A phase I study of bevacizumab (B) with fluorouracil (F) and hydroxyurea (H) with concomitant radiotherapy (X) (B-FHX) for poor prognosis head and neck cancer (HNC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5530-5530 ◽  
Author(s):  
T. Y. Seiwert ◽  
D. J. Haraf ◽  
E. E. Cohen ◽  
K. Stenson ◽  
A. M. Mauer ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Poor Prognosis ◽  
High Risk Patient ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Tumor Bed ◽  
Grade 5 ◽  
Unclear Etiology ◽  
Ecog Ps

5530 Background: Increased VEGF levels are found in HNC. Preclinical data suggest synergistic antitumor activity of B with radiation and chemotherapy. We conducted a Phase I dose escalation study to determine the maximum tolerated dose and dose limiting toxicity (DLT) of B, when added to infusional 5-FU, Hydroxyurea (HU), and daily radiotherapy administered every other week in patients (pts) with poor prognosis HNC. Methods: Eligible pts had recurrent, or newly diagnosed HNC with high risk of recurrence, ± metastatic disease requiring local control, ECOG PS ≤2, and life expectancy >12 weeks. Two week cycles were repeated 6–7 times (see table ). Results: 43 pts were treated (34 completed). DLT was reached at level 3 with 2 pts having gr 3 transaminase elevations and one pt gr 4 neutropenia. Treatment of 7 (6 evaluable) pts on level 4 resulted in one DLT (SMV thrombosis) and this dose level was chosen for expanded evaluation. In all level 4 pts (N = 27) gr 3 mucositis occured in 73.1% and gr 3 hand-foot syndrome in 15.4%. Additional gr 3 or worse toxicities in the expanded level 4 included: esophageal bleed (tumor bed, grade 5), stroke (grade 4), carotid rupture (3 wks post RT, grade 5), and neck ulceration with need for carotid stent (3 months post RT, grade 4). One sudden death of unclear etiology occurred. Median overall survival is 389 days. One/two year survival is 52.1/26%. Median survival for patients treated with re-irradiation for recurrent, non-metastatic HNC is 314 days; one/two year survival is 45.9/17.2%. With a median follow-up of 317 days 13 patients are still alive (12 are cancer free). Conclusions: B can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m2 every 2 weeks. While B related toxicities are seen, there appears to be no major synergistic toxicity. Long term activity is observed in this very high risk patient population. A randomized phase II trial of FHX with or without B in a lower risk population is ongoing. [Table: see text] No significant financial relationships to disclose.

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]

Phase I/II study of docetaxel (D), gemcitabine (G), and bevacizumab (B) in patients (pts) with advanced or recurrent soft tissue sarcoma (STS)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10056-10056 ◽  
Author(s):  
C. F. Verschraegen ◽  
H. M. Fekrazad ◽  
I. Rabinowitz ◽  
R. Quinn ◽  
D. Snyder ◽  
...  
Keyword(s):  
Chest Pain ◽  
Phase I ◽  
Poor Prognosis ◽  
Bowel Perforation ◽  
Maximum Tolerated Dose ◽  
Weekly Schedule ◽  
Undifferentiated Sarcoma ◽  
Ecog Ps ◽  
Myxoid Sarcoma ◽  
Unacceptable Toxicity

10056 Background: The combination of G and D has shown efficacy against refractory STS (Hensley, JCO 2002). STS have a high content of VEGF, which is associated with poor prognosis. This phase I/II study assesses the safety, tolerability, efficacy, and pharmacodynamics (PD) of B in combination with G+D, given on a two-weekly schedule to minimize adverse events (AEs). We are reporting the phase I results. Methods: Untreated pts with advanced or recurrent STS and ECOG PS =2 were eligible. Some pts were treated in a neoadjuvant setting, when surgically appropriate. Planned doses were G 1,000, 1,250, and 1,500 mg/m2, D 50 mg/m2, and B 5 mg/kg iv, every 2 wks. G doses were escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of G with fixed doses of D and B. MTD was assessed on the first 2 cycles (1 cycle = 2 wks). Treatment was continued until progression or unacceptable toxicity. For neoadjuvant therapy, B was given only for 4 cycles, followed by 4 cycles without B in anticipation of surgery and pts came off study at that point. PD and antitumor efficacy were also assessed. Results: Nine pts have been treated on the phase I escalation arm, including 3 in the neoadjuvant setting. There were no dose limiting toxicities. After 4 cycles with G at 1,500 mg/m2, there was 1 asymptomatic grade 4 bowel perforation at the site of the tumor in a pt with initially inoperable leiomyosarcoma (LMS). After emergency surgery, the pt is free of disease. Observed grade 1 and 2 AEs include alopecia, diarrhea, fatigue (5 each), rigors (4), nausea, dyspnea, headaches (3 each), chest pain, epistaxis, stomatitis, anemia (2 each), rash, hypertension, neuropathy, leukopenia (1 each). There were 1 CR (angiosarcoma), 2 PR, (myxoid sarcoma, undifferentiated sarcoma), 4 NC (2 LMS, liposarcoma, PNST), and 2 PD (myxoid sarcoma, PNST). Necrosis was observed, including in NC disease. Three pts are free of disease after surgery. Conclusions: The combination of G, D, and B given every 2 weeks is safe and has demonstrated some activity in pts with advanced or recurrent STS. The phase II arm is ongoing at G 1,500 mg/m2 with 4 pts already enrolled. Mature data including PD will be reported at the meeting. No significant financial relationships to disclose.

Phase I Study of Bevacizumab Added to Fluorouracil- and Hydroxyurea-Based Concomitant Chemoradiotherapy for Poor-Prognosis Head and Neck Cancer

2008 ◽  
Vol 26 (10) ◽  
pp. 1732-1741 ◽  
Author(s):  
Tanguy Y. Seiwert ◽  
Daniel J. Haraf ◽  
Ezra E.W. Cohen ◽  
Kerstin Stenson ◽  
Mary Ellyn Witt ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Phase I ◽  
Head And Neck ◽  
Neck Cancer ◽  
Poor Prognosis ◽  
Maximum Tolerated Dose ◽  
Late Complications ◽  
Fistula Formation ◽  
Tissue Necrosis ◽  
Dose Escalation Study

PurposeWe conducted a phase I dose escalation study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of bevacizumab, when added to the standard FHX (fluorouracil [FU], hydroxyurea [HU], radiation) chemoradiotherapy platform in poor-prognosis head and neck cancer (HNC) patients.Patients and MethodsPatients with recurrent, previously radiated or poor-prognosis, treatment-naive HNC were eligible. Treatment was repeated every 14 days for seven cycles: Bevacizumab was escalated 2.5 to 10 mg/kg, FU 600 to 800 mg/m2(120 hours continuous infusion), and hydroxyurea from 500 to 1,000 mg (twice daily for 5 days), starting day 1. At the MTD, the cohort was expanded.ResultsForty-three patients were treated. DLT was reached at level 3 (bevacizumab 5 mg/kg, FU 800 mg/m2, HU 1,000 mg) with two grade 3 transaminase elevations and one grade 4 neutropenia, attributed to the combination of chemotherapy with bevacizumab. For level 4, chemotherapy doses were reduced (FU 600 mg/2, HU 500 mg), and bevacizumab escalation continued to 10 mg/kg. Treatment of six assessable patients resulted in one venous thrombosis; this dose level was expanded to 26 patients. Late complications included five patients with fistula formation (11.6%) and four with ulceration/tissue necrosis (9.3%). Serious toxicities (hemorrhage/thrombosis/death) were comparable to prior reirradiation reports. Median overall survival for reirradiated patients with recurrent, nonmetastatic disease was 10.3 months [95% CI, 5.6 to 13.5]; 2-year cumulative incidence of death resulting from disease was 51.7% (95% CI, 31.7 to 68.5).ConclusionBevacizumab can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m2every 2 weeks with decreased chemotherapy doses because of neutropenia. The regimen shows antitumor activity. Observed fistula formation/tissue necrosis may be bevacizumab related, and further investigation should proceed with careful monitoring.

A phase I study of talotrexin (PT-523) in patients with relapsed or refractory non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7142-7142 ◽  
Author(s):  
C. S. Rocha Lima ◽  
S. V. Orlov ◽  
J. Garst ◽  
G. M. Manikhas ◽  
A. Dowlati ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Cell Lines ◽  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Mean Values ◽  
Phase Ii Studies ◽  
Ecog Ps ◽  
Dose Levels

7142 Background: Talotrexin is a nonpolyglutamatable antifolate which has demonstrated improved antitumor activity in a broad spectrum of cancer models by targeting DHFR to inhibit tumor growth. Talotrexin binds more tightly (15-fold, Ki 0.35 pM) to DHFR than methotrexate (MTX). In lung cancer cell lines, talotrexin inhibits tumor cell proliferation at sub- to low nanomolar concentrations and is more potent than MTX in all cell lines tested. We conducted a dose escalation study of talotrexin administered as a 5-minute infusion on Days 1, 8, on a 21-day cycle. The primary objectives of this study are to determine the maximum tolerated dose (MTD), pharmacokinetic (PK) profile, as well as the safety and efficacy. Methods: Patients with confirmed NSCLC stage III/IV or recurrent/refractory disease, failed two-lines of therapy ± an EGFR TK inhibitor, ECOG PS 0–2, were enrolled. The starting dose was based on a Phase I solid tumor trial. Three patients were treated at each dose level in the absence of a dose limiting toxicity (DLT). Intrapatient dose escalation was allowed. All patients received folic acid and vitamin B12. Safety assessments were performed by standard laboratory and clinical DLT definitions. Responses were assessed based on RECIST criteria. Plasma talotrexin concentrations were analyzed by a LC/MS/MS method. Concentration-time profiles of talotrexin were analyzed by noncompartmental methods using WinNonlin. Results: Eighteen heavily pre-treated patients were enrolled and received a total of 61 cycles (median 3.4, range 1–7) of talotrexin at 5 dose levels (27–270 mg/m2/cycle), Male/Female: 14/4. The tentative MTD is 90 mg/m2/dose, with mucositis being the predominate DLT. Two partial responses and 9 stable diseases were observed. Talotrexin exhibits linear PK profile across the 5 dose levels evaluated. PK data (16 patients), Cmax and AUC0-∞ exhibited linear PK. Overall mean values (± SD) were CL, 1.31 ± 0.31 L/hr/m2, T1/2z, 6.5 ± 1.4 h, Vss 8.9 ± 2.5 L/m2. Conclusions: Talotrexin demonstrated acceptable tolerability with encouraging activity in relapsed or refractory NSCLC patients over multiple cycles of therapy. Phase II studies in NSCLC are planned. [Table: see text]

A nomogram based on Psoas muscle index and prognostic nutritional index predicts the prognosis of intrahepatic cholangiocarcinoma after surgery: a multi-center cohort study

2021 ◽  
Author(s):  
Wenming Bao ◽  
Liming Deng ◽  
haitao Yu ◽  
bangjie He ◽  
Zixia Lin ◽  
...  
Keyword(s):  
High Risk ◽  
Intrahepatic Cholangiocarcinoma ◽  
Poor Prognosis ◽  
High Risk Patient ◽  
Malignant Neoplasm ◽  
Psoas Muscle ◽  
Prognostic Nutritional Index ◽  
Nutritional Index ◽  
Risk Patients ◽  
Patient Prognosis

Abstract Background Intrahepatic cholangiocarcinoma (ICC) is a malignant neoplasm with a poor prognosis. Prediction of prognosis is critical for the individualized clinical management of patients with ICC. The purpose of this study is to establish a nomogram based on the psoas muscle index (PMI) and prognostic nutritional index (PNI) to identify the high risk-patient with ICC after curative resection. Methods ICC Patients after hepatectomy in multi-hospital from August 2012 to October 2019 were enrolled. The overall survival (OS) and recurrence-free survival (RFS) rates were analyzed by Kaplan-Meier. The independent factors were identified by univariate and multivariate Cox regression analyses. A nomogram based on independent factors was established to predict ICC patient prognosis. Results 178 ICC patients were included. The OS was worst in the patients with a combination of low PMI combined low PNI (p < 0.01). PMI, PNI, lymph node metastasis and tumor differentiation were the independent prognostic risk factors; these factors were used to establish the nomogram was established by it. The calibration curve revealed that the nomogram survival probability prediction model was in good agreement with the actual observation results. The nomogram has good reliability in predicting ICC patient prognosis (OS C-index = 0.692). The area under the receiver operating characteristic curve (AUC) for the nomogram's 3-year predicted survival was 0.752. Based on the stratified by nomogram, the median survival for low-risk patients was 59.8 months, compared with 16.2 months for high-risk patients (p༜0.001). Conclusion The nomogram based on the PMI and PNI can identify patients with the highest risk of poor prognosis after curative hepatectomy. It is a good decision-making tool for individualized treatment.

scholarly journals Phase I study of tomuzotuximab, a glycoengineered therapeutic antibody against the epidermal growth factor receptor, in patients with advanced carcinomas

ESMO Open ◽  
2018 ◽  
Vol 3 (2) ◽  
pp. e000303 ◽  
Author(s):  
Walter Fiedler ◽  
Sara Cresta ◽  
Henning Schulze-Bergkamen ◽  
Sara De Dosso ◽  
Jens Weidmann ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Phase I ◽  
Dose Escalation ◽  
Antitumour Activity ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Epidermal Growth

BackgroundChanges in glycosylation of the constant domain (Fc) of monoclonal antibodies (mAbs) enhance antibody-dependent cell-mediated cytotoxicity independently of downstream effects following receptor blockade by the antibody, thus extending their indication. We investigated the safety, pharmacokinetics, pharmacodynamics and antitumour activity of tomuzotuximab, an IgG1 glycoengineered mAb against the epidermal growth factor receptor with enhanced tumour cytotoxicity in a phase I dose-escalation study (NTC01222637).Patients and methodsForty-one patients with advanced solid tumours refractory to standard therapies received tomuzotuximab weekly (12–1370 mg) or two-weekly (990 mg) on a three-plus-three dose escalation design.ResultsA maximum tolerated dose was not reached. The most frequent treatment-related adverse events were infusion-related reactions in 31 (76%) patients (grade 3, 12%), mainly confined to the first dose, and skin toxicities (grade 1 or 2) in 30 (73%) patients. Hypomagnesaemia was observed in 9 out of 23 evaluable patients (39%). Similar to cetuximab, tomuzotuximab concentrations increased proportionally to dose from doses≥480 mg with a median terminal half life (t½) of 82 hours, range 55–113 hours. Antitumour activity included one complete response ongoing since more than 4.5 years in a patient with non-small-cell lung cancer and one partial response lasting 353 days in a patient with colorectal cancer. Twelve patients achieved stable disease (median, 166 days, range, 71–414 days) and two patients had prolonged control (>1 year) of their non-measurable disease.ConclusionTomuzotuximab was safe and showed promising antitumour activity in heavily pretreated patients with advanced metastatic disease. A phase IIb trial of chemotherapy and weekly tomuzotuximab or cetuximab followed with maintenance therapy with the corresponding mAb in patients with recurrent or metastatic head and neck squamous cell carcinoma is ongoing.

scholarly journals Pharmacokinetic and Maximum Tolerated Dose Study of Micafungin in Combination with Fluconazole versus Fluconazole Alone for Prophylaxis of Fungal Infections in Adult Patients Undergoing a Bone Marrow or Peripheral Stem Cell Transplant

2005 ◽  
Vol 49 (4) ◽  
pp. 1331-1336 ◽  
Author(s):  
J. Hiemenz ◽  
P. Cagnoni ◽  
D. Simpson ◽  
S. Devine ◽  
N. Chao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cancer Patients ◽  
Fungal Infections ◽  
High Risk Patient ◽  
Maximum Tolerated Dose ◽  
Saline Control ◽  
Control Group ◽  
Cell Transplant ◽  
Dose Escalation Study

ABSTRACT In this dose escalation study, 74 adult cancer patients undergoing bone marrow or peripheral blood stem cell transplantation received fluconazole (400 mg/day) and either normal saline (control) (12 subjects) or micafungin (12.5 to 200 mg/day) (62 subjects) for up to 4 weeks. The maximum tolerated dose (MTD) of micafungin was not reached, based on the development of Southwest Oncology Group criteria for grade 3 toxicity; drug-related toxicities were rare. Commonly occurring adverse events considered related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rash (4.1%), and rash (4.1%). Pharmacokinetic profiles for micafungin on days 1 and 7 were similar. The mean half-life was approximately 13 h, with little variance after repeated or increasing doses. Mean maximum concentrations of the drug in serum and areas under the concentration-time curve from 0 to 24 h were approximately proportional to dose. There was no clinical or kinetic evidence of interaction between micafungin and fluconazole. Five of 12 patients (42%) in the control group and 14 of 62 (23%) in the micafungin-plus-fluconazole groups had a suspected fungal infection during treatment which resulted in empirical treatment with amphotericin B. The combination of micafungin and fluconazole was found to be safe in this high-risk patient population. The MTD of micafungin was not reached even at doses up to 200 mg/day for 4 weeks. The pharmacokinetic profile of micafungin in adult cancer patients with blood or marrow transplants is consistent with the profile in healthy volunteers, and the area under the curve is proportional to dose.

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