Tabelecleucel in combination with pembrolizumab (Pembro) in platinum-pretreated, recurrent/metastatic Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (EBV+NPC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS6092-TPS6092
Author(s):  
Lillian L. Siu ◽  
Joshua Bauml ◽  
Douglas Adkins ◽  
A. Dimitrios Colevas ◽  
Cesar Augusto Perez ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Phase 2 ◽  
Open Label ◽  
Barr Virus ◽  
Duration Of Response ◽  
Phase 1B ◽  
Epstein Barr ◽  
Favorable Safety

TPS6092 Background: Approximately 25% of patients (pts) with NPC develop RM disease, which has a poor prognosis (median overall survival [mOS]: 12–16 mo), despite standard treatments with radiation and/or chemotherapy. NPC is an EBV-associated cancer in which programmed cell death ligand 1 (PD-L1) expression is upregulated upon EBV activation. Pembro showed antitumor activity in a phase 1b study of pts with RM-NPC (objective response rate [ORR]: 26%; mOS: 16.5 mo) (Hsu, J Clin Oncol 2017;35:4050-56). Targeting RM EBV+ NPC with tab-cel immunotherapy (off-the-shelf, allogeneic EBV-specific T cells) in pts has also shown promise, with 2-yr OS rates of 84% (Prockop, ASCO 2016;34:3012). The favorable safety profile of tab-cel offers the opportunity for combination immunotherapy with pembro for increased efficacy. Methods: This multicenter, open-label, single-arm phase 1b/2 study evaluates safety and efficacy of tab-cel in combination with pembro. Study participants are ≥12 yrs of age with incurable, locally recurrent or metastatic EBV+ NPC previously treated with platinum-containing therapy. Pts are checkpoint-inhibitor naïve (phase 1b/2) or refractory to anti-PD-1 or anti-PD-L1 therapy (phase 1b). Tab-cel is selected from a bank based on matching ≥2 HLA alleles, including ≥1 restricting HLA allele, between pts and donors. Tab-cel will be administered intravenously (IV) on days 1, 8, and 15 of a 21-day cycle. Initial tab-cel dose is 2x106 cells/kg and the de-escalated tab-cel dose (if needed) is 1x106 cells/kg. Pembro is administered at 200 mg IV Q3W in adults and 2 mg/kg IV Q3W in pts aged 12 to 17 yrs. Primary outcomes of phase 1b are to characterize dose-limiting toxicities, identify the maximum tolerated dose (MTD) or in the absence of MTD, the recommended phase 2 dose, and assess safety. Primary outcomes for phase 2 are ORR and safety. Secondary endpoints include progression-free survival, OS, and duration of response. Enrollment is ongoing for 12-24 participants in the phase 1b portion of the study with a 6+6 design. Phase 2 is expected to enroll 36 pts. Clinical trial information: NCT03769467.

An open-label, multicohort, phase I/II study to evaluate nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6025-6025 ◽  
Author(s):  
Jean-Pierre Delord ◽  
Antoine Hollebecque ◽  
J. P. De Boer ◽  
Jacques De Greve ◽  
Jean-Pascal H. Machiels ◽  
...  
Keyword(s):  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Immune Recognition ◽  
Open Label ◽  
Ongoing Research ◽  
Barr Virus ◽  
Epstein Barr ◽  
Ecog Ps

6025 Background: Treatment options for patients (pts) with R/M NPC are limited to palliative chemotherapy. NPC is often associated with the Epstein–Barr virus (EBV), a potential antigen for immune recognition, and high expression levels of the immune checkpoint receptor programmed death-1 (PD-1) and its major ligand PD-L1. Nivolumab disrupts PD-1–mediated signaling, restoring T-cell antitumor function. Methods: In CheckMate 358 (NCT02488759), PD-L1–unselected adults with R/M NPC, ECOG PS of 0–1, and ≤2 prior systemic therapies in the R/M setting were eligible to receive nivolumab 240 mg every 2 weeks until progression or unacceptable toxicity, as part of an ongoing multicohort study of 5 virus-associated cancers. Human papillomavirus-associated NPC and keratinizing squamous cell carcinoma (WHO Type 1) were excluded. Primary endpoints were objective response rate (ORR) and safety; secondary endpoints were duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: Of 24 treated pts with R/M NPC, median age was 51 years, 88% were male, 62% were white, 88% were European, and 88% had EBV+ tumors. At a median follow-up of 26 weeks (range: 4–40), ORR was 20.8% and appeared to be higher in pts with no prior R/M therapy (Table). The disease control rate (ORR + SD) was 45.8%. Responses were observed regardless of PD-L1 or EBV status. Median PFS was 2.4 mo (95% CI: 1.5, NR); median OS was NR. Conclusions: Nivolumab demonstrated clinical activity and a manageable safety profile in R/M NPC, supporting ongoing research with nivolumab in this disease. Updated efficacy and biomarker data will be presented. Clinical trial information: NCT02488759. [Table: see text]

A phase Ib/II dose-escalation study evaluating triple combination therapy with a BRAF (encorafenib), MEK (binimetinib), and CDK 4/6 (ribociclib) inhibitor in patients (Pts) with BRAF V600-mutant solid tumors and melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9518-9518 ◽  
Author(s):  
Paolo Antonio Ascierto ◽  
Oliver Bechter ◽  
Pascal Wolter ◽  
Celeste Lebbe ◽  
Elena Elez ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Triple Combination Therapy ◽  
Phase 1B

9518 Background: The benefits of BRAF + MEK inhibition (dual combo) in pts with BRAF V600-mutant ( BRAFV600) melanoma are known. Preclinical data supports inhibiting CDK 4/6 and BRAF + MEK (triple combo) to improve antitumor activity. We report safety and preliminary efficacy from a phase 1b/2 study (NCT01543698) of encorafenib (ENCO; a selective BRAF kinase inhibitor), binimetinib (BINI; a MEK inhibitor), and ribociclib (RIBO; a CDK 4/6 inhibitor). Methods: Phase 1b of this open-label, multicenter study enrolled pts with confirmed BRAFV600advanced solid tumors. Escalating doses of RIBO 100 mg-600 mg QD for 3 wk on/1 wk off were administered with ENCO 200 mg QD + BINI 45 mg BID in successive cohorts (6 pts each) until the maximum tolerated or recommended phase 2 dose (RP2D) was reached. Due to potential pharmacokinetic interactions with RIBO, the ENCO dose was lower than the dual combo RP2D (450 mg QD). Dose escalations followed an adaptive Bayesian model. In phase 2, the triple combo was tested in pts with BRAFV600melanoma naïve to prior BRAF inhibitor treatment; the primary endpoint was objective response rate (ORR) per RECIST v1.1. Results: In phase 1b (n = 21), no dose-limiting toxicities were reported and the triple combo RP2D was ENCO 200 mg QD + BINI 45 mg BID + RIBO 600 mg QD. ENCO AUC was slightly lower than at the dual combo RP2D. In phase 2 (n = 42), 59.5% pts had an ECOG PS of 0 and 43% of pts had elevated lactate dehydrogenase. The most common (≥5%) grade 3/4 toxicities were neutropenia (26.2%), increased alanine transaminase (14.3%), diarrhea (7.1%), and anemia (7.1%). Ten pts (23.8%) discontinued treatment due to an AE, of which 4 were increased transaminases. The confirmed ORR was 52.4%, including 4 complete responses, 18 partial responses, and 15 pts with stable disease. Median duration of exposure in phase 2 was 9.1 mo (range, 0.0-21.6). Median progression-free survival was 9.0 mo (95% confidence interval, 7.0-11.1). Conclusions: Triple therapy with ENCO + BINI + RIBO in this small trial of pts with high disease burden was associated with responses in over half of pts and some evidence of increased toxicity. Clinical trial information: NCT01543698.

scholarly journals Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression

2021 ◽  
Author(s):  
Baek-Yeol Ryoo ◽  
Ann-Li Cheng ◽  
Zhenggang Ren ◽  
Tae-You Kim ◽  
Hongming Pan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Primary Endpoint ◽  
Objective Response ◽  
Progression Free Survival ◽  
Advanced Hepatocellular Carcinoma ◽  
Phase 2 ◽  
Open Label ◽  
Asian Patients ◽  
Open Label Phase ◽  
Phase 1B

Abstract Background This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression. Methods In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP). Results In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26–0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib. Conclusions Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression. Trial registration ClinicalTrials.gov NCT01988493.

scholarly journals CTNI-45. A PHASE 1B/2 CLINICAL STUDY OF NAPABUCASIN IN COMBINATION WITH TEMOZOLOMIDE FOR ADULT PATIENTS WITH RECURRENT OR PROGRESSED GLIOBLASTOMA MULTIFORME (GBM)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii52-ii52
Author(s):  
Andrew Chi ◽  
Paula DeRobles ◽  
Emma Foos ◽  
Matthew Hitron ◽  
Warren Mason
Keyword(s):  
Antitumor Activity ◽  
Objective Response ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Antitumor Effects ◽  
Patient Reported ◽  
Phase 1B ◽  
Grade 3

Abstract Napabucasin is an orally-administered NQO1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. This open-label, multicenter, phase 1b/2 study assessed napabucasin plus temozolomide for recurrent/progressive GBM. Phase 1b objectives were safety/tolerability, recommended phase 2 dose (primary), preliminary antitumor activity, and pharmacokinetics/pharmacodynamics (secondary). Phase 2 objectives were preliminary antitumor activity via 6-month progression-free survival (PFS-6 [20% projected]) (primary); disease control rate; median PFS; objective response rate (ORR); and overall survival (OS) (secondary). Arm A enrolled repeat surgical resection candidates; arm B enrolled patients ineligible for further resection. Patients received napabucasin (oral, 480 mg twice-daily) plus temozolomide (150 mg/m2, days 1–5, 28-day cycles). Arm A closed after 4 patients enrolled to prioritize Arm B enrollment. Arm B data are reported. Arm B enrolled/treated 30 patients (median age=56.5 [range=19–83] years; median napabucasin duration=55.0 [range=1–743] days; previous temozolomide=22 [73.3%] patients); all stopped therapy (radiologic progressive disease [PD], n=20; clinically unacceptable toxicities, n=7; follow-up loss, n=2; clinical PD, n=1). Mean relative dose intensity was 67.2% for napabucasin and 90.9% for temozolomide; 14/30 (46.7%) and 25/30 (83.3%) patients received ≥ 90% intended napabucasin and temozolomide doses, respectively. All patients reported ≥ 1 treatment-emergent adverse event (TEAE, grade ≤4); grade 3 TEAEs (≥ 10% patients) were diarrhea (23.3%, 7/30) and abdominal pain (16.7%, 5/30). One patient reported a grade 4 TEAE (seizure, treatment unrelated). PFS-6 was 28.1% (80% CI=16.8%-40.5%). Median PFS was 1.9 months (95% CI=1.8–3.3), with PFS-12 and PFS-18 both 16.8% (80% CI=7.8%-28.8%). ORR was 10% (95% CI=2.1%-26.5%), with 3 partial responses, 6 stable disease, 14 PD, and 7 patients not evaluated. OS-12 was 28.3%. The napabucasin-plus-temozolomide safety profile was consistent with that anticipated for each agent. Napabucasin (480 mg twice-daily) was associated with grade 3 diarrhea and suboptimal compliance. Antitumor effects were observed per the primary endpoint in this patient population.

Phase 2 study of brigatinib in patients (pts) with anaplastic lymphoma kinase (ALK)−positive, advanced non–small cell lung cancer (NSCLC) that progressed on alectinib or ceritinib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS9115-TPS9115 ◽  
Author(s):  
Edward S. Kim ◽  
Sai-Hong Ignatius Ou ◽  
Fabrice Barlesi ◽  
Tony S. K. Mok ◽  
Myung-Ju Ahn ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Resistance Mutations ◽  
Open Label ◽  
Secondary Resistance ◽  
Anaplastic Lymphoma ◽  
Duration Of Response

TPS9115 Background: Second-generation ALK tyrosine kinase inhibitors (TKIs) alectinib and ceritinib have demonstrated efficacy and acceptable safety in ALK TKI-pretreated and TKI-naive NSCLC. However, as with crizotinib, resistance to alectinib and ceritinib eventually develops, with secondary resistance mutations detected in approximately 50% of pts. Brigatinib is a next-generation ALK TKI designed to have potent and broad activity against ALK mutants. Post-crizotinib, brigatinib demonstrated high systemic and CNS objective response rates (ORR) and the longest reported median progression-free survival (PFS) of any ALK inhibitor in this setting (16.3–16.7 mo) (Huber. J Clin Oncol 2018;36; Bazhenova. Ann Oncol 2017;28); efficacy was demonstrated regardless of mutations. Based on nonclinical and clinical data, brigatinib may show efficacy in ALK+ NSCLC that has developed resistance or failed to respond to alectinib/ceritinib. This trial was designed to assess efficacy and safety of brigatinib in pts with ALK+ NSCLC that has progressed on alectinib or ceritinib. Methods: This is a phase 2, open-label, single-arm, multicenter, international trial (NCT03535740) in pts (≥18 y) with locally advanced/metastatic NSCLC and disease progression on alectinib or ceritinib (± prior crizotinib; ≤3 different systemic regimens for locally advanced/metastatic disease). Pts receive oral brigatinib 180 mg QD with 7-day lead-in at 90 mg QD. Treatment beyond progression or escalation to brigatinib 240 mg QD is permitted. Primary endpoint: independent review committee (IRC)−assessed confirmed ORR (cORR) per RECIST v1.1. Secondary endpoints: investigator (INV)-assessed cORR, duration of response (INV- and IRC-assessed), PFS, disease control rate, and time to response; in pts with baseline brain metastases: IRC-assessed intracranial cORR, duration of intracranial response, and intracranial PFS; OS; safety/tolerability; and HRQoL. Exploratory endpoints include biomarker analyses. The study was initiated in Dec 2018 at 78 sites (North America, Europe, Asia), with a planned sample size of 103 pts. Accrual is ongoing. Clinical trial information: NCT03535740.

804 A phase II study of the anti-programmed cell death-1 (PD-1) antibody penpulimab in patients with metastatic nasopharyngeal carcinoma (NPC) who had progressed after two or more lines of chemotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A853-A853
Author(s):  
Xiaozhong Chen ◽  
Wei Wang ◽  
Qingfeng Zou ◽  
Jingao Li ◽  
Chaosu Hu ◽  
...  
Keyword(s):  
Disease Progression ◽  
Receptor Occupancy ◽  
Complete Response ◽  
Hepatic Function ◽  
Open Label ◽  
Barr Virus ◽  
Duration Of Response ◽  
Epstein Barr ◽  
Grade 3 ◽  
Anti Tumor Activity

BackgroundNPC is rare but has a distinct geographic distribution, with a predominance in Southeast Asia. Favorable results with PD-1 inhibitors in NPC provide a strong rationale to investigate penpulimab in this disease. Penpulimab was engineered to eliminate FcγR binding and ADCC/ADCP completely,where ADCC/ADCP effects can induce T-cell apoptosis and clearance and then compromise anti-tumor activity. Penpulimab demonstrated a slower PD-1 antigen binding off-rate than marketed PD-1 antibodies, which result in better cellular activity and higher receptor occupancy. Penpulimab also showed numerous contacts with N58 glycosylation on the BC loop of PD-1 which could be an advantage to facilitate interaction of PD-1 antibody and may contribute to slower binding off-rate. These structural differentiations offer more robust biological effect and enhance anti-tumor activity of penpulimab.MethodsAK105-202 (NCT03866967) is a multicenter, single-arm, open-label study of penpulimab in metastatic NPC patients (pts) with disease progression after ≥2 prior lines of therapy including platinum-containing chemotherapy. All patients received penpulimab 200 mg q2w until progression or unacceptable toxicity. The primary endpoint was ORR based on RECIST v1.1 as assessed by an independent review committee (IRC). Key secondary endpoints included DCR, PFS, duration of response (DoR). Archived tissues were retrieved for the analysis of PD-L1 (Shuwen SAB-028). PD-L1 expression of tumor proportion score (TPS)≥50% was regarded as positive. Plasma Epstein-Barr virus DNA were obtained for biomarker correlative analysis.ResultsAs of 18 September 2020, the median follow-up was 7.9 months (range 0.9 to 16.9). The anti-tumor activity of penpulimab in the 111 pts with disease progression after ≥2 prior lines of therapy evaluable for efficacy (defined as pts who had an opportunity to be followed for at least 16 weeks and had measurable disease at baseline per RECIST v1.1) is shown in the table 1.Treatment-related adverse events (TRAEs, including unlikely related) occurred in 79.2% of pts (≥G3 in 14.6% [19/130], treatment discontinuation in 3.1% [4/130]). Treatment-related SAEs occurred in 10.0% [13/130]. Most frequent TRAEs (≥10%) were fever (24.5%), hypothyroidism (24.6%), anemia (23.1%), ALT increased (17.0%) and WBC decreased (10.8%). Grade ≥3 TRAEs (≥2%) were hepatic function abnormal (2.3%) and anemia (2.3%).Abstract 804 Table 1a. Including 1 complete response and 29 partial response. At data cutoff, 90% of responders remained ongoing.b.43 pts were PD-L1 positive (TPS≥50%) and 66 pts were PD-L1 negative (TPS<50%).c. Including 1 ongoing response awaiting confirmation classified under SD.ConclusionsPenpulimab demonstrated encouraging anti-tumor activity and favorable safety profile in pts with disease progression after ≥2 prior lines of therapy. A higher proportion of objective responses was observed in NPC pts with PD-L1–positive tumors receiving penpulimab than those with PD-L1–negative tumors.

A phase 2 study of pamiparib in the treatment of patients with locally advanced or metastatic HER2-negative breast cancer with germline BRCA mutation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1087-1087
Author(s):  
Tao Sun ◽  
Yanxia Shi ◽  
Jiuwei Cui ◽  
Yongmei Yin ◽  
Quchang Ouyang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brca Mutation ◽  
Objective Response ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Hormone Receptor Positive ◽  
Her2 Breast Cancer

1087 Background: Breast cancer is the most common cancer among women, with up to 37% of patients (pts) harboring germline BRCA1/2 mutations (g BRCA1/2m) that appear to be sensitive to poly (ADP-ribose) polymerase proteins 1 and 2 (PARP1/2) inhibition. Pamiparib is an orally administered selective PARP1/2 inhibitor that has the potential to cross the blood-brain barrier. This study evaluated the efficacy and safety of pamiparib in pts with locally advanced/metastatic human epidermal growth factor receptor 2-negative (HER2-) breast cancer, with deleterious or suspected deleterious g BRCA1/2m, who received ≤ 2 prior lines of chemotherapy. Methods: In this open-label, phase 2, multi-center study in China (NCT03575065), pts with locally advanced/metastatic HER2- breast cancer with deleterious or suspected deleterious g BRCA1/2m triple negative breast cancer (TNBC cohort) or hormone receptor-positive (HR+)/HER2- breast cancer (HR+ cohort) were enrolled. Pts received pamiparib 60 mg orally twice daily in 28-day cycles. The primary endpoint was objective response rate (ORR; RECIST v1.1) by independent review committee (IRC). Secondary endpoints included duration of response (DOR) and progression free survival (PFS) by IRC, overall survival (OS), safety and tolerability. Results: 88 pts were enrolled (median age 45.5 years), 76 pts (TNBC cohort n = 55; HR+ cohort n = 21) had measurable disease at baseline per IRC. 60 pts (68.2%) received 1 or 2 prior lines of chemotherapy; 42 pts (47.7%) were treated with platinum previously. Median follow-up was 13.77 months (TNBC cohort, 10.87 months; HR+ cohort, 18.45 months). In the TNBC cohort: confirmed ORR was 38.2% (95% CI: 25.4–52.3); median DOR (mDOR) was 6.97 months (95% CI: 3.94–not estimable[NE]); median PFS (mPFS) was 5.49 months (95% CI: 3.65–7.33); median OS (mOS) was 17.08 months (95% CI:13.70–NE). In the HR+ cohort: confirmed ORR was 61.9% (95% CI: 38.4–81.9); mDOR was 7.49 months (95% CI: 5.55–14.75); mPFS was 9.20 months (95% CI: 7.39–11.93); mOS was not reached (NR; 95% CI 18.10–NE). ≥ Grade 3 treatment emergent adverse events (TEAEs) occurred in 54 pts (61.4%); anemia was the most common TEAE, occurring in 77 pts (87.5%). Dose reduction due to TEAEs occurred for 57 pts (64.8%); discontinuations due to TEAEs occurred for 2 pts (2.3%). Conclusions: Pamiparib showed a promising response in pts with locally advanced/metastatic HER2- breast cancer with a g BRCA1/2m. The safety profile of pamiparib was considered acceptable and was generally consistent with therapies in the same class. Clinical trial information: NCT03575065 .[Table: see text]

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3505-3505
Author(s):  
Takayuki Yoshino ◽  
Maria Di Bartolomeo ◽  
Kanwal Pratap Singh Raghav ◽  
Toshiki Masuishi ◽  
Fotios Loupakis ◽  
...  
Keyword(s):  
Safety Profile ◽  
Topoisomerase I ◽  
Objective Response ◽  
Safety Data ◽  
Progression Free Survival ◽  
Drug Discontinuation ◽  
Phase 2 ◽  
Antibody Drug Conjugate ◽  
Primary Analysis ◽  
Open Label

3505 Background: T-DXd is an antibody–drug conjugate of a humanized anti-HER2 antibody bound to a topoisomerase I inhibitor by a cleavable linker. The primary analysis of DESTINY-CRC01 (DS8201-A-J203; NCT03384940), a phase 2, open-label, multicenter study of T-DXd in pts with HER2-expressing mCRC showed promising antitumor activity and a manageable safety profile (cohort A median follow-up [FU], 27.1 weeks; Siena S, ASCO 2020). We present updated longer-term efficacy and safety data. Methods: Pts had centrally confirmed HER2-expressing, RAS wild-type mCRC that progressed after ≥2 prior regimens. 6.4 mg/kg of T-DXd was administered every 3 weeks (Q3W) in 3 cohorts (A: HER2 IHC3+ or IHC2+/ISH+; B: IHC2+/ISH−; C: IHC1+). The primary end point was confirmed objective response rate (ORR) by independent central review in cohort A. Secondary end points were disease control rate (DCR; CR + PR + SD), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: At data cutoff (Dec 28, 2020), 86 pts (A, 53; B, 15; C, 18) received T-DXd. Median age was 58.5 y (range, 27-79), 53.5% were male, and 90.7% had left colon or rectum cancer. Median prior regimens for metastatic disease was 4 (range, 2-11). All pts had prior irinotecan; 30.2% in cohort A had prior anti-HER2 therapy. Median (m) treatment duration (all pts) was 3.0 mo (95% CI, 2.1-4.1; cohort A, 5.1 mo [95% CI, 3.9-7.6]). In cohort A (median FU, 62.4 weeks), confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6-59.6), DCR was 83.0% (44/53 pts; 95% CI, 70.2-91.9), mDOR was 7.0 mo (95% CI, 5.8-9.5), mPFS was 6.9 mo (95% CI, 4.1-8.7) with 37 (69.8%) PFS events, and mOS was 15.5 mo (95% CI, 8.8-20.8) with 36 (67.9%) OS events. These results are consistent with the primary analysis. Confirmed ORR was 43.8% (7/16 pts; 95% CI, 19.8-70.1) in pts with prior anti-HER2 therapy, 57.5% (23/40 pts; 95% CI, 40.9-73.0) in pts with IHC3+ status, and 7.7% (1/13 pts; 95% CI, 0.2-36.0) in pts with IHC2+/ISH+ status. In cohorts B and C, mPFS was 2.1 mo (95% CI, 1.4-4.1) and 1.4 mo (95% CI, 1.3-2.1); mOS was 7.3 mo (95% CI, 3.0-NE) and 7.7 mo (95% CI, 2.2-13.9), respectively. Treatment-emergent adverse events (TEAEs) of grade (G) ≥3 occurred in 65.1% of pts (56/86); the most common TEAEs were hematologic and gastrointestinal. TEAEs leading to drug discontinuation occurred in 13 pts (15.1%). 8 pts (9.3%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (4 G2; 1 G3; 3 G5). Conclusions: T-DXd at 6.4 mg/kg Q3W showed promising activity and durability with longer-term FU in this pt population. The safety profile was consistent with prior results; ILD continues to be recognized as an important identified risk that requires careful monitoring and intervention as needed. These results support continued exploration of T-DXd in pts with HER2-overexpressing mCRC. Clinical trial information: NCT03384940.

scholarly journals Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma

2020 ◽  
Vol 38 (29) ◽  
pp. 3398-3406 ◽  
Author(s):  
Ingo K. Mellinghoff ◽  
Benjamin M. Ellingson ◽  
Mehdi Touat ◽  
Elizabeth Maher ◽  
Macarena I. De La Fuente ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Isocitrate Dehydrogenase ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Adverse Event Rate ◽  
Low Grade ◽  
Lower Grade ◽  
Open Label ◽  
Isocitrate Dehydrogenase 1

PURPOSE Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 ( IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors. METHODS We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m IDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles. RESULTS In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors. CONCLUSION In patients with m IDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.

scholarly journals Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial

2020 ◽  
Vol 8 (1) ◽  
pp. e000798
Author(s):  
Lu Xie ◽  
Jie Xu ◽  
Xin Sun ◽  
Wei Guo ◽  
Jin Gu ◽  
...  
Keyword(s):  
Pulmonary Metastases ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Trial ◽  
Open Label Phase ◽  
High Grade Osteosarcoma

BackgroundResults of our previous study showed high objective response but short-term activity of apatinib in advanced osteosarcoma. We aimed to investigate the activity of apatinib in combination with camrelizumab in patients with inoperable high-grade osteosarcoma progressing after chemotherapy.MethodsThis open-label, phase 2 trial was conducted at Peking University People’s Hospital. We enrolled patients with advanced osteosarcoma progressed after chemotherapy. Patients received 500 mg apatinib orally once daily plus 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) and clinical benefit rate at 6 months, which were based on RECIST V.1.1.Results43 patients were enrolled between January 25 and September 4, 2018. With median follow-up time of 48.3 (Q1, Q3, 30.6, 66.6) weeks, 13 (30.23%, 95% CI 17.2%, 40.1%) of 43 patients were progression free at 6 months and the 6-month PFS rate was 50.9% (95% CI 34.6%, 65.0%). Until final follow-up, the objective response rate was 20.9% (9/43) and two patients with durable disease control were observed. Patients with programmed cell death 1 ligand-1 (PD-L1) tumor proportion score ≥5% and pulmonary metastases tended to have a longer PFS in comparison to the others (p=0.004 and 0.017, respectively). Toxic effects led to dose reductions, or interruptions, or both in 24 (55.8%) of 43 patients and permanent discontinuation in 4 (9.3%) patients. There were no treatment-related deaths.ConclusionsAlthough the combination of apatinib and camrelizumab seemed to prolong PFS in comparison to single agent apatinib in treating advanced osteosarcoma, it did not reach the prespecified target of 6-month PFS of 60% or greater. Overexpression of PD-L1 and the presence of pulmonary metastases only were associated with longer PFS.Trial registration numberNCT03359018.

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