Whole body HER3 quantification with radiolabelled Patritumab deruxtecan (HER3-DXd) PET/CT

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23], Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

3 Mar 2025 → ongoing

Decision date (initial)

2024-07-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-508233-14-00

ClinicalTrials.gov

NCT06222489

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response

- Identification of the optimal non-radiolabeled patritumab deruxtecan dose to be co-injected with 89Zr-Patritumab deruxtecan to allow optimal 89Zr-Patritumab deruxtecan PET imaging. The optimal imaging dose for 89Zr-Patritumab deruxtecan PET imaging is defined as the dose in milligrams of non-radiolabeled patritumab deruxtecan in which the circulation is adequately visualized at day 3 or day 6 post tracer injection, according to a dedicated nuclear medicine physician. Up to three cohorts of 2-3 patients each will be imaged with increasing amounts of non-radiolabeled patritumab deruxtecan per cohort. If results are inconsistent for the first two patients in a cohort, a third patient will be added to this cohort.
- Quantify tumor 89Zr-Patritumab deruxtecan uptake (visually and quantitatively, expressed as the standardized uptake value, SUV).

Secondary objectives 5

1. Correlate 89Zr-Patritumab deruxtecan tumor uptake with tumor HER3 expression (IHC and RNAseq)
2. Correlate 89Zr-Patritumab deruxtecan tumor uptake to patritumab deruxtecan treatment outcome (confirmed response according to the response evaluation criteria in solid tumors, RECIST version 1.1)
3. Characterize 89Zr-Patritumab deruxtecan tumor uptake heterogeneity between patients and within and between tumor lesions of the same patient
4. Assess organ uptake of 89Zr-Patritumab deruxtecan to evaluate drug biodistribution
5. Correlate 89Zr-Patritumab deruxtecan organ uptake with adverse events

Conditions and MedDRA coding

EGFR mutation positive advanced stage NSCLC

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Provision of informed consent prior to any study specific procedures.
2. Have a histologically or cytologically confirmed diagnosis of (locally) advanced stage EGFR mutation positive NSCLC, not amenable for curative intent treatment.
3. Have measurable disease according to RECIST 1.1.
4. At least two lesions with a long axis diameter ≥2 cm.
5. Have received at least one line of EGFR TKI treatment for (locally) advanced stage NSCLC.
6. In case the tumor is positive for T790M mutation, prior treatment with a third generation EGFR TKI is mandatory.
7. Patients must be ≥18 years of age.
8. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 at the time of Screening.
9. Has adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to Cycle 1, defined as: Platelet count ≥100 000/mm3 or ≥100 × 109/L (platelet transfusions are not allowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility), Hemoglobin (Hgb) ≥9.0 g/dL or 5.6 mmol/L (transfusion and/or growth factor support is allowed), Absolute neutrophil count (ANC) ≥1500/mm3 or ≥1.5 × 109/L, Creatinine clearance (CrCl) ≥30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl, Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤3 × ULN (if liver metastases are present, ≤5 ×ULN), Total bilirubin (TBL) ≤1.5 × ULN if no liver metastases (<3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or liver metastases), Alkaline Phosphatase (ALP) and Gamma Glutamyl Transferase (GGT) ≤2.5 x ULN for both ALP and GGT. Exceptions: ALP elevations ≤ 5 x ULN is allowed if confirmed to be of non-hepatic origin using GGT, fractionated alkaline phosphatase or 5’ nucleotidase test. Elevated GGT ≤ 5 x ULN is allowed in the absence of ALP elevation if ALT, AST and TBL meet inclusion criteria, Serum albumin ≥2.5 g/dL or 25 g/L, Prothrombin time (PT) or Prothrombin time- international normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT) ≤1.5 × (ULN), except for subjects on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator.
10. Be willing to provide a tumor tissue specimen. A pretreatment tumor biopsy or archival tumor tissue (when available and obtained after the first line of therapy) is required. Samples must be of sufficient quantity and of adequate tumor tissue content. A Baseline pretreatment tumor biopsy must be of the primary (if intact) and/or metastatic lesion(s) not previously irradiated and amenable to core biopsy. Any serious adverse event (SAE) directly related to the new biopsy should be reported as outlined in Section 8.
11. Female patients of reproductive/childbearing potential must have a negative pregnancy test (serum test within 14 days or urine test within 72 hours of enrollment). A positive urine pregnancy test result must be confirmed by a serum test. Patients must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 months after the last dose of study drug. Methods considered as highly effective contraception include: a. Hormonal or nonhormonal intrauterine device (IUD); b. Progestogen-only subdermal contraceptive implant; c. Bilateral tubal occlusion; d. Vasectomized partner; e. Complete sexual abstinence defined as refraining from heterosexual intercourse during and upon completion of the study and for at least 7 months for females after the last dose of study drug. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception. Penile/external condoms for male partners must be used in addition to the female patient’s hormonal contraception for the duration treatment intervention and until 7 months following the last dose of trial intervention. A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy) with surgery at least 1 month before the first dose or confirmed by follicle stimulating hormone (FSH) test.
12. Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration.
13. A male participant capable of producing sperm is eligible to participate if he agrees to the following during the intervention period and for at least the time needed to eliminate each trial intervention. The length of time required to continue contraception after last dose for each trial intervention is 4 months. Avoid donating sperm. Note: Preservation of sperm should be considered prior to enrollment/randomization in this trial. Use a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential, PLUS partner use of an additional contraceptive method (see below), as a condom may break or leak: a. Progestogen-only contraceptive implant; b. Hormonal or nonhormonal IUD; c. Bilateral tubal occlusion (includes tubal ligation); d. Combined (estrogen- and progestogen-containing) hormonal contraception (oral, intravaginal, transdermal, injectable); e. Progestogen-only hormonal contraception (oral, injectable); f. Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action; g. Cervical cap, diaphragm, or sponge with spermicide. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the trial interventions are more stringent than the requirements above, the local label requirements are to be followed. Note: If the participant is azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview), no contraception is required.
14. Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and for at least 4 months after the final study drug administration.

Exclusion criteria 19

1. Any history of interstitial lung disease (ILD) (including pulmonary fibrosis or radiation pneumonitis), has current ILD, or is suspected to have such disease by imaging during screening.
2. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, grade ≤1 or baseline. Subjects with chronic Grade 2 toxicities may be enrolled at the discretion of the Investigator after consultation with the Sponsor Medical Monitor or designee.
3. Has known hypersensitivity to either the drug substances or inactive ingredients in the drug product.
4. Has any primary malignancy other than locally advanced or metastatic NSCLC within 3 years prior to Cycle 1 Day 1, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated.
5. Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1, including: a. QT interval corrected by Fridericia's formula (QTcF) prolongation interval of >470 ms for females and >450 ms for males. b. Left ventricular ejection fraction (LVEF) <50% by either echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan. c. Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg. d. Myocardial infarction within 6 months. e. New York Heart Association (NYHA) Classes 2 to 4 within 28 days. f. Uncontrolled angina pectoris within 6 months. g. Cardiac arrhythmia requiring antiarrhythmic treatment.
6. Has active or uncontrolled hepatitis B virus infection Participants are eligible: Are HBsAg positive with chronic HBV infection (lasting 6 months or longer) and meet conditions below: HBV DNA viral load <2000 IU/mL Start or maintain antiviral treatment if clinically indicated as per the investigator. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST/ALT <3 × ULN, which are not attributable to HBV infection.
7. Has active or uncontrolled hepatitis C virus infection. Participants are eligible if: a. History of hepatitis C infection eligible if the HCV viral load is below the level of detection in the absence of antiviral therapy during the previous 4 weeks; b. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST/ALT < 3 × ULN, which are not attributable to HCV infection
8. Female subject who is pregnant or breastfeeding or intends to become pregnant during the study.
9. Has active or uncontrolled HIV infection. Participants must be tested for HIV viral load during the Screening Period if acceptable by local regulations or IRBs/IECs. Participants are eligible if: a. CD4+ T-cell count ≥350 cells/mm3 at the time of screening; b. Virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) at the time of screening and for at least 12 weeks before screening; c. No AIDS-defining opportunistic infections or conditions within the past 12 month; d. On stable ART regimen, without changes in drugs or dose modification, for at least 4 weeks before trial entry (Day 1) and agree to continue ART throughout the trial.
10. Prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s judgment, could affect the safety of the subject; alter the absorption, distribution, metabolism or excretion of the study drug; or confound the assessment of study results.
11. Clinically severe pulmonary compromise (based on investigator’s assessment) resulting from intercurrent pulmonary illnesses including, but not limited to: a. any underlying pulmonary disorder (eg, pulmonary emboli, severe asthma, severe chronic obstructive lung disease (COPD), restrictive lung disease, pleural effusion); b. any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis); OR prior pneumonectomy.
12. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent or any form of immunosuppressive therapy prior to Cycle 1 Day 1. Subjects who require use of bronchodilators, inhaled steroids, or local steroid injections may be included in the study.
13. Evidence of any leptomeningeal disease.
14. Has clinically significant corneal disease.
15. Any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses, active infection, psychiatric illness/social situations, geographical factors, substance abuse, or other factors which in the Investigator’s opinion makes it undesirable for the subject to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required.
16. Evidence of clinically active spinal cord compression or brain metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study. Subjects must have a stable neurologic status for at least 2 weeks prior to Cycle 1 Day 1.
17. Inadequate washout period prior to Cycle 1 Day 1, defined as: a. Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7 days. b. Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI)), <14 days or 5 half-lives, whichever is longer. c. Monoclonal antibodies other than immune checkpoint inhibitors, such as bevacizumab (anti-VEGF) and cetuximab (anti-EGFR) <28 days. d. Immune checkpoint inhibitor therapy < 21 days. e. Major surgery (excluding placement of vascular access) < 28 days. f. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation < 28 days or palliative radiation therapy < 14 days. g. Chloroquine or hydroxychloroquine ≤ 14 days.
18. Prior treatment with an HER3 antibody and/or antibody drug conjugate (ADC) that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, trastuzumab deruxtecan).
19. Live or live attenuated virus vaccination 28 days prior to Cycle 1 Day 1.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The optimal imaging dose patritumab deruxtecan to co-inject with 89Zr-Patritumab deruxtecan (HER3-DXd), defined by adequate visualisation of the circulation five days after tracer injection.

Secondary endpoints 1

1. SUV of tumor lesions.

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Joop de Langen

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Joop de Langen

Locations

1 EU/EEA country · 1 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

Serious breaches 2 · Art. 52 CTR

Results and documents

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

Documents 8 files

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

Application history

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