A Phase Ib, Open-Label, Multi-Center Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of AZD1775 Monotherapy in Patients with Advanced Solid Tumors: Expansion Cohorts.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. TPS2608-TPS2608 ◽  
Author(s):  
Todd Michael Bauer ◽  
Suzanne Fields Jones ◽  
Carol Greenlees ◽  
Carl Cook ◽  
Philip John Jewsbury ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase Ib ◽  
Multi Center Study ◽  
Anti Tumor Activity ◽  
Center Study

Phase I, first-in-human, open-label, dose-escalation study of U3-1565, a fully human anti-HB-EGF monoclonal antibody, in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2519-2519 ◽  
Author(s):  
Kathleen N. Moore ◽  
Johanna C. Bendell ◽  
Anthony J. Olszanski ◽  
Madhuri Desai ◽  
Mendel Jansen ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Anti Tumor Activity

2519 Background: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an EGF family member and a ligand for EGFR and Her4. U3-1565 is a fully human anti-HB-EGF monoclonal antibody with preclinical anti-tumor and anti-angiogenesis activity. In this study, we evaluated safety, tolerability, immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of U3-1565 in patients with advanced solid tumors refractory to standard treatment. Methods: The 3+3 method of enrollment and dose-escalation was used to test U3-1565 at 2, 8, 16, and 24 mg/kg once every two weeks (with the second dose given three weeks after the first), and at 24 mg/kg weekly. Results: 15 patients (11 females, 4 males; median age 62 (range 47-77) years; 5 CRC, 5 NSCLC, 3 ovarian and 2 other cancer) were enrolled, 3 in each dose level cohort. No dose-limiting toxicity was observed and a maximum tolerated dose was not reached. The highest administered dose of 24 mg/kg weekly generated Cmin above the predetermined target concentration corresponding to Cave resulting in 90% preclinical tumor growth inhibition. U3-1565 was safe and well tolerated with related AE consisting of infrequent and non-dose-related G2 (fatigue, anemia, and appetite loss, seen in 20, 13, and 7% of cases, respectively) and G1 toxicities. No anti-U3-1565 antibody was detected. U3-1565 showed bi-exponential disposition with Cmax and AUC increasing proportional to the dose across all dosing regimens. 13 patients discontinued the study, 12 due to progressive disease and 1 due to non-drug-related AE. After 6 months on study, 2 patients entered study extension phase: A 77 year-old female with NSCLC given 24 mg/kg every two weeks, showed SD (best SLD change -3%) for 26 weeks before progression; and a 76 year-old female with CRC given 24 mg/kg weekly, showed PR (best SLD change -35%) and remains on treatment after 71 weeks. Conclusions: U3-1565 is safe and well tolerated up to 24 mg/kg weekly. Anti-tumor activity was observed and is being further explored in an open-label, dose-expansion study. Clinical trial information: NCT0129041.

BBI608-201GBM: A phase Ib/II clinical study of napabucasin (BBI608) in combination with temozolomide (TMZ) for adult patients with recurrent glioblastoma (GBM).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13525-e13525 ◽  
Author(s):  
Warren P. Mason ◽  
Paula de Robles ◽  
Laura Borodyansky ◽  
Matthew Hitron ◽  
Waldo Feliu Ortuzar ◽  
...  
Keyword(s):  
Recurrent Glioblastoma ◽  
Open Label ◽  
Cancer Stemness ◽  
Phase Ib ◽  
Anti Cancer ◽  
First Recurrence ◽  
Multi Center Study ◽  
Anti Tumor Activity

e13525 Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Pre-clinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. PK studies demonstrated napabucasin penetration in the murine orthotopic GBM model. Methods: A phase Ib/II open-label, multi-center study in pts with GBM at first recurrence who have not received bevacizumab, was performed to determine safety and preliminary activity of napabucasin administered orally at 480mg BID po in combination with TMZ 150mg/m²/day po; days 1 through 5 of each 28 day cycle, until disease progression or unacceptable toxicity. A 6-patient safety cohort was planned to evaluate the occurrence of DLT during the first 28 days of combination treatment with napabucasin and TMZ. 4 additional patients have been enrolled under the RP2D expansion phase. Results: 11 pts have been enrolled to date; no DLT was observed in the safety cohort and the RP2D of the combination is 480 mg BID for napabucasin. The safety profile was consistent with that of each agent as monotherapy and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Two patients requested to withdraw treatment due to concurrent conditions and AE s. 9 patients were evaluable by RANO; Disease Control Rate was observed in 5 patients (55.5%) of which 4 achieved PR (44.4%) and 1 achieved SD (11.1%). The Overall response rate was 44.4% in the evaluable patients. Conclusions: This phase Ib/II study demonstrated that napabucasin at 480 mg BID can be safely combined with temozolomide at full dose and showed encouraging anti-tumor activity in patients with recurrent Glioblastoma. Clinical trial information: NCT02315534. [Table: see text]

A phase Ia/Ib trial of the anti-PD-L1 human monoclonal antibody (mAb), CS1001, in patients (pts) with advanced solid tumors or lymphomas.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2526-2526
Author(s):  
Lin Shen ◽  
Junning Cao ◽  
Jin Li ◽  
Hongming Pan ◽  
Nong Xu ◽  
...  
Keyword(s):  
Disease Progression ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Hepatic Function ◽  
Human Antibody ◽  
Advanced Solid Tumors ◽  
Phase Ib ◽  
Flat Dose ◽  
Tumor Types ◽  
Anti Tumor Activity

2526 Background: CS1001 is the first full-length, fully human anti-PD-L1 mAb developed by the OMT transgenic rat platform, which mirrors natural IgG4 human antibody with expected PK profiles, and may potentially reduce the risk of immunogenicity and toxicity in pts. This first-in-human Phase Ia/Ib study of CS1001 was conducted to evaluate the safety, tolerability, PK profile, and anti-tumor activity of CS1001 in pts with advanced solid tumors or lymphomas. Methods: Pts with advanced solid tumors or lymphomas were enrolled in the dose escalation Phase Ia, receiving CS1001, Q3W, IV, at escalating doses from 3, to 10, 20, 40 mg/kg and 1200 mg. Dose escalation was aided by a 3+3 dose escalation scheme. DLT was evaluated within 3 weeks after the initial dose. Pts with various tumor types were enrolled in the dose expansion Phase Ib to assess anti-tumor activity and safety, including NSCLC, esophageal carcinoma, GC, HCC, cholangiocarcinoma, etc. Safety was assessed by monitoring AEs and the associated grades per NCI CTCAE v4.03, tumor assessed per RECIST v 1.1 (solid tumors) or Lugano 2014 (lymphomas). Results: As of 30 Nov 2018, 29 pts, median age of 53 (23-75) yrs, were enrolled in Phase Ia, 3 mg/kg (N = 3); 10 mg/kg (4); 20 mg/kg (3); 40 mg/kg (3) and 1200 mg flat dose (16). A total of 20 pts discontinued treatment due to disease progression (14), death (2), withdrawal by pts (2) and AEs (2; Grade [G] 4 hepatic function abnormal and G3 pulmonary tuberculosis, both were not related to treatment). 9 pts remain on treatment. Median treatment duration was 126 (21-408+) days. No DLTs were observed. 27 of 29 pts had TRAEs with the most frequent TRAEs including anaemia (14), proteinuria (13) and blood bilirubin increased (8). G3 TRAEs include anaemia (2) and platelet count decreased (1). SAEs were reported in 6 pts and they were TRAEs. Three G4 AEs were reported: anaemia (1), hypokalaemia (1) and hepatic function abnormal (1), they were not TRAEs as determined by the investigators. irAEs occurred in 7 pts (24%). Among the 29 evaluable pts, 7 pts had PR and 8 had SD, mDoR was not reached. In Phase Ib, 97 pts were enrolled, with 65 pts on treatment and 32 pts discontinued from treatment. The most frequent reason on the discontinuation was disease progression (21). Phase Ib enrollment is still ongoing. Conclusions: CS1001 is well tolerated without DLT across tested dose levels. Evidence of anti-tumor activities was observed. Currently, 1200 mg flat dose Q3W is being explored in various tumor types in Phase Ib, and safety and efficacy results will be displayed in the presentation. Clinical trial information: NCT03312842.

A phase Ib/II, multicenter, open-label study of DSP-7888 dosing emulsion in combination with immune checkpoint inhibitors (CPI) nivolumab or pembrolizumab in adult patients (pts) with advanced solid tumors, including platinum-resistant ovarian cancer (PROC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6099-TPS6099
Author(s):  
Makoto Origuchi ◽  
Chris Korth ◽  
Zhonggai Li ◽  
Edgar E. Braendle
Keyword(s):  
Ovarian Cancer ◽  
Solid Tumors ◽  
Phase Ii ◽  
Metastatic Cancer ◽  
Objective Response ◽  
Clinical Activity ◽  
Induction Phase ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase Ib

TPS6099 Background: DSP-7888 is a therapeutic cancer vaccine composed of two synthetic peptides derived from Wilms’ tumor 1 (WT1) to promote both cytotoxic and helper T-lymphocyte-mediated immune responses against WT1-expressing tumors. WT1 is overexpressed in various solid tumors, including ovarian cancer. Combining cancer vaccines like DSP-7888 with a CPI may reduce resistance to immunomodulators and improve clinical benefit. A phase Ib/II study is being conducted to evaluate DSP-7888 in combination with a CPI in pts with advanced solid tumors, including PROC (NCT03311334). Methods: This phase Ib/II, open-label, multicenter, two-part dose-search/dose-expansion study investigates DSP-7888 + nivolumab or pembrolizumab in pts with advanced solid tumors (phase Ib), including PROC (phase II). The phase Ib primary objectives are safety, tolerability, and identification of the recommended phase II dose (RP2D). The phase II primary objective is evaluation of objective response rate (ORR); secondary objectives are clinical activity, safety, and tolerability. Pts aged ≥18 years with unresectable, metastatic cancer approved for treatment with nivolumab (phase Ib, Arm 1, n=6–12, 7 enrolled) or pembrolizumab (phase Ib, Arm 2, n=6–12, 6 enrolled), or with PROC (phase II) are eligible. Phase II will enroll ~40 pts into two groups based on programmed death-ligand 1 status (combined positive score of ≥10 [Group 1] or <10 [Group 2]). Clinical activity will be assessed continuously using Bayesian analysis and actual enrollment may increase by ~20 pts/group based on this analysis. Pts in phase II will receive DSP-7888 intradermally (RP2D from phase Ib) once a week (wk) for 6 wks in the induction phase then every 3 wks in the maintenance phase. Beginning Day 1, pembrolizumab will be administered intravenously every 3 wks. In phase II, objective disease will be assessed every 6 wks for 24 wks, then every 12 wks until progression. Endpoints include ORR (per RECIST v1.1) (primary), duration of response, disease control rate (DCR), progression-free survival (PFS), 6-month PFS rate (per RECIST v1.1), and overall survival, immune (i)ORR, iDCR, and iPFS (per iRECIST) (secondary). Exploratory endpoints include blood and tumor tissue biomarkers. Safety and tolerability, assessed by adverse events, will be evaluated throughout the duration of the study and follow-up. This study is currently recruiting patients. Clinical trial information: NCT03311334.

scholarly journals A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors

Oncotarget ◽  
2018 ◽  
Vol 9 (60) ◽  
pp. 31709-31718 ◽  
Author(s):  
Jordi Rodon ◽  
Giuseppe Curigliano ◽  
Jean-Pierre Delord ◽  
Wael Harb ◽  
Analia Azaro ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase Ib ◽  
Finding Study ◽  
Label Dose ◽  
Dose Finding Study

291 Phase Ib study of selicrelumab (CD40 agonist) in combination with atezolizumab (anti-PD-L1) in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A318-A318
Author(s):  
Fabrice Barlesi ◽  
Martijn Lolkema ◽  
Kristoffer Staal Rohrberg ◽  
Cinta Hierro ◽  
Aurelien Marabelle ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Dose Range ◽  
Injection Site Reaction ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Cell Lung Carcinoma ◽  
Phase Ib ◽  
Grade 3 ◽  
Anti Tumor Activity

BackgroundSelicrelumab is a human IgG2 agonistic anti-CD40 monoclonal antibody. Binding of the antibody to CD40 expressed on antigen-presenting cells results in T- cell priming and T-cell dependent anti-tumor activity. In response to T-cell activation, tumor cells express programmed-death ligand 1 (PD-L1) that can suppress effector T-cells. Atezolizumab interrupts this feedback loop by blocking PD-L1, thereby supporting the combination with selicrelumab.MethodsThis phase Ib open-label, multicenter, dose escalation (DE)/expansion clinical study (NCT02304393) investigated safety, pharmacokinetic (PK), pharmacodynamics (PD) and efficacy of selicrelumab in combination with atezolizumab in unselected patients with advanced/metastatic solid tumors, not amenable to standard therapy. In DE cohorts, a single dose of selicrelumab was given, either by intravenous (IV) infusion at a 16 mg fixed dose or subcutaneously (SC) at a range from 1 to 64 mg/dose. In dose-expansion cohorts (small bowel and colorectal cancer, head and neck squamous cell carcinoma [HNSCC] and non-small cell lung carcinoma), patients received multiple doses of selicrelumab SC at a dose of 16 mg. In all treatment cohorts, patients received atezolizumab at a fixed dose of 1200 mg IV Q3W.ResultsIn this study, 140 patients were treated. This included 95 patients in DE cohorts (6 patients in the IV cohort, 89 patients in the SC cohorts) and 45 patients in dose-expansion cohorts. In the IV cohort, infusion related reaction was the most frequent treatment-related adverse event (TRAE; 50%), while Grade ≥ 3 TRAE occurred in 1 patient (16.7%). In this cohort one dose-limiting toxicity (DLT) was reported (Grade 3 pancytopenia). In the SC cohorts, the most frequent TRAE was injection site reaction (ISR; 92%). Four DLTs were reported in four patients: three Grade 3 ISR and one Grade 3 transaminase increase. Grade ≥ 3 TRAE were reported in 22 patients (16.4%). Anti-tumor activity was observed across cohorts receiving SC selicrelumab (dose range 1 to 36 mg). Eight of 80 evaluable patients in DE cohorts experienced objective responses (9% ORR). In the dose-expansion HNSCC cohort, three of 16 evaluable patients responded (15.8% ORR). There were no objective responses in the IV cohort. Treatment with selicrelumab resulted in significant peripheral B-cell depletion and activation and CD8+ T cell proliferation.ConclusionsTreatment with selicrelumab in combination with atezolizumab was well tolerated in patients with advanced solid tumors. Signals of clinical and PD activity were observed. However, efficacy of the combination in this unselected population was limited, when compared to monotherapy efficacy of atezolizumab.Trial RegistrationNCT02304393Ethics ApprovalThis study was approved by the local IRB at each participating study site.

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