A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): Updated analysis of patients with metastatic urothelial cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 106-106 ◽  
Author(s):  
Daniel Peter Petrylak ◽  
Raymond P. Perez ◽  
Jingsong Zhang ◽  
David C. Smith ◽  
Joseph D. Ruether ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Phase I Study ◽  
Urothelial Cancer ◽  
Dose Range ◽  
Tolerability Profile ◽  
Antibody Drug Conjugate ◽  
Metastatic Urothelial Cancer ◽  
Metastatic Setting ◽  
Grade 3

106 Background: Enfortumab vedotin, an antibody–drug conjugate, delivers monomethyl auristatin E to tumors expressing Nectin-4, which is overexpressed in metastatic urothelial cancer (mUC). Methods: This Phase I study (NCT02091999) enrolled patients (pts) with solid tumors, including pts with mUC, treated with ≥1 prior chemotherapy regimen. All pts received different dose levels of IV enfortumab vedotin (0.5, 0.75, 1, 1.25 mg/kg) once weekly for 3 out of 4 wks. Nectin-4 expression was determined by IHC on archival tumor specimens and quantified by histochemical scoring (H-score). Primary endpoint was tolerability; secondary endpoint was antitumor activity assessed every 8 wks per RECIST v1.1. Results: As of 3 Jan 2017, 68 pts with mUC (46 M/22 F; median age, 67 yr [range: 41–84]) had been treated. Of these, 62% received ≥2 prior therapies in the metastatic setting and 40% had prior immune checkpoint inhibitor (CPI) therapy. In these pts, Nectin-4 expression was high and prevalent (median H-score, 280 [range: 32–300]). Treatment-related adverse events (TRAEs) were reported in 58 pts (85%); diarrhea, fatigue, nausea, and pruritus were TRAEs reported in ≥25% of pts. Most TRAEs were grade ≤2 in severity; 19 pts (28%) experienced a TRAE of grade ≥3. The most common grade ≥3 AEs (occurring in ≥5 pts), regardless of attribution to treatment, were urinary tract infection (10%) and hypophosphatemia (9%). No treatment-related deaths have occurred. Sixty pts had ≥1 post-baseline assessment. Antitumor activity was observed across the dose range; overall response rate (ORR) was 40% (95% CI: 27.6–53.5) for all evaluable pts (n = 60), 46% (95% CI: 25.6–67.2) in pts with prior CPI exposure (n = 24), and 44% (95% CI: 19.8–70.1) in pts with metastasis to the liver (n = 16). Complete responses were noted in 3 pts at doses ≥1 mg/kg. Median treatment duration was 26 wks (range: 5.1–64.6), median duration of response was 18 wks (95% CI: 8.4–40.1), and median progression-free survival was 17 wks (95% CI: 15.1–23.3). Study enrollment is ongoing. Conclusions: Enfortumab vedotin demonstrated a favorable tolerability profile with encouraging antitumor activity in heavily pretreated mUC, including pts for whom CPIs have failed. Clinical trial information: NCT02091999.

scholarly journals Phase II Trial of Cetuximab With or Without Paclitaxel in Patients With Advanced Urothelial Tract Carcinoma

2012 ◽  
Vol 30 (28) ◽  
pp. 3545-3551 ◽  
Author(s):  
Yu-Ning Wong ◽  
Samuel Litwin ◽  
David Vaughn ◽  
Seth Cohen ◽  
Elizabeth R. Plimack ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Single Agent ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
Free Survival ◽  
Metastatic Urothelial Cancer ◽  
Metastatic Setting ◽  
Previously Treated ◽  
Grade 3

Purpose The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. Patients and Methods Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m2 with or without paclitaxel 80 mg/m2 per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. Results We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). Conclusion Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.

Phase I Study of AVE9633, an AntiCD33-Maytansinoid Immunoconjugate, Administered as an Intravenous Infusion in Patients with Refractory/Relapsed CD33-Positive Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4548-4548 ◽  
Author(s):  
Francis Giles ◽  
Rodica Morariu-Zamfir ◽  
John Lambert ◽  
Srdan Verstovsek ◽  
Deborah Thomas ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Disulfide Bonds ◽  
Phase I Study ◽  
Dose Range ◽  
Microtubule Assembly ◽  
Treatment Schedule ◽  
Specific Tumor ◽  
M Phase ◽  
Grade 3

Abstract AVE9633 is an immunoconjugate created by conjugation of the cytotoxic maytansinoid, DM4, to the monoclonal IgG1 antibody, huMy9-6 (average of 3.5 molecules of DM4 per antibody). The huMy9-6 antibody is a humanized version of a murine monoclonal antibody, My9-6, which is specific for the CD33 antigen expressed on the surface of myeloid cells, including the majority of cases of AML. Because CD33 has little expression outside the hematopoietic system, it represents an attractive target for antibody-based therapy in patients with AML. The humanized antibody, huMy9-6, binds to the CD33 antigen with an apparent KD in the range of 10−10 M. Maytansinoids are anti-mitotics that inhibit tubulin polymerization and microtubule assembly, inhibiting cells during the G2/M phase of the mitotic cycle. In order to link maytansinoids to antibodies via disulfide bonds, a new thiol-containing maytansinoid (DM4) was synthesized. Attachment of potent maytansinoids to an antibody via disulfide bonds provides a satisfactory stability in the bloodstream. After the conjugate is bound at the specific tumor site it is internalized and the cytotoxic agent is released within the target cell. A phase I study of AVE9633 is being conducted in patients with refractory/relapsed CD33+ AML. The study regimen consists of AVE9633 IV infusion on Day 1 of a 3 weeks cycle. To date dose levels of 15 (N=3), 30 (N=5), 50 (N=4), 75 (N=4), 105 (N=2), 200 (N=3) and 260 (N=1) mg/m2 have been investigated. Hypersensitivity reactions during perfusion were noted, requiring prophylaxis with steroids. No other AVE9633- attributable extramedullary Grade 3 AE has been observed to date. Free DM4, measured by LC/MS/MS was detectable from the 75 mg/m2 dose level; its Cmax (at the end of infusion) increased from 10 ng/mL at the 75 mg/m2 dose level to 70 ng/mL at 200 mg/m2. Neither AVE9633-associated myelosuppression nor responses have been noted. Using Flow Cytometry Assay on peripheral blasts and monocytes, total saturation and down regulation of CD33 were observed following administration of doses ≥ 30 mg/m2. AVE9633 exposure (measuring, by ELISA method, all antibodies containing at lease one molecule of DM4) increased proportionally with the administered dose in the dose range 15 to 200 mg/m2. Updated PK results and potential explanations for the lack of efficacy using this treatment schedule will be presented.

A dose-finding study for irinotecan, cisplatin, and S-1 (IPS) in patients with advanced gastric cancer (OGSG 1106).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 144-144
Author(s):  
Hiroki Yukami ◽  
Masahiro Goto ◽  
Takayuki Kii ◽  
Tetsuji Terazawa ◽  
Toshifumi Yamaguchi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Activity ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Advanced Gastric Cancer ◽  
Phase I Study ◽  
Fixed Dose ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

144 Background: In Japan, S-1 plus cisplatin is regarded as one of the standard first line treatment of advanced gastric cancer (AGC). However, the prognosis of AGC remains dismal. The development of more effective chemotherapeutic regimen is thus warranted. A combination of irinotecan, cisplatin, and S-1 (IPS) can be a promising triplet therapy for advanced gastric cancer. We conducted a phase I study of IPS to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and recommended dose (RD), and to assess its safety and antitumor activity in patients with AGC. Methods: This phase I study was designed and conducted in a 3 + 3 manner to determine the recommended dose (RD) of IPS for the subsequent phase II study. Patients received an escalating dose of intravenous irinotecan (level 1: 100/level 2: 125/level 3: 150 mg/m²) on day 1, a fixed dose of intravenous cisplatin (60 mg/m²) on day 1, a fixed dose of S-1 (80 mg/m² b.i.d.) orally on days 1-14, every 4 weeks. Results: Twelve patients were enrolled between June 2013 and February 2017. During the first cycle, one of the six patients in level 1 and two of six patients in level 2 developed the DLT (grade 4 leucocytopenia and grade 3 febrile neutropenia). The MTD of irinotecan was 125 mg/m 2 (level 2) and the RD of irinotecan was considered to be 100 mg/m² (level 1). The most common grade 3 or 4 adverse events included neutropenia 75 % (9/12), anemia 25% (3/12), anorexia 8% (1/12), and febrile neutropenia 17% (2/12). Among six patients with measurable lesions, the response rate was 66.7% (4/6) [95% CI, 33.3-90.7%]. Two patients were performed R0 resection after IPS, with one patient achieved pathological complete response. The median survival time is under analysis. Conclusions: RD of IPS was determined to be 100 mg/m² of irinotecan, 60 mg/m² of cisplatin, and 80 mg/m² of S-1. Our data showed that this regimen provided acceptable antitumor activity and a favorable toxicity profile. Further evaluation of this regimen is warranted. Clinical trial information: UMIN000006864.

Phase I study of sunitinib (SU) in combination with pemetrexed (Pem) in patients (pts) with advanced solid tumors (ST)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14630-e14630
Author(s):  
K. Nakagawa ◽  
I. Okamoto ◽  
T. Shimizu ◽  
M. Miyazaki ◽  
J. Tsurutani ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Japanese Patients ◽  
Fixed Dose ◽  
Solid Malignancies ◽  
Grade 3 ◽  
Multitargeted Tyrosine Kinase Inhibitor ◽  
To Receive

e14630 Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSR-1, and shows antitumor activities in several types of solid malignancies. Non-small-cell lung cancer (NSCLC) xenograft data indicate SU enhanced the antitumor activity of Pem. This phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of combination therapy with the oral SU and Pem for Japanese patients with advanced ST. Methods: Pts with ST refractory to standard therapy were randomly assigned to receive either oral SU 50 mg/day for 2 weeks followed by 1 week rest (Schedule 2/1, S-2/1) or SU 37.5 mg continuous daily dose (CDD). Fixed-dose Pem (500mg/m2 IV) was administered on day1 every 21 days. A standard “3+3” design was employed in both treatment schedules and treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed. Results: A total of 12 pts (med. age 63 years, range 49–69; 10 Male/ 2 Female) have been enrolled (6 pts in the S-2/1 arm and 6 pts in the CDD arm). The most common cancer is NSCLC (9 pts, 75%). All patients completed their first cycle for DLT evaluation, and no DLTs were observed in either treatment arm. The most common toxicities were fatigue (n=8), anorexia (n=6), and thrombocytopenia (n=12). Treatment-related ≥ grade 3 adverse events (AEs) included fatigue (n=1), hypertension (n=1), neutropenia (n=4), leucopenia (n=3), thrombocytopenia (n=2), lymphopenia (n=2), and increased ALT (n=1). Three pts (S-2/1: 2, CDD: 1) required dose reduction of SU due to G3 toxicities. All toxicities were clinically manageable and reversible. One pt with NSCLC had a documented PR with cavity formation inside the tumor. Conclusions: SU 37.5 mg/day (CDD schedule) plus Pem 500mg/m2 every 21 days, and SU 50 mg/day (S-2/1 schedule) plus Pem 500mg/m2 every 21 days were well tolerated and associated with encouraging antitumor activity. [Table: see text]

A phase I study of dovitinib (TKI258) in Japanese patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3088-3088
Author(s):  
Hiroya Takiuchi ◽  
Masahiro Gotoh ◽  
Motoki Yoshida ◽  
Takayuki Kii ◽  
Keishi Yamashita ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Solid Tumors ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Dose Range ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Grade 3

3088^ Background: Dovitinib is a tyrosine kinase inhibitor with demonstrated inhibitory activity against FGFRs, VEGFRs, and PDGFRs in vivo. Based on responses observed in renal cell carcinoma, breast cancer, AML, melanoma, and multiple myeloma in clinical studies in the West, we investigated dovitinib in Japanese patients (pts). Methods: This multicenter phase I study determined the maximum tolerated dose (MTD) of dovitinib based on the occurrence of dose-limiting toxicity (DLT) in Japanese pts with advanced solid tumors. Following a 2-day pharmacokinetic (PK) run-in period, dovitinib was administered orally once daily on a 5-days-on/2-days-off schedule in 28-day cycles until disease progression or withdrawal. The planned dose range was 100-600 mg/day. A 2-parameter Bayesian logistic regression model based on the principle of escalation with overdose control was used to estimate the MTD. Results: In total, 28 pts received dovitinib: 100 mg (n = 3), 200 mg (n = 3), 300 mg (n = 7), 400 mg (n = 9), and 500 mg (n = 6). The median age was 58.5 years (range, 30-76); 16 of 28 pts (57%) were male. All pts had stage IV disease, with an ECOG performance status of 0 or 1. Pts completed a median of 3 cycles. One pt is currently ongoing in the study (peritoneal adenocarcinoma, 400-mg cohort, cycle 19), 23 discontinued due to disease progression, and 4 discontinued due to adverse events (AEs). All DLTs were grade 3: anorexia (n = 1; 300 mg), nausea/vomiting (n = 1; 400 mg), liver function disorder (n = 1; 400 mg), and increased alanine transaminase (n = 1; 500 mg). The most common grade 3/4 AEs (occurring in >10% of pts) suspected to be related to study drug were lymphopenia (18%), neutropenia (14%), abnormal hepatic function (14%), decreased white blood cell count (14%), decreased appetite (14%), and hypertension (14%). Best responses were confirmed partial response in 1 pt (4%; peritoneal adenocarcinoma, 400-mg cohort), stable disease in 9 pts (32%), and progressive disease in 10 pts (36%). No treatment-related deaths have been reported. Safety and PK parameters were comparable to those of non-Japanese pts in the global study. Conclusions: The study has completed enrollment. Dovitinib was found to be tolerable at doses up to 500 mg, which was declared as the MTD in Japanese pts.

A phase I study of ASG-5ME, a novel antibody-drug conjugate, in pancreatic ductal adenocarcinoma.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 176-176 ◽  
Author(s):  
Andrew L. Coveler ◽  
Daniel D. Von Hoff ◽  
Andrew H. Ko ◽  
Nancy Cherry Whiting ◽  
Baiteng Zhao ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Antitumor Activity ◽  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Human Antibody ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Grade 3 ◽  
Antibody Drug

176 Background: ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, an ion transporter expressed on >90% of pancreatic ductal adenocarcinoma (PDA). ASG-5ME comprises a fully human antibody covalently linked, with a protease-cleavable linker, to the microtubule-disrupting agent monomethylauristatin E (MMAE). Upon binding to SLC44A4 and internalization, MMAE is released by proteolytic cleavage, binds to tubulin, and subsequently induces cell cycle arrest and apoptosis. Selective targeting of tumor cells by an ADC represents a novel therapeutic approach for patients (pts) with PDA. Methods: This phase I, dose-escalation, multicenter study investigated the safety, PK, and antitumor activity of ASG-5ME in pts with metastatic PDA. Patients received ASG‑5ME IV in cohort-specific doses on Days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Results: Thirty-five pts (median age 63 yrs, range 32-73) were treated at doses of 0.3 to 1.5 mg/kg. All pts had metastatic PDA and ECOG status 0-1. Thirty-three pts (94%) had previously received chemotherapy for metastatic disease or in the perioperative setting; the median number of prior therapies for metastatic PDA was 3 (range 1-6; n=27). The maximum tolerated dose (MTD) was exceeded at the 1.5 mg/kg dose level, with 1 DLT of Grade 4 GI hemorrhage and 4 pts experiencing non-DLT Grade 3 or 4 neutropenia. Thus, 1.2 mg/kg was identified as the MTD and expanded (N=18). The most common AEs observed at the MTD were fatigue (50%), vomiting (44%), decreased appetite (39%), nausea (33%), and abdominal pain (33%); Grade 3 or 4 toxicities at the MTD included fatigue (28%), abdominal pain (22%), vomiting (17%), and neutropenia (17%). Antitumor activity was observed: 1 pt achieved an unconfirmed PR and 12 pts achieved SD. Five patients (14%) had reductions in CA19-9. Serum ASG-5ME exposures were approximately dose proportional. Of 23 pts with archived biopsies available for IHC analysis, 100% expressed SLC44A4 and 15 pts (65%) had high expression. Conclusions: ASG-5ME treatment was generally well tolerated in metastatic PDA pts, with preliminary evidence of antitumor activity. Further study of ASG-5ME in SLC44A4-expressing malignancies is warranted. Clinical trial information: NCT01166490.

Early results of TROPHY-U-01 Cohort 2: Sacituzumab govitecan (SG) in platinum-ineligible patients (pts) with metastatic urothelial cancer (mUC) who progressed after prior checkpoint inhibitor (CPI) therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5027-5027 ◽  
Author(s):  
Daniel Peter Petrylak ◽  
Scott T. Tagawa ◽  
Rohit K. Jain ◽  
Manojkumar Bupathi ◽  
Arjun Vasant Balar ◽  
...  
Keyword(s):  
Safety Profile ◽  
Phase 1 ◽  
Primary Objective ◽  
First Line ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Early Results ◽  
Metastatic Urothelial Cancer ◽  
Metastatic Setting ◽  
Grade 3

5027 Background: SG is an antibody-drug conjugate consisting of a humanized monoclonal anti–Trop-2 antibody coupled to the cytotoxic agent, SN-38, via a unique hydrolyzable linker. The epithelial cell surface antigen, Trop-2, demonstrates greater expression between UC vs normal tissue, and is a promising target. In a phase 1/2 basket study (IMMU-132-01), SG showed an overall response rate (ORR) of 31% and manageable toxicity in 45 pts with mUC who had a median of 2 (range 1–6) prior therapy lines (Tagawa 2019 ASCO GU). Recent interim results for cohort 1 of the TROPHY-U-01 study in 35 pts with mUC who progressed on platinum and CPI therapy demonstrated an ORR of 29% in pts with a median of 3 prior treatment lines (range 2–6) (Tagawa 2019 ESMO). The most common grade ≥3 treatment-related AE (TRAE) was neutropenia. Methods: TROPHY-U-01 (NCT03547973) is a global, open-label, phase 2 trial evaluating the antitumor activity of SG (10 mg/kg, days 1 and 8 of 21-day cycles) in pts with advanced UC with measurable disease and ECOG PS 0 or 1. Cohort 2 includes platinum-ineligible pts who progressed after CPI therapy in the first-line metastatic setting. The primary objective is ORR evaluated with RECISTv1.1 by central review. Secondary objectives include progression-free survival, overall survival, and duration of response. Results: 18 pts with baseline tumor assessment (50% male; median age 79 y [range 57–87], 67% visceral metastases; 28% liver metastases) received a median of 2 (range 1–5) prior therapies. At a median follow-up of 6 months, ORR was 28% (5/18) with 4 confirmed PRs, and 1 PR pending confirmation. The majority of pts (61% [11/18]) had target lesion reduction. The safety profile was consistent with prior reports. Key grade ≥3 TRAEs were neutropenia (39%), fatigue (33%), diarrhea (28%), leukopenia (22%), anemia (17%), and febrile neutropenia (11%). No events of interstitial lung disease, ocular toxicities, or grade > 2 neuropathy were reported. There were no treatment-related deaths. Conclusions: In cisplatin-ineligible pts, the ORR for currently approved first-line CPI treatments is ~23–29% (Balar 2017 Lancet; Vuky 2018 ASCO). These preliminary data with SG show a manageable safety profile with an encouraging ORR of 28% and support the development of SG in platinum-ineligible pts with mUC who have progressed after CPI therapy. Clinical trial information: NCT03547973 .

First-in-human phase I study of anti-HER2 ADC MRG002 in patients with relapsed/refractory solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1101-TPS1101 ◽  
Author(s):  
Jin Li ◽  
Ye Guo ◽  
Junli Xue ◽  
Wei Peng ◽  
Xiaoxiao Ge ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Single Agent ◽  
Locally Advanced ◽  
Salivary Gland Cancer ◽  
Antibody Drug Conjugate ◽  
Her2 Positive

TPS1101 Background: MRG002 is an antibody drug conjugate (ADC) composed of a humanized anti-HER2 IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG002 is presently being investigated in an ongoing phase I study for safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity in patients (pts) with solid tumors. Methods: MRG002 is evaluated as monotherapy for the treatment of pts with confirmed HER2 positive locally advanced or metastatic cancers, including breast cancer (BC), gastric cancer (GC), salivary gland cancer (SGC) and others. The primary objective is to determine the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D). Secondary objectives include evaluation of PK, tumor response, and immunogenicity. In the dose escalation phase with “3+3” design, approximately 24 pts will be enrolled to identify MTD. The starting dose of MRG002 is 0.3 mg/kg, followed by 0.6, 1.2, 1.8, 2.2, 2.6, and 3.0 mg/kg. In the dose expansion phase, about 50 pts with HER2 positive advanced cancers will be enrolled to further evaluate the safety, antitumor activity, and PK at an appropriate confirmed dose. In this phase I study, each pt receives single agent MRG002 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. Pts with BC and GC should have HER2 positive advanced solid tumors per College of American Pathologists (CAP) guidelines. For other cancers, pts must have IHC status of 2+ or 3+, regardless of FISH results. Pts should have either failed or are ineligible for standard treatments. All pts must have at least 1 measurable lesion per RECIST 1.1. ECOG should be 0-1, and bone marrow, hepatic, renal, cardiac functions should be adequate. Observations include adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity, which is assessed every two treatment cycles. Further clinical trial details can be found on chinadrugtrials.org.cn (CTR20181778). Enrollment is ongoing since November 2018. Clinical trial information: CTR20181778 .

Phase I study of A166 in patients with HER2-expressing locally advanced or metastatic solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1024-1024
Author(s):  
Xichun Hu ◽  
Jian Zhang ◽  
Rujiao Liu ◽  
Shuiping Gao ◽  
Yan Qing ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dry Eye ◽  
Phase I Study ◽  
Locally Advanced ◽  
Her2 Positive ◽  
Grade 3 ◽  
Positive Breast Cancer

1024 Background: A166 is an antibody-drug conjugate composed of a novel cytotoxic drug (Duo-5, anti-microtubule agent) site-specifically conjugated to an anti-HER2 antibody (transtuzumab) via a stable protease-cleavable valine citrulline linker. In a phase I trial in US patients (pts) with relapsed or refractory advanced solid tumor, A166 had an acceptable toxicity profile and best objective response rate (ORR) of 36% at efficacious dose levels (Yongheng Liu et al. ASCO 2020). Here we report a phase I study of A166 in Chinese pts with locally advanced or metastatic solid tumors (CTR20181301). Methods: KL166-I-01-CTP is a single arm, open-label, dose-escalation and dose-expansion phase I study evaluating A166 in pts with HER2-expressing locally advanced or metastatic solid tumors. Pts received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, 6.0 mg/kg IV Q3W. Dose cohorts were expanded at 4.8 and 6.0 mg/kg Q3W. The objectives were to determine the safety and tolerability, pharmacokinetics and antitumor activity of A166. Results: 57 pts (median age 53 [range 26-74], 50 female, 7 male) enrolled from Aug 1, 2018 to Nov 30, 2020. HER2 expression was available for all 57 pts: 51 HER2-positive (3+ or 2+/ISH+), 6 HER2-low (1+ or 2+/ISH-). 61.4% (35/57) had received ≥5 prior lines of therapy. No DLTs were observed in all dose groups. Any grade treatment-related AEs (TRAEs) were documented in 96.5% (55/57) of pts, with 31.6% (18/57) being grade 3 or higher. Common TRAEs were corneal epitheliopathy (73.7%), vision blurred (59.6%), peripheral sensory neuropathy (26.3%), dry eye (21.1%), anemia (19.3%), hyponatremia (19.3%). Most common grade ≥3 TRAEs were corneal epitheliopathy (17.5%), hypophosphatemia (5.3%), and dry eye (5.3%). Four pts had serious AEs, two of which were possibly related to the study drug, including thrombosis and fatigue. TRAEs led to 5.3% (3/57) dose reduction and 5.3% (3/57) treatment discontinuation. One death occurred during the treatment due to progressive disease. At the doses of 0.3-6.0 mg/kg, the exposure of ADC in serum were dose dependent and the mean half-life was found to be 1.17-11.04 days. Serum free toxins was about 0.1% and 0.2% of total A166 (ADC) on a molar basis with the Cycle 1 Cmax and AUC, respectively. At efficacious dose, 36 HER2-positive breast cancer pts with measurable disease were assessed for efficacy, best ORR were 59.1% (13/22) and 71.4% (10/14) in 4.8 and 6.0 mg/kg cohort, respectively. Median progression-free survival (PFS) was not reached, and one patient in 4.8 mg/kg cohort has undergone the treatment for more than 19 months. Conclusions: A166 had a manageable safety profile and high stability in the circulation with much lower acute hematological and gastrointestinal toxicities in terms of incidence rate and grade. It demonstrated promising antitumor activity with clinically meaningful responses in heavily pretreated subjects with HER2-positive breast cancer. Clinical trial information: CTR20181301 .

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