), III (37%), IV (36%) disease; 95% were performance status ≤1 at baseline. Median follow-up was 31.2 months (range 0-68). A total of 54% received 70Gy in 33-35# and 43% received 65-66 Gy in 30-33#. 66% received induction and 65% received concurrent chemotherapy. 9.5% had residual disease at the first follow-up scan. Subsequent locoregional or distant recurrence occurred in 5% and 12% respectively. At last assessment, 84% patients were alive, 16% had died (of which 70% had active disease). Acute treatment toxicity included: 63% of patients required enteral support (median duration 98 days) with 9% a feeding tube at 1 year post treatment. 18% G3 dermatitis, 53% G3 mucositis. 82% requiring opioids and 40% admitted for symptom management. 90 patients completed the PROs (76% response rate) at a median of 37.8 months post treatment (Table 1). These demonstrate significant QoL detriment: 28% report significant pain, 24% require regular analgesia, and 59% report significant impact on daily activity. This was found to persist at different timepoints (not shown). Excellent cancer survival outcomes are seen in a non-selected, non-endemic NPC population. However significant acute and late toxicity following radical treatment is identified which can profoundly negatively impact QoL in a relatively young cohort. This highlights the importance of ongoing efforts to reduce toxicity and supports the prospective evaluation of potential toxicity sparing technologies, such as proton beam radiotherapy.

Phase I first-in-human trial of ABT-301, an oral pan-HDAC inhibitor, in patients with advanced solid tumors.

e15137 Background: ABT-301 (previously known as MPT0E028) is a novel, oral pan-histone deacetylases (HDAC) inhibitor with potent inhibitory activity for HDAC 1, 2, 3 (class I), HDAC 6, 10 (class IIb), modest activity for HDAC 8 (class I) and HDAC 11 (class IV), but no activity for HDAC 4, 5, 7, 9 (class IIa). Preclinical studies showed that ABT-301 had a stronger apoptotic activity and inhibited HDAC activity more potently than vorinostat. ABT-301 exerts antitumor activity as a monotherapy in human colorectal cancer and B-cell lymphoma xenografts and synergistic antitumor activity with immune checkpoint inhibitor in CT26 syngeneic tumor model. Methods: This was a 3+3 Phase 1 dose escalation study to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetic (PK) /pharmacodynamic (PD) profiles for the ABT-301 in patients with locally advanced or metastatic solid cancers. 5 cohorts of 3 or 6 patients received ABT-301 once daily at gradually escalating doses starting from 50 mg. Results: 23 subjects (6 sarcomas and 17 carcinomas) were treated at 5 dose levels (3 at 50, 100, and 250 mg respectively, 6 at 150 mg, and 8 at 200 mg). Cycle 1 DLTs occurred in 5 subjects: 1 at 50 mg (G3 mucositis); 2 at 200 mg (G3 abdominal pain and G4 thrombocytopenia); 2 at 250 mg (G3 vomiting and G4 thrombocytopenia). The MTD was 150 mg. The most common treatment-related adverse events were thrombocytopenia (44%), anemia (18%), nausea (61%), vomiting (44%), anorexia (22%), hyperglycemia (22%), fatigue (18%), and mucositis (18%), which were generally G1 to G2 in severity. No cardiac abnormalities were observed. 1 had a partial response (PR), and 8 achieved SD, resulting in a disease control rate (DCR) of 39%. The PR (a patient with eccrine ductal carcinoma) lasted 24 weeks whereas 5/8 SD patients achieved a sustained condition of 16 to 53 weeks (hepatocellular carcinoma, 53 w; thymic cancer, 49 w; salivary gland carcinoma, 27 w; endometrial stromal carcinoma, 25 w; renal cell carcinoma, 16 w). DCR for 9 patients at MTD was 78% (7/9; 1 PR and 6 SD). Plasma PK showed a dose-dependent increase in ABT-301 exposure. Cmax is 5.5 µM and AUC0-inf is 11.5 µM*h at 150 mg. Increased acetylated histone 3 was observed across all cohorts. Conclusions: ABT-301 was well-tolerated at a daily dose of up to 150 mg and demonstrated objective responses and long-term SD across multiple tumor types at MTD. The safety profile of ABT-301 was superior to known HDAC inhibitors with only predictable HDAC inhibitor-related toxicities observed but no cardiac toxicity, neutropenia, nor lymphopenia elicited. Non-clinical and clinical results suggested the potential clinical development of ABT-301 in combination with myelosuppressive agents and immunotherapies. Phase 2 studies combining PD-1/PD-L1 blockade are being designed. Clinical trial information: NCT02350868 .

Treatments and outcomes of patients with localized extranodal NK/T-cell lymphoma (ENKL) diagnosed between 2014 and 2021: A cooperative study in Japan.

7565 Background: A previous cooperative study of patients (pts) with ENKL who were diagnosed between 2000 and 2013 in 31 institutes in Japan reported that the most common first-line treatment for localized ENKL was radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) (66%). The 2-year (yr) overall survival (OS) and progression-free survival (PFS) of pts with localized ENKL were 78% and 68%, respectively (JCO 2017). RT-DeVIC has been included as a preferred regimen of combined modality therapy in the NCCN guidelines. The treatments and outcomes of pts with localized ENKL in recent clinical practice are unknown. Methods: We conducted a cooperative study (NKEA-Next; UMIN000046300) by hemato-oncologists and radiation oncologists of pts with ENKL who were diagnosed between 2014 and 2021 in 45 institutes in Japan. The results were compared with those from the 2000-2013 cohort (JCO 2017). The primary endpoint was OS of pts with ENKL who received next-generation treatment in 2014-2021 at participating institutes. We analyzed the data of localized ENKL. Results: Of 351 pts in the 2014-2021 cohort, 235 (67%) had localized ENKL. First-line therapy was RT-DeVIC in 185 (79%) pts, sequential chemoradiotherapy in 17, RT alone in 15 pts, and chemotherapy alone in 12 pts. Six pts received no treatment due to poor performance status (PS). Only two pts (1%) received anthracycline-containing regimens. With a median follow-up of 3.4 yrs, the 2-yr OS and PFS of localized ENKL were 83% and 75%, respectively. Pts treated with RT-DeVIC showed the following clinical features: median age, 58 yrs (range, 13-82); age > 60 yrs, 45%; stage IIE, 34%; B symptoms present, 27%; elevated serum lactate dehydrogenase, 23%; ECOG PS 2, 4%; and soluble interleukin-2 receptor (sIL-2R) level > upper limit of normal (ULN), 31% (57/183). The complete response rate was 88% among the 179 pts who were evaluated for response. The 2-yr OS and PFS of RT-DeVIC were 87% and 79%, respectively. There was no treatment-related death due to RT-DeVIC. G3/4 mucositis was recorded in 32% (G3, n = 59; G4, n = 0). G3/4 febrile neutropenia occurred in 18% (G3, n = 32; G4, n = 2). sIL-2R > ULN was associated with worse OS ( P < 0.01). In comparison with pts with localized disease in the 2000-2013 cohort, pts in the 2014-2021 cohort received RT-DeVIC more frequently ( P < .001). There was no significant difference in OS ( P = 0.24) or PFS ( P = 0.10) between the two cohorts. Conclusions: RT-DeVIC was more frequently used for first-line treatment of localized ENKL, and its efficacy has been maintained, with 87% 2-yr OS in recent clinical practice in Japan, providing further evidence of RT-DeVIC as a preferred first-line regimen for localized ENKL. No obvious improvement in OS and a reduction in G3 mucositis were observed, suggesting that more efficacious and less toxic regimens need to be introduced.

Real-life use of cabozantinib as front-line therapy in metastatic renal cell carcinoma: The CabFRONT (Meet-URO 24) study.

e16539 Background: Cabozantinib is approved as first-line therapy for patients with intermediate-poor risk metastatic renal cell carcinoma (mRCC); however translating results from pivotal trials to an unselected real-world population remains a concern. Methods: CabFRONT is a retrospective observational multicentre Italian Network for Research in Urologic-Oncology (Meet-URO) study of a real-life population of treatment-naïve patients with intermediate-poor mRCC treated with cabozantinib as per clinical practice between September 2019 and September 2022. Results: 209 patients were enrolled. Median age was 65 years (36 - 85). 158 patients (76%) started with a dose of 60 mg, while 51 (24%) started with a dose of 40 mg. 140 patients (67%) were classified as intermediate and 69 (33%) as poor risk according to IMDC risk model. Clear-cell represented the most common histotype (172/209), followed by papillary (19/209), chromophobe (6/209) and NOS (4/209). Sarcomatoid features were present in 29 patients (14%). Lungs were the most frequent metastatic site, [137 (65%) patients], followed by lymph nodes [115 (55%)], and bones [72 (35%)]. 33 (16%) patients presented brain metastases. At a follow-up of 23 months (mo), the median progression-free survival (mPFS) was 9.6 mo (95% CI, 7.63-10.9 mo) and the median overall-survival was 21 mo (95% CI, 14-30 mo). As best overall response, 7 patients achieved a complete response, 73 a partial response and 77 stable disease for an objective response rate (ORR) of 38% and a disease control rate (DCR) of 75%. ORR for intermediate and poor population was respectively 29% and 10%, DCR was 56% for intermediate risk and 20% for poor risk population. mPFS for intermediate and poor population was respectively 12.73 and 5.27 mo (p < 0.0001). mPFS for intermediate with 1 risk factor was 17.2 and for intermediate with 2 risk factors was 9.7 mo (p 0.0033). Subsequent antineoplastic treatments were received by 41% (86/209) of patients. Subsequent nivolumab was received by 87% of patients. 191 patients (91%) reported at least 1 grade (G) 1 to 2 adverse event (AE). The most common G1 to G2 AEs were fatigue (113 [60%]), mucositis (100 [52%]), hand-foot syndrome (HFS) (91 [47%]), diarrhoea (79 [41%]), hypertension (67 [35%]), and hypothyroidism (60 [31%]). 78 G3 AEs ere reported: the most common were fatigue (19 [24%]) and diarrhoea (18 [23%]). Permanent discontinuations from the study owing to AEs was observed in 7 patients: three for G3 diarrhea, one of which manifested also G3 renal injury, two for G3 asthenia, one for G3 HFS and one for G3 mucositis. At least 131 patients (63%) required a dose reduction and 86 (41%) required a transitory interruption to manage toxic effects. Conclusions: Our data confirmed that front-line Cabozantinib is effective and safe in an unselected real-life population of patients with intermediate-poor mRCC, including non-clear cell histologies.

Effects of induction chemotherapy on nutrition status in locally advanced nasopharyngeal carcinoma: a multicentre prospective study.

Induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT) is the standard of care for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). This intensive treatment regimen increases acute toxicities, which could negatively impact patients' nutritional status. We conducted this prospective, multicentre trial to investigate the effects of IC and CCRT on nutritional status in LA-NPC patients, so as to provide evidence for further study of nutritional intervention, which was registered in ClinicalTrials.gov (NCT02575547). Patients with biopsy-proven NPC and planned for IC+CCRT were recruited. IC entailed two cycles of 3-weekly docetaxel 75mg/m2 and cisplatin 75mg/m2 ; CCRT entailed two to three cycles of 3-weekly cisplatin 100mg/m2 depending on the duration of radiotherapy. Nutritional status and quality of life (QoL) were assessed pre-IC, post-cycles one and two of IC, W4 and W7 of CCRT. Primary endpoint was the cumulative proportion of ≥ 5.0% weight loss (WL5.0 ) by the end of treatment (W7-CCRT). Secondary endpoints included body mass index, NRS2002 and PG-SGA scores, QoL, hypoalbuminaemia, treatment compliance, acute and late toxicitiesand survivals. The associations between primary and secondary endpoints were also evaluated. One hundred and seventy-one patients were enrolled. Median follow-up was 67.4 (IQR: 64.1-71.2) months. 97.7% (167/171) patients completed two cycles of IC, and 87.7% (150/171) completed at least two cycles of concurrent chemotherapy; all, except one patient (0.6%), completed IMRT. WL was minimal during IC (median of 0.0%), but increased sharply at W4-CCRT (median of 4.0% [IQR: 0.0-7.0%]) and peaked at W7-CCRT (median of 8.5% [IQR: 4.1-11.7%]). 71.9% (123/171) of patients recorded a WL5.0 by W7-CCRT, which was associated with a higher malnutrition risk (NRS2002≥3 points: 87.7% [WL≥5.0%] vs 58.7% [WL<5.0%], P<0.001) and requirement of nutritional intervention (PG-SGA≥9 points: 82.0% [WL≥5.0%] vs 66.7% [WL <5.0%], P=0.038). The median %WL at W7-CCRT was higher in patients who suffered from ≥ G2 mucositis (9.0% vs 6.6%, P=0.025) and xerostomia (9.1% vs 6.3%, P=0.003). Besides, patients with cumulative WL5.0 also reported a higher detriment on QoL at W7-CCRT compared with patients without, with a difference of -8.3 points (95% CI [-15.1, -1.4], P=0.019). We observed a high prevalence of WL among LA-NPC patients who were treated with IC+CCRT, which peaked during CCRT, and had a detriment on patients' QoL. Our data support the need to monitor patient's nutritional status during the later phase of treatment with IC+CCRT and inform on nutritional intervention strategies.

Phase I-II study to evaluate safety and efficacy of niraparib plus cabozantinib in patients with advanced urothelial/kidney cancer (NICARAGUA trial): Preliminary data of phase I study.

490 Background: Niraparib (N) is a (PARP)-1/-2 inhibitor and Cabozantinib (C) is a tyrosine kinase (TK) inhibitor that targets VEGF signalling via inhibition of multiple TK receptors including c-MET and TAM kinases (TYRO3, AXL, MER). The c-Met receptor TK is abnormally activated and could be decrease response to PARP inhibitors. Preclinical data reveals that treatment with c-Met inhibitors renders cells more sensitive to PARP inhibition. A phase (Ph) I-II study was designed to explore the safety and efficacy of the combination of N + C in genitourinary cancers. Methods: Multicenter, open-label Ph I-II study (NCT03425201). Confirmed histopathological diagnosis of either metastatic urothelial carcinoma (mUC) or advanced clear cell renal cell carcinoma previously treated with a maximum of two previous regimens. Adequate bone marrow, liver and renal functions were required. The Ph I portion aimed to identify the maximum tolerated dose (MTD) and recommended ph II dose (RP2D). Pt received N and C p.o. once daily in 28-day cycles: Dose level 1 (DL1) N/C 100/20 mg; DL2 200/20 mg; DL3 200/40 mg; DL4 200/60 mg. A further amendment developed DL1.1 100/40 mg. Pt were accrued to each dose level in cohorts of 6 pt until the MTD was achieved (defined as highest dose at which ≤1 out of 6 pt experience a DLT, evaluated during the first 2 cycles). Results: Nineteen evaluable pt for DLT were included, 14 of them had UC. There was no DLT at DL1. Two out of the first 6 evaluable pt in DL2 had DLT (G3 thrombopenia and anemia and G3 diarrhea respectively). Upon analysis of these pt it was agreed to include 3 additional new pt for evaluation. Two pt were included with one presenting a DLT (G3 hepatic toxicity). Enrolment then continued in a new DL 1.1 cohort and 1 of 6 pts had DLT (G3 mucositis), being then considered the RP2D. No toxic deaths were reported. Six pt (32%) received at least 10 cycles and 9 pt (47%) received at least 6 cycles. Three patients (16%) achieved partial response (all of them with mUC disease) and 14 (74%) stable disease. Conclusions: N plus C combination can be safely administered with a manageable toxicity profile and preliminary efficacy was reported in mUC heavily pretreated pts. The RP2D is N 100 mg plus C 40 mg qd. Ph II study is now recruiting mUC patients. Clinical trial information: NCT03425201. [Table: see text]

Stereotactic Body Radiotherapy (SBRT) for the Palliation of Unirradiated Mucosal Head and Neck Tumors

We report the treatment outcomes of palliative SBRT to primary mucosal unirradiated head and neck cancer (HNC) patients that were ineligible to receive conventional radiation therapy (RT) MATERIALS/METHODS: We retrospectively reviewed patients with primary mucosal HNC treated with SBRT from 2011-2020. Patients with histologies other than squamous cell carcinoma, with primary skin disease or with recurrent tumors were excluded. SBRT was used in this cohort of patients because of associated comorbidities that precluded full course RT. All patients were followed regularly with clinical examination and imaging. The endpoints were local failure (LF) defined as recurrence of tumor at the irradiated site, overall survival (OS), acute and late grade 3 and 4 toxicity.Sixty patients with a median age of 81 years were treated with SBRT technique. The median follow-up was 7.8 months. 8(13%), 38(63%), 13(22%) and 1(2%) were ECOG 1, 2, 3 and 4, performance status respectively. Oral cavity was the most common cancer site in our cohort (60%, 36 patients), followed by oropharyngeal cancer (15%, 9 patients), larynx (7%, 4 patients), hypopharynx (5%, 3 patients), parotid cancer (5%, 3 patients), unknown primary (5%, 3 patients) and nasal cavity/sinonasal cancer (3%, 2 patients). Tx-2 and T3-4 lesions were found in 18(30%) and 42(70%), respectively, while 32(53%) and 28(47%) were staged N0-1, N2-3, respectively. GTV was prescribed to 45 Gy in 5 fractions, most commonly used (55%), followed by 40 Gy in 5 fractions (37%). A high dose CTV was not used around GTV although an elective nodal volume of 25 Gy in 5 fractions was also used. 52 patients were treated twice a week completed in 13-20 days, 2 patients completed their treatments in 9 and 10 days, while 5 patients over 21-28 days. The cumulative incidence of LF at 6 and 12 months was 5.3% (95% CI 1.4-13.3) and 12.4% (95% CI 4.9-23.7), respectively. The median (OS) was 9.2 months. The 6 and 12 month OS rates were 67.9% (95% CI 56.6-81.4) and 41.4% (95% CI 29.2-58.7), respectively. Cancer was the cause of death in 12 patients (38%), while 20 deaths (62%) were not related to malignant disease. Acute G3 toxicity was observed in 23 patients, including G3 mucositis in 19 patients, G3 dermatitis in 2 patients and G3 dysphagia in 2 patients. Five patients developed G3+ late toxicity, including osteoradionecrosis (n = 3), soft tissue supraglottic ulceration (n = 1) and trismus (n = 1). Four of these 5 patients did not have evidence of concurrent local recurrence.HN SBRT has been largely reported in the re-irradiation setting, however, SBRT may have greater utility in the palliative management of previously untreated HNC patients. Despite the advanced age and performance status noted in this group of patients with mucosal SCC of the head and neck, who were not eligible for conventional RT, SBRT was associated with low local failure rates and reasonable toxicity profile. A randomized controlled trial is warranted to confirm the efficacy of HN SBRT in this setting.

A Phase I/II Study of Selinexor (SEL) with Sorafenib in Patients (pts) with Relapsed and/or Refractory (R/R) FLT3 Mutated Acute Myeloid Leukemia (AML)

Background: Responses to FLT3-inhibitors are usually transient due to emergence of resistance through the acquisition of kinase domain point mutations and other non-mutational mechanisms. SEL is a potent first-in-class Selective Inhibitor of Nuclear Export/SINE™ that exerted marked cell killing of human and murine FLT3 -mutant AML cells, including those with ITD, D835Y, ITD+Y842C or ITD+F691L mutations by modulating the cdk inhibitor p27 and anti-apoptotic Mcl-1 (Zhang W et al, Blood 2015 126). The combination of SEL+sorafenib had synergistic pro-apoptotic effects in FLT3-mutated AML cells by suppressing phosphorylation levels of FLT3 and its downstream signaling mediators ERK/AKT, and by inducing myeloid differentiation in ITD and D835 mutated cell lines.Methods: We designed a phase I/II trial of SEL with sorafenib for FLT3-ITD and/or -D835 R/R AML pts. In phase I, the primary objectives were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and dose-limiting toxicity (DLT) of the combination. In phase II, primary objectives included the rate of complete remission (CR) + CR with incomplete count recovery (CRi) + partial response + >50% blast reduction within 3 months of therapy initiation. Secondary objectives were safety and overall survival (OS). SEL was given orally twice a week for 3-weeks on and 1-week off in 28-day cycles and sorafenib was given continuously at a dose of 400mg twice daily from cycle 1 day 1 of SEL. In phase I, SEL dose was de-escalated in “3+3” fashion starting at dose level 0 and going down if DLTs were exceeded (dose levels 0, -1, -2 = 80, 60, 40 mg, respectively). Once MTD was established, the phase II enrolled pts in 2 cohorts: prior FLT3-inhibitor failure (cohort 1) and FLT3-inhibitor naïve (cohort 2). PB or BM samples were collected at pre-dose (C1D1), 24 h (C1D2) and day 28 (C1D28) of cycle 1, and apoptosis induction was determined by measuring annexin V positivity with FACS.Results: Fourteen pts with a median age of 71 years (range, 24-81) were enrolled. All pts had baseline next generation sequencing for AML specific mutations (Figure 1A). The median number of prior therapies was 3 (range, 1-5) as follows: salvage (S) 1: n=1, S2: n=5, S3+: n=8. 11 (79%) pts had prior FLT3-inhibitors: 1 prior FLT3-inhibitor (n=9); 2 prior FLT3-inhibitors: n= (2). Three pts had prior SCT. Four pts were treated at dose level 0 (SEL 80mg) with DLTs in 2 (Grade (G) 3 sepsis, n=1; G3 mucositis, syncope, adrenal insufficiency, n=1). Three pts were subsequently treated at dose level -1 (SEL 60mg) with no DLTs and this was established as the MTD/RP2D. Seven pts were treated in expansion: 6 had prior FLT3-inhibitor therapy (cohort 1) and 1 had no prior FLT3-inhibitor (cohort 2).The median duration of treatment for all 14 pts was 28 days (range, 14-122) and therapy is ongoing in 1 pt. All pts are evaluable for response. CRp/CRi and >50% blast reduction as best responses were seen in 4/14 (29%) and 2/14 (14%) pts, respectively. All 6 responders had a prior FLT3 inhibitor yielding a response rate of 55% (6/11) pts with prior FLT3 inhibitor therapy. 3 pts with CRp/CRi (2 with FLT3-ITD and 1 with ITD+D835) achieved negative RT-PCR for FLT3. (Figure 1B). One pt in CRi was bridged to SCT and remains alive at 1 year. The most common G 3/4 adverse events irrespective of causality were bleeding (gastrointestinal, n=4; intracranial, n=1), febrile neutropenia (n=4), pneumonia (n=3) and syncope (n=2). The reasons for discontinuing study therapy were disease progression (n=9; 64%), toxicity (n=3; 21%) and SCT (n=1; 7%). The median OS for pts on study was 3.5 months (range, 0.9-15). Translational analysis showed that SEL+sorafenib induced apoptosis in 4 of 5 tested patients, especially in the BM samples (Figure 1C)Conclusions: The combination of SEL and sorafenib is safe with clinical activity and apoptosis induction in R/R FLT3+ AML. The benefit was especially encouraging in pts exposed to prior FLT3 inhibitors, with a response rate of 55% (6/11; including 2 CRi and 2 CRp). The RP2D is 60 mg twice weekly of SEL and the study is accruing (NCT01607892). [Display omitted] DisclosuresDaver:Kiromic: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Otsuka America Pharmaceutical, Inc.: Consultancy; Incyte Corporation: Honoraria, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Immunogen: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. DiNardo:Celgene: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Cortes:BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding.

Gemcitabine/Clofarabine/Busulfan: A New Myeloablative Reduced-Toxicity Conditioning Regimen with High Activity for Allogeneic Stem-Cell Transplant (alloSCT) in Aggressive Lymphomas

INTRODUCTION:Stem-cell transplantation (SCT) is standard treatment of relapsed lymphomas. Patients in refractory relapse or relapsed after autoSCT are often considered for an alloSCT, aiming at a graft-vs.-lymphoma (GVL) effect. While reduced intensity conditioning regimens have substantially contributed safety to alloSCT, aggressive lymphomas often progress rapidly afterwards, partly due to tumor cell growth outpacing GVL. Outcomes are particularly poor for patients with active disease at the time of alloSCT. Thus, development of more efficacious conditioning regimens for aggressive lymphomas, avoiding mucotoxic drugs (such as melphalan), is a major need. We previously showed that the combination of 2 nucleoside analogues [gemcitabine (GEM) + clofarabine (CLO)] followed by busulfan (BU) is highly synergistic against B- and T-cell lymphoma cell lines, through inhibition of DNA damage repair. Those observations led us to clinically study a novel high-dose regimen of GEM/CLO/BU with alloSCT for aggressive lymphomas.METHODS:Eligibility included age 12-65; refractory DLBCL, T-cell and Hodgkin lymphomas; acceptable end-organ function, and an 8/8 HLA-matched (A, B, C and DRB1) sibling (MSD) or unrelated donor (MUD). GEM was escalated from dose level 1 to 3; it was given on days -6 (d-6) and d-4 as a loading dose of 75 mg/m2 followed by infusion at 10 mg/m2/min over 40-90 min (total daily dose 475, 675 or 975 mg/m2), to be followed by CLO (40 mg/m2/day x 4, d-6 to d-3) and BU (pharmacokinetically targeted to an average daily AUC of 4,000 μMol•min x 4, d-6 to d-3). AlloSCT was on d0. Patients receiving a MUD transplant received rabbit ATG (0.5, 1.5 and 2 mg/Kg on d-3, d-2, and d-1, respectively). Patients with CD20+ tumors received rituximab (375 mg/m2) on d-14, d-7, d+1 and d+8. The GVHD prophylaxis included tacrolimus (tapered after d+100) and mycophenolate mofetil (from d0 to d+60). Dose limiting toxicities (DLT) were defined as any G4-5 nonhematological organ toxicity, or as G3 skin or G3 mucositis lasting >3 days at peak severity. Dose escalation of gemcitabine followed a Bayesian design targeting a maximal DLT probability of 25%. Non-relapse mortality (NRM), relapse incidence, G II-IV or III-IV acute GVHD or chronic GVHD were calculated with the cumulative incidence method with consideration of competing risks.RESULTS:Between 11/12 and 06/17, 48 patients were enrolled: 25 DLBCL (5 double hit), 13 T-NHL and 10 HL (Table); 27 MSD, 20 MUD.All patients received PBPC. The MTD of gemcitabine was level 3. DLT was observed at the following frequencies: level 1: 12.5% (1/8), level 2: 9% (2/9), and level 3: 25% (4/16). Regimen-related toxicities were manageable, including mucositis (47% G2, 42% G3), self-limited transaminitis (21% G2, 49% G3), hyperbilirubinemia (no cases of VOD) (30% G2, 19% G3), and dermatitis (13% G2). There were no cardiac, pulmonary, renal or CNS toxicities. Neutrophils dropped to <0.1 in all patients on median d0 (d-3 to +2), and engrafted on median d+10 (d+9 to +20). Platelets engrafted on median d+12 (d+8 to +38).All patients engrafted; full donor chimerism was established early: a median of 100% (50-100%) on d+28, and 100% (98%-100%) on d+100. The rates of G II-IV and III-IV acute GVHD were 29.8% (35% MSD, 25% MUD) and 10.6% (19% MSD, 0% MUD), respectively. The rates of moderate-severe / severe chronic GVHD were 8.5% / 6.4%. 1/3 HL pts with prior exposure to anti-PD1 developed steroid-responsive hepatic chronic GVHD.The γ-H2AX levels in PBMNC (N=19) increased throughout treatment, to a median of 8.5 fold from baseline (range, 0.4-46.3) (P=0.0001) and PARP-1 decreased to 0.45 fold (0.2-6.3) (P=0.4), indicative of activation of DNA damage response and apoptosis, respectively. The overall response rates on d+30 (in 34 patients with measurable disease) are 77% (DLBCL), 100% (T-NHL), and 75% (HL). Their respective CR rates are 69%, 100% and 75%. The d+100 / 1-year NRM rates were 6.25% / 14.5%. NRM causes were infection (6) and GVHD (1). At median follow-up of 18 months (1-53) the EFS / OS rates of the entire population are 44% / 56%. Outcomes appear especially promising in the DLBCL (EFS / OS, 54% / 54%) and the T-NHL (62% / 69%) subgroups.CONCLUSIONS:GEM/CLO/BU is a new, myeloablative, reduced-toxicity alloSCT regimen with high activity in this population of heavily pretreated and refractory aggressive lymphomas, which warrants further study in disease-specific trials [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

P15.04 A Phase I/IB Trial of Pembrolizumab and Trametinib Focused on Advanced KRAS Mutant Non-Small Cell Lung Cancer

KRAS mutant NSCLC is heterogeneous with differential responses to MEK inhibition and immune checkpoint blockade that may be dependent on: KRAS amino acid substitution, associated co-mutations, smoking status, and tumor mutational burden. Preclinical models suggest sequencing of MEK inhibitor before or after PD-1 blockade differentially modulate the immune microenvironment, impacting anti-tumor activity of PD-1 blockade. This phase 1 study examined intercalated sequencing schemes of the MEK inhibitor trametinib and the PD-1 antibody pembrolizumab with planned dose expansion in KRAS mutant NSCLC. In this phase 1 dose escalation study, patients were treated with concurrent trametinib 1.5 to 2 mg PO daily D1-D10 and pembrolizumab 200 mg IV on a q21day cycle with either lead in trametinib alone for the first cycle (Cohort A) or lead in pembrolizumab alone for the first cycle (Cohort B). Key Eligibility: advanced non-squamous NSCLC with progression (PD) on prior platinum-based chemotherapy, age≥18, ECOG PS≤1, acceptable organ function, no significant autoimmune diseases, measurable disease and controlled brain metastases. Tissue biopsy performed at baseline and optional week 1-2 on treatment for PD-L1 IHC (22C3) and quantitative immunofluorescence for immune cell subsets and next-generation sequencing. Blood at baseline and at serial on-treatment timepoints were collected for ctRNA of PD-L1 and KRAS-mut, and changes in circulating immune cell subsets. T-Cell repertoire and cytokine levels were evaluated by flow cytometry and Luminex. Response was assessed by RECIST 1.1 and toxicity graded by CTCAE v5. Twelve patients enrolled thus far. Key clinical and molecular characteristics: 10 (83%) patients with KRAS mutation (5 p53 and 1 STK11 co-mutation), 1 pt with BRAF non-V600E/K mutation, 10 patients (83%) with smoking history, and 8 (66%) patients had prior immune checkpoint blockade. Baseline PD-L1 (22C3) TPS ranged from 0% to 100%. Five (42%) patients had ≥G3 AEs possibly, probably or definitely related to treatment (1 G5 pneumonitis, 1 G3 retinal detachment, 1 G3 diarrhea, 1 G3 anemia, 1 G3 mucositis). Six patients received trametinib 1.5 mg D1-10 (3 cohort A and 3 cohort B) and 6 patients at 2 mg D1-10 (3 Cohorts A and 3 Cohort B). There was 1 DLT in Cohort A at the 2 mg lead in trametinib dose (G3 mucositis). Eleven patients evaluable for response: (2 PR, 3 SD and 6 PD). One responding patient had progressed on prior nivolumab. 3/6 (50%) patients with lead in trametinib had PFS ≥6 months and 2 of these patients had prior PD-1 blockade. No patients with lead in pembrolizumab had PFS ≥6 months. The study continues to accrue patients at dose level 2 (trametinib 2 mg PO daily with both lead in schemes) with planned expansion cohort in KRAS mutant NSCLC. Results of tissue and blood correlative studies will be presented. Preliminary clinical activity has been observed thus far with trametinib and pembrolizumab, including in a patient with prior treatment on immune checkpoint blockade. The study is currently accruing patients at the highest planned dose levels and a dedicated expansion cohort at the MTD is planned in KRAS mutant NSCLC.

Preliminary Results of a Response-Adapted Study of Ibrutinib and Isavuconazole with Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, Rituximab (TEDDI-R) for Secondary CNS Lymphoma

Background: Secondary CNS B-cell lymphomas (SCNSL) are aggressive lymphomas with a very poor prognosis. Genetic subtypes of DLBCL with CNS tropism are enriched for chronic active B-cell receptor signaling and may respond to BTK inhibition (BTKi). CLL, MCL, and transformed lymphomas can also involve the CNS and are BTKi responsive. TEDDI-R achieves durable remissions in relapsed/refractory primary DLBCL of the CNS (PCNSL) but the profile of SCNSL tumors that are ibrutinib-responsive is unknown. We present preliminary results from a response-adapted trial of ibrutinib with TEDD-R in SCNSL. Methods: Pts with aggressive B-cell lymphomas with secondary CNS involvement are eligible if age ≥18 and adequate organ function. Pts must have relapsed after frontline therapy or can be untreated if brain parenchyma involved. Prior BTKi is allowed, but HIVinfection and EBV+ lymphomas are excluded. Baseline tests include brain MRI, FDG-PET brain and body, CSF with flow cytometry, Ommaya, and eye exam. Pts receive isavuconazole starting at 200mg BID x 3d prior to ibrutinib to prevent fungal infections associated with TEDDI-R and then 200mg daily unless ibrutinib stopped. Pts first receive ibrutinib 560mg daily x 14d in a window. If ≥20% reduction after ibrutinib, pts receive TEDDI-R for 4 cycles every 21d with IT cytarabine. Pts with &amp;lt;20% reduction after ibrutinib receive TEDD-R without ibrutinib for 4 cycles every 21d with IT cytarabine. No consolidation or maintenance is permitted. Surveillance for fungal infections includes chest CT after each cycle along with Beta-D glucan and aspergillus galactomannan in blood and CSF. Brain MRI and CT scans are performed after cycles 1, 2, and 4 to determine response. All remissions by MRI are confirmed with FDG-PET and CSF analysis. Surveillance brain MRI and CT scans are q3m for 1y, q4m x 1y, q6m x 1y, then annually. Results: 16 pts with a median age 67 (range 40-79) enrolled between June 2019 and July 2020. 15 (94%) pts had DLBCL comprising 9 (60%) non-GCB, 5 (33%) GCB, and 1 (7%) transformed from MZL. One pt had plasmablastic lymphoma. Eight (50%) pts had a MYC-rearrangement including 4 (25%) with both MYC and BCL2 or BCL6 rearrangements. Eight (50%) pts had isolated CNS disease and 8 (50%) had synchronous CNS and peripheral disease. All pts relapsed after a median of 2 (range 1-4) prior therapies and all (100%) pts received prior anthracycline. Seven pts (44%) had prior CNS prophylaxis and 8 pts (50%) had prior HD-MTX based salvage therapy. Toxicity was evaluated across 35 cycles. G3 and G4 neutropenia occurred in 49% and 29% of cycles, respectively, while febrile neutropenia occurred in 9% of cycles. The median (range) duration of neutropenia was 6 (1-13) days. Five (14%) cycles were complicated by ≥G3 infection, but no opportunistic infections (including Aspergillus) were observed. One pt developed a bacterial infection during cycle 1 and died. G3 and G4 thrombocytopenia occurred in 34% and 23% of cycles, respectively, and 1 pt developed G3 hematuria. G3 mucositis occurred in 9% of cycles and palmar-plantar-erythrodysesthesia led to dose reductions of liposomal doxorubicin in 5 (36%) pts. Of 15 pts who completed the 14d ibrutinib window and were evaluable, 8 (53%) were ibrutinib-responsive and 7 (47%) were ibrutinib-resistant (Figure 1). Clinical responses were concordant across anatomic compartments; of 8 pts with both CNS and peripheral disease, 5 (63%) responded to ibrutinib in both compartments while 3 (37%) did not respond in either compartment. All 8 ibrutinib responders had a non-GCB phenotype and six (75%) achieved CR. One died of treatment-related toxicity after a PR and 1 is still on therapy. Only two (29%) pts with ibrutinib-resistant tumors achieved PR and none have achieved CR. After a median follow-up of 5.1m, a landmark analysis starting after the ibrutinib window demonstrated the PFS for pts with ibrutinib-responsive compared to ibrutinib-resistant tumors was not reached vs. 0.9m (95% CI: 0.1-2m)(p=0.002)(Figure 2). Conclusions: Patients with SCNSL tumors that are ibrutinib-responsive achieve a high rate of complete response to TEDDI-R in both CNS and peripheral disease. Patients with tumors that are ibrutinib-resistant also respond poorly to TEDD-R. Toxicity is mainly hematologic, and no Aspergillus infections have occurred with the use of isavuconazole prophylaxis. Updated clinical results from this ongoing study (NCT03964090) and will be presented at the meeting. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: ibrutinib for use in secondary cns lymphoma as part of a clinical trial

Phase 1 Study of Escalating Doses of Ibrutinib and Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, Rituximab (TEDDI-R) with Isavuconazole for Relapsed and Refractory Primary CNS Lymphoma

Background: Primary DLBCL of the CNS (PCNSL) relies on chronic active B-cell receptor (BCR) signaling. Ibrutinib targets BCR signaling through BTK inhibition (BTKi), which may also impair innate immunity. We showed that ibrutinib and temozolomide, etoposide, liposomal doxorubicin, dexamethasone, rituximab (TEDDI-R) induces durable remissions in relapsed/refractory PCNSL but 7 (39%) pts developed Aspergillus infections without fungal prophylaxis. Newer triazoles are effective against Aspergillus but inhibit ibrutinib clearance through CYP3A4. Isavuconazole has less effect on CYP3A4 and less hepatotoxicity than voriconazole. We hypothesized that ibrutinib and isavuconazole could be safely co-administered in TEDDI-R and ameliorate the risk of Aspergillus while maintaining efficacy. We studied escalating doses of ibrutinib in TEDDI-R with isavuconazole to determine the safety profile, ibrutinib PK, and clinical activity in relapsed/refractory PCNSL. Methods: Pts with relapsed/refractory PCNSL, age ≥18, ECOG PS ≤2, and adequate organ function were enrolled. Previous BTKi, HIV, EBV+, and pregnancy were excluded. Pts had baseline MRI brain, FDG-PET brain and body, Ommaya placed, CSF with flow cytometry, and eye exam. Isavuconazole 200mg BID x 3d started prior to ibrutinib then 200mg daily. Three dose levels of ibrutinib (280mg, 420mg, 560mg) were given continuously through each cycle. Pts received up to 6 cycles of TEDDI-R with IT cytarabine. No one received maintenance or consolidation. If a DLT occurred in the first 3 pts at a given ibrutinib dose level, 3 more pts were treated before escalating. Full safety and PK data was reviewed after two dose levels prior to escalating. An expansion of 10 pts was planned at the highest ibrutinib dose level to confirm safety and clinical activity. Surveillance for fungal infections included chest CT mid-cycle 1 and after each cycle along with Beta-D glucan and aspergillus galactomannan in blood and CSF. Brain MRI was performed after cycles 1, 2, 4, and 6 to determine response and screen for CNS Aspergillus. All remissions by MRI were confirmed with FDG-PET and CSF analysis. Surveillance brain MRI were q3m for 1y, q4m x 1y, q6m x 1y, then annually. Primary objective was to identify the highest dose of ibrutinib safely co-administered with isavuconazole in TEDDI-R that achieves adequate PK concentrations. Results: 13 relapsed/refractory PCNSL pts enrolled between 11/2018 and 06/2020. 10 (77%) pts were male and the median age was 65 (range 46-77), including 3 pts ≥age 70. 13 (100%) pts had prior high-dose MTX, and 2 (15%) pts had prior autologous stem cell transplant (ASCT). Three evaluable pts received ibrutinib 280mg, 3 pts received ibrutinib 420mg, and 6 pts received ibrutinib 560mg. One pt in the 280mg cohort was not evaluable. Toxicity was evaluated in 13 pts across 49 cycles and the toxicity was mainly hematologic. G3 and G4 neutropenia occurred in 45% and 37% of cycles, respectively, while febrile neutropenia occurred in 8% of cycles. The median (range) duration of neutropenia was 4.5 (1-12) days. One pt with prior ASCT stopped after 4 cycles due to myelosuppression. Four (8%) cycles were complicated by ≥G3 infection, but no opportunistic infections (including Aspergillus) were observed. G3 and G4 thrombocytopenia occurred in 22% and 8% of cycles, respectively, and 1 pt developed melena with no overt GI bleeding. ≥G3 mucositis occurred in 6% of cycles and 1 patient stopped therapy after 5 cycles due to recurrent mucositis. Palmar-plantar-erythrodysesthesia led to dose reductions of liposomal doxorubicin in 9 (69%) pts, but only 1 G3 event occurred. Twelve pts were evaluable for response, and 11 (92%) pts have responded and all after receiving only 1 cycle (Figure 1). All 8 (100%) pts who have completed at least 4 cycles have achieved CR and the other 4 remain on therapy. Six (75%) pts who achieved CR remain in remission while 2 (25%) pts relapsed within 3 months of stopping therapy. After a median potential f/u of 5.2 months, the 1-year PFS is estimated at 60.0% (95% CI, 12.6-88.2) and the OS is 100%. Conclusions: Ibrutinib 560mg was safely co-administered with isavuconazole in TEDDI-R for relapsed/refractory PCNSL. No DLTs were observed, no cases of Aspergillus occurred, and no new safety signals. The first 8 (100%) patients who have completed therapy achieved complete response. Updated clinical results from this ongoing study (NCT02203526) will be presented at the meeting. Disclosures Lai: Abbvie: Consultancy; Agios: Consultancy; Jazz: Speakers Bureau; Macrogenics: Consultancy; Astellas: Speakers Bureau.

The Addition of Ibritumomab Tiuxetan (IT) to the ATG/TLI Preparative Regimen Is Safe and May Enhance Post-Transplant Response and Outcomes for Patients with Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

The Addition of Ibritumomab Tiuxetan (IT) to the ATG/TLI Preparative Regimen Is Safe and May Enhance Post-Transplant Response and Outcomes for Patients with Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

1126P - Treatment outcomes of head and neck cancer patients 70 years and older receiving different chemo-radiation combinations

BackgroundConcurrent chemoradiation (CRT) improves survival in squamous cell carcinoma of the head and neck (HNSCC). Little is known about the outcomes of elderly patients (pts, ≥70 years old) in terms of treatment efficacy and side effects. This retrospective study compares acute toxicity, response to therapy, and overall survival between elderly pts receiving different CRT combinations. MethodsPts. without dementia, deficit on instrumental activities of daily living, Charlson comorbidity index <2, and living at home with a family member received CRT. Pts received one of the following: 1) weekly carboplatin AUC 1 and paclitaxel 30mg/m2 for seven doses (CP), 2) cetuximab loading dose of 400mg/m² followed by 250mg/m² weekly for seven doses (CE), 3) weekly carboplatin AUC 1.5 for seven doses (CB), 4) weekly cisplatin 40mg/m2 for seven doses (CIS). Radiation was administered to a dose of 70Gy as definitive treatment or 66Gy as adjuvant treatment (2Gy/fraction). Results150 pts. (M/F: 111/39) with mean age 74.6 (range 70-88) were identified. 52 pts (34.7%) received adjuvant and 98 (65.3%) definitive CRT. Tumor site: oropharynx 74 (49.5%), oral cavity (17.5%), larynx 14%, others (19%). 60 pts (40%) were p-16 positive. 44 patients (29.5%) received CP, 43 (28.5%) CE 33 (22%) CB, and 30 (20%) CIS. 110 pts (73.5%) had a complete response (CR). 90 pts (60%) were admitted to the hospital during CRT, and pneumonia was the most common diagnosis (59 pts, 39.5%). 98 pts (65.5%) had percutaneous endoscopic gastrostomy tube (PEG) due to G3 mucositis. Two patients (1.3%) experienced G5 cardiovascular toxicity. At 6 months, 38 (25.3%) still had PEG, and was associated with CRT regimen (p=0.001): 6/44(14%) received CP, 22/43 (51%) CE, 4/33 (12%) CB, and 6/30 (20%) CIS. The overall survival at 3 yrs was 60% (95% confidence interval (CI), 52%-71%). The predictors for OS at 3 yrs were response to therapy (CR 78% (68%-88%), and non-CR 17% (7%-37%); P<0.0001), and CRT regimen (CB 41% (25%- 66%) vs others 66%, (57%- 78%); P=0.01). ConclusionsCRT can be administered to a selected elderly population with HNSCC. Single agent CB was associated with worse outcomes. CE seems to be related to a higher rate of long term PEG dependence. Legal entity responsible for the studyThe Ohio State University, James Cancer Hospital and Solove Research Institute. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Abstract CT083: A Phase I/II study of aurora kinase A inhibitor, LY3295668 erbumine (AK-01): Safety as monotherapy in patients with locally advanced or metastatic solid tumors

Abstract Background: LY3295668 erbumine (AK-01) is a selective, reversible, ATP-competitive small molecule inhibitor of aurora kinase A (AurA). LY3295668 erbumine treatment in xenograft and patient-derived xenograft models resulted in tumor growth arrest or regression of several tumor types with an acceptable safety profile. This study evaluated dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and safety of LY3295668 erbumine monotherapy in patients with locally advanced or metastatic solid tumors. Methods: This ongoing phase I/II, open-label, multicenter study enrolled patients with locally advanced or metastatic solid tumors, ECOG PS 0-1, estimated life expectancy ≥ 12 weeks, adequate organ function, disease progression after 1 - 4 regimens for locally advanced or metastatic disease and no history of clinically significant cardiac disease. The primary objective was to determine MTD; secondary objectives included evaluation of tolerability and overall safety profile of LY3295668 erbumine. All patients received oral, twice daily (BID) doses of LY3295668 erbumine in cycles of 21 days in a multiple ascending dose schedule. Adverse events (AEs) were graded per NCI CTCAE v4.03. Results: Twelve patients median age of 60 (range 39-74, 5 male and 7 female) were enrolled in the phase I study at the following dose levels: 25 mg (n=8); 50 mg (n=2); 75 mg (n=2). One patient in the 25 mg cohort experienced a DLT of grade (G) 3 mucositis. One patient in the 50 mg cohort experienced a DLT of G3 mucositis and G3 diarrhea. Both patients in the 75 mg cohort experienced DLTs (1=G3 mucositis, 1=G4 mucositis and G3 corneal deposits). The treatment-related AEs (TRAEs) observed in each cohort were as follows: in the 25 mg treatment group, six patients experienced various G1/2 TRAEs with only mucositis reported in &amp;gt; one patient (n=2); G3 TRAEs were anemia (n=1) and mucositis (n=1). In the two patients receiving 50 mg, G3 TRAEs were: mucositis (n=1), diarrhea (n=1), and upper chest rash (n=1). In the two patients receiving 75 mg, G3/4 TRAEs were: mucositis (n=2), corneal deposits (n=1), neutropenia (n=1) and diarrhea (n=1). There were no treatment-related deaths. During this study, three patients died due to disease progression: one patient died &amp;lt; 30 days and two patients died &amp;gt; 30 days after the last treatment dose. At the time of data lock, two of the eight patients in the 25 mg BID phase I cohort remained on treatment for ≥ 8 months. In addition to the 12 patients in phase I, one patient was enrolled in phase II after the MTD was determined, totaling 13 patients who received treatment in the entire study. Conclusion: The MTD of LY3295668 erbumine was determined to be 25 mg BID and found to be well tolerated in patients with locally advanced or metastatic solid tumors. Trial Registration: NCT03092934 Citation Format: Quincy Chu, Nathaniel Bouganim, Caroline Fortier, Sara Zaknoen, John R. Stille, Jill D. Kremer, Eunice Yuen, Yu-Hua Hui, Amparo de la Peña, Andrew Lithio, Patricia S. Smith, Gerald Batist. A Phase I/II study of aurora kinase A inhibitor, LY3295668 erbumine (AK-01): Safety as monotherapy in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT083.

Final Results of Phase I/II Study of Selinexor (SEL) with Sorafenib in Patients (pts) with Relapsed and/or Refractory (R/R) FLT3 Mutated Acute Myeloid Leukemia (AML)

Final Results of Phase I/II Study of Selinexor (SEL) with Sorafenib in Patients (pts) with Relapsed and/or Refractory (R/R) FLT3 Mutated Acute Myeloid Leukemia (AML)