A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with bevacizumab (BEV) for advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Lee S. Rosen ◽  
Francisco Robert ◽  
Daniela Matei ◽  
Jonathan Wade Goldman ◽  
David S. Mendelson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Solid Tumors ◽  
Phase Ii ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Cell Cancer ◽  
Single Agent ◽  
Vegf Receptor ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials

3059 Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-CD105 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, PK and preliminary efficacy of TRC105 in combination with BEV. Methods: Pts with advanced solid tumors, ECOG PS 0-1, and normal organ function were treated with escalating doses of IV TRC105 (3, 6, 8 or 10 mg/kg/wk) plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk. Results: Thirty one pts (median age = 62; M:F 14:17; median 4 prior regimens; primarily metastatic colorectal or ovarian cancer) were treated with TRC105 wkly + BEV. TRC105 3 mg/kg wkly + 15 mg/kg q3wk BEV was well tolerated. Concurrent administration of TRC105 6 mg/kg wkly + 15 mg/kg BEV q3wk resulted in headaches in 4 of 5 pts on cycle 1 day 1 (two grade 3). Dose escalation to the recommended single-agent phase II dose of 10 mg/kg TRC105 weekly + BEV (10 mg/kg q2wk) was tolerated when the initial TRC105 dose was introduced one week after BEV dosing and administered over 2 days. Headache was the only serious adverse drug reaction observed. Adverse events characteristic of each individual drug were not increased in frequency or severity. Target TRC105 serum concentrations were achieved at 6 mg/kg. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed beginning at 6 mg/kg and was dose proportional. Five of 19 heavily pretreated, BEV or VEGF receptor tyrosine kinase inhibitor (TKI) refractory pts with colorectal and ovarian cancer, each with marked tumor burden, experienced radiographic reductions in tumor volume (10-17%). Three of these patients remained on study longer than the prior VEGF inhibitor treatment and two are ongoing. Seven ongoing patients have been treated for 2-8 months. Conclusions: TRC105 10 mg/kg wkly was well tolerated with BEV 10 mg/kg q2wk. The combination demonstrated activity in BEV and VEGF TKI refractory pts. Randomized phase II trials of BEV +/- TRC105 have commenced in renal cell cancer and glioblastoma. Clinical trial information: NCT01332721.

A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with capecitabine for advanced solid tumors (including patients with progressive or recurrent HER2-negative metastatic breast cancer).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3057-3057 ◽  
Author(s):  
Ellis Glenn Levine ◽  
Andres Forero ◽  
Tracy O'Connor ◽  
Ben K. Seon ◽  
Manoj A Jivani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Phase Ii ◽  
Dose Escalation ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Grade 3

3057 Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-CD105 monoclonal antibody being studied in phase II trials that potentiates chemotherapy in preclinical models. Methods: Pts with advanced solid tumors (for purposes of dose escalation) or pts with metastatic HER2-negative breast cancer (following completion of dose escalation), ECOG PS 0-1, and normal organ function were treated with intravenously administered TRC105 wkly plus capecitabine at 1,000 mg/m2 BID for 14 of every 21 days, and assessed for safety, PK, and response. Results: Fourteen patients (median age = 52; M:F 4:10; median of 3 prior regimens; 10 with breast and 4 with colorectal cancer) were enrolled. Dose escalation proceeded from 7.5 mg/kg TRC105 to the recommended single agent phase II dose of 10 mg/kg of TRC105 in combination with capecitabine, without development of dose limiting toxicity. Fourteen pts were treated at 7.5 mg/kg (n=4) or 10 mg/kg (n=10) TRC105 wkly + 1,000 mg/m2 BID/14d capecitabine of repeating 21 day cycles. Patients experienced expected TRC105 related adverse events of grade 1 or grade 2 infusion reaction, epistaxis, gingival bleeding, telangiectasia, headache, rash, and fatigue. Grade 3 headache and grade 3 vomiting were each seen in one patient. Adverse events characteristic of each individual drug were not increased in frequency or severity when the two drugs were administered together. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed at both dose levels. A heavily pretreated male breast cancer patient remained on study for 9 months with a RECIST-defined partial response. Stable disease beyond 9 weeks was observed in three patients. Conclusions: The recommended single agent phase II dose of 10 mg/kg TRC105 wkly was well tolerated in combination with capecitabine. The combination treatment could be advanced in HER2-negative breast or colorectal cancer. Clinical trial information: NCT01326481.

Combination of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2530-2530 ◽  
Author(s):  
Rebecca Suk Heist ◽  
Leena Gandhi ◽  
Geoffrey Shapiro ◽  
Naiyer A. Rizvi ◽  
Howard A. Burris ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Skin Rash ◽  
Phase Ii ◽  
Dose Escalation ◽  
Mtor Inhibitor ◽  
Mapk Signaling ◽  
Low Grade ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Phase Ib

2530 Background: PI3K/mTOR and MAPK signaling pathways are often deregulated in tumors. Simultaneous inhibition of these pathways with the MEK1/2 inhibitor, pimasertib, plus the dual PI3K/mTOR inhibitor, SAR245409, (ClinicalTrials.gov NCT01390818) was investigated. Methods: This was a phase Ib, modified 3+3, dose-escalation trial in patients (pts) with advanced solid tumors. Pts received pimasertib and SAR245409 at the following dose levels (DLs): DL1, 15/30; DL2a, 30/30; DL2b, 15/50; DL3, 30/50; DL4a, 60/50; DL4b, 30/70; DL5, 60/70; DL6a, 90/70; DL6b 60/90 and DL7, 90/90 mg (once-daily, qd). After the qd maximum tolerated dose (MTD) was established, twice-daily (bid) dosing was tested: DL1a, 60/30; DL1b, 45/50 and DL2 60/50 mg bid. A recommended phase II dose (RP2D) was determined. Enrollment continued at the RP2D in four expansion cohorts (18 pts each): dual KRAS/PIK3CA mutated (mt) colorectal cancer (CRC), triple-negative breast cancer, KRAS mt non-small cell lung cancer (NSCLC) and BRAFmt melanoma. Results: 53 pts were treated qd and 7 pts bid. The most common tumors were CRC (n=16), NSCLC (n=8), ovarian and pancreatic (n=7, each). At DL6b 2/3 pts had dose-limiting toxicities (DLTs; both grade [Gr] 3 nausea/vomiting). DL6a was confirmed as the MTD for the qd schedule. At bid DL1a 2/4 pts (both Gr 3 skin rash) and at DL1b 2/3 pts (Gr 3 skin rash and Gr 3 asthenia) had DLTs. DL5 was the RP2D based on tolerability after prolonged exposure. The most common adverse events in qd schedule were: rash (62%, 13% Gr 3), diarrhea (56%, 4% Gr 3), fatigue (51%, 2% Gr 3), nausea (49%, 2% Gr 3), vomiting (45%, 2% Gr 3), peripheral edema and pyrexia (34%, each) and visual impairment with underlying serous retinal detachment (21%). Preliminary pharmacokinetic results suggest no drug-drug interaction. There were 4 partial responses: KRAS mt CRC (n=1) and low-grade ovarian cancer (n=3, 1 KRAS mt/PIK3CA mt and 2 wild-type). Enrollment in expansion cohorts at DL5 is ongoing. Conclusions: Continuousqd dosing of pimasertib and SAR245409 is tolerated and has shown signs of activity. Phase II trials are being planned. Clinical trial information: NCT01390818.

A phase I multiple-dose escalation study to assess the safety, tolerability, and pharmacokinetics of VEGF-receptor inhibitor telatinib (EOC315) in Chinese patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3061-3061
Author(s):  
Hongming Pan ◽  
Tianshu Liu ◽  
Jason Tsai ◽  
Yapeng Zhao
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Multiple Dose ◽  
Left Ventricular Systolic Dysfunction ◽  
Single Agent ◽  
Left Ventricular ◽  
Chinese Patients ◽  
Vegf Receptor ◽  
Advanced Solid Tumors

3061 Background: Telatinib (EOC315) is a highly selective inhibitor of VEGFR/PDGFR (VEGFR 1-3, PDGFR-β, and c-Kit tyrosine kinases). This phase I study was to assess the safety, tolerability, and pharmacokinetics (PK) of Telatinib in Chinese patients with advanced solid tumors. Methods: Telatinib was administered to Chinese patients with advanced refractory solid tumors as a single agent in 3+3 dose escalation design, starting from 600mg and escalated to 900mg and 1200mg, given orally twice daily. The PK profile, safety, and tolerability were evaluated per protocol. Efficacy was evaluated with RECIST 1.1 criteria every 6 weeks. Results: A total of 15 subjects (6 colorectal cancer, 4 lung cancer, 1 head and neck cancer, 1 melanoma, 1 thymic carcinoma, 1 esophageal carcinoma,1 peritoneal carcinoma) were enrolled per protocol between July 2017 and August 2018, and 13 subjects received at least second line therapies before enrollment. Telatinib was well tolerated in the three dose arms. No dose limiting toxicities (DLTs) occurred during the dose escalation phase. CTC grade 3 AEs observed include hypertension (46.7%, 7/15), fatigue (6.7%, 1/15), transaminase elevation (6.7%, 1/15), hand-foot syndrome (6.7%, 1/15), oral mucositis (6.7%, 1/15), neutropenia (6.7%, 1/15), urobilinogen elevation (6.7%, 1/15), left ventricular systolic dysfunction/decreased ejection fraction (6.7%, 1/15). No CTC grade 4 AE were observed. There were 2 drug related SAEs (hospitalization due to high blood pressure. The PK profile of Telatinib (EOC315) at 600, 900, 1200 mg in Chinese patient cohorts is summarized in Table. For 12 evaluable patients, DCR was 58.3%. For all patients, mPFS was 15 weeks (3.3-34.3w). Conclusions: This study demonstrated the safety and tolerability of Telatinib (EOC315) in a multiple dose escalation design at 600, 900, and 1200 mg PO bid in Chinese patients with advanced refractory solid tumor. Telatinib AUC increased dose-proportionally from 600 mg to 900 mg bid, where 900 mg Telatinib bid is the maximum feasible and recommended dose for future studies in Chinese patients with advanced tumors. Clinical trial information: NCT03175497. [Table: see text]

Phase II study of sorafenib (BAY 43–9006) in combination with gemcitabine in recurrent epithelial ovarian cancer: A PMH phase II consortium trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5084-5084 ◽  
Author(s):  
S. Welch ◽  
H. Hirte ◽  
R. J. Schilder ◽  
L. Elit ◽  
C. Townsley ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Recurrent Ovarian Cancer ◽  
Ca 125 ◽  
Vegf Receptor

5084 Background: Sorafenib (BAY 43–9006; SOR) is a novel multi-targeted kinase inhibitor that targets the RAF/MEK/ERK signaling pathway, vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor and flt-3. VEGFR is over-expressed in human ovarian tumors and this is associated with poor prognosis. Gemcitabine (GEM) is known to have single-agent activity in recurrent ovarian cancer (OC). A recent phase I study of GEM/SOR has demonstrated manageable toxicity and some objective responses in recurrent OC patients. We have designed a phase II trial to evaluate the efficacy of this novel combination in patients with recurrent OC. Methods: A two-stage, phase II clinical trial is underway for women with recurrent or refractory OC. Eligible patients may have received up to 2 prior lines of chemotherapy following recurrence, but must be GEM-naive. The treatment consists of SOR, 400mg PO bid continuously, in combination with GEM, IV weekly, 1000 mg/m2. Cycle 1 is an extended cycle of 7 weeks of GEM followed by a 1-week break. GEM is administered weekly for the first 3 weeks of each subsequent 4-week cycle. The primary endpoint is objective response rate, with response evaluated every 8 weeks. Results: 26 patients have been enrolled at 3 centers. 84 cycles have been administered (median 3; range 1–10). Median age was 57 (range: 37–77). 42% were ECOG PS 0 and 58% were PS 1. Of 18 patients evaluable for objective response, 1 patient had a confirmed PR by RECIST criteria and 5 patients had a confirmed PR by CA-125 criteria, yielding a combined RR of 33% in evaluable patients (RR by ITT = 23%). An additional 10 patients had SD. The median time to progression is 7.6 months (95% CI: 5.6-NA). 7 patients are inevaluable for objective response due to the following in cycle 1: withdrawal of consent (3), toxicity (2), and clinical PD (2). 1 patient on-study is yet to have a response evaluation. Grade 3 or 4 toxicities seen in more than 2 patients include: lymphopenia (8), thrombocytopenia (6), hypertension (3), hand-foot syndrome (3), pain (3), neutropenia (3) and hypokalemia (3). Conclusions: The preliminary results show encouraging activity with tolerable toxicity. This trial continues to accrue into a second stage. No significant financial relationships to disclose.

Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

1994 ◽  
Vol 12 (12) ◽  
pp. 2743-2750 ◽  
Author(s):  
A A Miller ◽  
J B Hargis ◽  
R C Lilenbaum ◽  
S Z Fields ◽  
G L Rosner ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Grade 3 ◽  
Dose Levels

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

PX-866 and docetaxel in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3024-3024 ◽  
Author(s):  
Antonio Jimeno ◽  
Neil N. Senzer ◽  
Charles M. Rudin ◽  
Wen Wee Ma ◽  
Balazs Halmos ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Synergistic Effects ◽  
Phase 1 ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Kras Mutations ◽  
Mutational Status

3024 Background: PX-866, an irreversible pan-isoform inhibitor of Class 1 PI-3K has additive to synergistic effects when combined with docetaxel in xenograft models of NSCLC and SCCHN. A phase I/II study of PX-866 and docetaxel was initiated to further evaluate this combination. Enrollment in phase I is complete, and the randomized, controlled phase II portion is now enrolling patients with either NSCLC or SCCHN. Phase I safety and pharmacokinetics were previously described; the recommended phase II dose of PX-866 was 8 mg daily, the same as the single agent MTD (Jimeno A, et al. AACR-NCI-EORTC, 2011). Updated phase I antitumor and biomarker results are presented here. Methods: Phase 1 consisted of dose escalation of PX-866 at 4, 6, or 8 mg po qd in combination with docetaxel 75 mg/m2 IV once every 21 days (d). Patients had advanced solid tumors for which docetaxel was compendia listed. Tumor restaging was performed every 2 cycles. Archived tumor biopsies were collected for assessment of potential biomarkers of response, including PIK3CA and KRAS mutations and PTEN expression. Results: 43 pts were enrolled: NSCLC (n=6), prostate (n=5), ovarian (n=5), SCCHN (n=3), and pancreatic (n=3) were the most common tumor types. Median time on study (TOS) was 81 d (5-361), with 9 pts still on study. 16 pts received ≥ 6 cycles (6-17), including 3 pts with NSCLC, and 4 pts with ovarian cancer. Biomarker data are available for 20 evaluable pts. Median days on study by mutational status was: PIK3CA/KRAS WT (n=13): 91 d (28-286); PIK3CA-MUT (n=5): 183 d (64-342); KRAS-MUT (n=3): 141 d (125-361); and PIK3CA/KRAS-MUT (n=2): 96 d (86-105). A trend toward longer TOS was observed in pts with PIK3CA-MUT vs PIK3CA/KRAS-WT (p=0.14). Assessment of PTEN is ongoing. Best response in 32 evaluable pts was 2 PR (6%), 22 SD (69%), and 8 PD (25%). The PRs were in NSCLC and ovarian cancer (both PIK3CA/KRAS WT). 8 other pts had ≥15% tumor shrinkage, including NSCLC (n=2). Conclusions: PX-866 with docetaxel was associated with a disease control rate of 75%, with 50% of evaluable pts demonstrating SD or better for ≥ 6 cycles. Based on available data, a trend for a longer TOS was seen with PIK3CA-MUT pts. This relationship will be further evaluated in phase II.

scholarly journals Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors

2021 ◽  
Vol 9 (2) ◽  
pp. e002015 ◽  
Author(s):  
Jason J Luke ◽  
Fabrice Barlesi ◽  
Ki Chung ◽  
Anthony W Tolcher ◽  
Karen Kelly ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Dose Escalation ◽  
Phase I Study ◽  
Bispecific Antibody ◽  
Advanced Solid Tumors ◽  
Recommended Phase Ii Dose ◽  
Dose Proportional

BackgroundCD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity.MethodsABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression.ResultsFifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population.ConclusionsABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer.Trial registration numberNCT02955251.

scholarly journals 470 A phase 1/2, open-label, dose escalation and expansion study of GI-101 as a single agent and in combination with a pembrolizumab, lenvatinib or local RT in advanced solid tumors (KEYNOTE-B59)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A499-A499
Author(s):  
Byoung Chul Cho ◽  
Sang Joon Shin ◽  
Jae-Lyun Lee ◽  
Byoung Yong Shim ◽  
Hyung Soon Park ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Interleukin 2 ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Part D ◽  
Anti Tumor Activity

BackgroundGI-101 is a novel bispecific fusion protein containing CD80 and interleukin-2 (IL-2) variant, designed to exhibit high affinity to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and preferential binding to IL-2Rβ subunit. In various animal models, GI-101 exerted strong anti-tumor efficacy, accompanied by robust stimulation of CD8+ T and NK cell proliferation without a significant increase in regulatory T cells. GI-101 also elicited synergistic anti-tumor efficacy when used in combination with pembrolizumab (anti-PD1 agents), lenvatinib (tyrosine kinase inhibitor) and radiation in in vivo.1 Given the complementary mechanisms of action of GI-101 via blocking CTLA4 with IL-2 activity to enhance the proliferation and activation of effector T and NK cells, it was hypothesized that GI-101 as a single agent or in combination with other immunotherapies, VEGF inhibitors or RT may exert anti-tumor activity in cancers with high unmet needs.MethodsKEYNOTE-B59 (NCT04977453) is an ongoing phase 1/2 study composed of 4 parts. This study is planned to enroll approximately 374 patients across the indications. Patients assigned to Part A and B receive either GI-101 monotherapy (Part A) or GI-101 + 200 mg of pembrolizumab (Part B) via IV infusion on every 3 weeks (q3w). In Part C, patients will receive GI-101 q3w in combination with lenvatinib (oral, once daily). In Part D, patients will be given GI-101 q3w in combination with local tumor irradiation. Each part is initiated with dose-escalation/optimization phases which will enroll patients with advanced solid tumors, except Part D that enrolls advanced melanoma and sarcoma only. This phase utilizes conventional 3+3 design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of GI-101 as a monotherapy and in combination. Once RP2D is determined, patients will be enrolled in dose-expansion phases of each part that includes specific tumor types, such as solid cancers failed on standard of care, treatment-naïve unselected or CPI-treated solid tumors. Patients with advanced solid tumors and recovered from prior therapy will be enrolled. This study will assess safety, tolerability, dose-limiting toxicities, MTD, RP2D, preliminary anti-tumor activity, and pharmacokinetics/pharmacodynamics of GI-101 as a single agent and in combination.ResultsThis study is currently enrolling patients with advanced or metastatic solid tumors.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by GI Innovation, Inc.Trial RegistrationNCT04977453ReferencePyo KH, Synn CB, Koh YJ, et al. Comprehensive preclinical study on GI-101, a novel CD80-IgG4-IL2 variant protein, as a therapeuticantibody candidate with bispecific immuno-oncology target. Cancer Res 2021;81(13_Suppl).Ethics ApprovalThis study was approved by Severance hospital institutions’ Ethics Review Board (IRB); approval number 4-2021-0185, Asan Medical center‘s IRB; approval number 2021-0669.

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.

Safety and pharmacokinetics of intravenous VEGF Trap plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in a combination phase I clinical trial of patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13161-13161 ◽  
Author(s):  
O. Rixe ◽  
C. Verslype ◽  
J. B. Méric ◽  
S. Tejpar ◽  
J. Bloch ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Vegf Receptor ◽  
Advanced Solid Tumors ◽  
Colon Cancers ◽  
Ecog Ps ◽  
Dose Levels ◽  
Vegf Trap

13161 Background: VEGF Trap is a potent angiogenesis inhibitor comprising portions of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (Flk-1) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF and neutralizes all VEGF-A isoforms plus placental growth factor. I-LV5FU2 is an approved chemotherapy regimen for the first-line treatment of metastatic colorectal cancer. This study was designed to evaluate the safety and pharmacokinetics (PK) of VEGF Trap plus I-LV5FU2 administered intravenously. Methods: Successive cohorts of 3–6 patients (pts) with relapsed or refractory solid tumors received intravenous VEGF Trap plus I-LV5FU2 every 2 weeks. Study endpoints included safety, PK, and immunogenicity. Antitumor activity was assessed by CT scan. Results: Ten pts (3 male/7 female), median age 59 (34–67), ECOG PS 0/1/2: 8/2/0, with a variety of advanced solid tumors, including 5 colorectal and 2 ovarian, have received a total of 50 cycles of VEGF Trap plus I-LV5FU2 across 2 VEGF Trap dose levels (2.0 mg/kg, 4.0 mg/kg) to date. Only 1 dose-limiting toxicity (G3 proteinuria >2 wks with normal plasma creatinine levels) has been encountered so far (4.0 mg/kg, Cycle 2). This pt also had controlled G2 HTN (renal biopsy pending). No other G3/4 VEGF Trap-related AEs have been reported so far. Preliminary free VEGF Trap clearance was 15.4 mL/kg/day. Three pts (synovial sarcoma, ovarian and colon cancers) achieved partial responses. Conclusions: VEGF Trap may be safely combined with I-LV5FU2 at the dose levels studied. Preliminary free VEGF Trap clearance did not differ significantly from that seen with single-agent exposure; chemotherapy PK analysis is pending. The maximum tolerated dose has not yet been reached, and dose escalation continues. Updated safety, pharmacokinetic, and preliminary efficacy results from this ongoing study will be presented. [Table: see text]

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