Phase I study of neoadjuvant 5-fluorouracil (5FU) chemoradiation (CRT) and trametinib in patients with locally advanced rectal cancers (LARC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 685-685
Author(s):  
Christina Sing-Ying Wu ◽  
Terence M Williams ◽  
Lai Wei ◽  
Hamida Umar ◽  
Sameh Mikhail ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Tumor Tissue ◽  
Mapk Pathway ◽  
Locally Advanced ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Braf Mutations ◽  
Expansion Cohort ◽  
Dose Levels

685 Background: RAS/BRAF mutations constitutively activate the MAPK pathway in colorectal cancer, and may promote resistance to CRT. We propose that trametinib, a MEK1/2 inhibitor, in combination with 5FU CRT for patients with LARC will improve outcome. Methods: Phase I study with standard 3+3 design in patients with Stage II/III rectal cancer with 3 dose levels of trametinib: 0.5, 1, and 2mg daily with 5FU 225mg/m2/day and 50.4 Gy. Trametinib was given over a 5-day lead-in and continued through the course of CRT. Patients undergo surgery 6-10 weeks after the completion of CRT. An expansion cohort at the maximum tolerated dose (MTD) with 12 patients is ongoing. Tumor tissue is collected prior to therapy, at day 4/5 of trametinib, and at surgery. The primary endpoint is to determine the MTD of trametinib with CRT. Results: 15 patients (10 males, 5 females) have been enrolled and 14 patients are evaluable for toxicities to date. Median age is 53 years (range 35-74). Patients have completed enrollment to all dose levels, with 1 dose-limiting toxicity of diarrhea attributed to 5FU CRT. No grade 4/5 toxicities, and toxicities are shown in the table. Generalized skin rash led to trametinib discontinuation after 2 weeks of therapy for 1 patient, and was held 3 days for 2 patients. At the trametinib dose level of 2mg, 3 out of 7 (43%) patients had a pathological complete response and the average neoadjuvant rectal (NAR) score is 8.1. Tumor RAS/BRAF mutation status is determined. Analysis of tumor tissue shows dose-dependent decrease in phosphorylated-ERK1/2 with increasing doses of trametinib. Conclusions: Initial evaluation shows that the combination of trametinib with 5FU CRT is tolerable and effective, and warrants further investigation in LARC. Clinical trial information: NCT01740648. [Table: see text]

Phase I study of trametinib with neoadjuvant chemoradiation (CRT) in patients with locally advanced rectal cancers (LARC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3612-3612
Author(s):  
Christina Sing-Ying Wu ◽  
Terence Marques Williams ◽  
Lai Wei ◽  
Hamida Umar ◽  
Sameh Mikhail ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Locally Advanced ◽  
Signal Transduction Pathway ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Braf Mutations ◽  
Mutational Status ◽  
Rectal Cancers ◽  
Dose Levels

3612 Background: The RAS/RAF/MEK signal transduction pathway is critical to the development of colorectal cancer, and tumors harboring KRAS, NRAS, and BRAF mutations were shown to be resistant to radiation. Thus, we conducted a phase I study of trametinib, a potent MEK1/2 inhibitor, in combination with CRT in patients with LARC. Methods: Phase I trial for patients with Stage II/III rectal cancers with a 3+3 design, and an expansion cohort of 12 patients at the maximum tolerated dose (MTD). Trametinib is given orally at 3 dose levels: 0.5mg, 1mg, and 2mg (Mon-Fri). CRT regimen is infusional 5-flourouracil (5FU) 225mg/m2/day (Mon-Fri) and daily fractions of 1.8 Gy (total 50.4Gy). There is a 5-day trametinib lead-in followed by trametinib and CRT. Six to 10 weeks after completion of CRT, patients then proceed to their surgery and adjuvant therapy. The primary endpoint is to identify the MTD and recommended phase 2 dose of trametinib with CRT. Immunohistochemistry staining for phosphorylated –ERK (pERK) and genomic profiling is performed on the tumor samples. Results: Enrollment is complete at all dose levels with18 patients, and 15 patients evaluable for toxicity and response as of Feb 6. One dose-limiting toxicity of diarrhea was observed at the 2mg dose. Grade 3 and most common toxicities are shown in Table 1. No grade 4/5 toxicities have been observed. At 2mg dose level, 3/9 (33%) patients had pathological complete response (pCR) and 2/9 (22%) had a near pCR. Correlative studies confirm decrease in pERK levels with increasing doses of trametinib. Correlation of genomic mutational status with toxicity, response, and outcomes is being analyzed. Conclusions: The combination of trametinib with 5FU CRT is tolerable with promising preliminary activity. Final results will be presented at the meeting. Toxicities. Clinical trial information: NCT01740648. [Table: see text]

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Children's Cancer Group.

1998 ◽  
Vol 16 (9) ◽  
pp. 3037-3043 ◽  
Author(s):  
H S Nicholson ◽  
M Krailo ◽  
M M Ames ◽  
N L Seibel ◽  
J M Reid ◽  
...  
Keyword(s):  
Phase I ◽  
Children And Adolescents ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Cancer Group ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity

PURPOSE The Children's Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI). PATIENTS AND METHODS Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m2 daily. RESULTS Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m2 daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m2 daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m2 daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m2 daily and in two of four patients (50%) at 215 mg/m2 daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up. CONCLUSION The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m2 daily and for those with prior CSI is 180 mg/m2 daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.

Phase I trial of imexon, Inj. plus gemcitabine in patients with advanced previously untreated pancreatic adenocarcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15058-15058
Author(s):  
S. J. Cohen ◽  
M. Zalupski ◽  
M. Modiano ◽  
P. Conkling ◽  
D. Mahadevan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Pancreatic Adenocarcinoma ◽  
Phase I Study ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Maximum Tolerated Dose ◽  
Pancreatic Cancer Cells ◽  
Dosing Regimens ◽  
Ecog Ps

15058 Background: Imexon for inj. (Amplimexon®, AMP) is an aziridine-containing iminopyrrolidone which causes G2 arrest, accumulation of reactive oxygen species, and induction of apoptosis in pancreatic cancer cells. AMP demonstrated synergy with gemcitabine (GEM) in preclinical pancreatic cancer models. This phase I study of AMP plus GEM was undertaken to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Secondary endpoints were pharmacokinetics for both agents (PK) and tumor response. Methods: Patients (pts) with previously untreated advanced pancreatic adenocarcinoma received one of two dosing regimens. The first 19 received 30 minute AMP IV days 1–5 and 15–19 followed by 30 minute GEM IV days 1, 8 and 15 Q4 wks (Regimen A). Dosing was modified after 19 pts to administer both AMP and GEM over 30 minutes days 1, 8 and 15 every 4 weeks (Regimen B). Dose levels (AMP/GEM, in mg/m2) for Regimen A: 200/800, 280/800, 200/1000, and 280/1000, and for Regimen B: 280/1000, 335/1000, 390/1000, 540/1000, and 750/1000. The current cohort is 1000/1000. Pts were assessed for response after cycles 2, 5 and 8. PK and pharmacodynamic (plasma thiol depletion) measurements were obtained during cycle one. Results: Forty-six pts have been treated to date, with 36 having complete toxicity data and evaluable. Pt characteristics: M/F (24/12), Age (mean 60.4 years, range 43–75), ECOG PS 0/1 (56%, 44%), metastatic/locally advanced (91%, 9%). The 36 pts have completed 122.5 cycles of therapy (median 2, range 0.5–12). Common toxicities: anemia (77%), fatigue (71%), nausea (60%), fever (54%), and leukopenia (54%). DLT were 1/6 at 280/1000 (Regimen A - febrile neutropenia), 1/6 at 280/1000 (Regimen B - gr 3 hypotension, gr 4 renal failure), and 1/9 at 390/1000 (gr 3 hyperbilirubinemia). Accrual continues at 1000/1000. Of 36 pts, 4 have had partial responses and 14 stable disease. PK and plasma thiol analysis are ongoing. Conclusions: Imexon can be administered safely with full dose gemcitabine. Accrual continues to define the combination MTD. The response rate in this phase I study compares favorably with historical gemcitabine monotherapy, and further phase II evaluation of this combination in advanced pancreatic cancer is warranted. No significant financial relationships to disclose.

A dose-escalating phase I study of biweekly docetaxel in older men with hormone refractory prostate cancer (HRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16117-e16117
Author(s):  
J. McDevitt ◽  
R. Hauser ◽  
J. Simon ◽  
L. Balducci
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Assessment Tool ◽  
Maximum Tolerated Dose ◽  
Self Report ◽  
Weekly Dose ◽  
Level 3 ◽  
Level 1 ◽  
Dose Levels

e16117 Background: Docetaxel has been shown to be effective and is used in the treatment of HRPC. This phase I study is designed to investigate the maximum tolerated dose, tolerability and activity of docetaxel administered on a biweekly schedule in older patients with HRPC. This study will also explore the feasibility of a self-report geriatric assessment tool in this population. Methods: HRPC patients with progression of metastatic disease during hormonal therapy received docetaxel q 2 wks at dose levels of 40 (level 0), 45 (level 1), 50 (level 2), or 55 mg/m2 (level 3). The trial is a conventional phase I 3+3 dose-escalation design. Treatment was continued until progression, refused further treatment, or unacceptable toxicity. Patients were given the Vulnerable Elders Survey (VES-13) for completion every 4 weeks. Results: 16 patients were enrolled in the study. All are evaluable for toxicity, 10 for response. Pts had a median (range) age 76 (72–87). Median doses administered was 6 (range 3–19). The maximum tolerated dose (MTD) was not reached in the study. No dose limiting side effects were reported for any of the dosing levels in the 8 week assessment period. Five patients had a ≥50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. Of the 10 patients with measureable disease, 2 patients (one at dose level 0 and one at dose level 3) achieved a complete response, 2 patients (one at dose level 1 and one at dose 2) achieved a partial response, and 3 patients had stable disease (one each at dose levels 1, 2, and 3). At the time of entry onto the study, 4 patients required narcotic analgesics for bone pain; after treatment, 1 (25%) discontinued their pain medications. The completion rate of the Vulnerable Elders Survey (VES-13) was 94.6%. Conclusions: Biweekly docetaxel can be safely administered in older metastatic HRPC patients and showed activity. For phase II evaluation, a bi-weekly dose of 55 mg/m2 appears to be suitable. The administration of the VES-13 was feasible in this population. [Table: see text]

A first-in-human phase I study of ER-α36 modifier icaritin in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2614-2614
Author(s):  
Ying Fan ◽  
Binghe Xu ◽  
Xiaoyan Ding ◽  
Fei Ma ◽  
Jiayu Wang ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Phase I Study ◽  
Chinese Herb ◽  
Hepatocellular Cancer ◽  
Fold Increase ◽  
Maximum Tolerated Dose ◽  
Multiple Cancer ◽  
Phase Ib ◽  
Dose Levels

2614 Background: ER-α36 was recently identified to be expressed in varieties of cancers and may play important roles in carcinogenesis and tumor progression. Icaritin, a natural prenylflavonoid derived from the Chinese herb Epimedium, is a first of its kind ER-α36 modifier, which demonstrated potent anti-tumor effect in multiple cancer cell lines and their xenograft models. This study aims to determine its safety, tolerability, pharmacokinetics (PK), and potential antitumor activity. Methods: This phase I study comprises phase Ia and Ib. In phase Ia part, patients with advanced breast cancer (ABC) were treated with escalating doses of Icaritin orally once daily on a continuous 28-day dosing schedule. In phase Ib part, dosing was fixed to 600 or 800mg twice daily and expansion was made to other selected malignancies including hepatocellular cancer (HCC), colorectal cancer (CRC) and intrahepatic cholangiocarcinoma (ICC) to further explore PK parameters and efficacy. Results: 24 patients were enrolled to receive Icaritin at six dose levels ranging from 50mg to 1600mg per day in phase Ia. No dose limited toxicity (DLT) was found even in the highest dose defined in the protocol, thus the maximum tolerated dose (MTD) was not reached. Only grade 1 drug-related adverse events were observed including neutropenia, ALT elevation, hypercholesteremia, fatigue, anorexia, hypertriglyceridemia, proteinuria, myalgia, hot flash and rash. PK data from the fed dosing showed 3-fold increase of Cmax and AUC compared with the fast dosing. Half life was around 2-7 hours. Among 22 evaluable subjects, no complete or partial response (CR or PR) was detected, 5 patients had stable disease(SD)for 3 months or longer. For phase Ib study, 24 patients had been enrolled. One ABC, 2 CRC and 3 ICC patients progressed after 2 months of medication. Among 7 HCC patients already evaluated, 1 obtained PR and progressed after one year of treatment and 2 remained in the study, stable for 5 months. Similar drug related toxicity profile was noted in phase Ib. Conclusions: Icaritin was generally well-tolerated without DLT across tested dose levels. Evidence of promising antitumor activity was observed in ABC and HCC. Final results will be presented at the meeting. Clinical trial information: NCT01278810.

Phase I Study of Intraventricular Administration of Rituximab in Patients With Recurrent CNS and Intraocular Lymphoma

2007 ◽  
Vol 25 (11) ◽  
pp. 1350-1356 ◽  
Author(s):  
James L. Rubenstein ◽  
Jane Fridlyand ◽  
Lauren Abrey ◽  
Arthur Shen ◽  
Jon Karch ◽  
...  
Keyword(s):  
Phase I ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Intraocular Lymphoma ◽  
Intraventricular Administration ◽  
Dose Escalation Study ◽  
Dose Levels ◽  
Craniospinal Axis

Purpose We previously determined that intravenous administration of rituximab results in limited penetration of this agent into the leptomeningeal space. Systemic rituximab does not reduce the risk of CNS relapse or dissemination in patients with large cell lymphoma. We therefore conducted a phase I dose-escalation study of intrathecal rituximab monotherapy in patients with recurrent CNS non-Hodgkin's lymphoma (NHL). Patients and Methods The protocol planned nine injections of rituximab (10 mg, 25 mg, or 50 mg dose levels) through an Ommaya reservoir over 5 weeks. The safety profile of intraventricular rituximab was defined in 10 patients. Results The maximum tolerated dose was determined to be 25 mg and rapid craniospinal axis distribution was demonstrated. Cytologic responses were detected in six patients; four patients exhibited complete response. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. High RNA levels of Pim-2 and FoxP1 in meningeal lymphoma cells were associated with disease refractory to rituximab monotherapy. Conclusion These results suggest that intrathecal rituximab (10 to 25 mg) is feasible and effective in NHL involving the CNS.

scholarly journals Phase I Study of Rivoceranib, a Selective VEGFR-2 Angiogenesis Inhibitor, Administered Daily in Patients With Advanced Solid Tumors

2021 ◽  
Author(s):  
Yoon-Koo Kang ◽  
Min-Hee Ryu ◽  
Yong Sang Hong ◽  
Chang-Min Choi ◽  
Tae Won Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Safety Profile ◽  
Phase I Study ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Potential Clinical Benefit ◽  
Dose Levels

Abstract Rivoceranib is a highly potent and selective inhibitor of VEGFR-2 and subsequent angiogenesis through this receptor signaling pathway. This phase I study was the first global study with rivoceranib outside of China in Korean and Caucasian patients and was designed to determine the safety profile (including maximum tolerated dose), pharmacokinetics, and efficacy in patients with advanced solid tumors. Thirty-one adult patients with advanced malignant solid tumors were enrolled to investigate 6 dose levels of rivoceranib. Twenty-five patients were initially enrolled to 5 dose levels of rivoceranib from 81 to 685 mg and an additional 6 patients were later enrolled in a supplemental study to evaluate the 805 mg dose level. Rivoceranib was very well tolerated. At the 805 mg dose level, 2 dose-limiting toxicities were observed but the 685 mg dose was well tolerated over multiple cycles of therapy. The maximum tolerated dose for rivoceranib was 685 mg (equivalent to 850 mg rivoceranib mesylate) and recommended for further study in patients with advanced solid tumors. The most common adverse events were hypertension (all grades %/≥G3%: 58/29), nausea (42/0), diarrhea (39/0), anorexia (32/3), and fatigue (29/6). Rivoceranib pharmacokinetics were proportional across all dose levels but interpatient variability was high. Of the 31 patients enrolled, 21 were evaluable for efficacy. In this evaluable group, partial response was recorded in 5 patients, stable disease in 10, and disease progression in 6. Results indicate the potential clinical benefit of daily rivoceranib in patients with advanced malignant solid tumors with a tolerable safety profile.Trial registration: NCT01497704 (ClinicalTrials.gov) registered on December 22, 2011 and NCT02711969 (ClinicalTrials.gov) registered on March 17, 2016.

scholarly journals Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or naturalkiller/T-cell lymphoma.

Haematologica ◽  
2020 ◽  
pp. 0-0
Author(s):  
Tiffany Tang ◽  
Peter Martin ◽  
Nagavalli Somasundaram ◽  
Cindy Lim ◽  
Miriam Tao ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Nuclear Export ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
Standard Dose ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
T Cell Lymphoma ◽  
High Dose

Selinexor is a selective inhibitor of nuclear export with anti-cancer properties. We performed a phase I study to determine the safety and maximum tolerated dose (MTD) of selinexor when combined with high-dose dexamethasone, ifosfamide, carboplatin and etoposide (DICE) in relapsed/refractory (R/R) T-cell lymphoma (TCL) and natural-killer/T-cell lymphoma (NKTL). Patients with R/R TCL and NKTL were treated with standard dose ICE, dexamethasone 20mg on days 3 to 7, and escalating doses of oral selinexor on days 3, 5 and 7 in a 3+3 design. Dose level (DL) 1, 2 and 3 were 40, 60 and 80mg respectively. Eleven patients with a median age of 60 were enrolled; 6 at DL1 and 5 at DL2. Patients had received a median of 2 (range 1-4) prior lines of treatment and 7 had primary refractory disease at study entry. Patients received a median of 3 cycles (range 1-6) of selinexor-DICE. The most common grade (G) 1/2 toxicities included nausea (64%), fatigue (55%), and anorexia (45%) and the most common G 3/4 toxicities included thrombocytopenia (82%), anemia (82%), neutropenia (73%), and hyponatremia (73%). Two patients developed doselimiting toxicities at DL2 and one at DL1. Five patients discontinued treatment for reasons other than disease progression or lack of response. Of the 10 evaluable patients, the overall and complete response rates were 91% and 82% respectively. The MTD of selinexor was 40mg when combined with DICE. The combination showed promising CR rates in patients with R/R TCL and NKTL but was poorly tolerated.

Phase I study of capecitabine combined with weekly carboplatin and intensity modulated radiation therapy (IMRT) for treatment of locally advanced squamous cell carcinomas of the head and neck (HNSCC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15522-15522
Author(s):  
C. Y. Thomas ◽  
P. Read ◽  
K. Sheng ◽  
D. Bliesner ◽  
P. Levine ◽  
...  
Keyword(s):  
Phase I ◽  
Locally Advanced ◽  
Intensity Modulated Radiation Therapy ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Stage Iii ◽  
Fixed Dose ◽  
Parotid Sparing ◽  
Grade 3 ◽  
Carboplatin Auc

15522 Background: Chemoradiotherapy (CRT) programs for locally advanced HNSCC that reduce toxicity but maintain efficacy are needed. Methods: A two-step phase I trial to determine the maximum tolerated dose (MTD) of capecitabine combined with fixed dose carboplatin, given prior to and during concomitant IMRT. Start dose of capecitabine =1500 mg/m2/d p.o. BID days 1–14 and 22–35 with carboplatin AUC =2 IV weekly x 6. With IMRT, the doses were adjusted to 1000 mg/m2/d and AUC =1.5, respectively. Parotid-sparing IMRT = 50 and 45 Gy/25 fractions to gross disease (GD) and low risk nodes, respectively; 3D conformal boost of 20 Gy/10 fractions to GD. Dose limiting toxicity (DLT) defined as ANC <750, ≥ grade 3/4 thrombocytopenia or selected non-hematologic toxicities. Results: 11 patients (pts) with stage III/IV (T2–4,N1–2C) HNSCCs of the oropharynx (7), oral cavity (2), both (1), or hypopharynx (1) were studied. 10/9 pts evaluable for toxicity after induction/concomitant chemotherapy, respectively; 2 pts had early disease progression (d22 and 43). During radiation, the MTD for capecitabine established as 825 mg/m2/d. At start dose, 2/3 pts developed thrombocytopenia as DLT; CRT-related toxicities = grade 3 mucositis (3), dysphagia (3), fatigue (1), anemia (1), and dermatitis (1). For induction chemotherapy, DLTs seen in 0/3 pts at capecitabine =1750 mg/m2 and 1/6 at lower doses (grade 4 diarrhea; no other Gr3/4 drug-related toxicities). Response of primary (or neck) tumors to induction: CR 3 (3), PR 6 (3), SD 1 (3), and PD 2 (2). After CRT, 8/9 pts achieved CR and are alive without disease (mean follow-up 6 months). Conclusions: Capecitabine 825 mg/ m2/d and carboplatin AUC =1.5 weekly given on the described schedule and in combination with IMRT produce moderate toxicity and a high complete response rate in stage III/IV HNSCC pts that received the same drugs as induction therapy. The latter combination was also well tolerated and had anti-tumor activity (capecitabine Y=1500–1750 mg/m2/d). Additional studies are warranted to determine if these regimens provide an effective but less toxic alternative to cisplatin or taxane-based CRT programs. Supported in part by Bristol-Myers-Squibb. No significant financial relationships to disclose.

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