Biomodulation of capecitabine by weekly paclitaxel and carboplatin in patients with advanced solid tumor malignancies: A dose-escalating phase I study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2569-2569
Author(s):  
M. B. Lustberg ◽  
J. Nuovo ◽  
J. P. Thomas ◽  
P. J. Monk ◽  
S. Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Dihydropyrimidine Dehydrogenase ◽  
Weekly Paclitaxel ◽  
Unknown Primary ◽  
Cancer Tissue ◽  
Phase Ii Trials ◽  
Two Phase ◽  
Phase Ii Studies

2569 Background: A principal determinant of the therapeutic index with capecitabine-based treatment is the grade of thymidine phosphorylase (TP) activity in malignant tissue. The beneficial interactions of paclitaxel and carboplatin in upregulation of TP promise to make capecitabine more tumor specific and to provide the expected synergy. On the basis of the time-dependency and transiency for this upregulation we performed a phase I study of capecitabine in combination with weekly paclitaxel and carboplatin (CTX). Methods: Patients with advanced solid tumors received carboplatin on day 1, paclitaxel on days 1, 8, 15 and capecitabine orally twice a day on days 8–21, every 4 weeks. There were 5 planned dose levels (DL 1–5). Paclitaxel was escalated from 60 mg/m2 to 80 mg/m2 (DL 4) then 100 mg/m2 (DL 5). Capecitabine from 500 mg/m2 bid to 750 mg/2 bid (DL 2) then 1000 mg/m2 bid (DL 3–5). Carboplatin dose was fixed at AUC 6. Paraffin-embedded tissue was evaluated for expression of TP, thymidylate synthase and dihydropyrimidine dehydrogenase by immunohistochemistry. Results: 32 patients from Ohio State University (OSU) were enrolled. 84% had prior therapy. The most common grade 3/4 toxicities were neutropenia (59%), leukopenia (56%), and fatigue (16%). DLTs included neutropenic fever (1), prolonged neutropenia or thrombocytopenia (2) and diarrhea (1). The MTD was at DL 2. There were 10 confirmed responses [4 CR (esophagus, stomach, unknown primary and ampullary); 6 PRs (Pancreas (3), unknown primary, anal and esophagus] and stabilization of disease > 3 months in 12 patients. In normal tissue, there was no difference in expression levels of both TS and TP. On the other hand, in cancer tissue, TP levels seem to correlate with response whereas TS did not. Conclusions: CTX demonstrates acceptable tolerability. The recommended doses for phase II studies are capecitabine 750 mg/m2 bid, paclitaxel 60 mg/m2/week and carboplatin AUC=6. The acceptable toxicity profile in this dose schedule, and the promising antitumor activity observed warrant further evaluation of this regimen. Two phase II trials are already underway at OSU using this regimen for patients with pancreatic cancer and adenocarcinomas of unknown primary, the latter already actively enrolling patients. Pretreatment tumoral TP levels may help predict patients that are more likely to respond to CTX. Correlation of IHC data with responses will be presented at the meeting. [Table: see text]

Combination of Oxaliplatin Plus Irinotecan in Patients With Gastrointestinal Tumors: Results of Two Independent Phase I Studies With Pharmacokinetics

1999 ◽  
Vol 17 (6) ◽  
pp. 1751-1751 ◽  
Author(s):  
Ernesto Wasserman ◽  
Caroline Cuvier ◽  
François Lokiec ◽  
François Goldwasser ◽  
Salima Kalla ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Two Phase ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Minute Period ◽  
Grade 3 ◽  
Febrile Episodes

PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of ≤2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m2 for oxaliplatin and 150 to 250 mg/m2 for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m2 plus irinotecan 200 mg/m2 in one study and oxaliplatin 110 mg/m2 plus irinotecan 250 mg/m2 in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2. At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU–resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

Bleeding Diathesis in Patients (pts) with Chronic Myelogenous Leukemia Receiving Dasatinib Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2958-2958 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Farhad Ravandi ◽  
Jan Burger ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Phase I ◽  
Median Time ◽  
Phase Ii ◽  
Phase I Study ◽  
Vaginal Bleeding ◽  
Myelogenous Leukemia ◽  
Bleeding Diathesis ◽  
Gingival Bleeding ◽  
Phase Ii Studies ◽  
Bleeding Episodes

Abstract Dasatinib (Sprycel®, Bristol-Myers Squibb) is an oral potent ATP-competitive multikinase inhibitor active against BCR-ABL and SRC family kinases (SFKs). Dasatinib is approximately 300-fold more potent than imatinib against BCR-ABL and is active against a wide array of imatinib-resistant BCR-ABL kinase mutants at clinically achievable concentrations. Dasatinib has demonstrated high efficacy and safety in patients (pts) with chronic myelogenous leukemia (CML). The most frequent non-hematologic side effects associated with dasatinib therapy are gastrointestinal, rash, and fluid retention syndromes. In addition, dasatinib therapy may be associated with increased risk of bleeding in some pts. We evaluated the incidence of bleeding episodes associated with dasatinib therapy among 138 consecutive pts (69 female) with CML treated at our institution between November 2003 and January 2006 after failure or resistance to imatinib. The median age for the entire cohort was 57 years (range, 15 to 81 years). Among 50 pts treated in the phase I study, 23 (46%) were in chronic (CP), 7 (14%) in accelerated (AP), and 20 (40%) in blastic phase (BP) at the time of dasatinib start, whereas 88 pts, 43 (49%) in CP, 25 (28%) in AP, and 20 (23%) in BP, received dasatinib in phase II studies. Fifteen (11%) pts started dasatinib at a dose <100 mg, 22 (16%) at 100 mg, 92 (67%) at 140 mg, and 9 (6%) at >140 mg daily. The median time on dasatinib therapy for the study group was 42 weeks (range, 4–120): 69 weeks (range, 18–120) for pts in the phase I study and 34 weeks (range, 4–61) for those in phase II studies. Thirty-seven bleeding episodes occurred in 32 (23%) pts, 11 (22%) treated in the phase I study and 21 (24%) in the phase II studies. Seven (5%) pts had grade 1, 16 (12%) grade 2, and 9 (7%) grade 3 bleeding. No grade 4–5 bleeding episodes were observed. The median time to development of bleeding was 6 weeks (range, 0.5–38), occurring within the first 3 months of therapy in 22 (69%) pts. Most bleeding episodes occurred in the gastrointestinal tract (81%) (lower gastrointestinal bleed [LGIB; n=22]; upper gastrointestinal bleeding [UGIB; n=8]. Other bleeding types included: gingival (n=4), vaginal (n=2), and epistaxis (n=1). Six (19%) pts experienced >1 concomitant bleeding type: 4 with LGIB and UGIB, 1 with LGIB, gingival bleeding, and scalp hematoma, and 1 with gingival and vaginal bleeding. In addition, 12 (37%) pts (5 CP, 2 AP, and 5 BP) had recurrent bleeding episodes: 8 LGIB (in 2 separate occasions in 3 of them), 1 UGIB, 2 gingival bleeding, and 1 vaginal bleed. Bleeding led to transient dasatinib interruptions in 15 (47%) pts, 8 with LGIB (2 of them also with UGIB), 6 with UGIB (2 of them also with LGIB), 2 with gingival bleeding, and 1 with vaginal bleeding. Bleeding episodes were observed in 12% of pts treated in CP, 31% in AP, and 35% in BP (p=0.02) and were more frequent among pts treated at daily doses ≥140 mg compared to those treated at ≤100 mg (84% vs 16%; p=0.001). Fifty-one percent of bleeding episodes were observed in pts with platelet counts ≥30×109/L, including 37% in pts with platelet counts >100×109/L. Basic coagulation studies (PT, aPTT, fibrinogen, D-Dimer) were normal in all but 1 BP patient. In conclusion, bleeding diathesis is a relatively frequent complication of dasatinib therapy, particularly among pts with advanced CML receiving dasatinib ≥140 mg. Early identification, transient dasatinib interruption, and dasatinib dose reduction are required to adequately manage pts with this complication.

Phase I study of imatinib in combination with gemcitabine and capecitabine

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13523-e13523
Author(s):  
R. C. Ramaekers ◽  
J. Elkahwaji ◽  
E. Reed ◽  
A. Ganti ◽  
J. Wang ◽  
...  
Keyword(s):  
Phase I ◽  
Stable Disease ◽  
Renal Cell ◽  
Phase I Study ◽  
Growth Factor Receptor ◽  
Dose Schedule ◽  
Unknown Primary ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Tumor Types

e13523 Background: Imatinib-mediated inhibition of platelet-derived growth factor receptor lowers tumor interstitial pressure allowing for improved intratumoral antineoplastic drug concentration. A phase I study of imatinib (Im) with the synergistic combination of gemcitabine (Gem) and capecitabine (Cape) was undertaken. Methods: Eligibility requirements included refractory solid tumors, ECOG 0/1 and adequate organ function. A 3-week treatment cycle was used with the dose levels (DL) 0 and -1 as outlined in the table. Dose limiting toxicity (DLT) was defined as occurring within the first 2 cycles of therapy. Patients remained on therapy unless DLT occurred or disease progression. Results: Twelve patients with a median age of 59.5 (range 44 - 77) were evaluable. Baseline characteristics included ECOG PS 0/1: 6/6; prior systemic therapies: median 3 (range 1–6); tumor types: renal (4), melanoma (2), prostate, esophageal, pancreatic, small cell lung, breast, unknown primary. At DL 0, 2 of 6 patients experienced DLT (gr. 3 thrombocytopenia; gr. 4 leucopenia). At DL -1, 1 of 6 patients experienced DLT (gr. 3 thrombocytopenia). No patient missed a dose; one patient in DL -1 completed only 1 cycle. Median cycles administered was 2 (range, 1 - 19). At cycle 2 evaluation, 7 pts had stable disease, 4 had progressive disease and 1 was not evaluable. Grade 3 or 4 toxicity included thrombocytopenia, leucopenia, hyperglycemia and weakness. All hematologic grade 3/4 toxicity was seen in patients having received ≥3 cytotoxic regimens previously. Most common grade 1/2 toxicities included anemia, nausea/emesis and fatigue. One patient with renal cell had stable disease (SD) for 15 cycles and one patient with melanoma had SD for 19 cycles. Conclusions: Im in combination with Gem and Cape is well tolerated in patients without extensive exposure to cytotoxic therapy. Activity is seen in various tumor types particularly melanoma and renal cell. The suggested dose for phase II studies is Im 400 mg/d, Gem 400 mg/m2 and Cape 400 mg/m2 in the dose schedule as described above. [Table: see text] [Table: see text]

Phase I study of c-Met inhibitor ARQ197 in combination with FOLFOX for the treatment of patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2544-2544
Author(s):  
Suzanne Fields Jones ◽  
Carla Kurkjian ◽  
Manish R. Patel ◽  
Jeffrey R. Infante ◽  
Howard A. Burris ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Stable Disease ◽  
Phase I Study ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Unknown Primary ◽  
Advanced Solid Tumors ◽  
Grade 3

2544 Background: C-Met protein is a receptor tyrosine kinase which is overexpressed or mutated in a variety of tumor types, causing cell proliferation, metastasis, and angiogenesis. Tivantinib is an orally bioavailable small molecule which binds to the c-Met protein. This phase I study was designed to determine the maximum tolerated dose (MTD) of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors. Methods: Patients with advanced solid tumors for which FOLFOX (5-FU IV 400 mg/m2 day 1; 5-FU CIV 2400 mg/m2 day 1; Leucovorin IV 400 mg/m2 day 1; Oxaliplatin IV 85 mg/m2 day 1) would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design. Dose-limiting toxicities (DLTs), non-dose-limiting toxicities (NDLTs), safety, and preliminary efficacy were evaluated. Results: Fourteen patients (50% colorectal) were treated across 3 dose levels: 120 mg (n=3); 240 mg (n=5); 360 mg (n=6). No DLTs were observed until the 3rd dose level (treatment delay ≥3 days, secondary to grade 3 neutropenia). Common related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (36%; 0%), neutropenia (0%; 29%), nausea (14%; 14%), vomiting (14%; 14%), dehydration (14%; 7%), and thrombocytopenia (14%; 0%). To date, 7 patients have been evaluated for response including 4 (57%) with stable disease evident at the 8-week evaluation (CRC, 2 patients; unknown primary favoring CRC, 1 patient; esophageal, 1 patient) and 3 (21%) with disease progression. The 4 patients with stable disease are continuing on treatment; three (CRC and unknown primary) had received prior FOLFOX. Conclusions: The addition of tivantinib to standard therapy FOLFOX appears tolerated up to its recommended phase II monotherapy dose of 360 mg. Preliminary efficacy is encouraging, and a phase II study is proceeding with this regimen for the first line treatment of advanced gastroesophageal patients. Clinical trial information: NCT01611857.

Impact of gender on multikinase inhibitors (MKIs) toxicity in patients (pts) with advanced pancreatic and gastrointestinal neuroendocrine tumors (NETs): A pooled analysis of two phase II trials with pazopanib and lenvatinib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4109-4109
Author(s):  
Jorge Hernando-Cubero ◽  
Enrique Grande ◽  
Daniel E. Castellano ◽  
Toni Ibrahim ◽  
Nicola Fazio ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Phase Ii ◽  
Liver Toxicity ◽  
Task Force ◽  
Pooled Analysis ◽  
Phase Ii Trials ◽  
Open Label ◽  
Two Phase ◽  
Phase Ii Studies ◽  
Grade 3

4109 Background: Retrospective data in some cancer types suggested a possible different toxicity profile with chemotherapy and targeted therapies according to gender. However, data from prospective studies are still very limited, especially in infrequent tumors such as NETs. Methods: Pts with advanced pancreatic and gastrointestinal NETs treated with pazopanib or lenvatinib in the multicenter open-label phase II studies PAZONET and TALENT respectively, were included in the analysis. Both studies were performed by Spanish Task Force Group for Neuroendocrine Tumors (GETNE). All toxicity grades with an incidence higher than 5% were considered for univariate review. Additionally, all grade 3-4 toxicities were analyzed separately. Results: 155 pts (47.7% female) with 1213 adverse events (AEs) (20% G3-4) divided in 121 categories were included. In female patients, liver toxicity, headache, pyrexia, nausea/vomiting, hair/skin disorders and dizziness were significantly more common (table). The only toxicity with higher incidence in men was dysphonia (OR 0.42, 95% CI 0.2-0.9, p 0.02). There were no gender differences in grade 3-4 toxicities. Conclusions: We observed significant differences in toxicity AEs by gender in two prospective phase II studies with MKIs in NETs patients. Potential different approach to manage toxicity may be adopted based on gender. [Table: see text]

Stage III non small lung cancer (NSCLC): Docetaxel (D), gemcitabine (G), and cisplatin (C) as induction chemotherapy, an Italian phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18201-18201
Author(s):  
S. De Santis ◽  
V. Donato ◽  
M. R. Migliorino ◽  
B. Tedesco ◽  
S. Condo ◽  
...  
Keyword(s):  
Phase I ◽  
Induction Chemotherapy ◽  
Phase Ii ◽  
Phase I Study ◽  
Objective Response ◽  
Stage Iii ◽  
Stage Iiia ◽  
Phase Ii Studies ◽  
Stage Iii Nsclc ◽  
Grade 3

18201 Background: Based on the several clinical trials, combined modality therapy became the standard of care for patients with stage III NSCLC “unresectable” with good performance status (Kathy S. Albain, Educational Book ASCO 2006, 453–461; Thomas E. Stinchcombe, Oncologist 2006, 11, 809–823). The most effective induction chemotherapy has yet to be determined. The objective of this prospective phase I study was to define the maximum tolerated dose (MTD), and to evaluate the activity and safety of one of the third generation triplets as a full dose neoadjuvant regimen in patients (pts) with unresectable Stage III NSCLC. Methods: In this study, chemotherapy-naïve pts with stage IIIA-N2 bulky and IIIB (except malignant pleural effusion) NSCLC were eligible. Inclusion into the trial and treatment decisions were done by multidisciplinary panel involving surgeons, medical oncologists and radiotherapists. All drugs were given intravenously on days 1 and 8, and repeated every 3 weeks up to 2 cycles followed by concurrent chemoradiation. D (30–35 mg/m2) was given first, followed by C (35 mg/m2) and G (1000 mg/m2). Results: From Jan ‘06 to Jul ‘06 twelve eligible pts were enrolled, 10/2 m/f gender; median age 63 (50–72), 1 patient with ECOG PS 0, 11 pts with PS 1; 5 pts with stage IIIA-N2 bulky, 7 pts with stage IIIB NSCLC; nine pts were smokers. All pts were evaluable for toxicity. Toxicity grade 3–4 by CTC criteria was: grade 3 neutropenia in 2/3 patients and grade 3 thrombocytopenia in 1/3 patients on the second dose level of chemotherapy (i.e. docetaxel 35 mg/m2), and was considered dose-limiting. Of 9 pts treated at the MTD (i.e. docetaxel 30 mg/m2), only 1 patient developed grade 4 neutropenia and 1 patient grade 3 thrombocytopenia; 3 patients (30%) had grade 2 neutropenia and grade 2 stomatitis. Of 12 evaluable pts for response, after induction chemotherapy eighty-three percent of patients (9/12 pts) had an objective response and 16,6% (2/9 pts) stable disease. Phase II is continuing for larger patient accrual. Conclusions: The recommended doses for further phase II studies are D (30 mg/m2) followed by C (35 mg/m2) and G (1000 mg/m2) every 3 weeks. This regimen is well tolerated and effective, and appears to be an excellent choice for stage III NSCLC. No significant financial relationships to disclose.

Phase II Trials of Clofarabine in Relapsed or Refractory Pediatric Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 684-684 ◽  
Author(s):  
Sima Jeha ◽  
Bassem I. Razzouk ◽  
Michael E. Rytting ◽  
Paul S. Gaynon ◽  
Richard Kadota ◽  
...  
Keyword(s):  
Median Survival ◽  
Phase Ii ◽  
Median Duration ◽  
Single Agent ◽  
Median Number ◽  
Phase Ii Trials ◽  
Open Label ◽  
Two Phase ◽  
Pediatric Leukemia ◽  
Phase Ii Studies

Abstract Background: Clofarabine, a next generation nucleoside analogue, was well tolerated and demonstrated activity in adult and pediatric Phase I trials conducted in heavily pretreated leukemia patients. Multicenter Phase II studies in pediatric leukemia have completed accrual in the US and are reported here. Methods: Two Phase 2, multicenter, open-label studies were conducted with clofarabine in children with refractory or relapsed ALL or AML. Clofarabine was administered intravenously over 2 hours at 52 mg/m2/day for 5 consecutive days. Cycles were repeated every 2 to 6 weeks based on response and toxicity. Results: The studies enrolled 100 patients (60 ALL and 40 AML). Currently, data are available for 84 patients (49 ALL, 35 AML). Median age is 12 years (range 1 to 22 years) and median number of prior regimens is 3 (range 1 to 6). Thirty-nine percent had received prior bone marrow transplant (BMT). As determined by independent review, preliminary data indicate overall response rates of 31% in ALL (6 CR, 4 CRp, and 5 PR) and 26% in AML (1 CRp and 8 PR). Median duration of remission for ALL is 9.7 weeks (range 1.0 to 28.6) and for AML is 16.2 weeks (range 1.7 to 56.6+). Thirteen of 24 responding patients (54%) proceeded to BMT. Median survival was 42 weeks (range 7.0 to 63.1+) for responding ALL patients (CR+CRp+PR) and 39 weeks (range 7.7 to 93.6+) for responding AML patients (CRp+PR). Patients who failed treatment or were non-evaluable had shorter median survival; 7.4 weeks (range 0.9 to 40.1+) and 12.4 weeks (range 1.6 to 84.9+) for ALL and AML, respectively. Among the patients who were refractory to the last prior chemotherapy, 7/30 (23%) with ALL and 4/22 (18%) with AML achieved a response with clofarabine. Median duration of remission in these patients is 4.6 weeks (range 2.3 to 24.4+) for ALL and 20 weeks (range 1.7 to 56.6+) for AML. Most drug-related adverse events were transient including febrile neutropenia, diarrhea, nausea/vomiting, fever, skin rash, headache, elevation in liver enzymes and bilirubin, and infusion-related flushing and anxiety. Conclusions: Clofarabine is active as a single agent in pediatric ALL and AML that are refractory to intensive salvage regimens. The overall safety profile is similar to that reported in other pediatric salvage studies. Clofarabine in combination with standard chemotherapy is currently under investigation in children.

Phase I study of NK105, a paclitaxel-incorporating micellar nanoparticle, in patients with advanced cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2018-2018 ◽  
Author(s):  
K. Kato ◽  
T. Hamaguchi ◽  
H. Yasui ◽  
T. Okusaka ◽  
H. Ueno ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Polymeric Micelle ◽  
Preclinical Study ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2018 Background: NK105 is a new polymeric micelle carrier system for paclitaxel (PTX). A preclinical study revealed that the plasma AUC and tumor AUC of NK105 were 90-fold higher and 25-fold higher, respectively, than those of free-PTX, i.e., the conventional PTX formulation. NK105 had higher in vivo antitumor activity and lower neurotoxicity than free-PTX. This phase I study was designed to examine the MTD, DLTs, recommended dose (RD) for phase II, and the pharmacokinetics of NK105. Methods: NK105 was administered as a 1-hour intravenous infusion every 3 weeks, without antiallergic premedication. The starting dose was 10 mg PTX equivalent/m2, and the dose was escalated according to the accelerated titration method. Results: To date, 17 patients (pts) have received the following doses: 10 mg/m2 (n=1); 20 mg/m2 (n=1); 40 mg/m2 (n=1); 80 mg/m2 (n=1); 110 mg/m2 (n=3); 150 mg/m2 (n=5); and 180 mg/m2 (n=5). The tumor types treated included pancreatic (n=9), bile duct (n=5), gastric (n=2), and colonic (n=1) cancers. Neutropenia was the most common hematological toxicity. Grade 3 fever developed in 1 pt given 180 mg/m2. No other grade 3 or 4 non-hematological toxicity, including neuropathy, was observed. DLTs occurred in pts given 180 mg/m2 (grade 4 neutropenia lasting for more than 5 days). This dose was designated as the MTD. Allergic reactions developed in only one pt at 180 mg/m2, who was sensitive to other drugs such as antibiotics anti-inflammatory. A partial response was observed in one pt with pancreatic cancer and pts with colonic and gastric cancer had stable disease. The Cmax and AUC of NK105 were dose dependent. The plasma AUC of NK105 at 180 mg/m2 was approximately 30-fold higher than that of the conventional formulation of PTX. Conclusions: Accrual is ongoing at the 150 mg/m2 dose level to determine the RD. DLT was Grade 4 neutropenia. NK105 produces prolonged high levels of PTX in plasma. A 1-hour infusion of NK105 every 3 weeks was feasible, well tolerated, and effective in patients with pancreatic cancer. Even after the long term usage, only grade 1 or 2 neuropathy was observed. NK105 will be evaluated in Phase II studies of patients with advanced pancreatic and gastric cancers. No significant financial relationships to disclose.

Safety summary of panitumumab (pmab) in combination with chemotherapy (ctx) from four clinical trials in patients (pts) with metastatic colorectal cancer (mCRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15005-e15005
Author(s):  
T. J. Price ◽  
M. Peeters ◽  
J. Douillard ◽  
E. Mitchell ◽  
A. Cohn ◽  
...  
Keyword(s):  
Phase Ii ◽  
Safety Data ◽  
Data Monitoring Committee ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Two Phase ◽  
Phase Ii Studies ◽  
Study Results ◽  
Phase Iii Trials ◽  
Phase Iii Studies

e15005 Background: Pmab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody approved in the US and EU (wild-type KRAS) as monotherapy for pts with mCRC. Safety data from 4 studies (Siena et al ASCO 2008; Peeters et al ASCO 2008; Cohn et al ASCO 2008; Mitchell et al WORLD GI 2008) of pmab in combination with ctx are summarized. Methods: Two studies are single-arm, phase II trials and two are randomized, phase III trials with pooled, blinded safety data that include ctx-controls. All studies were multicenter. Common pt eligibility criteria included: diagnosis of mCRC with measurable disease per modified RECIST criteria, age ≥ 18 years, and adequate hematologic, renal, hepatic, and metabolic function. All studies required pts to receive FOLFOX, FOLFIRI, or irinotecan ctx in combination with pmab. Pts received pmab 6.0 mg/kg Q2W with FOLFOX Q2W or FOLFIRI Q2W, or pmab 9.0 mg/kg Q3W with irinotecan Q3W. Results from planned interim analyses are available for 3 studies, and results from the final analysis are available for one study. Results: Among the 4-study safety data, 1213 pts received pmab + ctx; 703 pts received pmab + FOLFIRI, 455 pts received pmab + FOLFOX, and 55 pts received pmab + irinotecan. Approximately 1,200 pts were enrolled in each phase III study, and data are available from 1,003 pts who received pmab + ctx and 997 pts who received ctx alone. All pts in the phase III studies, regardless of treatment group, were included in the pooled, blinded interim analysis sets monitored by the data monitoring committee for each study. Safety results for the two phase II studies of pmab + ctx and two phase III studies of pmab ± ctx are summarized (Table). Conclusions: Phase II data are consistent with expectations, and phase III trials are ongoing. A consistent safety profile was observed across studies. [Table: see text] [Table: see text]

A phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR dual-action antibody, in patients (pts) with refractory/recurrent epithelial tumors: Expansion cohorts.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2568-2568 ◽  
Author(s):  
Andres Cervantes-Ruiperez ◽  
Dejan Juric ◽  
Manuel Hidalgo ◽  
Wells A. Messersmith ◽  
George R. Blumenschein ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Post Dose ◽  
Multiple Tumor ◽  
Phase Ii Studies ◽  
Best Response ◽  
Dual Action

2568 Background: Dysregulated human epidermal growth factor receptor tyrosine kinase (HER RTK) signaling is an important driver of tumor growth, metastasis, and survival. Extensive co-expression and heterodimerization suggest that simultaneous blockade of multiple HER RTKs may be more effective than blockade of a single RTK. MEHD is a novel dual-action human IgG1 antibody. Each antigen-binding fragment blocks ligand binding to HER3 or EGFR, and intended to inhibit signaling from all major ligand-dependent HER dimers. MEHD has single-agent activity in multiple tumor models including models resistant to anti-HER3 or anti-EGFR. Methods: This Phase I study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) activity of intravenous MEHD every 2 weeks (q2w). Tumor PD assessments were pre- and post-dose FDG-PET and IHC for pS6, pPRAS40 or pERK in tumor biopsies. Tumor CT assessments were performed q8w. No dose-limiting toxicity (DLT) was observed in six 3+3 cohorts from 1-30 mg/kg (n=30). We report results from 4 tumor-specific cohorts receiving 14 mg/kg MEHD (recommended Phase II dose). Results: As of 21 Nov 2011, 36 pts (CRC=12, NSCLC=9, SCCHN=10, pancreatic=5), median age 62.5 (35–87), all PS 0-1, median # prior regimens 3.5 (1-8), received a median of 4 doses (1-9) of MEHD; 18 pts remain on study. PK data are consistent with human anti-EGFR antibodies. No related Grade (G) ≥3 adverse events (AEs) have been observed. Common related G1/2 AEs included rash/dermatitis (53%), diarrhea (36%), fatigue (22%), paronychia (19%), dry skin, nausea, and decreased appetite (all 17%), asthenia and stomatitis/oral pain (all 14%). Related AEs ≤ 24 h after first infusion included G1/2 headache (42%), fever (33%), and chills (17%), and decreased in intensity and frequency with later infusions. Early PD data indicate target inhibition in 8/36 pts (SCCHN=2, NSCLC=2, CRC=4), and best response by RECIST includes 2 PR (both SCCHN), 6 pts with SD ≥ 8 weeks (NSCLC=2, CRC=4), 7/8 previously treated with EGFR inhibitors. Conclusions: MEHD at 14 mg/kg q2w has an encouraging safety profile and evidence of anti-tumor activity. Phase II studies are planned.

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