Early safety from a phase 1, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected into liver tumors.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 438-438 ◽  
Author(s):  
J. Randolph Hecht ◽  
Miklos Pless ◽  
Antonio Cubillo ◽  
Aitana Calvo ◽  
Steven Raman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Liver Tumors ◽  
Disease Incidence ◽  
Phase 1 ◽  
Cell Cancer ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

438 Background: T-VEC is a genetically modified HSV-1 oncolytic immunotherapy designed to preferentially replicate in tumors, produce GM-CSF, and stimulate anti-tumor immune responses. This study evaluates the safety of intrahepatic injection (inj) of T-VEC in patients (pts) with hepatocellular carcinoma (HCC) or liver metastases (mets). Methods: The primary objective is to assess the maximum tolerated dose. Eligible pts were ≥ 18 years (y) old, had progressive HCC or breast cancer (BC), colorectal cancer (CRC), gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer with liver mets, with measurable liver tumors suitable for inj. This dose escalation study comprised 2 groups: A (non-HCC) and B (HCC). T-VEC was given initially at 106 plaque-forming units (PFU)/mL followed by up to 4 mL of 107 PFU/mL (cohort 1) or 108 PFU/mL (cohort 2) every 21 (±3) days (Q21D), or up to 8 mL of the maximum tolerated concentration (MTC) Q21D (cohort 3). Inj volume was based on lesion size. Results: Results from cohorts 1 and 2 of group A are reported. 14 pts were treated; 12 (3 BC, 9 CRC) were DLT-evaluable: Median age was 65.5 y (range: 33, 73); median number of inj was 3; 1 pt received all 12 inj. MTC was 108 PFU/mL. There was 1 DLT, grade 3 aspartate aminotransferase (AST)/grade 2 bilirubin increase (inc), after 1 dose. In all treated pts, 4 (28.6%) had grade 3/4 treatment-related adverse events (TRAEs): anemia and inc gamma-glutamyltransferase, alanine aminotransferase (ALT), and AST. There were 2 deaths attributable to disease. Incidence of serious AEs (SAEs) is shown (Table). Conclusions: The MTC was 108 PFU/mL Q21D after initial inj at 106 PFU/mL. Repeated intrahepatic inj of T-VEC at the FDA-approved concentration for intralesional inj of melanoma was deemed tolerable and feasible in pts with liver mets. Additional investigation in combination with a PD-1 inhibitor is planned. Clinical trial information: NCT02509507. [Table: see text]

Early safety from a phase I, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected (inj) into liver tumors in combination with pembrolizumab (pem).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3015-3015 ◽  
Author(s):  
J. Randolph Hecht ◽  
Miklos Pless ◽  
Antonio Cubillo ◽  
Aitana Calvo ◽  
Hong Jae Chon ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Dose Escalation ◽  
Liver Tumors ◽  
Checkpoint Inhibitors ◽  
Cell Cancer ◽  
Median Number ◽  
Primary Objective ◽  
Open Label ◽  
Dose Escalation Study

3015 Background: T-VEC is a genetically modified, oncolytic HSV-1 designed to selectively replicate within tumors and produce GM-CSF to enhance systemic antitumor immunity. The safety and efficacy of T-VEC in treatment of advanced melanoma has been demonstrated as monotherapy and in combination with checkpoint inhibitors (Andtbacka JCO 2015, Chesney JCO 2017, Ribas Cell 2017). T-VEC has also demonstrated tolerable safety for intrahepatic inj (Hecht JCO 2018). This phase 1b, multicenter, open-label, dose escalation study (NCT02509507) evaluates the safety of intrahepatic inj of T-VEC in combination with intravenous (IV) pem in patients (pts) with hepatocellular carcinoma (HCC) or liver metastases (mets). Methods: The primary objective is to assess the maximum tolerated concentration (MTC) of T-VEC inj into liver tumors based on the incidence of dose-limiting toxicities (DLTs). DLT rate was evaluated with the mTPI up-and-down design. Eligible pts were ≥ 18 years, had progressive HCC or breast cancer, colorectal cancer, gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer liver mets, with measurable liver tumors suitable for inj. This dose escalation study comprised 2 groups: A (non-HCC) and B (HCC). T-VEC was given initially at 106 plaque-forming units (PFU)/mL followed by up to 4 mL of 107 PFU/mL (cohort 5) or 108 PFU/mL (cohort 6) every 21 (±3) days (Q21D). Inj volume was based on lesion size. Pem (200 mg) was given IV Q21D. Results: Here we report on three cohorts: A5 (107 PFU/mL T-VEC + pem), A6 (108 PFU/mL T-VEC + pem), and B5 (107 PFU/mL T-VEC + pem). Twenty-nine pts were treated: 7 in A5, 17 in A6, 5 in B5. Median age was 61 years (range: 30, 76). Median number of inj was 4 and median treatment duration was 88 days. One DLT of cholestatic hepatitis was observed out of 6 DLT evaluable pts in cohort A5. No DLTs were observed in cohort A6 and B5. MTC was 108 PFU/mL in non-HCC patients; exploration of MTC in the HCC population is ongoing. Treatment-emergent adverse events (TEAEs) were consistent across cohorts. The most common treatment-emergent treatment-related adverse events (TETRAE) were pyrexia (79.3%), chills (37.9%), and nausea (37.9%). Eight pts (27.6%) had grade 3/4 TEAEs: 2pts (6.9%) related to the combination therapy and the rest not related to treatment. No fatal AEs were observed. Conclusions: T-VEC intrahepatic inj in combination with IV pem at standard doses has thus far been demonstrated as feasible and tolerable to continue further investigation. Clinical trial information: NCT02509507 .

Tolerability of split-dose oprozomib (ONX 0912) in patients with advanced refractory or recurrent solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13077-e13077
Author(s):  
Kyriakos P. Papadopoulos ◽  
David S. Mendelson ◽  
Anthony W. Tolcher ◽  
Howard A. Burris ◽  
Michael S. Gordon ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Solid Tumors ◽  
Phase 1 ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Status Change ◽  
Dose Escalation Study ◽  
Split Dose ◽  
Grade 3

e13077 Background: Oprozomib (ONX0912), a structural analog of carfilzomib, is an orally bioavailable proteasome inhibitor that irreversibly binds to its target and is being evaluated in hematologic malignancies and solid tumors (ST). In a dose-escalation study of once-daily (qd) ONX0912, the maximum tolerated dose (MTD) was 150 mg/d. The protocol was subsequently amended to investigate the effects of a split-dose schedule. Presented here are the interim results from this patient (pt) group. Methods: This is an ongoing, phase 1 study in pts with advanced refractory or recurrent ST. The primary objective is to evaluate the safety and tolerability of ONX0912 and determine the MTD. ONX0912 is administered for 5 consecutive days in 14-day cycles. For pts under the amended regimen, treatment is initiated at 60 mg BID, with 4–6 h between doses. Daily doses are escalated in 30 mg increments in successive groups of 3 pts. Groups are expanded to include 6 pts in the event of a dose-limiting toxicity (DLT) or if the MTD is reached. All AEs, including serious AEs (SAEs), are defined per protocol and collected from screening to 30 days after the last dose. Results: 13 pts received a split dose of ONX0912 (4 pts: 60 mg BID; 3 pts: 90/60 mg; 6 pts: 90 mg BID). At least 1 dose reduction was required by 1 pt in the 90/60 mg group and 2 pts in the 90 mg BID group. 9 pts reported treatment-related GI AEs (vomiting, n=9; nausea, n=8; diarrhea, n=5). 2 SAEs, arthralgia and mental status change, were reported at 60 mg BID. 2 SAEs resulting in a dose delay were reported at 90/60 mg (Grade 3/4 anemia [ongoing, also required a dose reduction] and reversible fatigue). There was 1 DLT at 90 mg BID (Grade 3 reversible hypophosphatemia), and this cohort was therefore expanded. Treatment-related vomiting led to discontinuation for 1 patient at 60 mg BID. No AEs led to early withdrawal, and no deaths have been reported in the study. Conclusions: With qd administration, the MTD of ONX0912 was established at 150 mg/d. However, the MTD has not been reached on the split-dose regimen at cumulative doses up to 180 mg/d (90 mg BID). GI AEs were the most common treatment-related AEs. Based on these preliminary observations, split-dose ONX0912 may improve tolerability over qd dosing.

A phase I, open-label, multicenter, single-dose escalation and multi-dose study of a monoclonal antibody targeting CEACAM1 in subjects with selected advanced or recurrent malignancies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3094-3094
Author(s):  
Roni Shapira ◽  
Jeffrey S. Weber ◽  
Ravit Geva ◽  
Mario Sznol ◽  
Harriet M. Kluger ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Drug Disposition ◽  
Phase 1 ◽  
Primary Objective ◽  
Immune Checkpoints ◽  
Open Label ◽  
Trial Testing ◽  
Dose Study ◽  
Cea Gene ◽  
Grade 3

3094 Background: The carcinomembryonic antigen cell adhesion molecule 1 (CEACAM1, CD66a) is a member of the CEA gene family. CEACAM1 interacts homophilically and heterophilically with CEACAM5, and is involved in various anti-proliferative activities. CEACAM1 is expressed on a variety of epithelial and hematological cells, including multiple types of cancer and activated lymphocytes. High CEACAM1 expression in some tumor types is known to be associated with poor disease prognosis. Recently it was demonstrated CEACAM1 is co-expressed on exhausted lymphocytes with other immune checkpoints such as TIM-3 and may regulate downstream activity. CM24 is a novel humanized α-CEACAM1-specific antibody with nM affinity to the N terminal domain of CEACAM1, which blocks intercellular CEACAM1 interactions. Methods: The primary objective was to test the safety and tolerability of CM24 in adult patients with advanced or recurrent cancer. Secondary objectives included assessment of CM24 PK and PD profiles, anti-tumor response and the recommended Phase 2 dose. Patient received IV infusion of CM24 at 7 dose levels ranging between 0.01 and 10 mg/kg in a cycle of 4 doses administered q2wks followed by a 6-week observation only period and additional 6 cycles. Results: 27 patients (median pretreatment of 4 prior regimens; range 2-8, 11 colorectal, 7 melanoma, 4 ovarian, 3 gastric, 2 NSCLC; 13 males, 14 females, mean age of 60 years), were included. Treatment with CM-24 was overall well-tolerated without DLTs up to 10 mg/kg. The most frequent AE was grade 1-3 increased alanine aminotransferase (7 subjects) and the most severe AE was grade 3/4 increase in gamma-glutamyltransferase (4 subjects). Drug-related AEs were observed in 63% of the subjects with grade 3-5 occurred in 3.7%. Eight subjects (29.6%) had stable disease as the best overall response. Median overall survival was 4 (3.4, 8.0) and 6.2 (2.7, 10.2) months for the 3 and 10 mg/kg doses, suggesting dose response. Cmax, AUC and t1/2 increased with increasing dose with the longest t1/2 of 11.2 days obtained at 10mg/kg. The average target occupancy of CM24 at 3mg/kg and 10mg/kg were 75% and 93%, respectively. Conclusions: PK and target-mediated drug disposition analysis suggest that doses higher than 10mg/kg are needed for target saturation at a q2 week regimen while a q3 week regimen is less optimal. A phase 1/2 clinical trial testing CM24 in combination with anti-PD-1 therapy in patients with NSCLC including assessment of CEACAM1 expression is warranted. Clinical trial information: NCT02346955 .

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 .

scholarly journals A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours

2020 ◽  
Vol 123 (10) ◽  
pp. 1481-1489
Author(s):  
Christophe Le Tourneau ◽  
Jean-Pierre Delord ◽  
Nuria Kotecki ◽  
Edith Borcoman ◽  
Carlos Gomez-Roca ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Solid Tumours ◽  
Trial Registration ◽  
Hepatic Enzymes ◽  
Dna Breaks ◽  
Dose Escalation Study ◽  
Clinical Trial Registration ◽  
Grade 3

Abstract Background AsiDNA, a first-in-class oligonucleotide-mimicking double-stranded DNA breaks, acts as a decoy agonist to DNA damage response in tumour cells. It also activates DNA-dependent protein kinase and poly (adenosine diphosphate [ADP]-ribose) polymerase enzymes that induce phosphorylation of H2AX and protein PARylation. Methods The aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety and pharmacokinetics/pharmacodynamics of AsiDNA administered daily for 3 days in the first week then weekly thereafter. Twenty-two patients with advanced solid tumours were enrolled in 5 dose levels: 200, 400, 600, 900, and 1300 mg, using a 3 + 3 design. Results The MTD was not reached. IV AsiDNA was safe. Two DLTs (grade 4 and grade 3 hepatic enzymes increased at 900 and 1300 mg), and two related SAE at 900 mg (grade 3 hypotension and grade 4 hepatic enzymes increased) were reported. AsiDNA PK increased proportionally with dose. A robust activation of DNA-PK by a significant posttreatment increase of γH2AX was evidenced in tumour biopsies. Conclusion The dose of 600 mg was identified as the optimal dose for further clinical development. Clinical trial registration Clinical trial registration (NCT number): NCT03579628.

scholarly journals Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma

2021 ◽  
Vol 11 (2) ◽  
Author(s):  
Jacob P. Laubach ◽  
Sascha A. Tuchman ◽  
Jacalyn M. Rosenblatt ◽  
Constantine S. Mitsiades ◽  
Kathleen Colson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Duration Of Response ◽  
Label Dose ◽  
Grade 3

AbstractAdditional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50–77]) and a median of four prior regimens (range: 2–14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1–74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.

A phase I, first-in-human, dose escalation study of intravenous TK216 in patients with relapsed or refractory Ewing sarcoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS11626-TPS11626 ◽  
Author(s):  
Noah Federman ◽  
Paul A. Meyers ◽  
Najat C. Daw ◽  
Jeffrey Toretsky ◽  
James Bradley Breitmeyer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dose Escalation ◽  
Ewing Sarcoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Dose Escalation Study ◽  
Human Dose

TPS11626 Background: Ewing sarcoma (ES) is a rare cancer that affects children and young adults. Patients with recurrent/refractory ES have a poor prognosis (5-year survival 10-15%) with no improvement despite advances in cytotoxic and targeted therapies. Genomic rearrangements resulting in fusion proteins and over-expression of ets family transcription factors occur in 95% of ES. In particular, the EWS-FLI1 oncogenic fusion creates a constitutively active transcription factor that drives the malignant ES phenotype. Strategies to target the EWS-FLI1 fusion protein have been limited by lack of specificity. A promising approach is to target the interaction of the ets transcription factor with its critical protein partner, RNA helicase A (RHA). TK216 is a novel small-molecule that directly binds to EWS-FLI1 and inhibits its function by blocking binding to RHA. TK216 demonstrates potent anti-proliferative effects on ES cell lines and xenografts. Methods: We initiated a Phase 1, first-in-human, open-label, multi-center, dose-escalation/dose-expansion trial of TK216 in patients with recurrent/refractory ES who are ≥12 years of age (ClinicalTrials.gov: NCT02657005). TK216 is dosed based on body surface area and administered as a continuous intravenous infusion for 7 days followed by 14 days rest every 21 days. Treatment may continue in the absence of disease progression. One intrapatient dose escalation is allowed. Enrollment of 6 to 8 cohorts using a 3+3 dose-escalation design is anticipated. During dose expansion, a total of 18 patients with ES will be accrued at the recommended Phase 2 dose (RP2D). The primary objective of the study is to determine the maximum tolerated dose and RP2D of TK216. Secondary objectives are to assess the safety profile, pharmacokinetics, pharmacodynamics, and antitumor activity of TK216. Molecular assays will be performed to characterize EWS-FLI or EWS-ets abnormalities in archival tumor tissue. The overall response rate, duration of response, progression-free survival, and overall survival will be determined in the expansion cohort. Nine patients have been enrolled since June 2016. Accrual to cohorts 1, 2, and 3 completed and cohort 4 opened in January 2017. Clinical trial information: NCT02657005.

Final analysis of phase I study of ceritinib in pediatric patients with malignancies harboring activated anaplastic lymphoma kinase (ALK).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10505-10505
Author(s):  
Johannes H Schulte ◽  
Lucas Moreno ◽  
David Simon Ziegler ◽  
Lynley V. Marshall ◽  
C. Michel Zwaan ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Anaplastic Lymphoma Kinase ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Systemic Exposure ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Anaplastic Lymphoma ◽  
Grade 3

10505 Background: Activation of anaplastic lymphoma kinase has been detected in several pediatric malignancies, including anaplastic large-cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), neuroblastoma and others. Preliminary findings from this phase 1, multicenter, dose-escalation study (NCT01742286) indicated a Maximum Tolerated Dose (MTD)/Recommended Dose for Expansion (RDE) of the potent oral ALK inhibitor ceritinib to be 510 mg/m2 (fasted) and 500 mg/m2 (fed) in pediatric patients (pts). Here, we report final safety, pharmacokinetics (PK) and efficacy results. Methods: Children aged ≥1 to <18 years with advanced, mostly pretreated, ALK-aberrant malignancies were enrolled in this study. Dose escalation was conducted to determine the MTD/RDE of ceritinib (primary objective), in both fasted and fed states, following which pts entered an expansion phase to evaluate safety, tolerability, and efficacy at the MTD/RDE. Secondary objectives were evaluation of safety, PK, and efficacy (overall response rate [ORR], duration of response [DOR] and progression-free survival [PFS]). Results: A total of 83 pts (median age, 8 years) with ALK-aberrant malignancies were enrolled into dose-escalation (n = 40) and expansion (n = 43) study periods. Of these, 55 pts (neuroblastoma, n = 30; IMT, n = 10; ALCL, n = 8; others, n = 7) were treated with ceritinib at MTD/RDE (510 mg/m2 [fasted], n = 13; 500 mg/m2 [fed], n = 42). Systemic exposure of ceritinib between the two doses was comparable, so data were pooled for efficacy assessment. The ORRs (95% CI) were 75% (34.9-96.8) for pts with ALCL, 70% (34.8-93.3) for IMT and 20% (7.7-38.6) for neuroblastoma. The median DOR was 15 months (95% CI: 5.8, 22.2) for the 6/30 pts with neuroblastoma who had confirmed CR or PR treated at fasted/fed MTD/RDE. Median DOR was not reached for those with ALCL and IMT. Most common adverse events (AEs) (N = 83; all-grades, all-causality, ≥50% of pts): vomiting (86.7%), diarrhea (78.3%), increased ALT (65.1%), increased AST (59.0%), nausea (56.6%), and abdominal pain (50.6%). Grade 3/4 AEs were observed in 80.7% of pts (mostly transaminase elevations) and were manageable. Six pts (7.2%) were discontinued from ceritinib due to a grade 3/4 AE (mostly transaminase elevation). Conclusions: Substantial activity was observed with ceritinib at the RDE in pts with IMT, ALCL and heavily pretreated neuroblastoma. The toxicity profile of ceritinib in children was manageable and similar to that previously reported in adults. Clinical trial information: NCT01742286.

A phase 1/2 open-label study of KY1044, an anti-ICOS antibody with dual mechanism of action, as single agent and in combination with atezolizumab, in adult patients with advanced malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2624-2624
Author(s):  
Manish R. Patel ◽  
Aung Naing ◽  
Howard A. Burris III ◽  
Chia-Chi Lin ◽  
Giuseppe Curigliano ◽  
...  
Keyword(s):  
Treatment Duration ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Cancer Therapies ◽  
Open Label ◽  
Efficacy Measures ◽  
Grade 3 ◽  
Dual Mechanism

2624 Background: KY1044, is a fully human IgG1 anti ICOS antibody designed to stimulate Teffs and to deplete ICOS high Tregs in the tumor microenvironment. Methods: Patients with advanced/metastatic malignancies received escalating doses of KY1044 as a single agent and in combination with atezolizumab 1200 mg by IV infusion every 3 weeks until disease progression or unacceptable toxicity. Dose escalation was guided by a modified toxicity probability interval design. The primary objective was to determine safety, tolerability, and maximum tolerated dose. Cohorts that were tolerated were later enriched with more subjects. AEs were classified according to CTCAE v5 and efficacy measures performed according to RECIST v1.1 every 8 weeks for the first 16 weeks and then every 12 weeks. Results: As of 16-Dec-2020, a total of 103 patients have been enrolled in the study (38 patients as monotherapy in 6 cohorts at doses ranging from 0.8 to 240 mg and 65 in combination with atezolizumab in 5 cohorts at doses 0.8 – 80 mg). 63% and 55% of patients received ≥4 prior anti-cancer therapies in the single agent and combination cohorts, respectively. All cohorts were completed without DLTs during the first 21 days of treatment. In the KY1044 single agent cohorts, 47.4% of patients experienced treatment-related AEs (TRAEs), all were grades 1 or 2. In the combination cohorts, TRAEs were observed in 58% of patients. Most of the TRAEs were grade 1 or 2 apart from 8 TRAEs that were ≥grade 3 occurring in <8% of patients. Infusion-related reactions, pyrexia and lymphopenia were the most commonly occurring TRAEs in ≥10% of patients. TRAE leading to dose interruptions occurred in 1 patient in the single agent cohort and in 4 patients in the combination cohort. Only 1 patient discontinued treatment due to myositis that was considered related to the combination. Preliminary KY1044 PK data from 69 patients agree with the PK model predictions. Median treatment duration for all enrolled patients was 9 weeks. Treatment duration ≥16 weeks was observed in 24% (9/38) and 27% (17/64) patients in the single agent and combination cohorts, respectively. Five objective responses, including 1 CR in triple negative breast cancer (TNBC) and 4 PRs in TNBC, head and neck squamous cell carcinoma, penile and pancreatic cancer were observed. Four of the 5 responding patients were still on treatment at the data cut, with 3 patients on treatment for >43 weeks (range 45 to 66 weeks). Conclusions: KY1044 is well tolerated as single agent and in combination with atezolizumab. Objective responses have been observed in this phase 1 part of the study. The phase 1 expansion and phase 2 part of the study is ongoing. Clinical trial information: NCT03829501.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

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