scholarly journals A Phase IV Clinical Trial of Patients with Solid Tumors Receiving Lenograstim as Primary Prophylaxis for Chemotherapy-Induced Neutropenia, in a Docetaxel-Based Regimen

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Samuel J. Fourie ◽  
Alicia McMaster ◽  
Rashem Mothilal ◽  
Keith I. Maart
Keyword(s):  
Febrile Neutropenia ◽  
Solid Tumors ◽  
Primary Prophylaxis ◽  
Duration Of Treatment ◽  
Open Label ◽  
Recurrence Rates ◽  
Optimal Dosing ◽  
Grade 3 ◽  
African Patients ◽  
Phase Iv

Docetaxel-based chemotherapy regimens have substantially improved survival and recurrence rates for cancer patients. Safety profile of docetaxel regimens includes toxicities, particularly a high risk of neutropenia and febrile neutropenia. Granotax was a prospective, open label, multicentre, national phase IV study that evaluated the incidence and severity of neutropenia in adult patients with solid tumors being treated with a docetaxel-based regimen while receiving the GCSF lenograstim. Among the 394 enrolled patients the incidence of grade 3-4 neutropenia was 16.2% and of febrile neutropenia was 1.5%, far lower than the reported 85–100% and 30–40% incidence without G-CSFs. A total of 68 patients (17.3%) were reported to have experienced at least one grade 3-4 adverse event during the study. Two (0.5%) patients and 32 (8.1%) patients had dose delayed due to febrile neutropenia and neutropenia, respectively. Four (1.0%) patients and 32 (8.1%) patients had a dose changed due to febrile neutropenia and neutropenia, respectively. The low incidence of adverse effects and chemotherapy dose changes, delays, and withdrawals supports the use of lenograstim as effective primary prophylaxis in South African patients being treated with a docetaxel-based regimen. Furthermore, lenograstim may increase the patient’s exposure to chemotherapy allowing patients to receive optimal dosing and duration of treatment, benefitting survival.

Phase II trial of surufatinib plus toripalimab for disease progression after first-line chemotherapy with platinum and fluoropyrimidine in advanced gastric or gastroesophageal junction adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16040-e16040
Author(s):  
Lin Shen ◽  
Ming Lu ◽  
Zhendong Chen ◽  
Feng Ye ◽  
Yanqiao Zhang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
First Line ◽  
Duration Of Treatment ◽  
Efficacy Evaluation ◽  
Open Label ◽  
Grade 3

e16040 Background: Surufatinib is a novel small-molecule kinase inhibitor targeting VEGFRs, FGFR and CSF-1R, simultaneous targeting of angiogenesis through VEGFRs/FGFR1 and modulating tumor immune microenvironment through CSF-1R may be a uniquely potent strategy to enhance antitumor activity. Toripalimab is a monoclonal humanized IgG4 PD-1 antibody. Encouraging efficacy of surufatinib plus toripalimab treating patients with advanced solid tumors was reported at 2020 AACR. This is an ongoing, multicenter, open-label, single-arm, phase II study to evaluate the efficacy and safety of surufatinib in combination with toripalimab in various solid tumors. Here we report the results of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods: Patients with histologically confirmed gastric or GEJ adenocarcinoma who have failed first-line of systemic chemotherapy were enrolled. Surufatinib 250 mg once a day (QD) will be orally administrated and toripalimab 240 mg will be intravenously administered every 3 weeks. Primary endpoint was the objective response rate (ORR) per RECIST v1.1. Results: As of Dec 31, 2020, a total of 21 gastric or GEJ adenocarcinoma patients were enrolled. The median age was 58 years old, and 81% of the patients were male. Median duration of treatment was 3 months (surufatinib, 3 months; toripalimab, 3 months). Among 15 patients with at least one post-baseline efficacy evaluation, 2 patients achieved confirmed partial response (PR), with 3 additional unconfirmed PR. And there were 6 in stable disease (SD), 3 in progressive disease (PD) and one not evaluable per RECIST v1.1. There were 5 in PR, 7 in SD and 2 in PD per irRECIST, respectively. The confirmed and unconfirmed ORR were 13.3% (95% CI: 1.7%-40.5%) and 33.3% (95% CI: 11.8%-61.6%), respectively. The disease control rate (DCR) was 73.3% (95% CI: 44.9%-92.2%) per RECIST v1.1. Median PFS was 3.71 months (95% CI: 1.41-unknown). 14.3% (3/21) of patients had treatment-related adverse events (TRAEs) of ≥ Grade 3. The most common TRAEs of ≥ Grade 3 were herpes zoster (4.8%), lymphopenia (4.8%), lymphocyte count decreased (4.8%), white blood cell count decreased (4.8%), liver injury (4.8%) and anaemia (4.8%). 4.8% (1/21) of patients had serious TRAEs. One patient died due to unknown reasons. Conclusions: Surufatinib plus toripalimab appeared to show encouraging activity in advanced gastric or GEJ adenocarcinoma with manageable safety profile. Such combination could be a promising strategy for advanced gastric or GEJ adenocarcinoma in the future. Clinical trial information: NCT04169672.

Safety and efficacy of neratinib (HKI-272) in combination with vinorelbine in patients with solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14554-e14554
Author(s):  
S. A. Limentani ◽  
A. Awada ◽  
L. Dirix ◽  
J. Beck ◽  
V. Dieras ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Metastatic Breast ◽  
Duration Of Treatment ◽  
Open Label ◽  
Level Data ◽  
Tumor Measurements ◽  
Grade 3 ◽  
Age Range

e14554 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. Preclinical studies have shown synergistic antitumor activity with the combination of trastuzumab plus vinorelbine in metastatic breast cancer.The recommended dose of neratinib in monotherapy is 240 mg. In this phase 1 study, a combination dose of neratinib plus vinorelbine that is tolerable was determined in patients (pts) with solid tumors. Methods: This is an open-label, 2-part study of ascending multiple daily oral doses of neratinib (160 mg, 240 mg) in combination with 25 mg/m2 IV vinorelbine (administered on days 1, 8 every 3 wks). Tumor measurements were made every 6 wks by modified RECIST criteria. Results: 6 pts have been treated at each dose level. Data for 12 pts (5 pts still ongoing) as of 30 Oct 2008 are presented (median age [range] of 53.5 [38–75] yrs; 83% female). The median duration of treatment [range] was 1.9 [1.5–2.7] m. There was only 1 dose limiting toxicity (DLT) of grade 3 neuropathy (pt had preexisting grade 1 neuropathy) at 160 mg neratinib-25 mg/m2 vinorelbine, so the dose was escalated to 240 mg neratinib- 25 mg/m2 vinorelbine. In this cohort, there were no DLTs, and since the neratinib and vinorelbine doses reached full standard doses there was no need for further dose escalation. AEs, any causality, all grades in ≥ 15% of pts included diarrhea (92%), nausea (67%), constipation (50%), fatigue (42%), vomiting and anthralgia (33% each), abdominal pain and anorexia, (25% each), anemia and neutropenia (17% each). Grade ≥3 AEs that occurred in ≥1 pt included neutropenia (2 pts), pneumonia (1 pt) and peripheral neuropathy (2 pts). Preliminary efficacy data show that 1 pt with stomach cancer had stable disease, lasting ≥21 weeks. Conclusions: The combination of 240 mg neratinib and 25 mg/m2 vinorelbine was found to be tolerable and to demonstrate early evidence of clinical benefit in pts with solid tumors, to be assessed further in pts with metastatic ErbB-2+ breast cancer in part 2. [Table: see text]

A phase 1b, open-label, dose-escalation study to evaluate camidanlumab tesirine (Cami) as monotherapy in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2556-2556
Author(s):  
Igor Puzanov ◽  
Patricia LoRusso ◽  
Kyriakos P. Papadopoulos ◽  
Christopher T. Chen ◽  
Yvan LeBruchec ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Single Agent ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1B ◽  
Grade 3

2556 Background: Depletion of tumor-infiltrating CD25+ regulatory T cells (Tregs), which inhibit tumor-specific immune responses, could contribute to tumor eradication. Cami (ADCT-301), an anti-CD25, pyrrolobenzodiazepine-based antibody-drug conjugate, targets CD25+ Tregs. A mouse surrogate has shown potent antitumor activity in solid tumor models. Here we report preliminary data from the monotherapy arm of a phase 1b trial of Cami in pts with selected advanced solid tumors. Methods: The monotherapy dose-escalation part of this open-label study enrolled pts (aged ≥18 years) with selected advanced solid tumors and no suitable existing therapy. The primary objective was to characterize safety and tolerability, and to identify the recommended phase 2 dose of Cami monotherapy. Secondary and exploratory objectives included evaluation of preliminary antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Pts received Cami every 3 weeks (1 cycle) with dose escalation per a 3+3 design. Disease control rate (DCR) was assessed (complete and partial responses [CR, PR] and stable disease). Results: At data cut-off (Dec 17, 2020), 44 pts were enrolled, with primary tumor types (stage IVA/B: 27 pts; 61.4%) of colorectal (15 pts; 34.1%), pancreatic (14 pts; 31.8%), head and neck, ovarian/fallopian tube, and renal cell carcinoma (all 3 pts; 6.8%), non-small cell lung cancer (2 pts; 4.5%), gastric, esophageal/GEJ, melanoma, and triple-negative breast cancer (each 1 pt; 2.3%). Median (range) age was 60.5 (33–82) years; median (range) number of prior systemic therapies was 4 (1–9). Pts received a median (range) of 2 (1–6) Cami cycles at doses of 20–150 µg/kg. Median (range) treatment duration was 22 (1–178) days. No dose-limiting toxicities were reported. The maximum tolerated dose (MTD) was not reached. All-grade treatment-emergent adverse events (TEAEs) in ≥20% pts were nausea (18 pts; 40.9%), decreased appetite and fatigue (each 16 pts; 36.4%), constipation (13 pts; 29.5%), abdominal pain (11 pts; 25%), and rash (10 pts; 22.7%). The only Grade ≥3 TEAE in ≥10% pts was anemia (5 pts; 11.4%). Grade 3 autoimmune AEs (colitis, immune-mediated AE, systemic inflammatory response syndrome) and neurologic AEs (dysphagia and asthenia, but not GBS) were reported in 3 (6.8%) and 2 (4.5%) pts, respectively. 1 (2.3%) Cami-related TEAE led to treatment withdrawal; no Cami-related TEAEs were fatal. DCR was 25% (95% CI: 11.1, 34.7); 11/44 pts attained stable disease. No pts had CR or PR. Conclusions: Dose escalation of Cami monotherapy is complete. The safety profile is encouraging and MTD was not reached. PK/PD data will be presented. 150 µg/kg is the highest dose investigated for single-agent Cami and the highest to be investigated combined with pembrolizumab in selected advanced solid tumors in the current protocol. Funding: ADC Therapeutics SA NCT03621982. Clinical trial information: NCT03621982.

Pembrolizumab in microsatellite instability high (MSI-H)/mismatch repair deficient (dMMR) cancers: Updated analysis from phase 2 KEYNOTE-158 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2565-2565
Author(s):  
Michele Maio ◽  
Paolo Antonio Ascierto ◽  
Ludmila Manzyuk ◽  
Daniel Motola-Kuba ◽  
Nicolas Penel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tissue Sample ◽  
Guillain Barre Syndrome ◽  
Phase 2 ◽  
Contributing Factors ◽  
Open Label ◽  
Multiple Tumor ◽  
Guillain Barré Syndrome ◽  
Grade 3 ◽  
Guillain Barré

2565 Background: Approval of pembrolizumab for the treatment of unresectable or metastatic MSI-H/dMMR solid tumors that have progressed on prior therapy was supported by data from KEYNOTE-158 (NCT02628067). At the data cutoff of Dec 6, 2018, the ORR was 34.3% among 233 patients (pts) with MSI-H/dMMR solid tumors enrolled in all cohorts of KEYNOTE-158, 77.6% had duration of response (DOR) ≥24 mo, median PFS was 4.1 mo, and median OS was 23.5 mo. We present results from 351 pts enrolled in KEYNOTE-158 cohort K at the data cutoff of Oct 5, 2020. Methods: Cohort K of this phase 2, open-label study enrolled adults with any previously treated advanced noncolorectal MSI-H solid tumor, measurable disease per RECIST v1.1, and ECOG PS of 0–1. MSI-H/dMMR status was assessed locally from a tumor tissue sample and defined as ≥1 of 4 MMR proteins absent by immunohistochemistry or as ≥2 allelic loci size shifts of 5 microsatellite markers by PCR. Pts received pembrolizumab 200 mg Q3W for up to 35 cycles or until PD, unacceptable toxicity, investigator decision, or withdrawal of consent. The primary endpoint was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints were DOR and PFS per RECIST v1.1 by BICR, OS, and safety. Efficacy was assessed in all pts who received ≥1 dose of treatment with ≥6 mo follow-up; safety was assessed in all treated pts. Results: 351 pts were enrolled in KEYNOTE-158 cohort K across multiple tumor types, including endometrial (22.5%), gastric (14.5%), small intestine (7.4%), ovarian (7.1%), cholangiocarcinoma (6.3%), and pancreatic (6.3%). 41.0% had 1 prior line of therapy; 55.6% had ≥2 prior lines. Median time from first dose to database cutoff (Oct 5, 2020) was 37.5 (range, 0.2–55.6) mo; 16.0% were continuing treatment. The ORR among the 321 eligble pts was 30.8% (CR, 27; PR, 72); median DOR was 47.5 mo (Table). Treatment-related AEs occurred in 64.7% of pts (grade 3–5, 12.0%), led to discontinuation in 6.6%, and led to death in 3 pts (myocarditis, pneumonia, and Guillain-Barre syndrome). Immune-mediated AEs and infusion reactions occurred in 20.2% of pts (grade 3–4, 4.3%) and led to death in 2 pts with no other contributing factors (myocarditis [AE start, day 26; death, day 33] and Guillain-Barre syndrome [AE start, day 22; death, day 41]). Conclusions: Pembrolizumab demonstrated a high ORR (30.8%), durable clinical benefit, and a manageable safety profile in this heavily pretreated advanced MSI-H/dMMR noncolorectal pan-tumor population. Clinical trial information: NCT02628067. [Table: see text]

Phase I and Pharmacokinetic Study of Docetaxel and Irinotecan in Patients With Advanced Solid Tumors

2000 ◽  
Vol 18 (20) ◽  
pp. 3545-3552 ◽  
Author(s):  
Corinne Couteau ◽  
Marie-Laure Risse ◽  
Michel Ducreux ◽  
Florence Lefresne-Soulas ◽  
Alessandro Riva ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

Appropriateness of using granulocyte colony-stimulating factor (G-CSF) for primary prophylaxis of febrile neutropenia in solid tumors

2019 ◽  
Vol 26 (2) ◽  
pp. 428-433
Author(s):  
Elahe Laali ◽  
Jinous Fazli ◽  
Sanambar Sadighi ◽  
Mehdi Mohammadi ◽  
Kheirollah Gholami ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Solid Tumors ◽  
Prospective Observational Study ◽  
Cost Savings ◽  
Primary Prophylaxis ◽  
Granulocyte Colony Stimulating Factor ◽  
Substantial Cost ◽  
Prescription Pattern ◽  
Study Population ◽  
Stimulating Factor

Introduction Febrile neutropenia (FN) is one of the dose-limiting adverse effects of chemotherapy. Granulocyte-Colony Stimulating Factors (G-CSFs) minimize the incidence of FN and reduce the risk of neutropenia complications. This study was conducted to address the prescription pattern of G-CSF for primary prophylaxis of FN during the first cycle of chemotherapy in solid tumors. Method This prospective observational study was done to investigate the G-CSF prescription pattern in patients receiving the first cycle of chemotherapy for solid tumors and compare it with the NCCN guideline recommendations. Result Based on the guideline, prophylactic G-CSF administration was indicated in 26 of the 96 patients (27.1%) and all of them received G-CSF. On the other hand, 70 patients (72.9%) did not meet the guideline criteria for prophylaxis, but 60 (62.5%) of them received G-CSF. Seven doses of pegfilgrastim and 165 doses of filgrastim were used inappropriately in the study population, which was associated with an economic burden of about 224.7 million IRR (5350 USD). Conclusion Taken together, inconsistencies with the guideline were observed in this prospective evaluation, suggesting that submitting rationalized policies to decrease G-CSF prescription, especially in patients with a lower or intermediate FN risk, yields substantial cost savings.

Pegfilgrastim and Daily Granulocyte Colony-Stimulating Factor (G-CSF) Patterns of Use and Neutropenia-Related Outcomes in Cancer Patients in Spain: Results of the Learn Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4263-4263
Author(s):  
D. Almenar ◽  
J. Mayans ◽  
O. Juan ◽  
J.M. García Bueno ◽  
Ji Jalón ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Dose Reduction ◽  
Cancer Patients ◽  
Primary Prophylaxis ◽  
Antibiotic Consumption ◽  
Secondary Prophylaxis ◽  
Duration Of Treatment ◽  
Patterns Of Use ◽  
Treatment Use ◽  
Dose Delay

Abstract Background: Daily G-CSFs(Filgrastim, lenograstim) are widely used to reduce duration of chemotherapy-induced neutropenia(CIN) and incidence of febrile neutropenia(FN) in cancer patients(pts). Data on their patterns of use and effectiveness in routine clinical practice are however limited. The introduction of the once-per-cycle G-CSF pegfilgrastim(Neulasta®) in Spain in 2003 may have changed patterns of use of daily G-CSFs and CIN-related outcomes. Methods: Multicentre, retrospective, observational study of daily G-CSF and pegfilgrastim patterns of use and outcomes in adult subjects with non-myeloid malignancies receiving myelosuppressive chemotherapy(CT). Consecutive patient medical records with documented use of daily G-CSF or pegfilgrastim were abstracted from 10 Spanish centers during 2003. Endpoints: percentage of proactive(primary prophylaxis) vs reactive(secondary prophylaxis/treatment) use of G-CSFs, duration of treatment with G-CSF, and CIN-related outcomes(dose delay, dose reduction, incidence of FN, hospitalization and antibiotic consumption). Results: 248 charts documented pegfilgrastim or daily G-CSF use; 75 pts received pegfilgrastim only; 111 pts received daily G-CSF only(99 Filgrastim, 12 lenograstim); 62 pts received both daily G-CSF and pegfilgrastim during their CT(data not shown). Most common tumor types were lung(25%), breast(20%), malignant lymphomas(20%). Pattern of use (% pts on primary or secondary prophylaxis, or treatment at any time during CT) was:pegfilgrastim(39%,48%,17%, respectively) vs daily G-CSF(40%,48%,30%, respectively). Median number of injections/cycle in the daily G-CSF group was 6 (range 1–13) in primary prophylaxis, and 5 (range 1–11) in secondary prophylaxis and treatment. CIN-related outcomes are shown in the table below. Conclusions: Patterns of use of daily G-CSFs and pegfilgrastim were similar for primary and secondary prophylaxis, but a potential trend to less frequent treatment use in the pegfilgrastim group was observed. CIN-related complications, including incidence of FN, were observed to be lower in pts receiving pegfilgrastim. CT-related complications% pts (95% CI) Pegfilgrastim(n=75) Daily G-CSF(n=111) Dose Delay 44% (33; 55) 46% (36; 55) Dose Reduction 14.7% (8.2; 24.6) 20.7% (14.2; 29.2) Dose Reduction due to Neutropenia 6.7% (2.5; 15.0) 20.7% (14.1; 29.2) Febrile Neutropenia (FN) 10.7% (5.3; 19.9) 24.3% (17.2; 33.1) Hospitalization due to FN 9.3% (4.3; 18.3) 19.8% (13.4; 28.3) Antibiotic Consumption due to FN 8.0% (3.4; 16.7) 17.1% (11.2; 25.3)

Long-Term Treatment with Romiplostim in Patients with Chronic Immune Thrombocytopenic Purpura (ITP): 3-Year Update from An Open-Label Extension Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 402-402 ◽  
Author(s):  
David J Kuter ◽  
James B Bussel ◽  
Adrian Newland ◽  
Joost TM de Wolf ◽  
Troy Guthrie ◽  
...  
Keyword(s):  
Platelet Count ◽  
Term Treatment ◽  
Duration Of Treatment ◽  
Open Label ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Long Term Treatment ◽  
Open Label Extension ◽  
Grade 3

Abstract Chronic ITP is characterized by increased platelet destruction and suboptimal platelet production. Romiplostim is an investigational Fc-peptide fusion protein (peptibody) being studied for its ability to increase platelet counts in patients with chronic ITP. We report data from an open-label extension study of romiplostim in adult patients with chronic ITP. Collection of safety and efficacy data from long-term treatment of these patients is ongoing. Eligible patients had completed a prior romiplostim study and had platelet counts □50×109/L. Romiplostim was administered subcutaneously once weekly with dose adjustments to maintain a platelet count of 50–250×109/L. As of July 13 2007, 142 patients had been treated with romiplostim. Their median time since diagnosis was 6.4 years (range 0.6–46.4 years). Most were female (67%) and had previously undergone a splenectomy (60%). The median baseline platelet count was 17×109/L (range 1–50×109/L). The median duration of treatment was 65 weeks (range 1–156 weeks). Twenty-nine (20%) patients discontinued the study, 10 (7%) due to adverse events (AEs) [2 each of bone marrow reticulin and thrombosis; 1 each of bleeding, pain, cardiac arrest, pneumonia, hepatic and renal failure, and monoclonal gammopathy of undetermined significance]. Different measures of platelet count response were analyzed; any platelet counts within 8 weeks of receiving rescue medications were excluded from these analyses. Platelet counts were increased from baseline by ≥20×109/L more than 80% of the time in 54% of patients and more than 50% of the time in 73% of patients. Platelet counts remained above 20×109/L more than 90% of the time in 67% of patients and more than 50% of the time in 94% of patients. A platelet count >50×109/L and double baseline was achieved by 30% (42/138) of patients after the first dose, by 51% (71/138) of patients after the third dose, and by 87% (124/142) of patients overall. The durability of platelet count increases was analyzed: platelet counts >50×109/L were sustained for ≥10, ≥25, and ≥52 consecutive weeks in 78% (102/131), 54% (66/122), and 35% (29/84) of patients, respectively. The patient incidence of bleeding events both of any severity and of clinical significance (≥Grade 3) declined over time (Table). AEs were reported in 95% of patients, with most mild to moderate in severity. The most common were headache (37%); nasopharyngitis (32%); and contusion, fatigue and epistaxis (each 30%). AE frequency did not increase with time on study (Table). Bone marrow reticulin was present or increased in 8 patients with no evidence of progression to collagen fibrosis or chronic idiopathic myelofibrosis. Thrombotic events were reported in 7 (5%) patients; 6 had pre-existing risk factors for thrombosis. In conclusion, romiplostim increased platelet counts in most patients for most of the time, and clinically relevant bleeding was reduced over time. Romiplostim was well-tolerated and AEs did not increase with longer duration of treatment. Table. Summary of patient incidence of AEs by study period <24 wks (N=142) n (%) 24 to <48 wks (N=126) n (%) 48 to <72 wks (N=97) n (%) 72 to <96 wks (N=65) n (%) 96 to <120 wks (N=29) n (%) 120 to <144 wks (N=25) n (%) AEs 129 (91) 110 (87) 64 (66) 36 (55) 23 (79) 21 (84) Serious AEs 25 (18) 13 (10) 7 (7) 4 (6) 4 (14) 1 (4) Treatment-related AEs 48 (34) 14 (11) 12 (12) 7 (11) 4 (14) 3 (12) Treatment-related serious AEs 6 (4) 3 (2) 1 (1) 2 (3) 1 (3) 1 (4) Study withdrawals due to AEs 4 (3) 5 (4) 0 (0) 0 (0) 0 (0) 1 (4) Bleeding any grade 60 (42) 37 (29) 22 (23) 13 (20) 11 (38) 8 (32) Bleeding ≥ Grade 2 (moderate) 25 (18) 12 (10) 8 (8) 4 (6) 3 (10) 2 (8) Bleeding ≥ Grade 3 difference in thisresponsebetween refractory (severe) 9 (6) 1 (1) 1 (1) 1 (2) 0 (0) 0 (0)

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]

Safety and pharmacokinetics (PK) of AMG 706 in combination with gemcitabine for the treatment of patients (pts) with solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14005-14005 ◽  
Author(s):  
T. J. Price ◽  
L. Lipton ◽  
J. Williams ◽  
J. McGreivy ◽  
S. McCoy ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Multikinase Inhibitor ◽  
Vein Thrombosis ◽  
Finding Study ◽  
Label Dose ◽  
Grade 3 ◽  
Deep Vein

14005 Background: AMG 706 is an oral, investigational multikinase inhibitor (MKI) with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF and Kit receptors. Methods: This is a fully enrolled, phase 1b, open-label, dose- finding study. The objectives are to determine the maximum tolerated dose and to assess safety and PK of AMG 706 in pts with solid tumors receiving AMG 706 plus gemcitabine. Pts =18 years with ECOG 0–2 and no prior treatment with bevacizumab or VEGFr MKIs were assigned to cohorts receiving escalating doses of AMG 706 (50mg QD, 125mg QD or 75mg BID continuously from day 2 of cycle 1) plus gemcitabine (1000mg/m2 weekly for 7/8 wks, then 3/4 wks per cycle) for up to 11 cycles. Assessments include dose-limiting toxicities (DLT) (weeks 1–4) and tumor response (every 3 months). Results: 26 pts were enrolled and received at least 1 dose of AMG 706 (50mg QD n=11; 125mg QD n=6; 75mg BID n=9). All but 2 pts have completed the study. Median (range) age was 57 (25–77) yrs. 65% of pts received prior chemotherapy; 4 pts received prior gemcitabine (50mg QD n=2; 125mg QD n=1; 75mg BID n=1). There were 2 DLTs: grade 4 neutropenia (125mg QD), grade 3 deep vein thrombosis (75mg BID). Treatment-related adverse events (AE) occurring in = 10% of pts are shown in the table . The mean AMG 706 PK profiles were not markedly different when AMG 706 was dosed on the same day or 24 hours after gemcitabine administration. Objective tumor responses per RECIST for 26 evaluable pts were: 2 unconfirmed PR (50mg QD n=1; 125mg QD n=1), 7 SD (50mg QD n=3; 125mg QD n=1; 75mg BID n=3), 11 PD (50mg QD n=7; 125mg QD n=3; 75mg BID n=1), and 6 not available (125mg QD n=1; 75mg BID n=5). Conclusions: These preliminary data suggest that, in pts with solid tumors, AMG 706 combined with gemcitabine had an expected AE profile at the target once-daily dose of 125mg QD, with little effect on AMG 706 PK. The data provide a foundation for conducting further trials, potentially including biliary tumors. Final data will be presented. [Table: see text] No significant financial relationships to disclose.

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