Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Junning Cao ◽  
Pin Zhang ◽  
Paul L. de Souza ◽  
Bo Gao ◽  
Mark Voskoboynik ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Response To Treatment ◽  
Clinical Activity ◽  
Dose Cohort ◽  
Phase Ii Studies ◽  
Grade 3

3059 Background: Poly (ADP-ribose) polymerase (PARP) enzymes play critical roles in DNA damage detection and repair. IMP4297 is a novel, potent PARP1/2 inhibitor (IC50 6.27nM/1.57nM) and has demonstrated to be 20-fold more potent than Olaparib in anticancer animal models. Two phase I studies were performed to evaluate and characterize the tolerability and safety, pharmacokinetics, and antitumor activity of single agent IMP4297 in Chinese and Australian patients with advanced ovarian, breast, prostate and other solid tumors. Methods: Dose escalation used a 3+3 design with a modified Fibonacci escalation. Dose cohort expansion was planned after efficacy was observed at the lowest dose level. Patients received IMP4297 monotherapy orally once a day until disease progression or unacceptable toxicity. Results: As of Jan 12, 2019, 56 patients, including 23 BRCA mutation carriers (BRCA+), had been enrolled at 2-100 mg dose level. No DLT was observed. In these two studies, the most frequent treatment-related adverse events (TRAEs) were leukopenia (20%), followed by anemia (18%), nausea (18%) and thrombocytopenia (14%). The majority of TRAEs were grade 1 or 2. Grade 3 TRAEs occurred in five patients (anemia, n=2; vomiting, n=1; thrombocytopenia, n=1; elevated AST, n=1). Only one patient had a dose reduction due to grade 3 thrombocytopenia. No serious TRAEs were observed. In 15 BRCA+ patients who had measurable lesions, the ORR was 33% and the DCR was 80%. There were 4 BRCA+, platinum-sensitive ovarian cancer patients with an ORR of 75% and a DCR of 100%. One patient with somatic BRCA mutated urothelial carcinoma showed a 76% decrease in tumor size. Conclusions: IMP4297 has been well-tolerated with significant anti-tumor activity. The 100 mg daily dose was selected as the RP2D based on safety, pharmacokinetics and clinical activity, and will be further characterized in dose expansion and phase II studies. Tumor response to treatment (RECIST 1.1) in patients with measurable lesions. Clinical trial information: NCT03508011 and NCT03507543. [Table: see text]

Phase I dose-finding study of oral ERK1/2 inhibitor LTT462 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3640-3640
Author(s):  
Filip Janku ◽  
Elena Elez ◽  
Gopa Iyer ◽  
Noboru Yamamoto ◽  
Daniel Shao-Weng Tan ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Drug Exposure ◽  
Mapk Pathway ◽  
Single Agent ◽  
Human Study ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Grade 3

3640 Background: LTT462 is an investigational small molecule inhibitor of ERK1/2, which has demonstrated preclinical activity in multiple MAPK activated cancer cells and xenograft models. This first-in-human study was designed to evaluate the safety and tolerability of LTT462 in advanced solid tumors harboring MAPK pathway alterations (NCT02711345). Methods: The dose-escalation part of this Phase I, open-label study, enrolled adult and adolescent pts with advanced solid tumors harboring ≥1 documented MAPK pathway alteration with progressive disease (PD) despite standard therapy, or for whom there is no effective standard treatment. Oral LTT462 was given once daily (QD) at 45–600 mg or twice daily (BID) at 150 mg or 200 mg. Objectives were to determine the maximum tolerated dose (MTD) using a Bayesian hierarchical logistic regression model guided by escalation with overdose control, and characterize safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of LTT462. Results: Sixty-five pts (median age 60 years) including 1 pt aged 15 were enrolled in the dose-escalation; most pts (22%) had 3 prior therapies. Most common primary sites for cancer were in the colon (n = 21; 32%), ovary (n = 9; 14%), and pancreas (n = 7; 11%). All pts discontinued, the majority due to PD (n = 44; 68%). Eleven pts experienced DLTs; 6 pts experienced Grade 3 eye disorder DLTs (4 pts retinopathy, 2 pts chorioretinopathy). Treatment-related adverse events (TRAEs) were reported for 89% of pts, most commonly ( > 30%) diarrhea (n = 25; 38%) and nausea (n = 22; 34%). Grade 3/4 TRAEs were reported in 29% of pts; most common was retinopathy (n = 4; 6%). MTD of LTT462 was 400 mg QD and 150 mg BID. Overall, 8 pts (12%) had stable disease (SD) and 35 pts (54%) had PD. An unconfirmed partial response was reported in a pt with cholangiocarcinoma with BRAF mutation; best change in sum of target lesions per RECIST 1.1 was -33.9%. LTT462 increased plasma peak drug concentration and drug exposure at increasing doses between 45–450 mg QD. Exposure at LTT462 600 mg QD was lower than anticipated, indicating potential saturation of absorption at this dose. LTT462 inhibited ERK1/2 and reduced DUSP6 expression relative to baseline in most pts evaluated. Conclusions: LTT462 is well tolerated. Limited clinical activity was reported with single agent LTT462; best overall response was SD. An ongoing study is investigating LTT462 in combination with the RAF inhibitor, LXH254, in NSCLC and melanoma. Clinical trial information: NCT02711345 .

Design of a phase I clinical trial with PNT2258, a novel DNA interference oligonucleotide (DNAi), in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS3110-TPS3110
Author(s):  
Drew Warren Rasco ◽  
Anthony W. Tolcher ◽  
Amita Patnaik ◽  
Kyriakos P. Papadopoulos ◽  
Alex Amaya ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Drug Product ◽  
Single Agent ◽  
Upstream Region ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies

TPS3110 Background: With the knowledge that Bcl-2 facilitates drug resistance and cell survival, a DNA interference (DNAi) strategy was applied to silence Bcl-2 in cancer cells and promote apoptosis. DNAi differs from cytoplasmic mRNA targeting (antisense, RNAi, and miRNA targets) as it targets genomic DNA, blocking transcription. PNT100, a first in class DNAi, is a novel single-stranded 24-base unmodified DNA designed to bind to an upstream region of the Bcl-2 promoter. The drug product (PNT2258) is PNT100 encapsulated in a specialized pH tunable liposome and is being assessed for safety and tolerability in a phase I trial. PNT2258 avoids the toxicities associated with modified oligonucleotides and double-stranded RNAs; since the liposome formulation is anionic and contains no surface spacers, vehicle toxicities are minimal. Xenograft experiments demonstrated marked single agent activity in a diffuse large cell lymphoma, and therapy potentiation when combined with either rituximab in Daudi-Burkitt’s Lymphoma or docetaxel in A375 melanoma. Methods: An open-label, single-arm, first-in-man phase I dose-escalation study of PNT2258 in patients with advanced solid tumors was designed to evaluate safety, tolerability, dose-limiting toxicities, pharmacokinetics, and pharmacodynamics of PNT2258 to recommend a dose for phase II studies. In this phase I study, pharmacodynamic effects of PNT2258 will be evaluated through analyses of soluble serum and plasma markers and peripheral blood mononuclear cells. Patients will receive PNT2258 as an intravenous infusion over 2 hours once daily for 5 consecutive days (days 1-5) of each 21-day treatment cycle (3 weeks). The starting dose of 1 mg/m2 with PNT2258 administered to one patient per cohort and dose-escalation will proceed by dose-doubling in each successive cohort until a dose level of 64 mg/m2 is attained, provided no dose-limiting toxicities are observed in cycle 1. Thereafter, dose escalations shall proceed at 33% increments of the previous cohort dose-level to 85, 113, and 150 mg/m2 with expansions of up to six patients per cohort as needed. The ten planned dose cohorts have been completed with all patients enrolled.

Final results from a phase I trial of ixabepilone in patients with advanced malignancies and lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2039-2039
Author(s):  
C. Aghajanian ◽  
O. O’Connor ◽  
M. Cohen ◽  
R. Peck ◽  
H. Burris
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2039 Background: Ixabepilone is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixabepilone has shown clinical activity in a broad range of tumors. Methods: This Phase I trial was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), efficacy, safety, pharmacokinetics and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or lymphoma. Eligible patients were aged ≥18 years with histologically/cytologically confirmed non-hematologic cancer, or a pathologic diagnosis of relapsed/primary refractory non-Hodgkin’s lymphoma (NHL) or relapsed/primary refractory mantle cell lymphoma, with ≤CTC Grade 1 neuropathy. Ixabepilone doses ranged from 7.5–65 mg/m2. Response was assessed every 6 weeks using RECIST. DLT was defined as Grade 4 neutropenia and/or febrile neutropenia, thrombocytopenia, ≥Grade 3 nausea/vomiting and non-hematologic toxicity, or treatment delay of >2 weeks due to delayed recovery. Results: Of 61 patients (median age 58, range 18–81), 75% had solid tumors; 25% had lymphoma. 98% and 67% of patients had received one or ≥ two prior chemotherapy regimens, respectively. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The most common DLTs were neutropenia, myalgia, arthralgia and stomatitis/pharyngitis. A total of eight patients (13%) achieved a durable objective response. Complete responses were achieved in two patients with primary peritoneal cancer and NHL. A partial response was seen in six patients. The most common Grade 3/4 treatment-related adverse events (only observed at doses ≥40 mg/m2) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), nausea (5%), febrile neutropenia (5%) and neutropenia (5%). Recovery to baseline or ≤Grade 1 neuropathy occurred in some patients. Conclusions: The recommended dose of ixabepilone for the initiation of Phase II studies based on this study is 50 mg/m2 over 1 hour every 3 weeks. Ixabepilone demonstrates promising safety in patients with solid tumors or lymphoma who have failed standard therapy. Encouraging activity was reported in several tumor types. [Table: see text]

Phase I trial of combination becatecarin and oxaliplatin in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2561-2561
Author(s):  
S. Manda ◽  
C. Mauser ◽  
J. Bokar ◽  
M. Cooney ◽  
J. Brell ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Performance Status ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Level 2

2561 Background: Becatecarin (rebeccamycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase I trial to a) determine the maximum tolerated dose (MTD) of RA in combination with oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain data on pharmacokinetics and (d) observe for any antitumor activity. Methods: Eligibility criteria included patients with advanced solid tumors refractory to standard therapy; performance status 0–2; adequate hematologic, renal and liver function. Patients were treated with RA as a 1 hour infusion daily x 5 and oxaliplatin on day 5 only, after RA infusion. Treatment was repeated q 21 days. The following dose levels were evaluated: Dose level 1: RA 80 mg/m2/d and oxaliplatin 90 mg/m2; Dose level 2: RA 80 mg/m2/d and oxaliplatin 130 mg/m2; Dose level 3: RA 110 mg/m2/d and oxaliplatin 130 mg/m2. Results: A total of 15 evaluable patients were enrolled. Median age was 56 (8 male, 7 female). A variety of tumor types were enrolled. A total of 56 cycles were administered. DLT occurred at a dose of RA at 110 mg/m2/d x 5 days and oxaliplatin at 130 mg/m2 and consisted of grade 3 hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3 enrolled patients also developed grade 3 neutropenia. The MTD and recommended phase II dose was RA at 80 mg/m2/daily x 5 along with oxaliplatin 130 mg/m2 day 5 q 21 days. Three confirmed partial responses were observed in patients with hepatocellular, gallbladder and esophageal cancers. Six patients experienced stable disease. Conclusions: At the MTD combination RA and oxaliplatin is well tolerated and given the response rate and stable diseases observed, phase II studies are recommended. Supported by Grants U01 CA62502, MO1-RR-00080, K23 CA109348–01 from the National Institutes of Health. No significant financial relationships to disclose.

Phase I trial of cabazitaxel plus cisplatin in patients with advanced solid tumors.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 162-162 ◽  
Author(s):  
Albert C. Lockhart ◽  
Shankar Sundaram ◽  
John Sarantopoulos ◽  
Monica M. Mita ◽  
Alex R. Lane ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Combined Treatment ◽  
Primary Objective ◽  
Phase Iii ◽  
Clinical Activity ◽  
Primary Tumors ◽  
Grade 3

162 Background: Cabazitaxel (Cbz) is a novel taxane with broad in vivo efficacy in taxane-sensitive and -resistant tumors. Clinical activity of Cbz was confirmed in the Phase III TROPIC trial ( NCT00417079 ); Cbz significantly improved overall survival compared with mitoxantrone in patients (pts) with metastatic castration-resistant prostate cancer whose disease had progressed during or after a prior docetaxel-containing regimen. Therapeutic synergism of Cbz/cisplatin (Cis) has been demonstrated in tumor-bearing mice. Methods: The primary objective in part 1 of this Phase I study ( NCT00925743 ) was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz/Cis. Secondary objectives were safety, pharmacokinetics (PK) and efficacy. The primary objective of part 2 was to determine the antitumor activity at the MTD. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1, with confirmed metastatic or unresectable solid tumors for which Cis therapy was considered appropriate. A 3 + 3 dose escalation with a starting dose (level 0) of 20/75 mg/m2 (Cbz/Cis), administered IV Q3W, was used. The MTD was the highest dose at which 0/3 or ≤ 1/6 pts experienced a DLT in Cycle 1. Results: Pts (N = 25; 10 in part 1; 15 in part 2) with a median age of 56 yrs were enrolled. The most frequent primary tumors were lung (n = 4), prostate, ovary and pancreas (each n = 2). 2 of 6 evaluable pts experienced a DLT at dose level 0 (Grade 3 acute renal failure; febrile neutropenia). The MTD was 15/75 mg/m2 as no DLTs were observed. Eighteen pts were treated at the MTD and 60 cycles were administered (median = 3; range 1–8). The most frequent non-hematologic treatment-related adverse events (all Grade/Grade 3–4) were nausea (78%/22%), vomiting (72%/11%), fatigue (61%/17%), anorexia (67%/11%) and diarrhea (44%/0%). Incidence of Grade 3–4 neutropenia was 78% and 1 pt had febrile neutropenia. No PK interactions between Cbz and Cis were observed. Stable disease was seen in 11 pts. No objective responses were reported. Conclusions: The MTD of Cbz/Cis was 15/75 mg/m2. The combination had a manageable safety profile consistent with that of a platinum/taxane combination. No PK interactions were seen. Further investigations into the combined treatment combination are planned.

scholarly journals First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody–Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors

2020 ◽  
Vol 38 (16) ◽  
pp. 1824-1835 ◽  
Author(s):  
Raffit Hassan ◽  
George R. Blumenschein ◽  
Kathleen N. Moore ◽  
Alessandro D. Santin ◽  
Hedy L. Kindler ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Phase Ii Studies ◽  
Antibody Drug

PURPOSE This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody–drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin. PATIENTS AND METHODS This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week. RESULTS Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non–small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity. CONCLUSION Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.

Deflexifol (a novel formulation of 5FU): Phase 1 dose escalation study of infusional and bolus schedules after failure of standard treatment.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2529-2529
Author(s):  
Philip R. Clingan ◽  
Stephen P. Ackland ◽  
Marie Ranson ◽  
Daniel Brungs ◽  
Morteza Aghmesheh ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Standard Treatment ◽  
Phase 1 ◽  
Liver Function Tests ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Advanced Malignancy ◽  
Grade 3

2529 Background: 5-Fluorouracil (5FU) is administered in combination with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible as 5FU and LV are chemically incompatible, so the maximum possible interaction for benefit is not achieved Deflexifol, an all in one formulation of 5FU/LV with cyclodextrin (HP-β-CD 100mg/ml, 5-FU 15mg/ml & LV 1mg/ml) at physiological pH, was developed to improve efficacy and tolerance. Methods: A phase I dose-escalation trial to assess the safety, tolerability, MTD and DLT of Deflexifol given in two schedules has been completed. Secondary objectives included the pharmacokinetic (PK) profile and efficacy outcomes. Cohorts of patients with advanced malignancy after failure of standard treatment received Deflexifol as 46-h infusion Q2W or bolus weekly x6 in a standard 3+3 phase I design with no intra-patient dose escalation from dose level 1: 375mg/m² bolus or 1200mg/m² infusional up to dose level 5: 575mg/m² bolus or 3600mg/m² infusional. PK sampling of 5FU and dihydroFU was conducted on all patients to assess PK variability and adequacy of dosing. Results: 40 patients (21 infusional, 19 bolus) with breast (7), colorectal (24), other GI (6) & NSCLC (3) received a total 293 courses of treatment. No > grade 1 toxicity was noted at 375-475 mg/m2 bolus, or at 1200-2400 mg/m2 infusion. The DLT in bolus schedule was grade 3 diarrhea and myelosuppression at 575 mg/m2, with no DLT in the infusion schedule at the maximum dose 3600 mg/m2. The MTD have been established for both treatment arms: bolus 525mg/m²; 46-h infusion 3,600mg/m², with no grade IV toxicity observed. Other grade 3 toxicities were nausea, vomiting, and raised liver function tests. 5FU PK in this mixture is similar to 5FU alone. Encouraging efficacy results were seen with partial response in 1 patient and stable disease in 23 patients. Median PFS was (12.3 wks) and OS was (24.8 wks). Conclusions: Deflexifol has little toxicity and is effective in bolus and infusion schedules at doses equal to or greater than those feasible with 5FU and LV infused separately. A first-line phase II study in combination with oxaliplatin is planned. Clinical trial information: 044867.

Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

1994 ◽  
Vol 12 (12) ◽  
pp. 2743-2750 ◽  
Author(s):  
A A Miller ◽  
J B Hargis ◽  
R C Lilenbaum ◽  
S Z Fields ◽  
G L Rosner ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Grade 3 ◽  
Dose Levels

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

scholarly journals Phase I Escalation and Expansion Study of Bemarituzumab (FPA144) in Patients With Advanced Solid Tumors and FGFR2b-Selected Gastroesophageal Adenocarcinoma

2020 ◽  
Vol 38 (21) ◽  
pp. 2418-2426 ◽  
Author(s):  
Daniel V.T. Catenacci ◽  
Drew Rasco ◽  
Jeeyun Lee ◽  
Sun Young Rha ◽  
Keun-Wook Lee ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Gastroesophageal Junction ◽  
Single Agent ◽  
Phase Iii ◽  
Pharmacokinetic Parameters ◽  
Clinical Activity ◽  
Advanced Stage ◽  
Line Therapy

PURPOSE To evaluate the safety, pharmacokinetics, and preliminary activity of bemarituzumab in patients with FGFR2b-overexpressing gastric and gastroesophageal junction adenocarcinoma (GEA). PATIENTS AND METHODS FPA144-001 was a phase I, open-label, multicenter trial consisting of the following 3 parts: part 1a involved dose escalation in patients with recurrent solid tumors at doses ranging from 0.3 to 15 mg/kg; part 1b involved dose escalation in patients with advanced-stage GEA; and part 2 involved dose expansion in patients with advanced-stage GEA that overexpressed FGFR2b at various levels (4 cohorts; high, medium, low, and no FGFR2b overexpression) and 1 cohort of patients with FGFR2b-overexpressing advanced-stage bladder cancer. RESULTS Seventy-nine patients were enrolled; 19 were enrolled in part 1a, 8 in part 1b, and 52 in part 2. No dose-limiting toxicities were reported, and the recommended dose was identified as 15 mg/kg every 2 weeks based on safety, tolerability, pharmacokinetic parameters, and clinical activity. The most frequent treatment-related adverse events (TRAEs) were fatigue (17.7%), nausea (11.4%), and dry eye (10.1%). Grade 3 TRAEs included nausea (2 patients) and anemia, neutropenia, increased AST, increased alkaline phosphatase, vomiting, and an infusion reaction (1 patient each). Three (10.7%) of 28 patients assigned to a cohort receiving a dose of ≥ 10 mg/kg every 2 weeks for ≥ 70 days reported reversible grade 2 corneal TRAEs. No TRAEs of grade ≥ 4 were reported. Five (17.9%; 95% CI, 6.1% to 36.9%) of 28 patients with high FGFR2b-overexpressing GEA had a confirmed partial response. CONCLUSION Overall, bemarituzumab seems to be well tolerated and demonstrated single-agent activity as late-line therapy in patients with advanced-stage GEA. Bemarituzumab is currently being evaluated in combination with chemotherapy in a phase III trial as front-line therapy for patients with high FGFR2b-overexpressing advanced-stage GEA.

A phase I study of a novel taxane, TL310, orally administered every week in patients (pts) with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2544-2544 ◽  
Author(s):  
R. M. Glasspool ◽  
A. V. Boddy ◽  
T. R. Evans ◽  
M. J. Griffin ◽  
A. Anthoney ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Model Systems ◽  
Clinical Activity ◽  
Neutropenic Sepsis ◽  
Grade 3 ◽  
Ecog Ps

2544 Background: TL310 is a novel, oral taxane with potent pre-clinical activity in taxane-resistant model systems. This is the first study to evaluate the safety, tolerability and pharmacokinetics (PK) of TL310 in pts with advanced refractory solid tumors. Methods: Pts with adequate hematologic, renal, and liver function received TL310 administered orally on days 1, 8 and 15 of a 28-day cycle. Pts were continuously assessed for safety and dose-limiting toxicity (DLT) was based on first cycle toxicity only. A rapid dose escalation schedule was used (1 pt per dose level until ≥ grade 2 toxicity then 3–6 patients per cohort). The maximum tolerated dose (MTD) was defined as the dose level below that at which ≥ 2 of 3–6 pts experienced DLT. PK sampling was performed on days 1, 2, 3–4, 8, 15, 16, 17–18, 22 of cycle one. Serial imaging with CT was performed every 8 weeks to assess response. Results: 18 patients [M=11, F=7], ECOG PS ≤ 2 were treated with doses of 5 (1 pt), 10 (1pt), 20 (1pt), 40(2pts), 80 (5pts), 120 (3pts) and 160 mg/m2 (5pts). 1 pt had grade 2 vomiting at 80mg/m2. This, and subsequent, dose levels were expanded to include 3 pts. 3 pts (2 at 80 and 1 at 160 mg/m2) vomited immediately after drug administration during cycle 1 and were replaced. 1/5 patients experienced a DLT at 160 mg/m2 with G5 neutropenic sepsis, G4 neutropenia and G4 thrombocytopenia. No other grade 3/4 toxicities attributed to study drug have occurred. Of 18 patients assessable for response, 1 had a partial response (gastric cancer) at 80 mg/m2 and 6 had stable disease for > 2 cycles (esophageal 3, melanoma 1, ovary 1, cervix 1). The maximum concentration (Cmax) increased with dose up to 120 mg/m2, but appeared to plateau (86±6 ng/ml) in 4 of 5 patients at 160 mg/m2. TL310 has a half-life of up to 80 hours, but PK were very similar on successive courses of treatment. Conclusions: TL310 can be administered orally up to 160 mg/m2 on day 1, 8, 15 of a 28 day cycle and shows promising activity at doses below the MTD. The MTD has not yet been defined and dose escalation continues. No significant financial relationships to disclose.

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