NeoART – A phase Ib/II platform trial evaluating the safety and activity of neoadjuvant trastuzumab-deruxtecan containing combination therapies for HER2+, resectable esophagogastric adenocarcinoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06], Diseases [C] - Neoplasms [C04]

Trial duration

25 Mar 2025 → ongoing

Decision date (initial)

2025-06-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Daiichi-Sankyo

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To evaluate the feasibility and safety of different neoadjuvant T-DXd containing combinational treatment regimens in patients with HER2 positive, locally advanced, resectable esophagogastric adenocarcinoma (EGA)

Secondary objectives 2

1. To further evaluate the safety and tolerability of different neoadjuvant T-DXd containing combinational treatment regimens
2. To characterize the efficacy of different neoadjuvant trastuzumab-deruxtecan containing combinational treatment regimens

Conditions and MedDRA coding

HER2 positive resectable esophagogastric adenocarcinoma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Patient has given written informed consent
2. Patient is ≥ 18 years of age at time of signing the written informed consent
3. Patient has histologically proven locally advanced (cT2-4, any cN, M0 OR any cT, cN+, M0 stage) gastric, esophagogastric junction or lower esophageal adenocarcinoma that: a. Is considered technically resectable b. Does not involve distant site of the peritoneal cavity • confirmed by diagnostic laparoscopy for all patients with tumors located in the stomach and those with type 2 and 3 GEJ adenocarcinomas according to guideline recommendation [Lordick et al. 2022]. • Type 1 GEJ and lower esophageal tumors can be enrolled without diagnostic laparoscopy (which is in line with guidelines and the current routine practice in Germany)
4. Patient has a HER2 positive tumor (by local testing) defined by HER2 IHC 3+ or IHC 2+ plus ISH positive with a HER2:CEP17 ratio of ≥ 2 according to classically used criteria for defining HER2 positivity [Lordick et al. 2017] .
5. Patient has a ECOG performance status 0 or 1
6. Patient has adequate blood count, liver-enzymes, and renal function: a. ANC > 1,500 cells/μL without the use of hematopoietic growth factors b. Platelet count ≥ 100 x 109/L (>100,000 per mm3)** c. Hemoglobin ≥ 9 g/dL** d. Serum total bilirubin ≤ 1.5x institutional upper normal limit (ULN) e. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN f. Patients not receiving therapeutic anticoagulation must have an INR ≤ 1.5 ULN and aPTT ≤ 1.5 ULN. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least three weeks at the time of inclusion g. Serum Creatinine ≤ 1.5 x ULN and a calculated creatinine clearance rate ≥ 50 mL /min
7. Female patients defined as women of childbearing potential (WOCBP) must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for 6 months after last dose of chemotherapy or 7 months after the last dose of T-DXd, whatever is later.
8. Male patients with WOCBP partners must agree to remain abstinent (refrain from heterosexual intercourse) or use barrier contraceptive during the treatment period as well as up to 4 months after last dose of T-DXd or up to 6 months after last dose of chemotherapy, whatever is later. Male patients must refrain from donating sperm during this same period.

Exclusion criteria 22

1. Patient received previous (radio)chemotherapy or HER2-targeted therapy for the same condition or within the past five years for any other cancerous condition.
2. Patient received prior partial or complete esophagogastric tumor resection
3. Patient has known hypersensitivity to any component of the T-DXd formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein and/or any known contraindication (including hypersensitivity) to one of the study drugs.
4. Patient has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
5. Patient has lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within three months of the study enrolment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.).
6. Patient received a prior complete pneumonectomy
7. Patient has inadequate cardiac function (LVEF value < 50 %) as determined by echocardiography.
8. Patient has a known complete absence of dihydropyrimidine dehydrogenase (DPD) activity
9. Patient received treatment with brivudine, sorivudine or their chemically related analogues within 28 days prior to stud enrollment
10. Patients has pernicious anemia or other megaloblastic anemia due to vitamin B12 deficiency
11. Patient has peripheral sensitive neuropathy with functional deficits
12. Patient has a medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any MI related symptoms should have a cardiologic consultation during screening to rule out MI.
13. Patient has a corrected QT interval (QTc) prolongation to > 470 ms (females) or >450 ms (males) based on average of the screening triplicate12-lead ECG.
14. Patient has a history of malignancy other than EGA except for: a. Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study treatment and of low potential risk for recurrence. b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. c. Adequately treated carcinoma in situ without evidence of disease.
15. Patient has an uncontrolled infection requiring IV antibiotics, antivirals or antifungals
16. Patient has active primary immunodeficiency, known uncontrolled active HIV infection or active hepatitis B or C (HBV/HCV) infection. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. Subjects with past or resolved HBV infection are eligible only if they meet all of the following criteria*: • HBsAg(-) (for > 6 months off anti-viral treatment) • Anti-HBc(+) (IgG or total Ig) • HBV DNA undetectable • Absence of cirrhosis or fibrosis on prior imaging or biopsy • Absence of HCV co-infection or history of HCV co-infection • Access to a local hepatitis B expert during and after the study
17. Patient has any autoimmune, connective tissue or inflammatory disorders (e.g., Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) with a documented or suspected pulmonary involvement
18. Patient received live, attenuated vaccine within 30 days prior initiation of study drug
19. Patient has any other serious concomitant or medical condition that, in the opinion of the investigator, presents a high risk of complications to the patient or reduces the likelihood of clinical effect.
20. Patient participated in another interventional clinical study within 28 days prior to study enrollment or participation in a clinical study at the same time as this study, unless it is an observational/ non-interventional study or during the follow-up period of an interventional study.
21. Patient has taken an investigational drug within 28 days prior to initiation of study drug
22. Female patients, who are pregnant or breast feeding or planning to become pregnant within 7 months after the end of treatment. Female patients of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Feasibility rate, defined as proportion of patients receiving the protocol treatment according to the planned schedule before surgery without occurrence of at least one dose-limiting toxicity (DLT)

Secondary endpoints 4

1. Assessment of safety of the treatment as determined by the incidence, type, causality, frequency, timing and severity of adverse events using NCI CTCAE 5.0
2. Perioperative morbidity (Clavien-Dindo classification) and mortality
3. Pathological complete remission (pCR) rate by local assessment corresponding to the ypT0 ypN0 stage category
4. R0 resection rate

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Sponsor organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Address

Steinbacher Hohl 2-26, Praunheim Praunheim

City

Frankfurt Am Main

Postcode

60488

Country

Germany

Scientific contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial project manager

Public contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial project manager

Third parties 1

Locations

2 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 2 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 21 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications