A phase 1 multicenter, dose expansion study of ARX788 as monotherapy in patients with HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma (ACE-Gastric-01).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16059-e16059
Author(s):  
Yang Zhang ◽  
Miaozhen Qiu ◽  
Jufeng Wang ◽  
Yanqiao Zhang ◽  
Xianglin Yuan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Antibody Drug Conjugate ◽  
Her2 Positive

e16059 Background: ARX788 is a novel antibody drug conjugate (ADC) that consists of human epidermal growth factor receptor 2 (HER2) targeted monoclonal antibody (mAb) linked to a cytotoxic payload, AS269, a highly potent tubulin inhibitor. In a phase 1 study of ARX788 in HER2-positive advanced breast cancer (CTR20171162/ACE-Breast-01), the objective response rate (ORR) was 74 % (14/19) at 1.5 mg/kg Q3W. Here we present the safety, tolerability, and antitumor activity of ARX788 in HER2-positive advanced gastric and gastroesophageal junction (GEJ) cancer in the phase 1 (ACE-Gastric-01) study. Methods: participants with HER2+ gastric/GEJ cancer were administrated with ARX788 intravenously at dose levels of 1.3, 1.5, and 1.7 mg/kg Q3W to determine the maximum tolerated dose and recommended phase 2 dose; and to evaluate the antitumor activity. Efficacy endpoints included objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1. Results: As of Jan 29, 2021, a total of 23 participants including 9 at the 1.3 mg/kg and 14 at the 1.5 mg/kg received at least one dose of ARX788. All patients were heavily treated previously. The confirmed ORR was 42.9% and 46.2% at the 1.3 and 1.5 mg/kg, respectively. As of the cut-off date, six participants were still under treatment with two of them were treated for longer than 12 months. Most AEs were grade 1 or 2 and were manageable. There were 2 drug-related grade 3 AEs and no grade 4 or 5 AEs occurred. No DLT was observed and the MTD was not reached. The dose expansion at the 1.7 mg/kg Q3W cohort is still ongoing and the mature data will be presented later. Conclusions: ARX788 was well tolerated with promising antitumor activity in patients with HER2-positive advanced gastric and GEJ adenocarcinoma. Clinical trial information: CTR20190639. [Table: see text]

A phase II trial of [fam-] trastuzumab deruxtecan (T-DXd, DS-8201a) in subjects with HER2-positive, unresectable, or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS460-TPS460
Author(s):  
Charles S. Fuchs ◽  
Javad Shahidi ◽  
Lijoy Mathew ◽  
Amy Qin ◽  
Eric Van Cutsem
Keyword(s):  
Disease Progression ◽  
Topoisomerase I ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Her2 Status ◽  
Phase 2 ◽  
First Line ◽  
Antibody Drug Conjugate ◽  
Her2 Positive

TPS460 Background: Despite attempts, no HER2-directed therapies have been approved for gastric or GEJ cancer after disease progression on trastuzumab. [Fam-] trastuzumab deruxtecan (T-DXd, DS-8201a) is a novel HER2-targeted antibody-drug conjugate composed of a humanized monoclonal antibody specifically targeting HER2, a cleavable tetrapeptide-based linker (drug-to-antibody ratio of ≈8), and a potent topoisomerase I inhibitor payload. In a phase 1 study, T-DXd (5.4 or 6.4 mg/kg) showed promising antitumor activity in a variety of tumor types, including a confirmed objective response rate (ORR) of 43% among subjects with extensively pretreated HER2-positive gastric cancer (Shitara et al. Lancet Oncol. 2019;20(6):827-836). Here we describe the phase 2 trial evaluating the efficacy and safety of T-DXd in subjects with HER2-positive gastric/GEJ cancer previously treated with trastuzumab (NCT04014075). Methods: This is a single-arm, open-label, multicenter, phase 2 study in subjects with centrally confirmed, HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization positive), unresectable or metastatic gastric/GEJ cancer that progressed on or after first-line therapy with a trastuzumab-containing regimen. HER2 status will be confirmed by a fresh biopsy before enrollment. Subjects are excluded if they received anticancer therapy after a first-line trastuzumab-containing regimen. The study began in August 2019 and will recruit ≈ 72 subjects from 25 to 30 sites in North America and Europe. T-DXd at 6.4 mg/kg will be administered intravenously once every 3 weeks until disease progression. The primary efficacy endpoint is confirmed ORR by independent central review (ICR) using RECIST v1.1 criteria. Secondary endpoints include duration of response and progression-free survival by ICR and investigator assessment, ORR by investigator assessment, and overall survival. Additional endpoints include safety, disease control rate, and pharmacokinetic analyses. Health-related quality of life will also be measured. Clinical trial information: NCT04014075.

A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of solid tumors harboring specific HER2-activating mutations (DESTINY-PanTumor01).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3162-TPS3162
Author(s):  
Bob T. Li ◽  
Funda Meric-Bernstam ◽  
Soham D. Puvvada ◽  
Jacqui Rowbottom ◽  
Darren Jolliffe ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Objective Response Rate ◽  
Topoisomerase I ◽  
Response Rate ◽  
Phase 1 ◽  
Objective Response ◽  
Phase 2 ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Activating Mutations

TPS3162 Background: There are substantial data suggesting that a subset of human epidermal growth factor receptor 2 (HER2)–activating mutations induce ligand-independent constitutive HER2 signaling and promote oncogenesis. Direct therapeutic targeting of HER2 has transformed the treatment of patients with HER2-overexpressing breast and gastric cancers. However, currently no targeted treatments are approved for patients with tumors harboring HER2-activating mutations. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload that may be selectively internalized in tumors with HER2 mutations (Li BT, et al. Cancer Discov. 2020;10:674-687). In a phase 1 study (DS8201-A-J101), T-DXd demonstrated preliminary antitumor activity in patients with tumors harboring HER2 mutations, with confirmed responses observed in 9 of 19 patients (47.4%) (Tsurutani J, et al. Cancer Discov. 2020;10:688-701). Here we describe the DESTINY-PanTumor01 trial (NCT04639219). Methods: DESTINY-PanTumor01 is an open-label, multicenter, single-arm, phase 2 study evaluating T-DXd for the treatment of patients with unresectable and/or metastatic solid tumors (excluding non-small cell lung cancer) harboring prespecified HER2-activating mutations. Patients (N≈100) are required to have progressed following prior treatment for advanced or metastatic disease or have no satisfactory alternative treatment options. Prior HER2-targeting therapy is allowed. HER2 mutation status will be determined locally using next-generation sequencing or a validated nucleic acid–based methodology. The primary endpoint is confirmed objective response rate according to independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include duration of response, disease control rate, progression-free survival, investigator-assessed confirmed objective response rate, overall survival, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT04639219.

Phase Ib trial of docetaxel, prednisone, and pazopanib, in men with metastatic castration resistant prostate cancer (mCRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 275-275
Author(s):  
Daniel J. George ◽  
Susan Halabi ◽  
Patrick Healy ◽  
Sarah Gemberling ◽  
Carolyn Winters ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dose Escalation ◽  
Objective Response Rate ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Castration Resistant Prostate Cancer ◽  
Phase Ib

275 Background: Docetaxel prednisone (DP) is a standard of care for men with metastatic castrate resistant prostate cancer (mCRPC) with median progression-free survival (PFS) of 4-6 months and overall survival (OS) of 19 months, supporting a need for further treatment options. Pazopanib (PAZO) is a multi-targeted kinase inhibitor of VEGF receptors approved for treatment of kidney cancer and sarcoma. We performed a two center, Phase Ib study of DP + PAZO to evaluate the safety and early efficacy in mCRPC. Methods: This is a 2 site phase 1 DOD Prostate Cancer Clinical Trials Consortium trial of DP + PAZO once daily with ongoing ADT in men with mCRPC. The primary endpoint was safety; secondary endpoints included evaluation of a maximum tolerated dose (MTD) through a dose escalation and expansion design, pharmacokinetic assessments, PSA and radiographic responses, and toxicity. Results: Twenty-five men were treated over 6 dose levels using a 3+3 design. Pegfilgrastim (Neu) was added to the regimen after myelosuppression limited dose escalation. With Neu, our target MTD of D 75 mg/m2; P 10 mg QD and PAZO 800 mg QD was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. 17 patients had received prior Abi and/or Enza. The most common AEs were alopecia (86%), fatigue (69%), diarrhea (58%), and nausea (53%), and the most common Grade 3-5 SAEs were neutropenia (33%) and leukopenia (19%). Three deaths attributed to study treatment occurred: one from pneumonitis, one from respiratory failure, and one from intracranial hemorrhage. The proportion of 30%, 50% and 90 % PSA declines were 69%, 58% and 25%, respectively. The objective response rate was 31% (11/36). Median PFS was 18.6 months (95% CI: 6.5, 27.7) and OS was 22.2 months (95% CI: 14.7, -). Predicted median OS using the Halabi nomogram was 20.9 months (95% CI: 19.2, 23.0) with 23%, 34% and 43% of patients in low, intermediate and high risk groups, respectively. Conclusions: DP + PAZO (with Neu) were tolerable at full doses and demonstrated a surprisingly long PFS and high objective response rate in a relatively poor risk group of mCRPC patients. These data support further randomized studies of DP + Pazo in Abi/Enza refractory patients. Clinical trial information: NCT01385228.

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: A randomized, phase II, multicenter, open-label study (DESTINY-Gastric01).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4513-4513 ◽  
Author(s):  
Kohei Shitara ◽  
Yung-Jue Bang ◽  
Satoru Iwasa ◽  
Naotoshi Sugimoto ◽  
Min-hee Ryu ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Progression Free Survival ◽  
Her2 Status ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Open Label ◽  
Grade 3

4513 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor. In a phase 1 trial of T-DXd (5.4 or 6.4 mg/kg), the objective response rate (ORR) was 43.2% (19/44) and median progression-free survival (mPFS) was 5.6 mo in patients with advanced HER2+ gastric cancer (GC). DESTINY-Gastric01 (DS8201-A-J202; NCT03329690) is an open-label, multicenter, randomized, phase 2 study of T-DXd in HER2-expressing advanced GC or GEJ adenocarcinoma; results are from the primary analyses for ORR and interim overall survival (OS) in HER2+ patients. Methods: Patients with centrally confirmed HER2+ (IHC 3+ or IHC 2+/ISH+ on archival tissue) GC that progressed on ≥ 2 prior lines were randomized 2:1 (T-DXd 6.4 mg/kg q3w or physician’s choice [PC] irinotecan or paclitaxel). All patients received prior HER2 therapy. Stratification factors were region, ECOG PS (0;1), and HER2 status. The primary endpoint was unconfirmed ORR by independent central review. Secondary endpoints were OS (alpha controlled), PFS, disease control rate (DCR), duration of response (DOR), and safety. Results: 187 patients received T-DXd (n = 125) or PC (n = 62 [55 irinotecan; 7 paclitaxel]); 79.7% Japan, 20.3% Korea. Patients had a median of 2 prior lines of therapy, and 44.4% had ≥ 3. At data cutoff (8 Nov 2019), 22.4% of T-DXd and 4.8% of PC patients remained on treatment. ORR was 51.3% (61/119; 11 CR and 50 PR) with T-DXd vs 14.3% (8/56; all PR) with PC ( P < .0001); confirmed ORR, 42.9% vs 12.5% ( P < .0001); DCR, 85.7% vs 62.5% ( P = .0005); mDOR, 11.3 vs 3.9 mo; mPFS, 5.6 vs 3.5 mo (HR, 0.47 [95% CI, 0.31-0.71]; P = .0003). OS was significantly prolonged with T-DXd (mOS, 12.5 vs 8.4 mo; HR, 0.59 [95% CI, 0.39-0.88]; P = .0097; prespecified O'Brien Fleming boundary, P = .0202); 12-month OS, 52.1% vs 28.9%. Grade ≥ 3 AEs occurred in 85.6% of patients with T-DXd vs 56.5% with PC; the most common were neutrophil count decreased (51.2%; 24.2%), anemia (37.6%; 22.6%), and white blood cell count decreased (20.8%; 11.3%). 12 patients (9.6%) had T-DXd–related interstitial lung disease (ILD; 2 grade 3, 1 grade 4, no grade 5) vs 0 with PC. 1 drug-related death (pneumonia [non-ILD] in the T-DXd arm) occurred. Conclusions: T-DXd demonstrated statistically significant and clinically meaningful improvements in ORR and OS compared with standard chemotherapy (paclitaxel or irinotecan) in patients with HER2+ advanced gastric or GEJ adenocarcinoma. Clinical trial information: NCT03329690 .

Brentuximab vedotin for relapsed or refractory non-Hodgkin lymphoma: Preliminary results from a phase II study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8070-8070
Author(s):  
Ranjana Advani ◽  
Yasuhiro Oki ◽  
Andrei R. Shustov ◽  
Laurie E. Grove ◽  
Nancy Bartlett
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Objective Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
Non Hodgkin Lymphoma

8070 Background: Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL) after failure of other therapies. Based on the high objective response rate observed in patients with systemic ALCL, a type of non-Hodgkin lymphoma that is characterized by homogeneous CD30 expression, a study was initiated in other non-Hodgkin lymphomas that express the CD30 target. Methods: A phase 2 open-label single-arm study is underway in patients with relapsed or refractory CD30-positive non-Hodgkin lymphoma, excluding ALCL (NCT01421667). Brentuximab vedotin is administered IV at 1.8 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint is objective response rate assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Tumor specimens are assessed by central lab in order to characterize the relationship of CD30 expression with antitumor activity. Results: Ten patients (age range 28–83; 5 M, 5 F) have enrolled to date. Diagnoses include diffuse large B-cell lymphoma (DLBCL, n=2), EBV-positive DLBCL of the elderly (n=3), primary mediastinal B-cell lymphoma (n=2), peripheral T-cell lymphoma NOS (n=2), and angioimmunoblastic T-cell lymphoma (AITL). Patients had received 1–6 prior chemotherapy regimens; 3 patients had prior stem cell transplants. Of 6 patients who have completed the cycle 2 response assessment, 2 attained complete remission, 1 with DLBCL (90% CD30+) and 1 with AITL (8% CD30+), 1 had stable disease, and 3 had progressive disease. Treatment-related serious adverse events observed to date were rash, febrile neutropenia, and mastoiditis. Conclusions: Preliminary results suggest that brentuximab vedotin may have antitumor activity in patients with relapsed or refractory CD30-expressing non-Hodgkin lymphomas, in addition to the efficacy previously observed in systemic ALCL. Updated study results will be presented.

A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4509-4509 ◽  
Author(s):  
Xinan Sheng ◽  
Ai-Ping Zhou ◽  
Xin Yao ◽  
Yanxia Shi ◽  
Hong Luo ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Locally Advanced ◽  
Visceral Metastasis ◽  
Her2 Positive ◽  
Metastatic Urothelial Carcinoma

4509 Background: Urothelial carcinoma (UC) is the third largest cancer type with HER2 positive cancer. RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). This study was to evaluate the activity of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma (mUC). Methods: This study is an open-label, multicenter, single-arm, non-randomized phase II study. Eligibility criteria include: histologically confirmed UC, HER2-positive (IHC 2+ or 3+), ECOG PS 0-1, treated with ≥1 prior systemic treatment. The patients received RC48-ADC treatment alone (2 mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety was also assessed. Results: Patient enrollment for this study was completed in November 2018. A total of 43 patients were enrolled, with a median age of 64 years old. At baseline, most patients (37/43) had visceral metastasis. Fourteen (32.6%) patients had received ≥ 2 lines treatment and 8 (18.6%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 60.5% (95% CI: 44.4%, 75.0%) and the DCR was 90.7% (39/43). As of Jan 23, 2019, the median PFS for the overall study population was not yet reached, and the median PFS was 7.8 months (95% CI: 4.9, 10.7) for the 9 patients who started RC48-ADC prior to Jun 30, 2018. The ORR was 70.6% (12/17) in patients with HER2 FISH+ or IHC3+. The ORR was 64.9% (24/37) in patients with visceral metastasis and was 70.0% (14/20) in liver metastasis patients especially. The ORR was 64.3% in patients post to ≥ 2 lines treatment and 75.0% in patients post to immunotherapy. Common treatment-related AEs were leukopenia (51.2%), hypoesthesia (41.9%), alopecia (41.9%), neutropenia (37.2%), fatigue (34.9%), ALT increase (32.6%), and AST increase (32.6%); Most were Grade 1 or 2. Conclusions: RC48-ADC has demonstrated a clinically meaningful ORR of 60.5% in pretreated HER-2 positive mUC patients including those who underwent failure to the immunotherapy. Clinical trial information: NCT03507166.

Dose escalation and expansion from the phase I study of DS-1062, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), in patients (pts) with advanced non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9619-9619 ◽  
Author(s):  
Aaron Elliott Lisberg ◽  
Jacob Sands ◽  
Toshio Shimizu ◽  
Jonathan Greenberg ◽  
Penny Phillips ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Standard Treatment ◽  
Phase 1 ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Dose Effect ◽  
Antibody Drug Conjugate ◽  
Grade 3 ◽  
Experienced Grade

9619 Background: TROP2 is an intracellular calcium signaling transducer overexpressed in NSCLC, portending poor survival. DS-1062 is a TROP2-targeting ADC with a novel topoisomerase 1 inhibitor (exatecan derivative, DXd) and promising preclinical antitumor activity. Updated results inclusive of 24 additional dose escalation pts and 32 dose expansion pts from an ongoing phase 1 study of DS-1062 in advanced/metastatic NSCLC are reported (NCT03401385/J101). Methods: Pts aged ≥18 (US) or ≥20 (Japan) with unresectable NSCLC refractory to/relapsed from standard treatment with measurable disease (RECIST v1.1) and available tumor for retrospective TROP2 evaluation were eligible. Primary objectives include maximum tolerated dose (MTD) identification, safety, and tolerability and secondary objectives include efficacy, pharmacokinetics, and incidence of anti-drug antibodies against DS-1062. Pts were eligible regardless of TROP2 level. Results: As of November 16, 2019, 95 pts were treated with ≥1 dose of DS-1062. 63 pts were treated during escalation at 0.27 (n = 4), 0.5 (n = 5), 1.0 (n = 7), 2.0 (n = 6), 4.0 (n = 6), 6.0 (n = 19), 8.0 (n = 8), and 10.0 (n = 8) mg/kg and 32 pts were treated in expansion at the MTD of DS-1062, 8 mg/kg. 59 pts (62%) discontinued (25 [42%] due to progressive disease per RECIST v1.1). Pts were exposed to a median of 3 treatment cycles (range, 1-19). In 88 response-evaluable pts, 22 had partial response (1 PR/6 pts at 2.0 mg/kg, 2 PR/6 pts at 4.0 mg/kg, 5 PR/18 pts at 6.0 mg/kg, 13 PR/34 pts at 8.0 mg/kg, and 1 PR/8 pts at 10.0 mg/kg; 14 PRs were confirmed and 8 PRs are awaiting confirmation). Treatment emergent adverse events (TEAEs) regardless of causality were reported in 91 of 95 pts (96%; 44 pts [46%] experienced ≥grade 3, 30 pts [32%] had serious events). Treatment-related TEAES were reported in 76 of 95 pts (80%; 17 pts [18%] experienced ≥grade 3, 8 pts [8%]) had serious events). Potential interstitial lung disease (ILD) occurred in 8 pts (8%; 2 at 6.0 mg/kg and 6 at 8.0 mg/kg); 6/8 with potential ILDs adjudicated as treatment-related (1 at 6.0 mg/kg [grade 2] and 5 at 8.0 mg/kg [1 grade 1, 2 grade 2, 1 grade 3, and 1 grade 5]). 14 escalation pts and 22 expansion pts remain on trial. Updated trial details/results will be presented. Conclusions: In this first-in-human study of DS-1062, treatment was well tolerated up to 8 mg/kg, and a dose effect on antitumor activity was observed over 2.0-10.0 mg/kg in heavily pretreated pts with prior progression on standard treatment. Clinical trial information: NCT03401385 .

KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer (mG/GEJc): A double-blind, randomized, placebo-controlled phase III study.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS463-TPS463
Author(s):  
Hyun Cheol Chung ◽  
Yung-Jue Bang ◽  
Charles S. Fuchs ◽  
Shukui Qin ◽  
Taroh Satoh ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Objective Response Rate ◽  
Cell Activation ◽  
Response Rate ◽  
Performance Status ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Phase Iii ◽  
Double Blind ◽  
End Points

TPS463 Background: Combination therapy with the anti-HER2 antibody trastuzumab plus fluoropyrimidine and platinum is the current standard of care for patients with HER2+ mG/GEJc. We hypothesize that combination anti–PD-1 and anti-HER2 therapy will result in T-cell activation, augment antibody-dependent, cell-mediated cytotoxicity, and potentiate antitumor immune response in HER2+ patients. A phase 2 study in HER2+ mG/GEJc demonstrated the safety and preliminary efficacy of trastuzumab/pembrolizumab/chemotherapy; the objective response rate was 87%, and the disease control rate was 100% (Janjigian YY, ASCO GI 2019). KEYNOTE-811 (ClinicalTrials.gov, NCT03615326), a global, multicenter, randomized, placebo-controlled, phase 3 study, is underway. Methods: Key eligibility criteria are age ≥18 years; previously untreated unresectable or metastatic HER2+ (centrally confirmed IHC 3+ or IHC 2+/ISH > 2.0) G/GEJ cancer; life expectancy > 6 months with RECIST v1.1 measurable disease; and adequate organ function and performance status (ECOG PS of 0 or 1). Patients will be randomly assigned 1:1 to receive chemotherapy with pembrolizumab 200 mg intravenously (IV) or placebo with trastuzumab 6 mg/kg (after 8 mg/kg load) every 3 weeks (Q3W) up to 2 years or until intolerable toxicity or disease progression. Investigator-choice chemotherapy will include day 1 cisplatin 80 mg/m2 IV and 5-fluorouracil 800 mg/m2/day IV (days 1-5) or oxaliplatin 130 mg/m2 IV and capecitabine 1000 mg/m2 BID days 1-14 (Q3W). Primary end points are progression-free survival and overall survival. Secondary end points are objective response rate, duration of response, and safety and tolerability. Adverse events are graded per CTCAE v4.0 and will be monitored for 30 or 90 days after treatment. Patients will be followed up for survival. Planned enrollment is approximately 692 patients. Clinical trial information: NCT03615326.

Uplift (ENGOT-ov67): A pivotal cohort to evaluate XMT-1536 (upifitamab rilsodotin), a NaPi2b-directed antibody drug conjugate for platinum-resistant ovarian cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5607-TPS5607
Author(s):  
Debra L. Richardson ◽  
Erika P. Hamilton ◽  
Ana Oaknin ◽  
Leslie M. Randall ◽  
Susana N. Banerjee ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Advanced Ovarian Cancer ◽  
Primary Objective ◽  
Antibody Drug Conjugate ◽  
Regulatory Review ◽  
Platinum Resistant

TPS5607 Background: XMT-1536 (upifitamab rilsodotin), is a first-in-class Dolaflexin ADC targeting NaPi2b, a sodium-dependent phosphate transport protein, broadly expressed in solid tumors such as serous epithelial ovarian cancer (OC) and non-small cell lung adenocarcinoma. XMT-1536 uses the Dolaflexin platform to deliver approximately 10 DolaLock auristatin payload molecules per antibody and is being evaluated in a Phase I study (NCT03319628). Observation of preliminary antitumor activity was reported in the ovarian cancer expansion cohort, including in patients previously treated with bevacizumab and PARPi (Tolcher et al, ASCO 2019; Richardson et al, ASCO 2019; Hamilton et al, ESMO 2020). Updated data on the OC cohort included 31 patients with higher NaPi2b expression as of December 2020 (Mersana Therapeutics, 2021). In these patients, the ORR was 32% and the DCR was 74%. Complete responses were observed in 2 patients with platinum-resistant ovarian cancer, both of whom had received prior treatment with bevacizumab and PARP inhibitors. Platinum resistant ovarian cancer remains a serious unmet medical need as treatment options are limited and response rates to these treatments are low. Based on the favorable safety and efficacy profile of XMT-1536, UPLIFT was designed as a Phase 2 single-arm registrational cohort of patients with platinum resistant ovarian cancer as part of the ongoing Phase I FIH dose escalation and expansion study to accelerate development and provide a streamlined pathway to regulatory review. Methods: The UPLIFT cohort is enrolling patients with platinum resistant high grade serous ovarian, fallopian tube and primary peritoneal cancer with up to 4 prior lines of therapy. The RP2D of XMT-1536 was determined to be 43 mg/m2 administered intravenously every 4 weeks (q4w) and will be the dose evaluated in the UPLIFT cohort. UPLIFT will enroll approximately 180 patients with platinum-resistant advanced ovarian cancer to obtain approximately 100 patients with higher NaPi2b expression. Prior bevacizumab is required for those patients with 1 or 2 prior lines of therapy. Tumor samples (fresh or archived) will be collected prior to enrollment for retrospective tumor tissue evaluation of NaPi2b expression. The primary objective is assessment of confirmed objective response rate to XMT-1536 as assessed by Investigator in patients with higher NaPi2b expression. Secondary endpoints include confirmed objective response rate regardless of NaPi2b expression, duration of response, and adverse events. Correlative aims include assessing blood and tissue biomarkers for association with clinical benefit. This study is being conducted in collaboration with ENGOT and GOG. Patients will be enrolled globally. Clinical trial information: NCT03319628.

A phase I study of MM-121 in combination with multiple anticancer therapies in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2609-2609 ◽  
Author(s):  
Monica Arnedos ◽  
Crystal Shereen Denlinger ◽  
Wael A. Harb ◽  
Olivier Rixe ◽  
John Charles Morris ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Clinical Benefit ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Clinical Benefit Rate

2609 Background: MM-121 is a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3. ErbB3 has been implicated in driving cancer growth and in the development of resistance to conventional chemotherapies across multiple malignancies. Here we present results of an open-label, Phase 1, multicenter, non-randomized, dose-escalation trial which recently completed enrollment evaluating MM-121 in combination with one of the following chemotherapies: Gemcitabine (Arm A, n=11), carboplatin (Arm B, n=11), pemetrexed (Arm C, n=10), or cabazitaxel (Arm D, n=11). Methods: Patients were treated in a dose escalation “3+3” design to assess the safety, tolerability and pharmacokinetics (PK) of MM-121 administered weekly in combination with anticancer therapies in subjects with advanced cancer. Doses were escalated until the maximum tolerated dose (MTD) was identified or the combination was shown to be tolerable at the highest planned doses. Secondary objectives included: Determining the objective response rate, clinical benefit rate, PK and immunogenicity of MM-121. Data summarized are as of 1/17/2013 from a live database. Results: Overall, 43 patients, [22 (51%) female and 21 (49%) male] have been treated with a median treatment duration of 57 days (range 1-302). The median age was 59 years (range 42-84) and patients had received a median of four prior lines of therapy (range 0-13). Common (>20%) adverse events of any grade and causality across all arms included diarrhea (74%), nausea (54%), fatigue (51%), anemia (44%), vomiting (33%), hypokalemia (30%), decreased appetite (26%), thrombocytopenia (26%), peripheral edema (23%), neutropenia (21%), and constipation (21%). Four DLTs were observed: Two in combination with carboplatin (G4 thrombocytopenia and G3 rash), one with gemcitabine (G4 thrombocytopenia), and one with pemetrexed (G4 hyperuricemia). Overall 38 (88%) patients were evaluable for response and the overall clinical benefit rate (PR or SD >18 weeks), is 32% (12/38). Conclusions: MM-121 can be combined at its recommended single agent dose with standard doses of gemcitabine, pemetrexed, and cabazitaxel and adapted doses of carboplatin. Clinical trial information: NCT01447225.

Sign in / Sign up

Export Citation Format

Share Document