CTNI-58. EFFICACY AND SAFETY OF LAROTRECTINIB IN ADULT AND PEDIATRIC PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION-POSITIVE PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi73-vi74
Author(s):  
François Doz ◽  
Cornelis M van Tilburg ◽  
Birgit Geoerger ◽  
Karsten Nysom ◽  
Ingrid Øra ◽  
...  
Keyword(s):  
Disease Control ◽  
Objective Response ◽  
Disease Control Rate ◽  
Cns Tumors ◽  
Low Grade ◽  
Grade 3 ◽  
Round Blue Cell Tumor ◽  
Glioneuronal Tumors ◽  
Favorable Safety ◽  
Systemic Therapies

Abstract BACKGROUND NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a first-in-class, highly selective TRK inhibitor approved for patients with TRK fusion cancer, with a 75% objective response rate (ORR) in 206 evaluable patients with various non-CNS cancers (Hong et al, ASCO 2021). We report data on patients with TRK fusion-positive primary CNS tumors. METHODS Patients with TRK fusion-positive primary CNS tumors in 2 clinical trials (NCT02637687, NCT02576431) were identified. Objective responses were investigator-assessed. RESULTS As of July 2020, 33 patients with TRK fusion-positive primary CNS tumors were identified (19 high-grade gliomas [HGG], 8 low-grade gliomas [LGG], 2 glioneuronal tumors, 2 neuroepithelial tumors, 1 CNS neuroblastoma, 1 small round blue cell tumor). Median age was 8.9 years (range 1.3-79.0). Patients were heavily pre-treated, with 45% having ≥ 2 prior systemic therapies. ORR was 30% (95% CI 16-49): 3 complete responses (all pediatric), 7 partial responses, 20 stable disease, and 3 progressive disease. ORR in patients with HGG and LGG were 26% (95% CI 9-51) and 38% (95% CI 9-76), respectively. Median time to response was 1.9 months. Responses were seen regardless of the number of prior systemic therapies. The 24-week disease control rate was 73% (95% CI 54-87). Median PFS was 18.3 months (95% CI 6.7-not estimable [NE]) and median overall survival (OS) was not reached (95% CI 16.9-NE) at a median follow-up of 16.5 months; 12-month OS rate was 85% (95% CI 71-99). Treatment duration ranged from 1.2 to 31.3+ months. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 3 patients (9%). There were no treatment discontinuations due to TRAEs. CONCLUSIONS In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and favorable safety regardless of age or number of prior systemic therapies.

scholarly journals RARE-07. EFFICACY AND SAFETY OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION-POSITIVE PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i42-i42
Author(s):  
Sébastien Perreault ◽  
François Doz ◽  
Birgit Geoerger ◽  
Karsten Nysom ◽  
Ingrid Øra ◽  
...  
Keyword(s):  
Disease Control ◽  
Pediatric Patients ◽  
Objective Response ◽  
High Grade Glioma ◽  
Disease Control Rate ◽  
Cns Tumors ◽  
Glioneuronal Tumor ◽  
Low Grade ◽  
High Grade ◽  
Gene Fusions

Abstract Background NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a highly selective TRK inhibitor approved to treat patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). We report updated data on pediatric patients with TRK fusion-positive primary CNS tumors. Methods Patients aged <18 years with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed. Results By July 2020, 26 pediatric patients with TRK fusion-positive CNS tumors were treated. Tumor histologic subtypes included high-grade glioma (n=13), low-grade glioma (n=7), glioneuronal tumor (n=2), neuroepithelial tumor (n=2), CNS neuroblastoma (n=1), and small round blue cell tumor (n=1). Median age was 7.0 years (range 1.3–16.7). The ORR was 38% (95% CI 20–59%): 3 complete responses, 7 partial responses (including 2 pending confirmation), 14 stable disease, and 2 progressive disease. The ORR in patients with high-grade glioma was 38% (95% CI 14–68%). Nineteen of 21 patients (90%) with measurable disease had tumor shrinkage. The 24-week disease control rate was 77% (95% CI 56–91%). Median duration of response (DoR), PFS and overall survival (OS) were not reached. The 12-month rates for DoR, PFS and OS were 75%, 65%, and 86%, respectively. Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events were reported for 15 patients (58%) and were Grade 3–4 in 3 patients (12%), with no discontinuations related to larotrectinib. Conclusions In pediatric patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated durable responses, high disease control rate, and good tolerability. These results support testing for NTRK gene fusions in pediatric patients with CNS tumors.

Vorasidenib (VOR; AG-881), an inhibitor of mutant IDH1 and IDH2, in patients (pts) with recurrent/progressive glioma: Updated results from the phase I non-enhancing glioma population.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2504-2504 ◽  
Author(s):  
Ingo K. Mellinghoff ◽  
Katherine B. Peters ◽  
Timothy Francis Cloughesy ◽  
Howard A. Burris III ◽  
Elizabeth Anne Maher ◽  
...  
Keyword(s):  
Phase 1 ◽  
Objective Response ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Eligibility Criteria ◽  
Dual Inhibitor ◽  
Study Results ◽  
Grade 3 ◽  
Mutant Idh1 ◽  
Favorable Safety

2504 Background: Isocitrate dehydrogenase 1 and 2 mutations (m IDH1/2) occur in approximately 70% and 4% of low-grade gliomas (LGGs), respectively, promoting oncogenesis via increased production of D-2-hydroxyglutarate. In this ongoing phase 1 trial, VOR, a potent, oral, reversible, brain-penetrant, first-in-class dual inhibitor of mIDH1/2, is being evaluated in advanced m IDH1/2 solid tumors, including gliomas. Safety and preliminary results were presented previously (Mellinghoff et al., J Clin Oncol 2018). Here, we report updated data for the non-enhancing glioma pt population. Methods: Pts with recurrent/progressive m IDH1/2 glioma received VOR daily (continuous 28-day cycles). Key eligibility criteria included: ≥18 years; histologically or cytologically confirmed glioma with documented m IDH1/2; ECOG 0-2; and evaluable disease by RANO-LGG criteria. Dose escalation cohorts enrolled using a Bayesian logistic regression model (BLRM) escalation guided by the overdose control (EWOC). Tumor response was evaluated by MRI every 8 weeks using RANO-LGG criteria by local assessment. Results: As of 28 Nov 2019, 22 pts with non-enhancing glioma had received VOR and 8 (36%) remain on treatment. M/F, 8/14; grade 2/3, 17/5; median age, 47 years; m IDH1/2, 20/1; 1p19q intact, 9/22; median (range) number of prior systemic therapies, 2 (1–4). Common (≥5 pts) treatment-emergent adverse events (AEs) of any grade and regardless of causality included increased ALT/AST (63.6%/59.1%), headache (45.5%), nausea (40.9%), neutropenia (31.8%), fatigue and hyperglycemia (27.3% each), and seizures and decreased white blood cell count (22.7% each). Transaminase elevations were grade 1 in severity at dose levels < 100mg and were less frequent (5 [38.5%] of 13 pts). Three subjects had related grade ≥3 AEs; 2 discontinued due to AEs. Objective response rate was 13.6% (1 partial response, 2 minor responses), and 17 (77.3%) pts achieved stable disease. 60.5% of pts were progression free and alive at 24 months. Conclusions: In this previously treated population with non-enhancing glioma, VOR was associated with a favorable safety profile. The study results also show encouraging preliminary activity within that population, with PFS duration extending to 24 months or longer in 60% of participants. A global randomized phase 3 study of VOR in grade 2 non-enhancing glioma pts who have had surgery only is currently enrolling (NCT04164901). Clinical trial information: NCT02481154 .

151 A RANDOMIZED,OPEN CLINICAL TRIAL TO COMPARE THE EFFICACY AND SAFETY OF ANLOTINIB PLUS IRINOTECAN VERSUS IRINOTECAN IN PATIENTS WITH ESCC

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Feng Wang ◽  
Xiangrui Meng ◽  
Hangrui Liu ◽  
Qingxia Fan
Keyword(s):  
Disease Control ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Progression Free Survival ◽  
Thyroid Stimulating Hormone ◽  
Disease Control Rate ◽  
Control Group ◽  
Trial Group ◽  
Grade 3

Abstract   The benefit of systemic treatment in esophageal squamous cell carcinoma (ESCC) which has progressed after chemotherapy is still uncertain. Anlotinib (AL3818) is a novel multi-target TKI, inhibiting tumor angiogenesis and proliferation. A phase II trial (NCT02649361) has demonstrated that anlotinib has a durable antitumor activity with a manageable adverse event profile in refractory metastatic ESCC. This study (NCT03387904) aimed at comparing the effects and safety of Anlotinib Plus Irinotecan versus Irinotecan in patients with ESCC. Methods We conducted a prospective randomized, multicenter, phase II trial to compare the efficacy of Anlotinib Plus Irinotecan with Irinotecan in recurrent ESCC patients who had resistance to platinum or taxane-based chemotherapy. Eligible patients were adults with pathologically confirmed recurrent ESCC, and 82 patients were randomized 1:1 to Irinotecan (65 mg/m2/day 1 and day 8) with or without anlotinib (12 mg qd day 1 to 14) of a 21-day cycle till progression or intolerable. The primary endpoint is the disease control rate (DCR) and progression-free survival (PFS) and the secondary end points are objective response rate (ORR) and overall survival (OS). Results Between 13/1 2019 and 20/1 2020, a total of 43 patients were enrolled and randomly assigned to either the anlotinib plus irinotecan (n = 22) or the irinotecan group (n = 21).The mPFS was longer in trial group than in control group (89 days vs 66 days, HR = 0.447, P = 0.055). The Disease control rate (DCR) was 54.5% in trial group and 38.1% in the control group. The treatment-related adverse events (&gt;10%) were fatigue (59.1%), nausea (50.0%), decreased appetite (36.4%), hoarseness (27.3%), thyroid-stimulating hormone elevation (22.7%), diarrhea (9.1%), and decreased lymphocytes count(9.1%) in trial group. Grade 3 AEs included fatigue (4.5% vs 4.8%), nausea (4.5% vs 0%) and diarrhea (4.5% vs 0%) in two groups. Conclusion Anlotinib plus irinotecan was similarly tolerable but prolonged PFS compared to irinotecan monotherapy as a second-line treatment in patients with recurrent ESCC.

Efficacy and safety of larotrectinib in adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive primary central nervous system tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2002-2002
Author(s):  
Sébastien Perreault ◽  
Cornelis Martinus van Tilburg ◽  
Birgit Geoerger ◽  
Karsten Nysom ◽  
Ingrid Ora ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Disease Control ◽  
Pediatric Patients ◽  
Disease Control Rate ◽  
Cns Tumors ◽  
Low Grade ◽  
Gene Fusions ◽  
Receptor Kinase

2002 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in various tumor types, including central nervous system (CNS) tumors. Larotrectinib is a first-in-class, highly selective TRK inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across 175 adult and pediatric patients with various non-CNS cancers (McDermott et al, ESMO 2020). We report data on patients with TRK fusion-positive primary CNS tumors. Methods: Patients with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed. Results: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified: 19 high-grade gliomas (HGG), 8 low-grade gliomas (LGG), 2 glioneuronal tumors, 2 neuroepithelial tumors, 1 CNS neuroblastoma, and 1 small round blue cell tumor. The patients had gene fusions involving NTRK2 (n = 24; 73%), NTRK1 (n = 5; 15%), and NTRK3 (n = 4; 12%). Median age was 8.9 years (range 1.3–79.0); 26 patients were pediatric ( < 18 years). Patients were heavily pre-treated with 45% having 2 or more prior lines of systemic therapy. The ORR in all patients was 30% (95% CI 16–49): 3 complete responses (all in pediatric patients), 7 partial responses (2 pending confirmation), 20 stable disease (including 15 pts > 6 months), and 3 progressive disease. The ORR in patients with HGG and LGG were 26% (95% CI 9–51) and 38% (95% CI 9–76), respectively. In all patients, the 24-week disease control rate was 73% (95% CI 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The median time to response was 1.9 months. Median duration of response (DoR) was not reached (95% CI 3.8–not estimable [NE]) at a median follow-up of 12.0 months. The 12-month DoR rate was 75% (95% CI 45–100). Median PFS was 18.3 months (95% CI 6.7–NE) at a median follow-up of 16.5 months. Median overall survival (OS) was not reached (95% CI 16.9–NE) at a median follow-up of 16.5 months, with a 12-month OS rate of 85% (95% CI 71–99). Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events (TRAE) were reported by 20 patients and were Grade 3–4 in 3 patients (9%). There were no treatment discontinuations due to TRAEs. Conclusions: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile. These results support testing for NTRK gene fusions in patients of all ages with CNS tumors. Clinical trial information: NCT02637687, NCT02576431.

Safety and efficacy of tazemetostat, a first-in-class EZH2 inhibitor, in patients (pts) with epithelioid sarcoma (ES) (NCT02601950).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11003-11003 ◽  
Author(s):  
Silvia Stacchiotti ◽  
Patrick Schoffski ◽  
Robin Jones ◽  
Mark Agulnik ◽  
Victor Manuel Villalobos ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Disease Control ◽  
Tumor Regression ◽  
Phase 1 ◽  
Epithelioid Sarcoma ◽  
Objective Response ◽  
Locally Advanced ◽  
Grade 3 ◽  
Favorable Safety

11003 Background: ES is a rare soft tissue sarcoma that metastasizes in approximately 30% to 50% of cases. More than 90% of ES tumors lack expression of INI1, an important component of epigenetic regulation. Loss of INI1 function allows another epigenetic modifier, EZH2, to become an oncogenic driver in tumor cells. Tazemetostat, a first-in-class, selective, oral inhibitor of EZH2, has demonstrated tumor regression and favorable safety in phase 1/2 trials. Methods: Data from a phase 2 open-label, multicenter trial of pts with locally advanced or metastatic ES are reported. Efficacy was assessed with primary and secondary endpoints including objective response rate (ORR) by RECIST 1.1, disease control rate (DCR; objective confirmed response of any duration or stable disease [SD] lasting ≥32 weeks), duration of response (DOR), progression-free survival (PFS), overall survival (OS); safety and tolerability were also evaluated. Results: As of September 17, 2018, 62 INI1-negative ES pts were enrolled and treated with tazemetostat 800 mg BID. The median number of prior lines of therapy was 1 (range: 0-9). There were 9/62 (15%) confirmed partial responses (PRs) with an ORR of 15% and DCR of 26%. The DOR ranged from 7.1+ weeks to 103.0+ weeks (median: not reached) with a median OS of 82.4 weeks (95% CI: 47.4, not estimable) for all 62 pts. Tazemetostat was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild to moderate with the most commonly reported adverse events (AEs; ≥10% incidence) regardless of attribution being fatigue (24/62; 39%), nausea (22/62; 35%), and cancer pain (20/62; 32%). Any treatment-related TEAEs of grade ≥3 were reported in 10/62 (16%) pts. TEAEs grade ≥3 reported in ≥2 pts included anemia (6%) and decreased weight (3%). There were no drug-related deaths and a low discontinuation rate (1.7%). Conclusions: In the largest prospective clinical trial of ES to date, tazemetostat achieved disease control in 26% of pts with advanced ES who entered this study. Durable clinical response of the drug was documented. Tazemetostat demonstrated favorable safety with few pts with treatment-related AEs grade ≥3. Clinical trial information: NCT02601950.

The preliminary efficacy and safety of KN046 plus concurrent chemoradiation therapy in recurrent and metastatic esophageal squamous cell carcinoma.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 223-223
Author(s):  
Bing Song Qin ◽  
Qi Zhao ◽  
Dong Yan Liu ◽  
Jiao Xue ◽  
Xing Jia Zhu
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Disease Control ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Objective Response ◽  
Chemoradiation Therapy ◽  
Disease Control Rate ◽  
Concurrent Chemoradiation ◽  
Grade 3

223 Background: Definitive or palliative chemoradiation therapy has been employed in the management of esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitor has improved outcomes in metastatic stage IV pts. Here we report the addition of KN046, a PD-L1/CTLA-4 bispecific antibody, to concurrent chemoradiation (CRT) therapy to determine the safety and efficacy of this approach (ChiCTR2000031544). Methods: Pts with recurrent or metastatic ESCC, not been treated by CRT or other systemic treatment within 6 months, were recruited and received palliative CRT consisting of cisplatin (75 mg/m2 IV Q3W for 4~6 cycles), paclitaxel (135~175 mg/m2 IV Q3W for 4-6 cycles) and radiation (SBRT or conventional and dose are determined at the investigator’s discretion according to institutional standard). KN046 at ascending doses of 1, 3 and 5 mg/kg Q3W was added within 7-14 days after the completion of radiation therapy (RT) and concurrently with chemotherapy, followed by KN046 Q2W maintenance. Dose limiting toxicities (DLTs) were assessed for the first treatment cycle of KN046. Anti-tumor activity was assessed according to RECIST 1.1 every 6 weeks within the first year, and every 12 weeks thereafter. Results: As of June 30, 2020, 18 subjects were enrolled and received KN046 treatment (1mg/kg, n = 3; 3mg/kg, n = 11; 5mg/kg, n = 4). The median KN046 exposure was 11.5 weeks. No DLT was reported. 3 (16.7%) subjects experienced Grade 3, KN046 related adverse events (1 Grade 3 pneumonitis and 2 Grade 3 colitis recovered after steroid and antibiotic Tx). For 18 evaluable subjects, the disease control rate and objective response rate were 94.4% and 44.4%, respectively. DOR and PFS were not matured yet as of cutoff date. At 3 mg/kg, objective response was observed in 5 out of 9 subjects (55.6%) with measurable disease and disease control rate was 100%; 7/9 (77.8%) subjects experienced further tumor reduction after initiation of KN046 treatment. It is worth to note that, 2 subjects at 3mg/kg achieved complete response after receiving KN046 treatment. Conclusions: The addition of KN046 to CRT was well tolerated and showed promising efficacy signal in recurrent or metastatic ESCC. This pilot study enables further investigation of a new treatment modality of KN046 with CRT in this detrimental disease with poor prognosis. Clinical trial information: 2000031544.

scholarly journals RARE-45. ACTIVITY OF LAROTRECTINIB IN TRK FUSION CANCER PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM TUMORS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi231-vi231 ◽  
Author(s):  
Francois Doz ◽  
Birgit Geoerger ◽  
Steven G DuBois ◽  
Juneko E Grilley-Olson ◽  
Cornelis M van Tilburg ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Disease Control ◽  
Objective Response ◽  
Cns Tumors ◽  
Clinical Activity ◽  
Molecular Testing ◽  
Low Grade ◽  
Gene Fusions ◽  
Duration Of Treatment

Abstract BACKGROUND TRK fusions are oncogenic drivers of a variety of tumors, many of which can involve the central nervous system (CNS). Larotrectinib is a selective TRK inhibitor FDA-approved for the treatment of TRK fusion cancers (Drilon et al., NEJM 2018). Here we report on the clinical activity of larotrectinib in an expanded set of TRK fusion-positive primary CNS tumors. METHODS Patients with primary CNS tumors harboring a TRK fusion treated with larotrectinib on two clinical trials (NCT02637687 and NCT02576431) were identified by local molecular testing. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator assessed (RANO). Data cutoff: February 19, 2019. RESULTS 18 patients with various histological types of glial tumors (11 high-grade, 4 low-grade, 3 unknown) were identified. The patients had gene fusions involving NTRK2 (n=13), NTRK1 (n=2) and NTRK3 (n=2); one was not determined. Median age was 10 years (range 1–79); 14 patients were pediatric (< 18). In 14 evaluable patients, the objective response rate was 36% (2 CR, 3 PR), with responses seen in high- and low-grade disease and across histologies. Nine patients had SD. The 24-week disease control rate was 71%. The duration of treatment ranged from 0.03+ to 16.6+ months. One patient (3.7 years old) with glioblastoma progressed after 5.5 months on larotrectinib. Sequencing revealed a solvent front mutation and the patient was subsequently enrolled in compassionate use protocol for BAY2731954 (formerly known as LOXO-195). CONCLUSION Larotrectinib is active in patients with TRK fusion cancer with intracranial disease. Confirmed responses and durable disease control were seen in primary CNS tumors of various grades and histologies. These results further support expanded testing for NTRK gene fusions in patients with primary CNS tumors.

scholarly journals Combination Therapy With Anti-PD-1 or PD-1 Antibody Alone in Asian Pediatric Patients With Relapsed or Refractory Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Yi Que ◽  
Juan Wang ◽  
Jia Zhu ◽  
Na Li ◽  
Junting Huang ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Disease Control ◽  
Pediatric Patients ◽  
Response Rate ◽  
Objective Response ◽  
Primary Objective ◽  
Disease Control Rate ◽  
Hematologic Toxicity ◽  
Retrospective Case ◽  
Grade 3

There is limited experience of PD-1 antibody combined with other therapies in children. We aimed to explore the antitumor activity and safety of PD-1 antibody monotherapy or combination with other regimens in relapsed or refractory pediatric cancer. This is a retrospective-case study conducted in two Chinese expert centers. The primary objective of this study was to describe the overall response rate (ORR) and disease control rate (DCR). Secondary objectives included characterizing toxicities. Of the 22 pediatric patients with cancer who received PD-1 inhibitors, the median follow-up for all patients after the commencement of PD-1 therapy with or without other regimens was 12.3 months (0 - 43 months). PD-1 antibody monotherapy demonstrated antitumor activity in a population of pediatric patients with Hodgkin lymphoma (HL), with an objective response rate (ORR) and disease control rate (DCR) of 83.3% (3CR and 2PR) and 100%, respectively. However, no objective response was observed in patients with melanoma or Burkitt lymphoma evaluated in this study. We reviewed responses for patients with chemotherapy, decitabine or everolimus combination therapies with PD-1 antibodies, and found that PD-1 antibody combined with decitabine showed potential efficacy in pediatric patients with advanced embryonal rhabdomyosarcoma and lymphoepitheliomatoid-like carcinoma. There were no severe treatment-related adverse events (TRAEs) directly attributed to PD-1 antibody monotherapy in Asian pediatric patients with lower incidence of hematologic toxicity and nonhematologic toxicity. The Grade ≥3 TRAEs were attributed to the combination chemotherapy.

scholarly journals Primary CNS Tumors and Leptomeningeal, Disseminated and/or Multicentric Disease in Children Treated in Phase II Studies with Antineoplastons A10 and AS2-1

2016 ◽  
Vol 5 (2) ◽  
pp. 38 ◽  
Author(s):  
Stanislaw Burzynski ◽  
Tomasz J Janicki ◽  
Gregory S Burzynski
Keyword(s):  
Phase Ii ◽  
Objective Response ◽  
Complete Response ◽  
Cns Tumors ◽  
Low Grade ◽  
Mri Imaging ◽  
Phase Ii Studies ◽  
Atypical Teratoid ◽  
Prospective Phase ◽  
Grade 3

<p class="cco-body"><span lang="EN-GB">It is estimated that as many as 30% of patients with primary CNS tumors have leptomeningeal, disseminated, and/or multicentric disease (LDM). These patients respond poorly to conventional therapy. Fifty-seven children with LDM (median age of 7.1 years) were treated in multiple prospective phase II clinical studies of high- and low-grade primary CNS tumors with Antineoplastons A10 and AS2-1 (ANP). Their inclusion in this analysis was based on MRI imaging. Patients with glioblastoma were excluded. The patients received ANP therapy 6 times daily; A10: 8.77 g/kg/d; AS2-1: 0.35 g/kg/d. The response to ANP was monitored by MRIs every 8 weeks. Patients evaluable for efficacy (<em>N </em>= 40) received 12 or more weeks of ANP or developed progressive disease (PD) before 12 weeks. 10 patients (17.5%) achieved an objective response (OR) with 4 (7%) achieving a complete response (CR) and 6 (10.5%) had a partial response (PR). Stable disease (SD) was maintained in 7 patients (12.3%) and PD developed in 23 patients (40.4%). Survival analysis of the 57 children showed 2- and 5-year overall survival (OS) were both 28% while 10- and 15-year OS were both 26%. One of the patients achieving an OR had atypical teratoid/rhabdoid tumor (AT/RT) while nine had low-grade gliomas (LGGs). Grade 3 and 4 toxicities included hypokalemia (14.0%); fatigue, anemia, hypernatremia and leukopenia (3.5% each); diarrhea, hypertension, joint pain, thrombocytopenia, and somnolence (1.8% each). These findings suggest the need for a single-arm, phase II study of ANP in children with LDM.</span></p>

scholarly journals CTNI-67. EFFICACY AND SAFETY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: AN EXPANDED DATASET

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii58-ii58
Author(s):  
Sébastien Perreault ◽  
François Doz ◽  
Alexander Drilon ◽  
Birgit Geoerger ◽  
Valentina Boni ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Disease Status ◽  
Cns Tumors ◽  
Low Grade ◽  
Best Response ◽  
Treatment Beyond Progression ◽  
Duration Of Response ◽  
Report Data ◽  
Grade 3

Abstract BACKGROUND TRK fusion proteins are oncogenic drivers of various CNS and non-CNS tumors. Larotrectinib, a highly selective FDA- and EMA-approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% across various non-CNS cancers (Hong et al. Lancet Oncol. 2020). We report data in an expanded set of TRK fusion primary CNS tumors treated with larotrectinib. METHODS Patients with primary CNS tumors harboring an NTRK gene fusion treated with larotrectinib in two clinical trials (NCT02637687, NCT02576431) were identified. Disease status was investigator-assessed (RANO). Data cutoff: July 15, 2019. RESULTS Twenty-four patients with TRK fusion primary CNS tumors were identified. Eighteen patients had gliomas (13 high-grade and five low-grade). Median age was 8.0 years (range 1.3–79.0), with 20 patients &lt; 18 years old. ORR was 29% (95% CI 13–51%); best responses were two complete responses, five partial responses (two pending confirmation), 15 stable disease, and two progressive disease. The 24-week disease control rate was 63% (95% CI 41–81%). For the five confirmed responders, median time to best response was 1.8 months and median duration of response was 4.9 months (range 1.7+ to 10.1+). Median progression-free survival was 11.0 months (range 1.1 to 19.8+) and median overall survival was not reached (range 1.9+ to 21.4+) at a median follow-up of 6.0 months. Treatment duration ranged from 1.2 to 21.4+ months; three patients continued treatment beyond progression. Treatment-emergent adverse events (TEAEs) were mainly Grade 1 and 2. Grade 3–4 TEAEs occurred in 10 patients, with two deemed related to larotrectinib. The most common neurological TEAE was headache in three patients (Grade 1–2). No patients discontinued larotrectinib due to AEs. CONCLUSIONS Larotrectinib was active and well tolerated in patients with TRK fusion primary CNS tumors. These results support testing for NTRK gene fusions in patients with primary CNS tumors.

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