scholarly journals HGG-01. ENTRECTINIB IN RECURRENT OR REFRACTORY SOLID TUMORS INCLUDING PRIMARY CNS TUMORS: UPDATED DATA IN CHILDREN AND ADOLESCENTS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii344-iii344
Author(s):  
Giles Robinson ◽  
Ami Desai ◽  
Ellen Basu ◽  
Jennifer Foster ◽  
Karen Gauvain ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Progressive Disease ◽  
Kinase Inhibitor ◽  
Bone Fractures ◽  
Phase 1 ◽  
Objective Response ◽  
Cns Tumors ◽  
Cns Neoplasms ◽  
Alk 5 ◽  
Best Responses

Abstract STARTRK-NG (phase 1/2) is evaluating entrectinib, a CNS-penetrant oral, TRK/ROS1/ALK tyrosine kinase inhibitor, in patients <21 years with recurrent/refractory solid tumors, including primary CNS tumors. After determining the recommended dose, 550mg/m2/day, in all-comers, expansion cohorts with gene-fusion-positive CNS/solid tumors (NTRK1/2/3, ROS1) are being enrolled. As of 5Nov2019 (data cut-off), 39 patients (4.9m–20y; median 7y) have been evaluated for response, classified as complete (CR) or partial response (PR), stable (SD) or progressive disease (PD) using RANO (CNS), RECIST (solid tumors), or Curie score (neuroblastoma). Responses in patients with fusion-positive tumors were Investigator-assessed (BICR assessments are ongoing) and occurred at doses ≥400mg/m2. Best responses in fusion-positive CNS tumors (n=14) were: 4 CR (GKAP1-NTRK2, ETV6-NTRK3 [n=2], EML1-NTRK2); 5 PR (KANK1-NTRK2, GOPC-ROS1, ETV6-NTRK3, TPR-NTRK1, EEF1G-ROS1); 3 SD (BCR-NTRK2, ARHGEF2-NTRK1, KIF21B-NTRK1); 2 PD (PARP6-NTRK3, EML4-ALK); and in fusion-positive solid tumors (n=8) were: 3 CR (ETV6-NTRK3 [n=2], DCTN1-ALK); 5 PR (EML4-NTRK3, TFG-ROS1 [n=3], KIF5B-ALK). Responses (Investigator-assessed) in non-fusion tumors (n=17) were: 1 CR (ALK F1174L mutation), 3 SD, 10 PD, 3 no data/unevaluable. The objective response rate (CR+PR/total) in patients with fusion-positive tumors was 77% (17/22) versus 6% (1/17) in those with non-fusion tumors. All 39 patients experienced ≥1 adverse event (AE); the most frequent AEs included weight gain and anemia (both 48.7%); increased ALT, increased AST, cough and pyrexia (all 46.2%); increased creatinine and vomiting (both 43.6%); and bone fractures (n=10, in 9 patients). Entrectinib has produced striking, rapid, and durable responses in solid tumors with target gene fusions, especially high-grade CNS neoplasms.

Updated entrectinib data in children and adolescents with recurrent or refractory solid tumors, including primary CNS tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 107-107 ◽  
Author(s):  
Ami Vijay Desai ◽  
Giles W. Robinson ◽  
Ellen M. Basu ◽  
Jennifer Foster ◽  
Karen Gauvain ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Solid Tumors ◽  
Tyrosine Kinases ◽  
Bone Fractures ◽  
Phase 1 ◽  
Objective Response ◽  
Cns Tumors ◽  
Response To Treatment ◽  
Grade 3 ◽  
Best Responses

107 Background: The phase 1/2 STARTRK-NG trial (NCT02650401) is evaluating entrectinib, a CNS-penetrant oral inhibitor of TRK, ROS1 and ALK tyrosine kinases, in children and adolescents < 21 years old with recurrent/refractory solid tumors, including primary CNS tumors. Methods: After determining the recommended dose as 550mg/m2/day in all-comers, expansion cohorts with gene-fusion-positive CNS/solid tumors ( NTRK1/2/3 and ROS1) are being enrolled. Results: As of 1 July 2019 (data cut-off), 34 patients (4.9 months to 20 years old; median age 7 years) have been evaluated for response to treatment with entrectinib. Responses were classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) using RANO for CNS tumors, RECISTv1.1 for solid tumors, or Curie score for neuroblastomas. Responses in fusion-positive patients were assessed by blinded independent central review (BICR), and occurred at doses ≥400mg/m2. Best responses in patients with fusion-positive CNS tumors (n = 8) were four CR ( ETV6-NTRK3, EML1-NTRK2, GOPC-ROS1, and TPR-NTRK1), two PR ( KANK1-NTRK2 and EEF1G-ROS1), and two PD ( EML4-ALK and PARP6-NTRK3). In patients with fusion-positive solid tumors (n = 6) best responses were three CR ( DCTN1-ALK, ETV6-NTRK3, and ETV6-NTRK3), and three PR ( TFG-ROS1, EML4-NTRK3, and KIF5B-ALK). Responses (Investigator-assessed) in patients with non-fusion tumors (n = 20) were one CR ( ALK F1174L mutation), four SD, ten PD, and five patients were unevaluable or had no data. The objective response rate (defined as the total number of CR and PR) in fusion-positive patients was 86% (12/14) versus 5% (1/20) in non-fusion patients. Similarly, PFS was 17.5 months (95% CI 7.4–NE) in fusion-positive patients versus 1.9 months (1.8–5.7; p = 0.0002) in non-fusion patients. Most commonly reported treatment-related adverse events included weight gain (n = 14 [5 Grade 3/4]), elevated creatinine (n = 13), anemia (n = 13), nausea (n = 11), increased ALT (n = 10 [1 Grade 3/4]), increased AST (n = 10 [1 Grade 3/4]), decreased neutrophils (n = 9 [6 Grade 3/4]), and bone fractures (n = 7, of which 4 were treatment related). Conclusions: In children and adolescents < 21 years old, entrectinib has produced striking, rapid, and durable responses in solid tumors with target gene fusions, especially in high-grade CNS neoplasms. Clinical trial information: NCT02650401.

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.

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.

scholarly journals PDCT-13. ENTRECTINIB IN CHILDREN AND ADOLESCENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS INCLUDING PRIMARY CNS TUMORS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi186-vi186
Author(s):  
Giles Robinson ◽  
Ami Desai ◽  
Karen Gauvain ◽  
Ellen Basu ◽  
Kathleen Dorris ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tyrosine Kinases ◽  
Target Gene ◽  
Phase 1 ◽  
Cns Tumors ◽  
Recommended Dose ◽  
High Grade ◽  
Gene Fusions ◽  
Evaluable Population ◽  
Cns Neoplasms

Abstract The phase 1/2 STARTRK-NG trial is evaluating entrectinib, a CNS-penetrant oral inhibitor of TRK, ROS1 and ALK tyrosine kinases, in children with solid tumors, including primary CNS tumors. Eligible patients are ≤22y with recurrent/refractory solid tumors. The recommended dose was determined in all-comers, and then expansion cohorts of CNS and solid tumors with NTRK1/2/3, ROS1 or ALK gene fusions, and neuroblastomas (NBL) regardless of mutation spectrum, were enrolled. Investigator-assessed response was classified as complete (CR) or partial response (PR), stable (SD) or progressive disease using RANO (CNS), RECIST (solid tumors), or Curie score (NBL). By the clinical data cut-off, 01 April 2019, 32 patients were enrolled. As of 31 Oct 2018 (enrollment data cut-off), 29 patients were enrolled and included in the evaluable population. Median age was 7y (range 4.9m to 20y). Entrectinib was well tolerated; phase 1 dose-limiting toxicities were: elevated creatinine, dysgeusia, fatigue, and pulmonary edema. The recommended dose was 550mg/m2 daily; all responses occurred at doses ≥400mg/m2. In 6 patients with high-grade CNS tumors, all gene-fusion-positive, ORR was 100% (Investigator-assessed responses): 2 CR (ETV6-NTRK3, EML1-NTRK2); 4 PR (TPR-NTRK1, KANK1-NTRK2, EEF1G-ROS1, GOPC-ROS1). In extracranial solid tumors 6/8 had a fusion; of these, 2 achieved a confirmed CR (DCTN1-ALK, ETV6-NTRK3), and 4 achieved PR (ETV6-NTRK3, EML4-NTRK3, TFG1-ROS1, KIF5B-ALK). Central imaging review is being performed and will be provided. Duration of therapy ranged from 0.2 to 22.2 months for all 32 patients. In responding patients, time to response ranged from 1 to 8.3 months. In children with refractory CNS tumors harboring NTRK1/2/3 or ROS1 fusions, entrectinib produced striking, rapid, and durable responses. No responses were seen in tumors lacking target gene fusions. These results support the continued evaluation of entrectinib in solid tumors with target gene fusions, especially high-grade CNS neoplasms.

scholarly journals A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1425
Author(s):  
Filippo de Braud ◽  
Jean-Pascal H. Machiels ◽  
Daniela Boggiani ◽  
Sylvie W.H. Rottey ◽  
Matteo Duca ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Gamma Glutamyl Transferase ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Number Of Patients ◽  
Glutamyl Transferase

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80–220 mg/day; Arm C) with 60–80 mg/m2/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (n = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (n = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.

Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4074-4074 ◽  
Author(s):  
Jean-Charles Soria ◽  
John H. Strickler ◽  
Ramaswamy Govindan ◽  
Seungjean Chai ◽  
Nancy Chan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Ecog Performance Status ◽  
Grade 3

4074 Background: Erdafitinib (JNJ-42756493) is a potent, oral pan-FGFR tyrosine kinase inhibitor that demonstrated encouraging preliminary clinical activity and manageable adverse events (AEs) in its first-in-human phase 1 study in advanced solid tumors (NCT01703481). Here we report results from pts with CCA from this study. Methods: This 4-part study enrolled pts age ≥ 18 years (y) with advanced solid tumors. Dose escalation (part 1) followed a 3+3 design, with pts receiving ascending doses of erdafitinib continuously or intermittently (7 days on/7 days off). Subsequent parts required FGFR gene alterations in the tumor, including activating mutations and translocations or other FGFR-activating aberrations. Part 2 was a pharmacodynamics cohort. Parts 3 and 4 were dose-expansion cohorts for recommended phase 2 doses of 9 mg once daily (QD) and 10 mg intermittently, respectively. Results: Eleven pts with FGFR-aberrant CCA were treated at 9 mg QD (n = 1) or 10 mg intermittent (n = 10). Median age was 60 y; 7 of 11 pts were female (64%). 73% of pts had ECOG performance status 1. All had prior systemic therapy. Median treatment duration with erdafitinib was 5.3 months (mo). Systemic erdafitinib exposure, per Cmax and AUC, in CCA pts was similar to other indications. The most common AEs were stomatitis (82%), hyperphosphatemia (64%), dry mouth (55%), dysgeusia (45%), dry skin (45%), and asthenia (45%), mostly grade 1/2 severity. No drug-related grade ≥3 AEs were reported in > 1 pt except grade 3 stomatitis (n = 2; 18%). The objective response rate, all confirmed partial responses (PRs) per RECIST 1.1, was 27.3% (3/11; 95% CI 6, 61); an additional 27.3% (3/11) had stable disease as their best response. Overall disease control rate was 55%. All 3 PRs were at the 10 mg intermittent dosage, and the median duration of response was 12.9 mo. With a median follow-up of 5.1 mo, median progression-free survival was 5.1 mo (95% CI 1.6, 16.4). As of the cutoff date, 2 pts continue on study treatment. Conclusions: Erdafitinib showed encouraging clinical activity and minimal toxicity in pts with advanced CCA and FGFR alterations. These results warrant further study. Clinical trial information: NCT01703481.

Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10009-10009 ◽  
Author(s):  
Giles W. Robinson ◽  
Amar J. Gajjar ◽  
Karen Marie Gauvain ◽  
Ellen M. Basu ◽  
Margaret E Macy ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tyrosine Kinases ◽  
Phase 1 ◽  
Complete Response ◽  
Cns Tumors ◽  
Recommended Dose ◽  
High Grade ◽  
Specific Expansion ◽  
Elevated Creatinine ◽  
Cns Neoplasms

10009 Background: Entrectinib is a CNS-penetrant oral inhibitor of TrkA/B/C, ROS1 and ALK tyrosine kinases. We report the efficacy of entrectinib in children with recurrent/refractory solid or CNS tumors. Methods: Patients ≤ 20y old with recurrent/refractory solid tumors were eligible. After determination of the recommended dose in all-comers, disease-specific expansion cohorts of CNS and solid tumors harboring target aberrations in NTRK1/2/3, ROS1 or ALK, and neuroblastoma (NBL), regardless of mutation spectrum, were enrolled. Response, assessed by Investigator, was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) using RANO for CNS tumors, RECIST for solid tumors, and Curie score for NBL. Results: Between May 2016 and October 2018, 29 patients aged 4.9m–20y (median 7y) were enrolled and 28 were evaluated for response. Entrectinib was well tolerated. Dose limiting toxicities were elevated creatinine, dysgeusia, fatigue and pulmonary edema. The recommended dose was 550 mg/m2 daily. All responses occurred at doses ≥ 400 mg/m2. In CNS tumors (n = 6), all high-grade with gene fusions: 1 achieved a CR ( ETV6-NTRK3); 3 achieved a PR ( TPR-NTRK1, EEF1G-ROS1, EML1-NTRK2); 1 achieved an unconfirmed PR ( GOPC-ROS1); and 1 has yet to be evaluated ( KANK1-NTRK2). In extracranial solid tumors (n = 8), 6 had a fusion of whom 1 achieved a CR ( DCTN1-ALK) and 5 achieved a PR ( TFG1-ROS1, EML4-NTRK3, ETV6-NTRK3, KIF5B-ALK, ETV6-NTRK3). In NBL (n = 15): 1 achieved a CR ( ALK F1174L). Median duration of therapy was 85d (6–592d) for all patients; 56d (6–338d) for non-responders; and 281d (56–592d) for responders. Median time to response was 57d (30–58d). Conclusions: Entrectinib produced striking, rapid and durable responses in all children with refractory CNS and solid tumors harboring NTRK1/2/3, ROS1 or ALK fusions (11 out of 11) as well as in an ALK-mutated NBL. No responses were seen in tumors lacking aberrations in target kinases. These results support the continued evaluation of entrectinib as a targeted therapeutic in solid tumors with NTRK1/2/3, ROS1 and ALK fusions, especially in high-grade CNS neoplasms. Clinical trial information: NCT02650401.

403 Early results from a phase 1 study to evaluate safety, pharmacokinetics, and efficacy of AMG 404, a programmed death-1 (PD-1) antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A428-A428
Author(s):  
Timothy Price ◽  
Sant Chawla ◽  
Gerald Falchook ◽  
Hans Prenen ◽  
Iwona Lugowska ◽  
...  
Keyword(s):  
Partial Response ◽  
Solid Tumors ◽  
Clear Cell ◽  
Phase 1 ◽  
Cell Cancer ◽  
Objective Response ◽  
Study Endpoint ◽  
Primary Study ◽  
Pharmacokinetic Parameters ◽  
Advanced Solid Tumors

BackgroundEnhancement of antitumor immunity through inhibition of the checkpoint PD-1 receptor has been effective in the treatment of many malignancies. AMG 404 is a monoclonal antibody (mAb) targeting PD-1. This phase 1, open-label, multicenter first-in-human study (NCT03853109) will evaluate the safety, tolerability, pharmacokinetics, and efficacy of AMG 404 monotherapy in adult patients with advanced solid tumors.MethodsThe primary study endpoint is dose-limiting toxicity (DLT) and safety; key secondary endpoints include pharmacokinetic parameters, objective response rate (assessed Q8W), duration of response, and progression-free survival. Key inclusion criteria include histologically or cytologically proven metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation for which standard therapies have been exhausted or not available. Prior anti-PD-(L)1 or other checkpoint inhibitors were not allowed. Five dose-finding cohorts, including 2 expansion cohorts, ranged from 3–20 patients each. AMG 404 was given until disease progression, intolerance, or consent withdrawal.ResultsAs of the data cutoff date of May 4, 2020, 62 patients received at least 1 dose of AMG 404 and were included in the safety and efficacy analysis sets. Fifty percent were men, 72% had ECOG 1 performance status, median age was 62 years (range: 28–83), and 42% had ≥3 lines of prior anticancer therapy. Median AMG 404 exposure was ~3 months (maximum: ~12 months). No DLTs were observed. Treatment-related adverse events (TRAEs) were reported for 29 patients (47%): those reported for ≥2 patients were fatigue (n=7); hypothyroidism (n=6); increased blood thyroid stimulating hormone and nausea (n=4 each); increased aspartate aminotransferase, decreased appetite, and pyrexia (n=3 each); and increased alanine aminotransferase, arthralgia, diarrhea, and increased weight (n=2 each). AEs leading to withdrawal of AMG 404 were reported for 3 patients (5%); all were serious and considered to be not related to AMG 404. Sixteen (26%) patients died on study; no deaths were considered related to AMG 404. Preliminary pharmacokinetic results were consistent with those of other therapeutic anti-PD-1 mAbs. Three patients had a confirmed partial response (pancreatic cancer, clear cell cancer, and pleomorphic sarcoma); an additional 4 patients had one scan with a partial response and are pending a confirmatory scan (clear cell renal carcinoma, undifferentiated nasopharyngeal carcinoma, sarcomatoid carcinoma of unknown primary, and colon cancer).ConclusionsAMG 404 is tolerable at the tested doses with no DLTs reported. All observed TRAEs are consistent with other anti-PD-1 therapies. Encouraging anti-tumor activity has been observed in heavily pretreated patients. The study is continuing enrollment into additional cohorts.Trial RegistrationNCT03853109Ethics ApprovalThe study was approved by the Ethics Board of each institution involved in this study and can be produced upon request.

scholarly journals Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e001095 ◽  
Author(s):  
Lillian Siu ◽  
Joshua Brody ◽  
Shilpa Gupta ◽  
Aurélien Marabelle ◽  
Antonio Jimeno ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Palliative Radiation ◽  
Cell Counts ◽  
Palliative Radiation Therapy ◽  
Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

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