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.

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 Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

2020 ◽  
Vol 4 (17) ◽  
pp. 4091-4101
Author(s):  
Arne Kolstad ◽  
Tim Illidge ◽  
Nils Bolstad ◽  
Signe Spetalen ◽  
Ulf Madsbu ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
Overall Response ◽  
Non Hodgkin Lymphoma ◽  
Anti Cd20

Abstract For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20–based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the “cold” anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

scholarly journals Evaluation of the Optimal Number of Lesions Needed for Tumor Evaluation Using the Response Evaluation Criteria in Solid Tumors: A North Central Cancer Treatment Group Investigation

2009 ◽  
Vol 27 (19) ◽  
pp. 3205-3210 ◽  
Author(s):  
Shauna L. Hillman ◽  
Ming-Wen An ◽  
Michael J. O'Connell ◽  
Richard M. Goldberg ◽  
Paul Schaefer ◽  
...  
Keyword(s):  
Treatment Group ◽  
Cancer Treatment ◽  
Solid Tumors ◽  
Overall Response Rate ◽  
Response Rate ◽  
Evaluation Criteria ◽  
Response Evaluation ◽  
North Central ◽  
Overall Response ◽  
Response Evaluation Criteria

Purpose In February 2000, the criteria for measuring tumor shrinkage as an indicator of antitumor activity were redefined by the Response Evaluation Criteria in Solid Tumors (RECIST). This resulted in simplifying bidimensional to unidimensional measurement of lesions. Under RECIST, all lesions, up to 10, must be measured. Scanning and measuring multiple lesions is costly, time-consuming, and a disincentive to participation in clinical trials. We investigated whether fewer than 10 lesions can be measured without compromising the accuracy of assessing a regimen's activity. Patients and Methods Thirty-two North Central Cancer Treatment Group trials including 2,374 patients were analyzed. Twelve studies were conducted before RECIST; 20 were conducted post-RECIST. Agreement between objective status by cycle, confirmed response, overall response rate, and time to progression (TTP) was evaluated based on all 10 versus the largest one through five lesions. Results The median number of lesions reported on RECIST trials did not differ from pre-RECIST trials (median = 2.0). One lesion at baseline was reported in 49% of patients, two lesions in 28% of patients, three lesions in 12% of patients, four lesions in 6% of patients, and five lesions in 5% of patients in post-RECIST trials. Utilizing the largest two lesions produced excellent concordance with that using all lesions for all end points. In no trial did the overall response rate differ by more than 3% when two versus all lesions were considered. Evaluating more than two lesions did not significantly improve agreement. Conclusion Based on these trials, the assessment of more than two lesions did not alter the conclusions regarding a treatment's efficacy as judged by response rate or TTP.

scholarly journals Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial

2021 ◽  
Author(s):  
Daniel J. DeAngelo ◽  
Deepti H. Radia ◽  
Tracy I. George ◽  
William A. Robinson ◽  
Albert T. Quiery ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Systemic Mastocytosis ◽  
Remission Rate ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Severe Thrombocytopenia ◽  
Phase 2 ◽  
Overall Response ◽  
Primary Endpoints

AbstractAdvanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (NCT02561988) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30–400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.

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.

SWOG 1609 (DART): A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2658-TPS2658 ◽  
Author(s):  
Sandip Pravin Patel ◽  
Megan Othus ◽  
Young Kwang Chae ◽  
Frank Giles ◽  
Jourdain Hayward ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Solid Tumors ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Alternative Hypothesis ◽  
Performance Status ◽  
Overall Response ◽  
Rare Tumors

TPS2658 Background: Immune checkpoint blockade, in particular anti-CTLA-4 and anti-PD-1-directed approaches, have improved outcomes in various tumor types. However, little is known about the efficacy of these agents in advanced rare solid tumors. We sought to investigate the activity of ipilimumab and nivolumab in previously unstudied rare solid tumors, with planned biomarker evaluation pending including whole exome sequencing, RNAseq, and multiplex immune profiling via the NCI CIMACs. Methods: We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1mg/kg iv q6weeks) plus nivolumab (240mg iv q2weeks) across 37 cohorts of rare tumors. Eligible patients had incurable rare cancer, defined histologically with an incidence of less than 6 in 100,000 per year, and did not have an approved or standard therapy available that had been shown to prolong overall survival. Patients were required to be 18 years of age or older, have a Zubrod performance status of 0-2, with absolute neutrophil count ≥ 1,000/mcL, platelets ≥ 75,000/mcL, hemoglobin ≥ 8 g/dL, creatinine clearance ≥ 50 mL/min, total bilirubin ≤ 2.0 x institutional upper limit of normal (IULN), AST and ALT ≤ 3.0 x IULN, TSH or free T4 serum ≤ IULN, and normal adrenocorticotropic hormone (ACTH) ≤ IULN. The primary endpoint was overall response rate (ORR) by RECIST v1.1 (complete (CR) and partial responses (PR)); secondary endpoints included progression-free (PFS) and, overall survival (OS), stable disease (SD) ≥ 6 months, and toxicity. The primary objective of this Phase II trial was to evaluate the overall response rate (ORR, confirmed complete and partial responses [CR and PR]) by RECIST v1.1. Our objective was to distinguish between a true ORR 15% (null hypothesis) versus 30% (alternative hypothesis). A Simon’s two-stage design was used, which required an analysis on the first 6 eligible patients who received therapy. If 1 or more of the 6 patients had a response (confirmed CR or PR), an additional 10 patients were to be accrued. The study was activated on 1/13/17 with the first patient treated on 3/1/17. The trial is currently open at 862 sites across the NCTN (with 352 sites having enrolled patients) and 554 patients enrolled to date. Clinical trial information: NCT02834013.

scholarly journals Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

Blood ◽  
2016 ◽  
Vol 128 (14) ◽  
pp. 1821-1828 ◽  
Author(s):  
Torben Plesner ◽  
Hendrik-Tobias Arkenau ◽  
Peter Gimsing ◽  
Jakub Krejcik ◽  
Charlotte Lemech ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Adverse Events ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
Overall Response ◽  
Key Points ◽  
The Individual ◽  
Good Partial Response

Key Points Daratumumab plus lenalidomide/dexamethasone elicited an overall response rate of 81% (63% very good partial response or better). Adverse events were manageable and in accord with the individual toxicity profiles of daratumumab and lenalidomide/dexamethasone.

scholarly journals An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5661-5670 ◽  
Author(s):  
Ravi Vij ◽  
Michael Wang ◽  
Jonathan L. Kaufman ◽  
Sagar Lonial ◽  
Andrzej J. Jakubowiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 2 ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Overall Response ◽  
To Receive

Abstract Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy—17.1% overall (1 grade 3; no grade 4)—in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.

scholarly journals Safety and Antitumor Activity of the Anti–Programmed Death-1 Antibody Pembrolizumab in Patients With Advanced Esophageal Carcinoma

2018 ◽  
Vol 36 (1) ◽  
pp. 61-67 ◽  
Author(s):  
Toshihiko Doi ◽  
Sarina A. Piha-Paul ◽  
Shadia I. Jalal ◽  
Sanatan Saraf ◽  
Jared Lunceford ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Esophageal Carcinoma ◽  
Solid Tumors ◽  
Overall Response Rate ◽  
Response Rate ◽  
Interferon Γ ◽  
Overall Response ◽  
Programmed Death ◽  
Programmed Death 1

PurposeThe anti–programmed death-1 antibody pembrolizumab was evaluated in KEYNOTE-028, a multicohort, phase IB study of patients with programmed death ligand-1 (PD-L1)–positive advanced solid tumors. Results from the esophageal carcinoma cohort are reported herein.Patients and MethodsEligible patients with squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction in whom standard therapy failed and who had PD-L1–positive tumors received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed disease progression or intolerable toxicity. Response was assessed every 8 weeks up to 6 months and every 12 weeks thereafter. Primary end points were safety and overall response rate, determined by investigator review per Response Evaluation Criteria in Solid Tumors (version 1.1).ResultsAmong 83 patients with esophageal carcinoma and samples evaluable for PD-L1 expression, 37 (45%) had PD-L1–positive tumors, and 23 were enrolled. Median age was 65 years; 78% had squamous histology; and 87% received ≥ two prior therapies for advanced/metastatic disease. As of the data cutoff (February 20, 2017), median follow-up was 7 months (range, 1 to 33 months). Nine patients (39%) experienced treatment-related adverse events, most commonly decreased appetite, decreased lymphocyte count, generalized rash, and rash (two patients [9%] each). No grade 4 adverse events or deaths were attributed to pembrolizumab. Overall response rate was 30% (95% CI, 13% to 53%); median duration of response was 15 months (range, 6 to 26 months). A six-gene interferon-γ gene expression signature analysis suggested that delayed progression and increased response occur among pembrolizumab-treated patients with higher interferon-γ composite scores.ConclusionPembrolizumab demonstrated manageable toxicity and durable antitumor activity in patients with heavily pretreated, PD-L1–positive advanced esophageal carcinoma.

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