Phi-53: (NCI#7251): Phase I trial of belinostat (PXD101) in combination with 13-cis-retinoic acid (13c-RA) in advanced solid tumor malignancies—A California Cancer Consortium NCI/CTEP sponsored trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2526-2526 ◽  
Author(s):  
Thehang H. Luu ◽  
Paul Henry Frankel ◽  
Dean Lim ◽  
Mihaela C. Cristea ◽  
Jan Hendrik Beumer ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Phase I ◽  
Solid Tumors ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Qtc Interval ◽  
Advanced Solid Tumors ◽  
Eligibility Criteria ◽  
Grade 3

2526 Background: Belinostat has a reported maximum tolerated dose (MTD) of 1,000 mg/m2 given days 1 to 5 every 21 days as a single agent, although in one study in hepatocellular carcinoma belinostat was given at 1,400 mg/m2on the same schedule. Pre-clinical evidence suggests HDAC inhibitors enhance retinoic acid signaling with a synergistic impact in a variety of solid tumors. We conducted a phase I study of belinostat and 13c-RA in advanced solid tumors. Methods: Dose limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity: ≥grade 3 that not resolved to <grade 1 within 1 week or non-hematologic toxicity: ≥grade 3. We sought the MTD of belinostat days 1-5 with 13-cRA days 1-14, every 21 days, in patients (pt) with advanced solid tumors. Eligibility criteria included normal organ function and QT/QTc interval; 4 weeks from previous therapy. Results: 51 pt were treated: median age 61 (range 40-80); 29 men; 57% ECOG 0, 41% ECOG 1, 2% ECOG 2; 13 lung, 11 breast, 8 colorectal, 3 pancreatic. 11 dose levels (DL) were tested starting from belinostat 600 mg/m2/day and 13c-RA 50 mg/m2/day to belinostat 2000 mg/m2/day and 13c-RA 100 mg/m2/day. Only two DLTs were observed: a grade 3 hypersensitivity reaction with dizziness and hypoxia at DL 8 (belinostat 1700 mg/m2/day, 13c-RA 100 mg/m2/day); and a grade 3 allergic reaction in a patient with an ECOG PS 2 at DL 11 (belinostat 2000 mg/m2/day, 13c-RA 100 mg/m2/day). The MTD was not reached. Pharmacokinetics of belinostat suggests dose proportionality. Median number of cycles: 2 (range 1–56). 10 patients had SD including: 1 neuroendocrine pancreatic stable for 56 cycles; 1 breast pt for 12 cycles; 1 lung pt 8 cycles. 2 pt had PRs: a keratinizing squamous cell carcinoma (tonsil) and a lung cancer pt. Conclusions: Belinostat 2000 mg/m2 days 1-5and 13-cis-Retinoic acid 100 mg/m2days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single agent MTD. Future studies building on this combination to belinostat are warranted. Support: U01CA062505 and P30CA033572 (City of Hope); U01CA099168 and P30CA047904 (University of Pittsburgh).

Phase I and Pharmacokinetic Study of Docetaxel and Irinotecan in Patients With Advanced Solid Tumors

2000 ◽  
Vol 18 (20) ◽  
pp. 3545-3552 ◽  
Author(s):  
Corinne Couteau ◽  
Marie-Laure Risse ◽  
Michel Ducreux ◽  
Florence Lefresne-Soulas ◽  
Alessandro Riva ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

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 dose escalation study of sunitinib plus capecitabine in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3592-3592 ◽  
Author(s):  
C. Sweeney ◽  
C. Verschraegen ◽  
G. Chiorean ◽  
F. Lee ◽  
S. Jones ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Antiangiogenic Therapy ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Curative Therapy ◽  
Grade 3

3592 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This phase I study assesses the safety, tolerability and pharmacokinetics (PK) of SU in combination with capecitabine (C). Methods: Pts with advanced solid tumors not amenable to curative therapy, previously treated with =2 prior chemotherapy regimens, and ECOG PS =1 were eligible. Prior antiangiogenic therapy was not permitted. Three SU schedules were evaluated: 4 wks on treatment followed by 2 wks off in 6-wk cycles (4/2 schedule); 2 wks on followed by 1 wk off in 3-wk cycles (2/1 schedule), and continuous dosing (CD schedule). In all cases C was administered orally bid on days 1–14. SU and C doses were alternately escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of SU for all schedules using a standard 3 + 3 design. PK and antitumor efficacy were also assessed. Results: A total of 50 pts have been enrolled; 28 pts have been treated on the 4/2 schedule: SU 50 mg + C 1,000 mg/m2, and SU 37.5 mg + C 1,250 mg/m2 were not tolerated. Dose limiting toxicities (DLTs) included: grade 3 myalgia (n=1), grade 3 fatigue (n=2), and grade 3 hand- foot syndrome (n=2). The MTD for the 4/2 schedule was SU 37.5 mg/day + C 1,000 mg/m2. No DLTs nor dose reductions were observed among 9 pts treated at the MTD. Preliminary PK data do not indicate drug-drug interactions between SU and C. 3 pts (1 each with breast cancer, neuroendocrine carcinoma, and thyroid carcinoma) achieved confirmed partial responses. On the 2/1 schedule patients are being accrued to SU 37.5 or 50 mg + C 1,000 mg/m2 and doses of SU 37.5 mg + C 1,000 mg/m2 or SU 25 mg + C 1,250 mg/m2 are being explored on the CD schedule. Conclusions: The combination of SU 37.5 mg/day (4/2 schedule) with C 1,000 mg/m2 in pts with advanced solid tumors appears tolerable. SU may be administered in combination with C with no apparent drug-drug interaction. Subsequent cohorts will define the MTD of SU administered on the 2/1 and CD schedules. Further studies of this combination in breast cancer are warranted. No significant financial relationships to disclose.

Phase I dose-escalation study to evaluate the safety, pharmacokinetics, and pharmacodynamics of CEP-9722 (a PARP1-2 inhibitor) as single‑agent and in combination with temozolomide in patients with advanced solid tumors (NCT00920595).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3052-3052 ◽  
Author(s):  
Mario Campone ◽  
Ruth Plummer ◽  
Peter Stephens ◽  
Zahir Brakchi ◽  
Louiza Aissat-Daudigny ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Mononuclear Cells ◽  
Excision Repair ◽  
Single Agent ◽  
Recommended Dose ◽  
Parp Inhibition ◽  
Advanced Solid Tumors ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Grade 3

3052 Background: Poly-ADP-ribose (PAR) polymerases (PARPs) are essential in cellular processing of DNA damage via the base excision repair pathway. CEP-9722, an orally available PARP1-2 inhibitor, demonstrated single-agent antitumor activity and synergy with temozolomide (TMZ) in xenograft models. This phase I study evaluated the pharmacokinetics, pharmacodynamics, and the maximum tolerated dose (MTD) of CEP-9722 in monotherapy and combination with TMZ. Methods: Adult patients with advanced solid tumors were enrolled in cohorts of 3-6 patients to receive a 14-day cycle of CEP-9722 (days 1-5), followed by 28-day cycles of CEP-9722 (days 1-5) plus TMZ (150 mg/m2 days 1-5). The dose of CEP-9722 was 150 mg/day in the first cohort and was escalated depending on the occurrence of dose-limiting toxicities (DLTs) during cycles 1 and 2. The safety, pharmacokinetics, and pharmacodynamics (PAR levels in peripheral blood mononuclear cells) of CEP-9722 were analyzed. Results: Overall, 26 patients (18F,8 M) 18 to 71 years of age were enrolled in 5 cohorts of 3-9 patients and treated with CEP-9722 at 150-1000 mg/day. The MTD of CEP-9722 in combination with TMZ (150 mg/m2) was reached at 1000 mg/day. The recommended dose was 750 mg/day. A total of 9 patients were treated at the recommended dose. DLTs were observed in 2 patients during cycle 1 (1 grade 3 myositis at 750 mg/day and 1 grade 3 asthenia at 1000 mg/day) and 2 patients during cycle 2 (1 grade 3 asthenia at 300 mg/day and 1 persistent grade 2 weight loss at 1000 mg/day). Overall during this study, 4 grade 3 treatment-related adverse events were observed. The pharmacokinetics showed high intra- and inter-patient variability at all doses. The pharmacodynamic analysis demonstrated PARP inhibition at all doses, but the high inter- and intra-patient variability prevented any conclusion regarding a dose / PARP inhibition relationship. Conclusions: TheMTD of CEP-9722 when administered with TMZ was 1000 mg days 1-5 and the combination CEP-9722/TMZ was well tolerated. In addition, a clear signal of PARP inhibition was demonstrated.

Phase I study of c-Met inhibitor ARQ197 in combination with FOLFOX for the treatment of patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2544-2544
Author(s):  
Suzanne Fields Jones ◽  
Carla Kurkjian ◽  
Manish R. Patel ◽  
Jeffrey R. Infante ◽  
Howard A. Burris ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Stable Disease ◽  
Phase I Study ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Unknown Primary ◽  
Advanced Solid Tumors ◽  
Grade 3

2544 Background: C-Met protein is a receptor tyrosine kinase which is overexpressed or mutated in a variety of tumor types, causing cell proliferation, metastasis, and angiogenesis. Tivantinib is an orally bioavailable small molecule which binds to the c-Met protein. This phase I study was designed to determine the maximum tolerated dose (MTD) of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors. Methods: Patients with advanced solid tumors for which FOLFOX (5-FU IV 400 mg/m2 day 1; 5-FU CIV 2400 mg/m2 day 1; Leucovorin IV 400 mg/m2 day 1; Oxaliplatin IV 85 mg/m2 day 1) would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design. Dose-limiting toxicities (DLTs), non-dose-limiting toxicities (NDLTs), safety, and preliminary efficacy were evaluated. Results: Fourteen patients (50% colorectal) were treated across 3 dose levels: 120 mg (n=3); 240 mg (n=5); 360 mg (n=6). No DLTs were observed until the 3rd dose level (treatment delay ≥3 days, secondary to grade 3 neutropenia). Common related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (36%; 0%), neutropenia (0%; 29%), nausea (14%; 14%), vomiting (14%; 14%), dehydration (14%; 7%), and thrombocytopenia (14%; 0%). To date, 7 patients have been evaluated for response including 4 (57%) with stable disease evident at the 8-week evaluation (CRC, 2 patients; unknown primary favoring CRC, 1 patient; esophageal, 1 patient) and 3 (21%) with disease progression. The 4 patients with stable disease are continuing on treatment; three (CRC and unknown primary) had received prior FOLFOX. Conclusions: The addition of tivantinib to standard therapy FOLFOX appears tolerated up to its recommended phase II monotherapy dose of 360 mg. Preliminary efficacy is encouraging, and a phase II study is proceeding with this regimen for the first line treatment of advanced gastroesophageal patients. Clinical trial information: NCT01611857.

Phase I study of the HSP90 inhibitor AUY922 in combination with capecitabine as treatment for patients with advanced solid tumors.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 475-475
Author(s):  
Johanna C. Bendell ◽  
Lowell L. Hart ◽  
Shubham Pant ◽  
Jeffrey R. Infante ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Standard Dose ◽  
Heat Shock Protein 90 ◽  
Competitive Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Grade 3

475 Background: Heat shock protein 90 (HSP90) is a molecular chaperone involved in the maintenance and function of client proteins, many of which are integral to key oncogenic processes. AUY922 is a competitive inhibitor of HSP90, with demonstrated activity in a variety of preclinical models. Further preclinical evidence suggests potential synergy between inhibition of HSP90 and fluorouracil treatment (Burkitt et al. 2007). This phase I study was designed to determine the maximum tolerated dose (MTD) of AUY922 in combination with standard dose of capecitabine as treatment for patients with advanced solid tumors. Methods: Patients with refractory solid tumors for which capecitabine was an appropriate therapy received AUY922 with capecitabine in a standard 3+3 dose escalation. Capecitabine 1000mg/m2 was administered twice daily for days 1-14 of 21-day cycles, with escalating doses of AUY922 administered by intravenous (IV) infusion on days 1, 8, and 15; the 6th dose level combined the MTD of AUY922 with capecitabine 1250mg/m2. Dose-limiting toxicities (DLTs), safety, and efficacy were evaluated. Results: 23 patients were treated at 6 dose levels: 22mg/m2 (n = 3); 28mg/m2 (n = 3); 40mg/m2 (n = 3); 55mg/m2 (n = 5); 70mg/m2 (n = 3); 70mg/m2 with capecitabine 1250mg/m2 (n = 6). There were no DLTs observed until the 6th dose level (grade 3 diarrhea). Common adverse events (all grades) included: diarrhea (61%), nausea (57%), fatigue (43%), hand-foot skin reaction (39%), anorexia (39%), vomiting (35%), rash (30%), and darkening vision (22%). Myelosuppression was uncommon, with no instances of grade ≥3 thrombocytopenia, and only 2 patients (9%) with grade 3/4 neutropenia (1 patient each). Of the 19 patients evaluable for response per RECIST 1.1, unconfirmed partial response (PR) was noted in 3 patients (13%; colorectal, 1; breast, 1; stomach, 1), with 1 additional confirmed PR (4%; colorectal); two of these had progressed on prior fluorouracil. Stable disease was noted in 8 patients (35%). Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.

A call for global harmonization of phase I oncology trials: Results from two parallel, first-in-human phase I studies of DS-7423, an oral PI3K/mTOR dual inhibitor in advanced solid tumors conducted in the United States and Japan.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2536-2536
Author(s):  
Tomoya Yokota ◽  
Johanna C. Bendell ◽  
Patricia LoRusso ◽  
Takahiro Tsushima ◽  
Ved Desai ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
The United States ◽  
Maximum Tolerated Dose ◽  
Serum Glucose ◽  
Advanced Solid Tumors ◽  
Dual Inhibitor ◽  
Phase I Studies ◽  
Akt Phosphorylation ◽  
Grade 3

2536 Background: The aim of this study was to determine the safety, maximum-tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of DS-7423, a novel inhibitor of PI3K/mTOR, in US and Japanese population. We further compared toxicities and recommended phase 2 dose (RP2D) of DS-7423 and approved oncology drugs in the two populations. Methods: We conductedparallel, first-in-human studies in US and Japan in patients with advanced solid tumors. We conducted a Pubmed search of pivotal and corresponding phase I studies to compare the RP2D and final approval doses of molecularly targeted agents (MTA) between US and Japan. Results: 69 patients were enrolled (n = 42 from US and n = 27 from Japan). Between populations, the only difference at baseline was body weight (BW) and body mass index (BMI). Dose-limiting toxicities included grade 3 rash (48 mg), grade 3 stomatitis (240 mg), grade 3 lung infection (240 mg), grade 4 hyperglycemia (240mg), grade 3 fatigue (320 mg), and grade 3 dehydration (320mg). The MTD and RP2D was 240 mg/d in both populations. Frequent treatment-related adverse events included diarrhea, fatigue, decreased appetite, rash, and stomatitis. No remarkable difference in AUC and Cmax were observed between populations. Prolonged stable disease was seen in cholangiocarcinoma, thymic cancer, non-small cell lung cancer, squamous cell carcinomas, carcinoid, and sarcoma. DS-7423 demonstrated PD effects on serum glucose, C-peptide and Akt phosphorylation and 18F-FDG uptake in tumors. The final RP2D of 17 MTA approved in US and Japan from 2001 to 2015 was near identical. The approved doses in both regions were identical. Conclusions: Despite differences in BW, BMI, and ethnicity, DS-7423 showed no difference in PK, PD, toxicity or efficacy between populations. We found near identical RP2D in phase I oncology studies and approved doses in pivotal studies. This supports increased international collaboration in the conduct of phase I oncology trials. Clinical trial information: NCT01364844, Japic CTI, 12766.

Phase I study of sorafenib in children with refractory solid tumors: A Children's Oncology Group Phase I Consortium trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10012-10012 ◽  
Author(s):  
B. C. Widemann ◽  
E. Fox ◽  
P. C. Adamson ◽  
S. Baruchel ◽  
A. Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Eligibility Criteria ◽  
Starting Dose ◽  
Hand Foot Syndrome ◽  
Normal Alt ◽  
Grade 3 ◽  
Dose Levels

10012 Background: Sorafenib, an oral multitargeted kinase inhibitor, is indicated for treatment of adults with refractory renal cell or hepatocelluar carcinoma. We performed a phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of sorafenib in children with refractory solid tumors. Methods: Sorafenib was administered q12h for 28 consecutive day cycles. Cohorts of 3–12 patients were enrolled at 105, 130, 150, 200, and 250 mg/m2/dose dose levels. Results: 34 eligible pts [16M, median age 14.6 yrs, (range, 5–21)] with osteosarcoma (n = 8), rhabdomyosarcoma (n = 3), other sarcomas (n = 13), hepatoblastoma (n = 3), or other solid tumors (n = 7) received 1–22 cycles (median 2). Grade 3 dose-limiting toxicity (DLT) occurred in 4/6 pts at the starting dose (150 mg/m2) and included hypertension (n = 1), rash/urticaria (n = 1), back pain (n = 1), thrombocytopenia (n = 1) and ALT/AST (n = 1). No DLTs were observed at 105 (n = 6) or 130 (n = 3) mg/m2, and the dose was re-escalated to 150 mg/m2 with modified eligibility criteria (normal ALT) and revised guidelines for grading and management of hypertension. Gr 3 DLTs occurred in 1/6 pts (lipase) at 150 mg/m2 and 2/2 pts (hyponatremia, hand-foot syndrome) at 250 mg/m2. At 200 mg/m2 only 1/6 pts experienced DLT (gr 3 ALT). No objective responses were observed, but 2 pts had tumor shrinkage. Sorafenib AUC did not increase proportionally with dose - the mean AUC0–24h was similar at 150 mg/m2 (28±24 μg · h/mL, n = 9) and 200 mg/m2 (28±17 μg · h/mL, n = 4). Tmax was prolonged and variable (10±11 h, n = 19). Plasma VEGFR (n = 13) decreased from 9.9±1.6 ng/mL at baseline to 8.3±1.7 ng/mL by d 28 (p < 0.001). Conclusions: The MTD of sorafenib in children with solid tumors is 200 mg/m2, similar to the adult recommended dose (400 mg). No significant financial relationships to disclose.

A phase I study of carboxyamidotriazole orotate (CTO) in of advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2518-2518
Author(s):  
Alan Sandler ◽  
Matthew Hiram Taylor ◽  
Walter John Urba ◽  
Antonio Marcilio Padula Omuro ◽  
Barry Douglas Anderson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Solid Tumors ◽  
Squamous Cell ◽  
Cell Lung Cancer ◽  
Pik3ca Mutation ◽  
Malignant Gliomas ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Eligibility Criteria ◽  
Grade 3

2518 Background: CTO is an orotate salt of carboxyamidotriazole (CAI), which is an inhibitor of calcium-dependent intracellular and extracellular signal transduction pathways (presumably affecting VEGF and PI3K) and has tumor anti-proliferative and anti-invasive properties. The activity of CTO alone and in combination with temozolomide or 5Efluorouracil was demonstrated in human glioblastoma, melanoma, and colon tumor xenografts. Methods: This study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics and activity of CTO monotherapy in 34 patients (pts) with advanced solid tumors meeting eligibility criteria with adequate organ function. The CTO study NCT01107522 enrolled pts in 8 cohorts receiving continuous daily oral CTO capsules at doses ranging from 50mg- 555mg/m2/day. The MTD has not been determined. Pharmacokinetic (PK) sampling was performed during cycle 1 at each dose level. CT scans were performed at baseline and after 8 weeks to assess anti-tumor effect. Patients remained on study if they achieved stable disease (SD) or tumor response and did not experience dose limiting toxicities (DLT). Results: The most frequently recorded adverse events (Grade 1 and 2) were fatigue, nausea, vomiting, and dizziness. DLTs of grade 3 fatigue (219 mg/m2) and grade 3 creatine kinase elevation (555 mg/m2) occurred in one pt each. No cardiac QTc prolongations have been recorded. PK data demonstrated therapeutically relevant CAI levels beginning at the 219mg/m2 dose. Nine pts continued CTO dosing beyond 2 cycles. Tumor assessments demonstrated SD at different doses of CTO: i) 75mg/m2 renal carcinoma (1, 12 cycles); ii) 219 mg/m2-small cell lung cancer (1, 4 cycles), squamous cell lung cancer with PIK3CA mutation (1, 10 cycles and continuing), and lung adenocarcinoma with EGFR mutation (1, 10 cycles and, continuing); iii) 285 mg/m2-1 colon cancer with BRAFV600E mutation (1, 6 cycles), and squamous cell carcinoma (tonsil) with PI3KCA and NRAS mutations (1, 9 cycles, and continuing). Conclusions: CTO given as monotherapy up to 555mg/m2/day is safe and tolerable and without MTD. Six patients with different malignancies and genomic markers achieved SD; combinatorial investigations in malignant gliomas have started. Clinical trial information: NCT01107522.

Pegylated Interferon Alfa-2b Treatment for Patients With Solid Tumors: A Phase I/II Study

2002 ◽  
Vol 20 (18) ◽  
pp. 3841-3949 ◽  
Author(s):  
Ronald Bukowski ◽  
Marc S. Ernstoff ◽  
Martin E. Gore ◽  
John J. Nemunaitis ◽  
Robert Amato ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Objective Response ◽  
Pegylated Interferon ◽  
Interferon Alfa ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Pegylated Interferon Alfa ◽  
Grade 3 ◽  
Moderate Nausea

PURPOSE: The efficacy of interferon alfa has been established in treating advanced melanoma and renal cell carcinoma (RCC) patients. We conducted a phase I/II study to determine the maximum-tolerated dose (MTD), the safety and tolerability, and the preliminary efficacy of once-weekly pegylated interferon alfa-2b (IFNα-2b) in patients with advanced solid tumors (primarily RCC). PATIENTS AND METHODS: To determine the MTD, 35 patients with a variety of advanced solid tumors received 0.75 to 7.5 μg/kg/wk of pegylated IFNα-2b by subcutaneous injection for 12 weeks. An additional 35 previously untreated RCC patients received 6.0 and 7.5 μg/kg/wk for up to 12 weeks. Patients with a response or stable disease after 12 weeks were eligible for the extension protocol and were treated for up to 1 year or until disease progression. RESULTS: The MTD for pegylated IFNα-2b at 12 weeks was 6.0 μg/kg/wk. One year of 6.0 μg/kg/wk was well tolerated with appropriate dose modification; no grade 3 or 4 fatigue occurred, and safety was comparable with that with nonpegylated IFNα-2b. The most common nonhematologic adverse events included mild to moderate nausea, anorexia, and fatigue. Six patients had grade 3 or 4 hematologic toxicity. Twenty-nine patients continued on the extension protocol. Four patients had a complete response, and five patients had a partial response. Among 44 previously untreated RCC patients, the objective response rate was 14%. Median survival for all RCC patients was 13.2 months. CONCLUSION: Pegylated IFNα-2b was active and well tolerated in patients with metastatic solid tumors, including RCC, at doses up to 6.0 μg/kg/wk.

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