A phase I study of the anti-insulin like growth factor type 1 receptor (IGF-1R) antibody dalotuzumab in pediatric patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10026-10026
Author(s):  
Didier Frappaz ◽  
Lisa M. McGregor ◽  
Andrew DJ Pearson ◽  
Lia Gore ◽  
Steven G. DuBois ◽  
...  
Keyword(s):  
Growth Factor ◽  
Solid Tumors ◽  
Ewing Sarcoma ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Growth Factor Signaling ◽  
Advanced Solid Tumors ◽  
Insulin Like Growth Factor ◽  
Factor Type ◽  
Dose Levels

10026 Background: Insulin-like growth factor signaling plays an important role in several pediatric cancers. Dalotuzumab is a highly specific, humanized IgG1 monoclonal antibody against IGF-1R. This multicenter phase 1 study explored the safety and pharmacokinetics (PK) of dalotuzumab in pediatric patients with advanced solid tumors. Methods: Dalotuzumab was administered intravenously every 3 weeks. Dose-escalation was performed according to a modified Toxicity Probability Interval (mTPI) design starting at 900 mg/m2. The PK profile of dalotuzumab was evaluated with the primary goal of confirming that the Day 22 mean serum trough concentration exceeded 25 μg/mL. Results: 24 patients were enrolled and 20 treated (median age, 10.5 years; range, 3–17 years). Six patients had recurrent Ewing sarcoma. Patients received a median of 2 cycles (range, 1-10). No dose-limiting toxicity was observed in any of the three dose levels explored (900, 1200 and 1500 mg/m2). Main treatment-related toxicities were Grade 3 elevated transaminases. PK data showed dose dependent increases in AUC0-∞ (105,000, 164,000 and 281,000 hr*mg/mL, for the 900, 1200 and 1500 mg/m2 dose levels, respectively), Ctrough (65.2, 71.6, 148 mg/mL) and Cmax (559, 643, 888 mg/mL). The mean half-life was 247, 394 and 376 hours respectively. The Cmax exhibited mild variability (4.8-35% Coefficient of Variation), whereas variability was moderate to high on the Ctrough (39-200%), apparent t1/2 (28-154%), AUC0-∞ (29-106%) and clearance (52-161%). Except for one patient at the 1200 mg/m2 dose level, all patients met the PK target, a Ctrough of 25 μg/mL, suggesting 900 mg/m2as the recommended phase 2 dose (RP2D). One patient with Ewing sarcoma had a confirmed partial response; 2 patients with Ewing sarcoma and one with nephroblastoma had stable disease for at least 7, 5 and 6 months, respectively. Conclusions: Dalotuzumab is well tolerated in pediatric patients with advanced malignancies. The RP2D of 900 mg/m2 was chosen based on tolerability and PK parameters. Preliminary data confirm prior reports suggesting activity in Ewing sarcoma. Clinical trial information: NCT01431547.

scholarly journals Dual inhibition of the vascular endothelial growth factor pathway: A phase 1 trial evaluating bevacizumab and AZD2171 (cediranib) in patients with advanced solid tumors

Cancer ◽  
2014 ◽  
Vol 120 (14) ◽  
pp. 2164-2173 ◽  
Author(s):  
David S. Hong ◽  
Ignacio Garrido-Laguna ◽  
Suhendan Ekmekcioglu ◽  
Gerald S. Falchook ◽  
Aung Naing ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Solid Tumors ◽  
Phase 1 ◽  
Vascular Endothelial ◽  
Advanced Solid Tumors ◽  
Phase 1 Trial ◽  
Dual Inhibition ◽  
Endothelial Growth Factor

Phase I and pharmacokinetic (PK) study of lenalidomide (LEN) in pediatric patients with relapsed/refractory solid tumors or myelodysplastic syndrome (MDS): A Children's Oncology Group Phase I Consortium study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10023-10023
Author(s):  
S. L. Berg ◽  
H. Russell ◽  
M. Cairo ◽  
A. M. Ingle ◽  
P. C. Adamson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Fixed Dose ◽  
Ischemic Event ◽  
Thromboembolic Risk ◽  
Once Daily ◽  
Antiproliferative Effects ◽  
Dose Levels

10023 Background: LEN, which has immunomodulatory, antiangiogenic, and antiproliferative effects, is indicated for the treatment of adults with MDS and multiple myeloma. We report the final results of a phase 1 and PK study of LEN in children with recurrent or refractory solid tumors (ST) or MDS. Methods: LEN was administered by mouth once daily for 21 of 28 days. Cohorts of 3 to 12 children with ST were enrolled at 15, 25, 40, 55 and 70 mg/m2/d dose levels. Children with MDS received a fixed dose of 5 mg/m2/d. PK and correlative biology studies were performed in cycle 1. Results: 49 patients (23 female), median age 16 years (range, 1–21) were enrolled and received a median of 1 cycle (range 1–11). 39/46 ST patients and 3/3 MDS patients were fully evaluable for toxicity. 0/3 patients with MDS had DLT. At 15 mg/m2/d, 1/6 ST patients developed DLT (Gr 3 hypercalcemia). At 25 mg/m2/d 1 patient had a cerebrovascular ischemic event of uncertain relationship to LEN; future subjects were screened for thromboembolic risk factors prior to enrollment. At 40 mg/m2/d 3/12 patients developed DLTs (Gr 3 hypophosphatemia/hypokalemia; Gr 4 neutropenia delaying the start of the next cycle for > 7 days; Gr 3 somnolence); at 55 mg/m2/d 1/6 patients developed DLT (Gr 3 urticaria). At 70 mg/m2/d 0/6 patients had DLT. No further dose escalation was attempted. No objective responses were observed. LEN enhanced IL-2 and IL-15 concentrations; NK expansion and activation; and NK and LAK cytotoxicity (Ayello, ASH, 2008). The median apparent LEN clearance and half-life were 135 ± 45 ml/min/m2 and 2.3 ± 1.1 hr. Conclusions: LEN is well tolerated at doses up to 70 mg/m2/d x 21d of 28 days in children with recurrent or refractory ST. Enhancement of immune function is significant. PK parameters in children are similar to those in adults. No significant financial relationships to disclose.

Phase I study of regorafenib in combination with vincristine and irinotecan in pediatric patients with recurrent or refractory solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10507-10507
Author(s):  
Michela Casanova ◽  
Francisco Bautista ◽  
Quentin Campbell Hewson ◽  
Guy Makin ◽  
Lynley V. Marshall ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Ewing Sarcoma ◽  
Pediatric Patients ◽  
Wilms Tumor ◽  
Standard Dose ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Grade 3

10507 Background: In pediatric patients with solid tumors, regorafenib demonstrated acceptable tolerability and preliminary anti-tumor activity. This phase 1 study evaluated regorafenib in combination with vincristine/irinotecan in pediatric patients with rhabdomyosarcoma (RMS) and other solid tumors. Methods: Patients with relapsed/refractory tumors received intravenous vincristine (1.5 mg/m2, Days 1 and 8) and irinotecan (50 mg/m2/day, Days 1–5) plus once-daily oral regorafenib (patients 6– < 24 months: 60 mg/m2 escalating to 65 mg/m2; patients 2– < 18 years: 72 mg/m2 escalating to 82 mg/m2) on either Days 1–14 (concomitant dosing) or Days 8–21 (sequential dosing) during each 21-day cycle. As per protocol, at least 50% of patients were required to have RMS. Results: At the time of the cut-off, of 21 treated patients (RMS, n = 12; Ewing sarcoma, n = 5; neuroblastoma, n = 3; Wilms tumor, n = 1), two had concomitant (72 mg/m2) and 19 had sequential (72 mg/m2, n = 6; 82 mg/m2, n = 13) dosing. Median age was 10 years (1.5–17.0). Patients received a median of 3 cycles (1–17); dose reductions of irinotecan occurred in 62% of patients. Grade 3 dose-limiting toxicities were reported in both patients receiving concomitant dosing (peripheral neuropathy and liver injury; pain, vomiting, febrile aplasia) and one patient each in the sequential groups (rash and elevated AST; thrombocytopenia). Concomitant dosing was discontinued. The maximum tolerated dose and recommended phase 2 dose (RP2D) of regorafenib in the sequential combination was 82 mg/m2. The most common grade ≥3 treatment-emergent adverse events were neutropenia (71%), thrombocytopenia (33%), leukopenia (29%), anemia (24%), and ALT increased (24%). The response rate was 38%, including 1 complete (RMS) and 7 partial responders (5 RMS, 2 Ewing sarcoma); 3 of whom had prior irinotecan. Six (4 with alveolar subtype) of 12 patients with RMS had a response. Nine patients (43%) had stable disease (maximum duration 17 cycles). After the cut-off, partial response was reported for two additional patients (1 RMS, 1 Ewing sarcoma). Conclusions: Regorafenib can be combined at its single agent RP2D of 82 mg/m2 with standard-dose vincristine/irinotecan (with appropriate dose modifications) in pediatric patients with refractory/relapsed solid tumors in a sequential dosing schedule. Clinical activity was observed in patients with sarcoma. Clinical trial information: NCT02085148.

Pharmacokinetic/pharmacodynamic (PK/PD) profile of AG-120 in patients with IDH1-mutant cholangiocarcinoma from a phase 1 study of advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4082-4082 ◽  
Author(s):  
Bin Fan ◽  
Lipika Goyal ◽  
Maeve Aine Lowery ◽  
Shuchi Sumant Pandya ◽  
Erika Manyak ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Half Life ◽  
Phase 1 ◽  
Patient Specific ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Tumor Biopsy ◽  
Multiple Doses ◽  
Dose Levels

4082 Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) produce the oncometabolite D-2-hydroxyglutarate (2-HG). AG-120 is a first-in-class selective inhibitor of mutant IDH1 (mIDH1) under evaluation in an ongoing phase 1 study in patients with mIDH1 advanced solid tumors, including cholangiocarcinoma (CC) (NCT02073994). Objectives for this abstract were to 1) characterize the PK profile of AG-120 and the relationship between AG-120 exposure and 2-HG suppression, and 2) evaluate the influence of intrinsic patient factors on AG-120 clearance, in patients with mIDH1 CC. Methods: AG-120 was administered orally once daily (QD) or twice daily (BID) in continuous 28-day cycles. As of Dec 5, 2016, 60 of 73 patients enrolled with mIDH1 CC had PK/PD samples available for analysis at 100 mg BID, 300 mg QD, 400 mg QD, 500 mg QD, 800 mg QD, and 1200 mg QD in dose escalation (n = 24) and 500 mg QD (n = 36) in dose expansion. Blood (n = 60) and fresh tumor biopsy samples (n = 14) were collected to assess AG-120 and 2-HG using qualified liquid chromatography-tandem mass spectrometry methods. Results: Following both single and multiple doses, AG-120 plasma exposure increased less than dose proportionally from 100 to 1200 mg. Mean terminal half-life was 38.4–85.8 h, supporting a QD dosing regimen. Following multiple doses, steady state was reached within 15 days, with approximately 2-fold accumulation in plasma AG-120 exposure. No patient-specific factors were identified as clinically significant covariates affecting AG-120 plasma clearance. After multiple doses, plasma 2-HG levels were reduced (up to 98.4% inhibition, achieving levels similar to those in healthy volunteers) and tumor biopsy 2-HG levels were also substantially reduced (by up to 99.9%) at all dose levels tested. The 500 mg QD dose resulted in the largest magnitude of 2-HG inhibition vs. other dose levels. Conclusions: AG-120 demonstrated a long half-life in patients with mIDH1 CC and robustly inhibited 2-HG in plasma and tumor samples. These PK/PD data, along with emerging safety and clinical activity data, support the selection of 500 mg QD for future clinical investigation. Clinical trial information: NCT02073994.

ADVL1412: Initial results of a phase I/II study of nivolumab and ipilimumab in pediatric patients with relapsed/refractory solid tumors—A COG study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10526-10526 ◽  
Author(s):  
Kara L. Davis ◽  
Elizabeth Fox ◽  
Joel M. Reid ◽  
Xiaowei Liu ◽  
Charles G. Minard ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Pediatric Patients ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Pleural Effusions ◽  
Elevated Liver Enzymes ◽  
Dose Levels

10526 Background: Checkpoint inhibitors have produced impressive responses in cancer. We report results of a Phase 1 study of nivolumab (nivo) alone and in combination with ipilumumab (ipi) in children with relapsed/refractory solid tumors and activity of nivo in patients with osteosarcoma (OS) and Ewing sarcoma (EWS) treated with the RP2D. Methods: Children with relapsed/refractory solid tumors (excluding CNS tumors or metastases) were eligible for Phase I Cohorts A and C. Using a rolling 6 design, Cohort A tested nivo at the adult RP2D, 3mg/kg Q14d (cycle = 28d). Cohort C tested nivo + ipi at 2 dose levels (DLs): DL1 nivo 1mg/kg + ipi 1mg/kg and DL2 nivo 3mg/kg + ipi 1mg/kg Q21d x 4 then nivo alone Q14d. At the RP2Ds, 6 additional patients were enrolled in each cohort for pharmacokinetics (PK). Phase II expansion cohorts enrolled patients with measurable OS (Cohort B2, n = 10) or EWS (Cohort B4, n = 10) respectively to assess activity of the RP2D of single agent nivo. Results: Twelve evaluable patients enrolled in Cohort A, none had DLTs. The pediatric RP2D of nivo alone was identified as 3 mg/kg Q14d. Five evaluable patients enrolled in Cohort C:DL1 without DLT, then 12 patients enrolled in Cohort C:DL2 with one DLT within the 21d reporting period (Gr 2 creatinine increase), defining the RP2D of nivo 3mg/kg + ipi 1mg/kg at the schedule above. In 39 patients treated in cohorts A, B2, B4 and C, pleural effusions occurred in 7 with variable attributions to drug, leading to a protocol amendment mandating supportive care and corticosteroids for pleural effusions on study. Common toxicities included anemia, elevated liver enzymes, rash, fatigue, and nausea, generally Grade 1. In Cohort A, nivo Cmax, t1/2 and Clpvalues were 63.2±15.7 mg/mL, 10.7±1.8 d and 0.196±0.075 ml/h/kg, respectively. In the Phase II expansion cohorts, no objective responses were observed in OS or EWS. Conclusions: Nivo alone or with ipi at the doses tested is safe in pediatric patients with relapsed/refractory solid tumors. The pediatric RP2D of nivo is 3mg/kg alone or in combination with ipi 1mg/kg. Single agent nivo did not have antitumor activity in OS or EWS. Enrollment to other expansion cohorts with nivo or nivo/ipi is ongoing. Clinical trial information: NCT02304458.

Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2037-2037
Author(s):  
Jason D. Lickliter ◽  
Ross Jennens ◽  
Charlotte Rose Lemech ◽  
Ganessan Kichenadasse ◽  
Dongpo Cai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Radiation Treatment ◽  
Phase 1 ◽  
Dose Range ◽  
Malignant Gliomas ◽  
Advanced Solid Tumors ◽  
Biomarker Analysis ◽  
Dose Levels

2037 Background: ACT001, an orally-available parthenolide derivative targeting NF-κB and STAT3 signaling pathways, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). The updated data in this report summarizes clinical findings from this first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were adults with ECOG PS 0-1 and satisfactory hematologic, renal and hepatic function. Additionally, GBM patients had progressive disease despite initial radiation and temozolomide, measurable tumor and no radiation treatment within 3 months prior to enrollment. ACT001 was given orally BID until intolerance or disease progression. Dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 24 patients were enrolled as of this report: 14 with primary GBM, 2 with secondary GBM, 2 with anaplastic astrocytoma, 2 with colorectal cancer and 1 with each of anaplastic oligioastrocytoma, diffuse intrinsic pontine glioma, non-small cell lung cancer and pleural epithelioid mesothelioma. Median age was 49 years old (range 32-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID, 900 mg BID and 1200 mg BID. Study drug treatment was well tolerated with no dose-limiting toxicity or ACT001-related SAE observed. The originally-planned maximum dose of 600 mg BID and the 1200 mg BID dose were expanded to 7 and 5 patients, respectively. The plasma half life of ACT001 was approximately 3-4 hours and no accumulation was observed after multiple dosing. Cmax and AUC0-last were approximately dose linear across the evaluated dose range. Of the 19 patients with recurrent malignant gliomas, a complete remission was observed in 1 patient with GBM (ongoing 27 months from starting ACT001) and stable disease lasting ≥ 6 months was seen in 3 patients. Preliminary biomarker analysis of PBMC samples revealed a post-treatment reduction in CD4+ Treg cells at some dose levels. Conclusions: In this first-in-human phase 1 study, ACT001 was well tolerated and showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in malignant glioma patients dosed at 400 mg BID or lower. A phase 1b trial in recurrent GBM patients of ACT001 at 200-400 mg BID in combination with anti-PD-1 therapy is planned. Clinical trial information: ACTRN12616000228482.

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