Criteria For Partial Response Research Articles

Application of a scoring system in Japanese patients diagnosed with atypical hemolytic uremic syndrome to assess the relationship between the score and clinical responses to eculizumab

BackgroundAtypical hemolytic uremic syndrome (aHUS) is caused by complement dysregulation and is generally diagnosed by exclusion from other disorders of thrombotic microangiopathy (TMA). Eculizumab, a terminal complement inhibitor, has been approved for aHUS treatment since 2013 in Japan. Recently, a scoring system was published to support diagnosis of aHUS. Herein we modified this scoring system to apply it to patients diagnosed with aHUS and treated with eculizumab, and assessed the association between the score and clinical responses to eculizumab.MethodsOne hundred eighty-eight Japanese patients who were clinically diagnosed with aHUS, treated with eculizumab, and enrolled in post-marketing surveillance (PMS) were included in this analysis. Some of parameters in the original scoring system were replaced with clinically similar parameters collected in the PMS to modify the system, hereafter referred to as the TMA/aHUS score, which ranges from -15 to 20 points. Treatment responses within 90 days after eculizumab initiation were also assessed, and the relationship between treatment response and TMA/aHUS scores calculated at TMA onset was explored.ResultsThe median (range) TMA/aHUS score was 10 (3–16). Receiver operating characteristic curve analysis showed that the cutoff value of TMA/aHUS score to predict treatment response to eculizumab was estimated as 10, and negative predictive value indicated that ≥ 5 points was appropriate to consider assessing the treatment response to eculizumab; 185 (98%) patients had ≥ 5 points and 3 (2%) had < 5 points. Among the patients with ≥ 5 points, 96.1% showed partial response and 31.1% showed complete response. One of the three patients with < 5 points met partial response criteria. No significant difference in the TMA/aHUS scores was observed between survivors and non-survivors, suggesting that the score was not appropriate to predict the outcome (i.e., survival/death) in patients treated with eculizumab.ConclusionAlmost all patients clinically diagnosed with aHUS scored ≥ 5 points and responded to eculizumab. The TMA/aHUS score system could become a supporting tool for the clinical diagnosis of aHUS and probability of response to treatment with a C5 inhibitor.Trial registrationThis study was conducted as per good PMS practice guidelines for drugs (MHLW Ministerial Ordinance No. 171 of 2004).

Abstract CT172: A phase 1, open-label, dose-escalation study of PRT1419, a selective induced myeloid leukemia cell differentiation protein (MCL-1) inhibitor, in patients (pts) with advanced/metastatic solid tumors

Abstract Introduction: PRT1419, a selective inhibitor of MCL-1, has demonstrated preclinical activity in solid tumors and hematologic malignancies. We report the results of a phase 1, open-label, multicenter, dose-escalation study of PRT1419 in pts with advanced/metastatic solid tumors (NCT04837677). Methods: Adults with select advanced/metastatic solid tumors were enrolled. Key inclusion criteria were absolute neutrophil count &amp;gt;1.0, platelets &amp;gt;75, hemoglobin &amp;gt;9, and left ventricular ejection fraction ≥50%. Key exclusion criteria were active central nervous system malignancy, significant cardiac disease, and concurrent strong CYP2C8 inhibitors. The study employed a 3+3 dose escalation design. PRT1419 was administered as a once-weekly (QW) infusion. Primary outcome measures were to evaluate dose-limiting toxicities (DLT) and establish the maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary outcome measures included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity. Results: Pts with melanoma (n=8), sarcoma (n=5), esophageal (n=4), cervical (n=3), head and neck (n=3), non-small cell lung, small cell lung, and triple-negative breast cancer (all n=1) were enrolled. Median age was 59.5 (range, 32-78) years, 61.5% pts were female, and median prior lines of systemic therapy was 3 (range, 1-8). Overall, 26 pts received ≥1 dose of PRT1419 (20 mg/m2 [n=4], 40 mg/m2 [n=4], 80 mg/m2 [n=15], and 120 mg/m2 [n=3]). Most pts (84.6%) discontinued treatment (primary reason: progressive disease, 72.7%). No DLTs, adverse events (AEs) of increased troponin or heart failure, or grade 5 (fatal) AEs were observed. Any grade treatment-related AEs (TRAE) occurred in 80.8% pts; the most common were nausea (50.0%), diarrhea (46.2%), and vomiting (46.2%). Grade 3/4 TRAEs occurred in 11.5% pts; the most common was neutropenia (11.5%), which was dose related. Due to neutropenia observed at doses &amp;gt;80 mg/m2, further dose escalation was not investigated. BAX and caspase 3 activation in peripheral blood monocytes was observed at 80 mg/m2 and 120 mg/m2. Stable disease was the best response observed. Tumor shrinkage was seen in 1 pt with melanoma (10% reduction) and 1 pt with lung cancer (4% reduction) but did not meet the criteria for partial response. At Week 3, mean clearance was 12.6 L/hr and mean half-life was 2.5 hrs; no PRT1419 accumulation was seen with QW dosing. Conclusions: PRT1419 demonstrated acceptable safety and tolerability in pts with advanced/metastatic solid tumors, with primary TRAEs of neutropenia, nausea, diarrhea, and vomiting. No cardiac toxicity was observed. BAX and caspase 3 activation was observed, suggesting potentially successful MCL-1 inhibition. Investigation of PRT1419 in pts with hematologic malignancy in a separate study is ongoing (NCT05107856). Citation Format: Gerald Falchook, Manish Patel, Meredith McKean, Alexander Philipovskiy, Rachel Chiaverelli, William Sun, Michael Fossler, William Novotny, Michael Kurman, Sarah Rowe, Deborah Hunter, Mohammed Milhem. A phase 1, open-label, dose-escalation study of PRT1419, a selective induced myeloid leukemia cell differentiation protein (MCL-1) inhibitor, in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT172.

P1160: RESULTS OF A PHASE 2 EXPANDED ACCESS STUDY OF ZANUBRUTINIB IN PATIENTS WITH WALDENSTRÖM MACROGLOBULINEMIA

Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for Waldenström macroglobulinemia (WM). Zanubrutinib (ZANU; BGB-3111) is a next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. ZANU was recently approved by the United States (US) Food and Drug Administration, Health Canada, and the European Union at a dose of 320 mg once daily (QD) or 160 mg twice daily (BID) for the treatment of adult patients (pts) with WM. BGB-3111-216 (NCT04052854) is a single-arm, expanded access study of ZANU for treatment-naïve (TN) pts who are unsuitable for standard chemoimmunotherapy or pts with relapsed refractory (R/R) WM. Aims: To provide real-world experience with ZANU in pts with WM. Methods: Eligible pts with TN or R/R WM were assigned to receive ZANU at a dose of 320 mg QD or 160 mg BID. The primary endpoint was the number of pts enrolled/treated and the number of enrolling sites. Secondary endpoints of safety and efficacy included treatment emergent adverse events (TEAEs) of special interest, disease response (overall response rate [ORR] and very good partial response or better [VGPR+]), progression-free survival (PFS), and overall survival (OS). Response was evaluated by investigator-assessment according to the 6th International Workshop on WM (Br J Haematol. 2013;160(2):171-6) every 6 months at minimum. The study was closed by the sponsor in July 2021 and active pts were transitioned to commercial ZANU via a patient assistance program. Results: Fifty pts with WM (17 TN; 33 R/R), were enrolled from December 2019 to June 2021 across 10 academic and community medical centers in the US. At study entry, median age was 72 years, 54% had intermediate-risk disease, 40% had high-risk disease, and median number of prior therapies for R/R pts was 2. Median treatment exposure was 9.2 months (range 1.4 to 20.0). Thirty-eight (76%) pts had ≥1 TEAE, and 36 (72%) experienced ≥1 TEAE of special interest (Table). Grade ≥3 TEAEs of special interest included hypertension (8%), infection (8%), atrial fibrillation or flutter (2%), neutropenia (2%), and second primary malignancy (2%). No new safety signals were observed. In the 41 pts with ≥1 response evaluation, 39.0% achieved a best overall response (BOR) of VGPR (16; 95% CI, 24.2-55.5). ORR was 85.4% (35; 95% CI, 70.8-94.4), and major response rate was 73.2% (30; 95% CI, 57.1-85.8). Of the 4 pts who achieved a BOR of progressive disease, 3 had IgM values that met partial response criteria before the first 6 months response assessment. PFS and OS were immature due to short follow-up, and the median was not met. Image:Summary/Conclusion: The results of this real-world expanded access study were consistent with the established ZANU profile in WM and other B-cell malignancies when administered as monotherapy at a daily dose of 320 mg orally (either as 160 mg BID or 320 mg QD) in pts with intermediate or high-risk R/R or TN WM.

A phase 2 expanded access study of zanubrutinib (ZANU) in patients (pts) with Waldenström Macroglobulinemia (WM).

e19522 Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. The next-generation BTK inhibitor ZANU (BGB-3111), designed to maximize BTK occupancy and minimize off-target inhibition of other kinases, is approved by the United States (US) Food and Drug Administration, Health Canada, and the European Union at a dose of 320 mg once daily (QD) or 160 mg twice daily (BID) for adult pts with WM. BGB-3111-216 is a single-arm expanded access study of ZANU in treatment-naïve (TN) pts who were unsuitable for standard chemoimmunotherapy or pts with relapsed refractory (R/R) WM. This study provides real-world experience with ZANU in pts with WM. Methods: Eligible pts with TN or R/R WM received ZANU 320 mg QD or 160 mg BID orally. Primary endpoint was the number of pts enrolled/treated and enrolling sites. Secondary endpoints included treatment-emergent adverse events (TEAEs) of special interest, disease response rate, progression-free survival (PFS), and overall survival (OS). Response was evaluated by investigator assessment according to the 6th International Workshop on WM ( Br J Haematol. 2013;160(2):171-6) every 6 mo at minimum. The study was closed by the sponsor in July 2021 and active pts were transitioned to commercial ZANU via a patient assistance program. Results: Fifty pts with WM (17, TN; 33, R/R) were enrolled between December 2019 and June 2021 across 10 academic and community medical centers in the US. Median age was 72 years, 54% had intermediate-, 40% had high-risk disease, and the median number of prior therapies for R/R pts was 2. Median treatment exposure was 9.2 mo (range, 1.4-20.0). Thirty-eight (76%) pts had ≥1 TEAE, and 36 (72%) had ≥1 TEAE of special interest. Grade ≥3 TEAEs of special interest were hypertension (8%), infection (8%), atrial fibrillation/flutter (2%), neutropenia (2%), and second primary malignancy (2%). No new safety signals were observed. In pts with ≥1 response evaluation, 39% achieved a best overall response (BOR) of very good partial response. Overall response rate was 85.4% and major response rate was 73.2% (Table). Of the 4 pts with BOR of progressive disease, 3 had IgM values that met partial response criteria before the 6-mo response assessment. PFS and OS were immature due to short follow-up, and the median was not met. Conclusions: These real-world expanded access study results were consistent with the established ZANU profile in WM or other B-cell malignancies when administered as oral monotherapy at 160 mg BID or 320 mg QD in pts with intermediate or high-risk R/R or TN WM. Clinical trial information: NCT04052854. [Table: see text]

A New Immunosuppressive Therapy for Very Severe Aplastic Anemia in Children with Autoantibodies.

At present, a number of very severe aplastic anemia (VSAA) patients cannot receive hematopoietic stem cell transplantation (HSCT) or standard immunosuppressive therapy (IST) due to the high cost of therapy, shortage of sibling donors, and lack of resources to support the HSCT. In addition, some VSAA patients with autoantibodies have no life-threatening infections or bleeding at the time of initial diagnosis. Considering the disease condition, economics and other factors, the present study designed a new and relatively mild treatment strategy: cyclosporine A plus pulsed high-dose prednisone (CsA+HDP). The present study retrospectively analyzed 11 VSAA patients, who were treated with CsA+HDP in our hospital from August 2017 to August 2019. The median follow-up time for these patients was 24.9 months. The overall response rate was 54.5% (6/11) at six months after the initiation of IST and 81.8% (9/11) at deadline. Five patients achieved complete remission and four patients met the criteria for partial response at the last follow-up. The median time to response for responders was 110 days. Three patients underwent HSCT due to the poor effect of CsA+HDP or to find a suitable transplant donor. Recurrence and clonal evolution were not found in any of these patients. The estimated 3-year overall survival rate and 3-year failure-free survival rate were 100.0% and 72.7%, respectively. In addition, the results revealed that the cyclosporine-prednisone-associated toxicity was mild and well-tolerated by most patients. The novel CsA+HDP regimen has good therapeutic effect and safety for VSAA patients with autoantibodies, who have no serious life-threatening infections or bleeding at the time of initial diagnosis.

Abstract P3-03-01: Functional tumor volume at 3 and 6-week MRI as an indicator of patients with inferior outcome after neoadjuvant chemotherapy

Abstract Purpose. Functional tumor volume (FTV) is a quantitative measure of tumor burden derived from dynamic contrast-enhanced breast MRI1, 2. In the I-SPY 2 TRIAL, FTV is measured during neoadjuvant chemotherapy (NAC) at pre-treatment (T0), 3 weeks (T1), 12 weeks (T2), and pre-surgery (T3) time points. In I-SPY2 protocol amendment 18, activated in Dec 2017, an optional MRI at 6 weeks (T1a) recommended at clinician’s discretion was added for patients with low response at T1. Patients are treated with standard NAC with or without addition of experimental agents. A treatment escalation option being planned for future I-SPY2 implementation will give patients with suboptimal response the opportunity to pursue more aggressive therapy. T1 and T1a MRI may be helpful to select candidates for this option. We retrospectively investigated the ability of FTV reduction at 3 and 6 weeks to detect non-responders. Methods. We included 104 patients who underwent T1a MRI between Jan 2018 and Mar 2021. FTV was measured using in-house software developed in IDL (Exelis Visual Information Solutions, Boulder, CO). FTV reduction at 3 and 6 weeks was dichotomized to under and over with a cutoff of 20% reduction from T0 to T1 and 65% reduction (the 3D equivalent of size-based partial response criteria by RECIST) from T0 to T1a, respectively. Treatment outcome was evaluated based on residual cancer burden (RCB) on surgical pathology, an established surrogate for survival outcome3. Patients with RCB 0/I were considered as responders and those with RCB II/III as non-responders. Fisher’s exact test was used to examine the association between FTV reduction and treatment outcome, with P &amp;lt;0.05 considered statistically significant. Ability of FTV reduction to detect non-responders was assessed by positive predictive value (PPV) and sensitivity, where non-responder was defined as “positive”. Results. Of the 104 patients, 49 patients (31 HR+HER2–;16 HR–HER2–; 2 HR+HER2+) who had both RCB and analyzable FTVs were included. Other patients were excluded because of missing RCB or FTV data (n = 18) or not having completed the assigned therapy (n = 37).FTV reduction at T1 and T1a was associated with outcome (P = 0.022 and &amp;lt;0.001, respectively) (Table 1). FTV reduction at T1a was also associated with outcome in 26 patients with &amp;lt;20% reduction at T1 (P = 0.047). The combined criteria of &amp;lt;20 % reduction at T1 and &amp;lt;65 % reduction at T1a detected non-responders with PPV of 82% and sensitivity of 95%, which outperformed the T1 only or T1a only criterion (Table 2†).Ability of combined criteria was experimentally tested using 20% cutoff for T1 and various cutoffs for T1a (Table 2). Criteria of &amp;lt;20 % reduction at T1 and &amp;lt;50 % reduction at T1a detected non-responders with PPV of 89% and sensitivity of 89%(Table 2‡). Conclusion. In this early small study, combined criteria using FTV reduction at 3 and 6 weeks of NAC showed high PPV and high sensitivity in early detection of non-responders as candidates for the treatment escalation option. Reference. 1. Radiology 263:663–672, 2012. 2. Radiology 279:44–55, 2016. 3. J Clin Oncol. 2007 Oct 01; 25(28) 4414-4422 Table 1.Association between FTV Reduction and Treatment ResponseCriteria based on FTV reduction at T1Total n = 49&amp;lt;20% reduction at T1 (n = 26)&amp;gt;20% reductionat T1 (n = 23)P-valueNon-responder (RCB II or III)281990.022*Responder (RCB 0 or I)21714Criteria based on FTV reduction at T1aTotal n = 49&amp;lt;65% reduction at T1a (n = 30)&amp;gt;65% reduction at T1a (n = 19)P-valueNon-responder (RCB II or III)28244&amp;lt; 0.001*Responder (RCB 0 or I)21615Combined criteria based on FTV reduction at T1 and T1aTotal n = 26&amp;lt;20% reduction at T1 &amp; &amp;lt;65% reduction at T1a (n = 22)&amp;lt;20% reduction at T1 &amp; &amp;gt;65% reduction at T1a (n = 4)P-valueNon-responder (RCB II or III)191810.047*Responder (RCB 0 or I)743 Table 2.Performance of FTV Reduction-based CriteriaCriteria to detect non-respondersPPVNPVSensitivitySpecificityTrue positiveFalse negativeFalse positiveTrue negativeTotalT1 &amp;lt;20% reduction†73%61%68%67%19971449T1a &amp;lt;65% reduction†80%79%86%71%24461549T1 &amp;lt;20% reduction &amp; T1a &amp;lt;40% reduction88%56%79%71%1542526T1 &amp;lt;20% reduction &amp; T1a &amp;lt;45% reduction89%62%84%71%1632526T1 &amp;lt;20% reduction &amp; T1a &amp;lt;50% reduction ‡89%71%89%71%1722526T1 &amp;lt;20% reduction &amp; T1a &amp;lt;55% reduction86%80%95%57%1813426T1 &amp;lt;20% reduction &amp; T1a &amp;lt;60% reduction86%80%95%57%1813426T1 &amp;lt;20% reduction &amp; T1a &amp;lt;65% reduction †82%75%95%43%1814326T1 &amp;lt;20% reduction &amp; T1a &amp;lt;70% reduction78%67%95%29%1815226T1 &amp;lt;20% reduction &amp; T1a &amp;lt;75% decrease75%50%95%14%1816126Note: Unless otherwise specified, data represent the number of patients Citation Format: Natsuko Onishi, Jessica E Gibbs, Wen Li, David C Newitt, Elissa R Price, Barbara LeStage, William F Symmans, Angela M DeMichele, Christina Yau, the I-SPY 2 TRIAL Imaging Working Group, the I-SPY 2 TRIAL Consortium, Laura J Esserman, Nola M Hylton. Functional tumor volume at 3 and 6-week MRI as an indicator of patients with inferior outcome after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-03-01.

EPCT-10. DEBIO1347, AN ORAL FGFR INHIBITOR: RESULTS FROM A SINGLE CENTER STUDY IN RECURRENT/REFRACTORY FGFR ALTERED PEDIATRIC GLIOMAS

BackgroundOncogenic driver alterations in FGFR are present in a subset of pediatric gliomas. Debio1347 is an orally available, highly selective FGFR 1–3 inhibitor that had a favorable safety profile and encouraging preliminary clinical activity in an adult phase 1 study. MethodsFive children with progressive/refractory CNS tumors harboring an FGFR gene alteration following prior therapy were treated with Debio1347 at Memorial Sloan Kettering Cancer Center on single patient use protocols. Patients were treated using the 20 mg tablet formulation at the adult recommended phase 2 dose (80 mg/1.73 m2 * BSA once daily). Toxicities were graded using CTCAEv5.0 and imaging response assessments were performed every 8–12 weeks. RESULTS All AEs were grade 1–2. Most common treatment-related adverse events were hyperphosphatemia, ALT increased and hypoalbuminemia (4 patients). Two patients met criteria for partial response and two patients had stable disease. A 13 month-old patient with a spinal cord high-grade glioma harboring two FGFR1 mutations (V592M, K687E) had tumor reduction of 91.7% maintained for 12 months. A 26-month-old patient with a pilomyxoid astrocytoma harboring an FGFR1-TACC1 fusion had a tumor reduction of 74.5% maintained for 9 months. Molecular characterization of recurrent tumor from this patient demonstrated an NF1 deletion as a novel molecular mechanism of acquired resistance to FGFR inhibition. Prolonged disease stabilization was noted in an eight year-old patient with metastatic suprasellar pilomyxoid astrocytoma harboring an FGFR1 mutation (9 months) and in a 14 year-old patient with posterior fossa glioneuronal tumor harboring an FGFR3-TACC3 fusion (24 months and ongoing). ConclusionsDebio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with refractory FGFR altered gliomas. Specific attention to growth velocity and clinical symptoms with incorporation of imaging assessment of bone growth is warranted. Candidate biomarkers (FGFR1 V592M and K687E SNVs, FGFR-TACC fusions) may guide patient selection. Further studies in this population are warranted.

EPCT-07. DEBIO1347, AN ORAL FGFR INHIBITOR: RESULTS FROM A SINGLE CENTER STUDY IN RECURRENT/REFRACTORY FGFR ALTERED PEDIATRIC GLIOMAS

BACKGROUNDOncogenic driver alterations in FGFR are present in a subset of pediatric gliomas. Debio1347 is an orally available, highly selective FGFR 1–3 inhibitor that had a favorable safety profile and encouraging preliminary clinical activity in an adult phase 1 study.METHODSFive children with progressive/refractory CNS tumors harboring an FGFR gene alteration following prior chemotherapy were treated with Debio1347 at Memorial Sloan Kettering Cancer Center on single patient use protocols. Patients were treated using the 20 mg tablet formulation at the adult recommended phase 2 dose (80 mg/1.73 m2 * BSA once daily). Toxicities were graded using CTCAEv5.0 and imaging response assessments were performed every 8–12 weeks.RESULTSAll AEs were grade 1–2. Most common treatment-related adverse events were ALT increased, hypoalbuminemia and hyperphosphatemia (4 patients). Two patients met criteria for partial response and two patients had stable disease. A 13 month-old patient with a spinal cord high-grade glioma harboring two FGFR1 mutations (V592M, K687) had tumor reduction of 91.7% maintained for 12 months. A 26-month-old patient with a pilomyxoid astrocytoma harboring an FGFR1-TACC1 fusion had a tumor reduction of 74.5% maintained for 9 months. Prolonged disease stabilization was noted in an eight year-old patient with metastatic suprasellar pilomyxoid astrocytoma harboring an FGFR1 mutation (9 months) and in a 14 year-old patient with posterior fossa glioneuronal tumor harboring an FGFR3-TACC3 fusion (18 months and ongoing).CONCLUSIONSDebio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with refractory FGFR altered gliomas. Further studies in this population are warranted.

CTNI-33. DEBIO1347, AN ORAL FGFR INHIBITOR: RESULTS FROM A SINGLE CENTER STUDY IN PEDIATRIC PATIENTS WITH RECURRENT/REFRACTORY FGFR ALTERED GLIOMAS

Abstract BACKGROUND Oncogenic driver alterations in fibroblast growth factor receptors (FGFRs) are present in a subset of pediatric gliomas. Debio1347 is an orally available, highly selective FGFR 1–3 inhibitor with a favorable safety profile and encouraging preliminary clinical activity in an adult phase 1 study. METHODS We treated five children with progressive/refractory CNS tumors harboring an FGFR gene alteration with Debio1347 on single patient use protocols. Patients were treated using the 20 mg tablet formulation at the adult recommended phase 2 dose (80 mg/1.73 m2 ′ BSA once daily). RESULTS All adverse events (AEs) were grade 1–2. Most common treatment-related AEs were hyperphosphatemia, ALT elevation and hypoalbuminemia. Two patients met criteria for partial response and two patients had stable disease. A 13-month-old patient with a spinal cord high-grade glioma harboring two FGFR1 mutations had tumor reduction of 96.3% maintained for 11 months. A 26 month-old patient with a pilomyxoid astrocytoma harboring an FGFR1-TACC1 fusion had a tumor reduction of 74.5% maintained for 9 months. Prolonged disease stabilization and clinically significant improvement in visual function was noted in an eight year-old patient with metastatic suprasellar pilomyxoid astrocytoma harboring two FGFR1 mutations (14 months overall and sustained for 6 months off therapy) and in a 14 year-old patient with posterior fossa glioneuronal tumor harboring an FGFR3-TACC3 fusion (26 months and ongoing). CONCLUSIONS FGFR targeted therapy with Debio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with recurrent/refractory FGFR altered gliomas. Further studies in this population are warranted.

Large Granular Lymphocyte Leukemia and Precapillary Pulmonary Hypertension

Large Granular Lymphocyte Leukemia and Precapillary Pulmonary Hypertension

Laporan Kasus: Transarterial Chemoembolization (Tace) Sebagai Terapi Pilihan Pada Karsinoma Hepatoselular

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and occupies the top 10 most cancers in Indonesia. Men are likely to develop HCC, and 90% cases of HCC develop in the background of chronic liver disease, which associates with hepatitis B and C virus infection. There are numerous treatment options for HCC, however in intermediate-advanced stage, palliative treatment such as transarterial chemoembolization (TACE) and systemic chemotherapy are the management of choice. A 51 years old male with HCC based on history, physical examination, radiology and laboratory result was referred to interventional radiology department for TACE consideration. Barcelona Clinic Liver Cancer (BCLC) B was concluded in this patient after thorough evaluation. There was history of hepatitis B infection, ascites, low albumin level, high AFP, and from Abdominal CT Scan with contrast showed large lobulated mass on the right lobe, without evidence of portal vein thrombosis. TACE was eligible and done using mixed of doxorubicin 50 mg and lipiodol, and embolization using gel foam. After 8 weeks CT evaluation was done and showed increase area of tumor necrosis, while tumor size was stable. Necrosis area expansion is the standard used for evaluating this patient which fell into partial response criteria. TACE is a palliative therapy of choice in accordance with BCLC B recommendation. Evaluation of TACE performance is more optimal by assessing the size of necrosis area compared to mass measurement.

PB2227 COMPASSIONATE USE OF ROPEGINTERFERON TO TREAT MYELOPROLIFERATIVE NEOPLASMS IN TAIWAN

Background:There is a high unmet medical need for therapeutic options for patients suffering from myeloproliferative neoplasms (MPN), who have failed or are not eligible to available treatment options. Ropeginterferon‐alfa‐2b (P1101) is a novel, third generation pegylated interferon‐alfa, recently approved by EMA to treat polycythemia vera (PV). Ropeginterferon‐alfa‐2b is also in the late stages of development in several countries for treatment of PV and other MPNs.Aims:Ropeginterferon‐alfa‐2b is a new and attractive treatment option for patients suffering from MPN who have exhausted all therapeutic options and require treatment. The Compassionate Use Program (CUP) was approved and initiated in Taiwan with the purpose of granting access to P1101 to patients with MPN disease with no therapeutic options who are not eligible to enroll in existing clinical trials for their disease.Methods:Patients were identified that had the potential to benefited from P1101 therapy and were eligible according to the protocol. Patients were treated at a starting dose of 250 ug with subsequent dose escalation every 2 weeks over a 6‐week period to 350 ug, 450 ug and 500 ug. Dose adjustments were permitted based on tolerability and efficacy.Results:The CUP currently contains 15 patients from two academic hospitals: 9 with PV, 2 with post‐PV myelofibrosis (MF), two with pre‐fibrotic MF, one with primary MF, and one essential thrombocythemia patient. The driver mutation was JAK2 in 13 patients, CALR in one, and another one was triple negative. Pre‐treatment with hydroxyurea and/or anagrelide was reported in 13 patients. P1101 was given for &gt; 12 weeks to 14 patients (range 4 ‐ 64 weeks). The highest administered dose of P1101 was: 500 ug in 11 patients (time to highest dose – 6 weeks in 9 patients, 10 weeks – in 1 and 20 weeks in another patient); 250 ug, 350 ug and 450 ug in three other patients. The need to decrease or temporarily interrupt P1101 therapy occurred in 4 patients, all due to transaminase(s) elevation. Notably, these events did not require permanent discontinuation of therapy and could be alleviated by appropriate dose modifications. The majority of observed adverse events were of grade 1 and included fatigue, arthralgia, myalgia, chills and dizziness. Grade 2 events included elevation of transaminases (in 3 patients), dizziness, pruritus and lower limbs pain (in 1 patient each). One patient developed elevation of transaminases of grade 3. Normalization of blood parameters within complete hematologic response range was observed in 3 PV and 2 post‐PV MF patients. Two PV patients fulfilled the partial response criteria. In other patients, decrease of platelet count (even in previously treatment‐resistant thrombocytosis) and symptomatic improvement were also observed. No major cardiovascular events were recorded. One pre‐PMF patient transformed into MF (grade 5). No patients progressed to acute myelogenous leukemia (AML) during the observation.Summary/Conclusion:In this cohort of MPN patients, not amenable for established treatment options, P1101 demonstrated good tolerability and substantial efficacy. The dose administration schema with a starting dose of 250 ug and escalation to the highest dose of 500 ug within the first 6‐8 weeks was feasible, tolerated and allowed rapid control of blood parameters. The observed efficacy demonstrate P1101 as a promising treatment option for patients with MPNs with limited or no alternate therapeutic option. These results mandate access to P1101 at earlier stages of disease as recommended by international MPN treatment guidelines.

A pilot safety study of gemcitabine and cisplatin (GC) with atezolizumab (A) as first-line therapy in patients (pts) with metastatic urothelial cancer (mUC).

4559 Background: GC has a high overall response rate (ORR) but a high relapse rate in pts with untreated mUC. Inhibition of programmed death-ligand 1 (PD-L1) with A can lead to long-term survival, but single-agent ORR is modest. We report the outcomes of GC+A in a cohort pts with mUC. Methods: This study was designed to assess the safety of GC + A in 10 pts with untreated mUC prior to testing GC + A in a neoadjuvant study in pts with muscle-invasive disease. The primary endpoint was safety as assessed by a predefined dose limiting toxicity (DLT) rate during the first cycle in the first 6 pts. Total accrual goal was 10 pts to collect preliminary data on ORR and progression-free survival (PFS). RECIST 1.1 assessments were performed every 9 wks. Pts received 6 cycles of GC + A induction and then A maintenance every 3 wks. Results: No DLTs occurred during the first cycle in the first 6 pts. Grades 3-4 neutropenia and anemia occurred in 6/10 and 7/10 pts, respectively. Three pts required gemcitabine dose reductions for hematologic toxicity and 2 pts had febrile neutropenia. One pt discontinued cisplatin after 2 cycles for grade 3 hearing impairment but completed induction with gemcitabine and A. Only 1 pt discontinued study therapy due to treatment-related adverse events (AEs), including A-related grade 4 encephalopathy and grade 3 polyneuropathy. Three of 10 pts had visceral (liver or bone) metastases. Of the 10 pts, 1 pt is completing induction but meets initial criteria for partial response (PR), 8 pts had confirmed PR, and 1 pt had progressive disease (PD). Of 9 pts with confirmatory scans, the median PFS was 10.6 months (95% CI 6.7, N/A). Of 8 pts with confirmed PR, 5 eventually had PD, 1 has just completed induction, 1 remains without PD at 25 months, and 1 had consolidation surgery with a pathologic complete response and remains disease-free at 21 months. Conclusions: This 10 pt study met its primary safety endpoint. The neoadjuvant study is ongoing (NCT02989584). Although there were a substantial number of grade 3-4 toxicities, therapy was discontinued due to treatment-related AEs in only 1 pt. Immune correlative studies are ongoing. Clinical trial information: NCT02989584.

Effectiveness and Predictors of Response to 1-Hz Repetitive Transcranial Magnetic Stimulation in Patients With Obsessive-Compulsive Disorder.

The present study aimed to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) treatment targeting either supplementary motor area (SMA) or orbitofrontal cortex (OFC) among patients with OCD in real-world clinical practice settings. Also, the present study explored for potential predictors of response to rTMS treatment. Retrospective review and analysis of records of 79 patients with medication-refractory OCD, all of whom had received 20 sessions of 1-Hz rTMS as part of routine clinical care. Of 79 patients, 46 received rTMS over the bilateral SMA and 33 over the left OFC. A reduction of 25% and 35% in Yale-Brown Obsessive Compulsive Scale (YBOCS) scores was used to classify outcome as partial and complete response, respectively. Statistical analysis was done using SPSS version 23.0. There was a significant decrease in mean YBOCS score from baseline to end of treatment (7.68 ± 5.62; t = 12.14, P < 0.001). Forty-five patients (57%) met criteria for partial response, of which 32 patients (40.5%) showed complete response. There was no significant difference in outcomes between patients receiving rTMS over SMA or OFC. Binary logistic regression analysis revealed presence of comorbid depression and higher baseline YBOCS score to be associated with lesser likelihood of response to rTMS. This study provided evidence for overall effectiveness of adjunctive 1-Hz rTMS treatment over either SMA or OFC in patients with medication-refractory OCD, and reported comorbid depression and higher pretreatment YBOCS scores as potential predictors of poor response to rTMS.

The Effect of Low-Frequency Repetitive Transcranial Magnetic Stimulation at Orbitofrontal Cortex in the Treatment of Patients With Medication-Refractory Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is a chronic debilitating psychiatric disorder, with significant proportion of patients failing to respond with current first-line treatments. The present study assesses the safety and effectiveness of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) over left-orbitofrontal cortex (Lt-OFC) as a potential augmentation strategy in treatment of patients with medication-refractory OCD in real-world clinical setting. The present report also aims to examine the factors affecting response to rTMS and the durability of effects produced by rTMS over 1 month of follow-up period. Retrospective review and analysis of clinical case files of 25 patients with medication-refractory OCD, all of whom had received 20 sessions of LF-rTMS over Lt-OFC as part of routine clinical care. A reduction of 25% and 35% in Yale-Brown Obsessive Compulsive Scale scores was used to determine the proportion of partial and complete responders, respectively. There was a significant decrease in mean Yale-Brown Obsessive Compulsive Scale score at the end of 20 sessions of rTMS compared with baseline (7.04 ± 5.07; P < 0.001), with no further significant change during the subsequent 1-month follow-up period (0.20 ± 1.38; P = 0.47). Thirteen patients (52%) met criteria for partial response, of which 11 patients (44%) showed complete response. Furthermore, higher number of failed medication trials was found to be significantly associated with greater chances of nonresponse to rTMS treatment. There is a role of applying LF-rTMS over Lt-OFC as an augmentation strategy in ameliorating clinical symptoms among patients with medication-refractory OCD.

Examination of Phosphoprotein Targets in Timed Samples from Patients with RAS-Mutated AML during Concurrent Treatment with Alpelisib and Binimetinib on the Phase Ib Clinical Trial CMEK162X2109

Activation of MAPK signaling is characteristic of many cancers, and approximately 15% of AML patients carry activating RAS mutations. The PI3K pathway is also constitutively activated in AML. Both pathways interact with each other extensively and provide compensatory signaling when one pathway is inhibited. It has been demonstrated in vitro that concurrent inhibition of both pathways is effective in blocking the proliferation of AML cell lines through an immediate decrease in pAkt and pErk, leading to inhibition of pS6 (Gritsman et al, J Clin Invest, 2014, 124(4):1794-1809). The combination of alpelisib (BYL-719), which inhibits PI3K (p110alpha), and binimetinib (MEK-162), which inhibits MEK (MAPK pathway), was tested in various tumor types in the Phase Ib Clinical Trial CMEK162x2109. We present here the clinical data and correlative phosphoprotein analysis of 6 patients with relapsed refractory RAS-mutated AML treated at Massachusetts General Hospital on Extension Arm 4A of this trial.Entry to this trial was restricted to adult patients with RAS-mutated AML previously treated with 1 or 2 prior chemotherapy regimens or for whom there was no known effective therapy. Patients received 200mg QD of alpelisib and 45mg BID of binimetinib concurrently and continuously with adjustments for toxicities. Hematologic toxicity could not be determined in these patients with active AML causing myelosuppression. There were responses in blood and/or bone marrow (BM) in 3 patients, but none made partial response criteria by IWG guidelines, mainly due to platelet counts <100,000/ul. Blast clearance from blood in the first month were seen in 2 patients, with a >50% reduction in a third patient. A rise in absolute neutrophil count was seen in 3 patients, 2 from below 100/ul to above 500/ul, and in 1 from 5,320/ul to 12,797/ul during the first month. BM partial responses were seen in 2 patients, with blast percentages dropping from 39% to 10% in 1 patient and from 12% to 5% in another.We analyzed the effects of this drug combination on signaling targets by collecting peripheral blood samples on day 1 pre-treatment and at 6 and 24 hours post-initiation of treatment. In 4 patients, we performed analysis of the phosphorylation of Akt, ribosomal protein S6, Erk, STAT5, and STAT3 on timed peripheral blood samples by immunoblotting. In all 4 cases at baseline, pAkt, pErk, and pS6 were detectable, while pSTAT5 and pSTAT3 levels were variable. In 3 of 4 cases, we observed a transient decrease in pAkt at 6 hours, but then a rebound at 24 hours. In 3 of 4 cases, we observed a lack of sustained pS6 inhibition. We observed sustained pErk inhibition at 24 hours in 2 cases. One patient who had blood blast clearance, improvement in ANC, and a drop in bone marrow blasts, showed strong inhibition of pAkt and pERK at 6 hours, although pS6 did not decrease. In another case we performed phospho-flow cytometry on timed whole blood samples. We observed an increase in pAkt, pS6, and pErk from baseline at 24 hours, both in CD34+38+blasts, and in the primitive CD34+38- cells. This second patient showed no clinical benefit from the treatment in terms of blood blast count, ANC, or platelets.We also performed immunohistochemistry for pS6, pErk, pAkt, pSTAT5, pSTAT3, p-eIF4E, and Caspase 3 on BM sections obtained at diagnosis and at one month and two months post-initiation of treatment, when available. These studies generally showed either persistence or an increase in the pS6 and p-eIF4E signals, both indicators of mTORC1 activity, in post-treatment BM samples. Levels of pAkt, pErk, pSTAT5 and pSTAT3 were highly variable in the post-treatment bone marrow samples.In conclusion, we demonstrated some initial target inhibition with the concurrent use of alpelisib and binimetinib in a subset of patients. However, inhibition of late downstream targets was not sufficiently sustained to achieve consistent clinical benefit in our patients with RAS-mutated AML. While the strategy of concurrent inhibition of various critical signaling pathways remains interesting, sustained inhibition of downstream signaling may require a different dosing schedule of the two drugs. Given the incomplete inhibition of mTORC1 targets pS6 and p-eIF4E in most cases, the addition of a third agent to inhibit pathways causing cross-activation downstream of mTORC1 may be required. [Display omitted] [Display omitted] DisclosuresWeinstock:Novartis: Consultancy, Research Funding. Fathi:Bexalata: Other: Advisory Board participation; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Agios Pharmaceuticals: Other: Advisory Board participation.

Hypo-Vascular Liver Metastases Treated with Transarterial chemoembolization: Assessment of Early Response by Volumetric Contrast-Enhanced and Diffusion-Weighted Magnetic Resonance Imaging

OBJECTIVE: To evaluate the value of anatomic and volumetric functional magnetic resonance imaging (MRI) in early assessment of response to trans-arterial chemoembolization (TACE) in hypovascular liver metastases. METHODS: This retrospective study included 52 metastatic lesions (42 targeted and 10 non-targeted) in 17 patients who underwent MRI before and early after TACE. Two reviewers reported response by anatomic criteria (Response Evaluation Criteria in Solid Tumor [RECIST], modified RECIST [mRECIST], and European Association for the Study of Liver Disease [EASL]) and functional criteria (volumetric apparent diffusion coefficient and contrast enhancement). Treatment endpoint was RECIST at 6 months. A 2-sample paired t test was used to compare the mean changes after intra-arterial therapy. P < .05 was considered statistically significant. RESULTS: Reduction in mRECIST and EASL at 1 month was significant in the whole cohort as well as in responders by RECIST at 6 months, and the changes fulfilled partial response criteria for both metrics in responders. Responders also had significant changes in volumetric apparent diffusion coefficient (P = .01 and P = .03) and contrast enhancement (P < .0001 and P < .0001) at 1 month for both readers, respectively. CONCLUSION: At 1 month post treatment, responders did not fulfill RECIST criteria but fulfilled mRECIST and EASL criteria. In addition, volumetric contrast-enhanced and diffusion-weighted MRI may be helpful in evaluating early treatment response after TACE in hypovascular liver metastases in patients who have failed to respond to initial chemotherapy.

Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature.

Resistance to imatinib has been recurrently reported in systemic mastocytosis (SM) carrying exon 17 KIT mutations. We evaluated the efficacy and safety of imatinib therapy in 10 adult SM patients lacking exon 17 KIT mutations, 9 of which fulfilled criteria for well-differentiated SM (WDSM). The World Health Organization 2008 disease categories among WDSM patients were mast cell (MC) leukemia (n = 3), indolent SM (n = 3) and cutaneous mastocytosis (n = 3); the remainder case had SM associated with a clonal haematological non-MC disease. Patients were given imatinib for 12 months −400 or 300 mg daily depending on the presence vs. absence of > 30% bone marrow (BM) MCs and/or signs of advanced disease–. Absence of exon 17 KIT mutations was confirmed in highly-purified BM MCs by peptide nucleic acid-mediated PCR, while mutations involving other exons were investigated by direct sequencing of purified BM MC DNA. Complete response (CR) was defined as resolution of BM MC infiltration, skin lesions, organomegalies and MC-mediator release-associated symptoms, plus normalization of serum tryptase. Criteria for partial response (PR) included ≥ 50% reduction in BM MC infiltration and improvement of skin lesions and/or organomegalies. Treatment was well-tolerated with an overall response rate of 50%, including early and sustained CR in four patients, three of whom had extracellular mutations of KIT, and PR in one case. This later patient and all non-responders (n = 5) showed wild-type KIT. These results together with previous data from the literature support the relevance of the KIT mutational status in selecting SM patients who are candidates for imatinib therapy.

Rebound growth of hepatic colorectal metastases after neo-adjuvant chemotherapy: effect on survival after resection

BackgroundA period of recovery is commonly allowed between completion of chemotherapy for colorectal liver metastases (CRLM) and resection, during which tumour progression may occur. The study-aim is to assess the growth of CRLM in this interval and association with outcome. MethodData on 146 patients were analysed. Change in tumour size was assessed by comparing size determined by imaging performed on completion of chemotherapy with that determined by examination of the resected specimen, categorised by RECIST criteria. ResultsIn the interval before surgery sixteen patients (11%) fulfilled criteria for partial response (PR), 48 (33%) had stable disease (SD) and 82 (56%) had progressive disease (PD). Among patients with PD following chemotherapy the median disease-free survival of patients who initially responded (26 months) was longer than in those who initially had stable disease (7 months) (P = 0.002). No association was noted between rate of tumour growth after completion of chemotherapy and disease-free survival. ConclusionChange in tumour size after completion of chemotherapy is variable and can be rapid, especially in patients who initially respond to treatment. However, disease-free survival is determined by tumour behaviour during treatment and not by change in size after completion of chemotherapy.

Imatinib Mesylate for the Treatment of Steroid-Refractory Sclerotic-Type Cutaneous Chronic Graft-versus-Host Disease

Sclerotic skin manifestations of chronic graft-versus-host disease (ScGVHD) lead to significant morbidity, including functional disability from joint range of motion (ROM) restriction. No superior second-line therapy has been established for steroid-refractory disease. Imatinib mesylate is a multikinase inhibitor of several signaling pathways implicated in skin fibrosis with in vitro antifibrotic activity. We performed an open-label pilot phase II trial of imatinib in children and adults with corticosteroid-refractory ScGVHD. Twenty patients were enrolled in a 6-month trial. Eight received a standard dose (adult, 400 mg daily; children, 260 mg/m2 daily). Because of poor tolerability, 12 additional patients underwent a dose escalation regimen (adult, 100 mg daily initial dose up to 200 mg daily maximum; children, initial dose 65 mg/m2 daily up to 130 mg/m2 daily). Fourteen patients were assessable for primary response, improvement in joint ROM deficit, at 6 months. Primary outcome criteria for partial response was met in 5 of 14 (36%), stable disease in 7 of 14 (50%), and progressive disease in 2 of 14 (14%) patients. Eleven patients (79%), including 5 with partial response and 6 with stable disease, demonstrated a positive gain in ROM (range of 3% to 94% improvement in deficit). Of 13 patients with measurable changes at 6 months, the average improvement in ROM deficit was 24.2% (interquartile range, 15.5% to 30.5%; P = .011). This trial is registered at http://clinicaltrials.gov as NCT007020689.