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Trial Overview

Dareon®-5 Part 2 is an expansion cohort of the Dareon®-5 trial enrolling patients with epNEC with DLL3 high expressing tumours who have progression or recurrence following at least one platinum-based regimen. Patients will be treated with the DLL3/CD3 T-cell engager obrixtamig at the selected target dose determined from the dose selection part of the Dareon®-5 trial (Part 1). This is an interventional phase II, multi-center, open-label, single arm trial.

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Trial Objective

The objectives of Part 2 are to evaluate the safety, tolerability and efficacy of obrixtamig monotherapy at the selected target dose.

The primary objective is to assess the anti-tumour activity of obrixtamig monotherapy at the selected dose adult patients with locally advanced or metastatic extrapulmonary neuroendocrine carcinoma (epNEC) whose tumours have DLL3 high expression, using objective response rate (ORR) according to RECIST v 1.1 as assessed by blinded independent central review.

The secondary objectives are to estimate median duration of response (mDOR) by blinded independent central review (BICR), proportion of patients with disease control (DCR) by blinded independent central review, median progression-free survival (PFS) by blinded independent central review and median overall survival (OS). Additional secondary objectives are to evaluate tolerability and safety (by incidence of treatment-emergent adverse events) and the assessment of patient-reported outcomes (PROs).

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Trial Duration

All patients will be treated until disease progression (PD) or until another reason requiring termination of treatment (e.g. undue toxicity, patient decision). Following PD, a patient may continue to receive treatment if based on the investigator’s medical judgement the patient is deriving clinical benefit. Treatment duration should not exceed 36 months.

Key Eligibility Criteria

Patients in the Dareon®-5 trial must be 18 years of age or older with:

  1. Histologically or cytologically confirmed epNEC (except Merkel cell carcinoma, Medullary thyroid cancer and Neuroendocrine prostate cancer) with centrally assessed DLL3 high expression status.

  2. Patients must have progressed or recurred after at least one platinum-based regimen.

  3. ECOG PS 0–1.

  4. ≥1 measurable lesion as defined per RECIST v1.1 within 21 days prior to the first dose of obrixtamig.

  5. Availability of archival formalin-fixed, paraffin-embedded tumour tissue samples (fine needle aspiration, cytology samples, and decalcified bone samples are not allowed).

  6. Adequate organ function.

  7. All toxicities related to previous anti-cancer therapies have resolved ≤ CTCAE Grade 1 prior to trial treatment administration (except for alopecia, peripheral neuropathy, fatigue and endocrinopathies controlled by replacement therapy which must be ≤ CTCAE Grade 2 and amenorrhea/menstrual disorders which can be any grade).

  8. Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use suitable methods of birth control.

Key Exclusion Criteria

  1. Untreated or symptomatic brain metastases. (Part 2: with mandatory assessment by brain MRI within 21 days before first trial drug administration.) Participants with treated, stable brain metastases are eligible provided they meet the following criteria:
    • Radiotherapy or surgery for brain metastases was completed at least 2 weeks prior to the first administration of obrixtamig.
    • Patient is off steroids for at least 7 days (physiologic doses of steroids are permitted), and the patient is off anti-epileptic drugs for at least 7 days or on stable doses of anti-epileptic drugs for malignant central nervous system (CNS) disease.

  2. Presence of leptomeningeal disease or, part 2: epidural disease including spinal cord compression.

  3. Part 2: Active/previous history of interstitial lung disease, pulmonary fibrosis, organizing pneumonia or non-infectious pneumonitis (any grade). Patients with a history of therapy-related pneumonitis that is considered clinically resolved are eligible.

  4. Participants who experienced severe, life-threatening immune-mediated adverse events or infusion-related reactions including those that lead to permanent discontinuation while on treatment with immuno-oncology agents.

  5. Prior anti-cancer therapy:
    • Patients who have been treated with any other anti-cancer drug within 4 weeks or within 5 half-life periods (whichever is shorter) prior to first administration of obrixtamig.
    • Patients who have been treated with extensive field radiotherapy including whole brain irradiation within 2 weeks prior to first administration of obrixtamig.

  6. Previous treatment with DLL3-targeting T cell engagers or cell therapies.

  7. Diagnosis of immunodeficiency or systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of obrixtamig. Physiological replacement of steroids is allowed.

  8. Unresolved toxicity from prior anti-tumour therapy, defined as per protocol. Further exclusion criteria apply.

Pipeline compound(s) are under pre-clinical and/or clinical investigation and have not been approved by regulatory authorities for commercial use in patients. Efficacy and safety have not been established and there is no guarantee that they will become commercially available for the use(s) under investigation.

MOA data are based on in vitro/in vivo data and the clinical significance have not been established.