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.

A Q7D phase I study of TPI 287, a novel taxane, in advanced malignancies: Imaging studies, pharmacokinetics (PK) and circulating tumor cell (CTC) quantitation

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12008-12008 ◽  
Author(s):  
J. J. Hwang ◽  
J. L. Marshall ◽  
S. Malik ◽  
H. Chun ◽  
T. Ahmed ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Circulating Tumor Cell ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Advanced Malignancies ◽  
Tumor Measurements ◽  
Grade 3

12008 Background: Taxanes have demonstrated activity across a broad range of cancers, but resistance remains an issue. TPI 287 is a third generation taxane designed to overcome issues of resistance secondary to mdr and mutant tubulin. The purpose of this Phase I study was to determine the maximum tolerated dose and pharmacokinetics of IV TPI 287. Methods: Phase I study: TPI 287 is administered IV on days 1, 8, 15 of a 28 day cycle (Q7D) with at least 3 patients treated per dose escalation, in a typical phase I design. Dosing began at 7 mg/m2 and has advanced to the fifth cohort of patients, who are being treated at a dose of 85 mg/m2. Tumor response is assessed after every second cycle via imaging and tumor measurements. Samples are collected for PK analysis and circulating tumor cell (CTC) quantitation. Results: Sixteen pts have been enrolled (9 males, median years = 60.11; 7 females, median years = 50.71: median number of previous chemotherapies = 4). Diagnoses included colorectal (4), prostate (3), breast, kidney, cervical, brain, lung, osteosarcoma, basal cell, endometrial, ovarian cancers. Of 16 pts, 8 and 5 have completed 1, 2 cycles, respectively. Only one drug related grade 3 adverse event (hypersensitivity reaction) occurred, at 14 mg/m2. No other reported toxicities are related to TPI 287. PK and CTC studies are ongoing. Conclusions: These initial results show that TPI 287 is well tolerated at a dose up to 56 mg/m2 administered Q7D, and dose escalation continues. [Table: see text]

Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of a novel treatment with promising activity.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3015-3015
Author(s):  
Andrew Eugene Hendifar ◽  
Sant P. Chawla ◽  
Doris Quon ◽  
Victoria S Chua ◽  
Lita Fernandez ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Minor Response ◽  
Grade 3

3015 Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to reverse the aerobic glycolytic phenotype of cancer cells. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR Meeting Abstracts 2011). Methods: A standard 3+3 phase I, dose-escalation study design was used in patients with advanced solid tumors refractory to standard treatment. Primary objectives were establishment of the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) correlates. Secondary objectives included exploratory pharmacodynamics (PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with advanced cancer who had failed multiple chemotherapeutic regimens had been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 elevation in PT/INR, otherwise there have been no grade 3/4 treatment related toxicities to date. The pharmacokinetics of BPM 31510 are linear and there were no sex differences in the parameters normalized by dose and body surface area. Tmax and Cmax are associated with the end of the infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective tumor responses have been noted at the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 minor response (pleomorphic sarcoma). Six patients (19%) have had disease stabilization (> 4 months). Conclusions: Interim data from this phase I study indicate that BPM 31510 is well tolerated with no dose limiting toxicities to date. A partial response and minor response were observed and correlates with dose escalation. Taken together, there is strong rationale for further clinical development of this compound as an anti-cancer agent.

scholarly journals A Phase I Study of IMGN529, an Antibody-Drug Conjugate (ADC) Targeting CD37, in Adult Patients with Relapsed or Refractory B-Cell Non-Hodgkin’s Lymphoma (NHL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1760-1760 ◽  
Author(s):  
Anastasios Stathis ◽  
Arnold S. Freedman ◽  
Ian W. Flinn ◽  
Kami J. Maddocks ◽  
Steven Weitman ◽  
...  
Keyword(s):  
B Cells ◽  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Early Onset ◽  
Research Funding ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Autologous Transplant ◽  
Grade 3

Abstract Background: While CD37 is widely expressed on malignant B cells in NHL and chronic lymphocytic leukemia (CLL), few therapies are in development exploiting this target. In normal tissues, high CD37 expression is restricted to blood cells and lymphoid tissues, making CD37 well suited to an ADC approach. IMGN529 is a CD37-targeting ADC consisting of a CD37-binding antibody with intrinsic pro-apoptotic and immune effector activities conjugated to the maytansinoid anti-mitotic, DM1. Its unique profile enables IMGN529 to potentially kill CD37-positive B cells via multiple mechanisms of action. In preclinical studies, IMGN529 exhibits targeted, potent activity against NHL cells via direct inhibition of cell survival and effector function by its antibody and tubulin-disruption by DM1. Methods: A Phase I study is being conducted to evaluate safety, pharmacokinetics, pharmacodynamics, exploratory biomarkers and preliminary evidence of activity of IMGN529 and to determine the maximum tolerated dose/recommended phase 2 dose of IMGN529 in adult patients (pts) with relapsed or refractory NHL. IMGN529 is given intravenously on Day (d) 1 of each 21d cycle (C). Efficacy is evaluated based on Cheson response criteria. CD37 is being evaluated by IHC in available tumor samples to assess expression of CD37 among different NHL subtypes. Results: To date, 31 pts have been enrolled (66% male), median age of 65 years: Diffuse large B-cell (DLBCL, n = 14), Follicular lymphoma (FL, n = 10), MCL (n = 5), MZL (n = 2). Dose escalation began at 0.1 mg/kg. Early onset, transient grade 3-4 neutropenia was reported in 6 patients receiving doses at or below 0.8 mg/kg, potentially attributed to cytokine release. Peri-infusional steroid administration was added to the study protocol, and the incidence and severity of this neutropenia was significantly reduced. Additional patients have been enrolled and increasingly higher dose levels evaluated. To date the highest dose evaluated is 1.0 mg/kg. Cytokine levels are currently being evaluated in trial patients to gain a better understanding of the mechanisms underlying the early onset neutropenia. At the 1.0 mg/kg dose cohort grade 3-4 neutropenia was reported (1 DLT of febrile neutropenia among 6 patients) around d10 of the cycle and granulocyte colony stimulating factor (G-CSF) was added as primary prophylaxis. The most common treatment-emergent adverse events (AEs) occurring in ≥ 20% of the 31 pts enrolled were neutropenia (30%), fever (27%), asthenia (20%) and fatigue (20%). A reduction in lymphocyte count seen early after dosing (d2) in the majority of pts suggests a CD37-mediated reduction in lymphocytes, consistent with the mechanism of action of a CD37-targeted therapy. Four objective responses have been reported in patients who had received multiple lines of prior therapy. At the 1.0 mg/kg dose level, two patients with DLBCL who were heavily pretreated and who relapsed following autologous transplant have achieved an objective response that is ongoing. One pt has achieved a PR and one patient has achieved a CR. As previously reported, at doses of 0.2 mg/kg and 0.4 mg/kg one pt with transformed FL, who progressed following an autologous transplant, and one pt with DLBCL achieved a PR. The maximum tolerated dose has not yet been achieved and dose escalation is ongoing with additional data expected. Conclusions: IMGN529, a CD37-targeting ADC, demonstrates clinical activity in patients with NHL and has the potential to be a novel therapeutic for B-cell lymphoproliferative malignancies. Disclosures Stathis: ImmunoGen, Inc: Travel assistance Other; Pfizer: Research Funding; Oncoethix SA: Research Funding. Flinn:ImmunoGen, Inc: Research Funding. Maddocks:Pharmacyclics, Seattle Genetics, MorphoSys: Advisory Board Other, Research Funding. Zucca:Roche, Mundipharma, Novartis, Jannsen, Celgene: Consultancy, Honoraria, Research Funding, travel assistance Other. Romanelli:ImmunoGen, Inc.: Employment, Equity Ownership; sanofi: Employment. Zildjian:ImmunoGen, Inc: Employment. Ruiz-Soto:ImmunoGen, Inc: Employment; Sanofi: Past employment within 1 year, Past employment within 1 year Other.

Phase I study of the novel anticancer drug PM00104 as a 24-hour IV infusion every 3 weeks (q3w) in patients (pts) with advanced solid tumors or lymphoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2568-2568
Author(s):  
J. Capdevila ◽  
S. Clive ◽  
J. Tabernero ◽  
P. Lardelli ◽  
A. Soto-Matos ◽  
...  
Keyword(s):  
Phase I ◽  
Safety Profile ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Grade 3 ◽  
Ecog Ps ◽  
Anti Tumor Activity

2568 Background: PM00104 is a novel synthetic alkaloid related to the marine compounds jorumycin and renieramycins. Preliminary preclinical studies suggest changes in cell cycle and DNA binding properties and transcriptional inhibition as main mechanisms of action. PM00104 has shown broad in vitro and in vivo anti-tumor activity (IC50 ≤ 10-8 M) with an acceptable toxicology profile. Methods: The aim of this phase I study was to assess the safety profile, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK), relationship between PK and pharmacodynamics (PD) and anti-tumor activity of PM00104 administered as a 24-hour i.v. infusion q3w. Sequential cohorts of 3–6 pts were treated at 133, 266, 400, 800, 900, 1600, 3200, 4000 and 5000 μg/m2. Results: Twenty nine pts have been treated (18 male, 11 female; median age: 59, range: 44–78; ECOG PS ≤2). Five pts developed DLTs: 2 pts at 5000 μg/m2 (grade 4 thrombocytopenia/neutropenia and grade 3 nausea/vomiting in 1 pt; and grade 3 nausea in 1 pt); 1 at 4000 μg/m2 (grade 4 neutropenia/thrombocytopenia and grade 3 asthenia); 1 at 3200 μg/m2 (grade 3 tumor pain) and 1 at 266 μg/m2 (grade 3 transaminase increase). The MTD was reached at 5000 μg/m2 and the RD at 4000 μg/m2. At the RD 6 more pts have been included in order to further evaluate the safety profile and anti-tumor activity. Other adverse events included nausea and vomiting (more frequent at doses ≥800 μg/m2), fatigue, anorexia and diarrhea; most of them being of ≤grade 2 severity. No objective responses were seen but 3 pts with pancreatic adenocarcinoma, hepatocarcinoma and lower esophagus adenocarcinoma presented stable disease lasting >3 months. PM00104 shows a dose-proportional PK profile, the half-life being 20–30 hours and the volume of distribution around 1000 L. Conclusions: PM00104 has shown an acceptable safety profile with signs of anti-tumor activity in pts with advanced malignancies when administered as a 24-hour i.v. infusion q3w. PM00104 is also being evaluated with other administration schedules as monotherapy and in combination with other anti-tumor agents. [Table: see text]

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

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

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

Phase I Study of Clofarabine Plus Idarubicin and Clofarabine Plus Idarubicin Plus Cytarabine (ARA-C) in Patients (PTS) with Relapsed and Primary Refractory Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Myeloid Blast Phase of Chronic Myeloid Leukemia (CML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1809-1809 ◽  
Author(s):  
Stefan Faderl ◽  
Alessandra Ferrajolil ◽  
William Wierda ◽  
Srdan Verstovsek ◽  
Farhad Ravandi-Kashani ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Acute Leukemias ◽  
First Remission ◽  
First Relapse ◽  
Grade 3

Abstract Phase I and II clinical studies demonstrated activity of Clofarabine in acute leukemias. In previous studies we have investigated clofarabine, plus ara-C combinations and reported a CR rate of 24% in relapsed AML and 52% in previously untreated AML ≥ 50 years (yrs) with acceptable toxicity profile. Anthracyclines are active in AML. To explore clofarabine further in AML combinations we conducted a phase I study of clofarabine with idarubicin with or without ara-C in pts with relapsed AML, MDS, and CML. Considered as dose-limiting toxicities (DLT) are ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) will be determined by “3+3” dose escalation scheme. On the clofarabine (C)/idarubicin (I) combination (CI), 9 AML pts are enrolled (2 primary refractory, 7 first relapse). Median age: 58 yrs (range 24–71). Median first remission duration (CRD1): 3.1 mos. (0–7.6). For the first dose level, C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d. Among the first 6 pts, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation of C to 15mg/m2 i.v. daily x 5 and I 8mg/m2 i.v. daily x 3. Among 3 pts, 1 ≥ gr.3 toxicity (↑ bili) was observed. No responses occurred. On the CI + ara-C arm (CIA), 7 AML pts are enrolled (1 primary refractory, 6 first relapse). Median age: 58 yrs. (24–78). Median CRD1: 11.2 mos. (0–13.1). First dose level: C 22.5mg/m2 i.v. daily x 5d, I 8mg/m2 i.v. daily x 3d, A 1g/m2 i.v. daily x 5d. Of 3 pts, 2 developed ≥ gr.3 toxicities (↑ bili, diarrhea) leading to the following de-escalation: C 15mg/m2 i.v. daily x 5d, I 6mg/m2 i.v. daily x 3d, A 0.75g/m2 i.v. daily x 5d. Of 4 pts (1 ≥ gr. 3 rash, ↑ bili), 3 pts achieved CR. The phase I study is ongoing until determination of DLT and MTD for each arm. Our preliminary results indicate clinical activity of CIA even at the low dose level.

Phase I Study of a Liposomal Carrier (CPX-351) Containing a Synergistic, Fixed Molar Ratio of Cytarabine (Ara-C) and Daunorubicin (DNR) in Advanced Leukemias

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2984-2984 ◽  
Author(s):  
Eric J. Feldman ◽  
Jeffrey Lancet ◽  
Jonathan E. Kolitz ◽  
Ellen Ritchie ◽  
Alan F. List ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Molar Ratio ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Refractory Aml

Abstract Background: CPX-351 is a liposomal formulation of Ara-C and DNR which fixes the synergistic 5:1 molar ratio found to enhance efficacy in both in vitro and in vivo preclinical leukemia models. CPX-351 overcomes the pharmacokinetic (PK) differences of each drug, enabling the maintenance of the 5:1 molar ratio for extended periods of time after IV administration and the delivery of this ratio to bone marrow. Preclinical data from in vitro models show that CPX-351 is actively internalized by leukemic cells within vacuoles and subsequently releases DNR intracellularly. A Phase I study was performed with CPX-351 in patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Objectives: to determine safety, tolerability, and pharmacokinetics of a 90 min IV infusion of CPX-351 given on days 1, 3, 5 to patients with advanced leukemia and MDS, and to seek preliminary evidence of antitumor activity. Methods: Patients with relapsed/refractory AML/ALL and MDS were eligible. A second induction course was permitted if the day 14 bone marrow showed evidence of antileukemic effect and persistent leukemia. Dosing started at 3 units/m2 (1 u = 1 mg Ara-C and 0.44 mg DNR) using single patient cohorts and dose doublings. Three patient cohorts and 33% dose increments began after evidence of antileukemic activity and continued until limiting toxicities (DLTs) completed dose escalation. PK samples were collected after each dose. Results: Forty-seven subjects received 69 courses of CPX-351: Male/Female = 31/16, median age = 62 years (range 23–81); 44 patients had AML and 3 patients had ALL; median number of prior regimens = 2 (1–7). Thirty-seven patients entered the escalation phase of the study and ten subjects, most in first relapse, were treated after completion of dose escalation to confirm safety. At 24 u/m2 antileukemic effects were observed leading to increased cohort size to 3 and decreased escalation rate to 33%. The MTD and recommended Phase 2 dose was 101 u (101 mg Ara-C + 44 mg DNR)/m2 after observing 3 DLTs (decreased LVEF, hypertensive crisis, prolonged aplasia) at 134 u/m2. Adverse events data are available for 36 of 37 patients from the escalation phase of the study. Nonhematologic grade 3–5 toxicities occurring in more than one patient included: infections (58%), dyspnea (11%), fever (11%), hypophosphatemia (8%), hypokalemia (6%), renal failure (6%), skin rash (6%), headache (6%) hyperglycemia (6%) hypoxia (6%) and respiratory failure (6%). Mucositis of any grade was observed in 42% of patients with 3% having grade 3 mucositis. Diarrhea of grade 1 and 2 severity occurred in 39% of patients. Interim analysis of PK data demonstrates maintenance of the 5:1 molar ratio and detectable encapsulated drug persisting up to 24 hours. The average half-lives were 35 hr for total Ara-C and 23 hr for DNR, significantly longer than reported for the conventional drugs. Overall, 11 patients achieved CR/CRp. Among the 19 patients treated at the MTD, 5 of the 13 patients evaluable for response achieved CR. Six patients were treated above the MTD (134 u/m2) and 2 achieved CR. Median time to CR was 43 days. Conclusions: The recommended phase 2 dose is 101 u/m2. CPX-351 was well tolerated, with no unexpected toxicities noted up to the MTD. GI toxicities and mucositis were transient and nearly always of mild to moderate severity. Reduced LV function was observed in two patients both with substantial prior anthracycline exposure. CRs were observed in heavily pre-treated patients with relapsed/refractory AML. Future plans include a randomized Phase 2 study comparing CPX-351 versus Cytarabine + Daunorubicin (“7 + 3”) in older (>60 yo) subjects with previously untreated AML, and a phase 2 study in patients with AML in 1st relapse.

A humanized antibody against CD40 (SGN-40) is well tolerated and active in non-Hodgkin’s lymphoma (NHL): Results of a phase I study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7534-7534 ◽  
Author(s):  
A. Forero-Torres ◽  
R. R. Furman ◽  
J. D. Rosenblatt ◽  
A. Younes ◽  
K. Harrop ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Phase I Study ◽  
Cell Function ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Cell Transplant ◽  
Humanized Antibody ◽  
Phase Ii Studies

7534 Background: CD40 is a member of the TNF receptor family and is widely expressed on hematologic malignancies of B-cell origin. SGN-40 is a humanized antibody against CD40 with effector cell function and mild agonistic activity. Preclinical toxicity studies and efficacy data supported initiation of a multi-institutional phase I study to test the safety, pharmacokinetics, immunogenicity, and efficacy of SGN-40 in patients with relapsed NHL. Methods: Cohorts of 3–6 pts were treated weekly with a maximum dose of 2, 3, or 4 mg/kg/wk SGN-40. A dose escalation schedule is used such that patients receive 1 mg/kg on D1 and D4, 2 mg/kg on D8, and higher doses on weeks 3–5. Responding patients may receive a second cycle. Further dose escalation up to 8 mg/kg is planned. Results: 16 pts have been treated with multiple histologic subtypes: follicular (1), marginal zone (MZL; 1), mantle cell (4), and diffuse large B-cell (DLBCL; 10). One patient (2 mg/kg) developed a reversible Grade 3 unilateral conjunctivitis and ipsilateral loss of visual acuity. No other dose limiting toxicity has been observed up to 4 mg/kg. Preliminary pharmacokinetic data suggest that the antibody has a relatively short half-life, perhaps reflecting a route of elimination or binding that is not saturated at current doses. Two partial responses have been observed at 3 mg/kg (1 MZL, 1 DLBCL) and one partial response has been observed at 4 mg/kg dose (DLBCL relapsed after autologous stem cell transplant with small volume tumor). Conclusions: Using an intra-patient dose escalation schedule, SGN-40 has been well-tolerated at doses up to 4 mg/kg/wk. Further dose-escalation is ongoing to determine the maximum tolerated dose. Three objective responses have been seen, including two in patients with extensively treated aggressive disease. Correlative studies are underway measuring soluble CD40, cytokine release, effect of FcR polymorphisms, and SGN-40-induced immunogenicity. Given the favorable tolerability and activity, phase II studies in NHL are planned. [Table: see text]

Phase I clinical trial of CX-3543, a pro-apoptotic antitumor agent

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3082-3082 ◽  
Author(s):  
R. F. Marschke ◽  
A. D. Ricart ◽  
D. D. Von Hoff ◽  
J. K. Lim ◽  
K. Papadopoulos
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Three Dimensional ◽  
Antitumor Agent ◽  
Maximum Tolerated Dose ◽  
Therapeutic Window ◽  
Disease Response ◽  
Grade 3 ◽  
Xenograft Tumor Growth

3082 Background: CX-3543 is a novel small molecule specifically designed to target three dimensional nucleic acid motifs, and thus induce apoptosis in cancer cells. Preclinically, CX-3543 demonstrated potency in suppressing xenograft tumor growth with a broad therapeutic window. The objectives of this phase I study are: to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), to establish the pharmacokinetics (PKs), and to determine the recommended dose for further clinical development of CX-3543. Methods: Eligible patients with advanced solid tumors or lymphomas whose tumors progressed on standard therapy or for whom there are no standard therapies receive CX-3543 in successive dose cohorts at: 10, 20, 40, 80 and 160 mg/m2. Dosing is by one hour intravenous infusion daily for five consecutive days repeated on a three week cycle. Therapy is continued until the patient shows signs of intolerance to CX-3543 or evidence of advancing disease. Response by RECIST criteria is determined after every 2 cycles. Results: Ten patients with solid tumors (3–4 per cohort) have received intravenous CX-3543. Doses have been well tolerated. Seven grade 3 adverse events have been reported during the study, but none of these are related to CX-3543. To date no objective responses have been observed. One patient with advanced refractory prostate cancer has stable disease of longer than 4 months duration. CX-3543 has demonstrated good linearity in PK parameters between the dose cohorts with a terminal half life of approximately 12 hours following the first dose. Conclusions: To date, CX-3543 has shown no drug related toxicity and has predictable PKs. No DLTs have yet been observed, and the MTD remains to be defined in this Phase I study. Further enrollment to the planned dose escalation cohorts is ongoing. [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]

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