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.

FIDES-02, a phase Ib/II study of derazantinib (DZB) as monotherapy and combination therapy with atezolizumab (A) in patients with surgically unresectable or metastaticurothelial cancer (UC) and FGFR genetic aberrations.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS590-TPS590
Author(s):  
Arvind Chaudhry ◽  
Cora N. Sternberg ◽  
Maria De Santis ◽  
Joaquim Bellmunt ◽  
Andrea Necchi ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Treatment Phase ◽  
Maximal Effect ◽  
Phase 2 ◽  
Open Label ◽  
Genetic Aberrations ◽  
Combination Methods ◽  
Phase 1B

TPS590 Background: Deregulation of the FGFR signaling pathway is implicated in various cancers. In UC, FGFR genetic aberrations include FGFR1/2/3 mutations (M) and, less commonly, fusions (F), while the role of amplifications warrants further research. Prognosis of UC patients is overall poor and treatment options are limited. DZB is an oral small-molecule FGFR1/2/3 and CSF1R kinase inhibitor, which demonstrated promising antitumor activity in preclinical studies, including FGFR-driven patient-derived xenograft models. Preclinical data show that DZB reduced CSF1-stimulated CSF1R phosphorylation in macrophages, with a maximal effect similar to the CSF1R inhibitor BLZ945, suggesting DZB could have an effect on tumor-associated macrophage regulation. Thus, DZB+A (PD-L1 immune-checkpoint blockade [ICB]) is a rationale combination for immunogenic tumors like UC. FIDES-02 is a multicenter, multicohort open-label Phase 1b/2 study evaluating the effect of DZB as monotherapy and DZB+A combination. Methods: The study evaluates 300 mg DZB p.o. daily or DZB+A (1200 mg i.v.) in UC patients with FGFR1-3 M/F per liquid or tissue biopsy-based NGS. Cohort 1 (C1) enrolls pts after one or more standard chemotherapy ± ICB regimens (Phase 2; treatment: DZB); C2 enrolls patients with any advanced solid tumor, any FGFR status, any prior treatment (Phase 1b; for RP2D of DZB+A); C3 enrolls first-line patients with cisplatin-ineligible, PD-L1-low UC (Phase 2; DZB v DZB+A); C4 enrolls UC patients resistant to FGFR inhibitor treatment (Phase 2; DZB v DZB+A). Treatment will continue until disease progression, intolerance, withdrawal of informed consent, or death. Using Simon’s two-stage designs, objective response rate (per RECIST 1.1 central review) is the primary endpoint to assess the antitumor activity of DZB or DZB+A in Ph2. Main secondary objectives include evaluation of median PFS, duration of response, safety profile, HR-QoL (incl., QLQ C30, FACT-Bl, EQ-5D), and symptom response from baseline. The study was initiated in July 2019 and C1 (N=71) and C2 (N=24) are currently open for enrollment. Clinical trial information: NCT04045613.

Brigatinib (BRG) in ALK+ crizotinib (CRZ)-refractory non-small cell lung cancer (NSCLC): Final results of the phase 1/2 and phase 2 (ALTA) trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9071-9071
Author(s):  
Scott N. Gettinger ◽  
Rudolf M. Huber ◽  
Dong-Wan Kim ◽  
Lyudmila Bazhenova ◽  
Karin Holmskov Hansen ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Long Term Follow Up

9071 Background: BRG is a kinase inhibitor approved for the treatment of patients (pts) with ALK+ metastatic NSCLC; specific details for BRG use vary by indication and country. We report long-term efficacy and safety results of the Phase 1/2 and Phase 2 (ALTA) trials of BRG. Methods: The Phase 1/2 study was a single-arm, open-label trial (NCT01449461) of BRG 30–300 mg/d in pts with advanced malignancies. ALTA (NCT02094573) randomized pts with CRZ-refractory ALK+ NSCLC to receive BRG at 90 mg qd (arm A) or 180 mg qd with 7-d lead-in at 90 mg (arm B). For the Phase 1/2 study, investigator assessments of confirmed objective response rate (cORR; RECIST v1.1), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety in pts with ALK+ NSCLC are reported. The primary endpoint of ALTA was cORR per investigator; secondary endpoints included cORR per independent review committee (IRC), DoR, PFS, and OS. Results: In the Phase 1/2 study, 137 pts received BRG; of these, 79 pts had ALK+ NSCLC (71/79 had prior CRZ; 28/79 received 180 mg qd [7-d lead-in at 90 mg]; 14/79 received 90 mg qd). In ALTA, 222 pts with CRZ-refractory ALK+ NSCLC were randomized (n = 112/110, arm A/B). At the end of the Phase 1/2 study (Feb 18, 2020), with median 27.7 mo follow-up (̃67 mo after last pt enrolled), 4 pts remained on BRG. At the end of ALTA (Feb 27, 2020), with median 19.6/28.3 mo follow-up in arm A/B (̃53 mo after last pt enrolled), 10/17 pts in arm A/B were still on treatment. Table shows efficacy results from final analyses with long-term follow-up. In ALTA, the IRC-assessed intracranial cORR in pts with measurable baseline brain metastases was 50% (13/26) in arm A and 67% (12/18) in arm B; Kaplan-Meier (KM) estimated median intracranial DoR was 9.4 mo (95% CI, 3.7, not reached [NR]) in arm A and 16.6 mo (3.7, NR) in arm B. With long-term follow-up, no new safety signals were identified. Treatment-emergent adverse events led to dose interruption (Phase 1/2: 59%; ALTA arm A/B: 49%/61%), dose reduction (13%; 8%/33%), or discontinuation (10%; 4%/13%). Conclusions: BRG showed sustained long-term activity, PFS, and manageable safety in pts with CRZ-refractory ALK+ NSCLC. The 180 mg/d dose after 7-d lead-in at 90 mg/d led to numerically higher median PFS and OS. Final results are similar to those reported for other approved ALK tyrosine kinase inhibitors in this setting. Clinical trial information: NCT01449461, NCT02094573. [Table: see text]

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.

A phase 1b, open label, single institution trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2614-TPS2614
Author(s):  
Ankit Madan ◽  
Benjamin Scott Jones ◽  
Ravi Kumar Paluri ◽  
Mary Jerome ◽  
Debi Miley ◽  
...  
Keyword(s):  
Growth Factor ◽  
Solid Tumors ◽  
Cancer Progression ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Advanced Solid Tumors ◽  
Single Institution ◽  
Open Label ◽  
Phase 1B

TPS2614 Background: Vascular endothelial growth factor (VEGF) is a potent factor in inducing angiogenesis. VEGF inhibitors have produced demonstrable but limited and transient clinical benefit for various cancers. One mechanism of resistance includes revascularization secondary to up-regulation of alternative pro-angiogenic signals such as platelet derived growth factor receptor (PDGF) and fibroblast growth factor receptor (FGFR) pathway. Nintedanib is an oral triple kinase inhibitor that blocks the VEGFR, PDGFR and FGFR pathways. Our study is using combination of Nintedanib (Nin) and Bevacizumab (Bev) which will block VEGF as well as salvage pathway of angiogenesis (PDGFR and FGFR). Phase I dose selection studies revealed that Nin is generally well tolerated (Clin Can Res 16:47, 2010). LUME-Lung 1 phase 3, international, double blind, placebo controlled trial using Nin and docetaxel in non-small cell lung cancer (NSCLC) showed significant improvement in progression free survival (PFS) regardless of histology and improvement in overall survival (OS) in lung adenocarcinoma (Lancet oncology 15:2, 2014). Methods: This is a phase 1b, open label, single institution trial with standard 3+3 design. Primary objective is to evaluate the safety and tolerability of combination of Nin and Bev. The secondary objective is to determine clinical efficacy (objective response), PFS, and evaluation of plasma levels of angiogenic and anti-angiogenic biomarkers like VEGF, PDGF, VEGF-R and FGF. Patients (pts) in cohort I will be treated with Bev 15 mg/kg day 1 intravenously every 3 weeks and Nin 150 mg orally (PO) twice daily (BID) from day 2-21. In the absence of dose limiting toxicities, Nintedanib dose will be increased to 200 mg PO BID in cohort II. Major inclusion criteria includes advanced solid tumors for which Bev has an indication (non-squamous, NSCLC, colon, ovarian, cervical and renal cancer), progression after at least 1 line of systemic treatment, and measurable disease. Pts with prior treatment with Bev can be enrolled. We will enroll 18 patients. Cohorts I has been completed without DLT (n = 3). Cohort II has enrolled 10 patients. Clinical trial information: NCT02835833.

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.

LEAP-005: A phase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the gastric cancer cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4030-4030
Author(s):  
Hyun Cheol Cheol Chung ◽  
Zarnie Lwin ◽  
Carlos A. Gomez-Roca ◽  
Federico Longo ◽  
Eduardo Yanez ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Activity ◽  
Advanced Gastric Cancer ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Tumor Imaging ◽  
Tissue Sample ◽  
Phase 2 ◽  
Open Label ◽  
Previously Treated

4030 Background: Lenvatinib, an anti-angiogenic multiple receptor tyrosine kinase inhibitor, in combination with the anti‒PD-1 antibody pembrolizumab, has demonstrated promising antitumor activity with manageable safety in the first- or second-line in a phase 2 trial of patients with advanced gastric cancer. LEAP-005 (NCT03797326) is a phase 2, multicohort, nonrandomized, open-label study evaluating efficacy and safety of lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors; here, we present findings from the gastric cancer cohort of LEAP-005. Methods: Eligible patients were aged ≥18 years with histologically or cytologically confirmed metastatic and/or unresectable gastric cancer, received at least 2 prior lines of therapy, had measurable disease per RECIST v1.1, ECOG PS of 0‒1, and provided a tissue sample evaluable for PD-L1 expression. Patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg Q3W for up to 35 cycles of pembrolizumab (approximately 2 years) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 years in patients experiencing clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR; comprising CR, PR, and SD), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 weeks, then Q12W to week 102, and Q24W thereafter. Results: 31 patients were enrolled in the gastric cancer cohort; 87% were male, 58% were aged < 65 years, and 71% had PD-L1 combined positive score (CPS) ≥1. Median time from first dose to data cutoff (April 10, 2020) was 7.0 months (range, 1.9‒11.9); 19 patients (61%) had discontinued treatment. ORR was 10% (95% CI, 2‒26); 1 patient had CR (3%), and 2 had a PR (6%). 12 patients (39%) had SD. Median DOR was not reached (range, 2.1+ to 2.3+ months). DCR was 48% (95% CI, 30‒67). Median PFS was 2.5 months (95% CI, 1.8‒4.2). Median OS was 5.9 months (95% CI, 2.6‒8.7). 28 patients (90%) had treatment-related AEs, including 13 patients (42%) with grade 3‒5 AEs. 1 patient had a treatment-related AE that led to death (hemorrhage). 8 patients (26%) had immune-mediated AEs: hypothyroidism (n = 5), hyperthyroidism (n = 2), and pneumonitis (n = 1). There were no infusion-related reactions. Conclusions: In patients with advanced gastric cancer who received 2 prior lines of therapy, lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile. Based on these data, enrollment in the gastric cancer cohort has been expanded to 100 patients. Clinical trial information: NCT03797326.

Efficacy and safety of anlotinib plus TQB2450 in patients with advanced soft tissue sarcoma: A multicenter, single armed, phase 1b trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11547-11547
Author(s):  
Jiayong Liu ◽  
Zhengfu Fan ◽  
Wei Guo ◽  
Tian Gao ◽  
Shu Li ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Kinase Inhibitor ◽  
Soft Part ◽  
Epithelioid Sarcoma ◽  
Objective Response ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
Phase 1B ◽  
Anthracycline Chemotherapy

11547 Background: Anlotinib, a multitargeted tyrosine kinase inhibitor, had been prove to be effective for the treatment of advanced or metastatic soft tissue sarcoma(STS) faild anthracycline chemotherapy. With the lack of prospective data of combination of PDL-1 inhibitor and antiangiogenic agent, we designed a phase 1b study to investigated the efficacy and safety of anlotinib plus TQB2450 in patients with STS. Methods: Eligible patients (age 18-70, ECOG 0-1, with histopathologically confirmed advanced STS, at least one measurable lesion according to RECIST 1.1, and previously received front-line anthracycline chemotherapy) were included and received anlotinib (12mg qd, D1-14, 21d/cycle) plus TQB2450 (1200 mg, IV, D1, 21d/cycle) until disease progression or intolerable toxicities.The primary endpoint was objective response rate (ORR), secondary endpoints included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR). Results: From January 2019 to January 2021, 30 pts were enrolled1, 12 alveolar soft part sarcoma and 18 others (7 synovial sarcoma, 4 leiomyosarcoma, 5 undifferentiated pleomorphic sarcoma, 1 fibrosarcoma and 1 epithelioid sarcoma). ORR by RECIST was 36.7%, DCR was 83.3%, 11/30 pts had PR, 14/30 (46.7%) had SD, 5/30 (16.7%) PD. Median PFS was 9.6 m in all pts and 4.9m. in non-ASPS, respectively. Median OS in non-ASPS was 10.27m, while mOS in all pts and both mPFS and mOS in ASPS had not been reached. Notably, to ASPS pts, ORR was 75%, and DCR was 100%. The most common 1-2 grade treatment-related adverse reaction (TRAE) was hypothyroidism (19/30,63.3%)，hypercholesterolemia (16/30, 53.3%) and hypertriglyceridemia (16/30, 53.3%), the most common ≥3 grade TRAEs were hypertriglyceridemia (3/30, 10%). 6 SAE (20%) occurred, including 2 pneumothorax, 1 Immune associated hapatic injury, 1 hypotension, 1 Immune myocarditis and 1 diabetic ketoacidosis. Conclusions: The combination of anlotinib and TQB2450 showed promising activity in second-line treatment of advanced STS, especially in ASPS, with well tolerance and acceptable toxicity.

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.

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