CTNI-24. A PHASE 1/2 STUDY OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi64-vi64
Author(s):  
Susan Chi ◽  
Antony Hsieh ◽  
Megan Foley ◽  
Hongliang Shi ◽  
Preethi Swamy ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Targeted Therapies ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Treatment Options ◽  
Objective Response ◽  
Germ Cell Tumors ◽  
Cns Tumors ◽  
Activation Loop ◽  
Open Label

Abstract Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor; response rates are only ~15% with targeted therapies. Germ cell tumors and high-grade glioma (HGG) are the most common with KIT alterations; sarcoma and HGG are the most common tumors with platelet-derived growth factor receptor alpha (PDGFRA) alterations. H3K27M gliomas are dependent on PDGFRA signaling and patients have an overall survival of ~1 year. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid or CNS tumors, or H3K27M gliomas. The selective KIT and PDGFRA inhibitor, avapritinib, demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50 < 2 nM), and PDGFRA activation-loop (D842V) mutants (IC50 = 0.24 nM); cellular IC50 of PDGFRA wild-type was 95 nM. CNS penetration in preclinical models (brain-to-plasma ratios at steady-state ranging from 0.74–1.00) demonstrated potential for CNS antitumor activity. Avapritinib is approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V) in the USA, and in the EU for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. Objectives of this 2-part phase 1/2, multicenter, open-label study are to assess avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients aged 2 to < 18 years with solid R/R tumors dependent on KIT or PDGFRA signaling, including H3K27M gliomas and no alternative treatment options. Part 1 will enroll ≥ 6 patients; primary endpoint is confirmed age and body surface area physiologically-based pharmacokinetic modeling dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥ 25 patients at the recommended avapritinib dose from Part 1; primary endpoint is objective response rate. Avapritinib once-daily will be administered in continuous 28-day cycles.

scholarly journals EPCT-05. A PHASE 1/2 STUDY OF AVAPRITINIB FOR KIT- OR PDGFRA-MUTANT PEDIATRIC RELAPSED/REFRACTORY SOLID TUMORS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i47-i47
Author(s):  
Susan Chi ◽  
Antony Hsieh ◽  
Megan Foley ◽  
Hongliang Shi ◽  
Preethi Swamy ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Primary Endpoint ◽  
Targeted Therapies ◽  
Pediatric Patients ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
Cns Tumors ◽  
Activation Loop ◽  
Overall Response

Abstract Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor; targeted therapies achieve response rates of only ~15%. Germ cell tumors and high-grade glioma (HGG) are the most common with KIT mutations; sarcoma and HGG are the most common tumors with platelet-derived growth factor receptor alpha (PDGFRA) mutations. Two-year overall survival is <10% for pediatric patients with diffuse intrinsic pontine glioma, often driven by PDGFRA mutations. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid tumors. The selective KIT and PDGFRA inhibitor, avapritinib, demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50 <2 nM), and PDGFRA activation-loop (D842V) mutants (IC50=0.24 nM). CNS penetration in preclinical models (brain-to-plasma ratios at steady-state ranging from 0.74–1.00) demonstrated potential for activity against CNS tumors. Avapritinib is approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V) in the USA based on an overall response rate ³84% with 59% response durations >6 months, and in the EU for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. The objectives of this 2-part phase 1/2 multicenter, open-label study, anticipated to enroll 31 patients from Q3 2021, are to assess avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients with KIT/PDGFRA-mutant solid R/R tumors. Eligible patients are aged 2 to <18 years with no alternative treatment options. Part 1 will enroll ≥6 patients; primary endpoint is confirmed age and body surface area physiologically-based pharmacokinetic modeling dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥25 patients at the recommended modeled avapritinib dose from Part 1; primary endpoint is overall response rate. Avapritinib once-daily will be administered in continuous 28-day cycles.

A phase I study of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 408-408
Author(s):  
Costantine Albany ◽  
Michael J. Spinella ◽  
Nabil Adra ◽  
Nasser H. Hanna ◽  
Lawrence Einhorn
Keyword(s):  
Germ Cell ◽  
Phase 1 ◽  
Objective Response ◽  
Germ Cell Tumors ◽  
Maximum Tolerated Dose ◽  
Neutropenic Fever ◽  
Epigenetic Therapy ◽  
Clinical Activity ◽  
Open Label ◽  
Platinum Refractory

408 Background: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Platinum-refractory germ cell tumors (GCT) showed significant DNA hypermethylation compared to platinum sensitive tumors. In preclinical studies, GCT were extremely sensitive to low dose decitabine which restored sensitivity to cisplatin in cell lines. We aimed to assess the safety and clinical activity of guadecitabine in combination with cisplatin in patients with platinum-refractory GCT. Methods: In this open-label, phase 1 study, patients with GCT refractory to or had relapsed after platinum-based treatment were treated with subcutaneous (SQ) guadecitabine, once-daily for 5 consecutive days, followed by cisplatin on day 8 with growth factor support (GFS) in a 28-day treatment cycle. A modified toxicity probability interval (mTPI) dose-escalation design was used in which we treated patients with guadecitabine doses of 30-45 mg/m2 plus cisplatin 100 mg/m2 up to 6 cycles until progression or intolerable toxicity. The primary objective was to assess safety and tolerability of the combination, determine the maximum tolerated dose (MTD). Secondary objective was objective response rate (ORR). Results: Fourteen patients with incurable disease were enrolled. Primary site were testis 11, mediastinum 2, and ovarian 1. All progressed after at least 2 lines of standard of care chemotherapy including HDCT. Dose-limiting toxicities were neutropenic fever. Most common toxicities were neutropenia (82% any grade), thrombocytopenia (42%), anemia (33%), neutropenic fever (8%), and diarrhea (8%). The maximum tolerated dose of guadecitabine was 30 mg/m2 x 5 days and cisplatin 100 mg/m2. We observed 2/14 complete response lasting more than 6 months, 2 partial response and 1 stable disease. ORR 28.5%. Conclusions: We report the first study of chemo-priming with epigenetic therapy in GCT. Guadecitabine 30 mg/m2 x 5 days and cisplatin 100 mg/m2 with GFS was safe and tolerable and showed promising activity with 4/14 responses in this highly treatment refractory patient population. Clinical trial information: NCT02429466.

Phase 1/2 study of the selective TRK inhibitor larotrectinib in pediatric patients with cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS10577-TPS10577 ◽  
Author(s):  
Noah Federman ◽  
Catherine Michelle Albert ◽  
Brian Turpin ◽  
Leo Mascarenhas ◽  
Ramamoorthy Nagasubramanian ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Objective Response ◽  
Cns Tumors ◽  
Spindle Cell Sarcoma ◽  
Phase 2 ◽  
Infantile Fibrosarcoma ◽  
Molecular Abnormalities

TPS10577 Background: Neurotrophin ligands and their receptors TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3) are important for growth regulation, differentiation and survival of neurons. Translocations involving the NTRK1/2/3 kinase domain, mutations involving the TRK ligand-binding site, and amplifications of NTRK, have been described in diverse tumor types and may contribute to tumorigenesis. A broad range of pediatric malignancies have been found to harbor NTRK fusions, including infantile fibrosarcoma (IFS), spindle-cell sarcoma, congenital mesoblastic nephroma, pediatric papillary thyroid cancer, pediatric gliomas and Ph-like acute lymphoblastic leukemia. Larotrectinib is the first small-molecule selective inhibitor of TRKA, -B, and -C in clinical development and preliminary data from the adult phase 1 trial demonstrate prolonged responses in patients with TRK fusions and a favorable safety profile. Methods: We have initiated an open-label, multi-center, international Phase 1/2 study with larotrectinib in pediatric patients with solid tumors and primary CNS tumors (NCT02637687). Patients with advanced cancer between the ages of 1 year and 21 years are eligible, as well as patients as young as 1-month of age with a documented NTRK fusion. Patients with IFS who have not had definitive surgery are also eligible. Larotrectinib is administered orally twice daily on a continuous 28-day schedule. Dosing is based on body surface area. Larotrectinib is available in an oral liquid formulation and capsules. Following identification of the maximum tolerated dose of larotrectinib in the phase 1 portion, the phase 2 portion will commence. The phase 2 portion will enroll patients with NTRK-translocated tumors and measurable disease into three cohorts: 1) infantile fibrosarcoma; 2) extracranial solid tumors; and 3) primary CNS tumors. The primary endpoint for the phase 2 portion is objective response rate, with duration of response and progression free survival as secondary efficacy endpoints. Each phase 2 cohort will enroll in a single stage of up to 10 patients per cohort. Molecular abnormalities will be characterized through the analysis of archival tissue. Enrollment began in December 2015 and is ongoing. Clinical trial information: NCT02637687.

Checkmate 649: A randomized, multicenter, open-label, phase 3 study of nivolumab (Nivo) plus ipilimumab (Ipi) versus oxaliplatin plus fluoropyrimidine in patients (Pts) with previously untreated advanced or metastatic gastric (G) or gastroesophageal junction (GEJ) cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS213-TPS213 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
Antoine Adenis ◽  
Jean-Sebastien Aucoin ◽  
Carlo Barone ◽  
Narikazu Boku ◽  
...  
Keyword(s):  
Phase 1 ◽  
Treatment Options ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Progression Free Survival ◽  
First Line ◽  
Open Label ◽  
Phase 3 ◽  
Multiple Tumor ◽  
Open Label Phase

TPS213 Background: The combination ofoxaliplatin and fluoropyrimidine is a standard-of-care (SOC) first-line treatment of pts with metastatic G/GEJ cancer, resulting in a median overall survival (OS) of 8–11 months and objective response rate (ORR) of 30%–50%. This is accompanied by up to 77% grade 3/4 toxicities. Therefore, new treatment options are needed to improve survival and decrease toxicity in G/GEJ cancer. Nivo, a fully human IgG4 monoclonal antibody (mAb) that targets programmed death 1 (PD-1) and ipi, a fully human IgG1 mAb that targets cytotoxic T-lymphocyte–associated protein 4, have demonstrated manageable safety profiles and efficacy in multiple tumor types and may have a synergistic effect. In a phase 1/2 study in chemotherapy-refractory pts with G/GEJ/esophageal cancer with or without PD-1 ligand 1 (PD-L1) expression, second-line nivo 1 mg/kg + ipi 3 mg/kg demonstrated a manageable safety profile and resulted in 26% ORR (44% ORR in pts with PD-L1+ tumors), median OS of 6.9 months, and a 34% OS rate at 12 months (Janjigian Y, et al. J Clin Oncol. 2016;34[suppl][abstract 4010]). This open-label, phase 3 trial will evaluate nivo + ipi as first-line therapy for pts with G/GEJ cancer (CheckMate 649; NCT02872116). Methods: In this study, 870 pts aged ≥ 18 years with untreated advanced or metastatic G/GEJ cancer with or without PD-L1 expression will be randomized to receive nivo + ipi (4 doses; followed by nivo monotherapy) or investigator’s choice of capecitabine/oxaliplatin (XELOX) or fluorouracil/leucovorin/oxaliplatin (FOLFOX). Tumor tissue for determination of PD-L1 status must be provided from ≤ 6 months before study treatment. Pts receiving chemotherapy or radiotherapy for G/GEJ cancer within the last 6 months or pts with suspected autoimmune disease, uncontrolled medical disorder, or active infection are excluded. Primary endpoint is OS in pts with PD-L1+ tumors. Secondary endpoints include OS in all pts and progression-free survival and time to symptom deterioration in all pts and pts with PD-L1+ tumors. Clinical trial information: NCT02872116.

A phase II clinical study of pomalidomide (CC-4047) monotherapy for children and young adults with recurrent or progressive primary brain tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10035-10035 ◽  
Author(s):  
Jason R. Fangusaro ◽  
Franco Locatelli ◽  
Maria Luisa Garré ◽  
Lynley V. Marshall ◽  
Maura Massimino ◽  
...  
Keyword(s):  
Adverse Event ◽  
Primary Endpoint ◽  
Progressive Disease ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
High Grade Glioma ◽  
Complete Response ◽  
Cns Tumors ◽  
Stage 1

10035 Background: Central nervous system (CNS) tumors are the most common cause of pediatric cancer mortality and novel therapies are needed for refractory disease. Pomalidomide (pom) is an oral immunomodulatory agent with CNS penetration, anti-angiogenic, anti-inflammatory and cytotoxic activity. Methods: This Phase 2 study evaluated both safety and efficacy of pom in pediatric patients with recurrent/progressive CNS tumors. Using a Simon’s two-stage design, patients were stratified to high-grade glioma [HGG], ependymoma, medulloblastoma or diffuse intrinsic pontine glioma [DIPG] cohorts. Patients received pom 2.6 mg/m2 for 21 days of a 28-day cycle. The primary endpoint was objective response rate (complete response [CR], partial response [PR]) or prolonged stable disease [SD] (defined as ≥ 6 cycles, or ≥ 3 for DIPG). Stage 1 required ≥ 2/9 subjects, within each cohort, to have a response or prolonged SD to move into Stage 2, and ≥ 5/20 responders or patients with prolonged SD at the end of Stage 2 for pom to be deemed effective. Results: Of 52 treated patients (median age 11.5 y/o; range 4-18), 47 were evaluable for primary endpoint. Median treatment duration was 2 cycles (range 1-16). Only the HGG cohort met protocol-defined criteria to advance to Stage 2, with one PR and one prolonged SD in Stage 1. Forty-six of 47 evaluable patients discontinued pom, due to adverse event (n = 1; pneumonia), withdrawal by parent/guardian (n = 2), death (n = 4; 3 progressive disease, 1 sepsis), or progressive disease (n = 39). Nineteen of 52 treated patients experienced ≥ 1 grade 3–4 treatment-emergent adverse event (TEAE) related to pom, neutropenia (n = 15) being the most commonly reported. Twenty-six patients died on study. All deaths were attributed to either disease progression or complications from disease. Conclusions: Single agent pomalidomide failed to meet a clinically meaningful level of efficacy in children with recurrent/progressive HGG, DIPG, medulloblastoma or ependymoma. However, it should be noted that a sustained response was observed in a child with HGG, replicating the outcome observed in one child with HGG in the Phase 1 (PBTC-043) trial. Clinical trial information: NCT03257631.

A phase III, multicenter, randomized, open label trial of [fam-] trastuzumab deruxtecan (DS-8201a) versus investigator’s choice in HER2-low breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS1102-TPS1102 ◽  
Author(s):  
Shanu Modi ◽  
Shoichiro Ohtani ◽  
Caleb C. Lee ◽  
Kongming Wang ◽  
Kapil Saxena ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapies ◽  
Topoisomerase I ◽  
Bystander Effect ◽  
Phase 1 ◽  
Objective Response ◽  
Phase Iii ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Her2 Breast Cancer

TPS1102 Background: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have greatly improved survival in HER2+ breast cancer (BC). However, there are many more BC patients with HER2-low expression (immunohistochemistry [IHC] 1+ or 2+/ in situ hybridization-negative), for whom no HER2-targeted therapies are approved. [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate with a humanized HER2 antibody, peptide-based cleavable linker, and a topoisomerase I inhibitor payload. It has a drug-to-antibody ratio of ~8 and the membrane permeability of the cleaved payload enables a cytotoxic bystander effect. In an ongoing phase 1 trial, T-DXd demonstrated an objective response rate (ORR) of 44.2% (19/43) with a manageable safety profile in heavily pretreated, advanced HER2-low BC (Oct 2018 data cutoff; Modi et al, SABCS 2018). Methods: DESTINY-Breast04 is a randomized, phase 3, 2-arm, open-label, multicenter study comparing efficacy and safety of T-DXd vs physician’s choice in HER2-low, unresectable and/or metastatic BC. Approximately 540 subjects will be randomized 2:1 to T-DXd (5.4 mg/kg intravenous every 3 weeks) or physician’s choice (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Randomization is stratified by HER2 IHC status, number of prior treatments, and prior CDK4/6 inhibitor therapy/hormone receptor (HR) status. HER2 IHC will be assessed and confirmed by central testing based on archival samples. The primary efficacy endpoint is progression-free survival (PFS) per mRECIST v1.1 determined by blinded independent central review. Secondary efficacy endpoints are investigator-assessed PFS, overall survival, confirmed ORR, and duration of response. Safety endpoints include serious adverse events (AEs), treatment-emergent AEs, and AEs of special interest (interstitial lung disease/pneumonitis, cardiotoxicity, and infusion-related reactions). Primary PFS analysis will occur when 318 events are observed in HR+ subjects; providing 90% power to detect a hazard ratio of 0.68 with 1-sided α of 0.025. Enrollment began in Dec 2018. Clinical trial information: NCT03734029.

Phase II clinical trial of novel agent PBI-05204 in patients with metastatic pancreatic adenocarcinoma (mPDA).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 698-698
Author(s):  
Marc Thomas Roth ◽  
Dana Backlund Cardin ◽  
Erkut Hasan Borazanci ◽  
Margaux Steinbach ◽  
Vincent J. Picozzi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Tumor Burden ◽  
Nerium Oleander ◽  
Orthotopic Model ◽  
Open Label

698 Background: Survival statistics for mPDA are dismal and with limited treatment options novel agents are needed to improve disease outcomes. PBI-05204 (Phoenix Biotechnology, Inc., San Antonio, TX) is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract’s major cytotoxic component, has demonstrated anti-tumor activity in various tumor cell lines. In a human PDA orthotopic model, this preparation reduced tumor burden as monotherapy. Pharmacodynamic studies suggest that PBI-05204’s mechanism of action is through inhibition of the PI3k/Akt/mTOR pathway. Methods: A phase II single-arm, open-label study to determine the efficacy of PBI-05204 in patients (pts) with mPDA refractory to standard therapy was conducted. The primary endpoint was overall survival (OS) with the hypothesis that 50% of pts would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Pts received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or pt withdrawal. Radiographic response was assessed every two cycles. Results: Forty-one pts were enrolled; two never received treatment and one was found to have a neuroendocrine tumor after pathological re-evaluation, leaving 38 pts for analysis. Median age at time of enrollment was 65.0 years. The median time from initial diagnosis to treatment was 16.9 months. The primary reason for withdrawal was PD (45.2%). Ten pts were alive at 4.5 months (26.3%) with a mPFS of 56 days (corresponding to first restaging). One objective response (2.6%) was observed for 162 days. Grade ≥3 treatment-emergent adverse events occurred in 63.2% of pts with the most common attributed to drug (all grades) being fatigue (36.8%), vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Conclusions: PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate an efficacious role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy, such as temozolomide, and radiotherapy. A randomized Phase II trial is currently being designed. Clinical trial information: NCT02329717.

796 A phase I/II trial combining avelumab and trabectedin for advanced liposarcoma and leiomyosarcoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A844-A844
Author(s):  
Michael Wagner ◽  
Qianchuan He ◽  
Yuzheng Zhang ◽  
Lee Cranmer ◽  
Elizabeth Loggers ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase 1 ◽  
Objective Response ◽  
Study Drug ◽  
Phase 2 ◽  
Open Label ◽  
Reduced Ejection Fraction ◽  
Grade 3

BackgroundLeiomyosarcoma (LMS) and liposarcoma (LPS) are soft tissue sarcoma subtypes that frequently express PD-L1 and are infiltrated with T cells. They are generally resistant to PD-1/PD-L1 inhibition, possibly due to infiltration with high levels of immunosuppressive tumor-associated macrophages (TAMs). Trabectedin is FDA-approved for refractory LMS and LPS. Prior studies demonstrated trabectedin activity against TAMs. We hypothesized that PD-L1 inhibition by avelumab would be enhanced by trabectedin through its inhibition of immunosuppressive TAMs.MethodsThis is a single-arm, open-label, Phase I/II study of avelumab combined with trabectedin for patients with advanced LMS and LPS. In the phase I portion, we evaluated safety and feasibility at 3 trabectedin doses (1, 1.2 and 1.5 mg/m2) with avelumab at standard dosing (10 mg/kg) in a 3+3 design. Primary endpoint of the phase II portion was the objective response rate (ORR) by RECIST 1.1. 24 patients were included for phase II endpoints. Secondary objectives were duration of response, progression free survival (PFS), clinical benefit rate (CBR) at 12 weeks, and overall survival.Results37 patients enrolled; 34 were evaluable. 23 had LMS. 11 had LPS. In Phase 1, there were DLTs in 2 of 6 patients at both higher doses of trabectedin including grade 3 GGT elevation, bilirubin and alanine aminotransferase (ALT) elevation, small bowel obstruction, and reduced ejection fraction. The recommended Phase 2 dose was 1.0 mg/m2 trabectedin and 10 mg/kg avelumab. At the Phase 2 dose, the most common adverse events (AEs) attributed to study drug were fatigue, ALT increase, diarrhea, anorexia, nausea, and infusion reaction. There were 8 instances of PORT inflammation or infection. The most common Grade 3 AEs attributed to study drug were neutropenia and ALT increase. There were no grade 4/5 AEs at the Phase 2 dose. 23 patients were evaluable for primary ORR endpoint. 2 (8.7%) had partial response (1 confirmed), 11 had stable disease as best response. CBR (PR+SD) at 12 weeks was 56%. 6 month PFS was 50.1%; median PFS is 23.4 months. 9 patients remain on study treatment. In a secondary analysis of all patients, ORR was 8.6% (3/35 with PR), median PFS was 6.1 months.ConclusionsAdministration of this combination was feasible with acceptable toxicity. The recommended Phase 2 dose was 1.0 mg/m2 trabectedin and 10 mg/kg avelumab. The combination failed to meet the primary endpoint of ORR, however the PFS appears favorable compared to prior studies of trabectedin in this population and warrants further study.Trial RegistrationNCT03074318Ethics ApprovalThe study was approved by the Fred Hutch IRB, number 9717.

scholarly journals LGG-49. SAFETY AND EFFICACY OF TRAMETINIB (T) MONOTHERAPY AND DABRAFENIB + TRAMETINIB (D+T) COMBINATION THERAPY IN PEDIATRIC PATIENTS WITH BRAF V600-MUTANT LOW-GRADE GLIOMA (LGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii375-iii375
Author(s):  
Eric Bouffet ◽  
James A Whitlock ◽  
Christopher Moertel ◽  
Birgit Geoerger ◽  
Isabelle Aerts ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Pediatric Patients ◽  
Objective Response ◽  
Safety Data ◽  
Dose Finding ◽  
Combination Group ◽  
Clinical Activity ◽  
Low Grade ◽  
Open Label ◽  
Independent Review

Abstract BACKGROUND Children with BRAF V600-mutant LGG have suboptimal response to standard chemotherapy. Previously, D (BRAF V600 inhibitor) monotherapy has demonstrated clinical benefit in this population. We report interim analysis results of pediatric patients with recurrent/refractory BRAF V600-mutant LGG treated with either T (MEK1/2 inhibitor) monotherapy or D+T combination therapy. METHODS This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772) in pediatric patients (<18 y) with refractory/recurrent tumors. The dose-finding phase, including dose confirmation stratified by age, was followed by disease-specific cohorts at recommended dose levels. Efficacy was determined by both investigator and independent review using RANO criteria. Adverse events (AEs) were assessed per NCI-CTCAE v4.03. RESULTS Of 49 pediatric patients with BRAF V600-mutant LGG (T, n=13; D+T, n=36) enrolled, pooled efficacy data was available for both treatments while safety data was available for 30 patients (T, n=10; D+T, n=20). Most patients (n=8/10) receiving T monotherapy withdrew/discontinued the treatment in contrast to 3/20 in the D+T group. Pyrexia occurred in 50% of patients (n=5/10) in the monotherapy group and was a frequent AE in the combination group (75%; n=15/20). Objective response rate per independent review was 15% (95% CI, 2%–45%) with T monotherapy and 25% (95% CI, 12%–42%) with D+T combination therapy. Seven patients (54%) on monotherapy and 33 patients (92%) on combination therapy had stable disease or better. CONCLUSION In pediatric patients with previously treated BRAF V600-mutant LGG, T monotherapy and D+T combination therapy demonstrated clinical activity, with pyrexia being a common AE.

scholarly journals EPCT-02. PBTC-051: FIRST IN PEDIATRICS PHASE 1 STUDY OF CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M IN PEDIATRIC SUBJECTS WITH RECURRENT/REFRACTORY BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii304-iii304
Author(s):  
Holly Lindsay ◽  
Arzu Onar-Thomas ◽  
Mehmet Kocak ◽  
Tina Young Poussaint ◽  
Girish Dhall ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Dose Level ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Pediatric Brain Tumor ◽  
Cns Tumors ◽  
Level 3 ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Antigen Presenting

Abstract BACKGROUND CD40 is a co-stimulatory molecule expressed on antigen presenting cells (APCs). APX005M is a CD40 agonist monoclonal antibody which stimulates innate and adaptive anti-tumor immunity through activation of APCs, macrophages, and antigen-specific CD8+T-cells. Pediatric Brain Tumor Consortium study PBTC-051 is the first investigation of APX005M in pediatric patients and is evaluating the safety, recommended phase 2 dose (RP2D), pharmacokinetics, and preliminary efficacy of APX005M in children with central nervous system (CNS) tumors. RESULTS Accrual of patients with recurrent/refractory primary malignant CNS tumors (stratum 1) began in March 2018. 16 patients (2 ineligible) have enrolled on this stratum; 14 were treated. Dose escalation through 3 planned dose levels of APX005M was completed without excessive or unanticipated toxicities. The highest dose level (0.6 mg/kg q3 weeks) is the presumptive RP2D, and an expansion cohort is currently enrolling at this dose. 2 patients at dose level 3 have received >12 cycles of therapy. Grade 3 or higher adverse events at least possibly attributable to APX005M include 11 lymphopenia, 5 neutropenia, 5 leukopenia, 3 ALT elevations, 1 AST elevation, 1 thrombocytopenia, and 1 hypoalbuminemia. PK data will be available March 2020. Stratum 2 is now enrolling patients with post-radiation/pre-progression DIPG beginning at dose level 2, with 1 patient currently enrolled. CONCLUSION The CD40 agonistic antibody APX005M has demonstrated preliminary safety in pediatric patients with recurrent/refractory primary malignant CNS tumors and has a likely RP2D of 0.6 mg/kg q3 weeks in this population. Preliminary efficacy data are pending.

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