A phase Ia/Ib, dose-escalation/expansion study of BI 907828 in combination with BI 754091 and BI 754111 in patients (pts) with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3660-TPS3660
Author(s):  
Anthony W. Tolcher ◽  
Navid Hafez ◽  
Noboru Yamamoto ◽  
Jaehong Park ◽  
Rolf Grempler ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Dose Escalation ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Wild Type ◽  
Phase Ib ◽  
Multiple Tumor ◽  
Recist 1.1 ◽  
Secondary Endpoints

TPS3660 Background: Preclinical data show that the combination of a murine double minute 2–tumor protein 53 (MDM2–TP53) antagonist with anti-PD-1 and anti-LAG3 antibodies produces an anti-tumor effect in multiple tumor types. This Phase Ia/Ib study aims to determine the safety, recommended dose for expansion (RDE), and preliminary efficacy of BI 907828, a MDM2–TP53 antagonist, with BI 754091, an anti-PD-1 antibody, and BI 754111, an anti-LAG-3 antibody, in a variety of TP53 wild-type cancers. Methods: In Phase Ia (dose escalation), ~30 pts with a confirmed diagnosis of any unresectable, advanced/metastatic solid tumor, irrespective of TP53 mutation status, will be enrolled. Pts will receive one dose of BI 907828 every 21 days (Q3W), at a starting dose of 10 mg orally, plus BI 754091 and BI 754111 (240 mg and 600 mg, respectively, Q3W, intravenously). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control. The primary endpoint is the maximum-tolerated dose of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle. Secondary endpoints include pharmacokinetics and DLTs in the treatment period (to determine the RDE). In Phase Ib (dose expansion), pts with previously treated, unresectable, advanced/metastatic TP53 wild-type tumors with ≥1 measurable target lesion will be enrolled into four expansion cohorts (1: NSCLC; 2: melanoma; 3: well-differentiated/dedifferentiated liposarcoma or undifferentiated pleomorphic sarcoma; 4: hepatocellular carcinoma). The RDE of BI 907828 will be administered with fixed doses of BI754091 and BI 754111 (Q3W). In the NSCLC cohort only, pts will be randomized to one of three arms: RDE of BI 907828 + 240 mg BI 754091 + 600 mg BI 754111 (arm A, 32 pts); 240 mg BI 754091 + 600 mg BI 754111 (arm B, 32 pts); RDE of BI 907828 + 240 mg BI 754091 (arm C, 16 pts). The primary endpoint is objective response (OR, per RECIST 1.1). Secondary endpoints include OR (per iRECIST), disease control (per RECIST 1.1 and iRECIST), progression-free survival (PFS), PFS rate at 12 and 24 weeks (cohort 3), and safety. Phase Ib will include at least 140 evaluable pts (80 pts in cohort 1 and 20 pts each in cohorts 2–4). Clinical trial information: NCT03964233 .

scholarly journals CTIM-03. PHASE II STUDY OF REGORAFENIB IN BEVACIZUMAB REFRACTORY RECURRENT GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii33-ii33
Author(s):  
Yasmeen Rauf ◽  
Cathy Schilero ◽  
David Peereboom ◽  
Manmeet Ahluwalia
Keyword(s):  
Dose Escalation ◽  
Therapeutic Option ◽  
Objective Response ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Weekly Dose ◽  
Cellular Functions ◽  
Molecule Inhibitor ◽  
Secondary Endpoints ◽  
Magnetic Resonance Imaging Mri

Abstract BACKGROUND Most patients with glioblastoma (GBM) receive bevacizumab as part of their treatment. There is no good therapeutic option after bevacizumab failure. Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic activity as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging (MRI). Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. METHODS Patients with progression of GBM after treatment with Bevacizumab will be eligible for the study. Oral administration of Regorafenib at 160 mg once daily will be administered for 3 weeks on /1 week off. Weekly dose escalation of regorafenib from 80 mg to 160 mg/day will be employed as per the Redos strategy. Patients start the treatment 80 mg/day in week 1, with weekly dose escalation to 120 mg in week 2, then 160 mg week in 3 if no significant drug-related toxicities are observed. They will be continued on treatment with Regorafenib 160 md /day till tumor progression or toxicity. They will get MRI brain every 4 weeks during the study. RESULTS Primary endpoint is median Overall survival. Secondary endpoints include progression free survival at 6 months and the median time to progression and objective response rate using the modified RANO criteria. The overall safety and tolerability of regorafenib by CTCAE version 5.0. will also be reported. CONCLUSION This is an ongoing clinical trial.

Randomized phase III study of panitumumab (pmab) vs. cetuximab (cmab) in chemorefractory wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC): Outcomes by hypomagnesemia (hypomag) in ASPECCT.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 705-705
Author(s):  
Timothy Jay Price ◽  
Marc Peeters ◽  
Tae Won Kim ◽  
Jin Li ◽  
Stefano Cascinu ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Exon 2 ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Dose Modifications ◽  
Kras Exon

705 Background: ASPECCT met its primary endpoint of non-inferiority of overall survival (OS) of pmab vs. cmab. We evaluate outcomes by hypomag, an on-treatment, anti-EGFR related adverse event that develops due to the inhibition of EGFR function. Conflicting reports have suggested hypomag is associated with survival. Methods: Patients with previously treated WT KRAS exon 2 mCRC were randomized 1:1 to receive pmab or cmab. The primary endpoint was non-inferiority of OS. Progression-free survival (PFS) and objective response rate (ORR) were secondary endpoints. Patients were categorized ± any grade hypomag during the study and data analyzed by treatment arm. Analysis of Mg supplementation during hypomag was not conducted. Results: 999 patients were randomized and treated: 499 pmab, 500 cmab. Any grade hypomag was 28.8% and grade ≥3 was 7.3% in the pmab arm vs. 18.9% and 2.6% in the cmab arm, respectively. Median time to first hypomag onset was 82 days in the pmab arm and 57 days in the cmab arm. In the pmab arm, 1.0% of patients discontinued treatment and 5% of patients had dose modifications due to hypomag vs. <0.5% and 3% in the cmab arm, respectively. Results are shown (Table). Conclusions: In ASPECCT, rates of hypomag were higher in the pmab vs. the cmab arm. Patients who developed any grade hypomag with pmab or cmab had higher ORR, PFS, and OS compared with those patients who did not. Clinical trial information: NCT00788957. [Table: see text]

Phase Ib study to assess the safety, tolerability, and clinical activity of gedatolisib in combination with palbociclib and either letrozole or fulvestrant in women with metastatic or locally advanced/recurrent breast cancer (B2151009; NCT02684032).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS1113-TPS1113 ◽  
Author(s):  
Andres Forero-Torres ◽  
Robert Wesolowski ◽  
Aditya Bardia ◽  
Haresh S. Jhangiani ◽  
Peter Kabos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Therapy ◽  
Primary Endpoint ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Mtor Pathway ◽  
Clinical Activity ◽  
Phase Ib ◽  
Metastatic Setting

TPS1113 Background: Hormone receptor positive (HR+) disease is the most common subset of both early and late stage breast cancer (BC). The majority of women with HR+ metastatic BC (MBC) ultimately develop resistance to endocrine therapy, with a median survival of ~2-3 years. A new standard-of-care strategy to treat HR+ metastatic disease involves the combination of hormone therapy and cyclin-dependent kinase (CDK) 4/6 inhibition, which has demonstrated improved progression-free survival (PFS) in both the first- and later-line metastatic setting. More recently, preclinical data with the dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor gedatolisib (PF-05212384) suggest synergy with the combination of hormone therapy, CDK 4/6 inhibition, and inhibition of the PI3K/mTOR pathway. Methods: This phase Ib study includes a dose escalation portion to evaluate dose-limiting toxicities (primary endpoint) and determine the recommended phase II dose for triplet therapy with gedatolisib combined with palbociclib/letrozole or palbociclib/fulvestrant in women with HR+ HER2-negative MBC or locally advanced/recurrent BC, in the first- and later-line setting. Thereafter, a 3-arm expansion for early signals of efficacy will investigate objective response rates (primary endpoint) with gedatolisib combined with palbociclib/letrozole (n = 26), palbociclib/fulvestrant in patients without prior CDK 4/6 inhibition (n = 28), and palbociclib/fulvestrant in patients who have previously received palbociclib (n = 27). The rates of objective response will be compared to historical controls. Secondary endpoints include safety, tumor response, PFS (expansion portion only), pharmacokinetics, and biomarker correlations associated with the PI3K/mTOR pathway. This trial is now recruiting. Clinical trial information: NCT02684032.

A phase ib trial of assessing the safety and preliminary efficacy of a combination therapy of geptanolimab (GB 226) plus fruquintinib in patients with metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15551-e15551
Author(s):  
Yuxian Bai ◽  
Nong Xu ◽  
Shan An ◽  
Wenhui Chen ◽  
Chao Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapy ◽  
Metastatic Colorectal Cancer ◽  
Human Monoclonal Antibody ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Once Daily ◽  
Phase Ib ◽  
Grade 3

e15551 Background: A combination of anti-vascular endothelial growth factor receptor(anti-VEGFR) and anti-programmed cell death-1/ligand 1 (PD-1/L1) may synergize with each other and lead to better anti-tumor efficacy. We aimed to assess the safety and preliminary efficacy of combination therapy with geptanolimab (GB226, a highly selective, fully human monoclonal antibody PD-1 mAb) plus fruquintinib (a VEGFR inhibitor) in previously treated metastatic colorectal cancer (mCRC) patients. Methods: In this phase Ib trial, we enrolled mCRC patients who had failed one or two standard therapies. Patients were given geptanolimab (3mg/kg every 2 weeks) and fruquintinib (once daily for 21 days on/7 days off with planned dose cohorts of 3mg, 4mg, and 5mg) on a 28-day cycle. A standard 3+3 design was employed to determine the primary endpoints of the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) based on dose-limiting toxicities (DLT). Secondary endpoints included objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Results: By December 15, 2020, 15 patients were enrolled: 1 with MSI-H, 12 with MSS, and 2 with MS unknown. Ten out of 15 patients (66.7%) had received ≥2 previous lines of treatment including chemotherapy in combination with anti-EGFR (33.3%) or anti-VEGF (53.3%). Seven patients (46.7%) were found to have the PD-L1 combined positive score (CPS)≥1. Two DLTs (one patient with grade 3 ALT and AST elevation and one patient with grade 3 proteinuria) were identified in fruqintinib 5mg cohort (6 patients enrolled). No DLT was observed in either 3mg (3 patients enrolled) or 4mg (6 patients enrolled) cohorts. RP2D of this combination was identified as geptanolimab (3mg/kg, every 2 weeks) and fruquintinib (4mg, once daily for 21 days on/7 days off). In all evaluable patients, the overall ORR was 26.7% (4/15, 3 confirmed PR, 1 unconfirmed PR), and the ORR was 33.3% (2/6) in the RP2D group. The DCR for all evaluable patients was 80%, and the median PFS (mPFS) was 7.33 months (95% CI: 1.91 – NE). The median DOR and median OS was not reached at the data cut-off date. Among 12 patients with MSS, the ORR was 25.0% (3/12, 2 confirmed PR, 1 unconfirmed PR), DCR was 75% and mPFS was 5.45 months (95% CI: 1.84-9.66). All patients had at least 1 treatment related AE (TRAE). The common TRAE were proteinuria (46.7%), hypertension (46.7%), and elevated aspartate aminotransferase (40.0%). Grade 3 AEs were observed in 46.7% of patients and the most common grade 3 AE was hypertension (20.0%). No grade 4 and 5 TRAE was observed. Conclusions: The combination of geptanolimab and fruquintinib had manageable safety profiles and encouraging anti-tumor activity in mCRC patients. Clinical trial information: NCT03977090.

Phase Ib extension study of eribulin mesylate in combination with carboplatin in patients with chemotherapy-naive advanced non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19145-e19145 ◽  
Author(s):  
Harry Raftopoulos ◽  
Joseph Aisner ◽  
Kirushna Kumar ◽  
Sanjay Goel ◽  
Christian Dittrich ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Advanced Nsclc ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Final Visit ◽  
Eribulin Mesylate ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Treatment Practices

e19145 Background: Eribulin mesylate as monotherapy has shown antitumor activity in patients with advanced NSCLC that progressed during or after platinum-based doublet chemotherapy (Spira AI et al. Clin Lung Cancer 2012; 13:31-38.). Following evidence of additive activity with eribulin and carboplatin in lung cancer cell lines, a phase Ib, dose-escalation study determined the maximum tolerated dose and optimum administration sequence of the combination as eribulin mesylate 1.1 mg/m2 (0.97 mg/m2 eribulin as free base) followed by carboplatin AUC 6. We report results from an extension arm that investigated the efficacy and safety of this combination in chemo-naïve patients with advanced NSCLC. Methods: Chemo-naïve patients with histologically or cytologically confirmed advanced NSCLC (stage IIIB or IV) with measurable disease were enrolled. Eribulin mesylate was administered intravenously (i.v.) on days 1 and 8 every 21 days, along with carboplatin i.v. on day 1. Efficacy assessments included best overall objective response rate (ORR; RECIST), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and duration of response (DOR). Adverse events (AEs) were also recorded. Results: 12 patients were accrued (11 male, 1 female) with a median age of 66.5 (range 42-74) years. For the 11 patients evaluable for efficacy, overall ORR was 27.3% (all partial responses) and DCR was 63.6%. Median (range) OS was 12.1 (1.6-12.1) months (5 patients still alive); PFS was 4.2 (0.03+-5.8+) months (upper value censored as 1 patient still responding at final visit); and DOR was 2.9 (2.8-3.1+) months. The most common AEs ≥grade 3 were thrombocytopenia (n=6), neutropenia (n=5), febrile neutropenia (n=4), anemia (n=3), and dyspnea, hypokalemia, leukopenia, and pneumonia (n=2 each). Conclusions: The combination of eribulin and carboplatin yielded no unexpected safety findings. Given the evolving treatment practices for NSCLC, further studies involving larger numbers of patients are warranted, with consideration given to specific histologic subgroups. Clinical trial information: NCT00268905.

Efficacy and safety of CetuGEX in recurrent/metastatic squamous cell carcinoma of the head and neck (RM-HNSCC): Results from the randomized phase II RESGEX study.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 59-59 ◽  
Author(s):  
Ulrich Keilholz ◽  
Andrzej Kawecki ◽  
Andreas Dietz ◽  
Bogdan Zurawski ◽  
Michael Schenker ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Primary Endpoint ◽  
Single Agent ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Primary Tumor Site ◽  
Randomized Phase Ii ◽  
Secondary Endpoints ◽  
Epidermal Growth

59 Background: Standard treatment for RM-HNSCC is a combination of cisplatin (P), 5-FU (F), and the epidermal growth factor receptor (EGFR) blocking monoclonal antibody cetuximab. CetuGEX is a new monoclonal antibody sharing the identical EGFR-binding domain with cetuximab, but a modified Fc part by a proprietary glycosylation method to optimize antibody dependent cellular cytotoxicity (ADCC). Methods: Patients with RM-HNSCC without relevant comorbidities were randomized to receive up to 6 cycles of P 100 mg/m2, F 4 x 1000 mg/m2/24hrs and CetuGEX vs. cetuximab. Initial dose of cetuximab was 400mg/m2, followed by weekly 250 mg/m2. CetuGEX was given as 990 mg, followed by weekly 720 mg. After end of combination treatment, patients received single agent antibody maintenance until disease progression or intolerable toxicity. Stratification factors included FcγRIIIa status, primary tumor site, EGFR pretreatment vs. naïve, and recurrent vs. metastatic disease. Primary endpoint was progression-free survival (PFS) by immune related response criteria (irRC). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR) and overall survival (OS) as well as safety and QoL. Results: During Jan 2014 and Feb 2016, 240 patients were accrued in 34 European centers, of which 123 received cetuximab and 117 CetuGEX. The median follow-up was 15 month until May 2017. No difference was observed for the primary endpoint of PFS by irRC [median 27.7 (CetuGEX) and 26.4 (cetuximab) weeks; HR 1.003; 95%-CI 0.738 – 1.363; p = 0.98]. No advantage of CetuGEX over cetuximab was observed for all other secondary efficacy endpoints and subgroup analyses by stratification factors. Infusion related reactions (IRR) were higher for CetuGEX (38.8%) than for cetuximab (5.7%) (Pearson chi2= 37.08; p < 0.0001), but without sequelae. Conclusions: The RESGEX study is the first head-to-head comparison of an ADCC-optimized to a conventional EGFR-directed antibody. The study failed to show superior efficacy of CetuGEX over cetuximab. Both compounds appear to have the same efficacy and a similar safety profile. Glycosylation changes in the Fc part induced more IRRs. Clinical trial information: NCT02052960.

A Ib/II study of the combination of lenvatinib (L) and eribulin (E) in advanced liposarcoma (LPS) and leiomyosarcoma (LMS) (LEADER).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11507-11507
Author(s):  
Tom Wei-Wu Chen ◽  
Chih-Wei Yu ◽  
Ruey-Long Hong ◽  
Chueh-Chuan Yen ◽  
Jhe-Cyuan Guo ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Randomized Study ◽  
Objective Response ◽  
Phase Iii ◽  
Treatment Benefit ◽  
Phase Ib ◽  
Angiogenic Inhibitor ◽  
Recist 1.1 ◽  
Choi Criteria

11507 Background: For advanced LPS and LMS, the two most common histologies in soft tissue sarcoma, there are limited treatment options that readily balance efficacy and toxicity. Patients (pts) treated with E had an improved median overall survival (OS) in a phase III randomized study compared to dacarbazine but with an unsatisfactory 4% objective response rate (ORR). Early studies of L, a multi-targeted anti-angiogenic inhibitor, had suggested efficacy in sarcoma pts. We hypothesized that the combination of anti-angiogenic agent and chemotherapy could potentiate treatment benefit and aimed to explore the safety and efficacy of L + E in advanced LMS and LPS. Methods: LEADER was a single-arm phase Ib/II study for advanced adult LMS and LPS pts who had received no more than 2 lines of systemic chemotherapy. The phase Ib part (starting dose: L 18mg/day, E 1.1mg/m2) had been reported and the recommended phase 2 dose (RP2D) was determined at L 14mg/day and E 1.1mg/m2 D1, D8 every 21 days. The primary endpoint of the phase II part was ORR by RECIST 1.1, secondary endpoints included ORR by Choi criteria, progression-free survival (PFS), 6-month PFS rate, and OS. With α = 0.05 and 80% power, the pts needed for stage I and total of the Simon 2-stage design was 13 and 27 pts, respectively. Results: As of Jan 22, 2020, 20 pts (F/M 13/7) had been treated with at least one cycle of L + E; 14 were LMS (5 uterine, 9 non-uterine) and 6 were LPS (4 dedifferentiated, 2 myxoid round cell). The median age was 51 (range 29-73); the median lines of treatment(s) received before enrollment was 1 (range 0-3). 18 pts were evaluable for primary endpoint: the ORR by RECIST 1.1 was 27 % (5/18) (95% CI 10-53%). The ORR by Choi criteria was 67 % (12/18) (95% CI 41-87%). With 8 PFS events, the median PFS and 6-month PFS rate was 56 weeks (95% CI 25-not reached) and 72%, respectively. There were no OS events. The ORRs by RECIST 1.1 between different L starting doses were not significantly different (18mg 33% (2/6) vs 14mg 25% (3/12), p = 0.7). 15 pts experienced at-least one grade (gr) 3 or 4 adverse event (AE); gr 3 or 4 AEs occurred in > 1 pts included (% of phase Ib, % of phase II pts) hypertension (n = 4) (67%, 0%); hand-foot-syndrome (n = 4) (50%, 7%), proteinuria (n = 3) (0%, 25%), febrile neutropenia (n = 2) (17% vs 5%), neutropenia (n = 6) (50% vs 25%). The RP2D was associated with overall lower gr3/4 AEs except for proteinuria. Conclusions: L + E had shown promising efficacy in advanced LMS and LPS. L at 14mg/day had a better AE profile without compromising activity. The exploratory biomarker study of LEADER is ongoing. Clinical trial information: NCT03526679 .

Prevalence and outcomes of patients (pts) with EGFR S492R ectodomain mutations in ASPECCT: Panitumumab (pmab) vs. cetuximab (cmab) in pts with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 740-740 ◽  
Author(s):  
Timothy Jay Price ◽  
Kathryn Newhall ◽  
Marc Peeters ◽  
Tae Won Kim ◽  
Jin Li ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Wild Type ◽  
Exon 2 ◽  
Free Survival ◽  
Droplet Pcr ◽  
Secondary Endpoints ◽  
To Receive ◽  
Clinical Trial Information

740 Background: Mutations resistant to anti-EGFR treatment (tx), beyond those in RAS, have been reported and include EGFR S492R. We report results for pts with EGFR S492R mutations in the phase 3 ASPECCT trial. Methods: Pts were randomized 1:1 to receive pmab or cmab. Crossover was not allowed. The primary endpoint was non-inferiority of overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. EGFR S492R was evaluated by digital droplet PCR in plasma samples collected pre-tx and post-tx (safety follow-up 4 wks after the last dose). Outcomes were analyzed by EGFR S492 status. Results: Of 999 pts randomized and treated, post-tx samples were available for EGFR S492 assessment from 53% of pts (261/496) in the pmab arm and 57% of pts (285/503) in the cmab arm. EGFR S492R was detected in 1% of pts in the pmab arm and 16% of pts in the cmab arm in post-tx samples. EGFR S492R was not detected in pre-tx samples. Results are shown (table). Conclusions: In a retrospective analysis of pts with available samples from ASPECCT, 16% of pts in the cmab arm and 1% of pts in the pmab developed EGFR S492R mutations. Pts with EGFR S492R in the cmab arm had longer tx duration before progressive disease (PD) and appeared to have worse OS vs pts with wild-type S492 in the cmab arm. Clinical trial information: NCT01001377. [Table: see text]

A phase IB study of CX-4945 in combination with gemcitabine plus cisplatin in the frontline systemic treatment of patients with advanced cholangiocarcinoma.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 294-294 ◽  
Author(s):  
Mitesh J. Borad ◽  
Joleen Marie Hubbard ◽  
Do-Youn Oh ◽  
Sun Young Rha ◽  
Kabir Mody ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Toxicity Assessment ◽  
Model Systems ◽  
Toxicity Profile ◽  
Phase 2 ◽  
Efficacy Evaluation ◽  
Dose Escalation Study ◽  
Phase Ib

294 Background: CX-4945 is a first-in-class casein kinase-2 (CK2) threonine kinase small molecule inhibitor. CK2 is pleiotropic and regulates key cellular processes such as proliferation and DNA damage repair, and has been shown to enhance efficacy of gemcitabine (G) and cisplatin (C) in cell line and xenograft CCA model systems. A Phase IB study of G+C with CX-4945 was conducted in advanced cholangiocarcinoma (CCA) patients. Methods: A multi-center “3+3” dose escalation study was conducted in advanced CCA patients. Eligible patients had ECOG PS 0-1 and adequate hematologic, hepatic, and renal function. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints included pharmacokinetic (PK) analyses, overall toxicity evaluation and preliminary assessment of efficacy. Routine clinical dosing for G (1000 mg/m2) and C (25 mg/m2), both on days 1 and 8 every 21 days, was used. Dose escalation cohort were CX-4945 given twice daily on days 0,1,2 and 7,8,9 at 200 mg (DL1), 400mg (DL2), 600 mg (DL3), 800 mg (DL4) and 1000 (DL5) mg. NCI CTCAE v4.03 was used for toxicity assessment and RECIST v1.1 for efficacy evaluation. Results: Nineteen patients were enrolled (DL1:n = 3; DL2:n = 4 DL3:n = 3; DL4:n = 4; DL5:n = 5). No dose limiting toxicities were encountered. MTD and RP2D were ascertained to be DL5. No grade 3 or 4 toxicities at prevalence > 10% were encountered and the overall toxicity profile of the combination was reflective of standard G+C toxicity profile. At data cut-off, preliminary efficacy evaluation demonstrated disease control rate (CR+PR+SD) of 64% (PR:32%, SD:32% and CR:0%), along with median progression-free survival (PFS) of 5 months (range 0-14 months). PK analyses showed no evidence of drug-drug interactions between G, C and CX-4945. Conclusions: RP2D for G+C with CX-4945 is DL5 (CX-4945 dosed on days 0,1,2 and 7,8,9 at 1000 mg PO bid with standard G and C dosing). Preliminary clinical efficacy and tolerability of the regimen support planned controlled, randomized Phase 2 evaluation. Clinical trial information: NCT02128282.

FPT155-001: A phase Ia/Ib study of FPT155 (CD80-FC) in patients with advanced solid tumors.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS42-TPS42
Author(s):  
Michael Millward ◽  
Hui Kong Gan ◽  
Anthony M. Joshua ◽  
James Chun-Yen Kuo ◽  
Amy Prawira ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Objective Response ◽  
Advanced Solid Tumors ◽  
Multiple Tumor ◽  
Secondary Endpoints ◽  
Phase 1B

TPS42 Background: Despite recent advances in immunotherapy, many patients with advanced solid tumors are refractory to available therapies or eventually relapse. Novel immune therapies are needed with differentiated mechanisms of action that result in improved response rates and durability across a broad range of tumors. FPT155 is a first-in-class therapeutic being developed to meet this need. FPT155 is a recombinant fusion protein composed of the extracellular domain of human CD80 fused with the Fc domain of human immunoglobulin G1. It is designed to act as a potent stimulator of anti-tumor immunity through CD28 and thereby co-stimulate T cell responses only in the presence of antigenic T cell receptor (TCR) signaling. FPT155 alone does not induce spontaneous cytokine release by primary human immune cells, in contrast to a CD28 superagonist antibody that exerts TCR stimulus-independent activity. FPT155 also blocks CTLA-4 from competing for endogenous CD80, allowing CD28 signaling to prevail in T cell activation. A murine surrogate of FPT155 is a potent inhibitor of tumor growth that induces complete tumor regression in multiple tumor models, including models that are insensitive to anti-PD1 or anti-CTLA4. Methods: The FPT155-001 study is a Phase 1a/1b open-label, multicenter, dose escalation and expansion study to evaluate the safety and tolerability of FPT155 monotherapy. Phase 1a dose escalation includes an accelerated titration design followed by a standard 3+3 design until the recommended dose for Phase 1b is determined by evaluation of all available safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Eligible patients with advanced solid tumors who are refractory to all standard therapy for their malignancy will be enrolled in Phase 1a. Phase 1b dose expansion will enroll patients with select tumor types. The primary endpoint is safety in both phases. Key secondary endpoints in Phase 1a include characterization of the FPT155 PK profile and immunogenicity. Key secondary endpoints in Phase 1b include objective response rate, duration of response, progression free survival, and disease control rate. The FPT155-001 trial opened for enrollment in October 2018 and is in progress. Clinical trial information: Submitted - awaiting registration number.

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