SWOG S1221: A phase 1 dose escalation study co-targeting MAPK-dependent and MAPK-independent BRAF inhibitor resistance in BRAF mutant advanced solid tumors with dabrafenib, trametinib, and GSK2141795 (ClinicalTrials.gov NCT01902173).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2578-2578 ◽  
Author(s):  
Alain Patrick Algazi ◽  
James Moon ◽  
Bartosz Chmielowski ◽  
Roger Lo ◽  
Kari Lynn Kendra ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Braf V600e ◽  
Advanced Solid Tumors ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Braf Mutant

2578 Background: Aberrant PI3K/AKT signaling in BRAF mutant cancers contributes to resistance to MAPK pathway blockade. We conducted parallel phase 1 dose escalation studies of the doublet of the BRAFi dabrafenib with the AKT inhibitor GSK2141795 and of the triplet of dabrafenib, the MEKi trametinib, and GSK2141795. Methods: Patients (pts) with BRAF-V600E/K mutant advanced solid tumors with adequate end-organ function were eligible regardless of prior BRAFi and MEKi exposure. All pts received dabrafenib at 150 mg twice daily (bid), in the doublet cohorts together with dose escalation (3 + 3 scheme) of GSK2141795 started at 50 mg daily (qd), and in the triplet cohorts with dose escalation of both trametinib starting at 1.5 mg qd and GSK2141795 starting at 25 mg qd. DLTs included significant grade 3 and 4 adverse events (CTCAE v4) within the first 56 days of treatment. Radiographic responses were assessed at 8-week intervals. Results: No DLTs were observed in the doublet cohorts (N = 8) up to dabrafenib 150 mg bid and GSK2141795 75 mg qd. In the triplet cohorts (N = 11), no DLTs were observed at doses of up to trametinib 1.5 mg daily with GSK2141795 75 mg daily. At the highest triplet dose with dabrafenib 150 mg bid, trametinib 2 mg qd with GSK2141795 75 mg qd, 1 of 2 evaluable pts had a DLT of grade 3 febrile neutropenia and grade 3 maculo-papular rash. 2/2 treatment-naïve in the doublet cohorts had PRs (1 melanoma and 1 thyroid) the latter lasting over 1 year. 1/6 BRAF inhibitor-refractory (melanoma) pts also had an objective response. In the triplet cohorts, 3 of 6 treatment-naïve pts had a PR (1 melanoma, 2 lung). One lung pt remains in PR at 2 months and the otherhas an uPR at 1.2 months. Conclusions: Inhibition of both MAPK and PI3K/AKT pathways was well tolerated, leading to durable objective responses in pts with metastatic melanoma, thyroid cancer, and lung cancer. Further study of dual pathway inhibition is warranted. Funding: Supported in part by NIH/NCI grants CA180888, CA180819; and in part by Novartis Pharmaceuticals Corporation and GlaxoSmithKline, LLC. Clinical trial information: NCT01902173.

scholarly journals CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study

2021 ◽  
Vol 9 (7) ◽  
pp. e002446
Author(s):  
Rachel E Sanborn ◽  
Omid Hamid ◽  
Elisabeth GE de Vries ◽  
Patrick A Ott ◽  
Javier Garcia-Corbacho ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Tolerability Profile ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Anal Squamous Cell Carcinoma ◽  
Grade 3

BackgroundProbody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing ‘off-tumor’ toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab.MethodsAdults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1).ResultsTwenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3–4 adverse events (AEs) and grade 3–4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients.ConclusionsThe MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.

scholarly journals Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e001095 ◽  
Author(s):  
Lillian Siu ◽  
Joshua Brody ◽  
Shilpa Gupta ◽  
Aurélien Marabelle ◽  
Antonio Jimeno ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Palliative Radiation ◽  
Cell Counts ◽  
Palliative Radiation Therapy ◽  
Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

scholarly journals Surufatinib Plus Toripalimab in Patients with Advanced Solid Tumors: A Single-Arm, Open-Label, Phase 1 Trial

2020 ◽  
Author(s):  
Yanshuo Cao ◽  
Ming Lu ◽  
Yu Sun ◽  
Jifang Gong ◽  
Jie Li ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Trial ◽  
Open Label Phase ◽  
Grade 3

Abstract BackgroundPreclinical studies have supported a potential synergistic antitumor activity between surufatinib and anti-programed death ligand-1 (PD-L1). We describe here the results of a single-arm, open-label phase 1 trial to evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) in patients with advanced solid tumors treated with surufatinib combined with toripalimab, an inhibitor of PD-L1.MethodsThis is an open-label, dose escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose escalation stage, 3 cohorts of patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with a fixed dose of toripalimab 240 mg, every 3 weeks (Q3W), to evaluate maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Additional patients were enrolled in the dose expansion phase to further assess the efficacy, safety, and PK profile.ResultsFrom April 1, 2019 to July 10, 2020, 31 patients were screened, of which 28 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity (DLT), a grade 3 hyperthyroidism. The top 3 most common treatment-related adverse events of ≥ grade 3 were transaminases increased (17.9%), hypertension (14.3%) and blood bilirubin increased (10.7%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Overall objective response rate was 22.2% [95% confidential interval (CI) 8.6‒42.3], and disease control rate reached 81.5% (95% CI 61.9‒93.7). ConclusionsSurufatinib plus toripalimab was well-tolerated, with no unexpected safety signals, and showed promising antitumor activity in patients with advanced solid tumors. Trial registrationclinicaltrials.gov, NCT03879057; Registered March 18, 2019, https://clinicaltrials.gov/ct2/show/NCT03879057

A phase 1 dose escalation study of RXDX-105, an oral RET and BRAF inhibitor, in patients with advanced solid tumors.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 2574-2574 ◽  
Author(s):  
Manish R. Patel ◽  
Marwan Fakih ◽  
Anthony J. Olszanski ◽  
Albert C. Lockhart ◽  
Alexander E. Drilon ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Braf Inhibitor ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

Dose escalation results from a first-in-human, phase 1 study of the glucocorticoid-induced TNF receptor-related protein (GITR) agonist AMG 228 in patients (Pts) with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2521-2521 ◽  
Author(s):  
Ben Tran ◽  
Richard D. Carvajal ◽  
Aurelien Marabelle ◽  
Sandip P. Patel ◽  
Patricia LoRusso ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Drug Disposition ◽  
Phase 1 ◽  
Objective Response ◽  
Transitional Cell ◽  
Costimulatory Molecule ◽  
Advanced Solid Tumors ◽  
Phase 1 Study

2521 Background: AMG 228 is an agonistic human IgG1 monoclonal antibody that binds to GITR (CD357), a TNFSFR costimulatory molecule expressed by effector/regulatory T cells. Dose escalation of this open label, first in human, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and maximum tolerated dose (MTD) and recommended phase 2 dose of AMG 228 in pts with advanced solid tumors. Methods: Pts with refractory advanced colorectal cancer (n = 13), squamous cell carcinoma of head and neck (n = 10), non–small cell lung cancer (n = 2), urothelial transitional cell carcinoma (n = 4), and melanoma (n = 1) received AMG 228 IV Q3W. Dose escalation was in two stages: single-pt cohorts until AMG 228-related grade > 2 adverse events (AEs), efficacy, or 90 mg dose reached (4 cohorts: 3, 9, 30, and 90 mg), followed by rolling six design (n = 2 to 6) until MTD or highest planned dose of 1200 mg reached (5 cohorts: 180, 360, 600, 900, and 1200 mg). Primary endpoints included incidence of dose-limiting toxicities (DLTs) and AEs and PK. Additional endpoints were objective response (RECIST 1.1) and evidence of biological activity. Results: In total, 30 pts (median age 63 y) were treated (3, 9, 30, and 90 mg, n = 1; 180 mg, n = 6; 360 mg, n = 4; 600 mg, n = 6; 900 mg, n = 4; 1200 mg, n = 6). Twenty-seven (90%) pts had treatment-emergent AEs; the most common were hypophosphatemia (23%), fatigue (23%), anemia (23%), nausea (20%), and pyrexia (20%). No DLTs occurred; the MTD was not reached. AMG 228 exposure was dose-related, with PK profiles at low doses (3 to 90 mg) consistent with target mediated drug disposition; doses > 360 mg achieved serum levels needed for 95% receptor occupancy on activated PBMCs. No evidence of T cell activation was observed despite complete target coverage in both tumor and peripheral blood. Among 29 evaluable pts, none had an objective response. Conclusions: In this population of pts with advanced solid tumors, AMG 228 Q3W was tolerable up to the highest tested dose (1200 mg), showing favorable PK. However, no clinical or immunological activity was observed in this limited number of pts. Clinical trial information: NCT02437916.

Preliminary results from a phase Ib/II, open-label, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9029-9029 ◽  
Author(s):  
Richard Kefford ◽  
Wilson H Miller ◽  
Daniel Shao-Weng Tan ◽  
Ryan J. Sullivan ◽  
Georgina Long ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Thyroid Cancer ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Braf Inhibitor ◽  
Advanced Solid Tumors ◽  
Skin Reactions ◽  
Phase 1B ◽  
Melanoma Patients ◽  
Braf Mutant

9029 Background: Clinical data indicate that combining a BRAF and a MEK inhibitor (BRAFi, MEKi) may be more effective than BRAFi monotherapy in BRAF-mutant metastatic melanoma and that a MEKi may overcome or delay resistance to a BRAFi. Methods: This ongoing phase 1b/2 study is evaluating the combination of LGX818, a potent, selective BRAF inhibitor, and MEK162, a selective MEK1/2 inhibitor, in BRAFi-naive and -pretreated patients with BRAF-mutant tumors. The objective of the phase 1b part is to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) for oral, daily LGX818 + MEK162 in BRAF V600–mutant advanced solid tumors. A Bayesian logistic regression model with overdose control guides the treatment dose escalation. Results: As of January 8, 2013, 20 patients (7 BRAFi-naive melanoma; 9 BRAFi-pretreated melanoma; 2 BRAFi-naive thyroid cancer; 1 BRAFi-naive metastatic colorectal cancer; 1 BRAFi-pretreated colorectal cancer) were treated with LGX818 qd + MEK162 bid at the following dose levels (DLs): 50 mg + 45 mg, 100 mg + 45 mg, 200 mg + 45 mg, and 400 mg + 45 mg. No dose-limiting toxicity has been observed at these DLs. The next DL of 600 mg + 45 mg is under investigation. The single agent RP2Ds for LGX818 and MEK162 are 450 mg and 45 mg, respectively. The most common adverse events (≥ 20%, all grades) suspected to be treatment related were nausea, abdominal pain, and headache. No events of fever, hand-foot-skin reactions, hyperkeratosis, or squamous cell carcinoma were observed. In patients with at least 1 post-baseline CT scan available for investigator-determined response, a complete response was observed in 1/7 (14%) BRAFi-naïve melanoma patients and partial responses were observed in 5/7 (71%) BRAFi-naive melanoma patients, 2/9 (22%) BRAFi-pretreated melanoma patients (starting at 50 mg + 45 mg DL), and 1/2 thyroid cancer patients. Conclusions: Preliminary data from this study indicate that LGX818 + MEK162 can be safely combined with promising clinical benefit. No febrile events or photosensitivity were reported suggesting a distinct safety profile for this BRAFi/MEKi combination vs others. Clinical trial information: NCT01543698.

First-in-human phase 1 study of the antibody-drug conjugate (ADC) SAR408701 in advanced solid tumors: Dose-expansion cohort of patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9072-9072 ◽  
Author(s):  
Anas Gazzah ◽  
Sophie Cousin ◽  
Valentina Boni ◽  
Charles Ricordel ◽  
Tae Min Kim ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Interim Analysis ◽  
Phase 1 ◽  
Surface Glycoprotein ◽  
Advanced Solid Tumors ◽  
Antibody Drug Conjugate ◽  
Cell Surface Glycoprotein ◽  
Grade 3 ◽  
Expansion Cohort

9072 Background: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a cell-surface glycoprotein highly expressed in several tumor types. This Phase 1, open-label, dose-escalation, dose-expansion study (NCT02187848) investigated SAR408701, a DM4 conjugated ADC targeting CEACAM5, in pts with advanced solid tumors. During dose escalation, maximum tolerated dose (MTD) of SAR408701 was 100 mg/m2 IV once every 2 weeks in 14-day cycles. Interim analysis of an ongoing expansion cohort in pts with NSQ NSCLC with CEACAM5 expression in ≥ 50% of the tumor cell population is reported. Methods: SAR408701 was administered at MTD. Primary endpoint: overall response rate (ORR; expansion phase). Secondary endpoints include safety and pharmacokinetics (PK). Tumor assessments were performed every 4 cycles (8 weeks). Results: As of Aug 2, 2018, 22 pts with NSQ NSCLC (21 adenocarcinoma; 1 not yet reported) received SAR408701 at MTD. Median age: 60 years; male: 72.7%; ECOG PS (n = 21): 0 = 38.1%, 1 = 61.9%. Median number of prior anticancer therapies for advanced disease was 3; 66.7% (14/21) received ≥ 3 lines; 59.1% had prior anti-tubulin-based treatments. Pts received a median of 6.5 cycles. 15 pts discontinued due to progressive disease and 1 due to an adverse event (AE; peripheral neuropathy); 6 pts remain on study. ORR was estimated at 22.7% (5/22 pts; 90% CI 11.5–39.9); 40.9% had stable disease. Most frequently occurring all-grade treatment-emergent AEs (TEAEs) were corneal events (40.9%; including keratitis 22.7% [1 Grade 3] and keratopathy 18.2%), dyspnea (31.8%; 5 Grade ≥ 3), asthenic conditions (31.8%) and diarrhea (27.3%). 6 pts had ≥ 1 dose modification due to a TEAE. PK analysis was performed in 14 pts at Cycle 1; mean Cmax, AUC, clearance and t1/2z were 53.1 µg/mL, 297 µg.day/mL, 0.685 L/day and 6.19 days, respectively. Conclusions: In pts with advanced NSQ NSCLC and CEACAM5 expression in ≥ 50% of tumor cells, SAR408701 had a favorable safety profile. Interim analysis of 22 pts achieved the predefined boundary for efficacy (≥ 4 of 30 pts). These data support further development in NSQ NSCLC. Funding: Sanofi Clinical trial information: NCT02187848.

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-1287 administered daily to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3611-3611
Author(s):  
Ben George ◽  
Donald A. Richards ◽  
William Jeffery Edenfield ◽  
Steven L Warner ◽  
Lars Mouritsen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

3611 Background: TP-1287 is a an orally bioavailable phosphate prodrug of alvocidib, a cyclin dependent kinase 9 (CDK9) inhibitor. TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of the BCL-2 family member, MCL-1, which in turn inhibits tumor growth in preclinical animal models of prostate, breast, and lung carcinomas. Methods: This is a multicenter, Phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-1287 in patients with advanced solid tumors. Patients will be added at the maximum tolerated dose (i.e. expansion cohort) to test TP-1287 as a single agent in patients with castrate resistant prostate cancer. Results: Twenty-two patients who were enrolled between December 2018 and January 2020 received a range of doses from 1 mg QD to 11 mg BID over 7 cohorts. Data are available for 20 patients as of the data cutoff date. TP-1287 plasma PK Cmax and AUC increased in near linear fashion over cohorts 1 thru 6, reaching 80 ng/mL and 499.3 ng*h/mL in cohort 6 for Cmax and AUC, respectively. TP-1287 treatment resulted in dose-dependent reductions of phospho-RNA Pol II, consistent with CDK9 inhibition, as measured by a flow cytometric assay assessing pharmacodynamic changes in phosphorylation state in PBMCs. The most frequently observed Grade 3 AE was unrelated anemia in 2 patients. All other events of Grade 3 (9 events/7 patients) and Grade 4 (1 event/seizure with new CNS mets) were unlikely related or unrelated. Clinical benefit was seen in one sarcoma patient with PR (15+cycles), one RCC patient with SD (7+cycles) and 2 bladder cancer patients with SD (6 and 8 cycles). Conclusions: These findings suggest that TP-1287 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, refractory solid tumors and further clinical development in selected indications is warranted. Clinical trial information: NCT03298984 .

SGN228-001: A phase I open-label dose-escalation, and expansion study of SGN-CD228A in select advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3652-TPS3652 ◽  
Author(s):  
Amita Patnaik ◽  
Funda Meric-Bernstam ◽  
Caio Max Sao Pedro Rocha Lima ◽  
Francisco Robert ◽  
Afshin Dowlati ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Metastatic Breast ◽  
Ductal Adenocarcinoma ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Disease Specific

TPS3652 Background: SGN-CD228A is an investigational antibody-drug conjugate (ADC) that targets CD228, a cell-surface oncofetal protein with prevalent expression in several types of cancer and limited expression on normal tissues. SGN-CD228A consists of a humanized IgG1 anti-CD228 monoclonal antibody conjugated to an average of 8 molecules of monomethyl auristatin E (MMAE) via a PEGylated β-glucuronidase cleavable linker. MMAE is a well-studied and highly active chemotype with an established safety profile. The proposed mechanism of action involves binding CD228 on cell surfaces, ADC internalization, and trafficking to lysosomes. MMAE is then released through β-glucuronidase cleavage of the glucuronide MMAE linker. MMAE then binds tubulin, which disrupts microtubule networks and causes cell cycle arrest and apoptosis. Methods: SGN228-001 (NCT04042480) is a phase 1, open label, multicenter, dose escalation, and expansion study enrolling up to 240 subjects to evaluate the safety, tolerability, PK, and antitumor activity of SGN-CD228A in select advanced solid tumors. Eligible subjects are ≥18 years of age and have metastatic cutaneous melanoma, malignant pleural mesothelioma, human epidermal growth factor receptor 2-negative metastatic breast cancer, advanced non-small cell lung cancer, metastatic colorectal cancer, or advanced pancreatic ductal adenocarcinoma. Subjects must have relapsed, refractory, or progressive disease, and should have no appropriate standard therapy available. Measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1, and adequate renal, hepatic, and hematologic function are required. The study includes dose escalation and dose expansion, with multiple disease-specific dose expansion cohorts and a biology cohort. Dose escalation will be conducted using the modified toxicity probability interval method (Ji 2010) to evaluate the safety and identify the maximum tolerated dose of SGN-CD228A. Following dose escalation, disease-specific expansion cohorts and a biology cohort (to evaluate exploratory biomarkers) are planned. Response assessments will be conducted every 6 weeks per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed regularly. Key efficacy endpoints include objective response rate, progression-free survival, and duration of objective response. Enrollment is ongoing in the US and planned in Europe. Clinical trial information: NCT04042480 .

Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4074-4074 ◽  
Author(s):  
Jean-Charles Soria ◽  
John H. Strickler ◽  
Ramaswamy Govindan ◽  
Seungjean Chai ◽  
Nancy Chan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Ecog Performance Status ◽  
Grade 3

4074 Background: Erdafitinib (JNJ-42756493) is a potent, oral pan-FGFR tyrosine kinase inhibitor that demonstrated encouraging preliminary clinical activity and manageable adverse events (AEs) in its first-in-human phase 1 study in advanced solid tumors (NCT01703481). Here we report results from pts with CCA from this study. Methods: This 4-part study enrolled pts age ≥ 18 years (y) with advanced solid tumors. Dose escalation (part 1) followed a 3+3 design, with pts receiving ascending doses of erdafitinib continuously or intermittently (7 days on/7 days off). Subsequent parts required FGFR gene alterations in the tumor, including activating mutations and translocations or other FGFR-activating aberrations. Part 2 was a pharmacodynamics cohort. Parts 3 and 4 were dose-expansion cohorts for recommended phase 2 doses of 9 mg once daily (QD) and 10 mg intermittently, respectively. Results: Eleven pts with FGFR-aberrant CCA were treated at 9 mg QD (n = 1) or 10 mg intermittent (n = 10). Median age was 60 y; 7 of 11 pts were female (64%). 73% of pts had ECOG performance status 1. All had prior systemic therapy. Median treatment duration with erdafitinib was 5.3 months (mo). Systemic erdafitinib exposure, per Cmax and AUC, in CCA pts was similar to other indications. The most common AEs were stomatitis (82%), hyperphosphatemia (64%), dry mouth (55%), dysgeusia (45%), dry skin (45%), and asthenia (45%), mostly grade 1/2 severity. No drug-related grade ≥3 AEs were reported in > 1 pt except grade 3 stomatitis (n = 2; 18%). The objective response rate, all confirmed partial responses (PRs) per RECIST 1.1, was 27.3% (3/11; 95% CI 6, 61); an additional 27.3% (3/11) had stable disease as their best response. Overall disease control rate was 55%. All 3 PRs were at the 10 mg intermittent dosage, and the median duration of response was 12.9 mo. With a median follow-up of 5.1 mo, median progression-free survival was 5.1 mo (95% CI 1.6, 16.4). As of the cutoff date, 2 pts continue on study treatment. Conclusions: Erdafitinib showed encouraging clinical activity and minimal toxicity in pts with advanced CCA and FGFR alterations. These results warrant further study. Clinical trial information: NCT01703481.

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