A phase I trial of MK 2206 in children with refractory solid tumors: A Children’s Oncology Group study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9581-9581
Author(s):  
Christine L. Phillips ◽  
Maryam Fouladi ◽  
John Peter Perentesis ◽  
Sarah Leary ◽  
Renee M. McGovern ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Pediatric Solid Tumors ◽  
Biological Studies ◽  
Grade 3 ◽  
Rhabdoid Tumors

9581 Background: AKT, a serine threonine protein kinase, is activated downstream of phosphatidylinositol 3-kinase (PI3K) which transmits signals from cytokines, growth factors and oncoproteins to multiple targets. Activated AKT regulates survival, proliferation, and growth. The PI3K/AKT pathway is downstream of most of the common growth factor tyrosine kinase receptors in cancer, e.g., EGFR, HER2, IGFR, etc., and is a driver of tumor progression in many cancers. AKT protein kinase is activated in many pediatric solid tumors, including glioblastoma, malignant rhabdoid tumors, neuroblastoma, synovial sarcoma, rhabdomyosarcoma and medulloblastoma. MK2206, an oral allosteric AKT1, 2,3 inhibitor, has demonstrated antitumor activity in in vitro and in vivo cancer models.A phase I trial evaluating MK2206 was conducted in children with refractory solid tumors. Methods: Using a rolling-6 design, MK2206 was administered either once every 7 days (schedule 1), or once every other day (schedule 2) in a 28-day cycle. Serial PK studies were obtained on day 1, cycle 1 and trough samples were obtained on days 7, 14, 21 and 28. Biological studies included analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence. Results: Forty-five patients [23 males, median age 13.6 years (range 3.1-21.9)] with malignant glioma (14), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2) or other tumors (22) were enrolled; 34 were fully evaluable for toxicity (schedule 1 n=17; schedule 2 n=17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m2; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m2. There were no DLTs at 35 mg/m2 and dose level 4 (58 mg/m2) is currently open for patient accrual with one enrollment. Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m2; grade 3 rash in 1/6 patients at 120 mg/m2), and grade 3 rash in 2/6 patients at 155 mg/m2. Conclusions: The recommended pediatric phase II dose of weekly MK2206 is 120 mg/m2 and the last cohort of patients to the every other day dosing schedule of MMK206 is enrolling. PK and PD data are currently being analyzed and will be presented.

scholarly journals Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole

2018 ◽  
Vol 10 ◽  
pp. 175883591878685 ◽  
Author(s):  
Hiroshi Umehara ◽  
Yoshimi Maekawa ◽  
Fumito Koizumi ◽  
Makiko Shimizu ◽  
Toshio Ota ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Drug Combination ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Her2 Positive ◽  
Grade 3 ◽  
Mcf 7

Background: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Methods: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Results: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. Conclusions: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.

A phase I trial and pharmacokinetic study of IMC-A12 in pediatric patients with relapsed/refractory solid tumors: A Children's Oncology Group Phase I Consortium study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10013-10013
Author(s):  
S. Malempati ◽  
B. Weigel ◽  
A. M. Ingle ◽  
C. H. Ahern ◽  
J. M. Carroll ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Protein Levels ◽  
Pediatric Solid Tumors ◽  
Igg1 Monoclonal Antibody ◽  
Grade 3 ◽  
Dose Levels

10013 Background: IMC-A12, a fully human IgG1 monoclonal antibody to the Insulin-Like Growth Factor-I Receptor (IGF-IR), is active preclinically in a variety of pediatric solid tumors. We performed a phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of IMC-A12 in children with refractory solid tumors. Methods: IMC-A12 was administered as a weekly 1 hr IV infusion, without interruption. Two dose levels, 6 and 9 mg/kg, were evaluated using a standard 3+3 cohort design. After defining initial safety, patients (pts) with refractory Ewing sarcoma (ES) were treated in an expanded cohort at each dose level. Results: 24 eligible patients (11 male), median 15.3 yrs (range, 7.0 to 21.5), were enrolled. Among the 12 pts enrolled on the dose-escalation component, DLT (grade 4 thrombocytopenia) occurred in 1/6 pts at 6 mg/kg. No DLTs occurred in 6 pts at 9 mg/kg or in the ES cohort. 1/10 evaluable pts with ES at the 6 mg/kg dose had a partial response; no CRs were observed. Grade 2 or higher non-DLTs possibly attributable to IMC-A12 observed in the first course include anemia (n=4), leukopenia (n=1), lymphopenia (n=2), neutropenia (n=2), opportunistic infection (n=1), ↑liver transaminases (n=2), and hyperglycemia (n=1). No ≥ grade 3 hyperglycemia occurred. Mean (± SD) trough IMC-A12 concentrations were 59.8 ± 31.1 and 117 ± 70.8 μg/ml at the 6 and 9 mg/kg dose levels, respectively. A majority of pts at both dose levels exhibited > 50% reduction in PBMC IGF-IR protein levels. Conclusions: In order to exceed target trough concentrations associated with optimal anti-tumor activity in pre-clinical models, 9 mg/kg IV weekly is the recommended Phase II IMC-A12 dose in children. A phase II protocol for children with refractory solid tumors will be performed. [Table: see text]

A phase I study of oral belinostat (PXD101) in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14092-14092 ◽  
Author(s):  
W. K. Kelly ◽  
T. Yap ◽  
J. Lee ◽  
U. Lassen ◽  
E. Crowley ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Standard Therapy ◽  
Tumor Imaging ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Grade 3

14092 Background: Belinostat (PXD101) is a hydroxamate HDAC inhibitor which demonstrates broad anti-neoplastic activity in vitro and in vivo. In Phase I studies in patients (pts) with advanced cancer, IV belinostat is well-tolerated up to 1000 mg/m2 daily x5. Preliminary results of an oral formulation of belinostat showed that the oral bioavailability was 20 - 50%. This Phase I trial of oral belinostat will determine the maximal tolerated dose (MTD) of once and twice daily dosing, tolerability and pharmacokinetics (PK) in pts with advanced solid tumors. Methods: Sequential cohorts of 3–6 pts with advanced solid tumors refractory to standard therapy or for which no standard therapy exists were administered belinostat 250–500mg once or twice daily in 4 week cycles. Fasting (day 1) and non-fasting (day 7) pharmacokinetic studies were performed on all patients along with serial ECGs to evaluate any potential effects on QTc prolongation. Patients were evaluated with routine blood work weekly and tumor imaging at the end of cycle 1 then every other cycle. Results: Sixteen pts have been treated in 3 dose levels at 250mg QD (6 pts), 500mg QD (6 pts) and 250mg BID (4 pts). The median number of cycles of therapy is 1 (range 1–5), nine pts continue to be treated. The most common reasons for discontinuation were adverse event (3 pts) and PD (3 pts). No DLTs were identified at 250mg QD or 250mg BID. DLTs of grade 3 dehydration and grade 3 fatigue were reported at 500mg QD. In pts from the first 3 dose cohorts, there were no grade 4/5 events reported. Other Grade 3 toxicities were fatigue (2 pts), abdominal pain (1 pt), ataxia (1 pt), prolonged INR (1 pt), prolonged PTT (1 pt) and confusion (1 pt). Symptoms were transient and usually resolved after drug was held. In > 500 ECG’s collected, there were no QTcF > 500 ms, and no QTcF increase > 60 ms above baseline. To date, the best clinical response observed has been SD in 7 patients. Conclusions: Oral belinostat at doses of 250mg QD and 250mg BID given on a continuous schedule appears to be well tolerated. Alternative dosing schedules are being explored to further dose escalate the belinostat. Updated safety, activity and pharmacokinetic data will be presented on these and alternate dose schedules. [Table: see text]

scholarly journals First-in-human phase I trial of anti-hepatocyte growth factor antibody (YYB101) in refractory solid tumor patients

2020 ◽  
Vol 12 ◽  
pp. 175883592092679
Author(s):  
Seung Tae Kim ◽  
Jung Yong Hong ◽  
Se Hoon Park ◽  
Joon Oh Park ◽  
Young Whan Park ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Phase I ◽  
Cancer Patients ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Safety And Efficacy ◽  
Hepatocyte Growth

Background: YYB101, a humanized monoclonal antibody against hepatocyte growth factor (HGF), has shown safety and efficacy in vitro and in vivo. This is a first-in-human trial of this antibody. Materials and Methods: YYB101 was administered intravenously to refractory cancer patients once every 4 weeks for 1 month, and then once every 2 weeks until disease progression or intolerable toxicity, at doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were studied. HGF, MET, PD-L1, and ERK expression was evaluated for 9 of 17 patients of the expansion cohort (20 mg/kg). Results: In 39 patients enrolled, no dose-limiting toxicity was observed at 0.3 mg/kg, and the most commonly detected toxicity was generalized edema ( n = 7, 18.9%) followed by pruritis and nausea ( n = 5, 13.5%, each), fatigue, anemia, and decreased appetite ( n = 4, 10.8%, each). No patient discontinued treatment because of adverse events. YYB101 showed dose-proportional pharmacokinetics up to 30 mg/kg. Partial response in 1 (2.5%) and stable disease in 17 (43.5%) were observed. HGF, MET, PD-L1, and ERK proteins were not significant predictors for treatment response. However, serum HGF level was significantly lowered in responders upon drug administration. RNA sequencing revealed a mesenchymal signature in two long-term responders. Conclusion: YYB101 showed favorable safety and efficacy in patients with refractory solid tumors. Based on this phase I trial, a phase II study on the YYB101 + irinotecan combination in refractory metastatic colorectal cancer patients is planned. Conclusion: ClinicalTrials.gov Identifier: NCT02499224

Phase I Assessment of the Pharmacokinetics, Metabolism, and Safety of Emitefur in Patients With Refractory Solid Tumors

2000 ◽  
Vol 18 (19) ◽  
pp. 3423-3434 ◽  
Author(s):  
J. Nemunaitis ◽  
R. Eager ◽  
T. Twaddell ◽  
A. Corey ◽  
K. Sekar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Prolonged Exposure ◽  
Circadian Variation ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Minimum Effective Concentration ◽  
Grade 3

PURPOSE: To determine the toxicities, dose-limiting toxicities (DLT), maximum-tolerated dose, and pharmacokinetic profile of emitefur (BOF-A2) in patients with advanced solid tumors. METHODS: This was a phase I dose-escalating trial in which cohorts of patients received BOF-A2 (cohort 1, 300 mg/m2 orally [PO] tid; cohort 2, 200 mg/m2 PO tid; cohort 3, 200 mg/m2 bid; and cohort 4, 250 mg/m2 bid) for 14 consecutive days followed by 1 week of rest (cycle 1). Pharmacokinetics, toxicity, and tumor response were monitored. RESULTS: Nineteen patients received 110 cycles (three patients in cohort 1, three patients in cohort 2, 10 patients in cohort 3, and three patients in cohort 4). DLT (grade 3 stomatitis, diarrhea, leukopenia) was observed in cohorts 1, 2, and 4. Pharmacokinetics indicated that prolonged systemic expression of fluorouracil (5-FU) is maintained after administration of BOF-A2 at a dose of 200 mg bid for 14 days. The mean steady-state concentration of plasma 5-FU was ≥ 24 ng/mL, which was 184-fold greater than the minimum effective cytotoxic concentration in vitro. Lack of variation of 5-FU trough levels within a day at steady-state indicates suppression of circadian variation. One patient in cohort 3 achieved a partial response and five patients maintained stable disease in excess of 6 months. CONCLUSION: BOF-A2 at a dose of 200 mg PO bid for 14 days followed by 7 days of rest is well tolerated. Prolonged exposure to 5-FU above the predicted preclinical minimum effective concentration is maintained, without evidence of circadian variation. Furthermore, evidence of antitumor activity is suggested.

Phase I study of intravenous CCI-779 in combination with bryostatin-1 in solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3067-3067 ◽  
Author(s):  
N. B. Haas ◽  
N. Lewis ◽  
R. B. Cohen ◽  
L. Malizzia ◽  
M. B. Einarson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Messenger Rna ◽  
Bryostatin 1 ◽  
Naive Patient ◽  
Peripheral Blood Mononuclear ◽  
Mtor Inhibition ◽  
Resistant Disease ◽  
Grade 3

3067 Background: mTOR regulates translation of messenger RNA critical for angiogenesis and cell growth. CCI-779 inhibits mTOR signaling through p70S6 kinase (S6K), which phosphorylates the ribosomal S6 protein (S6). CCI-779 is active in renal carcinoma (RCC) and other solid tumors. Based on our finding that bryostatin-1 (bryo) inhibits S6K, and that CCI-779 + Bryo additively inhibit S6K and RCC growth in vitro, we initiated a phase I trial to determine the maximum tolerable (MTD) doses and dose-limiting toxicities of this novel combination in patients with solid tumors. Methods: Bryo (20 μg/m2) was administered over 60 minutes IV followed by CCI-779 (10 and 15 mg, planned escalation to 75 mg) IV over 30 minutes, both weekly for 3 of 4 weeks. Serum and peripheral blood mononuclear cell (PBMC) samples were collected for analysis of pharmacokinetics and markers of mTOR inhibition (phospho-S6 and p21waf1). Results: Nine patients (median age 57, 6 RCC, 2 sarcoma and 1 neuroendocrine) are evaluable for toxicity (total cycles=27 cycles, median 4, range 1–7) at the initial 2 dose levels (Bryo 20 μg/m2, CCI-779 10 mg and 15 mg). Cycle 1 toxicity includes grade 3 hypophosphatemia and myelosuppression in one patient each and grade 2 fatigue, stomatitis, and anemia. One patient developed reversible grade 3 pneumonitis after 7 cycles. Of 7 patients with therapy-resistant disease, 5 (4 RCC and 1 sarcoma) had stable disease lasting up to 7 months. A therapy-naive patient with RCC has 23% tumor reduction after 2 cycles at dose level 2 (CCI-779=15 mg). PBMC proteins from 5 patients show consistent decreases in phospho-S6 at 2–6 hours-post treatment compared with pre-treatment baseline measurement, with recovery by 24–72 hours after dosing. In parallel with inhibition of phosphorylation of S6, PBMC levels of p21waf1 were completely inhibited in all 5 patients. Conclusions: The combination of bryo and CCI-779 is feasible, with antitumor activity in RCC and mTOR pathway inhibition observed at submaximal doses. Dose escalation is continuing. No significant financial relationships to disclose.

Final results from a phase I trial of ixabepilone in patients with advanced malignancies and lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2039-2039
Author(s):  
C. Aghajanian ◽  
O. O’Connor ◽  
M. Cohen ◽  
R. Peck ◽  
H. Burris
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2039 Background: Ixabepilone is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixabepilone has shown clinical activity in a broad range of tumors. Methods: This Phase I trial was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), efficacy, safety, pharmacokinetics and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or lymphoma. Eligible patients were aged ≥18 years with histologically/cytologically confirmed non-hematologic cancer, or a pathologic diagnosis of relapsed/primary refractory non-Hodgkin’s lymphoma (NHL) or relapsed/primary refractory mantle cell lymphoma, with ≤CTC Grade 1 neuropathy. Ixabepilone doses ranged from 7.5–65 mg/m2. Response was assessed every 6 weeks using RECIST. DLT was defined as Grade 4 neutropenia and/or febrile neutropenia, thrombocytopenia, ≥Grade 3 nausea/vomiting and non-hematologic toxicity, or treatment delay of >2 weeks due to delayed recovery. Results: Of 61 patients (median age 58, range 18–81), 75% had solid tumors; 25% had lymphoma. 98% and 67% of patients had received one or ≥ two prior chemotherapy regimens, respectively. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The most common DLTs were neutropenia, myalgia, arthralgia and stomatitis/pharyngitis. A total of eight patients (13%) achieved a durable objective response. Complete responses were achieved in two patients with primary peritoneal cancer and NHL. A partial response was seen in six patients. The most common Grade 3/4 treatment-related adverse events (only observed at doses ≥40 mg/m2) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), nausea (5%), febrile neutropenia (5%) and neutropenia (5%). Recovery to baseline or ≤Grade 1 neuropathy occurred in some patients. Conclusions: The recommended dose of ixabepilone for the initiation of Phase II studies based on this study is 50 mg/m2 over 1 hour every 3 weeks. Ixabepilone demonstrates promising safety in patients with solid tumors or lymphoma who have failed standard therapy. Encouraging activity was reported in several tumor types. [Table: see text]

A phase I trial of TAS-102 administered on a three times a day schedule in patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2053-2053 ◽  
Author(s):  
R. A. Wolff ◽  
P. M. Hoff ◽  
A. Mita ◽  
M. Fukushima ◽  
J. C. Blais ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Performance Status ◽  
Tumor Xenograft ◽  
Unknown Primary ◽  
Hematologic Toxicity ◽  
Prior Therapy ◽  
Grade 3 ◽  
And Performance

2053 Background: TAS-102 consists of trifluorothymidine (FTD) and an inhibitor of thymidine phosphorylase (TP). FTD, like 5-fluorouracil, is an inhibitor of thymidylate synthase. However, when orally administered, FTD is rapidly degraded to an inactive form, primarily by TP. Co-administration of FTD with an inhibitor of TP elevates FTD concentrations. Since tumor xenograft models demonstrated greater anti-tumor activity with divided daily dosing of TAS-102, and a phase I trial of once-daily TAS-102 showed a short FTD half-life, this trial was designed to explore a three times a day dosing schedule. Methods: Patients with advanced solid tumors having received prior therapy, with adequate organ function, and performance status Zubrod 0–2, were eligible. TAS-102 was administered orally three times a day for 5 days a week for two weeks, followed by two weeks off. Courses were repeated every 4 weeks. Results: A total of 15 patients (8 female, age 37–72 years) were enrolled into the study; three at 60 mg/m2/day, 6 each at 70 mg/m2/day and 80 mg/m2/day. Nine patients had colorectal cancer, 2 carcinoma of unknown primary, 2 pancreatic cancer, one each medullary thyroid cancer and cholangiocarcinoma. Toxicity was assessed throughout all courses of therapy. Grade 3 and 4 hematological toxicities were the most common, including 3 episodes of grade 3 neutropenia at 60 mg/m2/day, 5 at 70 mg/m2/day, 5 at 80 mg/m2/day with only 1 instance of grade 3 thrombocytopenia at 80 mg/m2/day. Non-hematological grade 3 toxicities included nausea/vomiting (1 at 70 mg/m2/day), colitis, gout, and hematuria (1 each at 70 mg/m2/day), and fatigue (1 at 70 mg/m2/day and 2 at 80 mg/m2/day) Two episodes of dose-limiting toxicity were observed at 80 mg/m2/day: grade 3 fatigue and grade 4 neutropenia. Although there were no objective responses, nine patients (60%) maintained stable disease with a median duration of disease stabilization of 4.3 months (range, 1.9 to 8.6 months). Conclusions: TAS-102 is well tolerated with manageable hematologic toxicity and few non-hematological toxicities. The most common grade 3 or 4 toxicity was neutropenia. The suggested phase II dose of TAS-102 is 70 mg/m2/day when administered orally three times a day for 5 days a week for two weeks followed by two weeks off every 4 weeks. [Table: see text]

A phase I trial of fazarabine in refractory pediatric solid tumors

1993 ◽  
Vol 11 (4) ◽  
pp. 309-312 ◽  
Author(s):  
Mark L. Bernstein ◽  
V. Michael Whitehead ◽  
Holcombe Grier ◽  
Ron Dubowy ◽  
Vita Land ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Pediatric Solid Tumors
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