scholarly journals Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial

2019 ◽  
Vol 20 (4) ◽  
pp. 570-580 ◽  
Author(s):  
Panagiotis A Konstantinopoulos ◽  
William T Barry ◽  
Michael Birrer ◽  
Shannon N Westin ◽  
Karen A Cadoo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Dose Escalation ◽  
Pi3k Inhibitor ◽  
Expansion Phase ◽  
Phase 1B

scholarly journals Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial

2021 ◽  
Vol 9 (12) ◽  
pp. e003645
Author(s):  
Victor Moreno ◽  
Maria-Pilar Barretina-Ginesta ◽  
Jesús García-Donas ◽  
Gordon C Jayson ◽  
Patricia Roxburgh ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dose Escalation ◽  
Response Rate ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Cell Infiltration ◽  
Expansion Phase ◽  
Platinum Resistant ◽  
Phase 1B ◽  
Tumor Selective

BackgroundTreatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors.MethodsWe conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration.ResultsOverall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade ≥3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was 10%, 35% of patients achieved stable disease and 65% of patients had a reduction in target lesion burden at ≥1 time point. Five out of six patients with matched pre-treatment and post-treatment biopsies treated with intravenous enadenotucirev plus paclitaxel had increased (mean 3.1-fold) infiltration of CD8 +T cells in post-treatment biopsies.ConclusionsIntravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer.Trial registration numberNCT02028117.

GEN-1 in Combination with Neoadjuvant Chemotherapy for Patients with Advanced Epithelial Ovarian Cancer: A Phase I Dose-Escalation Study

2021 ◽  
pp. clincanres.0360.2021
Author(s):  
Premal H. Thaker ◽  
William H Bradley ◽  
Charles A. Leath ◽  
Camille Gunderson Jackson ◽  
Nicholas Borys ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Phase I ◽  
Epithelial Ovarian Cancer ◽  
Dose Escalation ◽  
Dose Escalation Study ◽  
Advanced Epithelial Ovarian Cancer

scholarly journals Phase 1b safety study of farletuzumab, carboplatin and pegylated liposomal doxorubicin in patients with platinum-sensitive epithelial ovarian cancer

2016 ◽  
Vol 140 (2) ◽  
pp. 210-214 ◽  
Author(s):  
Kenneth H. Kim ◽  
Danijela Jelovac ◽  
Deborah K. Armstrong ◽  
Benjamin Schwartz ◽  
Susan C. Weil ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Safety Study ◽  
Platinum Sensitive ◽  
Phase 1B

A Phase 1b, Dose-Finding Study Of Ruxolitinib Plus Panobinostat In Patients With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF): Identification Of The Recommended Phase 2 Dose

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4045-4045 ◽  
Author(s):  
Vincen t Ribrag ◽  
Claire N Harrison ◽  
Florian H Heidel ◽  
Jean-Jacques Kiladjian ◽  
Suddhasatta Acharyya ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 2 ◽  
Advisory Committees ◽  
Expansion Phase ◽  
Phase 1B ◽  
Grade 3

Abstract Background Myelofibrosis (MF) is a myeloproliferative neoplasm associated with progressive, debilitating symptoms that impact patient quality of life (QoL) and reduce survival. Ruxolitinib (RUX), a potent dual JAK1/JAK2 inhibitor, demonstrated superiority in spleen volume and symptom reduction, improved health-related QoL measures, and prolonged survival compared with traditional therapies or placebo in the phase 3 COMFORT studies. Panobinostat (PAN) is a potent oral pan-deacetylase inhibitor (DACi) that inhibits JAK pathway signaling through increased acetylation of the JAK2 protein chaperone HSP90. In phase 1/2 studies in MF, PAN has shown reduction in splenomegaly and JAK2 V617F allele burden, and improvement of marrow fibrosis. RUX and PAN demonstrated synergistic anti-MF activity in JAK2-mutation–driven MF murine models. Here, we present the results of a phase 1b study to determine the recommended phase 2 dose (RP2D) of the combination of RUX and PAN in MF patients. Methods Patients with intermediate-1, -2, or high-risk MF by International Prognostic Scoring System criteria and with palpable splenomegaly ≥ 5 cm below the costal margin were enrolled. Dose escalation was guided by a Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) in the first cycle along with other safety findings. DLTs were defined as protocol-specified toxicities related to treatment but unrelated to disease progression, intercurrent illness, or concomitant medications, occurring up to and including cycle 1 day 28, that are considered severe enough to prevent continuation of treatment. Each dosing cohort consisted of ≥ 3 evaluable patients. Data for ≥ 9 patients were required to determine the preliminary RP2D and/or maximum tolerated dose (MTD). Following determination of the preliminary RP2D, additional patients were to be enrolled and treated at that dose in the safety-expansion phase. The range of dose levels tested for RUX was 5-15 mg twice daily (BID) and for PAN was 10-25 mg once daily, 3 times a week (TIW; days 2, 4, and 6), every other week (QOW) in a 28-day cycle. Serial blood samples collected following the first dose of RUX alone on day 1 and in combination with PAN on days 2 and 6 were evaluated for plasma concentrations of RUX (days 1, 2, and 6) and PAN (days 2 and 6) by LC-MS/MS. Pharmacokinetic parameters were derived using noncompartmental analysis. Spleen size was determined by palpation. Results A total of 38 patients have been enrolled across 6 cohorts in the dose-escalation phase. Preliminary data presented here are based on a cutoff date of March 7, 2013. Thirteen patients (34.2%) have discontinued study treatment. Reasons for discontinuation include disease progression (n = 4), adverse events (n = 7), withdrawal of consent (n = 1), and death due to pulmonary embolism (n = 1). The most common grade 3/4 adverse events were anemia (34.2%), thrombocytopenia (21.2%), abdominal pain (7.9%), and diarrhea (7.9%). QTc prolongation of > 500 ms was observed in 1 patient in cohort 4. DLTs are summarized in the Table. An approximate 50% increase in plasma exposure of both RUX and PAN on day 6 from respective baselines suggested drug-drug interaction (DDI) at 15 mg RUX and 25 mg PAN. The RP2D was defined at the cohort 6 dose and schedule. Evidence of preliminary activity was observed across all cohorts with 28 patients (73.7%) showing ≥ 50% decrease in palpable spleen length at some point during the study. Conclusions The combination of RUX and PAN has a tolerable safety profile, with few DLTs and acceptable rates of grade 3/4 anemia and thrombocytopenia. Also, encouraging splenomegaly reduction was seen in the dose-escalation phase. The MTD was not reached; however, due primarily to findings of anemia and potential DDI in dose cohort 6, preliminary RP2D was identified at RUX 15 mg BID/PAN 25 mg TIW/QOW and will be confirmed in the dose-expansion phase. Additional safety and efficacy data from patients in the expansion phase will be presented. Disclosures: Ribrag: Takeda: Membership on an entity’s Board of Directors or advisory committees; Bayer: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Johnson & Johnson : Honoraria, Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is approved for MF but panobinostat is not approved anywhere globally at this time for any indication. Harrison:S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Heidel:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kiladjian:AOP Orphan: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Acharyya:Novartis: Employment. Mu:Novartis: Employment. Liu:Novartis: Employment. Williams:Novartis: Employment. Giles:Novartis: Consultancy, Research Funding. Conneally:Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kindler:Novartis: Membership on an entity’s Board of Directors or advisory committees. Passamonti:sanofi-aventis: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Vannucchi:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

A phase I study of a hypomethylating agent azacitidine in combination with carboplatin in patients with platinum resistant epithelial ovarian cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5087-5087 ◽  
Author(s):  
S. Fu
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cancer Cells ◽  
Dose Escalation ◽  
Stable Disease ◽  
Complete Response ◽  
Ovarian Cancer Cells ◽  
Mixed Response ◽  
Hypomethylating Agent ◽  
Platinum Resistant

5087 Background: Hypermethylation is a common event associated with inactivation of a variety of genes and pathways involved in tumorigenesis and progression as well as drug resistance. Previous evidence displayed that hypomethylating agents could resensitize epithelial ovarian cancer cells to platinum treatment through reexpression of platinum sensitivity-related genes. Therefore, it is of great interest to use a hypomethylating agent to resensitize platinum resistant epithelial ovarian cancer cells to platinum treatment. Methods: This proof-of-concept study used a modified dose-escalation schema (3+3 design). All patients, who have progressed within the 6 months after a platinum-based regimen, are eligible if they have a pathologically confirmed epithelial ovarian cancer. All patients receive subcutaneous injection of azacitidine 75 mg/m2/day for 5 days on days 1–5 and intravenous infusion of carboplatin once on day 2 of each treatment cycle (28 days). Azacitidine is maintained at the same dosage during dose-escalation of carboplatin from AUC4 to AUC5. Results: Six patients have received a total of 16 cycles of treatment. There was no grade 2 or higher toxicity observed. Three patients were evaluable for response: 1 patient, who received 6 cycles of treatment, achieved complete response by CA125 criteria and stable disease by imaging criteria; 1 patient, who received 5 cycles of treatment, displayed stable disease; and the 3rd patient, who received 2 cycles of treatment, showed mixed response by imaging criteria. Conclusions: Preliminary data showed that a regimen of azacitidine 75 mg/m2/day for 5 days plus carboplatin AUC 5 on day 2 was well tolerated in patients with extensive prior treatment. No significant financial relationships to disclose.

Preliminary results from CLASSICAL-Lung, a phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2601-2601
Author(s):  
Michael Rahman Shafique ◽  
Terrence Lee Fisher ◽  
Elizabeth E. Evans ◽  
John E. Leonard ◽  
Desa Rae Electa Pastore ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Tumor Regression ◽  
Early Stage ◽  
Cell Activity ◽  
Open Label ◽  
Expansion Phase ◽  
Phase 1B ◽  
Grade 3

2601 Background: Rational combination therapies are needed to overcome resistance mechanisms in NSCLC. Pepinemab is an IgG4 humanized monoclonal antibody targeting semaphorin 4D (SEMA4D, CD100). In vivo preclinical models demonstrated antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the tumor. Importantly, preclinical combinations of anti-SEMA4D with various immunotherapies enhanced T cell activity and tumor regression. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Methods: This ongoing phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 patients (pts) with advanced (stage IIIB/IV) NSCLC (NCT03268057). The trial is split into dose escalation (n = 12) and dose expansion (n = 50) phases and includes 2 cohorts; 1) pts who are immunotherapy naïve, and 2) pts whose tumors progressed during or following immunotherapy (IO failure). Pts in the dose escalation cohorts received ascending doses of pepinemab i.v. (5, 10, 20 mg/kg, Q2W) in combination with avelumab i.v. (10mg/kg, Q2W). Results: Dose escalation is complete and the RP2D was selected as 10mg/kg pepinemab, Q2W. No pts experienced a TRAE leading to study discontinuation or death. The most frequent related AEs were grades 1 or 2 fatigue, pyrexia, or chills; no grade 3 AEs occurred in more than one subject. One DLT, a grade 3 pulmonary embolism occurred in the 10mg/kg pepinemab cohort, and resolved without reoccurrence. The disease control rate for pts treated > 2 months is 90% (19/21), and, at this early stage, a PR with a 49% reduction in target lesion was observed in at least 1 of 8 pts in the IO failure cohort. Updated data from the dose expansion phase will be presented. Conclusions: Preliminary data suggest the combination is well tolerated and shows initial signals of antitumor activity. Dose escalation is complete and the expansion phase is ongoing. Clinical trial information: NCT03268057.

scholarly journals A phase 1b dose escalation study of ipafricept (OMP 54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer

2019 ◽  
Vol 154 (2) ◽  
pp. 294-301 ◽  
Author(s):  
Kathleen N. Moore ◽  
Camille C. Gunderson ◽  
Paul Sabbatini ◽  
D. Scott McMeekin ◽  
Gina Mantia-Smaldone ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dose Escalation ◽  
Dose Escalation Study ◽  
Platinum Sensitive ◽  
Phase 1B
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