Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced hepatocellular carcinoma (HCC).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 296-296 ◽  
Author(s):  
R. K. Kelley ◽  
H. S. Nimeiri ◽  
M. T. Vergo ◽  
K. Chia ◽  
M. F. Mulcahy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Maximum Tolerated Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Hypertensive Urgency ◽  
Best Response ◽  
Hand Foot Syndrome

296 Background: SOR prolongs survival in patients (pts) with HCC. In preclinical studies, mammalian target of rapamycin (mTOR) inhibitors (I) impair HCC growth and angiogenesis. Adding mTOR-I to SOR augments antitumor effect. Phase I studies of mTOR-I plus SOR have shown tolerability but did not include cirrhotic pts. We developed a phase I trial of mTOR-I TEM plus SOR to determine safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) in pts with HCC. The study was approved and funded by the National Comprehensive Cancer Network (NCCN). Methods: Eligibility: Advanced HCC diagnosed histologically or clinically. No prior systemic therapy (Tx). Prior resection/local Tx permitted if ≥1 measurable site. ECOG score ≤2, Child-Pugh ≤7, bilirubin ≤2 mg/dL, platelets ≥75,000/mcL. Design: 3+3 escalation to MTD with dose-limiting toxicity (DLT) window 28 days; 6 pts at MTD for pharmacokinetics (PK). Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK. Results: 9 pts enrolled to date: 7 at DL1, 2 at DL-1. Toxicity: DL1: 1 DLT of Gr3 thrombocytopenia. 1 pt removed for hypertensive urgency, adjudicated not Tx-related. 1 pt not evaluable due to abscess. 1 pt removed for Gr3 hypersensitivity to TEM in cycle 2. All remaining pts required reduction and/or delay for adverse events (AE). Tx-related AE at DL1 include: fatigue 57%, Gr3 11%; weight loss 22%, all Gr1; anorexia 57%, all Gr1/2; diarrhea 71%, all Gr1/2; rash/hand-foot syndrome 71%, Gr3 11%; thrombocytopenia 57%, Gr3 11%; hypophosphatemia 77%, Gr3 57%, refractory 11%. Study de-escalated to DL-1 due to non-DLT cumulative AE. DL-1: 2 pts enrolled have not had DLT nor dose reduction to date. Response: 4 of 7 pts in DL1 were evaluable. 3 of 4 had stable disease as best response. Conclusions: Tx-limiting, class-related AE occurred at DL1 of this double-biologic regimen. MTD in pts with Child-Pugh Class A cirrhosis appears lower than in pts without liver disease. Tolerability and dose delivery must be achieved to determine efficacy. A phase II study with correlative endpoints is planned at RP2D. Updated accrual and results will be presented. [Table: see text] [Table: see text]

Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced hepatocellular carcinoma (HCC) with pharmacokinetic (PK) and biomarker correlates.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4102-4102 ◽  
Author(s):  
Robin Katie Kelley ◽  
Halla Sayed Nimeiri ◽  
Pamela N. Munster ◽  
Mary Frances Mulcahy ◽  
Maxwell Thomas Vergo ◽  
...  
Keyword(s):  
Phase 1 ◽  
Mammalian Target Of Rapamycin ◽  
Maximum Tolerated Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Best Response ◽  
Hand Foot Syndrome ◽  
Prior Systemic Therapy ◽  
Expansion Cohort ◽  
Cancer Network ◽  
Dose Limiting Toxicity

4102 Background: Mammalian target of rapamycin inhibitors added to SOR augment antitumor effect in HCC models. We developed a phase 1 trial to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of TEM plus SOR in HCC patients (pts). The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Pfizer, Inc., and conducted at 2 NCCN centers. Methods: Eligibility: ≥1 measurable site. No prior systemic therapy (Tx). ECOG ≤2, Child Pugh ≤7, bilirubin ≤2 mg/dL, platelets (PLT) ≥75,000/mcL. Design: 3+3 escalation. Dose-limiting toxicity (DLT) window 28 days. MTD expansion cohort of 9 pts for PK and biomarkers. Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK for TEM. Exploratory: Tumor necrosis, alpha fetoprotein (AFP)-L3, des-γ-carboxyprothrombin, and circulating tumor cells (CTC) by slide-based assay. Results: 21 pts enrolled. Median age: 60 (47-77). Male/Female: 15/6. Etiology: HCV 9 (43%), HBV 4 (19%), HBV+HCV 2 (10%), ETOH 2 (10%), unknown 4 (19%). Toxicity: DL1: 1 DLT Grade (Gr) 3 PLT. All pts required reductions for adverse events (AE); de-escalated to DL-1 for intolerability. DL-1: 1 DLT Gr3 hand-foot syndrome (HFS). Most common related ≥Gr 3 AE: HypoPO4 (52%); PLT (24%); transaminitis (19%); diarrhea, fatigue, HFS (10% each). Possibly related serious AE (SAE): Gr4 tumor rupture, Gr4 urosepsis, Gr3 dental infection with Gr2 ANC, Gr2 pneumonia (1 pt, 5% each). Best response: Confirmed partial response (PR) 2/21 (10%), stable disease (SD) 11/21 (52%), progression 1/21 (5%), 7/21 (33%) not evaluable. Time on study: Range <1 to 19+ months; median 3+ months for pts who completed ≥1 cycle (16/21). 16/21 (76%) had baseline elevated AFP ≥20; 8/16 (50%) had >50% decline. CTC were detected in 5/5 of tested samples. Decreased tumor enhancement on Tx was seen. Conclusions: DL-1 is MTD and RP2D, lower than a prior trial in pts without HCC; tolerability may be impacted by cirrhosis. Encouraging durable radiographic and AFP responses occurred. [Table: see text]

Phase I and Pharmacokinetic Study of Novel l-Nucleoside Analog Troxacitabine Given as a 30-Minute Infusion Every 21 Days

2002 ◽  
Vol 20 (10) ◽  
pp. 2567-2574 ◽  
Author(s):  
Karl Belanger ◽  
Malcolm Moore ◽  
Sharyn D. Baker ◽  
Jeanne Dionne ◽  
Martha Maclean ◽  
...  
Keyword(s):  
Phase I ◽  
Skin Rash ◽  
Maximum Tolerated Dose ◽  
Nucleoside Analog ◽  
Unknown Primary ◽  
Bone Lesions ◽  
Phase Ii Studies ◽  
Best Response ◽  
Metastatic Lung ◽  
Hand Foot Syndrome

PURPOSE: Troxacitabine (Troxatyl, BCH-4556; BioChem Pharma Inc, Basingstoke, United Kingdom) is a novel synthetic l-nucleoside analog with activity against a broad range of human tumors in preclinical models. Preclinical toxicity suggested a predictable toxicity profile consistent with an agent of this class, with evidence of interspecies differences. We conducted a phase I study of troxacitabine given as a 30-minute infusion once every 21 days. PATIENTS AND METHODS: The starting dose of troxacitabine was 0.025 mg/m2, based on toxicology data from the most sensitive species studied (cynomolgus monkey). Doses were doubled until grade 1 skin or mucosal or grade 2 other toxicity was encountered. A modified Fibonacci scale was used. RESULTS: A total of 45 patients were enrolled at 13 dose levels. Most common nonhematologic side effects were skin rash (44%), lethargy (29%), nausea (24%), alopecia, dry skin (18%), anorexia (13%), neurosensory symptoms (13%), and hand-foot syndrome (13%). In patients treated with prednisone 25 mg/d orally for 5 days, starting on day 1, skin rash was less problematic. Two patients at 12.5 mg/m2 experienced dose-limiting (grade 4) granulocytopenia. Confirmed partial responses were documented in one patient with previously untreated renal cell carcinoma with metastatic lung and bone lesions and in one patient with an unknown primary tumor. Eighteen patients had a best response of stable disease with a median duration of 5.1 months (range, 2.1 to 18.7 months). CONCLUSION: When given in this schedule, the maximum-tolerated dose of troxacitabine is 12.5 mg/m2, and the recommended dose for additional phase II studies is 10 mg/m2 once every 21 days with steroid premedication.

Phase I trial of sunitinib (S) and temsirolimus (T) in metastatic renal cell carcinoma (mRCC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 433-433
Author(s):  
Matthew T. Campbell ◽  
Randall E. Millikan ◽  
Emre Altinmakas ◽  
Lianchun Xiao ◽  
Nizar M. Tannir
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Mtor Inhibitors ◽  
Median Number ◽  
Primary Objective ◽  
Best Response ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Mean Time

433 Background: Anti-VEGF agents and mTOR inhibitors are mainstay therapies in mRCC. Pre-clinical data suggests synergistic anti-tumor effect when combining these 2 classes. A previous phase I trial using sunitinib (S) 25 mg/d 4 wks on, 2 wks off, and temsirolimus (T) 15 mg/wk was stopped after 2 of the first 3 pts developed dose limiting toxicity (DLT). Methods: Pts with any subtype mRCC (PS 0-1) were eligible. Each cycle consisted of daily S for 14 days on, 7 days off, and weekly T. The continuous reassessment method (CRM) was used. The primary objective was to find the maximum tolerated doses (MTD) of S and T. The total planned accrual was 60 pts. Results: Accrual was stopped after 20 pts received study drugs. Median age was 63.5 years; 13 pts received prior targeted therapy, 7 pts were treatment naïve; median number of prior treatments 1 (range 0-6). Treatment cohorts (#pts, S, T, dose in mg): 2 (S12.5,T6), 1 (S25,T12.5), 1 (S12.5,T8), 8 (S12.5alt25,T9), 2 (S25,T6), 2 (S25alt37.5,T6), 2 (S37.5,T6), 2 (S37.5,T8). Dose reduction was required in 6 of 20 pts; the most common DLT was mucositis in 3 of 20 pts, followed by thrombocytopenia in 2 of 20 pts. The mean number of cycles for all pts was 6.6±5.36, with mean time on study 159±120 days. One pt experienced DLT in cycle 1 and received no study related imaging, 1 had a partial response, 16 pts had stable disease, and 2 pts had progressive disease (PD) as best response. A total of 21 grade 3/4 adverse events (AEs) attributed to drug occurred in 11 of 20 pts. Reasons for study discontinuation were PD in 12 pts, toxicity in 6 pts, and pt preference in 2 pts. There were no treatment related deaths. Conclusions: The MTD of S and T using the CRM were not reached due to premature trial closure. However, we believe S 37.5 mg/d, 2 wks on, 1 wk off, and T 8-10 mg weekly may well be close to MTD. Clinical trial information: NCT01122615.

scholarly journals Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors

2020 ◽  
Vol 38 (27) ◽  
pp. 3195-3204 ◽  
Author(s):  
Timothy A. Yap ◽  
Brent O’Carrigan ◽  
Marina S. Penney ◽  
Joline S. Lim ◽  
Jessica S. Brown ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Gynecologic Cancer ◽  
Progression Free Survival ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Best Response ◽  
Recommended Phase Ii Dose

PURPOSE Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed.

Phase I Trial of the Novel Mammalian Target of Rapamycin Inhibitor Deforolimus (AP23573; MK-8669) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients With Advanced Malignancies

2008 ◽  
Vol 26 (3) ◽  
pp. 361-367 ◽  
Author(s):  
Monica M. Mita ◽  
Alain C. Mita ◽  
Quincy S. Chu ◽  
Eric K. Rowinsky ◽  
Gerald J. Fetterly ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Mammalian Target Of Rapamycin ◽  
Maximum Tolerated Dose ◽  
Target Of Rapamycin ◽  
Phase Ii Trials ◽  
Solid Malignancies ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Dose Levels

Purpose This phase I trial was conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of deforolimus (previously known as AP23573; MK-8669), a nonprodrug rapamycin analog, in patients with advanced solid malignancies. Patients and Methods Patients were treated using an accelerated titration design with sequential escalating flat doses of deforolimus administered as a 30-minute intravenous infusion once daily for 5 consecutive days every 2 weeks (QD×5) in a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and tumor response assessments were performed. Results Thirty-two patients received at least one dose of deforolimus (3 to 28 mg/d). Three dose-limiting toxicity events of grade 3 mouth sores were reported. The maximum-tolerated dose (MTD) was 18.75 mg/d. Common treatment-related adverse events included reversible mouth sores and rash. Whole-blood clearance increased with dose. Pharmacodynamic analyses demonstrated mammalian target of rapamycin inhibition at all dose levels. Four patients (one each with non–small-cell lung cancer, mixed müllerian tumor [carcinosarcoma], renal cell carcinoma, and Ewing sarcoma) experienced confirmed partial responses, and three additional patients had minor tumor regressions. Conclusion The MTD of this phase I trial using an accelerated titration design was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed encouraging antitumor activity across a broad range of malignancies when administered intravenously on the QD×5 schedule. On the basis of these overall results, a dose of 12.5 mg/d is being evaluated in phase II trials.

Phase I Trial of Intrathecal Liposomal Cytarabine in Children With Neoplastic Meningitis

2004 ◽  
Vol 22 (19) ◽  
pp. 3916-3921 ◽  
Author(s):  
L. Bomgaars ◽  
J.R. Geyer ◽  
J. Franklin ◽  
G. Dahl ◽  
J. Park ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Maintenance Phase ◽  
Maximum Tolerated Dose ◽  
Neoplastic Meningitis ◽  
Liposomal Cytarabine ◽  
Disease Stabilization ◽  
Recommended Phase Ii Dose

Purpose We performed a phase I trial of intrathecal (IT) liposomal cytarabine (DepoCyt; Enzon Pharmaceuticals, Piscataway, NJ and SkyePharma Inc, San Diego, CA) to determine the maximum-tolerated dose, the dose-limiting toxicities, and the plasma and CSF pharmacokinetics of IT lipsomal cytarabine in children ≥ 3 years of age with advanced meningeal malignancies. Patients and Methods Eighteen assessable patients received IT liposomal cytarabine through either an indwelling ventricular access device or via lumbar puncture. Liposomal cytarabine was given once every 2 weeks during induction, once every 4 weeks during consolidation, and once every 8 weeks during the maintenance phase of treatment. The initial dose was 25 mg, with subsequent escalations to 35 and 50 mg. CSF pharmacokinetic samples were obtained in a subset of patients. Results Arachnoiditis, characterized by fever, headache, nausea, vomiting, and back pain was noted in the first two patients at the 25 mg dose level. Therefore, subsequent patients were treated with dexamethasone, beginning the day of liposomal cytarabine administration and continuing for 5 days. Headache (grade 3) was dose limiting in two of eight patients enrolled at the 50 mg dose level. Eight of the 14 patients assessable for response demonstrated evidence of benefit manifest as prolonged disease stabilization or response. Conclusion The maximum-tolerated dose and recommended phase II dose of liposomal cytarabine in patients between the ages of 3 and 21 years is 35 mg, administered with dexamethasone (0.15 mg/kg/dose, twice a day for 5 days). A phase II trial of IT liposomal cytarabine in children with CNS leukemia in second or higher relapse is in development.

Phase I trial of lomeguatrib (PN) combined with dacarbazine (DTIC) for treatment of patients with melanoma and other solid tumors: Initial results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8016-8016 ◽  
Author(s):  
H. Tawbi ◽  
A. Tarhini ◽  
S. Moschos ◽  
M. Sulecki ◽  
F. Viverette ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Systemic Therapy ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Prior Chemotherapy ◽  
Best Response ◽  
Prior Systemic Therapy

8016 Background: TheDNA repair enzyme O6-Alkylguanine Alkyltransferase (AGT) directly reverses the O6-methylguanine (O6-MeG) base lesion induced by treatment with DTIC. Depletion of AGT using O6-MeG analogs enhances the cytotoxicity of DTIC in preclinical models and in early phase trials of O6-Benzylguanine. Lomeguatrib (Patrin, PN) is an orally bioavailable highly potent O6-MeG analog that is well tolerated as a single agent. We report the first phase I experience of PN combined with DTIC in patients who have failed prior systemic therapy. Methods: This open-label phase I study was performed to determine the toxicity profile and maximum tolerated dose (MTD) of PN given orally for 5 or 10 days (d) combined with a single dose of DTIC administered IV on d 2, repeated on a 21 d schedule. Of 30 pts enrolled 25 (83%) had metastatic melanoma, and all had ECOG PS ≤2. Dose escalation started at 40 mg of PN once daily for 5 d and 500 mg/m2 of DTIC. 6 pts failed prior chemotherapy, 16 failed prior immunotherapy, and 3 failed both. 5 pts had no prior systemic therapy. Results: Adverse events observed in more than 50% of pts included gr 1–2 nausea and vomiting and gr 1–2 fatigue. Hematologic toxicity was prominent with gr 3–4 neutropenia (13/30, 43%) and gr 3–4 thrombocytopenia (4/30, 13%) even at doses of DTIC 50% of usual clinical doses. Prolonged neutropenia accounted for all dose-limiting toxicities (DLT) observed so far. The MTD has not been reached, however hematologic toxicities requiring dose modifications of DTIC have been frequent (42% of all cycles administered). 16 pts (53%) had stable disease as their best response with a median time to progression of 53 days (95% C.I. 40–86 days). Conclusions: Oral administration of PN substantially alters the toxicity and tolerance of DTIC inducing prolonged hematologic toxicity at doses <50% of doses in routine usage. The study is ongoing to determine the MTD of PN combined with DTIC after which a phase II trial will be completed in pts who have not had prior chemotherapy. Pending completion of accrual (total of 40 pts by May 2006) the recommended phase II dosage appears to be PN 40 mg orally BID for 10 days combined with 400 mg/m2 of DTIC. [Table: see text]

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/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory metastatic colorectal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 450-450
Author(s):  
Michael J. Overman ◽  
Cathy Eng ◽  
Bryan K. Kee ◽  
David R. Fogelman ◽  
Christine Fark ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Cpg Islands ◽  
Chemotherapy Resistance ◽  
Maximum Tolerated Dose ◽  
Hematological Toxicity ◽  
Specific Pcr ◽  
Best Response

450 Background: Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and both clinical and preclinical studies have shown the ability to restore platinum sensitivity with the reversal of hypermethylation. CIMP is implicated in the pathogenesis of a subset of colorectal cancers termed CIMP-high. We sought to explore the safety and efficacy of the hypomethylator, azacitidine, in combination with CAPOX. Methods: We report the results of the phase I portion of a prospective phase I/II study in fluoropyrimidine and oxaliplatin refractory metastatic colorectal cancer (mCRC). The primary objectives were to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of this combination. Two dose levels were explored with a standard 3+3 design of azacitidine (75 mg/m2, SQ D1-5), oxaliplatin (90 and 110 mg/m2 IV D2), and capecitabine (1500 mg/m2/d, PO divided BID, D1-14) every 3 weeks, followed by an expansion of 6 patients at the MTD to evaluate for delayed hematological toxicity. The phase II portion is restricted to patients with CIMP-high (≥ 2/6 methylation-specific PCR markers: hMLH1, P16, P14, MINT1, MINT2, and MINT31). Results: 15 pts [M/F 8/7, median age: 60 yrs (range: 34-73), ECOG PS 0/1: 1/14] were enrolled from 8/2010 to 4/2011. Prior progression on fluoropyrimidine/oxaliplatin-based treatment met RECIST criteria in 13 pts. All pts were evaluable for toxicity and 13 for response. Twelve pts were treated at the highest dose level with no DLTs. Common grade 3-4 treatment-related toxicities were: neutropenia in 5 (33%), diarrhea in 2 (13%), oxaliplatin hypersensitivity reaction in 2 (13%). Best response was SD in 7 pts (54%) with a median duration of SD of 3.2 months (range: 2.2-6.9 months). Two pts remain on treatment. Two of 14 tested pts had CIMP-high tumors and both had progressive disease. Conclusions: Azacitidine and CAPOX was well tolerated in an unenriched oxaliplatin-refractory mCRC population. The recommended phase II dose of azacitidine with CAPOX is 75mg/m2, D1-5. Enrollment in the phase II cohort continues in fluoropyrimidine and oxaliplatin refractory CIMP-high metastatic colorectal cancer.

Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (LV) (SCOUT) in patients with advanced colorectal cancer (ACRC): A phase I/II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4084-4084
Author(s):  
H. Sheikh ◽  
J. W. Valle ◽  
K. Palmer ◽  
G. Wilson ◽  
A. Sjursen ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Hand Foot Syndrome ◽  
Label Dose ◽  
Grade 3

4084 Background: The feasibility of UFT (tegafur-uracil) plus LV with alternating irinotecan and oxaliplatin was investigated in a two-stage, phase I/II, open-label, dose-finding trial in patients with ACRC. The study is now closed. Here we present results from the phase II cohort and overall results from the phase I/II study. Methods: Eligible patients aged =18 years had histologically confirmed, advanced, inoperable, measurable metastatic disease, no prior chemotherapy other than adjuvant bolus 5-FU administered =6 months previously, and adequate hematologic, hepatobiliary, and renal function. Patients in the phase I study received irinotecan 180 mg/m2 on d1, oxaliplatin 85–100 mg/m2 on d15 plus UFT 200–300 mg/m2/d with LV 90 mg/d on d1–21 of a 28-d cycle. Diarrhea, lethargy, and vomiting were dose limiting. The maximum tolerated dose (MTD) established was irinotecan 180 mg/m2, oxaliplatin 100 mg/m2, UFT 250 mg/m2/d, and LV 90 mg/day. Patients were treated at the MTD in the phase II study. Primary endpoints in the phase II study were objective response rate (ORR) and time to progression (TTP). Results: Forty-five patients (median age 62 [range 24–79] years, median 4 marker lesions) were entered, 16 and 29 patients in the phase I and II studies, respectively. The ORR in all 38 evaluable patients was 66% (95% CI 49–80%), with clinical benefit (CB) in 89% (95% CI 75–97%). At a median follow-up of 10.3 months, median TTP was 8.5 months (95% CI -7.6 to 10.4 months) in 40 evaluable patients and median OS (ITT population; n=45) was 16.8 months (95% CI -11.3 to 28.3 months). In the phase II study (n=29) median TTP was 8.1 months (95% CI -6.7 to 11.3 months) and median OS was 19.6 months (95% CI -7.7 to >25.6 months); ORR in 25 evaluable patients was 68% (95% CI -46.5 to 85.1%) with CB in 100% (95% CI -86.3 to 100%). Of 30 patients with confirmed radiologic progression, 21 (70%) had second-line therapy. At the MTD, 3 patients (10%) had grade 3 diarrhea, 1 patient (3%) had grade 3 neurotoxicity, and 2 patients (7%) had grade 2 alopecia. No hand-foot syndrome (HFS) was seen. Conclusions: UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for patients with ACRC, with minimal alopecia and neurotoxicity and no HFS. No significant financial relationships to disclose.

Sign in / Sign up

Export Citation Format

Share Document