A phase I and pharmacokinetic study of continuous infusion EMD 121974 (EMD), an antiangiogenic αvβ3 and αvβ5 integrin antagonist, in patients with advanced solid malignancy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3052-3052 ◽  
Author(s):  
S. D. Undevia ◽  
L. Janisch ◽  
W. M. Stadler ◽  
S. M. Wittemer ◽  
M. J. Ratain
Keyword(s):  
Phase I ◽  
Continuous Infusion ◽  
Dose Level ◽  
Half Life ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Pharmacokinetic Analysis ◽  
Published Data ◽  
Pharmacokinetic Studies ◽  
Dose Levels

3052 Background: Integrins αvβ3 and αvβ5 are cell-surface receptors that play a significant role in angiogenesis by mediating the ligation signal that allows endothelial cells to attach to the extracellular matrix. These integrins share the binding epitope Arg-Gly-Asp (RGD). EMD is an RGD-containing cyclic pentapeptide. In clinical studies to date, EMD has been administered in an intermittent fashion. However, EMD has a short half-life of 3–5 hours with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion EMD. Methods: EMD was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 hours after infusion bag change. Results: To date 21 patients (15 male/6 female, median age 56, median Karnofsky performance status 90%) have been treated at the following dose levels: 1, 2, 4, 8, 12, 18, and 27 mg/h. Hematologic toxicities have been limited to grade 2 anemia and grade 3 lymphopenia. Non-hematologic toxicities have been limited to grade ≤ 2 and include alopecia, anorexia, diarrhea, fatigue, hypokalemia, hyponatremia, hypophosphatemia, insomnia, mucositis, nail changes, nausea, and transaminase elevation. One patient treated at 27 m/h experienced an unobserved death of unknown cause after two weeks of therapy. Pharmacokinetic analysis has been completed for patients treated at the 12 mg/h dose level and below. Mean values for half-life, clearance, and volume of distribution were comparable across dose levels, and steady-state concentration increased proportionally to dose. Conclusions: EMD can be safely administered as a continuous infusion at doses of up to at least 18 mg/h. No single toxicity has been consistently observed. A patient death in cycle 1 has resulted in the expansion of the 27 mg/h dose level. The pharmacokinetics of continuous infusion EMD were predictable and in general agreement with the published data of twice weekly infusion. Study enrollment is ongoing. [Table: see text]

Final results of phase I and pharmacokinetic study of SJG-136 administered on a daily x 5 schedule

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13506-e13506 ◽  
Author(s):  
T. M. Kadia ◽  
S. Faderl ◽  
Z. Estrov ◽  
M. Konopleva ◽  
S. George ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Median Number ◽  
Clinical Activity ◽  
Vascular Leak ◽  
Ecog Performance Status ◽  
Acute Leukemias ◽  
Number Of Patients ◽  
Dose Levels

e13506 Background: SJG-136 is a pyrrolobenzodiazepine dimer that forms covalent DNA crosslinks in a sequence-specific manner in the minor groove. In vitro testing demonstrated a broad pattern of antitumor activity in sub-nmol concentrations. A phase I study in patients (pts) with solid tumors revealed clinical activity, defined MTD as 30 mg/m2/d administered on daily x 3 schedule, and confirmed manageable toxicity. Here we report the results of a CTEP-sponsored phase I trial of SJG-136 administered on a daily x 5 schedule in pts with relapsed or refractory (R/R) leukemias. Methods: Previously treated pts with R/R acute leukemias (AML, ALL, high risk MDS, CML blast phase) or R/R CLL with adequate organ function and ECOG performance status of ≤ 2 were eligible for the study. The starting dose level was 6 mcg/m2 given intravenously daily x 5 days on a 21 day cycle. Pts were sequentially enrolled in cohorts of 3 and the dose was escalated in a classic 3+3 schema at the dose levels: 6, 12, 24, and 36 mcg/m2. Repeat courses and intrapatient dose escalation were allowed. Results: Sixteen pts (11M, 5 F) were enrolled on the study. The median age of the patients was 53 (21–84). Thirteen (81%) pts had R/R AML, and 3 (19%) had R/R ALL of which 5 (31%) had diploid and 6 (38%) had adverse cytogenetics. Median number of prior therapies was 3 (2–6). Pts enrolled at each dose level (mcg/m2) were: 6 (3 pts), 12 (5 pts), 24 (4 pts), 36 (4 pts). The median number of cycles delivered was 1 (0–5). The dose of 36 mcg/m2 was found to be above the MTD, with the DLT being grade 3 soft tissue edema. Other manifestations of vascular leak including grade I, II hypoalbuminemia, edema, and pleural effusions were seen in a number of patients starting at dose level 24 mcg/m2 and above. Other non-dose limiting toxicities included nausea, dyspnea, fatigue, bloating, and insomnia. One pt had a PR, 8 pts had stable disease, and 6 had progression. Pharmacokinetic characteristics in this population will be reported. Conclusions: SJG-136 is safe and active in patients with advanced leukemias. Edema and other vascular leak syndromes are characteristic toxicities of the agent at higher dose levels. 24 mcg/m2 is the recommended phase II dose for the daily x 5 schedule. No significant financial relationships to disclose.

Vorinostat in combination with gemcitabine and cisplatinum in patients with advanced non-small cell lung cancer (NSCLC): A Phase I dose-escalation study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8049-8049 ◽  
Author(s):  
J. Trédaniel ◽  
R. Descourt ◽  
D. Moro-Sibilot ◽  
J. Misset ◽  
E. Gachard ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Ecog Performance Status ◽  
Dose Escalation Study ◽  
Platinum Agent ◽  
Elevated Creatinine ◽  
Expansion Cohort ◽  
Dose Levels

8049 Background: Preclinical data indicate that vorinostat, a histone deacetylase inhibitor, enhances the efficacy of gemcitabine and platinum chemotherapy agents. This study investigated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of vorinostat plus gemcitabine and a platinum agent in patients (pts) with advanced NSCLC. Methods: Eligible pts (aged ≥18 years; stage IIIB/IV NSCLC, ECOG performance status ≤1, no prior systemic chemotherapy [except adjuvant]) were sequentially enrolled on escalating doses of vorinostat plus gemcitabine and a platinum agent (standard 3+3 design) for ≤6 cycles ( Table ). Carboplatin regimens were to be investigated if dose levels 1 or 2 exceeded the MTD. Results: 28 pts enrolled to date (M/F: 22/6; median age: [range] 55 [34–70] years; 20 chemonaïve) at 5 dose levels ( Table ). Two pts had DLTs: elevated creatinine leading to cisplatin dose reduction (dose level 2) and febrile neutropenia (dose level 5) ( Table ). Dose level 5 was achieved without reaching the MTD; however, based on clinical tolerability, dose level 4 was chosen as the recommended dose (RD). 24 pts had adverse events (AEs): 86% mild/moderate, 53% not considered treatment-related. The most common drug-related Grade 3/4 AEs were thrombocytopenia (19 events) and neutropenia (14 events). Serious AEs occurred in 15 pts, and 5 deaths occurred (1 ‘probably‘ and 4 ‘definitely not‘ treatment-related). Of 19 evaluable pts at 5 dose levels, 9 (47%) had a partial response, 8 stable disease, and 2 disease progression ( Table ). Updated results of pts treated at the RD in an expansion cohort will be presented. Conclusions: These phase I data suggest that vorinostat can be administered with standard doses of gemcitabine and cisplatin and the combination is active in the initial treatment of metastatic NSCLC: randomized trials are needed to determine whether addition of vorinostat improves outcomes in such pts. [Table: see text] [Table: see text]

Specific Targeting, Biodistribution, and Lack of Immunogenicity of Chimeric Anti-GD3 Monoclonal Antibody KM871 in Patients With Metastatic Melanoma: Results of a Phase I Trial

2001 ◽  
Vol 19 (19) ◽  
pp. 3976-3987 ◽  
Author(s):  
Andrew M. Scott ◽  
Fook-Thean Lee ◽  
Wendie Hopkins ◽  
Jonathan S. Cebon ◽  
Jennifer M. Wheatley ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Metastatic Melanoma ◽  
Half Life ◽  
Normal Tissue ◽  
Phase I Trial ◽  
Attractive Potential ◽  
Pharmacokinetic Analysis ◽  
Specific Targeting ◽  
Dose Levels

PURPOSE: KM871 is a chimeric monoclonal antibody against the ganglioside antigen GD3, which is highly expressed on melanoma cells. We conducted an open-label, dose escalation phase I trial of KM871 in patients with metastatic melanoma. PATIENTS AND METHODS: Seventeen patients were entered onto one of five dose levels (1, 5, 10, 20, and 40 mg/m2). Patients received three infusions of KM871 at 2-week intervals, with the first infusion of KM871 trace-labeled with indium-111 (111In) to enable assessment of biodistribution in vivo. Biopsies of metastatic melanoma sites were performed on days 7 to 10. RESULTS: Fifteen of 17 patients completed a cycle of three infusions of KM871. No dose-limiting toxicity was observed during the trial; the maximum-tolerated dose was therefore not reached. Three patients (at the 1-, 5-, and 40-mg/m2 dose levels) developed pain and/or erythema at tumor sites consistent with an inflammatory response. No normal tissue uptake of 111In-KM871 was observed, and tumor uptake of 111In-KM871 was observed in all lesions greater than 1.5 cm (tumor biopsy 111KM871 uptake results: range, 0.001% to 0.026% injected dose/g). The ratio of maximum tumor to normal tissue was 15:1. Pharmacokinetic analysis revealed a 111In-KM871 terminal half-life of 7.68 ± 2.94 days. One patient had a clinical partial response that lasted 11 months. There was no serologic evidence of human antichimeric antibody in any patient, including one patient who received 16 infusions over a 12-month period. CONCLUSION: This study is the first to demonstrate the biodistribution and specific targeting of an anti-GD3 antibody to metastatic melanoma in patients. The long half-life and lack of immunogenicity of KM871 makes this antibody an attractive potential therapy for patients with metastatic melanoma.

Vincristine Sulfate Liposomes Injection (VSLI, Marqibo): Interim Results From a Phase I Study in Children and Adolescents with Refractory Cancer

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1497-1497
Author(s):  
Nirali N Shah ◽  
Melinda Merchant ◽  
Diane Cole ◽  
Kelly Richards ◽  
Cindy Delbrook ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Pediatric Patients ◽  
Pharmacokinetic Analysis ◽  
Motor Neuropathy ◽  
Vincristine Sulfate ◽  
Level 1 ◽  
Dose Levels

Abstract Abstract 1497 Background: Vincristine is active in many pediatric cancers, but cumulative neuromuscular toxicity is often dose limiting and requires a maximum dose cap. Liposomal carriers are capable of increasing the therapeutic index of anticancer agents by altering pharmacokinetic behavior. Vincristine sulfate liposomes injection (VSLI, Marqibo®) is a novel preparation of standard vincristine encapsulated in sphingomyelin/cholesterol liposomes. Clinical trials have demonstrated safety, tolerability and activity in adults with leukemias, lymphomas and solid tumors. Pediatric experience with VSLI is limited. Design: This single center Phase I dose-escalation study is designed to determine the maximum tolerated dose (MTD) and to assess safety, pharmacokinetics and activity of VSLI in pediatric patients with relapsed/refractory cancer. Patients with active central nervous system disease or ≥grade 2 sensory or motor neuropathy are excluded. Dose escalation is per a standard 3 + 3 Phase I trial design with enrollment following a rolling 6 strategy. VSLI is administered IV over 60-minutes every 7 days (± 3 days) for 4 consecutive weeks for a 28-day treatment cycle (4 doses/cycle). Cycles may be delayed by up to 1 week for toxicity. Two dose levels have been tested to date: 1.75 mg/m2 and 2.25 mg/m2(adult MTD). No individual dose cap is employed. A validated HPLC tandem mass spectrometry assay was used to quantitate total (liposomal encapsulated and non-encapsulated) vincristine. Results: 9 patients have been treated (Table): 6 with acute lymphoblastic leukemia (ALL) and 3 with solid tumors. All patients were heavily pre-treated and 2 had prior stem cell transplants. 6 of 9 completed at least 1 cycle of therapy, with 1 each removed early for alternative therapy, complications of ALL, or dose-limiting toxicity (DLT). Most treatment-related adverse events were reversible grade 1 and 2 severity including hepatic transaminase elevation, parasthesia, low white blood cell count, neutropenia and fatigue. 2 patients evaluable for hematologic toxicity developed grade 4 neutropenia that spontaneously and rapidly resolved. No DLT occurred on dose level 1. Grade 4 aspartate aminotransferase elevation was observed in one patient at the second dose level and this dose level is being expanded. 1 patient treated at dose level 1 had dose de-escalation starting with Cycle 2 Dose 3 due to neuropathy. No patient was taken off study due to neurotoxicity. 7 of 9 patients received a VSLI dose that exceeded the 2 mg dose limit set for standard vincristine. 6 patients were evaluable for response: 1 had a complete remission (CR) (minimal residual disease negative by flow cytometry); 3 had stable disease (SD); and 2 had progressive disease (PD). First-dose pharmacokinetic analysis revealed wide interpatient variation (Table). The median (range) maximum concentrations (Cmax) of total vincristine (ng/ml) were 1,485 (845-2,120) and 2,450 (1,690-3,690) at dose levels 1 and 2 respectively. The median plasma half-life (T½) was 8.5 and 13.5 hours at dose levels 1 and 2 respectively (range 1.8 to 40.4 hours). Conclusions: VSLI appears to be safe, tolerable and demonstrates preliminary activity in pediatric patients with refractory ALL and solid tumors. The toxicity spectrum appears to be similar in children and adults. Clearance of total vincristine in our study is approximately 100-fold lower in comparison to administration of standard vincristine. VSLI allows for intensification of vincristine therapy in children with cancer. Accrual to the Phase I component at the adult recommended dose is ongoing and an expanded Phase II cohort in pediatric patients with ALL is planned. This study was sponsored by Talon Therapeutics and is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Disclosures: No relevant conflicts of interest to declare.

A phase I trial of RX-0201 (AKT anti-sense) in patients with an advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3564-3564 ◽  
Author(s):  
J. Marshall ◽  
J. Posey ◽  
J. Hwang ◽  
S. Malik ◽  
R. Shen ◽  
...  
Keyword(s):  
Phase I ◽  
Continuous Infusion ◽  
Cancer Cells ◽  
Advanced Cancer ◽  
Cancer Progression ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Current Phase

3564 Background: Akt-1, a proto-oncogene, plays a vital role in cancer progression by stimulating proliferation and inhibiting apoptosis of cancer cells. RX-0201, a 20-mer oligonucleotide with sequence complementary to Akt-1 mRNA, is designed to inhibit the expression of Akt-1 within cancer cells in cancer patients (pts). Non-clinical studies conducted on RX-0201 demonstrated that RX-0201 bears significant in vitro and in vivo anti-cancer activities with favorable safety. Purposes: The aims of the current phase I trial were to determine the maximum tolerated dose (MTD) and to establish pharmacokinetic (PK) and safety profiles of RX-0201 in pts with an advanced cancer. Methods: RX-0201 was administered to pts with an advanced cancer by up to 2 cycles of continuous infusion; each cycle of infusion lasted for 14 days which was followed by a 7-day rest. Rapid dose escalation had been used until at least a grade (G) 2 toxicity was observed, and then a traditional dose escalation followed. Entry criteria included Karnofsky Performance Status score =70, advanced cancer, tumor accessible for paired biopsy, and signed informed consent. 17 pts were enrolled and treated at a dose level ranging from 6 to 315 mg/m2/d on D1–14, repeated q 21 d. Results: G 3 fatigue was observed in two pts at the 315 mg/m2/d dose; three pts dosed at 250 mg/m2/d were not noted with any G 3 toxicity, which make this dose (250 mg/m2/d) the recommended phase II trial dose. No other significant, compound-related, adverse events were observed in those 17 pts participated. Pts PK profiles of RX-0201 and AKT-1 immunohistochemistry results on pts’ tumor biopsy samples will also be presented. Conclusion: MTD of RX-0201 is 315 mg/m2/d in pts with an advanced cancer when the compound is administered in the current continuous infusion regimen. No significant financial relationships to disclose.

scholarly journals A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5218-5218
Author(s):  
Sonia Christian ◽  
Kelley E. Kozma ◽  
Stephanie Barath ◽  
Ardaman Shergill ◽  
Damiano Rondelli ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
De Novo ◽  
Standard Of Care ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Induction Regimen ◽  
Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Phase I Study of a Weekly Schedule of Irinotecan, High-Dose Leucovorin, and Infusional Fluorouracil as First-Line Chemotherapy in Patients With Advanced Colorectal Cancer

1999 ◽  
Vol 17 (3) ◽  
pp. 907-907 ◽  
Author(s):  
Udo Vanhoefer ◽  
Andreas Harstrick ◽  
Claus-Henning Köhne ◽  
Wolf Achterrath ◽  
Youcef M. Rustum ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Advanced Colorectal Cancer ◽  
High Dose ◽  
Weekly Schedule ◽  
First Line ◽  
Dose Levels ◽  
Line Chemotherapy

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies.

1993 ◽  
Vol 11 (3) ◽  
pp. 499-506 ◽  
Author(s):  
J Weber ◽  
J C Yang ◽  
S L Topalian ◽  
D R Parkinson ◽  
D S Schwartzentruber ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Interleukin 6 ◽  
Phase Ii Trials ◽  
Organ Toxicity ◽  
Advanced Malignancies ◽  
Major Organ ◽  
Dose Levels ◽  
Grade Iii

PURPOSE Based on preclinical evidence in murine models that interleukin-6 (IL-6) mediates regression of metastatic tumors, we performed a phase I study of recombinant human IL-6 in patients with refractory advanced malignancies to determine its pharmacokinetics, toxicities, and possible immunologic and antitumor effects. PATIENTS AND METHODS Recombinant IL-6 was administered as a single subcutaneous dose daily for 7 days, with 7 days off therapy followed by another 7 days of IL-6. Doses were escalated in cohorts of three patients starting at 3 micrograms/kg/d, provided that toxicity at the preceding dose level was not dose-limiting. Dose-limiting toxicity was defined as grade III or IV major organ toxicity that did not resolve to grade II or less in 24 hours after stopping IL-6, using the National Cancer Institute Common Toxicity Criteria. Patients were treated with 3, 10, and 30 micrograms/kg/d IL-6 subcutaneously. RESULTS Three patients each were treated at the 3- and 10-micrograms dose levels. Two of five patients treated with 30 micrograms/kg/d IL-6 subcutaneously had grade III major organ toxicity that required IL-6 therapy to be discontinued. All patients experienced fever, chills, and minor fatigue. Significant increases in C-reactive protein (CRP), fibrinogen, platelet counts, and lymphocyte IL-2 receptor levels were seen in patients at the 10- and 30-micrograms/kg dose levels. Decreases in albumin and hemoglobin were observed, particularly at the 30-micrograms/kg dose level. The half-life (T1/2 beta) was 4.2 hours, with a peak IL-6 level at 5 hours. No antitumor responses were seen. CONCLUSION A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.

Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2

2019 ◽  
Vol 37 (3) ◽  
pp. 230-238 ◽  
Author(s):  
Teresa Macarulla ◽  
Roberto Pazo-Cid ◽  
Carmen Guillén-Ponce ◽  
Rafael López ◽  
Ruth Vera ◽  
...  
Keyword(s):  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Ductal Adenocarcinoma ◽  
Tolerability Profile ◽  
Ecog Performance Status ◽  
Actuarial Survival ◽  
Number Of Patients

Purpose Gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (GA) significantly improved survival compared with gemcitabine alone in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and a Karnofsky performance status (PS) of 70% or greater. Because of the low number of patients with reduced PS, the efficacy of this regimen in fragile patients remains unclear. This study aimed to evaluate the efficacy and tolerability of different GA dosing regimens in patients with a poor PS. Patients and Methods In the phase I part of this study, patients were randomly assigned to one of the following four parallel GA treatment arms (six patients per arm): a biweekly schedule of NAB-paclitaxel (150 mg/m2 [arm A] or 125 mg/m2 [arm C]) plus gemcitabine 1,000 mg/m2 or a standard schedule of 3 weeks on and 1 week off of NAB-paclitaxel (100 mg/m2 [arm B] or 125 mg/m2 [arm D]) plus gemcitabine 1,000 mg/m2. The two regimens with the better tolerability profile on the basis of predefined criteria were evaluated in the phase II part of the study, the primary end point of which was 6-month actuarial survival. Results Arms B and D were selected for the phase II part of the study. A total of 221 patients (111 patients in arm B and 110 patients in arm D) were enrolled. Baseline characteristics including median age (71 and 68 years in arms B and D, respectively), sex (51% and 55% men in arms B and D, respectively), and metastatic disease (88% and 84% in arms B and D, respectively) were comparable between arms. The most frequent grade 3 or 4 toxicities in arms B and D were anemia (12% and 7%, respectively), neutropenia (32% and 30%, respectively), thrombocytopenia (7% and 11%, respectively), asthenia (14% and 16%, respectively), and neurotoxicity (11% and 16%, respectively). In arms B and D, there were no significant differences in response rate (24% and 28%, respectively), median progression-free survival (5.7 and 6.7 months, respectively), and 6-month overall survival (63% and 69%, respectively). Conclusion NAB-paclitaxel administered at either 100 and 125 mg/m2 in combination with gemcitabine on days 1, 8, and 15 every 28 days is well tolerated and results in acceptable safety and efficacy in patients with metastatic pancreatic ductal adenocarcinoma and a poor PS.

Phase I/II Study of Escalating Doses of Vinorelbine in Combination With Oxaliplatin in Patients With Advanced Non–Small-Cell Lung Cancer

2001 ◽  
Vol 19 (2) ◽  
pp. 458-463 ◽  
Author(s):  
Isabelle Monnet ◽  
Patrick Soulié ◽  
Hubert de Cremoux ◽  
Sabine Saltiel-Voisin ◽  
Mohammed Bekradda ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Fixed Dose ◽  
Platinum Compound ◽  
Small Cell Lung ◽  
Dose Levels

PURPOSE: Oxaliplatin is a platinum compound active in non–small-cell lung cancer (NSCLC) patients, and vinorelbine (VNB) is an active reference agent. This phase I/II study was performed to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the recommended dose (RD) of a VNB/oxaliplatin combination given to previously untreated patients with advanced NSCLC. PATIENTS AND METHODS: Oxaliplatin was given at the fixed dose of 130 mg/m2 (2-hour intravenous [IV] infusion) on day 1. VNB was administered on days 1 and 8 (10-minute IV infusion), with doses starting at 22 mg/m2/d and escalated by 2 mg/m2 increments until MTD. Treatment was repeated every 3 weeks. No special hydration measures or prophylactic granulocyte colony-stimulating factors were used. RESULTS: Twenty-seven patients (20 men, 7 women) received 110 cycles total at six different VNB dose levels. Neutropenia was the DLT. Although no patient experienced DLT at the highest dose level (32 mg/m2/d), multiple treatment delays (54% of cycles) and dose reductions (34% of cycles) were required at this dose level. Others toxicities were mainly limited to grade 1 peripheral neuropathy and grade 1/2 nausea/vomiting. The relative dose-intensity of administered VNB from dose levels 3 to 6 (26 to 32 mg/m2) remained stable, whereas grade 3/4 neutropenia increased. All patients were assessable for activity; there were 10 objective responses, including one complete response (37% response rate). CONCLUSION: The present combination can be safely administered in an outpatient setting. The RD is VNB 26 mg/m2 days 1 and 8 with oxaliplatin 130 mg/m2 day 1 every 3 weeks.

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