Phase I trial of dose escalation with growth factor support in patients with previously untreated diffuse aggressive lymphomas: determination of the maximum-tolerated dose of ProMACE-CytaBOM.

1996 ◽  
Vol 14 (4) ◽  
pp. 1275-1281 ◽  
Author(s):  
L I Gordon ◽  
J Anderson ◽  
T M Habermann ◽  
J N Winter ◽  
J Glick ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Bone Marrow Involvement ◽  
Stage Iv ◽  
Dose Intensity ◽  
Maximum Tolerated Dose ◽  
Phase Ii Trials ◽  
Gm Csf

PURPOSE The aim of this study was to determine the maximum-tolerated dose (MTD) of cyclophosphamide, doxorubicin, etoposide, prednisone, bleomycin, cytarabine, methotrexate, and leucovorin (ProMACE-CytaBOM) when the myelotoxic drugs cyclophosphamide, doxorubicin, etoposide, and cytarabine are escalated. PATIENTS AND METHODS Thirty-eight eligible patients with diffuse aggressive non-Hodgkin's lymphoma were treated on a phase I trial of dose escalation using the ProMACE-CytaBOM regimen and granulocyte-macrophage colony-stimulating factor (GM-CSF; Schering, Kenilworth, NJ). Patients were treated with recombinant (r)GM-CSF 10 microg/kg/d subcutaneously from day 9 to 19. Twenty-seven patients had stage IV disease, four had stage III, and seven had bulky stage II. Half of the patients had bone marrow involvement. The median age was 45 years. RESULTS We found that the MTD was 200% for the escalated drugs in this regimen (although we never escalated above the MTD or defined by dose-limiting toxicity) and that the normalized dose-intensity (NDI; defined as the ratio of the received dose-intensity to the 100% dose-intensity of ProcMACE-CytaBOM) decreased with each cycle and was lower for the day-8 drug (cytarabine) than for the day-1 drugs. The complete response (CR) rate was 66%, and 92% of patients who achieved CR are alive without disease with a median follow-up time for survival of 3.6 years. CONCLUSION The MTD of cyclophosphamide, doxorubicin, etoposide, and cytarabine in the ProMACE-CytaBOM regimen given with growth factor support is 200%, and this dose should be tested in larger phase II trials.

A three schedule phase I trial of CP-4055, weekly and q2 weeks in patients with advanced or metastatic solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2067-2067 ◽  
Author(s):  
T. Delaunoit ◽  
E. Raymond ◽  
A. Awada ◽  
F. Savinelli ◽  
S. Culine ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Dose Intensity ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Ecog Ps ◽  
Tumor Types

2067 Background: CP-4055 (ELACYT, ara-C 5’-elaidic acid ester) is a novel cytotoxic agent with broad preclinical antitumor activity in solid tumors. CP-4055 is based on Lipid Vector Technology and has a different cellular uptake compared to ara-C. An initial phase I trial of a day 1–5 q4 weeks (w) schedule (sch) determined a recommended dose of 200 mg/m2/day and showed clinical activity (Aamdal et al, AACR 2005). We report a multiple sch, parallel, dose intensity-guided dose escalation phase I trial, with pharmacokinetic (PK) assessment, intended to determine Maximum Tolerated Dose (MTD). Methods: Patients (pts) with refractory solid tumors received i.v. CP-4055 over 2 hours according to 3 sch: days 1, 8 q3w (Sch 1); days 1, 15 q4w (Sch 2); days 1, 8, 15 q4w (Sch 3). Dose escalation: dose level (DL) 1: 80 mg/m2/w, DL2: 160; DL3: 240; DL4: 320; DL5: 400; DL6: 440; DL7: 520, with standard definitions of dose limiting toxicity (DLT). Results: Since June 2004, 45 pts have been treated in 4 European centers; 3 are still ongoing, 37 discontinued for progressive disease, 3 for refusal, 2 for AE (1 treatment-related grade [gr] 3 paresthesia), trial is ongoing. Demographics: male/female: 27/18; median age 54 (range 35–79); ECOG PS 0/1/2: 19/24/2. Main tumor types: colorectal 6, breast 5, head & neck 5; median 3 lines prior chemotherapy (range 0–5). Exposure: 128 cycles administered, including 5 pts with ≥ 6 cycles. MTD: No DLT has been observed and dose escalation is ongoing. Safety (NCI-CTCAE v3): 45 pts assessable. Principal toxicities by pt (gr 1–2/3): anemia 34/1; nausea and vomiting 29/3; asthenia 24/1; neutropenia 12/2; headache 8/0; thrombocytopenia 3/0. No clear association with sch or DL was observed for this mild/moderate toxicity. There were no dose reductions. PK: ara-U/ara-C AUC ratio exceeds by 3-fold the standard ara-U/ara-C AUC ratio. Efficacy: 41 pts were assessable, 10 pts had stable disease (lasting > 6 months in 4 pts: 2 NSCLC, 1 colorectal, 1 kidney). Conclusions: CP-4055 shows preliminary evidence of activity and is well tolerated up to a dose of 440 mg/m2/w. PK results indicate that a majority of ara-U in plasma originates from intracellular deamination of ara-C from CP-4055, confirming intracellular retention of CP-4055. Accrual is ongoing at the DI of 520 mg/m2/w. [Table: see text]

scholarly journals First-in-human phase I trial of anti-hepatocyte growth factor antibody (YYB101) in refractory solid tumor patients

2020 ◽  
Vol 12 ◽  
pp. 175883592092679
Author(s):  
Seung Tae Kim ◽  
Jung Yong Hong ◽  
Se Hoon Park ◽  
Joon Oh Park ◽  
Young Whan Park ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Phase I ◽  
Cancer Patients ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Safety And Efficacy ◽  
Hepatocyte Growth

Background: YYB101, a humanized monoclonal antibody against hepatocyte growth factor (HGF), has shown safety and efficacy in vitro and in vivo. This is a first-in-human trial of this antibody. Materials and Methods: YYB101 was administered intravenously to refractory cancer patients once every 4 weeks for 1 month, and then once every 2 weeks until disease progression or intolerable toxicity, at doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were studied. HGF, MET, PD-L1, and ERK expression was evaluated for 9 of 17 patients of the expansion cohort (20 mg/kg). Results: In 39 patients enrolled, no dose-limiting toxicity was observed at 0.3 mg/kg, and the most commonly detected toxicity was generalized edema ( n = 7, 18.9%) followed by pruritis and nausea ( n = 5, 13.5%, each), fatigue, anemia, and decreased appetite ( n = 4, 10.8%, each). No patient discontinued treatment because of adverse events. YYB101 showed dose-proportional pharmacokinetics up to 30 mg/kg. Partial response in 1 (2.5%) and stable disease in 17 (43.5%) were observed. HGF, MET, PD-L1, and ERK proteins were not significant predictors for treatment response. However, serum HGF level was significantly lowered in responders upon drug administration. RNA sequencing revealed a mesenchymal signature in two long-term responders. Conclusion: YYB101 showed favorable safety and efficacy in patients with refractory solid tumors. Based on this phase I trial, a phase II study on the YYB101 + irinotecan combination in refractory metastatic colorectal cancer patients is planned. Conclusion: ClinicalTrials.gov Identifier: NCT02499224

Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma.

1998 ◽  
Vol 16 (6) ◽  
pp. 2169-2180 ◽  
Author(s):  
A L Yu ◽  
M M Uttenreuther-Fischer ◽  
C S Huang ◽  
C C Tsui ◽  
S D Gillies ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Target Cells ◽  
Complement Dependent Cytotoxicity ◽  
Clinical Responses

PURPOSE To evaluate the toxicity, immunogenicity, and pharmacokinetics of a human-mouse chimeric monoclonal antibody (mAb) ch 14.18 directed against disialoganglioside (GD2) and to obtain preliminary information on its clinical efficacy, we conducted a phase I trial in 10 patients with refractory neuroblastoma and one patient with osteosarcoma. PATIENTS AND METHODS Eleven patients were entered onto this phase I trial. They received 20 courses of mAb ch 14.18 at dose levels of 10, 20, 50, 100, and 200 mg/m2. Dose escalation was performed in cohorts of three patients; intrapatient dose escalation was also permitted. RESULTS The most prevalent toxicities were pain, tachycardia, hypertension, fever, and urticaria. Most of these toxicities were dose-dependent and rarely noted at dosages of 20 mg/m2 and less. Although the maximum-tolerated dose was not reached in this study, clinical responses were observed. These included one partial (PR) and four mixed responses (MRs) and one stable disease (SD) among 10 assessable patients. Biologic activity of ch 14.18 in vivo was shown by binding of ch 14.18 to tumor cells and complement-dependent cytotoxicity of posttreatment sera against tumor target cells. An anti-ch 14.18 immune response was detectable in seven of 10 patients studied. CONCLUSION In summary, with the dose schedule used, ch 14.18 appears to be clinically safe and effective, and repeated mAb administration was not associated with increased toxicities. Further clinical trials of mAb ch 14.18 in patients with neuroblastoma are warranted.

scholarly journals Phase I study of tomuzotuximab, a glycoengineered therapeutic antibody against the epidermal growth factor receptor, in patients with advanced carcinomas

ESMO Open ◽  
2018 ◽  
Vol 3 (2) ◽  
pp. e000303 ◽  
Author(s):  
Walter Fiedler ◽  
Sara Cresta ◽  
Henning Schulze-Bergkamen ◽  
Sara De Dosso ◽  
Jens Weidmann ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Phase I ◽  
Dose Escalation ◽  
Antitumour Activity ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Epidermal Growth

BackgroundChanges in glycosylation of the constant domain (Fc) of monoclonal antibodies (mAbs) enhance antibody-dependent cell-mediated cytotoxicity independently of downstream effects following receptor blockade by the antibody, thus extending their indication. We investigated the safety, pharmacokinetics, pharmacodynamics and antitumour activity of tomuzotuximab, an IgG1 glycoengineered mAb against the epidermal growth factor receptor with enhanced tumour cytotoxicity in a phase I dose-escalation study (NTC01222637).Patients and methodsForty-one patients with advanced solid tumours refractory to standard therapies received tomuzotuximab weekly (12–1370 mg) or two-weekly (990 mg) on a three-plus-three dose escalation design.ResultsA maximum tolerated dose was not reached. The most frequent treatment-related adverse events were infusion-related reactions in 31 (76%) patients (grade 3, 12%), mainly confined to the first dose, and skin toxicities (grade 1 or 2) in 30 (73%) patients. Hypomagnesaemia was observed in 9 out of 23 evaluable patients (39%). Similar to cetuximab, tomuzotuximab concentrations increased proportionally to dose from doses≥480 mg with a median terminal half life (t½) of 82 hours, range 55–113 hours. Antitumour activity included one complete response ongoing since more than 4.5 years in a patient with non-small-cell lung cancer and one partial response lasting 353 days in a patient with colorectal cancer. Twelve patients achieved stable disease (median, 166 days, range, 71–414 days) and two patients had prolonged control (>1 year) of their non-measurable disease.ConclusionTomuzotuximab was safe and showed promising antitumour activity in heavily pretreated patients with advanced metastatic disease. A phase IIb trial of chemotherapy and weekly tomuzotuximab or cetuximab followed with maintenance therapy with the corresponding mAb in patients with recurrent or metastatic head and neck squamous cell carcinoma is ongoing.

Phase i Trial with Peptichemio

1979 ◽  
Vol 65 (1) ◽  
pp. 99-104
Author(s):  
Lucien Israel ◽  
Maurice Kohn ◽  
Alain Depierre ◽  
Jacques Aguilera
Keyword(s):  
Drug Treatment ◽  
Phase I ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Hematological Toxicity ◽  
Cytostatic Drug ◽  
Cytostatic Drugs ◽  
Phase Ii Trials ◽  
Repeated Administrations ◽  
Infusion Fluid

Thirty-two patients with tumor progression, even after conventional cytostatic drug treatment, were treated with peptichemio, with increasing doses for groups of 4 patients. The maximum tolerated dose (with minimum hematological toxicity and without any other evident toxicity) with repeated administrations, was 1.2 mg/kg twice weekly. The recommended doses for phase II trials are, as shown by the detailed analysis of the results, 0.9 mg/kg, twice weekly and administered alone, and 1.3 mg/kg, once weekly combined with other cytostatic drugs, in 500 ml of infusion fluid, with 25 mg of heparin and 25 mg of hydrocortisone to minimize the frequent risk of local phlebosclerosis.

A phase I trial of nab-paclitaxel/bevacizumab (AB160) nano-immunoconjugate therapy for unresectable stage IV malignant melanoma (MM): MC1371 (NCT02020707).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22020-e22020
Author(s):  
Matthew Stephen Block ◽  
Vera J. Suman ◽  
Wendy Kay Nevala ◽  
Heidi Diann Finnes ◽  
Jill Schimke ◽  
...  
Keyword(s):  
Phase I ◽  
Targeted Delivery ◽  
Clinical Benefit ◽  
Phase I Trial ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Eligibility Criteria ◽  
Unresectable Stage ◽  
Previously Treated

e22020 Background: The combination of nab-paclitaxel (NP) and bevacizumab (BEV) in patients with MM has shown promising clinical activity. AB160 is a 160 nm nano-immunoconjugate of NP nanoparticles non-covalently coated with BEV for targeted delivery into high VEGF expressing tissues. Preclinical data showed that AB160 improved tumor targeting/ tumor inhibition more than NP followed by BEV. Methods: A 3+3 phase I trial was conducted in patients (pts) with MM who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. Dose level 1 (DL1) was 125 mg/m2 NP /50 mg/m2 BEV. Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT < 25,000, serum creatinine ≥ 2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Tumor evaluations (RECIST) were conducted every 8 weeks. Treatment continued until progression or intolerability. Results: 21 pts (11 ♀) aged 36-78 years old were enrolled. One of the first 3 pts on DL1 developed a G2 colonic perforation; this was considered a DLT. One of the next 3 pts on DL1 had a DLT: G4 neutropenia. Of the 3 pts on DL-1 (100 mg/m2 NP/40 mg/m2 BEV), 2 had no DLTs and 1 died of sepsis after C1D1 dose. Enrollment was suspended until an amendment modifying the eligibility criteria was approved by the IRB. The trial reopened. One of the 4 pts on DL-1 and 1 of the 5 pts on DL1 had a DLT: G3 pain and G3 fatigue, respectively. Enrollment ended after 2 of the 3 pts on DL2 (150 mg/m2 NP/ 60 mg/m2 BEV) developed G4 neutropenia. Thus, MTD is DL1. A median of 3 cycles was administered. Treatment ended due to progression (9), intolerability (9), refusal (2) and death (1). There were no objective tumor responses. Common G3-4 toxicities were: neutropenia (33%) and thromboembolic events (19%). Conclusions: AB160 was found to have insufficient clinical benefit in patients with previously treated MM to justify further development. However, parallel phase I testing in gynecologic cancers suggests clinical benefit (abstract #300225). Clinical trial information: NCT02020707.

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