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.

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.

A phase I dose escalation study of oral MK-2206 (allosteric Akt inhibitor) with oral selumetinib (AZD6244; ARRY-142866) (MEK 1/2 inhibitor) in patients with advanced or metastatic solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13599-e13599 ◽  
Author(s):  
Khurum Hayat Khan ◽  
Li Yan ◽  
Janusz Mezynski ◽  
Amita Patnaik ◽  
Victor Moreno ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Akt Inhibitor ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Simultaneous Inhibition ◽  
Investigational Agents ◽  
Dose Levels

e13599 Background: Simultaneous inhibition of both the PI3K-Akt and RAF/MEK/ERK pathways may yield greater benefits than inhibiting either pathway alone. This phase I study (NCT01021748) examined the safety, pharmacokinetics (PK), pharmacodynamics (PD), maximal tolerated dose (MTD), and preliminary antitumor activity of the combination of a MEKi (selumetinib) and AKTi (MK-2206). Methods: Eligible patients (pts) with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered either once daily (QD) or twice daily (BID). Results: 51 pts with advanced solid tumors (15 colon, 8 NSCLC, 6 ovarian, 5 pancreatic, 3 breast and 14 others) were treated across 9 dose levels. There were 2 confirmed partial response (PR) (1 NSCLC, ongoing > 52 wks; 1 ovarian, on treatment for 47 weeks; both KRAS mutation positive), 1 unconfirmed PR (pancreatic, on treatment 20 wks), and 24 pts with stable disease (ranged from 6 to 47 wks). Preliminary assessment of PK data suggested no apparent drug-drug interactions with unaltered PK profiles of each drug when administered in combination. Conclusions: In combination the maximum tolerated doses of MK-2206 and selumetinib are 135 mg QW and 100 mg QD, respectively. This combination of investigational agents demonstrated preliminary antitumor activity in pts with advanced cancer. [Table: see text]

Phase I and Pharmacokinetic Study of Topotecan Administered Orally Once Daily for 5 Days for 2 Consecutive Weeks to Pediatric Patients With Refractory Solid Tumors

2004 ◽  
Vol 22 (5) ◽  
pp. 829-837 ◽  
Author(s):  
Najat C. Daw ◽  
Victor M. Santana ◽  
Lisa C. Iacono ◽  
Wayne L. Furman ◽  
Dana R. Hawkins ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Pediatric Patients ◽  
Radiation Recall ◽  
Time Curve ◽  
Once Daily ◽  
Injectable Formulation ◽  
P 16 ◽  
Grade 3 ◽  
Oral Topotecan

Purpose We conducted a phase I trial of the injectable formulation of topotecan given orally once daily for 5 days for 2 consecutive weeks (qd × 5 × 2) in pediatric patients with refractory solid tumors. Patients and Methods Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m2/d every 28 days for a maximum of six courses. Twenty patients (median age, 10.6 years) received a total of 51 courses. Eight patients received topotecan capsules during course 2 only. Results Dose-limiting toxicity occurred at 2.3 mg/m2/d and consisted of prolonged grade 4 neutropenia (n = 2), grade 3 stomatitis as a result of radiation recall (n = 1), grade 3 hemorrhage (epistaxis) in the presence of grade 4 thrombocytopenia (n = 1), and grade 3 diarrhea in the presence of Clostridium difficile infection (n = 1). Dose-limiting, prolonged grade 4 neutropenia and thrombocytopenia occurred in one patient at 1.4 mg/m2/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m2/d; the mean (± standard deviation) area under the plasma concentration-time curve for topotecan lactone at this dosage was 20.9 ± 8.4 ng/mL · h. The population mean (± standard error) oral bioavailability of the injectable formulation was 0.27 ± 0.03; that of capsules was 0.36 ± 0.06 (P = .16). Disease stabilized in nine of 19 assessable patients for 1.5 to 6 months. Conclusion Oral topotecan (1.8 mg/m2/d) on a qd × 5 × 2 schedule is well tolerated and warrants additional testing in pediatric patients.

Phase I Study of O6-Benzylguanine and Temozolomide Administered Daily for 5 Days to Pediatric Patients With Solid Tumors

2005 ◽  
Vol 23 (30) ◽  
pp. 7646-7653 ◽  
Author(s):  
Katherine E. Warren ◽  
Alberta A. Aikin ◽  
Madeleine Libucha ◽  
Brigitte C. Widemann ◽  
Elizabeth Fox ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Pediatric Patients ◽  
Maximum Tolerated Dose ◽  
Biologically Active ◽  
Conventional Dose ◽  
Daily Schedule ◽  
Dose Levels ◽  
Dose Limiting Toxicity ◽  
Active Dose

Purpose This pediatric phase I trial of O6-benzylguanine (O6BG) and temozolomide (TMZ) on a daily schedule for 5 days, every 28 days was performed to determine the maximum-tolerated dose of TMZ when given with a biologically active dose of O6BG and to define the toxicity profile of the combination in children with solid tumors. Patients and Methods Patients ≤ 21 years old with refractory solid tumors were eligible. O6BG was administered intravenously over 60 minutes daily for 5 days. TMZ was administered orally 30 minutes after completion of each O6BG infusion. Starting doses of O6BG and TMZ were 60 mg/m2/d and 28 mg/m2/d, respectively. O6BG was escalated to 90 and 120 mg/m2/d; TMZ was subsequently escalated to 40, 55, 75, and 100 mg/m2/d. Cycles were repeated every 28 days. Results Forty-one patients were enrolled; 32 patients were assessable for toxicity. The combination of O6BG and TMZ was tolerable at TMZ doses less than half of the conventional dose of 200 mg/m2/d. Myelosuppression occurred sporadically at all dose levels and was the dose-limiting toxicity (DLT) at 100 mg/m2/d of TMZ combined with 120 mg/m2/d O6BG. Nonhematologic toxicities were generally mild. Evidence of antitumor activity was observed at 120 mg/m2/d O6BG combined with TMZ doses of 55 mg/m2/d and above. Conclusion The recommended doses of O6BG administered with TMZ on a 5-day schedule in children are 120 mg/m2/d of O6BG and 75 mg/m2/d of TMZ. Evidence of activity was observed at these doses. Myelosuppression was the DLT.

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.

Vincristine Sulfate Liposomes Injection (VSLI, Marqibo): Interim Results From a Phase I Study in Children and Adolescents with Refractory Cancer

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1497-1497
Author(s):  
Nirali N Shah ◽  
Melinda Merchant ◽  
Diane Cole ◽  
Kelly Richards ◽  
Cindy Delbrook ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Pediatric Patients ◽  
Pharmacokinetic Analysis ◽  
Motor Neuropathy ◽  
Vincristine Sulfate ◽  
Level 1 ◽  
Dose Levels

Abstract Abstract 1497 Background: Vincristine is active in many pediatric cancers, but cumulative neuromuscular toxicity is often dose limiting and requires a maximum dose cap. Liposomal carriers are capable of increasing the therapeutic index of anticancer agents by altering pharmacokinetic behavior. Vincristine sulfate liposomes injection (VSLI, Marqibo®) is a novel preparation of standard vincristine encapsulated in sphingomyelin/cholesterol liposomes. Clinical trials have demonstrated safety, tolerability and activity in adults with leukemias, lymphomas and solid tumors. Pediatric experience with VSLI is limited. Design: This single center Phase I dose-escalation study is designed to determine the maximum tolerated dose (MTD) and to assess safety, pharmacokinetics and activity of VSLI in pediatric patients with relapsed/refractory cancer. Patients with active central nervous system disease or ≥grade 2 sensory or motor neuropathy are excluded. Dose escalation is per a standard 3 + 3 Phase I trial design with enrollment following a rolling 6 strategy. VSLI is administered IV over 60-minutes every 7 days (± 3 days) for 4 consecutive weeks for a 28-day treatment cycle (4 doses/cycle). Cycles may be delayed by up to 1 week for toxicity. Two dose levels have been tested to date: 1.75 mg/m2 and 2.25 mg/m2(adult MTD). No individual dose cap is employed. A validated HPLC tandem mass spectrometry assay was used to quantitate total (liposomal encapsulated and non-encapsulated) vincristine. Results: 9 patients have been treated (Table): 6 with acute lymphoblastic leukemia (ALL) and 3 with solid tumors. All patients were heavily pre-treated and 2 had prior stem cell transplants. 6 of 9 completed at least 1 cycle of therapy, with 1 each removed early for alternative therapy, complications of ALL, or dose-limiting toxicity (DLT). Most treatment-related adverse events were reversible grade 1 and 2 severity including hepatic transaminase elevation, parasthesia, low white blood cell count, neutropenia and fatigue. 2 patients evaluable for hematologic toxicity developed grade 4 neutropenia that spontaneously and rapidly resolved. No DLT occurred on dose level 1. Grade 4 aspartate aminotransferase elevation was observed in one patient at the second dose level and this dose level is being expanded. 1 patient treated at dose level 1 had dose de-escalation starting with Cycle 2 Dose 3 due to neuropathy. No patient was taken off study due to neurotoxicity. 7 of 9 patients received a VSLI dose that exceeded the 2 mg dose limit set for standard vincristine. 6 patients were evaluable for response: 1 had a complete remission (CR) (minimal residual disease negative by flow cytometry); 3 had stable disease (SD); and 2 had progressive disease (PD). First-dose pharmacokinetic analysis revealed wide interpatient variation (Table). The median (range) maximum concentrations (Cmax) of total vincristine (ng/ml) were 1,485 (845-2,120) and 2,450 (1,690-3,690) at dose levels 1 and 2 respectively. The median plasma half-life (T½) was 8.5 and 13.5 hours at dose levels 1 and 2 respectively (range 1.8 to 40.4 hours). Conclusions: VSLI appears to be safe, tolerable and demonstrates preliminary activity in pediatric patients with refractory ALL and solid tumors. The toxicity spectrum appears to be similar in children and adults. Clearance of total vincristine in our study is approximately 100-fold lower in comparison to administration of standard vincristine. VSLI allows for intensification of vincristine therapy in children with cancer. Accrual to the Phase I component at the adult recommended dose is ongoing and an expanded Phase II cohort in pediatric patients with ALL is planned. This study was sponsored by Talon Therapeutics and is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Disclosures: No relevant conflicts of interest to declare.

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.

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.

scholarly journals EPCT-11. PHASE 1 STUDY OF FLUVASTATIN-CELECOXIB COMBINATION IN CHILDREN WITH RELAPSING/REFRACTORY OPTICO-CHIASMATIC LOW-GRADE GLIOMA OR HIGH-GRADE GLIOMAS (FLUVABREX): FINAL RESULTS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii305-iii306
Author(s):  
Nicolas Andrew ◽  
Arthur Sterin ◽  
Caroline Solas ◽  
Marie-Cécile Le Deley ◽  
Alicia Probst ◽  
...  
Keyword(s):  
Phase I ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Low Grade ◽  
High Grade ◽  
Phase 2 Study ◽  
Starting Dose ◽  
Grade 3 ◽  
Dose Levels

Abstract BACKGROUND Preclinical data support the activity of celecoxib and fluvastatin in high grade (HGG) and low grade gliomas (LGG). A Phase I study was designed to evaluate this combination in children with refractory/relapsed glioma. AIM: To assess the safety, pharmacokinetics (PK), maximum tolerated dose, Recommended Dose for Phase II (RDP2). METHOD: Multicenter phase I trial, including patients aged 6 to 21 year old. Fluvastatin starting dose was 2 mg/kg/day, 14/28 days, with fixed dose of celecoxib (200–800 mg /day). Four dose levels of fluvastatin (2, 4, 6, 8 mg/kg/day) were evaluated. A Continual Reassessment Method was used for dose escalation. Dose-limiting toxicities (DLT) were determined on the 1st cycle. PK samples were obtained at D1 and D14 of cycle 1, pre-dose of cycle 2. RESULTS 20 patients were enrolled with a median age of 12 years (5.9–19). They previously received a median of 3 (1–7) lines of treatment. Ten patients were treated for LGG and 10 for HGG, receiving a median of 3.5 cycles (1–21). Patients with LGG received a median of 9 cycles (1–21). Among the 17 patients evaluable for DLT, 2 DLTs were reported: 1 grade 3 maculo-papular rash (4 mg/kg), and 1 grade 4 increase of CPK (6 mg/kg). The RP2D of fluvastatin is 6 mg/kg/day. CONCLUSION In children with refractory/relapsed glioma, the RDP2 of fluvastatin associated with celecoxib is 6 mg/kg/day. This combination is well tolerated encouraging a phase 2 study in LGG.

Phase 1/2a trial of daily oral BAL101553, a novel tumor checkpoint controller (TCC), in advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2532-2532 ◽  
Author(s):  
Rebecca Sophie Kristeleit ◽  
T.R. Jeffry Evans ◽  
Alvaro Henrique Ingles Garces ◽  
Sarah Slater ◽  
Yvette Drew ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Spindle Assembly Checkpoint ◽  
Phase 1 ◽  
Therapeutic Window ◽  
Advanced Solid Tumors ◽  
Tumor Cell Death ◽  
Once Daily ◽  
Vascular Toxicity ◽  
Antiproliferative Effects ◽  
Definition Of

2532 Background: BAL101553 (prodrug of BAL27862) is a small molecule TCC that binds microtubules and promotes tumor cell death by activation of the spindle assembly checkpoint. In a previous study (NCT01397929, Lopez et al. JCO 34, 2016; abstr 2525), 2-h IV infusion on Days 1, 8, 15 (q28d) of BAL101553 up to 80 mg/m2 (maximum administered dose, MAD) showed vascular toxicities, including transient hypertension, which appeared to be Cmax related. The recommended Phase 2 dose (RP2D) was 30 mg/m2 weekly IV. Based on nonclinical models, antiproliferative effects of BAL27862 are driven by AUC. This trial explores whether once daily oral administration of BAL101553 reduces Cmax-related toxicity and improves the therapeutic window (NCT02490800). Methods: Patients (pts) with advanced solid tumors who failed standard therapy, received QD oral BAL101553 (28-d cycles) in a 3+3 dose-escalation design to determine the MTD. Adverse events were assessed by CTCAEv4 grade (G); tumor response by RECIST 1.1; serial PK on Day 1 of Cycles 1 and 2. Results: In the ongoing study, 19 pts (9M/10F; median age 67 y) received doses of 2, 4, 8, 16 or 30 mg oral BAL101553 QD. The MAD was 30 mg with DLTs of reversible G2 hallucination and asymptomatic, reversible G3 electrolyte imbalances. No DLTs were observed at ≤ 16 mg. Dosing is ongoing between 16 and 30 mg QD to determine the MTD. BAL27862 exposures after oral QD dosing of BAL101553 compared to weekly 2-h infusions suggested high relative oral bioavailability. The BAL27862 weekly AUC at the oral MAD (30 mg QD) compared to the RP2D of 30 mg/m2 for 2-h IV was more than 5-fold higher (19,656 vs 3,584 ng*h/mL) and Cmax was 1.5-fold lower (171 vs 266 ng/mL). Both Cmaxand AUC were dose-proportional, with low/moderate variability. Oral BAL101553 had no effects on blood pressure and showed no vascular toxicity. 5 pts had stable disease (2 pts [cholangiocarcinoma, neuroendocrine pancreatic cancer] > 4 cycles). Conclusions: Daily oral BAL101553 enables higher weekly exposures of BAL27862 with lower Cmax levels compared with a 2-h weekly infusion, due to the absence of Cmax related vascular toxicity. Doses up to 16 mg QD are well tolerated. The MAD has been identified as 30 mg QD; definition of the MTD is ongoing. Clinical trial information: NCT02490800.

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