Phase I and pharmacokinetic evaluation of enzastaurin combined with gemcitabine and cisplatin in advanced cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2046-2046 ◽  
Author(s):  
L. Beerepoot ◽  
J. Rademaker-Lakhai ◽  
E. Witteveen ◽  
S. Radema ◽  
C. Viseren-Grul ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Phase I ◽  
Solid Tumors ◽  
Pancreatic Head ◽  
Low Grade ◽  
Qtc Interval ◽  
Tumor Cell Death ◽  
Clinical Benefits ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

2046 Background: Enzastaurin (Enz), an oral PKC inhibitor that also suppresses PI3K/AKT pathways, blocks tumor angiogenesis and tumor cell proliferation and induces tumor cell death. Gemcitabine (Gem) and cisplatin (Cis) combination is often used for treatment of solid tumors. Addition of Enz to the regimen has the potential for enhanced clinical benefits without increasing toxicity. Methods: In this phase I, dose-escalation trial, patients (pts) with advanced, refractory, solid tumors received a lead-in treatment (cycle 1) with oral Enz for 14 days to achieve steady-state exposures. Starting with cycle 2, pts received Enz orally (350 mg qd to 500 mg bid) on days 1–21 combined with Gem (1000 or 1250 mg/m2) as a 30-min iv infusion on days 1,8 and Cis (60 or 75 mg/m2) as a 3-h iv infusion on day 1, every 21 days, for up to 7 cycles. Results: 33 pts (22 males, 11 females; ECOG: 0–2), with a median age of 58 yrs (range: 38–79 yrs), were enrolled in 7 dose levels. The MTD was not identified. Two DLTs were reported, 1 grade (Gr) 2 QTc interval prolongation and 1 Gr 3 fatigue, both during cycle 1 in bid cohorts. Laboratory toxicities included Gr 3/4 neutropenia (3/6 pts), thrombocytopenia (1/6 pts), and Gr 3 leukopenia (2 pts), hyperglycemia (1 pt), and creatinine (1 pt). Gr 3 toxicity reported in >1 pt was fatigue (5 pts). Enz bid (≥ 250 mg bid) was associated with more discontinuations in early cycles, more Enz dose adjustments, higher numbers of possibly-related SAEs, and increased numbers of low-grade CTC toxicities compared to the corresponding qd dosing. Exposures of Enz in the presence of Gem and Cis decreased slightly but the decrease was not clinically significant as the mean exposure remained above the targeted exposure of 1400 nM. Gem and Cis exposures were not altered when given in combination with enz, as compared to historical data. Of 24 evaluable pts, 3 pts (pancreatic, head/neck, and ovarian cancer) achieved a partial response, whereas 13 achieved stable disease for ≥ 2 cycles. Conclusions: Based on safety and PK data, the recommended phase II dose is Enz 500 mg qd, Gem 1250 mg/m2, and Cis 75 mg/m2. This regimen is generally well tolerated across all dose levels and there are no significant alterations in PK parameters of any drug, when given in combination. [Table: see text]

Phase I study of ON-01910.Na, a novel cell cycle inhibitor in adult patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13026-13026 ◽  
Author(s):  
R. C. Donehower ◽  
A. Jimeno ◽  
J. Li PhD ◽  
K. Galvin ◽  
F. Anthony ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Cross Resistance ◽  
Dose Escalation Study ◽  
Cell Cycle Inhibitor ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

13026 Background: ON-1910.Na is a new chemical entity, novel cell cycle inhibitor which arrests cells in G2/M, affects phosphorylation of several regulatory kinases and lacks cross resistance to other standard chemotherapy agents. This is a first-in-man Phase I dose escalation study to determine the dose limiting toxicities, recommended Phase II dose, and pharmacokinetic (PK) profile, and to document any antitumor activity of ON-01910.Na. Methods: Patients had histologically confirmed solid tumors refractory to standard therapy. ON-1910.Na, formulated as a solution in PEG400, was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 followed by a 10 day observation period for a total of 28 days per cycle. The initial dose was 80 mg and was escalated using an accelerated titration schedule; one patient was treated per cohort until grade 2 toxicity was documented. A dose confirmation cohort of up to 12 patients will be treated at the maximun tolerated dose (MTD). A comprehensive PK study was performed on days 1 and 15 of the first cycle, plus trough samples were collected. Results: Thirteen patients (7F, 6M; ages 46–73) have received 20 cycles. Dose levels of 80, 160, 320, 480, 800, 1280, 2080, and 3120 mg were evaluated in 8 patients, and a further dose of 4370 mg has been evaluated in 5 patients. Toxicities have been anemia (2 G1, 1 G2), leucopenia (1 G1, 1 G2), hyperglycemia (2 G1), elevated AST/ALT (1 G1, 1 G2), nausea (3 G1), diarrhea (3 G1), skeletal pain (5 G1, 1 G2), abdominal pain (2 G1), tumor pain (1 G2), and fatigue (3 G1, 1 G2), and have clustered at the latter 3 dose levels. PK analysis shows increasing ON-1910.Na exposure with increasing doses. ON-1910.Na has a low clearance (13 L/h), long half-life (20 h), distribution in excess of blood volume (58 L) and PK parameters are similar on days 1 and 15. Approximately 3-fold and 5-fold inter-subject variation in ON-1910.Na clearance was observed on days 1 and 15, respectively. No antitumor activity has been documented by standard criteria. Conclusions: Dose escalation is continuing. [Table: see text]

A phase I study of bevacizumab in children with refractory solid tumors: A Children’s Oncology Group study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9017-9017 ◽  
Author(s):  
J. L. Glade Bender ◽  
P. C. Adamson ◽  
S. Baruchel ◽  
Y. Shaked ◽  
H. X. Chen ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation Study ◽  
Pediatric Solid Tumors ◽  
Humanized Monoclonal Antibody ◽  
Disease Stabilization ◽  
Clinical Models ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

9017 Background: Bevacizumab is a humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF-A) that has demonstrated significant growth inhibition in several pre-clinical models of pediatric solid tumors. However, the agent has never been tested in pediatric patients. Methods: A phase I dose escalation study in children with refractory solid tumors was conducted to define the dose limiting toxicities (DLTs), and to determine the pharmacokinetics (PK) and recommended phase II dose of bevacizumab administered by IV infusion every 2 weeks in 28-day cycles. Cohorts were enrolled at dose levels of 5, 10, and 15 mg/kg; the final dose level was expanded to include at least 3 children <6 years of age. Serial blood samples were collected for PK, plasma VEGF concentration, and circulating mature and progenitor endothelial cells (CECs/CEPs). Results: 20 patients (10 male), median age 13 yrs (range 1–21), were enrolled at dose levels 5 (n=3), 10 (n=3), and 15 (n=14) mg/kg. 18 patients were fully evaluable for toxicity (one withdrew consent prior to treatment and the second was removed for rapid disease progression). A total of 67 cycles were administered with a median of 3 per patient (range 1–16). Treatment was well tolerated and no DLTs were observed. Only one grade 3 toxicity, lymphopenia, was attributed to drug. Non-dose limiting, grade 1–2 toxicities included infusional reaction (n=3), rash (n=3), mucositis (n=2), and proteinuria (n=3). There was no hypertension, hemorrhage or thrombosis reported. There were no partial or complete responses; 3 pts with Ewings and 2 pts with soft tissue sarcoma had disease stabilization for > 3 months. The serum exposure to bevacizumab as measured by AUC appeared to increase in proportion to dose. The median clearance of bevacizumab was 4.1 ml/day/kg (range 3.2–15.9), and the median T1/2 was 11.8 days (range 3.9–14.6). In some patients, a rapid rate of rise in plasma VEGF, increase in mature CECs or decrease in CEPs was observed. Conclusion: Bevacizumab at doses up to 15mg/kg every two weeks is well tolerated in children with solid tumors. No significant financial relationships to disclose.

Phase I experience with first in class TnMUC1 targeted chimeric antigen receptor T-cells in patients with advanced TnMUC1 positive solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14513-e14513
Author(s):  
Rodolfo Gutierrez ◽  
Payal D Shah ◽  
Omid Hamid ◽  
Alfred L. Garfall ◽  
Avery Posey ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Dose Escalation ◽  
Intracellular Signaling ◽  
Antigen Receptor ◽  
Low Grade ◽  
Gi Symptoms ◽  
Dose Levels

e14513 Background: MUC1 is a glycoprotein that is expressed in healthy tissues on the luminal surface of simple and glandular epithelium. In tumors that arise from these cells, an alternate form with aberrant glycosylation is frequently over expressed and distinguishes tumor associated TnMUC1 from normal MUC1. We have generated a novel chimeric antigen receptor (CAR) targeting the TnMUC antigen comprised of a mouse anti-human scFv derived from the monoclonal antibody 5E5 which recognizes the epitope comprising Tn glycan of MUC1, a CD8a transmembrane region and dual CD2 and CD3z intracellular signaling domains. CD2 signaling in T-cells has been demonstrated to result in delayed exhaustion. The novel incorporation of this co-stimulatory domain may lead to enhanced persistence of the CART cells which is believed to be critical for efficacy in solid-tumors. Methods: This is a multi-center first in human Phase I study to evaluate the safety and preliminary efficacy of CART-TnMUC1-Cells for the treatment of solid-tumors. Solid-tumors included in the dose-escalation phase include metastatic treatment-resistant ovarian cancer (OC), pancreatic adenocarcinoma (PC), triple-negative breast cancer (TNBC) or non-small lung cancer (NSCLC). All patients must have TnMUC1 expression as determined by immunohistochemistry. Results: As of January 2021, a total of six patients were treated. Three in Cohort 1 (no lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 OC, 1 TNBC and 1 PC) and 3 in Cohort 2 (flu/cy lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 NSCLC and 2 OC). None of the patients treated experienced DLT’s. The trial is currently enrolling to Cohort 3 (flu/cy lymphodepletion, 5-6 x 107 TDN). No CRS, neurotoxicity, serious adverse reactions and no on-target/off-tumor toxicity was observed at these dose levels. The most common AE’s were low-grade GI symptoms (e.g., nausea, abdominal pain) in 5/6 patients (83.3%), generalized disorders (e.g., chills, fatigue) in 5/6 (83.3%) and hematologic disorders (e.g., anemia, neutropenia) in 3/6 (50%) of patients. CAR expansion was demonstrated in all patients and was improved in Cohort 2 following LD chemotherapy. Preliminary efficacy assessed by RECIST v1.1 at Day +28 demonstrate SD in all patients in Cohort 2. Conclusions: This is the first report of a novel CART-TnMUC1 construct containing a CD2 co-stimulatory domain that has been used in clinical trials for the treatment of refractory solid-tumor malignancies. While the study is still early in dose-escalation having completed only 2 of 6 planned dose levels there is no evidence of safety concerns or on-target/off-tumor toxicity. Additional safety, efficacy and biomarker data is currently being reviewed and will be presented. Clinical trial information: NCT04025216.

Phase I and Pharmacokinetic Study of the Oral Farnesyltransferase Inhibitor Lonafarnib Administered Twice Daily to Pediatric Patients With Advanced Central Nervous System Tumors Using a Modified Continuous Reassessment Method: A Pediatric Brain Tumor Consortium Study

2007 ◽  
Vol 25 (21) ◽  
pp. 3137-3143 ◽  
Author(s):  
Mark W. Kieran ◽  
Roger J. Packer ◽  
Arzu Onar ◽  
Susan M. Blaney ◽  
Peter Phillips ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Pharmacokinetic Study ◽  
Pediatric Brain Tumor ◽  
Maximum Tolerated Dose ◽  
Low Grade ◽  
Farnesyltransferase Inhibitor ◽  
Continual Reassessment ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

Purpose A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib ( SCH66336 ) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured. Patients and Methods Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m2/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment. Results Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer. Conclusion Although the estimated MTD by the CRM model was 98.5 mg/m2/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m2/dose administered twice daily by mouth with concurrent loperamide.

scholarly journals A phase I/II study of rovalpituzumab tesirine in delta-like 3—expressing advanced solid tumors

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Aaron S. Mansfield ◽  
David S. Hong ◽  
Christine L. Hann ◽  
Anna F. Farago ◽  
Himisha Beltran ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Medullary Thyroid Cancer ◽  
Large Cell ◽  
Antibody Drug Conjugate ◽  
Medullary Thyroid ◽  
Neuroendocrine Prostate Cancer ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Neuroendocrine Carcinomas

AbstractDelta-like protein 3 (DLL3) is highly expressed in solid tumors, including neuroendocrine carcinomas/neuroendocrine tumors (NEC/NET). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Patients with NECs and other advanced DLL3-expressing tumors were enrolled in this phase I/II study (NCT02709889). The primary endpoint was safety. Two hundred patients were enrolled: 101 with NEC/NET (large-cell NEC, gastroenteropancreatic NEC, neuroendocrine prostate cancer, and other NEC/NET) and 99 with other solid tumors (melanoma, medullary thyroid cancer [MTC], glioblastoma, and other). The recommended phase II dose (RP2D) was 0.3 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17%), thrombocytopenia (15%), and elevated aspartate aminotransferase (8%). Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.

scholarly journals 412 First-in-human phase I/IIa trial to evaluate the safety and initial clinical activity of DuoBody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A437-A437
Author(s):  
Elena Garralda ◽  
Ravit Geva ◽  
Eytan Ben-Ami ◽  
Corinne Maurice-Dror ◽  
Emiliano Calvo ◽  
...  
Keyword(s):  
T Cells ◽  
Informed Consent ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Therapeutic Window ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Link Type ◽  
Dose Levels

BackgroundAgonistic 4-1BB monoclonal antibodies were preclinically validated as promising cancer immunotherapies, both as monotherapy and as potentiators of the activity of PD-(L)1–blocking agents. However, toxicity and a narrow therapeutic window have hampered their clinical development. DuoBody-PD­-L1×4-1BB, a first-in-class, bispecific, next-generation checkpoint immunotherapy, was designed to overcome these limitations by activating T cells through conditional 4-1BB costimulation, while simultaneously blocking the PD-L1 axis. We present preliminary data from the ongoing, first-in-human, open-label, phase I/IIa trial of DuoBody-PD-L1×4-1BB in advanced solid tumors (NCT03917381).MethodsDuring dose escalation, patients with metastatic or unresectable solid tumors not eligible for standard therapy received flat-dose DuoBody-PD-L1×4-1BB (25–1200 mg) intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included pharmacokinetic parameters and antitumor activity (RECIST 1.1). Pharmacodynamic biomarkers and antitumor activity (iRECIST) were assessed as exploratory endpoints.ResultsAs of June 22, 2020, 61 patients were enrolled (median age: 59 years). The most common cancer types were colorectal (19.7%), ovarian (14.8%), pancreatic (9.8%), and NSCLC (9.8%). Patients had previously received a median (range) of 3 (1–11) treatments; 44.2% had prior anti-PD-(L)1 immunotherapy. Patients received a median (range) of 4 (1–15) treatment cycles; Cmax was observed shortly after the end of infusion (mean T½: 2.3–10.3 days). Maximum tolerated dose was not reached; 6 patients experienced DLTs. The most common (=10%) treatment-related AEs (all grades; grades 3–4) were transaminase elevation (24.6%; 9.8%), hypothyroidism (16.4%; 1.6%), and fatigue (13.1%; 1.6%). Treatment-related grade-3 transaminase elevations decreased upon corticosteroid administration; no treatment-related bilirubin increases or grade-4 transaminase elevations occurred. Disease control, including stable disease at first assessment and partial responses in triple-negative breast cancer, ovarian cancer, and immune checkpoint inhibitor (ICI)–pretreated NSCLC, occurred in 40/61 patients (65.6%). Pharmacologic activity, as measured by modulation of adaptive immunity mediators, was observed across a broad range of dose levels. Peripheral proliferating (Ki67+) CD8+ effector memory T cells and serum interferon-gamma levels showed maximum induction relative to baseline (p=0.01) 8 days following treatment.ConclusionsDuoBody-PD-L1×4-1BB demonstrated biologic activity and a manageable safety profile. Encouraging early clinical activity across different dose levels was observed in a heavily pretreated population with advanced solid tumors, including those resistant to prior immunotherapy or typically less sensitive to ICIs. Expansion cohorts of patients for whom DuoBody-PD-L1×4-1BB treatment could be relevant and biologically sound have started enrollment. Updated data will be presented.AcknowledgementsThe authors thank Manish Gupta, Lei Pang, and Thomas Breuer at Genmab A/S; Alice Bexon, Alexander Muik, and Friederike Gieseke at BioNTech SE; and Zuzana Jirakova (formerly at BioNTech SE) for their valuable contributions. This trial was funded by Genmab A/S and BioNTech SE.Trial RegistrationClinicalTrials. gov; trial number: NCT03917381Ethics ApprovalThis trial is undertaken following full approval of the final protocol, amendments, informed consent form, applicable recruiting materials, and subject compensation programs by the Independent Ethics Committee/Institutional Review Board.ConsentWritten informed consent, in accordance with principles that originated in the Declaration of Helsinki 2013, current ICH guidelines including ICH-GCP E6(R2), applicable regulatory requirements, and sponsor policy, was provided by the patients.

First-in-human dose escalation of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2547-2547
Author(s):  
Justin C Moser ◽  
Mark Voskoboynik ◽  
Nehal J. Lakhani ◽  
Michael Millward ◽  
Diwakar Davar ◽  
...  
Keyword(s):  
T Cell ◽  
Colorectal Carcinoma ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Low Grade ◽  
Checkpoint Inhibition ◽  
Human Dose ◽  
Cd28 Costimulation ◽  
Advanced Malignancies ◽  
Dose Levels

2547 Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating favorable safety in preclinical toxicology studies. Methods: This is a cohort-based, open-label dose escalation and expansion study of ALPN-202 in adults with advanced solid tumors or lymphoma (NCT04186637). Subjects with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two planned single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity of ALPN-202. Disease assessments are evaluated by RECIST v1.1 for solid tumors or by Lugano Classification for lymphoma. Results: As of January 2021, 20 subjects with advanced malignancies have received ALPN-202. Dose-dependent PK and target saturation have been preliminarily observed. So far, ALPN-202 has been well tolerated at dose levels ranging from 0.001 to 1 mg/kg weekly, with no DLTs. Low-grade skin toxicities (grade 1-2 rash) have been observed in 4 subjects (20%). Among 11 evaluable subjects, an unconfirmed partial response has been observed in one subject with colorectal carcinoma, while stable disease has been observed in 5 subjects with colorectal carcinoma, mesothelioma (2), cholangiocarcinoma, and renal cell carcinoma -- for a preliminary clinical benefit (PR+SD) rate of 100% (4/4) at dose levels of 0.3 mg/kg and higher, or 54% (5/11) overall (table). The meeting presentation will update this data, which is expected to include the conclusion of Q1W dose escalation, as well as immune correlates. Conclusions: First-in-human dose escalation with ALPN-202 has been well tolerated at doses capable of engaging CD28 costimulation in vivo in association with dual PD-L1/CTLA-4 checkpoint inhibition, with early signs of anti-tumor activity. These findings suggest that CD28 agonism can be safely achieved in humans, and further suggest that dose expansion with ALPN-202 is warranted to assess the relevance of controlled CD28 costimulation as a novel approach to cancer immunotherapy. Clinical trial information: NCT04186637. [Table: see text]

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

1998 ◽  
Vol 16 (7) ◽  
pp. 2494-2499 ◽  
Author(s):  
A M Langevin ◽  
D T Casto ◽  
P J Thomas ◽  
S D Weitman ◽  
C Kretschmar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Malignant Tumors ◽  
Hepatic Metabolism ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Recommended Phase Ii Dose

PURPOSE A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

scholarly journals Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors

2020 ◽  
Vol 38 (19) ◽  
pp. 2140-2150 ◽  
Author(s):  
Jayesh Desai ◽  
Hui Gan ◽  
Catherine Barrow ◽  
Michael Jameson ◽  
Victoria Atkinson ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
First Generation ◽  
Objective Response ◽  
Reversible Inhibitor ◽  
Low Grade ◽  
Entire Study ◽  
Ras Mutations

PURPOSE Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF– or K-RAS/N-RAS–mutated solid tumors. METHODS During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. RESULTS The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF–mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAFV600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAFV600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAFV600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF–mutated non–small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS–mutated endometrial cancer and K-RAS codon 12–mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS–mutated colorectal cancer (n = 20). CONCLUSION Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAFV600–mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS–mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.

Phase I study of bortezomib and oxaliplatin (BOX) in solid tumors: Improved neurotoxicity (NT) profile with lower bortezomib (B) dose

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12007-12007
Author(s):  
R. A. Kosloff ◽  
J. Wright ◽  
P. Ivy ◽  
J. Escalon ◽  
B. Norwood ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Major Contributor ◽  
Organ Function ◽  
Dose Escalation Study ◽  
Adequate Organ Function ◽  
Dose Levels ◽  
Platinum Agents

12007 Background: B inhibits proteasome function and may be synergistic in causing apoptotic death with platinum agents. We were interested in combining B with OX but concerned with dose limiting (DL) NT based on our prior B phase I study [Hamilton et al., JCO 2005]: therefore this Phase I dose-escalation study (alternating increases of B and OX) focusing on NT was planned. Methods: Patients (pts) with metastatic solid tumors, PS 0–2, platinum or taxane naive, no peripheral neuropathy and adequate organ function, received B (D1, 4, 15, 18) and OX (D1, 15) every 28 days in a dose escalation design (see table ). Baseline and monthly assessments were performed by an independent neurologist. Results: 27 (18 gastrointestinal, 3 melanoma, 3 ovarian, 3 others) were accrued; pt characteristics: 14 male/13 female; median age 55 years (range 35–75); 2 median cycles (range 1–10). NT was not DL because it did not occur within the first cycle. Late and limiting NT was observed in levels 2–5 after 2–9 cycles, but serial neurologic evaluations showed reversible NT. With an amended new dose level to lower B to 1.0 mg/m2 (level 6) to avoid late NT, NT was not observed. Of 22 evaluable pts, there were 3 partial responses (ampullary, GE junction, biliary), 6 stable disease, and 13 disease progression by RECIST criteria. Conclusions: biweekly BOX is tolerable at B 1.0 mg/m2 and OX 85 mg/m2 with no DL NT. Additional observations on late NT are ongoing. This suggests B is a major contributor to NT observed in dose levels 2–5 and may potentiate the effects of OX. [Table: see text] [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document