scholarly journals A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1425
Author(s):  
Filippo de Braud ◽  
Jean-Pascal H. Machiels ◽  
Daniela Boggiani ◽  
Sylvie W.H. Rottey ◽  
Matteo Duca ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Gamma Glutamyl Transferase ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Number Of Patients ◽  
Glutamyl Transferase

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80–220 mg/day; Arm C) with 60–80 mg/m2/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (n = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (n = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.

Phase I study of volasertib (BI 6727) combined with afatinib (BIBW 2992) in advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2521-2521
Author(s):  
Marc Peeters ◽  
Jean-Pascal H. Machiels ◽  
Korinna Pilz ◽  
Marina De Smet ◽  
Natalja Strelkowa ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Ecog Ps ◽  
Anti Tumor Activity

2521 Background: Volasertib is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases (Plk). Volasertib and afatinib, an irreversible ErbB family blocker, have shown single agent anti-tumor activity and manageable safety profiles in patients (pts) with advanced solid tumors. This dose escalation study was designed to determine the maximum tolerated dose (MTD) of two combination schedules of volasertib and afatinib in pts with advanced solid tumors refractory to or not amenable to standard therapy. Methods: In a 3 + 3 design, cohorts of 3–6 pts received volasertib 150–300 mg IV d1 Q3W + afatinib 30–50 mg PO QD d2–21 Q3W (Schedule A) or afatinib 50–90 mg d2–6 Q3W (Schedule B). Up to 12 additional pts were enrolled at the MTD. Primary endpoint was the MTD per schedule. Secondary endpoints included pharmacokinetics (PK), safety and efficacy (RECIST). Results: 57 pts (median 58 yr; ECOG PS 0/1/2: 35%/60%/5%) were treated (n=29, Schedule A; n=28, Schedule B). MTD was volasertib 300 mg/afatinib 30 mg (Schedule A) and volasertib 300 mg/afatinib 70 mg (Schedule B). Cycle 1 dose limiting toxicities (DLTs) were experienced by 5 (Schedule A) and 7 (Schedule B) pts. Most common DLTs were diarrhea (n=5), neutropenia (n=3), fatigue (n=2) and decreased ejection fraction (n=2) in Schedule A, and thrombocytopenia (n=6), neutropenia (n=5), diarrhea (n=4) and febrile neutropenia (n=3) in Schedule B. Most common grade 3/4 adverse events were neutropenia (n=8), thrombocytopenia (n=6), diarrhea (n=3) and febrile neutropenia (n=3). Volasertib exhibited multi-exponential PK behavior with a long half-life (130 hr), moderate clearance (900 mL/min) and large volume of distribution (Vss >6000 L). Co-administration of volasertib and afatinib had no effect on the PK profile of either drug. Two pts in Schedule A (volasertib 300 mg/afatinib 30 mg) achieved partial responses (tumor types: NSCLC, head and neck). Conclusions: MTD of volasertib was 300 mg Q3W combined with afatinib 30 mg d2-21 (Schedule A) or afatinib 70 mg d2-6 (Schedule B). Both agents could be combined at previously shown active single agent doses. At the MTD, treatment was manageable and showed preliminary anti-tumor activity. Clinical trial information: NCT01206816.

A phase I dose-escalation study of volasertib (BI 6727) combined with nintedanib (BIBF 1120) in advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2556-2556 ◽  
Author(s):  
Filippo G. De Braud ◽  
Stefano Cascinu ◽  
Gianluca Spitaleri ◽  
Korinna Pilz ◽  
Laura Clementi ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Safety Profile ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Day Treatment ◽  
Single Agent ◽  
Safety Data ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

2556 Background: Volasertib (V) is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. Nintedanib (N) is a triple angiokinase inhibitor of VEGF, PDGF, and FGF receptors. Both have shown clinical activity with a manageable safety profile in patients (pts) with advanced solid tumors. This study was designed to determine the maximum tolerated dose (MTD) of V combined with N in these pts. Methods: Cohorts of 3–6 pts received V (100–450 mg IV Q3W) + oral standard dose N (200 mg BID continuously, except V infusion day). Treatment continued until clinical progression. Up to 12 pts were treated at the MTD for additional safety data. Primary endpoint was the MTD; secondary endpoints were pharmacokinetics (PK), overall safety, and preliminary efficacy. Results: 30 pts were treated (median age, 56.5 yr; ECOG PS 0/1/2, 33%/60%/7%; ≥3 prior therapies, 87%). At V doses >200 mg, 7 pts experienced 13 dose-limiting toxicities (DLTs) during cycle 1: increased alanine aminotransferase [ALT] or aspartate aminotransferase [AST], neutropenia and thrombocytopenia. The MTD was V 300 mg (Table). At the MTD, the most common all grade (Gr) adverse events (AEs) were neutropenia (69%), asthenia and thrombocytopenia (62% each), increased ALT, increased AST and diarrhea (54% each). Median (range) duration on treatment was 4 (1–18) cycles. Treatment was discontinued due to progressive disease (80%), DLT (3%) and other non-AE related reasons (17%). 2 objective responses were observed (1 complete [breast cancer] and 1 partial [NSCLC]), both with the 300 mg dose. 6 pts had SD for ≥ 6 mo. PK data will be presented at the meeting. Conclusions: MTD of V + standard dose N (200 mg BID) was determined to be 300 mg Q3W (the same as the recommended phase II single agent dose of V in solid tumors). This combination had a manageable safety profile without unexpected or overlapping toxicities and showed preliminary antitumor activity. Clinical trial information: NCT01022853. [Table: see text]

First-in-human (FIH) phase 1 (Ph1) study of MORAb-202 in patients (pts) with advanced folate receptor alpha (FRA)-positive solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5544-5544 ◽  
Author(s):  
Toshio Shimizu ◽  
Yutaka Fujiwara ◽  
Kan Yonemori ◽  
Takafumi Koyama ◽  
Akihiko Shimomura ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Folate Receptor ◽  
Phase 1 ◽  
Dose Range ◽  
Objective Response ◽  
Gamma Glutamyl Transferase ◽  
Antibody Drug Conjugate ◽  
Eribulin Mesylate ◽  
Grade 3 ◽  
Glutamyl Transferase

5544 Background: MORAb-202 is an antibody drug conjugate consisting of farletuzumab (a humanized monoclonal antibody that binds to FRA) paired with a cathepsin B-cleavable linker to eribulin mesylate (a microtubule dynamics inhibitor). We report preliminary results from a FIH Ph1 study of MORAb-202 in pts with FRA-positive solid tumors. Methods: This open-label, ongoing, FIH study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose, and/or the recommended dose of MORAb-202 (Part 1: Dose finding part with accelerated modified toxicity probability interval design; Part 2: Expansion part). Eligible pts had FRA-positive solid tumors who failed standard therapy and an ECOG PS of ≤1. MORAb-202 was administered by intravenous injection once every 3 weeks and dose-limiting toxicities (DLTs) were assessed during the first 21-day cycle. Efficacy endpoints were assessed with RECIST v1.1 by investigator assessment. Results: As of Nov 16, 2018, 16 pts with confirmed FRA-positive tumors were enrolled and treated with MORAb-202 across 4 dose levels in Part 1 (0.3mg/kg: n = 3 [2 endometrial and 1 ovarian], 0.45mg/kg: n = 3 [3 ovarian], 0.68mg/kg: n = 3 [1 NSCLC, 1 ovarian, and 1 TNBC], 0.9mg/kg: n = 7 [4 ovarian, 1 endometrial, 1 NSCLC, and 1 TNBC]); all completed > 1 cycle. One pt in the 0.9mg/kg cohort experienced DLTs of alanine aminotransferase increased (grade 3) and gamma-glutamyl transferase increased (grade 3). Treatment-emergent adverse events (TEAEs) occurred in 15 pts (93.8%). The most common TEAEs were leukopenia and neutropenia (50% each). The objective response rate based on RECIST v1.1 was 37.5% (6/16 pts) in Part 1 with 1 complete response (ovarian) at 0.9mg/kg and 5 partial responses including 2 pts (both ovarian) at 0.9mg/kg, 1 pt (endometrial) at 0.3mg/kg, and 2 pts (1 TNBC and 1 NSCLC) at 0.68mg/kg. The disease control rate was 75% (12/16 pts). Exposure to MORAb-202 was dose proportional across the dose range investigated. Conclusions: MORAb-202 escalation to 0.9mg/kg was manageable with encouraging initial antitumor activity in pts with FRA-positive solid tumors. Clinical trial information: NCT03386942.

A first-in-human phase dose-escalation study of YH002, a recombinant humanized agonistic anti-OX40 IgG1 monoclonal antibody, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Kate Wilkinson ◽  
John J. Park
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Cancer Breast ◽  
Dose Levels

e14501 Background: YH002 is a recombinant humanized IgG1 antibody that targets the human OX40 receptor. Preclinical studies have demonstrated the specificity, potency, and anti-cancer efficacy of YH002 in a comprehensive panel. The totality of nonclinical data supports progression of YH002 into clinical studies in adult patients (pts) with advanced solid tumors. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced or metastatic refractory solid tumors received YH002 as single agent by IV administration at 0.01 to12.0 mg/kg dose levels every 21 days (Q3W), to evaluate the safety, tolerability and preliminary efficacy. An accelerated titration dose escalation design followed by a traditional 3+3 dose algorithm were utilized to assess dose-limiting toxicity (DLT) and identify MTD and/or RP2D. Tumor assessments were performed per RECIST v1.1 every 9 weeks. Results: By December 31 2020, six patients were enrolled and treated at escalating dose levels of 0.01 (n=1), 0.03 (n=1), 0.1 (n=1) and 0.3mg/kg (n=3), with tumor types including colon cancer, thymic cancer, prostate cancer, colorectal cancer, breast cancer and bladder cancer. Median treatment duration was 10.2 weeks (range 2 – 18). The median age of patients was 67 years old (range 47-78). These patients had progressed after a median of 2 prior lines of available standard therapy. As of data cutoff, no dose limiting toxicities (DLTs), no Grade (G) 3 or above adverse events (AE) or AEs leading to treatment discontinuation were reported. Drug-related adverse events (AEs) were all G1/2 events and occurred in 4 patients, including 8 G1 AEs (pneumonitis, rash, pruritus, arthralgia, myalgia, fatigue, lethargy, rash pruritic) and 3 G2 AEs (1 pneumonitis and 2 fatigue). Out of 5 patients having tumor assessment by RECIST, one pt with Thymic SCC at 0.3 mg/kg had best response of stable disease at week 9, one pt with prostate cancer at 0.1 mg/kg experienced Non-CR/Non-PD, and rest of 3 pts experienced progressive disease. Conclusions: These preliminary results demonstrate that YH002 was safe and tolerable up to 0.3mg/kg. Updated safety and antitumor activity will be presented. Clinical trial information: NCT04353102.

scholarly journals Phase 1 dose‐escalation study of single‐agent veliparib in Japanese patients with advanced solid tumors

2017 ◽  
Vol 108 (9) ◽  
pp. 1834-1842 ◽  
Author(s):  
Tadaaki Nishikawa ◽  
Koji Matsumoto ◽  
Kenji Tamura ◽  
Hiroyuki Yoshida ◽  
Yuichi Imai ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2566-2566 ◽  
Author(s):  
Patricia LoRusso ◽  
Geoffrey Shapiro ◽  
Shuchi Sumant Pandya ◽  
Eunice Lee Kwak ◽  
Cheryl Jones ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Fdg Pet ◽  
Metabolic Response ◽  
Phase 1 ◽  
Single Agent ◽  
Pi3k Inhibitor ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Phase Ib

2566 Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are deregulated in many tumor types. Targeting both pathways may be more efficacious than targeting either pathway alone. In preclinical models, concurrent administration of GDC‑0973, a potent, selective, MEK1/2 inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved efficacy compared to either agent alone dosed continuously or intermittently. Methods: A phase Ib dose-escalation study with 3+3 design was initiated in patients (pts) with advanced solid tumors to evaluate the safety and pharmacokinetics (PK) of oral dosing of GDC-0973 and GDC-0941. Pts received: concurrent GDC-0973 + GDC-0941 once daily (qd) on a 21 day on/7 day off (21/7) schedule; intermittent GDC-0973 on Days 1, 4, 8, 11, 15, 18 of a 28 day cycle + GDC-0941 qd on a 21/7 schedule (MEK int); or GDC-0973 + GDC-0941 qd on a 7 day on /7 day off schedule (7/7). Starting doses were 20 mg GDC-0973 + 80 mg GDC-0941 (21/7), 100 mg GDC-0973 + 130 mg GDC-0941 (MEK int); 40 mg GDC-0973 + 130 mg GDC-0941 (7/7). Serial plasma PK samples, FDG-PET, and CT scans were obtained. Results: 78 pts have enrolled. DLTs were G3 lipase (n=1), G4 CPK elevation (n=1). Compared to the 21/7 MTD of 40 mg GDC-0973 + 100 mg GDC-0941, higher doses of GDC-0973 + GDC-0941 were tolerated on the MEK int schedule. Overall, adverse events related to the study drug combination in ≥ 20% pts were diarrhea, rash, nausea, fatigue, vomiting, decreased appetite, dysgeusia, and elevated CPK. Preliminary analysis indicated PK of GDC-0973 and GDC-0941 are not altered when dosed in combination. Of 46 evaluable pts, 26 had an FDG-PET partial metabolic response (≥ 20% decrease in mean SUVmax from baseline) at ≥1 time points. Partial responses were observed in 3 pts (mBRAF melanoma, mBRAF pancreatic ca, mKRAS endometrioid ca); 5 pts had stable disease ≥ 5 months. Conclusions: Combination dosing of GDC‑0973 and GDC-0941 is generally well tolerated, with toxicities similar to those observed in single agent GDC-0973 and GDC-0941 phase 1 trials. There are early signs of anti-tumor activity. Dose escalation on MEK int and 7/7 schedules continues and updated data will be presented.

A phase 1 dose-escalation study of BBI503, a first-in-class cancer stemness kinase inhibitor in adult patients with advanced solid tumors.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 2527-2527 ◽  
Author(s):  
Scott Andrew Laurie ◽  
Derek J. Jonker ◽  
William Jeffery Edenfield ◽  
Joe Stephenson ◽  
Deborah Keller ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Adult Patients ◽  
Advanced Solid Tumors ◽  
Cancer Stemness ◽  
Dose Escalation Study

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654 administered daily for 28 days to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3586-3586
Author(s):  
Ignacio Garrido-Laguna ◽  
Patrick Michael Dillon ◽  
Stephen Patrick Anthony ◽  
Margit Janat-Amsbury ◽  
Nissa Ashenbramer ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear

3586 Background: TP-3654 is an oral, second generation, potent PIM-1 kinase inhibitor with activity against PIM 2, 3 and favorable selectivity against other kinases. These cytoplasmic serine/threonine kinases are highly expressed in many cancers and their oncogenic potential has been largely attributed to supressing apoptosis downstream of stimuli including inflammatory cytokines and other immune effectors. TP-3654 has efficacy in various hematologic and solid tumor models inducing stromal Pim-1 also has been shown to mediate various aspects of the tumor microenvironment. Thus, Pim kinases are attractive targets for the treatment of many human malignanices. Methods: A first in human, 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-3654 in patients with advanced solid tumors. Results: Ten patients were enrolled between 30Apr and 31Dec2019 receiving 480, 720, and 1080 mg respectively. Grade 3 AEs were scrotum wound infection, altered mental status, anemia, fall, and lower extremity edema, none were related to study drug and all were manageable with supportive care. There were no Grade 4 or 5 AEs and no DLTs. Median duration of SD was 5.5 months (6/10) and with prolonged SD > 16wks (4/10). One CRC patient with 4 lines of prior therapy had a 22% reduction in tumor volume (SD > 5+ mos). TP-3654 plasma PK values (Cmax, AUC) continuously increased through all 3 cohorts. Average Cmax (ng/mL) and AUC0-24 (ng*hours/mL) were 195, 1965 (480mg); 357, 3310 (720mg); 735, 6922 (1080mg), respectively. PK values increased linearly with higher doses without reaching saturation. Peripheral Blood Mononuclear Cells were isolated from subjects prior and up to 24hours after treatment. Western Blot from protein lysates revealed a decrease in phosphorylation of BAD and p70s6K proteins, both regulated by PIM-1 kinase. Conclusions: These findings suggest that TP-3654 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, and resistant solid tumors warranting further clinical development in selected indications.

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