scholarly journals A Phase 1 Trial and Pharmacokinetic Study of Cediranib, an Orally Bioavailable Pan–Vascular Endothelial Growth Factor Receptor Inhibitor, in Children and Adolescents With Refractory Solid Tumors

2010 ◽  
Vol 28 (35) ◽  
pp. 5174-5181 ◽  
Author(s):  
Elizabeth Fox ◽  
Richard Aplenc ◽  
Rochelle Bagatell ◽  
Meredith K. Chuk ◽  
Eva Dombi ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Solid Tumors ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Thyroid Stimulating Hormone ◽  
Left Ventricular ◽  
Fixed Dose ◽  
Time Curve ◽  
Once Daily ◽  
Grade 3

Purpose To determine the toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of cediranib administered orally, once daily, continuously in children and adolescents with solid tumors. Patients and Methods Children and adolescents with refractory solid tumors, excluding primary brain tumors, were eligible. DLT at the starting dose of 12 mg/m2/d resulted in de-escalation to 8 mg/m2/d and subsequent re-escalation to 12 and 17 mg/m2/d. Pharmacokinetic and pharmacodynamic studies were performed during cycle 1. Response was evaluated using WHO criteria. Results Sixteen patients (median age, 15 years; range, 8 to 18 years) were evaluable for toxicity. DLTs (grade 3 nausea, vomiting, fatigue in one; hypertension and prolonged corrected QT interval in another) occurred in patients initially enrolled at 12 mg/m2/d. Subsequently, 8 mg/m2/d was well tolerated in three patients. An additional seven patients were enrolled at 12 mg/m2/d; one had DLT (grade 3 diarrhea). At 17 mg/m2/d, two of four patients had DLTs (grade 3 nausea; intolerable grade 2 fatigue). Non–dose-limiting toxicities included left ventricular dysfunction, elevated thyroid stimulating hormone, palmar-plantar erythrodysesthesia, weight loss, and headache. The MTD of cediranib was 12 mg/m2/d (adult fixed dose equivalent, 20 mg). At 12 mg/m2/d, the median area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) was 900 ng·h/mL, which is similar to adults receiving 20 mg. Objective responses were observed in patients with Ewing sarcoma, synovial sarcoma, and osteosarcoma. Conclusion The recommended monotherapy dose of cediranib for children with extracranial solid tumors is 12 mg/m2/d administered orally, once daily, continuously. A phase II study is in development.

A dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of mTORC1/2 inhibitor XP-105 (BI 860585) as monotherapy and in combination with exemestane or paclitaxel in patients (pts) with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3127-3127
Author(s):  
Filippo G. De Braud ◽  
Wentao Jason Wu
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Mtor Inhibitors ◽  
Complete Response ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Once Daily ◽  
Sustained Reduction ◽  
Grade 3 ◽  
Combination Regimens

3127 Background: Resistance to mTORC1 inhibition may develop through feedback loop leading to upregulation of mTORC2. XP-105, also known as BI 860585, is a potent dual mTORC1/2 inhibitor designed to overcome such resistance. This Phase 1 trial (NCT01938846) was performed to determine the MTD and activity of XP-105 alone or in combination with exemestane or paclitaxel in pts with advanced solid tumors. Methods: A 3+3 escalation design was used; Pts received XP-105 (5–300 mg/day) monotherapy or (40–220 mg/day) combined with fixed-dose exemestane 25 mg/day, or 80–160 mg/day combined with paclitaxel 60 or 80 mg/m2/week. A reduction of pAKT/total AKT ratio was used as a PD marker of target inhibition. Results: 90 pts were treated (41 with monotherapy, 25 and 24 in combination with exemestane, or paclitaxel respectively). XP-105 MTD was defined as 220 mg daily for monotherapy, and 160mg daily with exemestane 25 mg/d or paclitaxel 80 mg/m2/week. In the monotherapy arm, stable disease (SD) was reported in 8 pts (20%), with a median duration of 11 months. In the exemestane combination arm, 4 (16%) partial responses (PR) were reported. In the paclitaxel combination arm, 1 complete response (CR) and 4 PRs were reported (OR rate 21%). Disease control rate (CR/PR/SD) was 20%, 28%, and 58% in the monotherapy, XP-105/exemestane, and XP-105/paclitaxel arms, respectively. A sustained reduction in pAKT/total AKT to < 50% of baseline levels was observed with XP-105 ≥120mg daily. Overall, XP-105 was well tolerated; in the XP-105/paclitaxel combination the most frequent drug-related AEs were diarrhea and fatigue (58.3% each), hyperglycaemia (54.2%), anaemia (50%). Grade ≥3 AEs were hyperglycaemia, fatigue, diarrhea, anaemia, leukopenia. No PK interaction was observed. Conclusions: The MTD for XP-105 monotherapy and in combination with exemestane or paclitaxel was defined as 220 mg and 160mg once daily, respectively. Combination regimens showed higher activity as compared to monotherapy with durable OR in about 20% of pts. The observed safety profile of XP-105 compared favorably to those reported from other mTOR inhibitors. Clinical trial information: NCT01938846.

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.

Tolerability of split-dose oprozomib (ONX 0912) in patients with advanced refractory or recurrent solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13077-e13077
Author(s):  
Kyriakos P. Papadopoulos ◽  
David S. Mendelson ◽  
Anthony W. Tolcher ◽  
Howard A. Burris ◽  
Michael S. Gordon ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Solid Tumors ◽  
Phase 1 ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Status Change ◽  
Dose Escalation Study ◽  
Split Dose ◽  
Grade 3

e13077 Background: Oprozomib (ONX0912), a structural analog of carfilzomib, is an orally bioavailable proteasome inhibitor that irreversibly binds to its target and is being evaluated in hematologic malignancies and solid tumors (ST). In a dose-escalation study of once-daily (qd) ONX0912, the maximum tolerated dose (MTD) was 150 mg/d. The protocol was subsequently amended to investigate the effects of a split-dose schedule. Presented here are the interim results from this patient (pt) group. Methods: This is an ongoing, phase 1 study in pts with advanced refractory or recurrent ST. The primary objective is to evaluate the safety and tolerability of ONX0912 and determine the MTD. ONX0912 is administered for 5 consecutive days in 14-day cycles. For pts under the amended regimen, treatment is initiated at 60 mg BID, with 4–6 h between doses. Daily doses are escalated in 30 mg increments in successive groups of 3 pts. Groups are expanded to include 6 pts in the event of a dose-limiting toxicity (DLT) or if the MTD is reached. All AEs, including serious AEs (SAEs), are defined per protocol and collected from screening to 30 days after the last dose. Results: 13 pts received a split dose of ONX0912 (4 pts: 60 mg BID; 3 pts: 90/60 mg; 6 pts: 90 mg BID). At least 1 dose reduction was required by 1 pt in the 90/60 mg group and 2 pts in the 90 mg BID group. 9 pts reported treatment-related GI AEs (vomiting, n=9; nausea, n=8; diarrhea, n=5). 2 SAEs, arthralgia and mental status change, were reported at 60 mg BID. 2 SAEs resulting in a dose delay were reported at 90/60 mg (Grade 3/4 anemia [ongoing, also required a dose reduction] and reversible fatigue). There was 1 DLT at 90 mg BID (Grade 3 reversible hypophosphatemia), and this cohort was therefore expanded. Treatment-related vomiting led to discontinuation for 1 patient at 60 mg BID. No AEs led to early withdrawal, and no deaths have been reported in the study. Conclusions: With qd administration, the MTD of ONX0912 was established at 150 mg/d. However, the MTD has not been reached on the split-dose regimen at cumulative doses up to 180 mg/d (90 mg BID). GI AEs were the most common treatment-related AEs. Based on these preliminary observations, split-dose ONX0912 may improve tolerability over qd dosing.

Phase I trial and pharmacokinetic (PK) study of satraplatin in children and young adults with refractory solid tumors including brain tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2554-2554
Author(s):  
Srivandana Akshintala ◽  
Leigh Marcus ◽  
Katherine E. Warren ◽  
Robert F. Murphy ◽  
Wendy J. Goodspeed ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Gliomatosis Cerebri ◽  
Maximum Tolerated Dose ◽  
Resistant Cell ◽  
Clinical Activity ◽  
Apparent Clearance ◽  
Orally Bioavailable ◽  
Grade 3 ◽  
Enzyme Elevation

2554 Background: Satraplatin is an orally bioavailable platinum analog. Based on pre-clinical activity (IC500.02-8 µg/ml) including activity in cisplatin resistant cell lines, and clinical activity without neuro-, nephro-, or ototoxicity in adults with refractory tumors, we developed a phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and PKs of satraplatin in children with refractory solid tumors. Methods: Satraplatin (10 and 50 mg capsules) was administered orally once daily on days 1 - 5 of a 28 day cycle to cohorts of 3-6 patients (pts) at 60 mg/m2/dose (DL 1) and 80 mg/m2/dose (DL 2). Plasma ultrafiltrate (PUF) platinum was measured using atomic absorption spectroscopy during cycle 1 for PK analysis. Results: 9 pts [5 male, 4 female, median age 17 years (range 8-19)] with malignant glioma (n=4), ependymoma (n=2), medulloblastoma (n=1), osteosarcoma (n=1), or hepatoblastoma (n=1) received 1-10+ cycles (median 2). The MTD was exceeded at DL 2 as 2/4 pts had dose limiting toxicities (DLT) of delayed and prolonged myelosuppression (grade 3 thrombocytopenia, n=1; grade 3-4 neutropenia, n=2). 0/5 pts at DL 1 had DLTs. Grade 1 ototoxicity was seen in 1 pt at cycle 10. Non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No objective responses were observed, but 1 pt with gliomatosis cerebri has had radiographic stable disease through cycle 10+. Satraplatin mean exposure (AUC) and peak concentration (Cmax) were similar at both dose levels [day 1 PUF AUC0-24h 1.22 ± 0.55 µg/ml*h at DL1 (n=3), 1.02 ± 0.45 µg/ml*h at DL2 (n=3); Cmax0.17 ± 0.08 µg/ml at DL 1 (n=3), 0.16 ± 0.05 µg/ml at DL 2 (n=3)]. Terminal half-life was 14 ± 6 h and apparent clearance was 76 ± 29 L/h (n=6). Conclusions: The MTD of oral satraplatin in children with solid tumors is 60 mg/m2/dose daily x 5 q28 days. The toxicity profile was similar to adults, and delayed myelosuppression was DLT. Satraplatin exposure appears higher in pediatric pts compared to adults (PUF AUC0-24h 0.25-0.47 µg/ml*h at 60-80 mg/m2/dose). DL 1 will be expanded to gain additional experience regarding toxicities and PKs in a broader age range. Clinical trial information: NCT01259479.

Phase I trial of chloroquine (CQ)/hydroxychloroquine (HCQ) in combination with carboplatin-gemcitabine (CG) in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3027-3027 ◽  
Author(s):  
Nagla Fawzy Abdel Karim ◽  
Imran Ahmad ◽  
Ola Gaber ◽  
Ihab Eldessouki ◽  
Olugbenga Olanrele Olowokure ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Early Stage ◽  
Therapeutic Option ◽  
Phase 1 ◽  
Late Phase ◽  
Survival Rates ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Grade 3

3027 Background: Autophagy is a catabolic process triggered in cells during periods of stress to enable their survival. Established tumors utilize autophagy to survive periods of metabolic or hypoxic stress. Inhibition of early stage autophagy can rescue cancer cells, while inhibition of late stage autophagy will lead to cell death due to accumulation of damaged organelles. The antimalarial drugs CQ and HCQ inhibit late phase autophagy. The goal of our study is to assess the safety, tolerability and activity of combining CQ/HCQ with CG in advanced solid tumor patients who either progressed on other therapies or in whom CG is a therapeutic option. Methods: This single institution phase 1 dose-escalation study was designed to evaluate the maximum tolerated dose (MTD) of CQ, later substituted with HCQ, in combination with CG in patients with previously treated advanced solid tumors. Secondary objectives were to determine ORR, PFS and OS. A starting dose of 50 mg of CQ/HCQ was used in conjunction with CG, and increased in increments of 50 mg in each dose cohort. Grade 3 or greater toxicity that is treatment-related, and was not self-limited, or controlled in less than 7 days was considered dose limiting toxicity (DLT). Results: Twenty-three patients were enrolled with a median follow up of 6 months. HCQ 100 mg was found to be the MTD in combination with CG with ≥Grade 3 thrombocytopenia and/or neutropenia as dose-limiting. Median OS was 11 months, and the 1- and 3- year overall survival rates were 30% and 7%, respectively. Median progression free survival was 5 months and the 6-, 12-, and 18-months progression-free survivals were 48%, 21% and 14%, respectively (Table). Conclusions: The MTD identified for CQ/HCQ was lower than previously reported with concomitant use of chemotherapeutic regimes, likely due to the myelosuppressive nature of CG. Clinical trial information: NCT02071537. [Table: see text]

Phase 1 study of MK-4166, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as monotherapy or with pembrolizumab (pembro) in patients (pts) with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9509-9509 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
Karen A. Autio ◽  
Talia Golan ◽  
Konstantin Dobrenkov ◽  
Elliot Chartash ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Drug Disposition ◽  
Phase 1 ◽  
Objective Response ◽  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Phase 1 Study

9509 Background: Ligation of GITR on immune cells decreases Treg-mediated suppression and enhances T cell proliferation. MK-4166 is a humanized IgG1 agonist monoclonal antibody targeting GITR. Data from the first-in-human phase 1 study (NCT02132754) of MK-4166 as monotherapy (mono) or in combination with pembro (combo) are presented. Methods: MK-4166 was tested alone (0.0015 mg IV-900 mg Q3W ×4 doses) or with pembro (fixed dose 200 mg IV Q3W up to 35 doses) in the absence of toxicity or progression. Study included a dose escalation/confirmation cohort (metastatic solid tumors) and an expansion cohort (treatment-naive and pretreated melanoma). A T cell–inflamed gene expression profile (GEP) was assessed using RNA from baseline tumor samples. End points – primary: safety/tolerability, maximum tolerated dose (MTD) of MK-4166; secondary: pharmacokinetics (PK), pharmacodynamics (PD); exploratory: objective response rate (ORR) per irRECIST1.1. Results: Of 113 pts, 48 received mono and 65 combo; 20 were in the melanoma expansion. Common AEs ( > 20%) were fatigue, infusion-related reaction, nausea, abdominal pain, and pruritus; 43 pts had grade ≥3 AEs (38.1%); 6 (5.3%) were treatment-related. One dose-limiting toxicity (bladder perforation in a urothelial pt with a neobladder) possibly related to study drug was observed with mono. MTD was not reached. No treatment-related deaths were observed. MK-4166 PK/PD showed target-mediated drug disposition concomitant with decreased GITR availability on T cells in blood with increasing doses. Four objective responses (4/45; ORR, 9%) were seen with combo in dose escalation. For ICI-naive melanoma pts (n = 13) in expansion, ORR was 69% (95% CI, 38-91), including 4 CRs and 5 PRs. No response was observed in 7 pts previously treated with ICI. High ORRs were observed in noninflamed and inflamed ICI-naive melanoma pts. Conclusions: MK-4166 at a dose up to 900 mg as monotherapy and in combination with pembro was well tolerated, with dose-related evidence of target engagement. Responses were observed with MK-4166 900 mg plus pembro, particularly in pts with melanoma naive to ICIs. Clinical trial information: NCT02132754.

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 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.

scholarly journals Surufatinib Plus Toripalimab in Patients with Advanced Solid Tumors: A Single-Arm, Open-Label, Phase 1 Trial

2020 ◽  
Author(s):  
Yanshuo Cao ◽  
Ming Lu ◽  
Yu Sun ◽  
Jifang Gong ◽  
Jie Li ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Trial ◽  
Open Label Phase ◽  
Grade 3

Abstract BackgroundPreclinical studies have supported a potential synergistic antitumor activity between surufatinib and anti-programed death ligand-1 (PD-L1). We describe here the results of a single-arm, open-label phase 1 trial to evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) in patients with advanced solid tumors treated with surufatinib combined with toripalimab, an inhibitor of PD-L1.MethodsThis is an open-label, dose escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose escalation stage, 3 cohorts of patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with a fixed dose of toripalimab 240 mg, every 3 weeks (Q3W), to evaluate maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Additional patients were enrolled in the dose expansion phase to further assess the efficacy, safety, and PK profile.ResultsFrom April 1, 2019 to July 10, 2020, 31 patients were screened, of which 28 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity (DLT), a grade 3 hyperthyroidism. The top 3 most common treatment-related adverse events of ≥ grade 3 were transaminases increased (17.9%), hypertension (14.3%) and blood bilirubin increased (10.7%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Overall objective response rate was 22.2% [95% confidential interval (CI) 8.6‒42.3], and disease control rate reached 81.5% (95% CI 61.9‒93.7). ConclusionsSurufatinib plus toripalimab was well-tolerated, with no unexpected safety signals, and showed promising antitumor activity in patients with advanced solid tumors. Trial registrationclinicaltrials.gov, NCT03879057; Registered March 18, 2019, https://clinicaltrials.gov/ct2/show/NCT03879057

A phase I clinical trial of vorinostat in combination with sFULV2 in patients with refractory solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4083-4083
Author(s):  
M. G. Fakih ◽  
L. Pendyala ◽  
M. J. Egorin ◽  
G. Fetterly ◽  
I. Espinoza-Delgado ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Phase I Clinical Trial ◽  
Fixed Dose ◽  
Over Expression ◽  
Dose Dependent Fashion ◽  
Grade 3

4083 Background: Thymidylate synthase (TS) over-expression is associated with 5-FU resistance. Pre-clinical studies demonstrate that vorinostat down-regulates intra-tumor TS in a dose-dependent fashion and augments 5-FU antitumor activity in xenograft models. We conducted a phase I clinical trial of an intermittent schedule of QD x 3 vorinostat in combination with a fixed dose of fluorouracil (5-FU) and leucovorin (LV) in patients (pts) with refractory solid tumors. Methods: Vorinostat was escalated in a standard 3 x 3 design in combination with a fixed dose of 5-FU and LV (simplified de Gramont regimen, sFULV2). Vorinostat was given QD x 3 on an every-2-week cycle. sFULV2 started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hrs followed by 5-FU 400 mg/m2 bolus and 5-FU 2400 mg/m2 over 46 hrs. Results: 24 pts were enrolled: Male/Female: 11/13; ECOG 0/1: 6/18; Age: median 60 (range 42–77) yrs. 21 pts had colorectal cancer (CRC), 1 had gastric, 1 had esophageal, and 1 had anal cancer. Vorinostat dose-levels (DL) were 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1700 mg, and 2000 mg. Dose-limiting toxicities (DLT), consisting of fatigue and hand-and-foot syndrome (H&F), were seen in 2 of 3 pts at the 2000 mg DL. None of the 6 pts at the 1700 mg DL had a DLT. Cycle 1 grade 3/4 toxicities consisted of thrombocytopenia, GI bleeding, fatigue, and H&F in 2 pts at the 2000 mg DL and a non-DLT G3 diarrhea (lasted <24 hrs) in 1 pt at the 1700 mg DL. Grade 2 nausea, fatigue, and anorexia were common; especially at DL ≥ 1700 mg. Antitumor activity was noted in pts with CRC despite prior refractoriness to 5-FU and failure to oxaliplatin, irinotecan, and cetuximab in all pts. 12/21 CRC pts had a confirmed SD (11) or PR (1). CRC pts had a median PFS of 4 months, a ≥ 6 months PFS rate of 43%, and a ≥ 8 months PFS rate of 33%. Conclusions: The maximum tolerated dose (MTD) of vorinostat in combination with sFULV2 is 1700 mg PO QD x 3 every 2 weeks. This combination is associated with considerable activity in pts with 5-FU-refractory CRC and warrants further investigation. An expanded MTD cohort is accruing to investigate 5-FU-vorinostat PK interaction and intra-tumor TS down-regulation. (This work was supported by a grant from CTEP and the ACS.) No significant financial relationships to disclose.

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