scholarly journals 949 First-in-human study of the first acid pH-sensitive and recycling CTLA-4 antibody that preserves the immune tolerance checkpoint to avoid immunotherapy-related adverse events in cancer patients

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A998-A998
Author(s):  
Tianhong Li ◽  
Mei Tang ◽  
Karen Kelly ◽  
Hui Amy Chen ◽  
Stacy Joo ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Solid Tumors ◽  
Drug Exposure ◽  
Human Study ◽  
Ph Sensitive ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Lysosomal Degradation ◽  
Acid Ph

BackgroundCTLA-4 is the first immune checkpoint target for cancer immunotherapy. However, the clinical benefit of targeting CTLA-4 has been limited by suboptimal doses and early discontinuation due to immunotherapy-related adverse events (irAE). Our preclinical studies suggest that acid pH-sensitive anti-CTLA-4 antibodies that preserve CTLA-4 recycling and avoid lysosomal degradation are more effective for immunotherapy but largely devoid of immunotherapy-related adverse events (irAE) [1-6]. To test this new hypothesis in human, we initiated first-in-human study evaluating the safety and tolerability of ONC-392 in patients with advanced solid tumors.MethodsONC-392-001 Part A is a dose finding study of ONC 392, IV infusion, Q3W. Patients (pt) with advanced solid tumors who had progressed to standard of care cancer therapies with ≥1 measurable tumor were enrolled. Intra-patient dose-escalation were performed for 4 doses (0.1, 0.3, 1.0 and 3.0 mg/kg) and 6 pts for the final dose of 10.0 mg/kg. The primary endpoints are the safety and tolerability of ONC-392 for identifying recommended Phase II dose (RP2D).ResultsTen pts have received 2-11 cycles of ONC-392 treatment at dose levels ranging from 0.1 to 10 mg/kg. Pt characteristics: median age 62 (range 43-81), female/male: 7/3, White/Asian/Black: 6/3/1. Tumor types: 4 ovarian, 4 NSCLC, 1 cervical and 1 GE junction cancer. Prior line of treatment: 2-7. Six pts were in 10 mg/kg dose level and received 2-4 doses of the drug as of this writing. None of the 10 pts experienced dose limiting toxicity (DLT) or Gr 3-4 adverse events (AEs) in DLT period. The RP2D for ONC-392 monotherapy is 10 mg/kg. After the DLT period, 1 patient developed Gr 3-4 elevated amylase/lipase at 10 weeks after 4 cycle of 10 mg/kg. No other treatment-related severe AE was observed. Among eight evaluable pts, 7/8 (87.5%) had stable disease (SD) after three cycle of treatment, and beneficial clinical efficacy activities was observed in 3/8 (37.5%) pts. Among them, a stage 4B ovarian cancer patient had stayed in treatment for 30 weeks till disease progression, and 2/2 evaluable PD(L)-1 antibody-refractory NSCLC patients were either eligible for surgery or had significant tumor shrinkage.ConclusionsONC-392 monotherapy is well tolerated with very low irAE rate. The RP2D for ONC-392 monotherapy is 10 mg/kg. The acid pH-sensitive anti-CTLA-4 mAb that preserves CTLA-4 recycling and avoids lysosomal degradation was safe and well tolerated. Our work paves the way for significant increase of drug exposure to reach full immunotherapeutic potential of CTLA-4 targeting.AcknowledgementsThe study is sponsored by OncoC4, Inc with the support of NCI SBIR grant R44CA250824.Trial RegistrationNCT04140526ReferencesDu X, et al. Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res 2018;28(4):433–447.Du X, et al. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res 2018;28(4):416–432.Liu Y, Zheng P. How does an anti-CTLA-4 antibody promote cancer immunity? Trends Immunol 2018;39(12):953–956.Zhang Y, et al. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Research 2019;29(8):609–627.Liu Y, Zheng P. Preserving the CTLA-4 checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol Sci 2020;41(1):4–12.Zhang P, et al. Mechanism- and immune landscape-based ranking of therapeutic responsiveness of 22 major human cancers to next generation anti-CTLA-4 antibodies. Cancers (Basel), 2020;12(2):284.Ethics ApprovalThis study obtained ethic approval from WIRB with Study #20193108. All participants gave informed consent before taking part of the study.ConsentN/A.

scholarly journals 478 COM701 in combination with BMS-986207 (anti-TIGIT antibody) and nivolumab – preliminary results of safety, tolerability and pharmacokinetics in patients with advanced solid tumors (NCT04570839)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A508-A508
Author(s):  
Ecaterina Dumbrava ◽  
Manish Sharma ◽  
Gini Fleming ◽  
Kyriakos Papadopoulos ◽  
Ryan Sullivan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Solid Tumors ◽  
Pharmacokinetic Parameters ◽  
Tolerability Profile ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Cancer Data ◽  
Preliminary Results ◽  
Favorable Safety

BackgroundCOM701, a novel first-in-class immune checkpoint inhibitor (ICI) binds to poliovirus receptor related immunoglobulin domain containing (PVRIG) leading to enhanced activation of T and NK-cells. COM701 in combination with nivolumab has a favorable safety profile, is well tolerated and demonstrates antitumor activity.1 We hypothesized that the addition of BMS-986207 as a triplet thereby inhibiting the DNAM axis will have an acceptable safety/tolerability profile. We present preliminary results on safety/tolerability and pharmacokinetics (PK) parameters.MethodsUsing an accelerated titration and 3+3 study design we enrolled 14 patients (pts) with advanced solid tumors. Doses of COM701 were 0.3, 1, 3, 10 or 20 [mg/kg IV Q4 wks]; in combination with nivolumab and BMS-986207 (both 480 mg IV Q4 wks). Key objectives were to evaluate the safety and tolerability, to determine the recommended dose for expansion (RDFE) and to characterize preliminary pharmacokinetic parameters. Key inclusion criteria: Age ≥ 18 yrs, histologically confirmed locally advanced or metastatic solid malignancy and has exhausted all available standard treatments. Key exclusion criteria: history of immune-related toxicities on prior immunotherapy treatment leading to discontinuation.ResultsIn the safety population [N=14], 12 pts reported treatment emergent adverse events (TEAEs). The most frequent TEAES [≥3 pts] were fatigue 5 pts (36%), pyrexia 3 pts (21%), vomiting 3 pts (21%). No DLTs were reported in any of the dose levels. The most frequent tumor types enrolled: CRC (n=3), and prostate, melanoma and OVCA/primary peritoneal cancer (n=2 each). Median number of prior therapies was 10 (range 1–19). Four pts had received prior immunotherapy. Serious adverse events [≥2 pts] were 2 pts (14%) with G3 abdominal pain, 2 pts (14%) with vomiting (1pt with G1/2 vomiting, 1 pt with G3 vomiting) all assessed by the investigator as unrelated to study drug. Preliminary PK profiles of COM701 were generally dose proportional.ConclusionsCOM701 in combination with BMS-986207 and nivolumab demonstrates a favorable safety, tolerability and PK profiles. COM701 20 mg/kg has been selected as the RDFE in combination with BMS-986207 and nivolumab (both 480 mg) all administered IV Q4 wks. The expansion cohorts are enrolling pts with platinum resistant ovarian cancer and endometrial cancer. Data cutoff 28 Jun 2021.AcknowledgementsThis study is in collaboration with Bristol Myers Squibb.Trial RegistrationNCT04570839ReferencesVaena, DA, Fleming GF et al. COM701 with or without nivolumab: Results of an ongoing phase 1 study of safety, tolerability and preliminary antitumor activity in patients with advanced solid malignancies (NCT03667716). J Clin Oncol 2021;39: (suppl 15; abstr 2504).Ethics ApprovalThe study obtained ethics approval form all the participating sites. All study participants gave informed consent before taking part.- 0002: START2020.15- 0003: 20210109- 0005: IRB20-1549- 0006: 21-060- 0007: IRB-AAAT4904- 0012: 2020-0755- 0013: STMW2020.16- 0015: 20210109

A phase I, first-in-human study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of IMGN853 in patients (Pts) with epithelial ovarian cancer (EOC) and other FOLR1-positive solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2573-2573 ◽  
Author(s):  
Carla Kurkjian ◽  
Patricia LoRusso ◽  
Kamalesh Kumar Sankhala ◽  
Michael J. Birrer ◽  
Maurice Kirby ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Drug Exposure ◽  
Cell Cancer ◽  
Human Study ◽  
Study Drug ◽  
Primary Study

2573 Background: IMGN853 is an antibody-drug conjugate (ADC) comprising a folate receptor 1 (FOLR1)-binding antibody and the potent maytansinoid, DM4. FOLR1 is over-expressed on many solid tumors, particularly EOC, endometrial cancer, non-small cell lung cancer (NSCLC), and clear-cell renal cell cancer. Methods: The primary study objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives include evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy. In dose escalation, patients with any type of FOLR1-expressing, refractory solid tumor may be enrolled. Once the MTD is defined, 3 expansion cohorts will evaluate patients with (1) primary platinum refractory or resistant EOC; (2) relapsed/refractory EOC, amenable to biopsy, and (3) relapsed/refractory NSCLC. Cohorts 2 and 3 will have IMGN853 PD assessment by pre-and post-dose tumor biopsy and by FLT-PET imaging, respectively. IMGN853 is given intravenously (IV) on Day 1 of each 21-day cycle. During dose escalation, an accelerated titration design was used. Responses are assessed using RECIST and GCIG criteria (as appropriate). Results: Eleven patients have been enrolled across 6 dose levels ranging from 0.15 to 5.0 mg/kg: 7 patients with EOC and 4 patients with endometrial cancer. No study drug-related serious adverse events (SAEs) or dose-limiting toxicity (DLT) have been reported. Among these 11 patients, 3 patients reported adverse events (AEs) considered study drug related; these were mild or moderate. At the 3.3 mg/kg dose level, one patient with serous EOC had an 82% reduction in CA125 (confirmation pending). The other 2 patients at this dose level, one with EOC and one with endometrial cancer, have stable disease. Drug exposure has been measured in 8 patients and has been found to generally increase linearly, with a half life at 3.3 mg/kg (3 patients) of approximately 4 days. Conclusions: IMGN853 is well tolerated at doses up to 3.3 mg/kg. Safety evaluation continues at 5 mg/kg and dose escalation is ongoing. Clinical trial information: NCT01609556.

Phase I first-in-human study of the polo-like kinase-1 selective inhibitor, GSK461364, in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3536-3536 ◽  
Author(s):  
D. Olmos ◽  
A. Allred ◽  
R. Sharma ◽  
A. Brunetto ◽  
D. Smith ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Performance Status ◽  
Human Study ◽  
Preliminary Evaluation ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Dose Levels

3536 Background: Polo-like kinase-1 (Plk1), part of a family of highly conserved serine-threonine kinases, has multiple roles in mitotic progression, is over-expressed and also associated with poor prognosis in some tumor types. GSK461364 is a potent and selective ATP-competitive inhibitor of Plk1 (Ki 2.2nM) with demonstrated antiproliferative activity in vitro and in vivo. Methods: Adult patients (pts) with relapsed/refractory advanced solid tumors with performance status of 0–2 and adequate organ function were eligible. Sequential cohorts of 2–6 patients each received escalating doses of GSK461364 administered as a 4h intravenous infusion (Schedule [Sch] 1: D1,8,15 q28 or Sch 2: D1,2,8,9,15,16 q28). Primary objectives were to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSK461364. Secondary objectives included preliminary evaluation of anti-tumor activity. Results: 27 pts (20 male, 7 female) were evaluated. Four dose levels, 50mg (n = 2), 100 mg (n = 3), 150 mg (n = 3) and 225 mg (n = 8) were evaluated in Sch 1. Three dose levels, 25 mg (n = 2), 50 mg (n = 2) and 100 mg (n = 7) were evaluated in Sch 2. Dose-limiting toxicities (DLTs) observed were Gr 4 sepsis, in Sch 1 at 225 mg dose, Gr 4 pulmonary embolism (PE) and Gr 4 neutropenia >7d in Sch 2, both at 100 mg dose. Other Sch 1 adverse events (AEs) with a maximum grade ≥3 were fatigue and anemia (both, n = 2), pleuritic pain, pelvic pain, abdominal discomfort, constipation, vomiting, neutropenia, and deep vein thrombosis (all, n = 1). Other Sch 2 AEs with a maximum grade ≥3 were PE, renal failure, thrombocytopenia, and catheter-related infection (all n = 1). The most common adverse events (AEs) regardless of attribution, Sch and dose level were phlebitis (n = 9), fatigue (n = 9), nausea (n = 7), anemia (n = 6), anorexia (n = 6), diarrhea (n = 6), and infusion site reaction (n = 5). Preliminary PK data indicate that AUC and Cmax were proportional across doses; mean values were CLs ∼72–85L/hr, Vss ∼550–1200L and t1/2 ∼11.5hr. Phospho-histone H3, a marker of mitotic arrest, was detected, in circulating tumor cells, 24 hrs after first dose. Stable disease >5m has been observed in 2 esophageal cancer pts. Conclusions: Dose escalation continues in Sch1, Sch2 has been expanded at 75mg. An MTD has not yet been defined. [Table: see text]

A phase I study of the tolerability, safety, pharmacokinetics and preliminary antitumor effects of KBP-5209, a novel pan-HER inhibitor, in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2565-2565
Author(s):  
Sarina Anne Piha-Paul ◽  
Sunil Sharma ◽  
Chengkon Shih ◽  
Bert H. O'Neil ◽  
Qinghong Zhou ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Human Study ◽  
Study Drug ◽  
Nausea And Vomiting ◽  
Advanced Solid Tumors ◽  
Irreversible Inhibitor ◽  
Antitumor Effects ◽  
Serious Adverse Events

2565 Background: KBP-5209 is a novel potent and irreversible inhibitor of tyrosine kinases of the human epidermal growth factor receptor (EGFR) family that preclinically has demonstrated potent antitumor activities in esophageal and gastric cancers and NSCLC. Methods: This first-in-human study (NCT02442414) was conducted to determine tolerability, safety, pharmacokinetics and antitumor activity of KBP-5209 administered QD or BID in patients (pts) with advanced solid tumors. Dose escalation (DE) initially was based on a modified accelerated titration plan and then shifted to a standard 3+3 design. The starting dose was 20 mg QD. Eligible patients were adults with advanced, refractory solid tumors with ECOG PS < 1. A cycle was 28 days. DLTs were evaluated for during the first cycle. DE enriched for patients with tumors having molecular alterations in EGFR or HER2/3. Dose escalation continues so dose expansion has not initiated. Results: As of 26 Nov, 2016, 23 pts (15 females, 8 males) are a part of the evaluable population with a median age 57 (37-79) treated at doses of 20mg (1), 40mg (3), 60mg (7), 70mg (4), 80mg (6) QD and 20mg BID (2).Tumor types included breast (6), CRC (4), ovarian (3), H&N (2), sarcoma (2), and NSCLC, sinus, gastric, gallbladder, pancreas, CUP tumor (1 each). Tumor genetic profiles were available for 20 pts. DLTs were G3 diarrhea, nausea, and vomiting, which occurred in 1 pt at 80mg QD and G3 Diarrhea, occurring in 1pt at 80mg QD. The most common adverse events related to study drug were diarrhea (60.9%), nausea (47.8%), vomiting (43.5%), fatigue (21.7%), decreased appetite (17.4%) and lipase increased (17.4%). Serious adverse events (SAEs) related to study drug were reported in 4pts: diarrhea (1 pt, 70mg QD; 1pt, 80mg QD), nausea and vomiting (1pt, 70mg QD), and diarrhea, nausea and vomiting (1 pt, 80mg QD). Stable disease has been observed in 7pts up to 24 weeks, in which 2/28 pts (7%) achieved tumor shrinkage. Conclusions: Based on the present data, KBP-5209 has been well tolerated with a safety profile similar to other pan-HER inhibitors. For QD dosing, maximum tolerated dose has been identified as 70mg QD. The BID dose escalation continues. Clinical trial information: NCT02442414.

Phase I dose-finding study of oral ERK1/2 inhibitor LTT462 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3640-3640
Author(s):  
Filip Janku ◽  
Elena Elez ◽  
Gopa Iyer ◽  
Noboru Yamamoto ◽  
Daniel Shao-Weng Tan ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Drug Exposure ◽  
Mapk Pathway ◽  
Single Agent ◽  
Human Study ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Grade 3

3640 Background: LTT462 is an investigational small molecule inhibitor of ERK1/2, which has demonstrated preclinical activity in multiple MAPK activated cancer cells and xenograft models. This first-in-human study was designed to evaluate the safety and tolerability of LTT462 in advanced solid tumors harboring MAPK pathway alterations (NCT02711345). Methods: The dose-escalation part of this Phase I, open-label study, enrolled adult and adolescent pts with advanced solid tumors harboring ≥1 documented MAPK pathway alteration with progressive disease (PD) despite standard therapy, or for whom there is no effective standard treatment. Oral LTT462 was given once daily (QD) at 45–600 mg or twice daily (BID) at 150 mg or 200 mg. Objectives were to determine the maximum tolerated dose (MTD) using a Bayesian hierarchical logistic regression model guided by escalation with overdose control, and characterize safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of LTT462. Results: Sixty-five pts (median age 60 years) including 1 pt aged 15 were enrolled in the dose-escalation; most pts (22%) had 3 prior therapies. Most common primary sites for cancer were in the colon (n = 21; 32%), ovary (n = 9; 14%), and pancreas (n = 7; 11%). All pts discontinued, the majority due to PD (n = 44; 68%). Eleven pts experienced DLTs; 6 pts experienced Grade 3 eye disorder DLTs (4 pts retinopathy, 2 pts chorioretinopathy). Treatment-related adverse events (TRAEs) were reported for 89% of pts, most commonly ( > 30%) diarrhea (n = 25; 38%) and nausea (n = 22; 34%). Grade 3/4 TRAEs were reported in 29% of pts; most common was retinopathy (n = 4; 6%). MTD of LTT462 was 400 mg QD and 150 mg BID. Overall, 8 pts (12%) had stable disease (SD) and 35 pts (54%) had PD. An unconfirmed partial response was reported in a pt with cholangiocarcinoma with BRAF mutation; best change in sum of target lesions per RECIST 1.1 was -33.9%. LTT462 increased plasma peak drug concentration and drug exposure at increasing doses between 45–450 mg QD. Exposure at LTT462 600 mg QD was lower than anticipated, indicating potential saturation of absorption at this dose. LTT462 inhibited ERK1/2 and reduced DUSP6 expression relative to baseline in most pts evaluated. Conclusions: LTT462 is well tolerated. Limited clinical activity was reported with single agent LTT462; best overall response was SD. An ongoing study is investigating LTT462 in combination with the RAF inhibitor, LXH254, in NSCLC and melanoma. Clinical trial information: NCT02711345 .

Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan–Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors

2015 ◽  
Vol 33 (30) ◽  
pp. 3401-3408 ◽  
Author(s):  
Josep Tabernero ◽  
Rastislav Bahleda ◽  
Rodrigo Dienstmann ◽  
Jeffrey R. Infante ◽  
Alain Mita ◽  
...  
Keyword(s):  
Growth Factor ◽  
Adverse Events ◽  
Fibroblast Growth Factor ◽  
Solid Tumors ◽  
Fibroblast Growth Factor Receptor ◽  
Human Study ◽  
Growth Factor Receptor ◽  
Advanced Solid Tumors ◽  
Fibroblast Growth ◽  
Grade 3

Purpose JNJ-42756493 is an orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. This first-in-human study evaluates the safety, pharmacokinetics, and pharmacodynamics and defines the recommended phase II dose (RP2D) of JNJ-42756493. Patients and Methods Eligible patients with advanced solid tumors received escalating doses of JNJ-42756493 from 0.5 to 12 mg administered continuously daily or JNJ-42756493 10 or 12 mg administered intermittently (7 days on/7 days off). Results Sixty-five patients were enrolled. The most common treatment-emergent adverse events included hyperphosphatemia (65%), asthenia (55%), dry mouth (45%), nail toxicity (35%), constipation (34%), decreased appetite (32%), and dysgeusia (31%). Twenty-seven patients (42%) experienced grade ≥ 3 treatment-emergent adverse events, and one dose-limiting toxicity of grade 3 ALT elevation was observed at 12 mg daily. Maximum-tolerated dose was not defined. Nine milligrams daily was considered as the initial RP2D; however, tolerability was improved with intermittent schedules, and 10 mg administered on a 7-days-on/7-days-off schedule was considered the final RP2D. Pharmacokinetics were linear, dose proportional, and predictable, with a half-life of 50 to 60 hours. Dose-dependent elevations in serum phosphate, a manifestation of pharmacodynamic effect, occurred in all patients starting at 4 mg daily. Among 23 response-evaluable patients with tumor FGFR pathway alterations, four confirmed responses and one unconfirmed partial response were observed in patients with glioblastoma and urothelial and endometrial cancer (all with FGFR2 or FGFR3 translocations); 16 patients had stable disease. Conclusion JNJ-42756493 administered at 10 mg on a 7-days-on/7-days-off schedule achieved exposures at which clinical responses were observed, demonstrated pharmacodynamic biomarker activity, and had a manageable safety profile.

388 Preliminary results from KEYNOTE-A36, a study of GB1275, a first-in-class oral CD11b modulator, alone and with pembrolizumab or chemotherapy in specified advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A413-A413
Author(s):  
Johanna Bendell ◽  
Wells Messersmith ◽  
Drew Rasco ◽  
Andrea Wang-Gillam ◽  
Wungki Park ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Tumor Tissue ◽  
Phase 1 ◽  
Cancer Center ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Serial Blood ◽  
Biomarker Analysis

BackgroundGB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs), repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. Preclinical anti-tumor activity was observed with single-agent therapy and in combination with chemotherapy or immuno-oncology therapies.1 We report results from the dose escalation portion of an ongoing, first-in-human study of GB1275 monotherapy and combined with pembrolizumab in patients with specific advanced solid tumors. (NCT04060342)MethodsThis study comprises phase 1 dose escalation followed by phase 2 expansion in specific tumor types. In phase 1, cohorts of 3 to 6 patients with histologically confirmed, locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, metastatic castrate-resistant prostate cancer, or triple negative breast cancer are sequentially assigned to one of the ascending dose levels of GB1275 orally twice daily (BID) in 1 of 3 regimens: A (GB1275 monotherapy); B (GB1275 + pembrolizumab) commenced after completion of two cohorts of A; and C (GB1275 + nab-paclitaxel + gemcitabine) will be initiated after A. Patients in Regimens A and B had previously exhausted standard of care treatment options. Dose escalation was based on safety, including dose-limiting toxicity (DLT). Serial blood samples were collected for pharmacokinetic (PK) and biomarker analyses; tumor tissue was also collected for biomarker analysis.ResultsAs of July 28, 2020, 36 patients were treated, 23 in Regimen A (GB1275 100 mg to 1200 mg BID) and 13 in Regimen B (GB1275 100 mg to 800 mg BID + pembrolizumab). No DLTs or adverse events requiring steroid treatment were reported. GB1275-related adverse events were reported in 19 (52.8%) patients; most were Grade 1 and most frequent events (≥10%) were dysesthesia (13.9%) and photosensitivity reaction (11.1%). Stable disease was reported in 4 (17%) patients in Regimen A and 6 (46%) in Regimen B with a median (range) exposure of 84 days (35–172). A dose-dependent increase in GB1275 exposure was observed. An increase in tumor infiltrating lymphocyte (TIL) counts was noted in both Regimens A and B. Other biomarker analyses in serial blood and tumor tissue are ongoing.ConclusionsDose escalation of GB1275, up to 1200 mg and 800 mg BID in Regimens A and B, respectively, demonstrated tolerability as monotherapy and combined with pembrolizumab. The maximum tolerated dose has not been reached. Preliminary observation of an increase in TILs after treatment is encouraging.Ethics ApprovalThis ongoing study is being conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was approved by the Ethics Boards of the University of Colorado Hospital, Washington University School of Medicine - Siteman Cancer Center, Memorial Sloan Kettering Cancer Center, The Sarah Cannon Research Institute/Tennessee Oncology, South Texas Accelerated Research Therapeutics, and The Royal Marsden NHS Foundation Trust.ReferencePanni RZ, Herndon JM, Zuo C, et al. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med 2019 Jul 3;11(499).

Phase I trial of the programmed death receptor 1 (PD-1) inhibitor, BI 754091, in patients (pts) with advanced solid tumors.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 212-212 ◽  
Author(s):  
Melissa Lynne Johnson ◽  
Manish R. Patel ◽  
Lillian L. Siu ◽  
Mark Kozloff ◽  
Raid Aljumaily ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Human Study ◽  
Advanced Solid Tumors ◽  
Activated T Cells ◽  
Serious Adverse Events ◽  
Anti Tumor Activity

212 Background: Tumors may achieve immune evasion by expressing PD ligand-1 (PDL-1) to bind to PD-1 expressed on activated T cells, initiating immunosuppressive signals within the tumor. Pro-inflammatory anti-tumor activity can be restored when this interaction is blocked by therapeutic PD-1 or PDL-1 inhibition. BI 754091 is a monoclonal IgG4Pro antibody directed against PD-1 that has demonstrated anti-tumor activity in vitro and in vivo. We present the results of the first in human study evaluating BI 754091 in patients with advanced solid tumors. Methods: Patients who had exhausted standard treatment (tx) options, including prior anti-PD-1 tx, were enrolled to receive BI 754091 IV every 3 weeks (Q3W) in one of 3 sequential dose escalation cohorts (80, 240 and 400 mg), 3 patients/cohort, to evaluate the safety and tolerability and establish the maximum-tolerated dose (MTD) or recommended Phase II Dose (RPIID). Additional anti-PD-1 naïve patients with select solid tumors are being enrolled in dose expansion to be treated with the selected RPIID. The objectives of the dose expansion cohort are to evaluate the safety, tolerability, PK and preliminary efficacy of the RPIID of BI 754091, in patients with advanced solid tumors. Results: 17 patients have enrolled to date, 9 patients in the dose escalation and 8 patients in the dose expansion cohorts. Both, safety and PK profile supported a RPIID of 240 mg. The most common all grade Treatment Related Adverse Events (TRAE) were fatigue 35% (6 patients), decreased appetite 18% (3 patients) and arthralgia 12% (2 patients). There were no dose-limiting toxicities, tx-related serious adverse events, or TRAEs ≥Grade 3 reported. To date, one patient (gastric cancer) has had a partial response, 8 had stable disease, and 8 patients continue on treatment. Additional efficacy data among patients in dose-expansion will be reported. Conclusions: BI 754091 is safe and well-tolerated across all dose levels tested for advanced solid tumors, with preliminary evidence of activity. A dose of 240 mg Q3W was selected for dose expansion and RPIID based upon the available safety and PK data. Clinical trial information: NCT02952248.

scholarly journals First-in-Human Phase I, Dose-Escalation and -Expansion Study of Telisotuzumab Vedotin, an Antibody–Drug Conjugate Targeting c-Met, in Patients With Advanced Solid Tumors

2018 ◽  
Vol 36 (33) ◽  
pp. 3298-3306 ◽  
Author(s):  
John H. Strickler ◽  
Colin D. Weekes ◽  
John Nemunaitis ◽  
Ramesh K. Ramanathan ◽  
Rebecca S. Heist ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Antibody Drug Conjugate ◽  
Median Response ◽  
Drug Conjugate ◽  
Antibody Drug

Purpose This first-in-human study evaluated telisotuzumab vedotin (Teliso-V), formerly called ABBV-399, an antibody–drug conjugate of the anti–c-Met monoclonal antibody ABT-700 and monomethyl auristatin E. Materials and Methods For dose escalation, three to six patients with advanced solid tumors were enrolled in eight cohorts (0.15 to 3.3 mg/kg). The dose-expansion phase enrolled patients with non–small-cell lung cancer (NSCLC) with c-Met–overexpressing tumors (c-Met positive; immunohistochemistry membrane H-score ≥ 150). Patients received Teliso-V monotherapy intravenously on day 1 once every 3 weeks. Safety, tolerability, pharmacokinetics, and maximum tolerated dose were determined. Results Forty-eight patients were enrolled (median age, 65 years; 35.4% NSCLC; median four prior therapies). One patient each in the 3.0-mg/kg (n = 9) and 3.3-mg/kg (n = 3) cohorts experienced dose-limiting toxicities. Although the maximum tolerated dose was not formally identified, the recommended phase II dose was defined as 2.7 mg/kg on the basis of overall safety and tolerability. The most frequent treatment-emergent adverse events (any grade) were fatigue (42%), nausea (27%), constipation (27%), decreased appetite (23%), vomiting (21%), dyspnea (21%), diarrhea (19%), peripheral edema (19%), and neuropathy (17%). The most frequent Teliso-V–related grade ≥ 3 adverse events were fatigue, anemia, neutropenia, and hypoalbuminemia (4% each). Teliso-V and total antibody pharmacokinetics were approximately dose proportional, with a mean harmonic half-life of 2 to 4 days each. Prospective screening identified 35 (60%) of 58 patients with c-Met–positive NSCLC. Of 16 patients with c-Met–positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, three (18.8%; 95% CI, 4.1% to 45.7%) achieved a partial response (median response duration, 4.8 months; median progression-free survival, 5.7 months; 95% CI, 1.2 months to 15.4 months). No other patients experienced a response. Conclusion Teliso-V monotherapy demonstrated favorable safety and tolerability profiles, with encouraging evidence of antitumor activity in patients with c-Met–positive NSCLC.

scholarly journals Clinical Trial Results from the Subgroup of Lymphoma/CLL in a Phase 1 Study of ARQ 092, a Novel Pan AKT-Inhibitor

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5116-5116 ◽  
Author(s):  
Wael Harb ◽  
Mansoor N. Saleh ◽  
Kyriakos P Papadopoulos ◽  
Feng Chai ◽  
Maria Larmar ◽  
...  
Keyword(s):  
Adverse Events ◽  
Malignant Lymphoma ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Human Study ◽  
Advanced Solid Tumors ◽  
Akt Inhibitor ◽  
Dosing Schedule ◽  
Mantle Cell ◽  
Expansion Cohort

Abstract Background: ARQ 092 is an oral allosteric, potent and selective AKT inhibitor with in vitro and in vivo activity in solid and hematological tumors. ARQ 092-101, the first clinical trial of ARQ 092, has enrolled more than 100 subjects with advanced solid tumors or recurrent malignant lymphoma. As reported previously, the dose escalation portion of the study has been completed and two dosing schedules (intermittent and weekly), are recommended for phase 2 studies. The recommended phase 2 dose (RP2D) for the intermittent dosing schedule is 200 mg once daily (QD) (one week on, one week off) and for the weekly dosing schedule is 300 mg twice daily (BID) (one day on, six days off). [1, 2] Enrollment in an expansion cohort at RP2Ds is ongoing. Here we report the results from 11 subjects with lymphoma/CLL. Material and Methods: Subjects with lymphoma/CLL have been enrolled and treated in the dose escalation and expansion cohorts with intermittent or weekly dosing schedule at the RP2Ds. Tumor responses for subjects with lymphoma were evaluated based on the Revised Response Criteria for Malignant Lymphoma. Adverse events were evaluated based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Blood samples were collected for PK analysis. Archival or biopsy tumor tissue samples were collected for genetic analysis. Results: As of 15 Jun 2015, 11 subjects with lymphoma/CLL (73% male; median age 78 years; 5 follicular, 3 mantle cell, 2 diffuse large B cell, 1 CLL; 4 in dose escalation cohorts, 7 in expansion cohort) have been enrolled and treated at initial doses of 120 to 270 mg QD intermittently (n=7) or 300 mg BID weekly (n=4). All subjects have received at least one prior systemic therapy (median 2, range 1-6). Median duration on study treatment for all 11 subjects was 8 weeks (range 1 to 30 weeks). One subject with CLL and two with follicular lymphoma experienced durable partial responses, respectively with times to response of 8, 8 and 24 weeks and response durations of 16, 8+, and 2+ weeks. The two follicular PR subjects, one of whom had an AKT1 (E17K) mutation, remain on study treatment. In addition, one subject with follicular and one with mantle cell lymphoma experienced stable diseases. Four subjects experienced progressive diseases and two were not evaluable for tumor responses due to early consent withdrawal and clinical disease progression. Table 1. Common drug-related adverse events (≥10%) included macula-papular rash 45%, hyperglycemia 36%, mucosal inflammation 18% and stomatitis 18%. Response Follicular N=5 CLL N=1 Mantle cell N=3 Diffuse large B cell N=2 Total N=11 PR 2 1 3 SD 1 1 2 PD 1 2 1 4 NE 1 1 2 ORR 40% 100% 0% 0% 27% DCR 60% 100% 33% 0% 45% Conclusions: The safety profile of lymphoma subjects is consistent with subjects with solid tumors enrolled in this study. Preliminary signs of single agent activity have been documented with 3 PRs in heavily pretreated lymphoma/CLL including one with AKT1 (E17K) mutation. [1] First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts. M. Saleh et al., Abstract LB-197, AACR 104th Annual Meeting, 6-10 Apr 2013. Washington, D.C. U.S. [2] First-in-human study with ARQ 092, a novel pan AKT-inhibitor, in subjects with advanced solid tumors or recurrent malignant lymphoma. M. Saleh et al., Abstract 320, EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics , 18-21 Nov 2014, Barcelona, Spain Disclosures Harb: Onyx Pharmaceuticals: Consultancy. Chai:ArQule, Inc.: Employment. Larmar:ArQule, Inc.: Employment. Abbadessa:ArQule, Inc.: Employment. Schwartz:ArQule, Inc.: Employment.

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