Safety and unique pharmacokinetic profile of ARX788, a site-specific ADC, in heavily pretreated patients with HER2-overexpresing solid tumors: Results from two phase 1 clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1038-1038
Author(s):  
Sara A. Hurvitz ◽  
Haeseong Park ◽  
Sophia Frentzas ◽  
Catherine M. Shannon ◽  
Katharine Cuff ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Salivary Gland Cancer ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Two Phase ◽  
Site Specific ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
A Site

1038 Background: ARX788 is a site-specific, homogeneous, and highly stable ADC. The payload AS269 is conjugated to the synthetic amino acids para-acetylphenylalanine (pAF) in a humanized anti-HER2 mAb. ARX788 demonstrated promising activity in HER2-positive, HER2-low, and T-DM1 resistant tumors in preclinical studies. Here we present the phase 1 clinical data evaluating the safety, antitumor activity, and PK of ARX788 in advanced solid tumors. Methods: The standard 3+3 design (0.33 - 1.5 mg/kg; Q3W or Q4W) is used to determine the MTD and/or RP2D in two phase 1 studies in HER2-positive solid tumors in U.S. and Australia (ACE-Pan tumor-01) and in HER2-positive breast cancers in China (ACE-Breast-01). The efficacy endpoints include ORR and DCR. Intensive PK sampling in first 3 cycles is performed to characterize serum PK profiles of ARX788, total Ab, and pAF-AS269. Results: 69 and 34 heavily pretreated patients received ARX788 monotherapy in the ACE-Breast-01 (median 6 prior lines of therapy) and ACE-Pan tumor-01 trial (including breast, gastric/GEJ, NSCLC, ovarian, urothelial, biliary track, endometrial, and salivary gland cancer) respectively. Dose escalation for both studies have been completed with no DLT reported. MTD has not been reached. ARX788 was generally well tolerated with most AEs being grade 1 or 2. The most common grade >3 AEs include ocular AEs (5.7 %) and pneumonitis (4.3%) in the ACE-Breast-01 trial; pneumonitis (2.9%) and fatigue (2.9%) in the ACE-Pan tumor-01 trial. Low systemic toxicities in terms of the incidence rate and grade (as shown in table). No treatment-related death. In the 1.5 mg/kg cohort, ORR was 74% (14/19) and 67% (2/3) for ACE-Breast-01 and ACE-Pan tumor-01, respectively. DCR was 100%. Median DOR or median PFS has not been reached. PK profiles for total antibody and ARX788 were generally comparable across all dose levels. Mean T1/2 for ARX788 and total antibody had approximately 100 hours at the dose of 1.5 mg/kg. Serum pAF-AS269 concentrations peaked with a median time of 168 h. Serum exposure of pAF-AS269 was low with the Cmax and AUC at cycle 1 being approximately 0.1% and 0.18% of those for ARX788 on a molar basis, respectively. Conclusions: High stability of ARX788 and low serum exposure of pAF-AS269 may underlie the low systemic toxicity, which differentiates it from other ADCs. Clinical trial information: NCT032550070 .[Table: see text]

Results of two phase I dose escalation studies of the oral heat shock protein 90 (Hsp90) inhibitor SNX-5422.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2617-2617
Author(s):  
Todd Michael Bauer ◽  
Jeffrey R. Infante ◽  
Ramesh K. Ramanathan ◽  
Glen Weiss ◽  
Jasgit C. Sachdev ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Hsp90 Inhibitor ◽  
Low Grade ◽  
Advanced Solid Tumors ◽  
Two Phase ◽  
Blurry Vision

2617 Background: SNX-5422 is a prodrug of SNX-2112, a highly potent, non-geldanamycin analog, HSP90 inhibitor with preclinical anti-tumor activity in multiple tumor models. These phase 1 studies were designed to evaluate safety and tolerability, determine dose limiting toxicities, maximum tolerated doses (MTDs), and describe pharmacokinetics of SNX-2112 and SNX-5422. Methods: Two phase 1, open-label, 3 + 3 dose-escalation studies evaluated SNX-5422 when given daily (QD) or every-other-day (QOD) during the first 30 days of treatment in patients (pts) with advanced solid tumors or lymphoma. Plasma concentrations of SNX-2112 and SNX-5422 were measured after the first and 11th (steady state) doses. Tumor assessments were performed every 8 weeks. Results: In both studies, pts received SNX-5422 QOD, 3 wks on/1 wk off, with doses ranging from 4 to 133 mg/m2 QOD. In one study, pts also received QD doses from 50 to 89 mg/m2, 3 wks on/1 wk off, and 50 mg/m2 QD continuously. Fifty-six pts (34M/22F; mean age 62 years) were enrolled. Treatment-related adverse events were mainly low grade (G), including diarrhea (64%), nausea (39%), vomiting (29%), fatigue (27%), abdominal pain (14%), and anorexia (14%). Reversible G 1 blurry vision, and G 1-2 blurry vision/vision darkening were reported by 1 pt on 100 mg/m2 QOD, and 4 pts treated with 50 to 89 mg/m2 QD. G 3 diarrhea was dose limiting in 2 of 3 pts (89 mg/m2 QD; 133 mg/m2 QOD). MTDs for the QOD and QD schedules were declared at100 mg/m2 and 67 mg/m2, respectively. The QD schedule was associated with higher incidences of treatment related adverse events. 38 pts were evaluable for response including 1 confirmed durable complete response, 1 unconfirmed partial response, and 17 with stable disease. Activity was seen in adrenal, lung, liver, neuroendocrine, GIST, and prostate. All but 2 were seen with the QOD schedule. Conclusions: SNX-5422 mono-therapy was generally well tolerated and showed promising signs of efficacy in pts with advanced solid tumors. Given the superior benefit-risk profile of QOD dosing over QD dosing based on these preliminary clinical findings, 100 mg/m2 QOD has been selected for further clinical testing. Clinical trial information: NCT00506805 and NCT01611623.

A phase 1/2 study of intermittent, high dose sunitinib in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2591-2591
Author(s):  
Maria Rovithi ◽  
Mariette Labots ◽  
Richard Honeywell ◽  
Albert J. Ten Tije ◽  
Rita Ruijter ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Population Expansion ◽  
Maximum Tolerated Dose ◽  
Blood Levels ◽  
High Dose ◽  
Advanced Solid Tumors ◽  
Treatment Benefit ◽  
Flat Dose ◽  
Heavily Pretreated

2591 Background: Despite widespread clinical integration, refinement of treatment with sunitinib is actively pursued. Sub-therapeutic blood levels rather than true resistance and tumor adaptation through drug accumulation have been accounted as reasons for treatment failure. Based on our preclinical data with high dose sunitinib and prospective analyses supporting the concept of intermittent dosing, we designed a phase 1 trial to investigate the feasibility and tolerability of high dose, once weekly (1w) or once every two weeks (2w) sunitinib (NCT02058901). Methods: Eligible were patients (pts) with advanced solid tumors, refractory to standard treatment, measurable disease, WHO ≤ 1. Sunitinib was administered orally 1w or 2w. Starting dose was 200 mg, with cohorts escalating in 100 mg steps until maximum tolerated dose (MTD). Response was evaluated by RECIST 1.1. Treatment continued until progression or unacceptable toxicity. Dedicated PK sampling was performed. Sunitinib plasma concentration was measured by LC-MS. Results: 34 (w) and 24 (2w) pts were included, predominantly with mCRC [56% (1w) and 55% (2w)]. MTD was set at 300 mg (1w) and 700 mg (2w). Most common adverse events were fatigue (79%, one pt with G3), nausea (71%, all G1-2), anorexia (29%, all G1-2). Median PFS of evaluable pts was 2.7 mo (1w) and 2.6 mo (2w), while 39% pts (1w) and 25% pts (2w) had PFS > 5 mo. CT scans in pts with treatment benefit showed extensive tumor necrosis. Mean sunitinib plasma Cmax was 190 [300 mg (1w), range: 185-295] and 476 ng/mL [(700 mg (2w), range: 323-580]. Accumulation was minimal. Conclusions: Once weekly or once every two weeks, high dose sunitinib is feasible and clinically efficacious in heavily pretreated pts with advanced solid tumors, while toxicity remains well manageable. Importantly, no accumulation was recorded and sunitinib exposure was significantly increased, compared to the universal, flat dose. Since increased sunitinib exposure has been correlated to improved outcome, we consider this alternative scheduling as promising strategy to produce enduring clinical benefit in a wider patient population. Expansion cohorts are ongoing. Clinical trial information: NCT02058901.

Preliminary safety and pharmacodynamic (PD) activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in a phase I dose escalation study of patients with selected advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15001-e15001
Author(s):  
Barbara Hickingbottom ◽  
Raphael Clynes ◽  
John Desjarlais ◽  
Caiyan Li ◽  
Ying Ding
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Clinical Symptoms ◽  
Standard Of Care ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Heavily Pretreated ◽  
Label Dose ◽  
Pretreated Patients

e15001 Background: Interim safety and PD data from an ongoing first-in-human, multi-center, open-label dose escalation study of XmAb20717 (XmAb20717-01; NCT03517488) are reported here. The primary objectives were to determine safety, tolerability, and the MTD and/or recommended doses (RDs). Secondary objectives included preliminary anti-tumor activity and PK/PD. Methods: A 3+3 dose escalation design was used to establish an MTD/RD(s) for infusions on Days 1 and 15 of each 28-day cycle. DLT evaluation was based on Cycle 1 through Day 28. Patients with selected solid tumors (in indications both with and without approved checkpoint therapy) who have exhausted standard of care are eligible. Results: As of 05FEB 2020, 34 patients were treated in cohorts 1-6 at fixed doses of 0.15 to 10 mg/kg. Patients had a median age of 57 years (range 32-81), a median time since initial diagnosis of 42 months (range 3 -313), and a median of 4 prior systemic therapies (range 0-9). 68% of patients had a TNM stage of III/IV, and 68% had been exposed to checkpoint therapy. XmAb20717 treatment was generally well tolerated through the highest dose cohort tested. Overall rates of Gr3/4 immune-related AEs occurred in 8 (24%) patients including elevations of transaminases 3 (9%), rash 2 (6%), lipase and amylase 1 (3%, without clinical symptoms or radiographic evidence of pancreatitis), lipase (alone) 1 (3%), pruritus 1 (3%), hyperglycaemia 1 (3%), arthritis 1 (3%) and colitis 1 (3%), all reversible. Responses were evaluated based on RECIST 1.1 criteria, and there was 1 CR reported (melanoma, progressed on prior pembrolizumab) at 10 mg/kg (highest dose level). Dose-dependent pharmacodynamic activity consistent with dual PD-1/CTLA-4 blockade was noted, namely a proliferative burst of both CD8 and CD4 T cells and induction of IFN-inducible chemokines (Table). Conclusions: XmAb20717 is generally safe and has demonstrated PD activity in heavily pretreated patients with selected advanced solid tumors. Dose escalation continues. Clinical trial information: NCT03517488 . [Table: see text]

scholarly journals A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors

2013 ◽  
Vol 15 (6) ◽  
Author(s):  
Clifford Hudis ◽  
Charles Swanton ◽  
Yelena Y Janjigian ◽  
Ray Lee ◽  
Stephanie Sutherland ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Akt Inhibitor ◽  
Her2 Positive ◽  
Phase 1 Study

scholarly journals A phase 1 study of the PI3Kδ inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL)

Blood ◽  
2014 ◽  
Vol 123 (22) ◽  
pp. 3398-3405 ◽  
Author(s):  
Brad S. Kahl ◽  
Stephen E. Spurgeon ◽  
Richard R. Furman ◽  
Ian W. Flinn ◽  
Steven E. Coutre ◽  
...  
Keyword(s):  
Clinical Study ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Key Points ◽  
Mantle Cell ◽  
Heavily Pretreated ◽  
Pretreated Patients

Key Points This clinical study assessed idelalisib, a selective PI3Kδ inhibitor, in 40 patients with relapsed/refractory MCL. In a dose-escalation trial in heavily pretreated patients, an overall response rate of 40% was observed with an acceptable safety profile.

Beyond the bevacizumab resistance, combined effects of erlotinib in heavily pretreated patients with recurrent ovarian cancers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16505-e16505
Author(s):  
Yoshihiro Kikuchi ◽  
Masashi Takano ◽  
Yuji Ikeda ◽  
Ryoko Kikuchi ◽  
Kazuya Kudoh ◽  
...  
Keyword(s):  
Growth Factor ◽  
Solid Tumors ◽  
Synergistic Effects ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Cytotoxic Agents ◽  
Ovarian Cancers ◽  
Heavily Pretreated ◽  
Pretreated Patients

e16505 Background: In heavily pretreated ovarian cancer patients, bevacizumab (B) combined with conventional chemotherapy has been reported to improve the response. However, responses to B are usually transient and resistance inevitably develops. The vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) are valid targets in many solid tumors, and their inhibitors have synergistic effects in preclinical studies. Methods: In 13 patients with heavily pretreated ovarian cancers, after development of B resistance erlotinib (E) (150 mg/day, 3 week, one week rest) and B (2 mg/kg/week, 3 week, one week rest) were administered with cytotoxic agents until development of disease progression or unmanageable adverse effects (AE). The primary endpoint in this study was response rate (RR) and progression-free survival (PFS). Results: Of 13 patients, 3 patients were not evaluable for response evaluation criteria in solid tumors (RECIST). Of 10 patients, 3 (30%) patients had partial responses (PR), 4 (40%) had stable diseases (SD), resulting in 70% clinical benefit rate (CBR). The PFS lasts more than 6 months in 4 (40%) patients. Although main AEs by E were rash, diarrhea and mucositis, all cases were manageable and tolerable. Conclusions: E administration after development of B resistance can reverse effects of B in 70% of heavily pretreated patients with recurrent ovarian cancers. AE of E was manageable and tolerable. These results warrant further studies in such clinical settings.

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 .

Sign in / Sign up

Export Citation Format

Share Document