A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients (pts) with unresected, locally advanced squamous cell carcinoma of the head and neck (LASCCHN).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5502-5502 ◽  
Author(s):  
Jordi Giralt ◽  
Andre Fortin ◽  
Ricard Mesia ◽  
Heikki Minn ◽  
Michael Henke ◽  
...  
Keyword(s):  
Human Monoclonal Antibody ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Mucosal Inflammation ◽  
Open Label ◽  
Hpv Status ◽  
Biomarker Analysis ◽  
Grade 3 ◽  
Fatal Adverse Events ◽  
Ecog Ps

5502 Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor. We evaluated the safety and efficacy in pts receiving CRT alone or CRT plus pmab (PCRT) as 1st‑line treatment of LASCCHN (sponsored and funded by Amgen Inc.). Methods: Pts with stage III, IVA, or IVB previously untreated LASCCHN of all sites excluding the nasopharynx were randomized 2:3 to open-label CRT or PCRT. CRT included cisplatin 100 mg/m2 for 3 cycles during standard fractionation radiotherapy (RT). PCRT included pmab 9.0 mg/kg + cisplatin 75 mg/m2, both administered with RT as in the CRT arm. The primary endpoint was local regional control (LRC) rate at 2 years; key secondary endpoints included PFS, OS, and safety. Preplanned HPV subset analysis, as determined by p16 immunohistochemistry, was performed on available samples. Results: Of 150 treated pts (87 pts PCRT, 63 pts CRT), 87% were men; median (range) age was 57 (39-77) years; ECOG PS 0: 68%. Of 99 pts with tumor evaluable for HPV, 42% were HPV+. Overall, the 2-year LRC rate (95% CI) was 61% (50%-71%) for PCRT and 68% (54%-78%) for CRT. PFS events occurred in 40% of the PCRT and 35% of CRT arm (HR [95% CI] 1.15 [0.68-1.96]; p=0.61). Death occurred in 36% of the PCRT arm vs 24% of the CRT arm (HR [95% Cl] for OS 1.63 [0.88-3.02]; p=0.12). Disease progression was the cause of death in 22% of PCRT pts and 10% of CRT pts. There were no differences in outcome by tumor HPV status. No difference in fatal adverse events (AEs) was seen between arms. Grade 3+ AEs occurred in 85% vs 68% of pts (PCRT vs CRT). Differences in grade 3+ toxicity between treatment arms (PCRT, CRT) were most pronounced for mucosal inflammation (55%, 24%), radiation skin injury (28%, 13%), dysphagia (40%, 27%), and rash (11%, 0%). RT delays of >10 days occurred in 16% of the PCRT arm and 3% of the CRT arm. Median cisplatin cumulative dose received was 223.1 mg/m2 in the PCRT arm and 296.9 mg/m2 in the CRT arm, reflective of differences in planned dose. Conclusions: The addition of pmab to CRT did not show an increase in efficacy and was associated with increased toxicity. Further results of HPV biomarker analysis will be presented.

GAIN-(L): Efficacy and biomarker findings of RG7160 (GA201), a novel, dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), in combination with first-line cisplatin and pemetrexed in metastatic nonsquamous NSCLC.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7544-7544
Author(s):  
James F. Spicer ◽  
Enriqueta Felip ◽  
Lionel Bosquée ◽  
Vanesa Gregorc ◽  
Iker Lopez Calderero ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Neoadjuvant Treatment ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Target Lesion ◽  
Mucosal Inflammation ◽  
Clinical Activity ◽  
Biomarker Analysis ◽  
Grade 3

7544 Background: GA201, a humanized, engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, has shown promising clinical activity in phase I and in the neoadjuvant treatment of head and neck cancer. This phase Ib study (NCT01185847) aimed to determine the safety, pharmacokinetics (PK), activity and recommended phase II dose (RP2D) of GA201 in combination with chemotherapy in non-squamous NSCLC. Methods: Successive cohorts received GA201 1000 mg or 1400 mg (IV d1, d8 then 2-weekly (q2W)) in combination with chemotherapy at standard doses. Data cut off was 7 months after enrolling the last patient. Results: 14 patients (4 female) with performance status 0-1 were enrolled. No maximum tolerated dose was reached. Most common adverse events (AEs – all grades) included rash (100%), hypomagnesaemia (71%), infusion-related reactions (64%), mucosal inflammation (57%) and anemia (50%). AEs of ≥ grade 3 included rash (71%), skin fissure (21%), dry skin (14%), paronychia (14%), and asthenia (14%). Median timeto improvement of rash grade 3 was 11 days. AEs led to dose reduction for 4 patients and discontinuation for 1 patient. There were 6 confirmed partial responses (43%, 5 in 1400 mg cohort) and 7 patients (50%) with stable disease >=9 weeks. Duration of response ranged between 5 and 42 weeks (3 patients still ongoing). Preliminary biomarker analysis shows a correlation between tumor-infiltrating CD16+ immune cells and target lesion shrinkage at first tumor assessment [R(spear)=-0.65 (p=0.02)]; no apparent correlation between EGFR H-score and response was found. PK data supports 1400 mg as the RP2D (d1, d8 then q2W). Conclusions: The RP2D of GA201 in combination with chemotherapy was established to be 1400 mg. The incidence of EGFR associated rash was high and guidelines to reduce its severity were implemented with a noted improvement in tolerability. Promising antitumor activity was observed. Biomarker data support the mode of action of GA201 via ADCC. A randomized phase II trial of this combination is ongoing and fully recruited.

Interim analysis of a phase II study of dose-modified FOLFIRINOX (mFOLFIRINOX) in locally advanced (LAPC) and metastatic pancreatic cancer (MPC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 256-256 ◽  
Author(s):  
Edward Samuel James ◽  
Xiaopan Yao ◽  
Xiangyu Cong ◽  
Stacey Stein ◽  
Kristin Kaley ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Interim Analysis ◽  
Historical Data ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Sensory Neuropathy ◽  
Open Label ◽  
Grade 3 ◽  
Ecog Ps

256 Background: Although FOLFIRINOX is superior to gemcitabine in MPC, the regimen is associated with significant toxicities (Conroy et al. N Engl J Med 2011;364:1817). In our prior retrospective analysis, efficacy was not compromised by dose attenuations of FOLFIRINOX (Gunturu et al. Med Oncol 2013;30:361). Based on this analysis, we are conducting a prospective phase II open label study to evaluate the efficacy & tolerability of mFOLFIRINOX in pts with advanced pancreatic cancer (PC). Methods: Previously untreated pts with MPC or LAPC received mFOLFIRINOX with 25% dose reductions of irinotecan & bolus 5-FU given every two wks until progression, unacceptable toxicity, or surgical resection. All pts received prophylactic pegfilgrastim. FDG-PET scans were obtained at baseline & after 2 cycles. CAT scans were obtained after every 4 cycles. Toxicities & response rate (RR) were compared to historical data reported by Conroy. Results: 53 pts with ECOG PS ≤1 have been enrolled to date between 11/11 and 08/13, Pt characteristics: LAPC 22; MPC 31; median age 62 yrs (range 46-86); male 30. Median # of cycles was 8 (range 1-21). Grade 3/4 toxicities were: anemia, febrile neutropenia (FN) & peripheral sensory neuropathy (PSN) – 3.8% each; ALT increased & thromboembolism – 5.7% each; diarrhea 7.5%; fatigue 11.3%; neutropenia 17%; thrombopenia 11.3% & vomiting 1.9%. Anemia ( p< 0.04), FN (p<0.04), PSN (p<0.04) and vomiting (p<0.02) were significantly decreased compared to historical data (Conroy). Response by RECIST (CR+PR) in 26 evaluable pts with MPC was 29% (0 CR, 9 PR, 14 SD, 3 PD) & similar to historical data (31.6%; p 0.85). 6/13 evaluable pts with LAPC underwent resection (46%).13/36 pts evaluable for PET response had a >50% decrease in SUV(max)(36%). Evaluation for OS & PFS is ongoing. Conclusions: Findings from our interim analysis suggests that mFOLFIRINOX, given along with prophylactic pegfilgrastim is associated with a similar RR and improved tolerability compared to full dose FOLFIRINOX in advanced PC. In pts with LAPC, neoadjuvant FOLFIRINOX appears to have substantial activity with 46% of evaluable pts undergoing resection. Accrual will continue to reach a goal of 70 pts. Clinical trial information: NCT01523457.

Capecitabine (X) compared to X + erlotinib (E) as first-line treatment in patients (pts) with metastatic colorectal cancer (MCRC): Interim efficacy results from a randomized phase II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14560-14560 ◽  
Author(s):  
M. Vincent ◽  
I. Kerr ◽  
B. Dingle ◽  
M. J. MacKenzie ◽  
M. Sanatani
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Growth Factor Receptor ◽  
First Line ◽  
Open Label ◽  
Dry Eyes ◽  
Open Label Phase ◽  
Grade 3 ◽  
Ecog Ps

14560 Background: The oral fluoropyrimidine X (Xeloda®) has efficacy, safety and convenience benefits vs. 5-FU/LV in adjuvant / first-line CRC. E (Tarceva®) inhibits epidermal growth factor receptor (EGFR), which predicts poor prognosis. A randomized open-label phase II study was performed to establish activity of X alone vs. X + E (XE) in first-line. Methods: Pts (ECOG PS 0–2 and/or elevated LDH) with MCRC not eligible for immediate surgical metastatectomy and unwilling/unable to undergo combination chemotherapy were randomized to X (1000mg/m2/d bid d1–14 q3w) or XE (X 1000mg/m2/d bid d1–14 q3w + E 150mg/d). A third arm (E alone) was included but dropped after 13 pts, following safety committee review of progressions at first CT scan. Primary endpoint: time to progression (TTP). Results: 59 pts (median age 65y, range 46–84; 44 M, 15 F) have been accrued (X=21; XE=25; E=13). Mean time on study: 3.8 months (range 0.2–12). 9 pts are on active treatment, 21 pts on follow-up and 29 pts have died. Interim efficacy results are available for 50 pts (X n=15; XE n=22, E n=13). There were no significant differences in response rate, median TTP (4.9 vs. 9.2 months) and median overall survival (18.2 vs. 15.1 months) for X vs. XE. Grade 3 adverse events (AEs) with X were diarrhea, nausea, hand-foot syndrome (HFS), angina, dyspnea (all 5%). Corresponding rates of grade 3 AEs with XE were diarrhea (20%), fatigue (16%), stomatitis (12%), HFS (8%), vomiting (8%), dehydration (8%), thrombosis, weight loss, decreased appetite, dry eyes, headache, anxiety, abdominal pain, anorexia, hyponatremia (all 4%). The only grade 4 AEs were skin rash (4%) and subjective weakness (4%) - both XE. Conclusions: Interim results indicate that XE is at least as effective as X alone in first-line MCRC. Recruitment is continuing and further follow-up may help fully determine the potential benefits of adding E to X. [Table: see text] No significant financial relationships to disclose.

Phase 1b/2, open label, multicenter study of intratumoral SD-101 in combination with pembrolizumab in anti-PD-1 treatment naïve patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6039-6039 ◽  
Author(s):  
Ezra E.W. Cohen ◽  
Lisle Nabell ◽  
Deborah J.L. Wong ◽  
Terry A Day ◽  
Gregory A. Daniels ◽  
...  
Keyword(s):  
Ct Scan ◽  
Open Label ◽  
Primary Tumors ◽  
Ifn Alpha ◽  
Hpv Status ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Ecog Ps ◽  
Antigen Presenting

6039 Background: SD-101, a synthetic CpG-ODN agonist of TLR9, stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells - activating T cell anti-tumor responses. Pembrolizumab has demonstrated activity in HNSCC. Study DV3-MEL-01 (NCT02521870) assesses safety and efficacy of SD-101 in combination with pembrolizumab in patients with recurrent/metastatic HNSCC. We have previously reported a 27.3% ORR in 22 patients receiving 8 mg SD-101/injection in the modified ITT after at least 2 CT scans due to late responses (Abstract 3560, ESMO 2018). Higher efficacy at a lower SD-101 dose, 2 mg/injection, has been reported in advanced melanoma patients (LBA 45, ESMO 2018). Consequently, this dose is now being assessed in HNSCC. We report preliminary data with the 2 mg/injection dose in 23 patients in mITT at the first CT scan. Methods: Anti-PD-1/PD-L1 naïve patients received 2 mg SD-101 intratumorally in 1 - 4 lesions (weekly x 4 doses then Q3W x 7 doses). Pembrolizumab is was administered IV at 200 mg Q3W. Responses were assessed per RECIST v1.1. Results: 28 patients enrolled: median age 63 y/o, male 68%; ECOG PS 0-1 (18%/82%); mean prior lines of systemic therapy 1 (0-3); mean treatment duration 70 days (1-253). Primary tumors: 19 (68%) oropharyngeal; 3 (10%) laryngeal; 2 (7%) hypopharyngeal; 4 (14%) unknown. Mean number of target lesions: 1.82 (1 to 5). HPV status: 7 (25%) +, 9 (32%) -, 12 (43%) unknown. 18 (64 %) discontinued treatment: 12 (42%) due to PD, 4 (16%) deaths, 1 (3%) consent withdrawn, 1 (3%) went to hospice. Mean follow up 2.70 months. Safety: 16 non-treatment-related SAEs in 9 patients. 2 treatment-related Grade ≥3 AEs: sepsis (4%) and lymphopenia (4% ). No treatment-related deaths. Efficacy: 23 patients in the mITT population with first CT scan at day 64: ORR: CR: 2, PR: 3 (22%); SD: 6 (26%), PD: 7 (30%), non-evaluable: 5 (22%). Disease control rate (48%). 5 patients on study have not had a CT scan. Conclusions: SD-101 with Pembrolizumab shows early promising data and is well tolerated. Additional follow-up scans from both dose cohorts are being evaluated and will be presented. Clinical trial information: NCT02521870.

Phase Ib study of olinvacimab (O) with pembrolizumab (P) in patients with recurrent glioblastoma (rGBM).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14545-e14545
Author(s):  
Anna K. Nowak ◽  
Lawrence Cher ◽  
Samantha Bowyer ◽  
Hui Kong Gan ◽  
Anne Poh Long ◽  
...  
Keyword(s):  
Dose Level ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Blurred Vision ◽  
Flat Dose ◽  
Best Response ◽  
Grade 3

e14545 Background: Recurrent GBM is difficult to treat. Single agent checkpoint blockade has not improved outcomes. Angiogenesis is a rational drug target for rGBM and targeting angiogenesis may benefit pseudoprogression and cerebral oedema. O is a fully human monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) with antiangiogenic and antitumour effects. P is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O combined with P and to establish a recommended phase 2 combination dose. Methods: From January to October 2019, we conducted a two-site, single arm, open-label study of O with P in patients with rGBM. Eligible patients (pts) were ≥18 years with at least one RANO-measurable lesion, KPS≥80, and had completed standard chemoradiotherapy and had no contraindications to O or P. No prior bevacizumab was allowed. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg day 1/8/15 q21d (dose level 1) or O 16mg/kg day 1/8/15 q21d (dose level 2) in combination with P 200mg flat dose day 1 q21d. Pts were reviewed weekly and underwent DCE-MRI at baseline and 6-weekly. Treatment continued to progression, toxicity or withdrawal. Results: 9 pts, median age 53 (range 34-67) were recruited and received at least one study treatment. Median time since diagnosis was 15.6 months. 7 (78%) had KPS 90 and 2 (22%) KPS 80. 3 pts received O 12mg/kg with P, completing a median 3 cycles (range 2-6). As no Dose Limiting Toxicities (DLTs) were seen, 3 pts were treated with O 16mg/kg with expansion total 6 when no DLTs were observed. At 16mg/kg, a median of 2 treatment cycles was received (range 2-6). Treatment was ceased due to progressive disease (PD) in 8 pts with one ongoing at data cutoff. No DLTs were observed in any pts. Three grade 3 treatment emergent adverse events (TEAEs) were noted (blurred vision, fatigue, and seizure). Hemangioma is a known toxicity of O and was seen in 6 pts, with 11 grade 1 and 1 grade 2 event. 4 pts (44%) had stable disease (SD) and 5 pts (56%) had PD as best response. Conclusions: The combination of O with P was safe and tolerable at the full single agent dose of each drug. No DLTs were observed. The combination did not show efficacy in this setting. Clinical trial information: NCT03722342.

281 JAVELIN Medley VEGF: phase 2 study of avelumab + axitinib in patients with previously treated non-small cell lung cancer (NSCLC) or treatment naive, cisplatin-ineligible urothelial cancer (UC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A307-A307
Author(s):  
Gabriella Galffy ◽  
Iwona Lugowska ◽  
Elena Poddubskaya ◽  
Byoung Chul Cho ◽  
Myung-Ju Ahn ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Maintenance Treatment ◽  
Locally Advanced ◽  
Small Cell Lung ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Open Label Phase ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Grade 3

BackgroundAvelumab, a human anti–PD-L1 monoclonal antibody, has shown a manageable safety profile and antitumor activity in multiple tumor types, including platinum-resistant metastatic or recurrent NSCLC,1 and is approved for patients with locally advanced or metastatic UC who have progressed after ≥1 previous line of platinum-based chemotherapy2 3 and as maintenance treatment for those who have not progressed with platinum-based chemotherapy.4 JAVELIN Medley VEGF (NCT03472560) evaluated the efficacy and safety of avelumab + axitinib, a potent inhibitor of VEGFR 1, 2, and 3, in patients with advanced or metastatic NSCLC or UC.MethodsEligible patients with NSCLC had received ≥1 prior platinum-containing therapy and ≤2 prior lines of systemic therapy for locally advanced or metastatic disease; patients with UC were treatment naive in the locally advanced or metastatic setting and ineligible for cisplatin-containing chemotherapy. Patients were immune checkpoint inhibitor naïve and received avelumab 800 mg intravenously every 2 weeks + axitinib 5 mg orally twice daily. The primary endpoint was confirmed objective response (OR) per investigator assessment (RECIST 1.1). Secondary endpoints included progression-free survival (PFS) and safety. PD-L1 expression was assessed in baseline tumor samples (Ventana SP263 assay). Data have not undergone standard quality checks and are subject to change due to COVID-19–related healthcare burden.ResultsA total of 41 patients with NSCLC and 20 with UC received avelumab + axitinib. The confirmed OR rate was 31.7% (95% CI, 18.1–48.1) in the NSCLC cohort and 10% (95% CI, 1.2–31.7) in the UC cohort (all partial responses); 16 patients (39.0%) and 5 (25.0%) had stable disease, respectively. Responses were observed regardless of PD-L1 expression status. Median PFS was 5.5 months (95% CI, 2.5–7.0) in the NSCLC cohort and 2.3 months (95% CI, 1.8–5.6) in the UC cohort. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 24 patients (58.5%) in the NSCLC cohort; the most common was hypertension (n=7 [17.1%]). Grade ≥3 TRAEs occurred in 9 patients (45.0%) in the UC cohort; the most common were amylase increased, asthenia, decreased appetite, and palmar-plantar erythrodysesthesia syndrome (n=2 [10%] each). One patient in each cohort experienced a TRAE that led to death (gastric perforation and urinary bladder hemorrhage).ConclusionsAvelumab + axitinib showed antitumor activity and a manageable safety profile in patients with advanced or metastatic NSCLC or UC consistent with findings from studies of each drug alone and in combination.Trial RegistrationNCT03472560Ethics ApprovalThe study was approved by each site’s independent ethics committee.ConsentN/AReferencesGulley JL, Rajan A, Spigel DR, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol 2017;18:599–610.Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 2018;19:51–64.Bavencio(avelumab) injection. [package insert] Darmstadt, Germany: Merck KGaA; 2019.US Food and Drug Administration. FDA approves avelumab for urothelial carcinoma maintenance treatment. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment. Accessed August 19, 2020.

Atezolizumab in combination with bevacizumab in patients with unresectable locally advanced or metastatic mucosal melanoma: Interim analysis of an open-label phase II trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9511-9511
Author(s):  
Lu Si ◽  
Meiyu Fang ◽  
Yu Chen ◽  
Lili Mao ◽  
Peng Zhang ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Mucosal Melanoma ◽  
Stage I ◽  
Efficacy Evaluation ◽  
Open Label ◽  
Full Analysis ◽  
Ecog Ps

9511 Background: Mucosal melanoma is a rare malignant melanoma in Caucasians but ranks the second most common subtype in the Asian population. It is more often diagnosed at an advanced stage and responds poorly to current PD-1/PD-L1 inhibitors. Here we report the interim analysis results of ML41186, an open-label, multicenter, single-arm phase II study, aiming to evaluate the efficacy and safety of atezolizumab in combination with bevacizumab in patients (pts) with advanced mucosal melanoma. Methods: Eligible pts aged 18 to 75 years with histologically confirmed unresectable locally advanced or metastatic mucosal melanoma had at least one measurable lesion per RECIST version 1.1 at baseline, with an ECOG PS 0 or 1 and adequate hematologic and organ function. ML41186 is a Simon two-stage design study, if 22 pts completed ORR evaluation and more than 3 pts respond in stage I, the study then continue to Stage II. Atezolizumab and bevacizumab were administered at a fixed dose of 1200 mg and 7.5 mg/kg Q3W respectively (on day 1 of each 21-day cycle) until unacceptable toxicity or loss of clinical benefit. The primary endpoint is the objective response rate (ORR). The secondary endpoints include progression-free survival (PFS), duration of objective response (DoR), disease control rate (DCR), and safety. Results: By the cut-off date of 9th September 2020, 35 pts has been enrolled, among whom 22 pts in the stage I analysis set has completed two efficacy evaluation, while 28 pts (full analysis set) has completed at least one efficacy evaluation. In ITT populations (n=35), mean age was 58.9 years with 10 (28%) pts had ECOG PS of 1. LDH level elevated in 9 (25.7%) pts. More than half pts (19, 54.3%) had metastatic mucosal melanoma, of whom 3 (15.8%) pts had more than 3 metastasis sites and 4 (21.1%) pts had liver metastasis. In stage I analysis set (n=22), the best confirmed ORR was 36.4% (95% CI, 17.0%-59.3%). Median progression-free survival was 5.32 months (95% CI, 1.58-not reached), and the best confirmed DCR was 59.1% (95%CI, 36.4%-79.3%). The median confirmed DoR was not reached (95% CI, 2.76-NR). In the full analysis set (n=28), the unconfirmed ORR was 42.9% (95%CI, 24.5%-62.8%). In ITT populations (n=35), 28 pts (80%) experienced at least one adverse event (AE) and 5 pts (14.3%) experienced at least one grade 3-4 AEs. Only one patient experienced AE leading to treatment discontinuation. One patient died of autoimmune lung disease. Conclusions: The combination of atezolizumab plus bevacizumab showed promising benefit and was tolerable in pts with advanced mucosal melanoma. At the time of this interim analysis, the primary endpoint did not cross the futility boundary, thus the study will run into Stage II. Clinical trial information: NCT04091217.

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]

CLO19-037: Reducing the Duration, Incidence and Severity of Mucosal Injury Due to Cancer Radiation therapy (RT); Positive Randomized Phase 2b Trial Results With GC4419 (Avasopasem Manganese), a Small Molecule Superoxide (SO) Dismutase (SOD) Mimetic

2019 ◽  
Vol 17 (3.5) ◽  
pp. CLO19-037
Author(s):  
Jon T. Holmlund ◽  
Carryn M. Anderson ◽  
Stephen T. Sonis ◽  
Robert Beardsley ◽  
Dennis Riley ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Mucosal Injury ◽  
Cheek Pouch ◽  
Hamster Cheek Pouch ◽  
Open Label ◽  
Who Grade ◽  
Normal Tissues ◽  
Intensity Modulated ◽  
Hpv Status ◽  
Radiation Induced

Introduction: RT-induced SO contributes to initiation of mucosal injury; eg, oral mucositis (OM) and esophagitis. GC4419 specifically mimics SOD’s dismutation of SO to hydrogen peroxide (H2O2), interdicting OM initiation. GC4419 reduced RT-severe OM (SOM) in a hamster cheek pouch model, and protected mucosa and other normal tissues from radiation-induced injury in other animal models. In a published phase 1b/2a open-label trial (Anderson et al, IJROBP, 1 Feb 2018), GC4419 attenuated SOM in patients (Pts) receiving intensity-modulated RT (IMRT) plus concurrent cisplatin (CDDP) for locally advanced head & neck cancer (HNC). Objectives: Determine whether GC4419 reduces duration, incidence, & severity of SOM. Methods: Pts with locally advanced oral cavity or oropharyngeal cancer; definitive or postoperative intensity-modulated (IM)RT (approximately 70 Gy [>50 Gy to > 2 oral sites]) plus CDDP (weekly or q3wk) were randomized (stratification: tumor HPV status, CDDP schedule) to 30 or 90 mg of GC4419, or placebo (PBO), 60-minute IV infusion, M–F, ending <60 minutes before IMRT delivered in 35 fractions over 7 weeks. WHO grade OM was assessed by trained evaluators biw during IMRT & qwk for up to 8 wks after IMRT. Primary endpoint: duration of SOM. Efficacy was tested for each active dose vs PBO (ITT population) by a sequential, conditional approach (2-sided alpha, 0.05). Results: 223 pts (44 sites): 90 mg (n=76), 30 mg (n=73), or PBO (n=74). Baseline patient and tumor characteristics and treatment delivery were balanced. Efficacy: At 90 mg GC4419 vs PBO, duration of SOM was significantly reduced (median, 1.5 vs 19 d; P=.024). SOM incidence (43% vs 65%; P=.009), and grade 4 incidence (16% vs 30%; P=.045) also improved. There were intermediate improvements with 30 mg. Safety was comparable across arms; no significant GC4419-specific toxicity; other known toxicities of IMRT/CDDP were not increased. Conclusions: GC4419 demonstrated a significant, clinically meaningful reduction of SOM duration, and dose-dependent improvements in other SOM parameters, with acceptable safety. A confirmatory phase 3 trial (NCT03689712) is in progress. Clinical trials to reduce RT-related esophagitis are also planned.

Bosutinib (SKI-606) Demonstrates Clinical Activity and Is Well Tolerated in Patients with AP and BP CML and Ph+ ALL.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1101-1101 ◽  
Author(s):  
Carlo Gambacorti- Passerini ◽  
Enrico Maria Pogliani ◽  
Michele Baccarani ◽  
Giovanni Martinelli ◽  
Hagop M Kantarjian ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Growth Factor Receptor ◽  
Treatment Interruption ◽  
Clinical Activity ◽  
Molecular Response ◽  
Cell Transplant ◽  
Open Label ◽  
Wide Range ◽  
Grade 3

Abstract Bosutinib (SKI-606) is an orally available, Src/Abl kinase inhibitor with minimal activity against platelet derived growth factor receptor (PDGFR) and c-kit. An open-label study of patients (pts) with Philadelphia chromosome positive (Ph+) accelerated phase (AP) and blast phase (BP) CML and Ph+ ALL who failed prior imatinib therapy is ongoing. Patients receive 500 mg/day of bosutinib. Preliminary data for 101 subjects, median age 51.5 yrs (range 18 – 84 yrs) and 56% male are reported. 44 pts were in AP, 35 in BP, 21 had Ph+ ALL, and 1 was unclassified. Prior therapy in addition to imatinib included interferon (35 pts), dasatinib (40 pts), nilotinib (15 pts) and stem cell transplant (11 pts). 49 pts failed imatinib (and received no other tyrosine kinase inhibitor [TKI]) and 52 pts failed both imatinib and other TKIs, with median duration of bosutinib treatment to date 4.4 mos (range 0.3 – 21.3 mos) and 2.0 mos (range 0.3 – 18.8), respectively. Among pts with no TKI exposure other than imatinib, complete hematological response (CHR) was obtained in 12/25 evaluable pts (48%), including 7/11 pts (64%) with AP-CML, 4/11 pts (36%) with BP-CML and 1 pt with Ph+ ALL. Major cytogenetic response (MCyR) was achieved in 16/22 evaluable pts (73%) with no TKI exposure other than imatinib, including 9/13 pts (69%) with AP-CML and 6/8 pts (75%) with BP-CML; 1 pt with Ph+ ALL achieved MCyR. Major molecular response (MMR) was achieved in 9/25 evaluable pts (36%) with no TKI exposure other than imatinib, including 1/7 pts (14%) with AP-CML, 4/10 pts (40%) with BP-CML and 4/8 pts (50%) with Ph+ ALL. Among pts with other TKI exposure in addition to imatinib, CHR was obtained in 3/15 evaluable pts (20%), all with AP-CML; MCyR was achieved in 6/20 evaluable pts (30%), including 3/12 pts (25%) with AP-CML and 2/7 pts (29%) with BP-CML; 1 pt with Ph+ ALL achieved MCyR. Of the 20 pts with other TKI exposure in addition to imatinib who were evaluable for MMR, 1 pt with Ph+ ALL (5%) achieved this response. Of 60 pts with baseline samples tested for mutations, 15 different mutations were found in 32 pts (53%), including 8 instances of T315I. CHR occurred in 2/8 evaluable pts (25%) with non-P-loop mutations; the 1 evaluable pt with a P-loop mutation did not achieve CHR. MCyR occurred in 4/11 evaluable pts (36%) with non-P-loop mutations and in 1/2 evaluable pts (50%) with P-loop mutations. Treatment was generally well tolerated. The most common adverse events among treated pts (n=101) were gastrointestinal (diarrhea [66%], nausea [46%] and vomiting [42%]) but these were usually grade 1 – 2, manageable and transient, reducing in frequency and severity after the first 3 – 4 weeks of therapy. Grade 3 – 4 non-hematologic toxicities occurring in ≥ 5% of pts were diarrhea (7%), vomiting (6%), pneumonia (6%) and increased ALT (5%). Fluid retention was reported as grade 1 – 2 in 18 pts and grade 3 – 4 in only 3 pts (including 2 pleural effusions, neither related to bosutinib). Grade 3 – 4 hematologic laboratory abnormalities reported include thrombocytopenia (68%), neutropenia (48%) and anemia (37%). 38 pts had at least 1 temporary treatment interruption and 22 pts had at least 1 dose reduction due to toxicity. 11 pts have permanently discontinued treatment due to adverse event. Bosutinib is effective in imatinib-resistant pts with advanced CML. Responses were observed across a wide range of Bcr/Abl mutations.

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