First Cycle Of Therapy Research Articles

CTNI-70. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA

Abstract BACKGROUND Mirdametinib is an investigational, oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration. We hypothesized that mirdametinib would benefit patients with pediatric low-grade gliomas (pLGG) and launched SJ901 (NCT04923126) to determine the recommended Phase 2 dose (RP2D), safety, and efficacy. METHODS For Phase 1 and Phase 1 expansion patients were required to be ≥2 and <25 years-old, MEKi-naive, and have recurrent/progressive pLGG with biopsy-proven MAPK pathway activation (except BRAF V600). Three dose levels (DL1: 2 mg/m2/dose BID, DL2: 2.5mg/m2/dose BID, DL3: 3mg/m2/dose BID administered continuously in 28-day cycles) were evaluated with an expansion cohort to assess the highest tolerated dose level in a total of 12 patients. RP2D was defined as the dose causing ≤3 dose-limiting toxicities (DLTs) in 12 patients within the first cycle of therapy. RESULTS Between June 2021 and December 2023, 23 patients enrolled (DL1=5, DL2=6, and DL3=12). Median age was 8.4 years (2.5-21.9); 52% female. Alterations were seen in BRAF (n=12;52%), FGFR1 (n=5;22%), NF1 (n=3;13%), RAF1 (n=2;9%), and MYB (n=1;4%). The median follow-up time was 14.6 months (3.2-27.8). One DLT was observed (grade-3 thrombocytopenia). Seventeen (74%) patients completed or remain on-therapy; 4(17%) stopped for progression (2 FGFR1; 1 MYB; 1 BRAF); 2 discontinued for toxicities [1 grade-2 rash; 1 grade-4 creatine phosphokinase (CPK) elevation]. Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity was observed. Twelve (63%) of 19 patients with measurable tumors achieved an objective response (1 major, 6 partial, 5 minor). The median time to ≥ minor response was 5.4 months (1.7-7.3). DL3 (3 mg/m2/dose BID) was declared the RP2D. CONCLUSIONS Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish safety and efficacy in newly diagnosed, recurrent/refractory tumors, and in patients with prior MEKi exposure.

Necrotizing Laryngitis in Patients with Hematologic Disease: The First Case-Report Due to PDR Acinetobacter baumannii and Literature Review.

Immunocompromised patients with hematologic diseases may experience life-threatening infections with rather uncommon manifestations. Laryngitis has been described as a potential infection in such vulnerable patients and may result in major complications, ranging from impending airway obstruction to total laryngeal necrosis. Immediate laryngoscopy is of paramount importance, as it provides quantification of laryngeal edema and evidence of necrosis. Documentation of the causative pathogen is usually feasible through tissue culture. In the literature, 14 cases of necrotizing laryngitis have already been published. Here, we present the case of a 38-year-old male with a recent diagnosis of multiple myeloma, who received the first cycle of therapy a few days before admission. The patient presented with neutropenic fever, diarrhea, and multiple organ dysfunction. His course was complicated with hemophagocytic lymphohistiocytosis and stridor. A diagnosis of necrotizing laryngitis attributed to Acinetobacter baumannii invasion of the larynx was established. This manuscript highlights that the management of patients with hematologic disease and necrotizing laryngitis should be coordinated in highly specialized centers and clinicians should have a high level of clinical suspicion and act promptly.

LGG-53. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA

Abstract BACKGROUND Mirdametinib is an investigational, oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration. We hypothesized mirdametinib would benefit patients with pediatric low-grade gliomas (pLGG) and launched SJ901 (NCT04923126) to determine the recommended Phase 2 dose (RP2D), safety, and efficacy. METHODS Phase 1 required patients to be >2 and <25 years-old, MEKi-naive, and have recurrent/progressive pLGG with biopsy-proven MAPK pathway activation (except BRAF V600). Three dose levels (DL1: 2 mg/m2/dose BID, DL2: 2.5mg/m2/dose BID, DL3: 3mg/m2/dose BID administered continuously in 28-day cycles) were evaluated with an expansion cohort planned to evaluate the highest tolerated dose level in a total of 12 patients. RP2D was defined as the dose causing ≤3 dose-limiting toxicities (DLTs) in 12 patients within the first cycle of therapy. RESULTS Between June 2021 and December 2023, 23 patients enrolled (DL1=5, DL2=6, and DL3=12). Median age was 8.4 years (2.5-21.9); 52% female. Alterations were seen in BRAF (n=12;52%), FGFR1 (n=5;22%), NF1 (n=3;13%), RAF1 (n=2;9%), MYB (n=1;4%). The median time of follow-up was 14.6 months (3.2-27.8). One DLT was observed (grade-3 thrombocytopenia). Seventeen (74%) patients completed or remain on therapy; 4 (17%) stopped for progression (2 FGFR1; 1 MYB; 1 BRAF); 2 discontinued for toxicities [1 grade-2 rash; 1 grade-4 creatine phosphokinase (CPK) elevation]. Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity was observed. Twelve (63%) of 19 patients with measurable tumors achieved an objective response (1 major, 6 partial, 5 minor). The median time to ≥ minor response was 5.4 months (1.7-7.3). DL3 (3 mg/m2/dose BID) was declared the RP2D. CONCLUSIONS Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish safety and efficacy in newly diagnosed, recurrent/refractory tumors, and in patients with prior exposure to MEKi.

Correlations between first cycle toxicity and overall survival in patients with rare cancers treated with immune checkpoint inhibitors (NCI/SWOG S1609).

2655 Background: Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity incidence and overall survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers to evaluate associations between irAEs and overall survival (OS) and progression-free survival (PFS) in a cohort of patients treated with combination checkpoint inhibitor therapy. Methods: We evaluated irAEs observed in the first cycle (6 weeks) of therapy that were possibly, probably, or definitely related to treatment; irAE grade was based on CTCAEv5. Patients received ipilimumab [1mg/kg intravenously (IV) every 6 weeks] plus nivolumab (240mg IV every 2 weeks). Landmarks methods were used to avoid immortal-time bias; PFS and OS were analyzed from day 43 with patients who died or progressed before that date excluded from analyses. Cox regression analyses were used to evaluate covariate associations. Results: We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer OS (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p<0.001) compared to no treatment-related irAE in the first cycle, while grade 3-4 irAEs were associated with shorter OS (HR=1.41, 95% CI=1.04-1.90, p=0.025). Similar, but weaker, associations were observed with PFS, grade 1-2 treatment-related irAEs: HR=0.83, 95% CI=0.67-1.01, p=0.067 and grade 3-4: HR=1.35, 95% CI=1.02-1.78, p=0.037 compared to no treatment-related irAE in the first cycle. Grade 1-2 dermatologic toxicity were associated with improved OS compared to other grade 1-2 toxicities (HR=0.67, 95% CI=0.52-0.85, p=0.002). There were no significant differences between OS among patients with Grade 1-2 gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities and fatigue and other Grade 1-2 toxicities. Conclusions: In this large cohort of patients with rare tumors receiving ipilimumab and nivolumab grade of irAE in the first cycle of therapy was prognostic for survival.

Clinical outcomes of patients receiving venetoclax and hypomethylating agents for AML in academic and academic-community partnerships.

e23235 Background: Prior studies have reported improved outcomes for acute myeloid leukemia (AML) in academic over nonacademic settings potentially due to the availability of multidisciplinary teams, clinical trials and increased resources (1,2). Our institution has partnered with community practices to further evaluate this disparity. In this study, we analyzed treatment outcomes when nonacademic centers partnered with academic centers to treat AML using a regimen of venetoclax and a hypomethylating agent. Methods: We reviewed 92 patients with newly diagnosed AML treated with venetoclax and either decitabine or azacitidine at an academic center (n = 57) or community practice with academic center support (n = 35). When partnering with the community, patients received the first cycle of therapy at an academic center. Before discharge, our team completed financial screening, scheduled follow up appointments and provided prescriptions. The primary objective was to evaluate the overall response rate (ORR) with a secondary evaluation of differences in chemotherapy management and complications. Results: Patients in the academic setting tended to have more adverse risk disease (80.7% vs. 74.3%, p = 0.36) according to the European LeukemiaNet (ELN) (table). The overall survival (OS) of all patients was 10.7 months (95% CI 9.4-15.7) with no significant difference between the groups. The ORR was similar between the community and academic settings (40.0% vs. 36.8%, p = 0.46). The complete remission (CR) rate was 11.4% in the community versus 19.3% in the academic setting (p = 0.67), and the CR rates were improved in the academic group versus the community after cycle 2 (12.9% vs. 0%, p = 0.72) and cycle 3 (25.0% vs. 0%, p = 0.46). Adverse events were comparable, except for increased rates of fatigue (80.7 vs. 54.3%, p = 0.01) and diarrhea (33.3 vs. 11.4%, p = 0.04) in the academic setting. Conclusions: Contrary to prior studies, our evaluation and ongoing partnerships support the transition of AML treatment to a community setting with academic consultation. Although there were some differences in adverse events, the OS and ORR were similar. Furthermore, this study did not identify any significant safety concerns that could prevent patients from receiving this regimen in either setting. Our goal is to continue evaluating this partnership, as we design prospective studies to improve the care of this patient population. 1. Giri S et al. OS of AML Treated at Academic Center Vs Nonacademic Center. Blood 2015. 2. Halpern AB et al. Practice patterns & outcomes for adults with AML. Hematol Am Soc 2020.[Table: see text]

Long-term Survival in a Patient With Transformation of Waldenström's Macroglobulinemia into DLBCL.

Waldenström's macroglobulinemia (WM) is a rare slow-growing B-cell lymphoma that is characterized by lymphoplasmacytic bone marrow infiltration and the production of monoclonal immunoglobulin M (IgM) paraprotein. In 5-10% of patients, WM undergoes transformation into diffuse large B-cell lymphoma (DLBCL), which is more aggressive, with poor prognosis and a low survival rate. Α 69-year-old woman was diagnosed with WM in 2009. She received six cycles of chemoimmunotherapy and a remarkable remission was achieved. However, in 2013 the disease transformed into DLBCL. The patient received chemotherapy and after the completion of the first cycle of therapy, the disease was significantly minimized. At the end of the therapy, there was no evidence of disease, and the patient remains disease-free. The cytogenetic profile of the patient did not reveal expression of BCL2 apoptosis regulator, BCL6 transcription repressor, Epstein-Barr virus small RNA, syndecan 1 nor cyclin D1. According to a staging system based on the platelet count, lactate dehydrogenase and previous treatment for WM, the described patient was classified as being at intermediate risk with an expected 2-year survival probability of 47% after WM transformation into DLBCL. However, the patient unexpectedly exceeded these prognostic indications. The findings for this patient are of great interest compared with the existing literature which suggests that the survival and prognosis for patients with transformed DLBCL are not favorable.

Abstract PR013: First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer

Abstract Background Glutathione S-transferase Pi (GSTP) has an important role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function which regulates key oncogenic pathways such as the KRAS and JNK. Since alternative or redundant pathways could compensate for the inhibition of a single kinase, targeting multiple pathways could lead to more effective therapy. NBF-006 is a novel drug product comprised of GSTP siRNA encapsulated within a proprietary lipid nanoparticle. It is designed to deliver siRNA to localized and metastatic lung tumors. As GSTP downregulation leads to inhibition of KRAS signaling through modulation of both MAPK and PI3K pathways, NBF-006 is being developed to treat KRAS mutant tumors. NBF-006-001 is a first-in-man dose escalation (Part A) and expansion (Part B) study evaluating safety, tolerability, PK, and preliminary efficacy of NBF-006 administered intravenously over 70 minutes, QW4 followed by a 2-week rest period. Part A of the study enrolled 21 patients with advanced non-small cell lung cancer (NSCLC), pancreatic, or colorectal cancer. No DLTs or treatment-related SAEs were observed. NSCLC disease control rate of 55% (6/11) was observed in heavily pre-treated patient population, warranting further investigations. Results from advanced KRAS-mutated NSCLC patients enrolled in NBF-006-001 are reported here. Results Thirty-four KRAS-mutated NSCLC patients received treatment at 0.6 mg/kg [n=12], 1.2 mg/kg [n=11], or 1.6 mg/kg [n=11]. NBF-006 was well tolerated with no treatment-related grade 4-5 AEs, SAEs, or DLTs. Two grade 3 events were assessed as possibly related to study treatment, anemia and bilateral pleural effusions (both at 0.6 mg/kg). The most common (>10 % of patients) NBF-006-related AEs were Grade 1 or 2 infusion related reactions (low grade IRRs) (20.6 %) and nausea (11.8 %). There was no dose relationship in the number of AEs or any observed AEs. Low grade IRRs (n=8 in seven patients), occurred in the first cycle of therapy and were generally well-managed. Only one patient discontinued study therapy due to recurring IRR. Substantial cytokine elevation was only noted in this patient. No clinically meaningful complement activation nor ADA response has been observed. PK analysis indicated a mean terminal half-life of 41 (± 13) hours with no accumulation. Cmax and AUC demonstrated dose-proportionality up to 1.2 mg/kg and no apparent increase in exposure at 1.6 mg/kg. Patients had received 1-7 prior lines of therapy (average 2.6; 1 line [n=10], 2 lines [n=9], and ≥ 3 lines [n=15] respectively). Two patients (treated at 1.2 and 1.6 mg/kg) experienced a durable PR, 14 patients experienced SD. One patient with PR and one patient with a mixed response stayed on study for >12 months. Conclusion The expansion part of the NBF-006-001 study confirmed the favorable safety profile of NBF-006 and demonstrated early signs of antitumor activity in KRAS-mutated NSCLC. The results suggest that further clinical development of NBF-006, alone or in combination with standard therapy, is warranted. Citation Format: Hirva Mamdani, Alberto Chiappori, Lyudmila Bazhenova, Alexander Spira, Wade Iams, Minal Barve, Anthony W Tolcher, Eli Gabayan, Andrae Vandross, Annie Huynh, Yael Cohen-Arazi, Zachary Albaugh, Joachim Gullbo, Sonya Zabludoff. First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR013.

Preliminary Results from a Phase 1/2 Study of Liposomal Annamycin (L-ANN) in Combination with Cytarabin for the Treatment of Patients with Acute Myeloid Leukemia (AML) That Is Refractory to or Relapsed (r/r) after Induction Therapy

Background: Anthracylines still remain the backbone for the treatment of patients with acute myeloid leukemias (e.g., “7 + 3”), however, the dose escalation is impeded by a significant cardiotoxicity of these compounds. The design of the novel liposomal L-annamycin (L-ANN) was the replacement of a basic amine at the C-3' position with a hydroxy group, which was shown to significantly reduce cardiotoxicity when compared with doxorubicin. Moreover, this modification not only decreased cardiotoxicity, but also led to increased activity against mdr-1 tumors. In addition, L-ANN was found to be a TOPO-II poison, and it has been hypothesized that the drug may not alter TOPO-IIβ, an isoform which is known to be a key pathway involved in anthracycline-induced cardiotoxicity. However, this hypothesis has not yet been confirmed experimentally. L-ANN as a monotherapy has been evaluated in r/r AML patients and demonstrated an ORR of 80% (240 mg, administered on three consecutive days, MB-105, NCT03388749, Gil et al. 2023) with no sign of cardiotoxicity noted in any patient. L-ANN is currently being evaluated in a phase 1b/2 study in combination with cytarabine for the treatment of AML (MB-106; NCT05319587). Study Design: MB-106 (NCT05319587) is aphase 1/2, multi-center, open-label, dose-escalation study to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of L-ANN in combination with cytarabine in adult r/r AML patients after induction therapy. Approximately 63 subjects will be enrolled, including up to 42 in the dose escalation phase, and up to 21 in the phase 2 expansion at the established recommended phase 2 dose (RP2D). The dose escalation phase of the study has explored 2 dose levels of L-ANN with a starting dose of 190 mg/m 2/day and 230 mg/m 2/day for 3 consecutive days. All patients will also receive cytarabine 2.0 g/m 2/day for 5 consecutive days starting on the first day of L-ANN treatment. The primary objectives of the phase 1b portion of the study are to evaluate the safety and identify the RP2D of L-ANN in combination with a standard regimen of cytarabine. Routine safety monitoring including ECHOs, ECGs, GLS measurements, cardiac biomarkers, laboratory evaluations, and bone marrow assessments (BMA) will be performed. Secondary objectives include CR/CRi and mOS. Dose escalation was halted after the 230 mg/m 2/day cohort due to the safety and efficacy data identifying this as the RP2D. Results: To date, 6 patients have completed therapy cohort 1 (n=3) and cohort 2 (230 mg/m 2/day, n=3) with no dose limiting toxicities (DLTs) noted. Prescheduled interim reviews of the data took place after completion of each dosing cohort. In the first cohort one patient achieved a CR following the first cycle of therapy which continued to exhibit durability at 5 months. In the second cohort one patient achieved a CRi and two patients showed progression. In light of the safety and efficacy data from this trial and the prior MB-105 trial, the current study has begun to expand enrollment of up to 21 additional patients at the 230 mg/m 2 L-ANN level to quantify efficacy. Conclusion: Initial data suggested that L-ANN is safe and active in heavily pretreated r/r AML patients with no signs of cardiotoxicity. This study is currently being conducted in Europe across 5 sites in Poland and 3 in Italy. Results from the Phase 2 portion of this study will be presented at the meeting.

“Dose-Dense” Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab Achieves High Rates of Rapid MRD-Negativity in Patients with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia: A Retrospective Analysis

Background: Mini-hyper-CVD plus inotuzumab ozogamicin (InO) followed by sequential blinatumomab (Blina) is effective in both older adults with newly diagnosed B-cell ALL and in relapsed/refractory disease. We hypothesized that concomitant administration of these agents in a “dose-dense” (DD) fashion would also be safe and effective in B-cell acute lymphoblastic leukemia (ALL), leading to rapid measurable residual disease (MRD) negativity. Methods: This is a retrospective analysis of patients (pts) with B-cell ALL who received DD mini-hyper-CVD + InO + Blina outside of a clinical trial. All pts received mini-hyper-CVD alternating with mini-methotrexate and cytarabine in combination with InO. To be evaluable for this analysis, Blina must have started prior to day 21 of the first cycle of therapy. Pts were included if they received this regimen for 1.) frontline induction, 2.) treatment of MRD-positive remission, or 3.) salvage therapy for relapsed/refractory (R/R) disease. Results: Between 7/2020 and 1/2023, 21 eligible pts were treated (Table 1 ). The median age was 48 years (range, 6-74 years); 3 pts (all in the R/R cohort) were <18 years old. 9 pts (43%) were treated as frontline therapy, 4 (19%) for treatment of MRD (3 for flow-positive MRD and 1 for persistent FISH for t[4;11]), and 8 (38%) for R/R disease. In the MRD cohort, 3 pts were in first CR and 1 was in second CR; 1 pt received prior InO and 1 had prior allogeneic stem cell transplant (alloSCT). In the R/R cohort, pts were heavily pretreated, with a median number of prior therapies of 3 (range, 1-7); 2 pts received prior InO, 3 pts received prior Blina, 3 pts had undergone prior allo SCT, and 3 pts had received prior chimeric antigen receptor T-cell (CAR-T cell) therapy. Three pts (all in the R/R cohort) had extramedullary (EM) disease, 2 outside of the CNS without marrow disease and 1 with CNS disease and bone marrow MRD by flow. Pts received a median of 2 cycles (range, 1-5) of a dose-dense regimen. All pts received 0.9 mg/m 2 InO in cycle 1, except for 1 pt in the R/R cohort who received 0.6 mg/m 2 due to myelosuppression with prior InO. Themedian cumulative dose of InO was 1.2 mg/m 2 (range, 0.6-2.7 mg/m 2). Blina was started on a median of day 4 (range, day 4-17) of the first cycle of chemotherapy. Blina was started by day 7 in 16 pts (76%). In the frontline cohort, all pts (100%) achieved CR/CRi (CR in 8 pt and CRi in 1 pt), all after cycle 1 ( Table 2). All pts in the frontline cohort achieved flow MRD negativity. 7 pts were evaluable for bone marrow next generation sequencing (NGS) MRD (sensitivity 10 -6). Of these, 4/6 (67%) achieved NGS MRD negativity after cycle 1, and all 7 evaluable pts (100%) achieved NGS MRD negativity. In the MRD cohort, all 3 flow-positive pts became flow MRD negative after cycle 1; the pt with positive FISH for t(4;11) became FISH-negative after cycle 2. 3 of the 4 pts in the MRD cohort (75%) became NGS MRD negative. Overall, 5 of the 8 pts (63%) in the R/R cohort achieved CR/CRi. Among 5 evaluable pts in the R/R cohort with marrow disease (including the pt with CNS disease and MRD-positive marrow), all achieved flow MRD negativity after cycle 1. Overall, 7 pts (33%) underwent consolidative alloSCT (2 in the MRD cohort and 5 in the R/R cohort), and 1 pt in the MRD cohort underwent consolidative CAR-T cell therapy. The treatment regimen was well tolerated. No patients developed sinusoidal obstruction syndrome/veno-occlusive disease. One pt had grade 1 CRS, and 2 pts had grade 1 tremor. With a median follow-up of 13.4 months (range, 0.5-20.6 months), 6 pts (29%) have died (1 in the frontline cohort, 1 in the MRD cohort and 4 in the R/R cohort). 3 deaths were due to complications of alloSCT, 2 were due to sepsis (1 in the setting of refractory leukemia and 1 during MRD-negative CR), and 1 from unknown cause. Among 18 responding pts, only 1 pt relapsed; the pt with MRD-positive t(4;11) by FISH relapsed 4.5 months after alloSCT. The median OS for the R/R cohort was 5.8 months and was not reached for the frontline or MRD cohorts. The 1-year OS rate for the frontline + MRD cohort was 83%. Conclusion: Dose-dense mini-hyper-CVD in combination with InO and Blina achieves rapid MRD-negative remissions in patients with B-cell ALL. All responding patients achieved flow MRD negativity after 1 cycle of therapy, with the majority also achieving NGS MRD negativity. This regimen is now being prospectively evaluated in an ongoing clinical trial in pts with R/R B-cell ALL and in older adults with newly diagnosed B-cell ALL.

Frequency and Outcomes of Obinutuzumab-Induced Thrombocytopenia

Introduction Obinutuzumab (Obi) is a third-generation anti-CD20 monoclonal antibody widely used in the treatment of B-lymphoproliferative disorders (B-LPD) including follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). It is infrequently associated with severe thrombocytopenia which can be life-threatening. The pathophysiology is unclear, but platelet clearance can be extremely rapid (<24 hours). Methods After obtaining local ethics review, we collected the total number of patients who received Obi as part of multi-agent chemotherapy for the following hematological diseases from 01/01/2015 -01/01/2023: FL (Obi-bendamustine +/- Obi maintenance; Obi-cyclophosphamide/vincristine/prednisone +/-doxorubicin +/- Obi maintenance, Obi-Zanubrutinib (Rosewood trial) and CLL (Obi-venetoclax; Obi-chlorambucil). All cases of clinically suspected Obi-induced thrombocytopenia were reviewed and presented below. All suspected cases were confirmed by evidence of temporal relationship with Obi, spontaneous resolution off Obi, and recapitulation with Obi rechallenge. Results Four out of 147 patients receiving Obi-based multi-agent chemotherapy were found to have Obi-induced thrombocytopenia (frequency 2.7%). Two patients were females (50%), and the median age was 78 (range, 72-82) years. Figure 1 demonstrates the trend of platelet and neutrophils in a patient who received Obi and venetoclax (Ven). Ven was postulated as the cause of the thrombocytopenia, but Ven cessation had no effect on the thrombocytopenia. After suspending Obi, there was a steady increase in the platelet count to 104 x 10 9/L. Obi was re-commenced at cycle 7 (eighth dose) which was followed by a prompt relapse to 4 x 10 9/L 48 hours later. A steady recovery in the platelet count was again seen after ceasing Obi. The other 3 patients received Obi-bendamustine for FL. For the first patient, thrombocytopenia occurred on day 7 of first cycle (41 x 10 9/L) with a nadir of 14 x 10 9/L on day 11. She received intravenous immunoglobulin (IVIg) and oral corticosteroids due to associated bleeding. The second patient had thrombocytopenia on day 28 of the first cycle (71 x 10 9/L) which decreased to a nadir 13 x 10 9/L while receiving Obi-maintenance. There was no bleeding and Obi was ceased followed by a gradual improvement in thrombocytopenia. For the third patient, thrombocytopenia (41 x 10 9/L) occurred on day 18 of first cycle without bleeding. Obi was changed to rituximab. Discussion This is the first known study on the frequency of Obi-induced thrombocytopenia (2.7%). Obi-associated thromboctopenia is severe, sudden-onset, not exclusive to the first cycle of therapy, and the mechanism remains unknown. The diagnosis may be challenging as patients are often receiving other myelosuppressive therapies. Various strategies may help to elucidate the cause, including correlation with timing of exposure and single agent elimination. Suspension of Obi on suspicion is both an important diagnostic and therapeutic strategy. Obi rechallenge can be considered however thorough patient discussion is required with close monitoring and strategies to manage thrombocytopenia. In multi-agent chemotherapy studies containing Obi, severe thrombocytopenia of any cause occurred in up to 13% of cases including fatal hemorrhage. The optimal management is unclear. As our cases demonstrate, thrombocytopenia may resolve spontaneously after withdrawing Obi. Analogous to ITP, steroids, and intravenous immunoglobulin (IVIg) have been associated with response whereas platelet transfusions may be ineffective. Two recent cases with severe thrombocytopenia were treated with thrombopoietin receptor agonist (TPO-RA). Other important considerations are regular blood count monitoring and withholding medications which may increase bleeding risk (e.g., anticoagulants) especially during the first cycle. Summary Obi is prevalent in the treatment of B-LPD, being used in 6 different regimens in local guidelines. However, clinicians need to be aware of the risk of thrombocytopenia which may be severe. The frequency was 2.7% in this single-center retrospective audit. Correlation with timing of exposure is important. The optimal management is unclear. It may be self-limiting whereas some cases have been treated with steroids, IVIg, and TPO-RA. Further studies are required to delineate the incidence, pathophysiology, diagnosis, and management.

SPECT at the speed of PET: a feasibility study of CZT-based whole-body SPECT/CT in the post 177Lu-DOTATATE and 177Lu-PSMA617 setting.

To evaluate the feasibility of using the StarGuide (General Electric Healthcare, Haifa, Israel), a new generation multi-detector cadmium-zinc-telluride (CZT)-based SPECT/CT, for whole-body imaging in the setting of post-therapy imaging of 177Lu-labeled radiopharmaceuticals. Thirty-one patients (34-89 years old; mean ± SD, 65.5 ± 12.1) who were treated with either 177Lu-DOTATATE (n=17) or 177Lu-PSMA617 (n=14) as part of standard of care were scanned post-therapy with the StarGuide; some were also scanned with the standard GE Discovery 670 Pro SPECT/CT. All patients had either 64Cu-DOTATATE or 18F-DCFPyL PET/CT prior to first cycle of therapy for eligibility check. The detection/targeting rate (lesion uptake greater than blood pool uptake) of large lesions meeting RECIST 1.1 size criteria on post-therapy StarGuide SPECT/CT was evaluated and compared to the standard design GE Discovery 670 Pro SPECT/CT (when available) and pre-therapy PET by two nuclear medicine physicians with consensus read. This retrospective analysis identified a total of 50 post-therapy scans performed with the new imaging protocol from November 2021 to August 2022. The StarGuide system acquired vertex to mid-thighs post-therapy SPECT/CT scans with 4 bed positions, 3 min/bed and a total scan time of 12 min. In comparison, the standard GE Discovery 670 Pro SPECT/CT system typically acquires images in 2 bed positions covering the chest, abdomen, and pelvis with a total scan time of 32 min. The pre-therapy 64Cu-DOTATATE PET takes 20 min with 4 bed positions on GE Discovery MI PET/CT, and 18F-DCFPyL PET takes 8-10 min with 4-5 bed positions on GE Discovery MI PET/CT. This preliminary evaluation showed that the post-therapy scans acquired with faster scanning time using StarGuide system had comparable detection/targeting rate compared to the Discovery 670 Pro SPECT/CT system and detected large lesions defined by RECIST criteria on the pre-therapy PET scans. Fast acquisition of whole-body post-therapy SPECT/CT is feasible with the new StarGuide system. Short scanning time improves the patients' clinical experience and compliance which may lead to increased adoption of post-therapy SPECT. This opens the possibility to offer imaged-based treatment response assessment and personalized dosimetry to patients referred for targeted radionuclide therapies.

Septic Shock and Septic Shock Mortality in Relation to Social Disorganization Index Among Children Being Treated for De Novo Acute Myeloid Leukemia on COG Clinical Trials

Introduction: Acute myeloid leukemia (AML) requires intensive chemotherapy that increases the risk of life-threatening complications such as septic shock (SS). The relationship between social determinants of health (SDOH) and risk of developing SS in children with AML is not well understood. We previously identified associations between race-ethnicity and public insurance and risk of SS in children receiving treatment for acute leukemias (PBC 2019 10.1002/pbc.27713 #2024). To explore this further, we examined associations between the Social Disorganization Index (SDI), an area-based composite measure of SDOH domains, and time to SS and SS-associated mortality (SS-mortality). We hypothesized that higher social disorganization is associated with decreased SS-free survival and higher SS-mortality. Methods: We used a previously assembled cohort of children with de novo AML treated on two Children's Oncology Group (COG) clinical trials merged with daily resource utilization data from the Pediatric Health Information System database (PHIS; PLOS One 2015 10:e0143480). We used the SDI (Health & Place 2017 10.1016/j.healthplace.2016.12.004) to characterize patients’ relative exposure to adversity across SDOH domains. The SDI was calculated using the American Community Survey 5-year estimates and the US Census Bureau's 5-digit national ZIP Code Tabulation Area-level data and linked to patients’ 5-digit ZIP code recorded on first admission. SDI is calculated as the sum of the following proportions: overall unemployment, households receiving public assistance, low-income households at <100% and at 100-149% poverty level, high school dropouts, female-headed households, renter-occupied houses, and moved households within the last year. Higher SDI values indicate a more disorganized neighborhood. To define their exposure to neighborhood disorganization, patients were grouped into one of 5 categories (from least to most disorganized) based on their nationally normed SDI. We used our previously developed and validated method to detect SS events in PHIS (PBC 2019 10.1002/pbc.27713 #2024) and used COG data for patient and disease characteristics and for treatment data. Our secondary outcome, SS-mortality, was defined as death within 2 weeks of antecedent SS event (Lancet Oncol. 2015 10.1016/S1470-2045(15)00197-7). Follow-up started 7 days from first chemotherapy until observed end of therapy to capture treatment-associated SS events. Patients were censored at relapse or death for the time to SS analysis. Time to first SS was summarized using Kaplan Meier estimates. Cox regression models were used to estimate unadjusted hazard ratios (HR) and associated 95% confidence intervals (CI) of SS outcome by SDI category. Results: We identified 701 COG-PHIS patients with AML who had at least 7 days of protocol therapy. Most patients were from SDI category 5 (highest disorganization; Table 1). Patients in higher SDI categories were more likely to be Hispanic or non-Hispanic Black and have public insurance compared to those in the lowest categories. There were 201 (28.7%) incident SS events observed during protocol therapy, which occurred a median of 78 days (IQR 34-122) from start of therapy. We found no significant difference in time to incident SS between SDI categories (log rank p=0.67) or in unadjusted HR for SS events among the SDI categories (Figure 1). Among patients who had SS events, 9 (4.4%) experienced SS-mortality, of which 8 (88.9%) were in higher disorganization categories (SDI 4 or 5). Seven (77.7%) patients who experienced SS-mortality were non-Hispanic White, 6 (66.7%) were female, and 6 (66.7%) had private insurance. SS-mortality occurred a median of 42 days (IQR 15-167) from start of therapy. Five (56%) of the 9 SS-mortality events occurred in cycle 1, 1 (11%) occurred in cycle 2, 3 (33%) occurred in either cycle 4 or 5. Conclusion: In our unadjusted model, neighborhood disorganization was not significantly associated with time to SS. Almost 90% of SS-mortality occurred among patients exposed to higher disorganization neighborhoods (SDI 4 or 5). Over half of SS-mortality occurred with the first cycle of therapy, suggesting a need to investigate associations between the SDI, severity at presentation, and AML induction mortality (Am J Hematol. 2017 10.1002/ajh.24605). We are designing multivariable-adjusted models to address potential confounding and competing risk analyses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Time to Count Recovery after Post-Remission Chemotherapy in AML Patients

Background Longer time to achieve complete remission (CR) and recover counts after initial induction chemotherapy in acute myeloid leukemia (AML) patients is associated with decreased overall survival (OS) and relapse-free survival. Prolonged time to count recovery is associated with increased risk of infection and bleeding, and can result in delay of planned subsequent therapies including further chemotherapy or allogeneic transplant. While CR with count recovery after induction chemotherapy typically occurs within 4-5 weeks, there is a paucity of data for count recovery after post-remission (also known as consolidation) chemotherapy. We sought to investigate the time to neutrophil and platelet recovery after the first cycle of consolidation chemotherapy and thereby to identify optimal post-remission chemotherapy regimens. Methods We retrospectively identified adults over 18 years with newly diagnosed WHO-defined AML/high grade myeloid neoplasms (>10% blasts) who received high intensity induction chemotherapy (cladribine, cytarabine, mitoxantrone, and G-CSF, also known as CLAG-M or GCLAM) between 5/1/2014 and 12/31/2019. Patients with variations to the CLAG-M backbone such as sorafenib, midostaurin, gemtuzumab ozogamicin, and decitabine were included as well. This study was approved by the local Institutional Review Board. Consolidation treatment was defined as the first cycle of therapy given once patients achieved CR in marrow by standard criteria and divided into 3 main types for analysis: CLAG-M, CLAG-M without mitoxantrone (CLAG or GCLA) and high dose cytarabine (HiDAC). Patients who did not receive post-remission therapy with these regimens (n=23) or had refractory disease/died before consolidation therapy (n=180) were excluded from analysis. Many patients were enrolled on a single-center clinical trial of CLAG-M with dose-escalated mitoxantrone (NCT02044796). The primary endpoint was evaluation of the number of days from the start of consolidation chemotherapy to the day when absolute neutrophil count (ANC) > 1,000/ml (defined as neutrophil recovery) and platelet count > 100,000/ml (defined as platelet recovery). Early death was defined as death within 28 days of receiving consolidation therapy. Results We identified 307 patients who met our inclusion criteria; of these, 207 patients (67%) received CLAG therapy, 60 patients (20%) with CLAG-M and 40 patients (13%) with HiDAC. Compared to HiDAC, the median age of patients who received CLAG or CLAG-M was lower (p=0.013). The majority of patients were treated off study in all groups. The highest proportion of patients treated on study received CLAG therapy (36%, p=0.03). Early death was a rare event overall (1% for CLAG; 2% for CLAG-M and HiDAC), and no significant differences in ELN 2017 risk, performance status, baseline WBC, platelets, creatinine, albumin, or TRM score were identified among the three groups. Median time to neutrophil recovery was 36 days for HiDAC, 37 days for CLAG, and 50.5 days for CLAG-M (Figure 1A). Median time to platelet recovery was 48 days for HiDAC, 52 days for CLAG, and 94 days for CLAG-M. In multivariable cause-specific hazard regression models controlling for age and study enrollment, no differences were noted between CLAG and HiDAC in time to neutrophil recovery (hazard ratio [HR] 1.2, 95% confidence interval [CI] 0.81-1.76), platelet recovery (HR 1.08, 95% CI 0.71-1.64), or both neutrophil and platelet recovery together (HR 1.06, 95% CI 0.69-1.61). When compared to HiDAC, CLAG-M was associated with a trend towards longer time to neutrophil recovery (HR 0.69, 95% CI 0.43-1.09), platelet recovery (HR 0.73, 95% CI 0.44-1.21), and both neutrophil and platelet recovery together (HR 0.68, 95% CI 0.41-1.13). Controlling for age and study enrollment status, CLAG-M was associated with significantly worse 8-year OS compared to HiDAC (p=0.030), but no significant difference was identified between CLAG and HiDAC (p=0.99) (Figure 1B). Conclusions Post-remission therapy with CLAG is another viable alternative to HiDAC with no significant differences in neutrophil recovery, platelet recovery, and OS. Early death was uncommon for all three groups, but a post-remission course of CLAG-M was associated with decreased OS. Future work will examine the effect of particular cytogenetic and molecular markers on count recovery after post-remission courses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase Ib/2 Study of Oral Decitabine/Cedazuridine (ASTX727) and Venetoclax in Combination with the Targeted Mutant IDH1 Inhibitor Ivosidenib or the Targeted Mutant IDH2 Inhibitor Enasidenib in IDH Mutated Acute Myeloid Leukemia

Background Isocitrate Dehydrogenase (IDH) 1 or 2 mutations occur in ~20% of acute myeloid leukemia (AML). Both venetoclax (VEN)-based and targeted IDH-inhibitor (IDHi) therapies are effective treatment options for IDH mutated AML in combination with hypomethylating agents (HMA). ASTX727 is an oral, fixed dose (35 mg/100 mg) combination of decitabine and cedazuridine approved for the treatment of myelodysplastic syndrome (MDS). Herein we report the interim results of the first all-oral triplet regimen of ASTX727 (day 1-5) + VEN (day 1-14) in combination with a targeted mutant IDH1i ivosidenib (IVO) or IDH2i enasidenib (ENA), for IDH mutated AML. Methods Eligible patients were > 18 years old with relapsed/refractory (R/R) IDH1 or IDH2 mutated AML, or newly diagnosed (ND) AML not eligible for intensive chemotherapy. For the R/R AML cohort, prior VEN, HMA or IDHi use was not exclusionary. The primary objectives were to determine safety and the recommended phase 2 dose (RP2D) of ASTX727 and VEN with ivosidenib (Arm A) or enasidenib (Arm B) [Phase 1b], and to determine the composite remission rate (CRc; CRh+CRi+CR) for both arms [Phase 2]. Results A total of 32 patients have enrolled, with 3 screen failures and 2 patients ongoing first cycle of therapy. There are currently 27 evaluable patients (arm A: 10, arm B: 17) with median follow up of 5.7 months. Median age at enrollment was 73 (50 - 81). 44% (n=12) had ND AML and 56% (n=15) had R/R AML. European LeukemiaNet (ELN) risk was intermediate or adverse in 52% and 44%, respectively. Patients received a median of 4 treatment cycles (ND: 5, R/R: 3). The CRc rate in the overall population was 72% (ND: 100%, R/R: 53%). Measurable residual disease (MRD) negative CRc by flow cytometry was achieved in 64% (ND: 83%, R/R: 42%). (Table 1) In the R/R cohort, 78% (n=11) patients had received prior treatment with either an HMA (azacitidine or decitabine), BCL2i and/or IDHi, with a median of 2 prior treatments. (Table 2) 5 patients did not have prior VEN exposure of which 4 (80%) achieved an MRD negative CRc. Four patients transitioned to stem cell transplant (ND: 2, R/R: 2). The most common non-hematologic grade 3/4 AEs in the overall population included hyperbilirubinemia (n=2, 7%), representing indirect bilirubin in enasidenib-treated patients and mucositis (n=2, 7%) with one considered a residual effect of prior cytoreduction. There were two patients with possible/probable differentiation syndrome which resolved with medical management (dexamethasone and diuresis). Two episodes of reversible grade 1 tumor lysis syndrome were also reported. 60-day mortality within the ND and R/R cohort was 8% (n=1) and 0%, respectively. The ND patient withdrew from the study and went home on hospice after an admission for febrile neutropenia. Conclusions The combination of ASTX727 + VEN with IDH1 or IDH2 inhibition appears to be an effective regimen for the treatment of IDH mutated AML with high response rates including MRD-negative CRc, most notably in de novo patients and R/R pts without prior VEN exposure. AEs are anticipated and tolerable. Enrollment to this study is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1b Study of IDH Inhibition with Enasidenib and MEK Inhibition with Cobimetinib in Patients with Relapsed or Refractory Acute Myeloid Leukemia Who Have Co-Occurring IDH2 and RAS Signaling Gene Mutations

Background: For patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with IDH2 and RAS-pathway mutations involving NRAS, KRAS, PTPN11, and CBL genes, low responses and poor survival remain unmet clinical needs. Although enasidenib, a potent inhibitor of IDH2, is approved in R/R IDH2-mutant AML, patients with co-occurring RAS-pathway mutations exhibit primary resistance.[1,2] , Additionally, new RAS mutations confer acquired resistance to IDH inhibitors.[3] Preclinical studies suggest that RAS and IDH2 mutations cooperate to promote leukemogenesis.[4] In IDH2-mutant AML, aberrant production of the oncometabolite 2-hydroxyglutarate (2HG) suppresses the TET2 demethylase leading to a hypermethylation phenotype. Inhibition of TET2 induces epigenetic silencing of key RAS negative regulators (Sprouty family of proteins).[4] Enasidenib promotes demethylation to restore expression of RAS negative regulators. Meanwhile, MEK inhibitors were shown to suppress RAS-signaling. Co-targeting of IDH2 and MEK in mice with IDH2 /NRAS-dependent AML resulted in greater improvement in splenomegaly and cytopenia than either drug alone. Thus, we designed a phase 1 study to evaluate combined targeting of IDH2 and MEK in patients with R/R AML. Study Design and Methods: This is an open-label, multi-center, phase 1b study evaluating the safety of the combination of MEK inhibitor cobimetinib and IDH2 inhibitor enasidenib in patients with R/R AML and RAS-pathway mutations. The study will consist of 1) a dose escalation cohort to determine the maximum tolerated dose and the recommended phase 2 dose (RP2D) and 2) a dose expansion cohort to better characterize safety of the combination as well as preliminary efficacy, both in patients with R/R AML. Key eligibility criteria include R/R AML or newly diagnosed AML not eligible for chemotherapy; presence of co-occurring IDH2 and either NRAS, KRAS, PTPN11, NF1, or CBL mutations. The study will evaluate two dose levels of cobimetinib 40mg (DL1) or 60mg (DL2) daily on days 1-21 of a 28 day cycle and the FDA approved dose of enasidenib 100mg daily. The study primary endpoint is safety. Dose-limiting toxicities will be defined during the first cycle of therapy (28 days) as ≥ grade 3 toxicities according to the NCI CTCAE version 5.0. Dose escalation will occur according to a 3+3 design. Secondary endpoints will include overall response (CR, CRi, MLFS, and PR) by ELN 2022 response criteria, median to first response, response duration, median and 1-year OS and EFS, pharmacokinetics, and pharmacodynamics (phospho-ERK by CYTOF). Correlative objectives include determining the expression of RAS negative regulators by RNA sequencing and epigenetic regulation of RAS regulators by bisulfite sequencing and H3K4me3 and H3K27Ac ChIP-Seq. The study will accrue at the City of Hope National Medical Center and Memorial Sloan Kettering Cancer Center. This trial is registered on clinicaltrials.gov: NCT04243785 1. Amatangelo MD, Quek L, Shih A, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017 Aug 10;130(6):732-741. 2. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017 Aug 10;130(6):722-731. 3. Wang F, Morita K, DiNardo CD, et al. Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia. Nature Communications. 2021 2021/05/10;12(1):2607. 4. Kunimoto H, Meydan C, Nazir A, et al. Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity. Cancer cell. 2018 Jan 8;33(1):44-59.e8. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dose finding studies for therapies with late-onset toxicities: A comparison study of designs.

An objective of phase I dose-finding trials is to find the maximum tolerated dose; the dose with a particular risk of toxicity. Frequently, this risk is assessed across the first cycle of therapy. However, in oncology, a course of treatment frequently consists of multiple cycles of therapy. In many cases, the overall risk of toxicity for a given treatment is not fully encapsulated by observations from the first cycle, and hence it is advantageous to include toxicity outcomes from later cycles in phase I trials. Extending the follow up period in a trial naturally extends the total length of the trial which is undesirable. We present a comparison of eight methods that incorporate late onset toxicities while not extensively extending the trial length. We conduct simulation studies over a number of scenarios and in two settings; the first setting with minimal stopping rules and the second setting with a full set of standard stopping rules expected in such a dose finding study. We find that the model-based approaches in general outperform the model-assisted approaches, with an interval censored approach and a modified version of the time-to-event continual reassessment method giving the most promising overall performance in terms of correct selections and trial length. Further recommendations are made for the implementation of such methods.

Factores pronósticos de eficacia y seguridad que afectan a la supervivencia global de los pacientes con cáncer de próstata metastásico sometidos a tratamiento con [177Lu]Lu-PSMA-617: estudio en un único centro

BackgroundDetermining the efficacy, safety, and prognostic factors affecting overall survival (OS) among metastatic prostate cancer patients undergoing PSMA-targeted radioligand therapy (PRLT). MethodIn this retrospective study, from November 2016 and December 2019, 43 heavily pretreated (90.7% on 1st line androgen deprivation therapy (ADT), 53.5% on 2nd line ADT, 58.1% on docetaxel) metastatic prostate cancer patients with median age of 71 years (range: 51-88 years) were enrolled. Treatment cycles were repeated every 8 weeks (range: 6-12 weeks). To evaluate the biochemical response after each cycle, prostate specific antigen (PSA) levels were measured and analyzed according to the Prostate Cancer Working Group 3 (PCWG3) criteria cutoffs. Possible adverse events after therapy were retrospectively classified according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. Kaplan-Meier and multivariable Cox proportional hazard regression analyses were used to identify factors associated with OS. ResultsA total of 112 cycles of PRLT with a median of 3 cycles (range: 1-6) and median administered activity per cycle of 6.29 GBq (range: 4.45-7.7 GBq) were used. PSA decline was observed in 65.1% of patients, and best PSA decline of ≥50% and ≥90% were achieved in 39.5% and 23.3% of patients, respectively. Major (grade III) anemia and thrombocytopenia occurred in 11.6% and 7% of patients, respectively. Median OS and median PSA progression-free survival were 52 and 20 weeks, respectively. In univariate analysis, baseline hemoglobin <11.2 g/dL, baseline platelets count ≥327,000/μL, PSA decline <20.94% after first cycle of therapy, Eastern Cooperative Oncology Group (ECOG) >2, baseline PSA ≥115 ng/ml, cumulative dose of 177Lu-PSMA <12.95 GBq, initial alkaline phosphatase ≥196.5 U/L, initial lactate dehydrogenase ≥380 U/L and superscan pattern in bone scintigraphy were associated with worse OS. In multivariable Cox regression analysis, higher baseline platelet count, lower baseline hemoglobin, superscan pattern, and lower cumulative dose of 177Lu-PSMA remained significant predictors of poor OS. ConclusionPRLT with 177Lu-PSMA is well-tolerated and effective in metastatic prostate cancer patients who have no other treatment options available. The novel prognostic markers found in this study (high platelet count, superscan pattern) were associated with poor overall survival.

OTHR-09. The prevalence and complex management of MEK inhibitor induced cutaneous side effects

BACKGROUND: Cutaneous side effects commonly occur with MEK inhibitor (MEKi) therapy and can be challenging to manage. METHODS: A retrospective chart review was performed on sixteen pediatric patients treated with MEKi therapy for at least three months. These patients were diagnosed with either a brain tumor, plexiform neurofibroma, Langerhans Cell Histiocytosis, or Parkes Weber Syndrome (PWS). OBJECTIVES: To describe cutaneous side effects from MEKi therapy, compare the side effect profiles of patients treated for different diagnoses, and compare the side effect profiles between different MEKi agents. RESULTS: The most prevalent cutaneous toxicities for all eligible patients were acneiform rash (81%, most common), paronychia (50%, second most common), hair changes and xerosis. Mean number of cutaneous skin toxicities were 3.2 (trametinib group: 3.4, selumetinib group: 2.8). Only one patient, treated with trametinib for PWS, did not experience a cutaneous side effect. The average number of interventions (new medication or over-the-counter product) recommended to prevent or treat cutaneous-related toxicities was 6.8 per person, the majority of those were for acne and paronychia. Over 75% of the interventions were topical. Of those who experienced an acneiform rash, the average number of recommended interventions were 3.1. Sixty two percent of these patients developed acne within the first cycle; average time to development was 2.6 months into therapy. Most exhibited improvement overtime following intervention. Those patients who experienced paronychia were treated with a mean of 3.1 interventions – 37.5% developed paronychia within the first cycle of therapy; average time to development was 3.9 months into therapy. CONCLUSIONS: Cutaneous side effects are common, occur early in therapy, and require multiple interventions. The number and complexity of these interventions may further complicate the overall management of cutaneous side effects given that the responsibility of the administration falls on the patient. This differs from traditional chemotherapy regimens.

Chemotherapy after PD-1 inhibitors in relapsed/refractory Hodgkin lymphoma: Outcomes and clonal evolution dynamics.

SummaryCheckpoint inhibitors (CPIs) are routinely employed in relapsed/refractory classical Hodgkin lymphoma. Nonetheless, persistent long‐term responses are uncommon, and one‐third of patients are refractory. Several reports have suggested that treatment with CPIs may re‐sensitize patients to chemotherapy, however there is no consensus on the optimal chemotherapy regimen and subsequent consolidation strategy. In this retrospective study we analysed the response to rechallenge with chemotherapy after CPI failure. Furthermore, we exploratively characterized the clonal evolution profile of a small sample of patients (n = 5) by employing the CALDER approach. Among the 28 patients included in the study, 17 (71%) were primary refractory and 26 (92%) were refractory to the last chemotherapy prior to CPIs. Following rechallenge with chemotherapy, response was recorded in 23 (82%) patients experiencing complete remission and 3 (11%) patients experiencing partial remission. The tumour evolution of the patients inferred by CALDER seemingly occurred prior to the first cycle of therapy and was characterized either by linear or branching evolution patterns. Twenty‐five patients proceeded to allogeneic stem cell transplantation. At a median follow‐up of 21 months, median PFS and OS were not reached. In conclusion, patients who fail CPIs can be effectively rescued by salvage chemotherapy and bridged to allo‐SCT/auto‐SCT.

A phase 1b/2 trial of the PLK1 inhibitor onvansertib in combination with FOLFIRI-bev in 2L treatment of KRAS-mutated (mKRAS) metastatic colorectal carcinoma (mCRC).

100 Background: CRC is a common cancer world-wide, accounting for ̃10% of cancer cases and mortality. Treatment options are limited, and survival is poor for pts with advanced disease, particularly those with mKRAS. After failure of 1L treatment for mCRC, regardless of KRAS mutation status, the ORR for FOLFIRI-bev is 5-13%, with PFS 4-6 mos, and OS 10-12 mos. Onvansertib is a highly selective, ATP-competitive, orally bioavailable PLK1 inhibitor that is synergistic with irinotecan and with 5FU in xenograft models of mKRAS CRC. We present preliminary safety, efficacy, and biomarker data from an ongoing Ph1b/2 trial of onvansertib + FOLFIRI-bev in pts with mKRAS mCRC progressing after 1L treatment with fluoropyrimidine + oxaliplatin, +/- bev. Methods: Pts with mCRC with a KRAS mutation detected by a CLIA-certified lab were eligible. In the Ph1b portion of the study, onvansertib was given on a 3+3 dose escalation at 12, 15 or 18 mg/m2 on days 1-5 and 15-19 of each 28-day cycle in combination with FOLFIRI-bev. The MTD was 15 mg/m2 and was chosen as the RP2D. The primary endpoint for the Ph2 was ORR, and radiographic response was assessed every 8 wks per RECIST v1.1. Safety was evaluated continuously, and AEs were recorded using CTCAE v5.0. Baseline and post-treatment blood samples were collected for biomarker analyses, including mutant allele frequency (MAF) of the pt’s known KRAS mutation. Results: As of 16Sep2021, a total of 50 pts had been treated: 18 on the Ph1b and 32 on the Ph2, including 35 pts at the RP2D, and median follow up was 4.7 mos (range 0.4-18). Of the 50 pts, 26 remain on treatment, as do 24 of 35 RP2D pts. The combination was well-tolerated: fatigue, neutropenia, and nausea were the most common treatment-emergent adverse events (TEAE) and were generally low-grade. Neutropenia was managed by removing the 5FU bolus from subsequent cycles of FOLFIRI and adding growth factor. Of the 50 pts, 44 were evaluable for efficacy, including 31 of 35 RP2D pts. ORR was 36% for the total group (1CR and 15 PR in 44 pts) and 35% for the RP2D group (1 CR and 10 PR in 31 pts). First responses were seen between 2 and 6 months after the start of therapy. Responses were observed across different KRAS variants. Pts achieving a CR or PR showed the greatest decreases in plasma MAF after the first cycle of therapy. Of the 50 pts, 24 pts have discontinued for the following reasons: progressive disease (13), toxicity (4), patient decision (4), proceeding to potentially curative surgery or other localized therapy (3). Conclusions: The combination of onvansertib with FOLFIRI-bev was well tolerated: observed TEAEs have been generally low-grade and manageable. The combination has demonstrated a promising ORR in 2L treatment of mCRC pts harboring various KRAS mutations, and efficacy was correlated with early changes in plasma mKRAS. Updated safety, efficacy, and biomarker analyses will be presented. Clinical trial information: NCT03829410.