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.

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.

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.

Phase I dose-escalating study of PM02734 in a 24-hour infusion schedule every 21 days in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2511-2511
Author(s):  
T. R. Evans ◽  
A. Oaknin ◽  
R. J. Jones ◽  
A. Vandermeeren ◽  
C. Coronado ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase Ii Studies ◽  
Flat Dose ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Escalating

2511 Background: PM02734 is a chemically synthesized depsipeptide with a broad spectrum of activity against solid tumors in vitro (breast, colon, lung, neuroblastoma, prostate, sarcoma and thyroid) and in vivo (breast, prostate, melanoma); as well as an acceptable non-clinical toxicology profile. Methods: Patients (pts) with metastatic or advanced solid tumors were enrolled in a phase I, open-label, dose-escalating study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT) and recommended dose (RD) of PM02734 infused over 24 hours every 21 days (d). The starting dose was 0.48 mg/m2. Cohorts of 1–6 pts were treated at different dose levels. Results: Thirty seven pts were treated in this study. The median age was 55 years (40–75), sex: males/females 20/19. The median PS was 1 (range 0–2). The most frequent cancer types were colon/ gastric/ sarcoma (n=8/5/5). Most patients were heavily pretreated, with a median of prior therapy lines of 4 (1–12). Patients were treated at 8 dose levels (0.48, 0.72, 1.0, 1.6, 2.4, 3.6, 5.4, and 6.8 mg/m2), the MTD was 6.8 mg/m2 and the RD was 5.4 mg/m2 (10 mg flat dose).Common toxicities grade ≤ 2 included asthenia, nausea/emesis, lymphopenia, injection site reactions and asymptomatic elevated transaminases (TAs). DLT were grade 3 asymptomatic, reversible TA elevations at 6.8 mg/m2. Preliminary PK data is characterized by long half life (>100 h), a wide distribution and high inter-patient variability. Clearance was not correlated with dose or body surface area (BSA), therefore, flat dose was implemented and the RD was explored with this schedule. Efficacy data showed one complete response (CR) of +28 months observed in a pt with metastatic large cell esophageal carcinoma, and five more showed stable disease (SD) for more than 3 months in different histologies. Conclusions: PM02734 shows to be safe, well tolerated and with evidence of activity (1 CR and 5 SD > 3 months) in pts with advanced solid tumors. The DLT was grade 3 asymptomatic and reversible TA elevations, and the RD for further phase II studies is 10 mg. [Table: see text]

Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of 17-Allylamino-17-demethoxygeldanamycin (17AAG) in children with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9022-9022 ◽  
Author(s):  
R. Bagatell ◽  
L. Gore ◽  
M. Egorin ◽  
R. Ho ◽  
N. Boucher ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Phase I ◽  
Linear Relationship ◽  
Solid Tumors ◽  
Mononuclear Cells ◽  
Heat Shock Protein 90 ◽  
Peripheral Blood Mononuclear ◽  
Associated Proteins ◽  
Grade 3 ◽  
Benzoquinone Ansamycin

9022 Background: 17AAG is a benzoquinone ansamycin that binds to heat shock protein 90 (Hsp90) and alters levels of cancer-associated proteins that are regulated by Hsp90. 17AAG has been well-tolerated in adults, but has not previously been administered to children. Methods: A Phase I study of 17AAG was initiated to define the maximally tolerated dose and toxicity profile of this drug in children. PK and PD were also studied. Cohorts of 3–6 patients with recurrent or refractory solid tumors were treated every 21 days with escalating doses of 17AAG twice weekly for two weeks. Plasma PK of 17AAG and its major metabolite, 17AG, were measured on day 1 by HPLC. Changes in levels of the inducible isoform of Hsp70 were assessed by Western blot using peripheral blood mononuclear cells (PBMCs) obtained 24 h after the 17AAG infusion. Actin was measured for comparison. Because 17AAG is a substrate for CYP3A4/5 and MDR1, pharmacogenetic analyses have been undertaken to determine if genotypes including CYP3A4*1B, CYP3A5*3, and MDR1 G2677T/A and C3435T influence 17AAG disposition. Results: 12 pts (median age 11 years, range 5–18) with neuroblastoma (5), osteosarcoma (4), Ewing’s family tumors (2), and desmoplastic small round cell tumor (1) have been treated with 17AAG. An MTD has yet to be defined though one dose limiting toxicity (Grade 3 hypoxia) was observed at Dose Level 4 (360 mg/m2). The AUC of 17AAG increased with dose, with a linear relationship between end of infusion 17AAG plasma concentration and AUC. The AUC of 17AAG increased with dose, with a linear relationship between end of infusion 17AAG plasma concentration and AUC. Clearance ranged between 12.5 and 29.6 l/hr/m2 (median, 21.6 l/h/m2) and did not change with increasing doses. Post-treatment increases in Hsp70 in PBMCs have been observed in pts treated with 17AAG doses at or above 150 mg/m2. Declines in Akt and IGF1R in PBMCs have been seen in some but not all pts following treatment. Conclusions: 17AAG is well tolerated in children at dose levels studied to date. 17AAG dose escalation continues and at the time of the meeting, updated data will be reported. No significant financial relationships to disclose.

A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3058-3058
Author(s):  
Amy Patricia Moore ◽  
Thach-Giao Truong ◽  
Kenneth Ted Thurn ◽  
Scott Thomas ◽  
Charles J. Ryan ◽  
...  
Keyword(s):  
Phase I ◽  
Histone Acetylation ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Phase I Trial ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Deacetylase Inhibitor ◽  
Grade 3

3058 Background: Preclinical and clinical data suggest pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase inhibitors. HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. In vitro data further suggest effective inhibition of HDAC2 is necessary for enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores the safety, tolerability, and maximum tolerated dose (MTD) of escalating doses of panobinostat given orally on days 1, 3, and 5 followed by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day cycles. Histone acetylation and HDAC2 expression are evaluated in pre- and post-treatment peripheral blood mononuclear cells (PBMCs) in all patients and in tumor cells of 16 patients treated at the MTD. Results: 36 patients have enrolled [10M/26F, median age 47 years (22-80)] in 5 panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include melanoma (n=6), breast (n=6), sarcoma (n=16), ovarian (n=2), lung (n=2), and one each of neuroblastoma, pancreatic, testicular, and colon cancer. Prior to enrollment, patients received a median of 3 (0-8) prior chemotherapy regimens and 40% had anthracyclines. Dose-limiting toxicities (DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation at 50 mg, defining 50 mg panobinostat as the MTD. Non-dose–limiting grade 3/4 hematological toxicities include neutropenia (n=19, 53%), febrile neutropenia (n=6, 17%), thrombocytopenia (n=6, 17%), and anemia (n=4, 11%). Of 34 evaluable patients, 5 had partial responses and 14 had stable disease in anthracycline-refractory sarcomas (4) and Her2neu positive breast cancer (2), and small cell lung cancer. Correlative studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5 suggesting sufficient histone deacetylase inhibition. Conclusions: Sequence-specific combination of panobinostat and epirubicin shows early activity without potentiating epirubicin toxicity. Dose expansion in anthracycline-pretreated sarcoma patients is ongoing.

Phase 1b study defining the optimal dosing combinations of the mTOR inhibitor AP23573 and Paclitaxel (PTX)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3509-3509 ◽  
Author(s):  
S. Cresta ◽  
D. Tosi ◽  
C. Sessa ◽  
L. Viganò ◽  
M. Maur ◽  
...  
Keyword(s):  
Mtor Inhibitor ◽  
Mononuclear Cells ◽  
Combined Therapy ◽  
Dose Finding ◽  
Peripheral Blood Mononuclear ◽  
Mtor Inhibition ◽  
Skin Biopsies ◽  
Grade 3 ◽  
Anti Tumor Activity

3509 Background: AP23573 is a novel mTOR inhibitor with demonstrated anti-tumor activity in clinical trials. In vitro, AP23573 exhibits at least additive anti-proliferative activity in combination with a variety of agents including taxanes. This trial studied the combination of AP23573 and paclitaxel (PTX) in patients with advanced solid tumors. Methods: This was a modified, sequential (3+3) dose finding study with starting doses of 25 mg AP23573 i.v. and 80 mg/m2 PTX i.v. as Dose Level 1 (DL1) on days 1, 8 and 15 of a 28 day cycle. Doses of either drug were adjusted in successive cohorts. Blood samples and skin biopsies were collected for pharmacokinetic (PK) and pharmacodynamic (PD) studies. Dose limiting toxicity definitions included neutrophils <500/μL; thrombocytopenia = Grade 3 (CTC), any non- hematologic toxicities = Grade 2; missing 2 consecutive doses due to any toxicity. For PK and PD analysis, AP23573 and PTX were administered one day apart at the start of Cycle 1, reversing the sequence at Day 8. Results: Enrollment is complete and 29 patients with a variety of tumors (sarcoma, pancreatic, H&N, melanoma, thymoma) have been treated. Grade 3 thrombocytopenia and Grade 2 mouth sores were seen at DL1 as well as missed doses due to moderate (Grade 2) neutropenia. Adverse events include mouth sores and fatigue which were mild and reversible. Available PK data for AP23573 and PTX suggest no interaction. PD analysis in peripheral blood mononuclear cells demonstrates no interference by PTX on mTOR inhibition by AP23573. PD data in skin biopsies are forthcoming. Both 12.5 mg AP23573/80mg/m2 PTX and 37.5mg AP23573/60mg/m2 PTX are maximal dose combinations that appear to be well tolerated. Activity has been observed at multiple AP23573 mg/PTX mg/m2 dose levels (25/60, 12.5/80, 25/80). Five patients have been on study for >4 cycles, including 2 patients with partial responses (H&N and pancreatic). Conclusions: Combined therapy with AP23573 and PTX is safe. It is notable that evidence of anti-tumor activity was observed at modest doses of each drug when in combination. Combinations of these agents at both doses cited would be recommended for evaluation in trials examining efficacy in specific tumors. No significant financial relationships to disclose.

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]

A phase I study of R-(-)-gossypol (AT-101) in combination with cisplatin (P) and etoposide (E) in patients with advanced solid tumors and extensive-stage small cell lung cancer (ES-SCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13502-e13502
Author(s):  
T. B. Leal ◽  
W. Schelman ◽  
A. Traynor ◽  
J. Kolesar ◽  
R. Marnosha ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Unknown Primary ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Objective Evidence ◽  
Level 1 ◽  
Grade 3

e13502 Background: AT-101 [R-(-)-gossypol acetic acid] (AT) is an orally-administered BH3 mimetic that lowers the threshold for apoptosis by direct binding to Bcl-2, Bcl-xL, Mc1–1, Bcl-W, and through upregulation of the proapoptotic proteins Noxa and Puma. Bcl- 2 is over-expressed in >80% of SCLC. In vitro study using SCLC cells showed that treatment with EP had synergistic cytotoxic effects in suppression of Bcl-2. This is a phase I dose-escalation study of AT in combination with EP with an expanded cohort of patients with ES-SCLC. This study is being conducted to determine the maximum tolerated dose (MTD), pharmacokinetics and activity of AT with EP ± pegfilgrastim (F) in patients with advanced, refractory solid tumors and/or ES-SCLC. Methods: This study used standard eligibility criteria except patients must not have received prior therapy that inhibits the Bcl-2 family. At dose level 1, patients received P 60 mg/m2 on day 1 and E 100 mg/m2 on days 1, 2, and 3 every 21 days. AT was administered 30 mg orally BID on days 1, 2 and 3 of each cycle. Results: 10 patients have been enrolled; 7 men, 3 women. Tumor types: 6 lung; 2 prostate; 1 head & neck; 1 unknown primary. 2 of 5 patients enrolled at dose level 1 experienced a DLT of neutropenic fever in cycle 1. Three subsequent patients were enrolled to dose level -1 (20 mg BID x 3 days, d1–3) which was well tolerated. Additional patients are being enrolled at dose level 1a (EP+AT with F). Grade 3/4 toxicities related to AT without F at dose level 1 and -1 were as follows: ANC (8), leucopenia (7), febrile neutropenia (2), low hemoglobin (1), thrombocytopenia (1), elevated AST (1), cardiac ischemia/MI (1), diarrhea (1). There were no reported grade 3/4 toxicities in two patients at level 1a. Four patients had stable disease; two progressive disease and four patients were unevaluable. Conclusions: The MTD without F was established at AT 20mg orally BID, P 60 mg/m2 on day 1, and E 100 mg/m2 on days 1, 2, and 3 every 21 days. The MTD with F has not yet been established. Accrual continues at dose level 1a. Subjective and objective evidence of clinical activity has been observed in patients with refractory solid tumors. This study was supported by NCI, UO1 CA062491, SAIC 25XS097 and 1ULRR025011. No significant financial relationships to disclose.

Phase I dose-finding and pharmacokinetic study of a combination of elisidepsin (E) and erlotinib (T) in patients (pts) with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3093-3093
Author(s):  
Sanjay Goel ◽  
Teresa Moran ◽  
Cinthya Coronado ◽  
Santiago Viteri Ramirez ◽  
Imran Chaudhary ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Standard Dose ◽  
Therapeutic Option ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Grade 3

3093 Background: E is a new marine compound that has shown synergism with T in vitro even in T-resistant non-small-cell lung cancer (NSCLC) cell lines. Based on these findings, a phase I clinical trial was undertaken to identify the maximum tolerated dose (MTD) and recommended dose (RD) of E (3-h iv, days 1, 8 and 15) followed by T (once daily) in 3-week cycles. Secondary objectives were evaluation of safety and feasibility, PK and preliminary efficacy results. Methods: Patients (pts) with advanced solid tumors with no standard therapeutic option were recruited. Cohorts of 3-6 pts were included at each dose level (DL), with escalating doses of E in increments of 25-50% according to toxicities, and 2 different T doses (100 and 150 mg/day). Results: Thirty pts (median age, 57 years; 19 females) were evaluable. Main tumor types included NSCLC, colorectal, melanoma, and ovarian cancer. Six DLs were assessed. Starting DL was E 0.33 mg + T 100mg. One dose-limiting toxicity (DLT) out of 6 pts (grade 3 bilirubin increase) was observed at DL3 (E 0.75 mg + T 150 mg). Another DLT (dose omissions due to ALT increase) was found at DL6 (E 2.25 mg + T 100 mg). Frequent toxicities were diarrhea (53%), nausea (23%), vomiting (33%), rash (47%), pruritus (43%), dry skin (27%) and acneiform dermatitis (17%). Grade 3/4 toxicities included diarrhea (2 pts), rash (2 pts) and pruritus (1 pts). Main biochemical abnormalities were ALT (grade 3/4 in 4 pts) and total bilirubin increase (grade 3 in 2 pts). No severe hematological abnormalities were observed. Most toxicities were related to T; therefore, T dose was reduced to 100 mg/day. No PK interaction between E and T was observed. No objective responses were reported. Six pts attained stable disease >3 months (3 NSCLC; 1 ovarian cancer, 1 colorectal cancer, 1 invasive thymoma). Conclusions: E + T was a manageable combination; however, the difficulty of combining E with the standard dose of T (150mg) and the lack of activity made this combination unattractive for further development in the current schedule. Possibly, other schedules may demonstrate more efficacy.

Phase I study of indenoisoquinolines LMP776 in adults with relapsed solid tumors and lymphomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2558-2558 ◽  
Author(s):  
Geraldine Helen O'Sullivan Coyne ◽  
Shivaani Kummar ◽  
Robert S. Meehan ◽  
Howard Streicher ◽  
Naoko Takebe ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Central Line ◽  
Maximum Tolerated Dose ◽  
Resistant Cell ◽  
Dna Breaks ◽  
Common Grade ◽  
Grade 3

2558 Background: Indenoisoquinolines (ID) are non-camptothecin inhibitors of topoisomerase (TOP1) identified following a COMPARE analysis of the National Cancer Institute’s (NCI) in vitro anticancer drug discovery screen. IDs have improved characteristics over camptothecin top1 inhibitors, with better chemical stability (lacking the labile hydroxylactone E-ring) producing stable DNA breaks that are resistant to reversal of the trapped DNA-TOP1 cleavage complex and at different DNA sequence sites to camptothecins (Kohlhagen et al. Mol Pharmacol. 2005). IDs have shown more activity against camptothecin-resistant cell lines and mouse models, as well as in cells overexpressing the ATP-binding cassette (ABC) transporters, and multidrug resistance (MDR-1/ABCB1) genes. A parallel first-in-human Phase I study conducted at the NCI of LMP400 in patients with refractory solid tumors and lymphomas showed this molecule to be well tolerated (Kummar et al, Cancer Chemother Pharmacol. 2016). A trial of LMP776 (NSC725776), has completed accrual. Primary Objectives: define the maximum tolerated dose (MTD) of LMP776 and the dose-limiting toxicities (DLTs). Methods: Phase I trial using Design 4 of the Simon accelerated titration designs (Simon et al. JNCI, 1997), with doses escalated based on toxicity during cycle 1. LMP776 was administered via central line QD over 1 hour on days 1–5 q 28-days. Response is defined by RECIST 1.1 on CT. Results: 32 of 34 patients (pts) were evaluable for toxicity and response. Enrollment was expanded at dose level (DL) 2 to 6 pts due to a hypocalcemia DLT, with subsequent enrollment on a 3+3 design. MTD was established at DL7 (12mg/m2, DLT myelosuppression). Common Grade 3/4 adverse events by CTCAE v.4 included anemia (5 pts, 15%), thrombocytopenia (5), lymphopenia (5) and neutropenia (3 pts, 9%). 12 (37%) pts experienced stable disease (SD), with a median of 4 cycles of treatment (range 2-9). 10 (30%) pts with SD remained on study for ≥4 months, with 4 pts on study ≥6 months. Conclusions: LMP776 is overall well tolerated. Explorative correlatives and additional trials are being considered. Clinical trial information: NCT01051635.

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