scholarly journals Phase I study protocol: NKTR-255 as monotherapy or combined with daratumumab or rituximab in hematologic malignancies

2021 ◽  
Author(s):  
Nina Shah ◽  
Miguel-Angel Perales ◽  
Cameron J Turtle ◽  
Mitchell S Cairo ◽  
Andrew J Cowan ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Multiple Cancer ◽  
Cancer Models ◽  
Anti Cancer ◽  
Recommended Phase Ii Dose ◽  
And Function ◽  
Anti Tumor Activity

NKTR-255 is an investigational polyethylene glycol-modified recombinant human IL-15 (rhIL-15) receptor agonist, designed to improve the immunotherapeutic and anti-cancer benefit observed with rhIL-15 while circumventing the toxicities associated with this therapy. In preclinical studies, NKTR-255 has demonstrated enhanced proliferation and function of CD8+ T cells and natural killer cells, as well as enhanced anti-tumor activity and survival both as monotherapy and in combination with monoclonal antibodies in multiple cancer models. Here, we describe the rationale and design of the first-in-human Phase I, dose-escalation and dose-expansion study of NKTR-255 alone and in combination with daratumumab or rituximab in adults with relapsed/refractory multiple myeloma or non-Hodgkin's lymphoma that will determine the maximum tolerated dose and recommended Phase II dose for NKTR-255.

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 weekly albumin-bound paclitaxel (ab-P) plus weekly cetuximab (Cet) plus intensity-modulated radiation therapy (IMRT) in patients with stage III/IVb head and neck squamous cell carcinoma (HNSCC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6034-6034 ◽  
Author(s):  
Matthew G. Fury ◽  
Eric Jeffrey Sherman ◽  
Shyam S. Rao ◽  
Suzanne L. Wolden ◽  
Stephanie Smith-Marrone ◽  
...  
Keyword(s):  
Oral Cavity ◽  
Phase I ◽  
Phase I Study ◽  
Intensity Modulated Radiation Therapy ◽  
Maximum Tolerated Dose ◽  
Stage Iii ◽  
Unknown Primary ◽  
Neck Node ◽  
Entire Study ◽  
Recommended Phase Ii Dose

6034 Background: There is a clinical need to improve the efficacy of standard Cet + concurrent RT for pts with stage III/IVB HNSCC. Taxanes have potent activity against HNSCC, and ab-P may offer therapeutic advantages in comparison with other drugs of this class. Methods: This was a single institution phase I study with a modified 3 + 3 design. 4 dose levels (DLs) of weekly ab-P were explored (30, 45, 60, and 80 mg/m2) during IMRT. Standard Cet (450 mg/m2 loading dose followed by 250 mg/m2 weekly) concurrent with IMRT (total dose, 70 Gy) was prescribed for all pts. The maximum-tolerated dose (MTD) would be exceeded if >2/6 pts experienced DLTs at a given dose level. NCI CTCAE v.3 was used, and DLT monitoring extended until 2 wks after IMRT. Results: 25 eligible pts (20M, 5F) enrolled, with median age 58 years (range, 46-84) and median KPS 90 (range 80-100). Primary tumor sites were oropharynx, 20 (10 HPV pos, 5 HPV neg, 5 not done); neck node with unknown primary, 2; and larynx, oral cavity, and maxillary sinus, 1 each. Two pts never received ab-P and were deemed inevaluable. At DL 1 (ab-P, 30 mg/m2), there was one DLT (g.4 pneumonia) among 6 pts. At DL2 (ab-P, 45 mg/m2), there were 2 DLTs (g.4 cerebrovascular accident; g.3 decrease in L. ventricle ejection fraction/CHF exacerbation) among 6 pts. At DL3 (ab-P, 60 mg/m2), there was 1 DLT (g.3 supraventricular tachycardia) among 6 pts. MTD was exceeded at DL4 (ab-P, 80 mg/m2) with 3 DLTS (g.3 neuropathy, g.3 dehydration, g.3 anemia) among 5 evaluable pts. For the entire study population, most common ≥ g3 AEs were: lymphopenia 100%, functional mucositis, 56%, and pain in throat/oral cavity, 52%. There were no treatment-related deaths. Among 23 evaluable pts at a median follow up of 29 months, 2y PFS rate is 64% (95% CI: 41-80%) and 2y OS rate is 90% (95% CI: 66-97). Conclusions: The recommended phase II dose is ab-P 60 mg/m2 weekly when given concurrently with IMRT and standard weekly Cet. This regimen merits further study as an alternative to IMRT + Cet alone for pts who require a non-platinum regimen. This study was approved and funded by the NCCN from general research support provided by Celgene, Inc. Clinical trial information: NCT00736619.

Prolonged Low Dose Therapy with a Pan-Deacetylase Inhibtor, Panobinostat (LBH589), in Patients with Myelofibrosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 794-794 ◽  
Author(s):  
John Mascarenhas ◽  
Alice Mercado ◽  
Amelyn Rodriguez ◽  
Min Lu ◽  
Carla Kalvin ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Disease Process ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Deacetylase Inhibitor ◽  
Clinical Responses ◽  
Systemic Symptoms ◽  
Recommended Phase Ii Dose

Abstract Abstract 794FN2 LBH589 is a novel pan-deacetylase inhibitor (DACi) that has demonstrated clinical activity in phase I/II studies in patients with a variety of hematologic malignancies. Our group has previously presented preliminary results of a phase I study of LBH589 in patients with myelofibrosis (MF) (Mascarenhas et al, ASH 2009, a308) while a phase II trial using higher doses of LBH589 has also been reported (DeAngelo et al, ASH 2010,a630). Both studies identified reversible thrombocytopenia as the DLT and reported evidence of clinical responses. The final results of our phase I study and the effects of extended treatment with LBH589 are reported here. We enrolled 18 patients at 3 dose levels. Fifty-five percent of these patients had PMF, 28% Post-PV MF and 17% Post ET MF; all were intermediate/high risk based on Lille classification. Twenty-five mg PO TIW was determined to be the recommended phase II dose. All patients experienced resolution of their systemic symptoms and 10/11 patients with baseline palpable splenomegaly, who were evaluable after 1 month of therapy, had a median reduction of 30%, range 0–100%. Five patients entered into an extension phase of the trial and received > 6 months of therapy with a mean dose of 20mg PO TIW at time of optimal response (Table 1). Of these patients, 2 were initially enrolled in the 20 mg PO TIW cohort, 1 in the 30 mg PO TIW cohort and 2 in the 25 mg PO TIW cohort. Both patients at the lowest dose achieved clinical improvement (CI) by IWG-MRT response criteria at 6 months as did one patient at the 25 mg dose. The remaining 2 patients had SD at 30 and 25 mg. A mean reduction in palpable splenomegaly at 3 and 6 months of 55% and 83%, respectively, was observed in this group. Two of these patients had marked and durable improvement in anemia (patients 1 and 4). Patient 4 achieved a near CR at 16 months with resolution of palpable splenomegaly, elimination of peripheral blood dacrocytes and leukoerythroblastosis, a 4g/dL increase in hemoglobin, improvement in overall marrow cellularity and megakaryocyte atypia with an increase in erythroid precursors and a significant reduction of reticulin/collagen fibrosis. Patient 1 was heavily transfusion dependent requiring RBC transfusions weekly to maintain a mean hemoglobin of 6.5g/dL and after 6 months on LBH589 achieved >50% reduction in transfusion dependence maintaining a mean hemoglobin of 9g/dL. Patient 2 had resolution of palpable splenomegaly and leukoerythroblastosis by cycle 6 and the bone marrow at cycle 26 was characterized by a reduction in marrow fibrosis from grade 4 to 1. A phase II study is ongoing, 14 patients are currently enrolled, with a planned goal of 22 patients. Pharmacokinetic and pharmacodynamic studies as well as cytokine profiling of the phase I patients are being analyzed and will be presented at the meeting. We conclude that low doses of LBH589 delivered for greater than 6 months in patients with MF are capable of ameliorating symptoms, improving clinical features and reversing pathologic marrow changes. Disclosures: Off Label Use: Oral histone deacetylase inhibitor that targets epigenetic changes in malignant myelofibrosis cells with an goal to modify the disease process.

Open-label, multicenter, phase I study to assess safety and tolerability of adavosertib plus durvalumab in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2562-2562 ◽  
Author(s):  
Manish R. Patel ◽  
Gerald Steven Falchook ◽  
Judy Sing-Zan Wang ◽  
Esteban Rodrigo Imedio ◽  
Sanjeev Kumar ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Human Monoclonal Antibody ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Drug Induced ◽  
Recommended Phase Ii Dose

2562 Background: Adavosertib (AZD1775; A) is a highly selective inhibitor of WEE1. This Phase I study (NCT02617277) investigated a range of doses and schedules for oral A plus IV durvalumab (DV), a human monoclonal antibody targeting PD-L1, to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors. Methods: Four 28-day schedules (Sch) were evaluated with pts receiving DV 1500 mg on day (d) 1 of each schedule (Table). Patients continued treatment if they showed clinical benefit in the absence of any discontinuation criteria. Pts received A monotherapy for PK analysis prior to the start of combination therapy in Sch B, C (d –7 to –5) and D (d –9 to –5). MTD was determined using a 3+3 dose-escalation cohort design. Predefined dose-limiting toxicities (DLTs) were evaluated during the first cycle of study treatment. Results: 54 pts received A (most common primary tumor sites: colon, 19%; lung, 13%; breast, 11%). The most common grade ≥3 AEs were fatigue (15%), diarrhea (11%) and nausea (9%). DLTs were nausea (n = 2) and diarrhea (n = 1). 7 pts (13%) had A-related SAEs, including reversible and confounded drug-induced liver injury (Sch B 125 mg and Sch C; 1 each). Disease control rate (DCR) for the total cohort was 36%. Preliminary PK at 150 mg BID suggests adequate coverage for cell kill activity and no drug–drug interaction. Conclusions: The MTD/RP2D was A 150 mg BID (3 d on, 4 d off; treatment d 15–17, 22–24) with DV 1500 mg (d 1 Q4W); safety profile was considered acceptable. Preliminary evidence of antitumor activity was observed. Clinical trial information: NCT02617277. [Table: see text]

scholarly journals Phase I study of intraperitoneal bevacizumab for treating refractory malignant ascites

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052098666
Author(s):  
Furong Kou ◽  
Jifang Gong ◽  
Yan Li ◽  
Jian Li ◽  
Xiaotian Zhang ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Total Duration ◽  
Abdominal Distension ◽  
Malignant Ascites ◽  
Maximum Tolerated Dose ◽  
Duration Of Treatment ◽  
Grade 3 ◽  
Anti Tumor Activity

ObjectiveThis prospective, dose-escalation phase I study evaluated the safety and efficacy of intraperitoneal bevacizumab in managing refractory malignant ascites and explored the recommended dose of bevacizumab for further study.MethodsPatients with refractory malignant ascites were enrolled. Bevacizumab was intraperitoneal administered weekly at an initial dose of 2.5 mg/kg, with dose escalation to 5 and 7.5 mg/kg performed following the standard “3 + 3” rule. The total duration of treatment was 2 or 3 weeks.ResultsBetween December 2013 and September 2014, 13 patients (2.5 mg/kg, n = 4; 5 mg/kg, n = 3; 7.5 mg/kg, n = 6) with refractory malignant ascites were enrolled. Bevacizumab was well tolerated, and the most common treatment-related adverse events were abdominal pain (5/13), abdominal distension (2/13), and fatigue (2/13). The dose-limiting toxicity at 7.5 mg/kg was grade 3 bowel obstruction (1/13). The maximum tolerated dose (MTD) was not reached. The overall response and disease control rates were 7.7 and 61.5%, respectively.ConclusionsIntraperitoneal bevacizumab safe and well tolerated for treating malignant ascites, and the MTD was not reached at doses of 2.5 to 7.5 mg/kg. Intraperitoneal bevacizumab at 7.5 mg/kg weekly is recommended for further study to verify its anti-tumor activity. Trial registration: Clinical Trials NCT01852409.

Phase I study to determine tolerability and pharmacokinetics (PK) of SB-743921, a novel kinesin spindle protein (KSP) inhibitor

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2000-2000 ◽  
Author(s):  
K. D. Holen ◽  
C. P. Belani ◽  
G. Wilding ◽  
S. Ramalingam ◽  
J. L. Heideman ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Tumor Regression ◽  
Human Tumor ◽  
Maximum Tolerated Dose ◽  
Potent Inhibition ◽  
Elevated Bilirubin ◽  
Recommended Phase Ii Dose ◽  
Tumor Types

2000 Background: SB-743921, a potent and selective inhibitor of KSP (Ki =100 pM; >40,000-fold selectivity vs other kinesins), causes mitotic arrest, potent inhibition of tumor cell proliferation, and demonstrates activity in a broad range of human tumor xenografts. Methods: A phase I study was conducted to determine the maximum tolerated dose (MTD) and PK profile of SB-743921 when administered IV over 60 minutes every 21 (Q 21) days (d). Results: 44 patients (pts) (M/F 19/25), median age 61.5 yrs (range 32–80, with solid tumors were treated at doses of 2 (n=2), 4 (n=27), 5 (n=6), 6 (n=3), and 8 (n=6) mg/m2 (median cycles 2, range 1–10, total cycles 101). Frequent tumor types included colorectal (n=11), ovarian (n=5), NSCLC (n=5), esophageal (n=4), and pancreatic (n=4). Dose-limiting toxicities (DLTs) at 8 mg/m2 consisted of (max CTC grade/pt) prolonged grade (gr) 4 neutropenia (n=2), gr 3 elevated ALT/AST (n=1), and gr 3 elevated bilirubin (n=1). DLTs at 6 mg/m2 were gr 3 hyponatremia (n=1) and prolonged gr 4 neutropenia (n=1). DLTs at 5 mg/m2 were limited to febrile neutropenia (n=2). The 4 mg/m2 dose level was determined as the phase II dose. Toxicities at 4 mg/m2 included gr 1 fatigue (n=8) and neutropenia [gr 1 (n=4), gr 2 (n=7), gr 3 (n=3), gr 4 (n=2)]. Neutropenia nadir was day 6–8 with recovery to gr ≤2 by day 15. Gr 3 non-hematologic toxicities at 4 mg/m2 included gr 3 ALT (n=1), gr 3 AST (n=2), gr 3 hyperbilirubinemia (n=1), gr 3 hypophosphatemia (n=1), and gr 3 alkaline phosphatase elevation (n=1). Median PK values in cycle 1 at 4 mg/m2 were: Cmax 473 ng/ml, AUC0-∞ 5207 ng.hr/ml, and t½ 36 hr. AUC0-∞ and Cmax were proportional to dose. No consistent correlation was observed between DLTs and PK parameters. Stable disease for ≥ 4 cycles (range 4–11) was observed in 6 pts (4 pts at 4 mg/m2; 1 pt at 6 mg/m2; 1 pt at 8 mg/m2). A pt with cholangiocarcinoma had evidence of radiographic tumor regression (post cycle 10) and a >50% decrease in her CA 19–9. Conclusions: The recommended phase II dose of SB-743921 on the Q 21 day schedule is 4 mg/m2. The observed toxicities at the recommended phase II dose are manageable and reversible. The onset and duration of neutropenia is predictable. [Table: see text]

Phase I study of LY573636-sodium, an acylsulfonamide anti-cancer compound with a novel mechanism of action, administered as 2-hour IV infusion in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2515-2515 ◽  
Author(s):  
R. L. Ilaria ◽  
G. R. Simon ◽  
M. Sovak ◽  
M. K. Burton ◽  
A. L. Cleverly ◽  
...  
Keyword(s):  
Phase I ◽  
Mechanism Of Action ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Lean Body Weight ◽  
Flat Dose ◽  
Elimination Half ◽  
Anti Cancer ◽  
Grade 3

2515 Background: LY573636 -sodium (hereafter referred to as LY573636 ) is a novel anti-cancer compound that induces apoptosis by a mitochondrial-mediated mechanism. Methods: A phase I study was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of LY573636 administered as an intravenous infusion over 2 hours every 21 days. Results: 53 patients (pts) were enrolled on study, 16 males, 37 females, with a median age of 58 (range: 18–83). LY573636 was dose-escalated using a flat dosing paradigm in the first 34 patients (range 100 mg to 2400 mg). PK analysis of this cohort revealed that LY573636 had a low total plasma clearance (CL = 0.02L/hr) and terminal elimination half-life of approximately 340 hours due to high-albumin binding (∼99%). The dose limiting toxicity (DLT) for the flat dose escalation was bone marrow (BM) suppression, which included CTC (ver2) grade 3/4 thrombocytopenia/neutropenia. In some patients, significant BM suppression occurred in cycle 2 and later, attributed to the accumulation of albumin-bound drug with repeated flat dosing. Based on these findings, the dose-finding strategy was modified to an idealized dosing paradigm which calculated LY573636 doses based on pt lean body weight, and used a loading/maintenance dose regimen to achieve a specific Cmax target value. All 3 pts in the first 400 μg/mL Cmax cohort completed at least 2 cycles and no DLTs were reported. Of the 16 pts enrolled to the 420 μg/mL targeted dose group: 1 pt reported a DLT, a transient grade 3 elevation of ALT/AST which did not recur in subsequent cycles; 8/16 pts received 4 or more cycles prior to disease progression and 2 remain on treatment. Overall, 23/53 pts had stable disease (SD) after 2 or more cycles. Seven pts received >8 cycles (SD > 6 mos), including heavily pre-treated pts with ovarian cancer, non-small cell lung cancer, soft tissue sarcoma, and thymoma. Conclusions: LY573636 is a novel anti-cancer compound with a unique mechanism of action. The most common DLT was BM suppression. The individualized, target Cmax dose of 420 μg/mL has been taken forward into phase II clinical trials. No significant financial relationships to disclose.

Phase I study of LY573636-sodium, an acylsulfonamide anti-cancer compound with a novel mechanism of action, administered as 24-hour continuous infusion in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2542-2542 ◽  
Author(s):  
C. A. Slapak ◽  
P. M. LoRusso ◽  
D. Mendelson ◽  
A. K. Sykes ◽  
D. P. De Alwis ◽  
...  
Keyword(s):  
Phase I ◽  
Mechanism Of Action ◽  
Half Life ◽  
Phase I Study ◽  
Uterine Cancer ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Flat Dose ◽  
Anti Cancer ◽  
Dosing Strategy

2542 Background: LY573636 -sodium (hereafter referred to as LY573636 ) is a novel anti-cancer compound that induces apoptosis by a mitochondrial-mediated mechanism. Methods: A phase I study was conducted to determine the maximum tolerated dose and pharmacokinetic (PK) profile of LY573636 administered as a 24-hour continuous intravenous (IV) infusion every 28 days. Results: 26 patients (pts) were enrolled on study, 12 males and 14 females, with a median age of 57 (range: 41–74). LY573636 was dose-escalated using a flat dosing-based schema. No dose limiting toxicity (DLT) was observed until the 2,000 mg cohort, when 1 pt developed CTCAE grade 3 hyperbilirubinemia. PK analysis revealed that LY573636 had a low total plasma clearance (CL = 0.02L/hr) and a terminal elimination half-life of approximately 340 hours due to high-albumin binding (∼99%). One additional pt in the 2,000 mg flat dose cohort developed grade 4 thrombocytopenia in cycle 2, possibly due to the accumulation of albumin-bound drug. Based on these PK and clinical data, the dosing strategy was revised to a flat loading/maintenance dose regimen of 2,500 mg/1,750 mg every 28 days by 24-hour continuous IV infusion. Thirteen pts were treated at this dose level, with 1 pt experiencing a DLT of grade 4 leukopenia. Overall, 8/26 pts had stable disease (SD) after 2 or more cycles, with 2 pts still on study. Five pts received ≥ 4 cycles (SD ≥ 4 mos), including heavily pre-treated pts with ovarian cancer, soft tissue sarcoma, and uterine cancer. Conclusions: LY573636 is a novel anti-cancer compound with a unique mechanism of action. The most common DLT was BM suppression. Because of the long half-life of LY573636 , and the encouraging findings of a separate IV bolus phase 1 study, an IV bolus-based regimen will be taken forward into phase 2 study. No significant financial relationships to disclose.

Phase I study of vinorelbine, cisplatin, and concomitant thoracic radiation in the treatment of advanced chest malignancies.

1998 ◽  
Vol 16 (6) ◽  
pp. 2157-2163 ◽  
Author(s):  
G A Masters ◽  
D J Haraf ◽  
P C Hoffman ◽  
L C Drinkard ◽  
S A Krauss ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Concurrent Chemotherapy ◽  
Unresectable Stage ◽  
Thoracic Radiation ◽  
Recommended Phase Ii Dose ◽  
Group B ◽  
Dose Levels

PURPOSE The cisplatin-vinorelbine regimen has superior activity in advanced non-small-cell lung cancer (NSCLC). We conducted a phase I trial to identify the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of this regimen with concomitant thoracic radiation (RT) in patients with advanced chest malignancies. PATIENTS AND METHODS Patients with advanced chest malignancies that required RT were enrolled onto this phase I study of standard chest radiation (30 daily 2-Gy fractions for a total of 60 Gy) and concurrent chemotherapy with cisplatin starting at 100 mg/m2 every 3 weeks and vinorelbine starting at 20 mg/m2/wk. RESULTS Thirty-seven patients were treated on this study. Two of three patients treated at the maximum-administered dose of cisplatin 100 mg/m2 per cycle and vinorelbine 25 mg/m2/wk experienced acute DLT (neutropenia), which required deescalation. The dose level of cisplatin 100 mg/m2 and vinorelbine 20 mg/m2/wk, although tolerated acutely, produced delayed esophagitis, which proved dose-limiting. The recommended phase II dose was cisplatin 80 mg/m2 every 3 weeks and vinorelbine 15 mg/m2 given 2 of every 3 weeks with concomitant chest RT. CONCLUSION Concomitant chemoradiotherapy with cisplatin and vinorelbine is feasible. The recommended phase II dose is cisplatin 80 mg/m2 every 3 weeks with vinorelbine 15 mg/m2 given twice over 3 weeks on a day 1/day 8 schedule. Esophagitis is the DLT, with neutropenia occurring at higher dose levels. A Cancer and Leukemia Group B (CALGB) phase II trial is currently underway to evaluate further the efficacy and toxicities of this regimen in unresectable stage III NSCLC.

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