Neratinib + TDxD for Esophageal and Stomach Cancer
Recruiting in Palo Alto (17 mi)
+2 other locations
Overseen byNamrata Vijavergia, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Namrata Vijayvergia
Must not be taking: Strong inhibitors, Strong inducers
Disqualifiers: Untreated brain metastases, Ongoing diarrhea, Interstitial lung disease, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This trial is testing a combination of two drugs, Neratinib and TDxD, in patients with advanced stomach cancer that overexpresses HER2. These patients have not responded to previous treatments. The drugs work by blocking cancer growth and directly killing cancer cells.
Do I need to stop my current medications for the trial?
The trial protocol does not specify if you need to stop all current medications, but you cannot take any medications that strongly affect Neratinib or TDxD. It's best to discuss your current medications with the trial team.
What data supports the effectiveness of the drug Neratinib + TDxD for esophageal and stomach cancer?
Trastuzumab deruxtecan (part of the treatment) has been shown to be effective in improving response and overall survival in patients with advanced HER2-positive gastric or gastroesophageal junction cancer, as demonstrated in the DESTINY-Gastric01 and DESTINY-Gastric02 trials.
12345Is the combination of Neratinib and TDxD safe for treating esophageal and stomach cancer?
Fam-Trastuzumab Deruxtecan-nxki (TDxD) has been used in treating various cancers and has shown some serious side effects like lung disease, low white blood cell count, and heart problems. Common side effects include nausea, fatigue, and hair loss. While these safety concerns are noted in other conditions, they may still be relevant for esophageal and stomach cancer.
14678What makes the drug Neratinib + TDxD unique for esophageal and stomach cancer?
Neratinib + TDxD is unique because it combines two drugs: Neratinib, which blocks signals that help cancer cells grow, and TDxD, an antibody-drug conjugate that targets and delivers chemotherapy directly to HER2-positive cancer cells. This combination targets HER2, a protein that can promote the growth of cancer cells, and is being explored for its effectiveness in treating esophageal and stomach cancers, which have limited treatment options.
145910Eligibility Criteria
This trial is for adults over 18 with advanced gastro-esophageal cancer that's HER2-overexpressing and has worsened despite previous chemotherapy and HER2 therapy. Participants need good blood counts, organ function, no severe heart issues or uncontrolled illnesses, not pregnant or breastfeeding, willing to use contraception, and able to take oral meds.Inclusion Criteria
Hemoglobin > 9 gm/dl
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
Age > 18 years
+16 more
Exclusion Criteria
Has a QT interval corrected by Fridericia's formula (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male subjects) based on average of the Screening triplicate12-lead ECG
Patients may not be receiving any other investigational agents for advanced cancer and must not have received prior treatment with TDxD
Patients with known untreated brain metastases are excluded from this study because of their poor prognosis and frequent development of neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Treated brain metastases are allowed (requires stability on MRI at least 4 weeks after initial treatment). Patients with treated brain metastases are allowed to be treated with steroid and/or anti-convulsants if the dose remains stable or decreases over the last 4 weeks prior to C1D1
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Neratinib oral daily days 1-21 plus TDxD on day 1 administered intravenously of a 21-day treatment cycle
21 days per cycle
1 visit per cycle (in-person)
Dose Limiting Toxicity (DLT) Assessment
Assessment of dose-limiting toxicities to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D)
28 days
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 weeks
1 visit every 12 weeks (in-person)
Participant Groups
The study tests the combination of Neratinib (a pill) with Fam-Trastuzumab Deruxtecan-Nxki (TDxD) in a Phase 1 trial to find safe dosages. It uses a '3+3' method where small groups are given increasing doses until the maximum tolerated dose is found for patients who've had prior treatments fail.
1Treatment groups
Experimental Treatment
Group I: Neratinib plus TDxDExperimental Treatment2 Interventions
Neratinib oral daily days 1-21 plus TDxD on day 1 administered intravenously of a 21 day treatment cycle.
Fam-Trastuzumab Deruxtecan-Nxki (TDxD) is already approved in United States, European Union, Japan for the following indications:
🇺🇸 Approved in United States as Enhertu for:
- Metastatic breast cancer
- Gastric adenocarcinoma
- Gastroesophageal junction adenocarcinoma
🇪🇺 Approved in European Union as Enhertu for:
- Metastatic breast cancer
- Gastric adenocarcinoma
🇯🇵 Approved in Japan as Enhertu for:
- Metastatic breast cancer
- Gastric adenocarcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Fox Chase Cancer CenterPhiladelphia, PA
Stanford Cancer CenterPalo Alto, CA
Roswell Park Comprehensive Cancer CenterBuffalo, NY
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Who Is Running the Clinical Trial?
Namrata VijayvergiaLead Sponsor
Fox Chase Cancer CenterLead Sponsor
National Comprehensive Cancer NetworkCollaborator
Puma Biotechnology, Inc.Industry Sponsor
References
Trastuzumab Deruxtecan in Anti-Human Epidermal Growth Factor Receptor 2 Treatment-Naive Patients With Human Epidermal Growth Factor Receptor 2-Low Gastric or Gastroesophageal Junction Adenocarcinoma: Exploratory Cohort Results in a Phase II Trial. [2023]To investigate efficacy and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-low gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Trastuzumab Deruxtecan: A Review in Gastric or Gastro-Oesophageal Junction Adenocarcinoma. [2023]Trastuzumab deruxtecan (Enhertu®) is a human epidermal growth factor receptor type 2 (HER2)-directed antibody-drug conjugate that is approved in several countries globally for adults with advanced HER2-positive gastric or gastro-oesophageal junction (GOJ) adenocarcinoma who have received a prior trastuzumab-based regime. In the phase II DESTINY-Gastric01 trial, intravenous trastuzumab deruxtecan was significantly more effective than standard chemotherapy (physician's choice of intravenous irinotecan or paclitaxel) in achieving objective response and improving overall survival in Japanese or South Korean adults with advanced HER2-positive gastric or GOJ adenocarcinoma who had received two or more previous therapies. In the phase II DESTINY-Gastric02 trial, trastuzumab deruxtecan was able to induce durable response in adults from the USA or Europe with unresectable or metastatic HER2-positive gastric or GOJ adenocarcinoma. Trastuzumab deruxtecan was generally tolerable in these patients; the most common adverse events included nausea, neutropenia, fatigue and decreased appetite. Trastuzumab deruxtecan carries regulatory warnings (including boxed warnings in the USA) for interstitial lung disease/pneumonitis and embryo-foetal toxicity. Current evidence indicates that trastuzumab deruxtecan is an effective treatment option, and is generally tolerable, in previously treated adults with advanced HER2-positive gastric or GOJ adenocarcinoma.
Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. [2023]Approximately 15-20% of advanced gastric and gastro-oesophageal junction cancers overexpress HER2. In DESTINY-Gastric01, the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan improved response and overall survival versus chemotherapy in patients from Japan and South Korea with locally advanced or metastatic HER2-positive gastric or gastro-oesophageal junction cancer whose disease progressed after two lines of previous therapy including trastuzumab. Here, we report primary and updated analyses of the single-arm, phase 2 DESTINY-Gastric02 trial, which aimed to examine trastuzumab deruxtecan in patients living in the USA and Europe.
US Food and Drug Administration Approval Summary: Fam-Trastuzumab Deruxtecan-nxki for Human Epidermal Growth Factor Receptor 2-Low Unresectable or Metastatic Breast Cancer. [2023]The US Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd) for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry 1 + or immunohistochemistry 2+/in situ hybridization-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.
Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study. [2023]Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that consists of an anti-human epidermal growth factor receptor 2 (HER2) antibody bound by a cleavable tetrapeptide-based linker to a cytotoxic topoisomerase I inhibitor. Prior to marketing approval in Japan in September 2020, this expanded-access study was conducted to provide T-DXd to previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas.
FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. [2022]On December 20, 2019, the FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki [DS-8201a; T-DXd; tradename ENHERTU (Daiichi Sankyo)] for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. Approval was based on data from study DS8201-A-U201 (DESTINY-Breast01) with supportive safety data from study DS8201-A-J101. The primary efficacy endpoint in DESTINY-Breast01 was overall response rate (ORR) based on confirmed responses by blinded independent central review (ICR) using RECIST v1.1 in all participants who were assigned to receive the recommended dose of 5.4 mg/kg while secondary endpoints included duration of response (DoR). The confirmed ORR based on ICR in these 184 patients was 60.3% [95% confidence interval (CI): 52.9-67.4] and the median DoR was 14.8 months (95% CI: 13.8-16.9). Interstitial lung disease, including pneumonitis, was experienced in patients treated with T-DXd and can be severe, life threatening, or fatal. In addition, neutropenia and left ventricular dysfunction were included as Warnings and Precautions in labeling. Other important common adverse reactions were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, diarrhea, and thrombocytopenia. Overall, the totality of efficacy and safety data supported the accelerated approval of T-DXd for the intended indication.
Trastuzumab deruxtecan for the treatment of HER2-positive gastric cancer. [2022]Introduction: Trastuzumab deruxtecan (T-DXd) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate with a humanized anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. The phase II trial DESTINY-Gastric01 has demonstrated that T-DXd exhibits antitumor activity in patients with HER2-positive advanced gastric cancer (AGC) who had received at least two previous therapies, including trastuzumab.Area covered: T-DXd was approved for previously treated HER2-positive AGC in Japan. The US Food and Drug Administration also approved on 15 January 2021. In this article, we review the development of T-DXd, its pharmacology, and its safety profile in patients with HER2-positive AGC.Expert opinion: T-DXd has demonstrated a significantly higher objective response rate and a longer overall survival in HER2-positive AGC patients with two or more previous lines of systemic chemotherapy, including trastuzumab. Safety profile was acceptable. Currently, there are several ongoing clinical trials of T-DXd in combination with cytotoxic chemotherapy or an immune checkpoint inhibitor.
A Review of Fam-Trastuzumab Deruxtecan-nxki in HER2-Positive Breast Cancer. [2021]To review the pharmacology, efficacy, and safety of antibody-drug conjugate fam-trastuzumab deruxtecan-nxki in the treatment of advanced, unresectable, or metastatic breast cancer.
Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond. [2022]Despite the substantial improvements made in human epidermal growth factor receptor 2 (HER2)-targeted therapies since the approval of trastuzumab more than 20 years ago, there is still considerable unmet need in patients with HER2-expressing breast cancer (BC) and other solid tumors. Trastuzumab deruxtecan (T-DXd) is a newer antibody-drug conjugate approved for the treatment of metastatic breast cancer (BC) and gastric cancer (GC) and is under active investigation in other solid tumors, including non-small cell lung cancer, colorectal cancer, and HER2-low tumors.
Exploring DESTINY: the Past, Present, and Future of Trastuzumab Deruxtecan. [2023]HER2-positive breast cancer accounts for 10-15% of all breast cancers and fam-trastuzumab deruxtecan (T-DXd) has played a major role in moving the treatment of HER2-expressing disease forward.