scholarly journals Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Danielle Shafer ◽  
Mary Beth Tombes ◽  
Ellen Shrader ◽  
Alison Ryan ◽  
Dipankar Bandyopadhyay ◽  
...  
Keyword(s):  
Phase I ◽  
Progression Free Survival ◽  
Dimethyl Fumarate ◽  
Maximum Tolerated Dose ◽  
Newly Diagnosed ◽  
Relapsing Remitting ◽  
Common Grade ◽  
Grade 3 ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Dose Levels

Abstract Background Dimethyl fumarate (DMF), an oral agent approved for the treatment of relapsing–remitting multiple sclerosis (RRMS), has promising preclinical activity against glioblastoma (GBM). This phase I study sought to determine the recommended phase 2 dose (RP2D) of DMF and evaluate its safety and toxicity when combined with standard concurrent radiotherapy (RT) and temozolomide (TMZ) followed by maintenance TMZ in patients with newly diagnosed GBM. Methods Using a standard 3 + 3 dose-escalation design with 3 dose levels, patients received daily DMF with 60 Gy RT and concurrent TMZ 75 mg/m2 daily, followed by maintenance DMF (continuously) and TMZ 150–200 mg/m2 on days 1–5 of each 28-day cycle for up to 6 cycles. The maximum tolerated dose (MTD) was determined by evaluation of dose-limiting toxicity (DLT) during the first 6 weeks of therapy. Results Twelve patients were treated at the 3 dose levels, and no DLTs were observed. There were no unexpected toxicities. The most common grade 3/4 treatment related adverse events (AEs) were lymphopenia (58%), decreased CD4 count (17%), and thrombocytopenia (17%). Four patients completed all planned treatment; seven patients had progression on treatment. One patient chose to withdraw from the study during maintenance. The median progression-free survival (PFS) for all patients was 8.7 months with no difference in PFS between those with stable disease or a partial response; median overall survival was 13.8 months. Conclusions DMF may be safely combined with RT and TMZ in patients with newly diagnosed GBM. The RP2D for DMF is 240 mg three times daily.

Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma multiforme.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2060-2060 ◽  
Author(s):  
Danielle A. Shafer ◽  
Zhi-jian Chen ◽  
Timothy Harris ◽  
Mary Beth Tombes ◽  
Ellen Shrader ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Malignant Gliomas ◽  
Maintenance Phase ◽  
Dimethyl Fumarate ◽  
Maximum Tolerated Dose ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Dose Levels

2060 Background: Evidence is increasing for altered immune responses in malignant gliomas. Tumor-associated microglia/macrophages infiltrate human glioma tissue and produce cytokines that promote glioma growth, invasion and angiogenesis. Dimethyl fumarate (DMF), approved for relapsing-remitting multiple sclerosis, is toxic to in vitro activated microglial cells. Based on pre-clinical data demonstrating synergism with radiation (RT) and temozolomide (TMZ), we conducted a phase I study of DMF in patients with newly-diagnosed glioblastoma (GBM) in combination with RT and TMZ. Methods: Using a standard 3+3 dose escalation design (3 dose levels: 120 mg bid, 240 mg bid and 240 mg tid), newly-diagnosed GBM patients received daily DMF with RT (60 Gy) and concurrent TMZ 75 mg/m2 daily, followed by adjuvant DMF (continuously) and TMZ for up 6 maintenance cycles (150-200 mg/m2 on days 1-5 of each 28 day cycle). The maximum tolerated dose (MTD) was defined as the dose with ≤ 1/6 dose-limiting toxicities (DLT). The MTD was determined by evaluation of DLTs during the first 6 weeks of therapy. Results: Twelve patients were treated at the three dose levels, and no DLT was identified. There were no unexpected toxicities. The most common toxicities were lymphopenia (11 grade 3/4 events) and thrombocytopenia (2 grade 3/4 events). The only grade 3/4 non-heme toxicity was a grade 3 hemorrhoid event. Of the 12 evaluable patients, one remains on active treatment in maintenance phase. Three patients completed all treatment (concurrent and maintenance) with stable disease. Two patients had a partial response (RANO criteria) but then experienced disease progression during maintenance. Five patients had disease progression during study treatment and one patient chose to withdraw from the study during maintenance. Conclusions: These data suggest that DMF may be safely combined with RT and TMZ in GBM patients. A phase II study is under consideration. Clinical trial information: NCT02337426.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1723-1723
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Peter Anglin ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Oral Cyclophosphamide ◽  
Varicella Zoster ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Dose Levels

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

Phase I Study of the Combination of Carfilzomib and Panobinostat for Patients with Relapsed and Refractory Myeloma: A Multiple Myeloma Research Consortium (MMRC) Clinical Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 32-32 ◽  
Author(s):  
Jonathan L. Kaufman ◽  
Todd Zimmerman ◽  
Cara A Rosenbaum ◽  
Ajay K. Nooka ◽  
Leonard T Heffner ◽  
...  
Keyword(s):  
Phase I ◽  
Research Funding ◽  
Phase I Study ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Significant Activity ◽  
Free Survival ◽  
Common Grade ◽  
Grade 3

Abstract Introduction: Patients with myeloma ultimately become refractory to current therapies, requiring new approaches to treatment. Carfilzomib is a second generation proteasome inhibitor that has demonstrated significant activity in patients with relapsed and refractory disease. Panobinostat is a pan-deacetylase inhibitor that has been shown to be effective and overcome resistance in combination with bortezomib in refractory patients. In addition, patients treated with a combination of bortezomib/dexamethasone/panobinostat had a significant improvement in progression free survival (PFS) compared to bortezomib/dexamethasone alone. Based on preclinical data supporting combined HDAC and proteasome inhibition, we hypothesized that carfilzomib and panobinostat would be safe and effective in relapsed/refractory myeloma patients. Herein we report the initial findings of the MMRC multicenter phase I study of the combination. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of the combination of panobinostat and carfilzomib using a standard 3+3 alternate dose escalation design with 4 cohorts. An additional 12 patient expansion group will be treated at the MTD to further assess the activity and safety of the combination. Secondary objectives are to evaluate the extended safety of this combination and to assess response, response duration and progression free survival (PFS). Panobinostat is administered orally three times weekly for three of four weeks, ranging from 15 to 20 mg. Carfilzomib is administered IV days 1, 2, 8, 9, 15, and 16, ranging from 20/27 mg/m2 to 20/45mg/m2. Cycles are repeated every 4 weeks. Dose limiting toxicities (DLT) are determined in the first cycle, and all adverse events are assessed according to CTCAE V4. Responses are assessed using IMWG criteria (plus MRs as per the EBMT criteria). Results: To date, 20 patients in four cohorts have been enrolled and all have completed the first cycle. Median age is 64.5 years (48-75). All patients had refractory and progressive disease; with a median number of 4) prior treatment lines. Three DLTs occurred. One patient had grade 4 thrombocytopenia with grade 3 acute kidney injury, one patient developed persistent grade 4 thrombocytopenia without bleeding and one patient had grade 3 diarrhea uncontrolled by maximal medical therapy. The MTD is panobinostat 20 mg and carfilzomib 20/36 mg/m2. The most common grade 3 toxicities were hematologic. Regardless of causality, grade 3 or higher anemia, thrombocytopenia and neutropenia occurred in 35%, 35%, and 20% of patients, respectively. The most common grade 3/4 or higher nonhematologic toxicities were fatigue (15%), anorexia (10%), hyponatremia (10%) and nausea (10%). The overall response rate is 50% with 30% PRs and 20% VGPR or better. The median PFS is 14.3 months. Conclusion: The combination of carfilzomib and panobinostat is well tolerated with no unexpected toxicities. Response, durability of response, and PFS are encouraging and warrant further study. Disclosures Kaufman: Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Off Label Use: Carfilzomib treatment in amyloidosis . Zimmerman:Onyx: Honoraria. Heffner:Amgen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Dana Farber CI: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Idera: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Spectrum: Honoraria, Research Funding; Talon Therapeutics: Honoraria, Research Funding. Harvey:Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Acetylon: Research Funding; Amgen: Research Funding. Gleason:Celgene: Consultancy; Novartis: Consultancy. Lewis:Array BioPharma: Consultancy. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

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 dose and schedule finding study of pegylated liposomal doxorubicin (D) and weekly docetaxel (T)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12012-12012 ◽  
Author(s):  
O. S. Shaye ◽  
A. B. El-Khoueiry ◽  
A. Garcia ◽  
D. Wei ◽  
S. Groshen ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Metastatic Breast ◽  
Pegylated Liposomal Doxorubicin ◽  
Dose Intensity ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Salivary Gland Carcinomas ◽  
Common Grade ◽  
Grade 3

12012 Background: The combination of D and T has many potential applications, particularly in breast and ovarian cancers. A phase 3 trial is examining D + T versus T in first-line metastatic breast cancer ( NCT00091442 ). D has better tumor localization and penetration in solid tumors than conventional doxorubicin. In previous studies, the maximum tolerated dose (MTD) of the combination was identified as D 30 mg/m2 and T 75 mg/m2 q4 weeks (wks), with a recommended dose and schedule of D 30 mg/m2 and T 60 mg/m2 q3wks without G-CSF. We conducted a phase I study to determine the MTD of D with weekly T. Our hypothesis was that the lower incidence of myelosuppression with weekly T would allow for higher doses of both drugs. Methods: There were 2 schedules. Arm A: D q4wks starting at 25 mg/m2 with weekly T for 3 wks starting at 30 mg/m2. Arm B: D q2wks starting at 15 mg/m2 with weekly T for 3 wks starting at 30 mg/m2. One cycle was 28 days. Standard 3+3 design was used with MTD defined as the highest dose level causing dose limiting toxicity (DLT) in ≥ 2/6 patients (pts). Results: 32 pts were treated; 13 females, 19 males, median age of 60 years. Median number of cycles administered was 2 (1–13) with a median follow-up of 11.5 months. Tumor types included lung (16%), thyroid (9%), esophagus (9%), nasopharynx, breast, colorectal, stomach and kidney (6% each). Arm A (13 pts) was closed after 2/7 evaluable pts at dose level 2 (D 33mg/m2; T 30 mg/m2) experienced DLT in the form of grade 3 stomatitis. The most common grade 3/4 toxicities were neutropenia (3/13), stomatitis (3/13) and fatigue (3/13). Arm B accrued 19 pts. The trial was closed at the highest planned dose in Arm B (D 20mg/m2 q2wks and T 35 mg/m2 weekly) with only 1/6 evaluable pts experiencing DLT in the form of grade 4 fatigue and weakness. The most common grade 3/4 toxicities in Arm B included neutropenia (5/19 pts), fatigue (5/19 pts) and stomatitis (2/19 pts). There was no grade 3/4 hand-foot syndrome or cardiotoxicity. 2 partial responses were observed in nasopharyngeal and salivary gland carcinomas, with 13 pts achieving stable disease. Conclusions: The combination of D q2 wks and T weekly for 3/4 wks is well tolerated and results in a higher dose intensity of both drugs than in previously evaluated regimens. [Table: see text]

A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6055-6055 ◽  
Author(s):  
P. H. Morrow ◽  
B. S. Glisson ◽  
L. E. Ginsberg ◽  
S. M. Lippman ◽  
M. S. Kies ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Cell Cancer ◽  
Maximum Tolerated Dose ◽  
Vitamin Supplementation ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels ◽  
Neck Squamous Cell Cancer

6055 Background: Despite recent advances in therapy, patients (pts) with recurrent or metastatic HNSCC continue to demonstrate a poor median survival. In these pts, early trials with pemetrexed, a novel antimetabolite that acts upon several enzymes involved in pyrimidine and purine synthesis, have demonstrated promising efficacy and tolerability. Prior studies found that the administration of oral dexamethasone with pemetrexed reduced the incidence of skin rash. Later, vitamin supplementation (B12 and folic acid), given in addition to the dexamethasone, further diminished side effects. However, no trial has yet evaluated the appropriate steroid dose and its relation to the dosing of pemetrexed, in the setting of vitamin supplementation. We conducted a phase I trial to determine the maximum tolerated dose, toxicity, and preliminary efficacy of pemetrexed when given with different schedules of, or in the absence of, dexamethasone in pts with advanced HNSCC who had been treated with at least one or more chemotherapy regimens. Methods: Eligible pts had metastatic or recurrent HNSCC, prior treatment with one or more chemotherapy regimens, ECOG PS =2, and life expectancy >3 months. A conventional algorithm-based dose escalation design was applied, with three predefined dose levels (DL) of pemetrexed (500 mg/m2, 600 mg/m2, and 700 mg/m2) within each schedule of dexamethasone (none, 20 mg IV on day 1, and 4 mg orally bid for 3 days). Results: A total of 23 pts have been enrolled; 18 pts were evaluable. Median age was 57 years (range 47–82). Median ECOG PS was 1 (range 0–2), and 75% of pts were male. Number of prior chemotherapy regimens were as follows: 1 (40%), 2 (35%), 3 (15%), and 4 (10%). Preliminary data demonstrated only 2 treatment-related adverse events that were grade 3 or greater: anemia (DL1) and pneumonia (DL 1). In all, 13 pts have received pemetrexed with less than standard recommended dexamethasone dosing (none or IV), including 7 pts who received no dexamethasone. Of the 18 evaluable pts, 1 pt had a partial response and 2 pts had stable disease. Conclusions: This represents the first study that demonstrates that steroids may not be required as premedication with pemetrexed. Due to the limited toxicity observed, trial enrollment continues with dose escalation. [Table: see text]

Long-term follow-up results of a phase I/II study of concurrent chemoradiotherapy for localized nasal NK/T-cell lymphoma (NKTCL): JCOG0211.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8050-8050
Author(s):  
Motoko Yamaguchi ◽  
Kensei Tobinai ◽  
Masahiko Oguchi ◽  
Naoki Ishizuka ◽  
Yukio Kobayashi ◽  
...  
Keyword(s):  
Phase I ◽  
Concurrent Chemoradiotherapy ◽  
Elevated Serum ◽  
Progression Free Survival ◽  
Disease Recurrence ◽  
Newly Diagnosed ◽  
Long Term Follow Up ◽  
Grade 3

8050 Background: Concurrent chemoradiotherapy has been regarded as one of the standard management for localized nasal NKTCL. However, its long-term efficacy and toxicity is not known. Methods: The JCOG0211 trial is a phase I/II study of concurrent chemoradiotherapy consisting of radiotherapy (RT) of 50 Gy and 3 cycles of DeVIC (carboplatin, etoposide, ifosfamide, dexamethasone) for newly diagnosed, localized nasal NKTCL (JCO 2009). Patients (Pts) with newly diagnosed, localized diseases (IE & contiguous IIE with cervical node involvement) who were 20-69 yrs of age with PS 0-2 were eligible. 3-D conformal RT planning with a wide margin (+ 2 cm to the gross tumor, the entire nasal cavity and the nasopharynx) and a 2-step cone down were required. 33 pts were enrolled in the study, 27 of whom were treated with RT and a 2/3-dose of DeVIC, which was selected as the recommended phase II dose in the preceding phase I portion of the trial. All pts completed RT without any protocol violations. Long-term follow-up results on overall survival (OS), progression-free survival (PFS) and toxicity were evaluated. Results: The median follow-up was 69 months (range, 62-96). The pt (N=33) characteristics were as follows: median age 54 yrs (range, 21-68); stage IIE 33%; B symptom (+) 36%; elevated serum LDH 21%. %5-yr OS and PFS were 73% (95%CI, 54-85%) and 67% (95%CI, 48-80%), respectively. 11 pts (33%) experienced disease recurrence. Two achieved a 2nd CR by salvage chemotherapies followed by allogeneic stem cell transplantation, and the remaining 9 pts died of disease. There was no observed death and disease progression after 34 and 31 months, respectively. One pt experienced Grade 3 irregular menstruation for 3 years. No other Grade 3 or 4 late non-RT-associated adverse events (AEs) were observed. One pt received plastic surgery due to Grade 4 RT dermatitis. No other Grade 3 or greater RT-associated late AEs were encountered. Conclusions: Both survival benefit and disease control from concurrent chemoradiotherapy with RT and DeVIC are maintained during a 5-yr follow-up, indicating the excellent efficacy of this approach as a first-line therapy for localized nasal NKTCL. Long-term toxicity is acceptable.

Phase I trial of docetaxel (D), cisplatinum (C), and continuous capecitabine (CAP) (TCX) in advanced esophagogastric cancer (AEC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14587-e14587
Author(s):  
Simon Gollins ◽  
Arwel Lloyd ◽  
Jackie Morris ◽  
Nick Smith ◽  
Brian Haylock ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Free Survival ◽  
Best Response ◽  
Esophagogastric Cancer ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity

e14587 Background: This phase I study assessed the combination of D, C, and continuous CAP in AEC to develop a regimen of acceptable toxicity to take forward to phase II study. Methods: Patients with AEC were treated in cohorts of 3, at one of 3 dose levels (DL). DL0: D at 60 mg/m2 IV on day 1, C at 60 mg/m2 IV on day 1, CAP at 1,000 mg/m2 per day in two divided doses days 1-21, every 3 weeks. DL1: CAP increased to 1,250 mg/m2 per day. DL2: D increased to 75 mg/m2 IV day 1 and CAP to 1,250 mg/m2 per day. Prophylactic colony stimulating factors were not used. Patients received a maximum of 6 cycles. Blood counts and biochemistry were assessed twice weekly and daily for grade 3/4 abnormality. Results: Between 1.11.07 and 24.6.09 15 patients were enrolled: male/female:14/1, WHO PS:0/1:10/5, median age 63 yr (range 46-69), primary site oesophagus/GOJ/stomach:7/3/5, adeno/squamous:14/1, T2/3/4:2/9/4, N0/1/2:1/13/1, M0/1:1/14. 6 patients were treated at DL0, 6 at DL1 and 3 at DL2. All patients received 6 cycles apart from 2 at DL 1 who received 3 because of disease progression. Dose intensity: DL0: D 95%, C 100%, CAP 85%; DL1: D 91%, C 98.2%, CAP 79%; DL2: D 86%, C 100%, CAP 79%. There were no deaths on chemotherapy or within 30d of the last dose. The main dose limiting toxicity was febrile or infective neutropenia developing in 1/6 DL0, 2/6 DL1 and 3/3 DL2 (see table of most common treatment-related adverse events below: serious toxicity is gr 3 unless specified gr 4). The maximum length of gr 4 neutropenia was 5d. Best response (RECIST): 1 CR, 11PR, 2 SD and 1PD. 11 patients received second-line chemotherapy. Median and 1 yr overall survival: 17.5m and 60%. Median and 1 yr progression-free survival: 7m and 27%. Conclusions: TCX DLO is recommended for further study in a phase II trial. Encouraging response and survival were seen. [Table: see text]

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