Phase 1 study of pevonedistat (MLN4924) a NEDD8 activating enzyme inhibitor, in combination with temozolomide (TMZ) and irinotecan (IRN) in pediatric patients with recurrent or refractory solid tumors (ADVL1615).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10019-10019
Author(s):  
Jennifer Foster ◽  
Joel M. Reid ◽  
Charles G. Minard ◽  
Emasenyie Isikwei ◽  
Xiaowei Liu ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Solid Tumors ◽  
Dose Level ◽  
Pediatric Patients ◽  
Enzyme Inhibitor ◽  
Alkylating Agents ◽  
Phase 1 ◽  
Phase 2 ◽  
Combination Methods

10019 Background: Pevonedistat (PEV), a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation of key regulatory proteins important in cell survival. In adults with solid tumors, the maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m2. Antitumor activity of PEV has been demonstrated in preclinical models of childhood cancer. In vivo additive activity has been demonstrated for PEV in combination with IRN and alkylating agents. The objectives of this study are to determine the MTD and recommended Phase 2 dose of PEV in combination with IRN and TMZ and describe the toxicities, pharmacokinetic (PK), and pharmacodynamics (PD) properties of this combination. Methods: We conducted a phase 1 trial of PEV in combination with IRN and TMZ in pediatric patients (pts) with recurrent or refractory solid tumors and brain tumors. During cycle 1, PEV was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50mg/m2) and TMZ (orally, 100mg/m2), on days 8-12 of a 28 day cycle. In subsequent cycles, PEV was administered on days 1, 3, and 5, with IRN and TMZ on days 1-5 of a 21 day cycle. Dose escalation was determined using the Rolling 6 Design. Results: 30 pts enrolled. All pts were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) assessment. Median (range) age was 13 (1-21) years; 19 (63%) were male. Eleven pts had brain tumors, and 19 pts had solid tumors. Six pts each enrolled on PEV dose levels (DL) 1 (15mg/m2), 2 (20mg/m2), 3 (25mg/m2) and 4 (35mg/m2) as well as an expanded PK cohort at DL4. Cycle 1 grade 3/4 toxicities include lymphopenia (n = 5), leukopenia (n = 4), neutropenia (n = 2), elevated ALT (n = 2), elevated AST (n = 1), diarrhea (n = 1), flu-like symptoms (n = 1). The most frequent non-dose limiting AEs in cycle 1 were anemia (87%), WBC decreased (77%), nausea (57%), diarrhea (53%), ALT increased (50%), AST increased (50%), and vomiting (50%). PK analyses showed the mean area under the curve at the 25 mg/m2 dose level on day 8 (in combination with irinotecan and temozolomide) was 1300 hr•ng/mL, half-life (T ½) was 5-6 hours, time to maximum concentration (Tmax) was 1 hour, and mean clearance was 20 L/hr/m2. There were 3 DLTs, 2 of which were related to protocol therapy (diarrhea and thrombocytopenia), among 12 patients on DL4. Thus the MTD was not exceeded at any dose level. PK at the 25 mg/m2 dose level are comparable to those in adult patients. PK from the 12 patients on DL4 (35mg/m2) as well as responses of all patients are pending. Conclusions: PEV in combination with IRN and TMZ is well tolerated in children with solid or brain tumors. PEV PK was not altered by the addition of irinotecan and temozolomide. Further PK and PD analyses are ongoing to establish the recommended phase 2 dose. Clinical trial information: NCT03323034.

Phase 1 study of pevonedistat (MLN4924) in combination with temozolomide (TMZ) and irinotecan (IRN) in pediatric patients with recurrent or refractory solid tumors (ADVL1615).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e21521-e21521
Author(s):  
Jennifer Foster ◽  
Jodi Ann Muscal ◽  
Charles G. Minard ◽  
Xiaowei Liu ◽  
Joel M. Reid ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Solid Tumors ◽  
Pediatric Patients ◽  
Alkylating Agents ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Combination Methods ◽  
Grade 3

e21521 Background: Pevonedistat, a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation of key regulatory proteins important in cell survival. In adults with solid tumors, the maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m2. Antitumor activity of pevonedistat has been demonstrated in preclinical models of childhood cancer. In vivo additive activity has been demonstrated for pevonedistat in combination with IRN and alkylating agents. The objectives of this study are to determine the MTD and recommended phase 2 dose of pevonedistat in combination with IRN and TMZ and describe the toxicities, pharmacokinetic (PK), and pharmacodynamics (PD) properties of this combination. Methods: Using a rolling six design, we conducted a phase 1 trial of pevonedistat in combination with IRN and TMZ in pediatric patients (pts) with recurrent or refractory solid tumors and brain tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50mg/m2) and TMZ (orally, 100mg/m2), on days 8-12 of a 28 day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN and TMZ on days 1-5 of a 21 day cycle. Results: 18 pts enrolled. All pts were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) assessment. Median (range) age was 13 (1-21) years; 11 (61%) were male. Six pts had brain tumors, and 12 pts had solid tumors. Six pts each enrolled on pevonedistat dose levels 1 (15mg/m2), 2 (20mg/m2), and 3 (25mg/m2). There were no DLTs; DLT assessment is pending for 1 pt on dose level 3. Grade 3/4 toxicities included grade 4 lymphocyte count decreased (n = 2), grade 3 white blood cell decreased (n = 2), and 1 pt each with grade 3 anemia, elevated AST, and elevated ALT. The most frequent AEs were anemia (83%), nausea (61%), elevated AST (61%), and diarrhea (61%). Pharmacokinetic analysis is pending. Conclusions: Pevonedistat in combination with IRN and TMZ is well tolerated in pts with solid or brain tumors. PK and PD analyses are ongoing to establish the recommended dose. Clinical trial information: NCT03323034.

FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3157-TPS3157 ◽  
Author(s):  
David Michael Hyman ◽  
Lipika Goyal ◽  
Petros Grivas ◽  
Funda Meric-Bernstam ◽  
Josep Tabernero ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Tumor Type ◽  
Phase 2 ◽  
Alternative Treatment Option

TPS3157 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR fusions is implicated in many cancers. Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Preliminary data from an ongoing phase 1 trial show efficacy and tolerability in patients (pts) harboring FGFR 1-3 fusion irrespectively of tumor type. We present the design for a multicenter, basket, 2-stage, adaptive single arm Phase 2 trial investigating Debio 1347 in pts with solid tumors harboring FGFR1-3 fusion/rearrangement. Methods: Adults with locally advanced/unresectable or metastatic tumors with documented FGFR1-3 gene fusion/rearrangement who require systemic therapy and have progression after ≥1 prior standard treatment or have no satisfactory alternative treatment option are eligible. Three cohorts are included: biliary tract cancer (cohort 1), urothelial cancer (cohort 2) and all other solid tumors (cohort 3). Primary brain tumors are excluded. Other key exclusion criteria include prior treatment with FGFR1-3 selective inhibitor; clinically significant corneal/retinal disorder; history of calcium/phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification, and symptomatic/unstable brain metastases < 1 month before enrollment. Genomic screening of tumor tissue is done at local or central laboratory with post-hoc central confirmation by RNA sequencing. Eligible pts will receive Debio 1347, 80 mg PO once daily in 28-day cycles until occurrence of progression or unacceptable toxicity. Primary Endpoint is objective response rate (ORR) based on independent central review using RECIST v.1.1. The targeted sample size (N=125) will provide approximately 90% power to reject H0: ORR ≤ 15% at an overall 5% significance level based on an expected ORR of 30% in at least one of the cohorts. Secondary endpoints are: duration of response, disease control rate, progression-free survival, overall survival, safety, tolerability, and quality of life. An interim analysis for futility and homogeneity will be performed after 27 evaluable pts. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. Accrual is opened in US, EU, Asia and Australia. Clinical trial information: NCT03834220.

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 I/II study of eribulin mesilate (ERI) plus irinotecan (IRI) in children with refractory or recurrent solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10535-10535
Author(s):  
Michela Casanova ◽  
Christof Kramm ◽  
Dirk Reinhardt ◽  
Franco Locatelli ◽  
David R. D'Adamo ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Ewing Sarcoma ◽  
Phase 1 ◽  
Pharmacokinetic Parameters ◽  
Treatment Schedule ◽  
Phase 2 ◽  
Pediatric Cancers ◽  
Grade 3 ◽  
Dose Reductions

10535 Background: ERI is an inhibitor of microtubule dynamics. IRI is used to treat pediatric sarcomas. In the pediatric preclinical testing program, ERI was well tolerated and had promising activity compared with vincristine (a common chemotherapeutic for pediatric cancers) for various solid tumors ( in vivo xenograft panels). Methods: Children with relapsed/refractory solid tumors (excluding active central nervous system tumors) were enrolled. Prior treatment with IRI was allowed. Dose escalation was conducted for 2 schedules with the primary objective (phase 1) of determining the maximum tolerated dose and the recommended phase 2 dose: (A) ERI 1.4 mg/m2 IV infusion (Days 1 + 8 of 21-day cycle) + IRI 20 or 40 mg/m2 IV infusion (Days 1–5 of 21-day cycle); (B) ERI 1.4 mg/m2 IV infusion (Days 1 + 8 of 21-day cycle) + IRI 100 or 125 mg/m2 IV infusion (Days 1 + 8 of 21-day cycle). Safety and pharmacokinetic parameters were assessed. Results: 13 patients (pts) were enrolled (median age: 9 years [range: 3–17]); 4 pts had rhabdomyosarcoma (RMS), 2 had non-RMS soft tissue sarcoma, 2 had Ewing sarcoma, 2 had hepatoblastoma, 2 had nephroblastoma, and 1 had neuroblastoma. Overall, 7 pts previously received IRI. No dose-limiting toxicities (DLTs) were reported for either schedule. At data cut-off (July 14, 2019), 4 pts (with Ewing sarcoma, neuroblastoma, RMS, or hepatoblastoma) continued treatment (A, n = 2; B, n = 2) and 9 pts discontinued treatment (primarily for radiographic progression, n = 7 [A, n = 4; B, n = 3]). All pts experienced ≥1 treatment-emergent adverse event (TEAE); the most common any grade TEAE was neutropenia (n = 10; A, n = 5; B, n = 5). 11 pts had grade ≥3 TEAEs (A, n = 6; B, n = 5); the most frequent grade ≥3 TEAE was neutropenia (n = 9; A, n = 5; B, n = 4). No pt withdrew ERI or IRI due to an AE; 3 pts had dose reductions for ERI (A, n = 1; B, n = 2) and 3 pts had dose interruption of ERI (A, n = 2; B, n = 1) due to AEs. No pt had dose reductions for IRI, and 3 pts had dose interruption of IRI (A, n = 2; B, n = 1) due to AEs. 3 deaths occurred; 2 deaths were the result of tumor progression (A, n = 1; B, n = 1), and the cause of 1 was unknown (B). 1 pt with neuroblastoma treated according to schedule A had a partial response. Systemic exposures of ERI, IRI, and SN-38 (IRI active metabolite) were similar between schedules and doses. Conclusions: No DLTs were observed. Toxicity was manageable. Administration of IRI treatment on Days 1–5 is widely used in pediatric cancers; enrollment for phase 2 is ongoing with treatment Schedule A (ERI 1.4 mg/m2 Days 1 + 8 of 21-day cycle; IRI 40 mg/m2 Days 1–5 of 21-day cycle). Clinical trial information: NCT03245450.

CTNI-49. PHASE 1 STUDY OF ST101, A FIRST-IN-CLASS PEPTIDE ANTAGONIST OF CCAAT/ENHANCER-BINDING PROTEIN ß, IN PATIENTS WITH ADVANCED SOLID TUMORS, WITH A PHASE 2 EXPANSION IN RECURRENT GLIOBLASTOMA MULTIFORME

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi71-vi71
Author(s):  
Stefan Symeonides ◽  
Jeff Evans ◽  
Hendrik-Tobias Arkenau ◽  
Meredith McKean ◽  
Nehal Lakhani ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Solid Tumors ◽  
Human Cancer ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 2 ◽  
Tumor Cell Death ◽  
Recurrent Glioblastoma Multiforme ◽  
Peptide Antagonist

Abstract BACKGROUND C/EBPβ is a transcription factor that is active during embryofetal development but held in an inactive state in most mature cells (Zahnow 2009). C/EBPβ is upregulated or overactivated in multiple cancers, where it inversely correlates with disease prognosis and survival due to activation of a gene signature that promotes tumor cell proliferation and survival. ST101 is a cell-penetrating peptide antagonist of C/EBPβ. ST101 exposure leads to selective tumor cell death in multiple human cancer cell lines, including GBM, without impacting normal cell viability. In vivo, ST101 displays rapid uptake into multiple organs, the ability to cross the blood-brain barrier, and a long plasma half-life due to its resistance to degradations. It has potent anti-tumor activity in multiple GBM models, as a single agent or in combination, which supported moving into clinical development. TRIAL DESIGN This phase 1-2 study is enrolling patients ≥ 18 years of age with advanced, unresectable metastatic solid tumors refractory to or intolerant of other therapeutic options. We began recruitment in August 2020. The primary objective of phase 1 is to evaluate safety and tolerability of ST101. Secondary objectives include the recommendation of a dose and regimen of ST101 for further evaluation, pharmacokinetics, several pharmacodynamic measures, and preliminary efficacy. Patients receive intravenous ST101 once weekly in a standard 3 + 3 design. Enrollment is ongoing, and by 21 May 2021, 15 patients have been recruited in four dose-escalation cohorts up to 4 mg/kg; a 5th cohort (6 mg/kg) is ongoing. The recommended phase 2 dose will be used in a 15-30 patient GBM expansion cohort, with a Simon 2-stage design, which requires one response or two patients with PFS6 in the first cohort to continue the study. Up to 120 patients are planned in a total of four expansion cohorts, which should be enrolling by Q3 2021.

A phase I trial of TRC102 (methoxyamine HCl) with temozolomide (TMZ) in patients with solid tumors and lymphomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2518-2518 ◽  
Author(s):  
Robert S. Meehan ◽  
Geraldine Helen O'Sullivan Coyne ◽  
Shivaani Kummar ◽  
Jerry M. Collins ◽  
Larry Anderson ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Dna Damage ◽  
Solid Tumors ◽  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Phase 1 ◽  
Phase 2 ◽  
Genetic Characteristics ◽  
Pharmacodynamic Profile ◽  
Expansion Cohort

2518 Background: TRC102 inhibits BER by binding to abasic sites and acting as a topo II poison to cause DNA strand breaks; it potentiates the activity of alkylating agents including TMZ in murine models. In xenograft studies, TRC102 efficiently enhanced the antitumor effect of TMZ regardless of cell line genetic characteristics, e.g., O6-methylguanine DNA-methyltransferase, mismatch repair (MMR), or p53 status. This is the first report for the expansion phase (the escalation phase was reported previously (ASCO2016)). Methods: We conducted a phase 1 trial of TRC102with TMZ in patients (pts) with refractory solid tumors. Eligibility criteria included adults that had progressed on standard therapy, ECOG PS of 0-2, and adequate organ function. TRC102 and TMZ were given orally days 1-5, in 28-day cycles. The pharmacokinetic and pharmacodynamic profile of TRC102 with TMZ was evaluated. Antitumor responses were determined using RECIST 1.1 criteria. The DNA damage response (DDR) markers γH2Ax, pNbs1, and Rad51 were evaluated in the expansion cohort at DL6, tested by previously described methods on paired tumor biopsies prior to and after the first course of therapy. Results: After the recommended Phase 2 Dose was defined as DL6 (TRC102 125mg, TMZ 150mg/m2 D1-5), 15 pts were accrued to the expansion cohort between 9/2015 to 11/2016. A total of 52 pts were enrolled (37 escalation, 15 expansion). Grade 3/4 adverse events included neutropenia (13%), anemia (the DLT;10%), thrombocytopenia (7%), hemolysis (5%) or hypophosphatemia (3%). 4 pts had a partial response (PR) (NSCLC, ovarian (2), and colon); 13 pts had stable disease (SD), 29 progressive disease (PD), and 6 were not evaluable; three pts remain on study. 11/14 paired biopsies were suitable for analysis. Rad51 signal was induced in 6/11pts. One patient showed γH2Ax and 2 showed pNbs1 induction. 4/5 colon cancer specimens had evidence of DDR marker induction. Conclusions: The combination of TRC 102/TMZ is active with 4 PRs and 13 SDs, and the side effect profile is manageable. DDR markers were induced in 4 of 5 paired colon biopsies indicating DNA damage following treatment. A phase 2 trial of patients with colon cancer, NSCLC, and granulosa cell ovarian cancer is accruing. Clinical trial information: NCT01851369.

scholarly journals 482 Phase1/2 study of an anti-galectin-9 antibody, LYT-200, in patients with metastatic solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A512-A512
Author(s):  
Aleksandra Filipovic ◽  
Zev Wainber ◽  
Judy Wang ◽  
Johanna Bendell ◽  
Filip Janku ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
New York ◽  
Solid Tumors ◽  
Dose Level ◽  
T Cell Activation ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 2 ◽  
New York University ◽  
Potential Biomarker

BackgroundGalectin-9 (gal-9) acts as a pivotal immuno-suppressor that disables immune mediated activity through modulation of T cells, macrophages and other immune functions. As such it has emerged as a powerful biological target for cancer immunotherapy and a potential biomarker of response and/or prognosis. Patients exhibiting high gal-9 expression in tumors and blood often have poor prognosis and tumors with aggressive and immunosuppressed molecular features (Chen L. et al, AACR 2020-LB-350). LYT-200 is a fully human IgG4 monoclonal antibody targeting gal-9. LYT-200 has high affinity, high specificity, stability, and blocks galectin-9 interactions with its binding partners in biochemical and human cell-based assays. In murine models of melanoma and pancreatic cancer, LYT-200 significantly reduced tumor growth, extended survival and modulated the intra-tumoral immune microenvironment. LYT-200 treated patient derived tumor organoids showed an increase in T cell activation (Chen L. et al, SITC 2019-P765).MethodsLYT-200 is now being evaluated in the USA, in the first part of an adaptive Phase 1/2 trial (NCT04666688) in relapsed/refractory solid tumors. Patients with solid tumor malignancy that is metastatic or unresectable and refractory to prior therapy are included. Patients are treated with LYT-200 by IV infusion, every 2 weeks (Q2W), until disease progression or toxicity. Phase 1 of the study uses the continuous reassessment design (CRM), and entails recruiting two patients per dosing level. Starting dose level was 0.2mg/kg Q2W. Additionally, the protocol stipulates six patients must be treated at the dose level intended to be declared recommended phase 2 dose (RP2D), for more robust assessment of safety/tolerability. RP2D may be the maximum tolerated dose or the optimal biological dose. The primary objective of the ongoing Phase 1 is to assess the safety and tolerability of LYT-200 and to identify the RP2D. The Phase 1 is also assessing LYT-200’s pharmacokinetics, immunogenicity and pharmacodynamics (measuring circulating gal-9 and cytokine levels, immunophenotyping peripheral blood mononuclear cells and tumor tissue). Preliminary efficacy is captured as an exploratory endpoint in Phase 1. Phase 2 expansion cohorts would implement the Simon’s two-stage design to further assess LYT-200 as a single agent and/or in combination with chemotherapy and tislelizumab. Phase 2 is currently planned in pancreatic cancer and other/different tumor types for Phase 2 may be guided by results of the Phase 1.AcknowledgementsAll clinical trial sites participating in the LYT-200 study. Shohei Koide, Linxiao Chen and George Miller and their teams at New York University Langone Health & New York University School of Medicine, NY for all the preclinical work on LYT-200.Trial RegistrationNCT04666688

scholarly journals CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study

2021 ◽  
Vol 9 (7) ◽  
pp. e002446
Author(s):  
Rachel E Sanborn ◽  
Omid Hamid ◽  
Elisabeth GE de Vries ◽  
Patrick A Ott ◽  
Javier Garcia-Corbacho ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Tolerability Profile ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Anal Squamous Cell Carcinoma ◽  
Grade 3

BackgroundProbody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing ‘off-tumor’ toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab.MethodsAdults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1).ResultsTwenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3–4 adverse events (AEs) and grade 3–4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients.ConclusionsThe MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

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 &gt;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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