Phase 1 First-in-Human Trial — DLL3 T-Cell Engager (BiTE) in R/R ES-SCLC

Inclusion / Exclusion Criteria

Authored against DLL3 TCE precedent (tarlatamab DeLLphi-301/304) and TCE class-effect safety (CRS, ICANS, on-target neuroendocrine effects). Design intent: protect against the cycle-1 CRS/ICANS window while keeping a heavily pretreated ES-SCLC population enrollable.

INCLUSION CRITERIA

Disease
1. Histologically or cytologically confirmed extensive-stage small cell lung cancer (ES-SCLC).
2. Relapsed or refractory disease after ≥1 prior platinum-based regimen. (FIH dose-escalation: do not over-restrict prior lines — allow ≥1 to maximize the eligible pool; a sensitive- vs. platinum-refractory stratification factor is preferable to an exclusion.)
3. At least one measurable lesion per RECIST v1.1.
4. Available archival or fresh tumor tissue (DLL3 expression may be collected as a biomarker but not required for eligibility in a FIH study, to preserve enrollability and characterize the expression–response relationship).

Performance / reserve
5. ECOG performance status 0–1.
6. Life expectancy ≥12 weeks.

Organ function (within 7–14 days of first dose)
7. ANC ≥1.5 ×10⁹/L (≥1.0 acceptable if documented marrow involvement).
8. Platelets ≥100 ×10⁹/L (≥75 if marrow involvement).
9. Hemoglobin ≥9.0 g/dL, transfusion-independent for ≥2 weeks.
10. Total bilirubin ≤1.5× ULN (≤3× ULN if Gilbert's or hepatic metastases).
11. AST/ALT ≤3× ULN (≤5× ULN if hepatic metastases).
12. Creatinine clearance ≥50 mL/min (Cockcroft-Gault) or serum creatinine ≤1.5× ULN.
13. Adequate coagulation if on anticoagulation: INR/aPTT within therapeutic range.

Safety-context (TCE-specific)
14. Adequate cardiac reserve to tolerate CRS hemodynamic stress: LVEF ≥50%; no QTc prolongation (>470 ms women / >450 ms men).
15. Adequate pulmonary reserve: baseline O₂ saturation ≥92% on room air, no supplemental-oxygen dependence — CRS-associated hypoxia is a key cycle-1 hazard.
16. Baseline normal/near-normal neurologic exam with documented baseline ICE score, to enable ICANS detection.
17. Willing/able to be hospitalized for inpatient monitoring during step-up/priming doses (cycle 1).
18. Recovered to ≤Grade 1 from prior-therapy toxicities (excluding alopecia, stable neuropathy).

EXCLUSION CRITERIA

CNS / neurotoxicity risk (heightened priority for a TCE — ICANS)
1. Active, untreated, or symptomatic CNS metastases. (Treated, stable, asymptomatic brain mets — radiographically stable ≥4 weeks, off steroids ≥7 days — may be ALLOWED; precedent permits this and excluding all brain mets would gut SCLC enrollability.)
2. Leptomeningeal disease / carcinomatous meningitis (absolute exclusion — disproportionate ICANS danger).
3. History of seizure disorder, or active CNS autoimmune/inflammatory disease (confounds and amplifies ICANS).

Immune / infection (CRS confounders)
4. Active autoimmune disease requiring systemic immunosuppression within the prior 2 years (well-controlled endocrinopathies on replacement, e.g., thyroid, are permitted).
5. Chronic systemic corticosteroids >10 mg/day prednisone-equivalent or other immunosuppression at screening (blunts efficacy, confounds CRS grading) — taper required pre-dose.
6. Active, uncontrolled infection (CRS masks/worsens sepsis); known active HIV (unless controlled per protocol), active HBV/HCV.

Cardiopulmonary (CRS tolerance)
7. Myocardial infarction or unstable angina within 6 months; NYHA Class III/IV heart failure; clinically significant uncontrolled arrhythmia.
8. Interstitial lung disease/pneumonitis requiring steroids, or clinically significant baseline hypoxia.

General oncology
9. Insufficient washout from prior anticancer therapy (≥3–4 weeks or 5 half-lives, whichever shorter; ≥2 weeks for palliative RT).
10. Second malignancy requiring active treatment (excluding adequately treated in-situ/non-melanoma skin cancers).
11. Uncontrolled intercurrent illnes

Below is a Phase 1, first-in-human, dose-escalation/expansion trial eligibility framework for a DLL3 T‑cell engager (BiTE) in relapsed/refractory extensive-stage SCLC (ES‑SCLC). It is written to balance:

• ✅ Patient safety (CRS/ICANS, cytopenias, cardiopulmonary stress)
• ✅ Real-world enrollability in heavily pretreated ES‑SCLC
• ✅ Consistency with DLL3 TCE and IO precedents

Key Design Assumptions (Operational Context)

• Step-up (priming) dosing in Cycle 1
• Inpatient monitoring during initial doses
• Tocilizumab and corticosteroids immediately available
• Standard CRS/ICANS grading per ASTCT

Inclusion Criteria

1. Disease Characteristics

1. Histologically or cytologically confirmed small cell lung cancer.
2. Extensive-stage disease at study entry.
3. Relapsed or refractory after:
   - ≥1 prior platinum-based regimen (must have received platinum/etoposide)
   - Prior PD-1/PD-L1 therapy unless contraindicated or not available.
4. Measurable disease per RECIST v1.1.
5. Radiographic progression on or after most recent therapy.

2. Performance Status and Prognosis

6. ECOG performance status 0–1
   (Consider allowing ECOG 2 in dose-expansion once safety is characterized.)
7. Estimated life expectancy ≥ 12 weeks.

3. Organ Function (within 7–14 days of first dose)

Hematologic

• ANC ≥ 1.5 × 10⁹/L
  (≥1.0 × 10⁹/L allowed if marrow involvement)
• Platelets ≥ 100 × 10⁹/L
  (≥75 × 10⁹/L if marrow involvement)
• Hemoglobin ≥ 9.0 g/dL (transfusion allowed)

Hepatic

• Total bilirubin ≤ 1.5 × ULN
  (≤3 × ULN if Gilbert’s or liver metastases)
• AST/ALT ≤ 3 × ULN
  (≤5 × ULN if liver metastases)

Renal

• Creatinine clearance ≥ 50 mL/min (Cockcroft-Gault)
  OR serum creatinine ≤ 1.5 × ULN

4. CNS Disease (Balanced for Enrollability)

8. Treated brain metastases are allowed if:
   - Definitively treated (radiation or surgery)
   - Clinically stable ≥2 weeks
   - Off steroids or on physiologic replacement only (≤10 mg prednisone equivalent)

9. Asymptomatic untreated brain metastases ≤2 cm may be allowed in dose-expansion only, provided:
   - No mass effect
   - No edema requiring steroids

(Important for enrollability in ES-SCLC while mitigating ICANS risk.)

5. CRS/ICANS Safety-Specific Inclusion

10. Baseline neurologic exam without clinically significant deficits.
11. No history of grade ≥3 immune-related neurologic toxicity from prior IO.
12. Oxygen saturation ≥ 92% on room air.
13. Adequate cardiac reserve:
    - No symptomatic heart failure
    - No MI within 6 months
    - No unstable arrhythmias

6. Washout Periods

14. ≥2 weeks from prior chemotherapy or radiation (≥4 weeks for nitrosoureas/mitomycin C).
15. ≥4 weeks from prior investigational biologic agents.
16. Toxicities from prior therapy recovered to Grade ≤1 (except alopecia, stable neuropathy ≤Grade 2).

Exclusion Criteria

1. CNS / Neurologic Risk (ICANS Mitigation)

1. Active, untreated, or symptomatic brain metastases.
2. Leptomeningeal disease.
3. History of:
   - Seizure disorder requiring anti-epileptics
   - Stroke within 6 months
   - Clinically significant CNS hemorrhage
4. Active autoimmune neurologic disease (e.g., MS, myasthenia gravis).
5. Baseline ≥ Grade 2 cognitive impairment.

2. CRS Risk Amplifiers

6. Active uncontrolled infection (including sepsis).
7. Known active hepatitis B, C with viremia.
8. HIV with detectable viral load.
9. Ongoing systemic immunosuppression:
   - >10 mg prednisone equivalent daily within 7 days of first dose.
10. Active autoimmune disease requiring systemic therapy within past 2 years (replacement therapy allowed).

3. Cardiopulmonary Risk (CRS Hemodynamic Stress)

11. NYHA Class III or IV heart failure.
12. LVEF < 45–50% (if clinically indicated to assess).
13. Clinically significant pericardial effusion.
14. Baseline QTcF > 470 ms.
15. Significant baseline hypo

Phase 1 First-in-Human Trial of DLL3 T-Cell Engager (BiTE) in Relapsed/Refractory ES-SCLC

Inclusion/Exclusion Criteria

INCLUSION CRITERIA

Disease & Prior Treatment

1. Histologically or cytologically confirmed extensive-stage small cell lung cancer (ES-SCLC).
2. Relapsed or refractory disease after ≥1 prior platinum-based chemotherapy regimen (platinum-etoposide or equivalent).
3. Measurable disease per RECIST v1.1 (≥10 mm in short axis on CT/MRI).
4. Time since last prior chemotherapy ≥3 weeks (or ≥5 half-lives of the agent, whichever is longer) to allow washout and recovery.

Performance & Life Expectancy

5. ECOG performance status 0 or 1.
6. Estimated life expectancy ≥12 weeks.

Organ Function

7. Hematologic:
   - Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L
   - Platelets ≥100 × 10⁹/L (≥75 × 10⁹/L if marrow involvement by tumor)
   - Hemoglobin ≥9.0 g/dL, transfusion-independent for ≥1 week prior to enrollment

8. Hepatic:
   - Total bilirubin ≤1.5 × ULN (≤3 × ULN if documented Gilbert's syndrome or hepatic metastases)
   - AST/ALT ≤3 × ULN (≤5 × ULN if liver metastases present)
   - Albumin ≥2.8 g/dL

9. Renal:
   - Creatinine clearance (Cockcroft-Gault) ≥50 mL/min or serum creatinine ≤1.5 × ULN

10. Cardiac:

    • Left ventricular ejection fraction (LVEF) ≥50% by ECHO or MUGA (required because CRS imposes hemodynamic stress)
    • QTc (Fridericia) ≤470 ms (women) or ≤450 ms (men)
    • No history of congenital long-QT syndrome

Informed Consent & Special Populations

11. Signed informed consent; willingness to comply with intensive cycle-1 inpatient monitoring and frequent follow-up.
12. If of childbearing potential: agreement to highly effective contraception during treatment and ≥3 months after final dose (T-cell engagers carry unknown teratogenic risk; adopt precautionary standard).

EXCLUSION CRITERIA

Central Nervous System & Neurotoxicity Risk

1. Active, untreated, or symptomatic CNS metastases or leptomeningeal disease.
   - Rationale: ICANS risk is amplified in the presence of active brain disease; step-up dosing and neuro monitoring alone may be insufficient.
   - Exception: Patients with treated and radiographically stable CNS metastases (no progression for ≥4 weeks off CNS-directed therapy) may be enrolled only with mandatory baseline/on-treatment ICE (Immune Effector Cell-Associated Encephalopathy) scoring, frequent neuro exam, and MRI monitoring.

2. Active seizure disorder or uncontrolled epilepsy; ongoing antiepileptic medication is a relative risk factor for ICANS and complicates CRS monitoring.

3. History of stroke, intracranial hemorrhage, or posterior reversible encephalopathy syndrome (PRES) within 12 months.

4. Known or suspected carcinomatous meningitis.

Autoimmune & Immunosuppression

5. Active autoimmune disease requiring systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressive therapy at enrollment.
   - Rationale: Baseline immunosuppression blunts T-cell engager efficacy and confounds CRS grading/management; excludes patients requiring chronic high-dose steroids.
   - Exception: Autoimmune thyroiditis, vitiligo, psoriasis, or other stable, mild conditions managed with topical/low-dose therapy are permitted.

6. History of severe allergic reaction or hypersensitivity to biologic agents or monoclonal antibodies.

Cardiac & Hemodynamic Reserve

7. Uncontrolled or poorly compensated heart failure (NYHA Class III or IV).
8. Recent myocardial infarction, unstable angina, or significant coronary artery disease within 6 months.
9. Uncontrolled hypertension (systolic >160 mmHg or diastolic >100 mmHg) despite antihypertensive therapy.
   - Rationale: CRS causes significant hemodynamic stress (tachycardia, hypertension, capillary leak); inadequate baseline reserve increases severe CRS and organ injury risk.

Infection & Hematologic Reserve

10. Active, uncontrolled

Here's the proposed inclusion/exclusion criteria for a Phase 1 first-in-human trial of a DLL3 T-cell engager (BiTE) in patients with relapsed/refractory extensive-stage small cell lung cancer (ES-SCLC), designed to balance safety against enrollability while considering the risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of extensive-stage SCLC.
2. Documented relapsed or refractory disease after at least one prior platinum-based regimen (exact line of therapy will be defined per protocol).
3. Presence of measurable disease as per RECIST v1.1 criteria.
4. ECOG performance status of 0 or 1.
5. Adequate organ function as determined by the following lab thresholds:
   - Hematologic: ANC ≥ 1,000 cells/mm³, Platelets ≥ 75,000 cells/mm³, Hemoglobin ≥ 9 g/dL.
   - Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (ULN), AST/ALT ≤ 2.5 times ULN (or ≤ 5 times ULN in presence of liver metastases), Albumin ≥ 3 g/dL.
   - Renal: Creatinine clearance (CrCl) ≥ 30 mL/min or serum creatinine ≤ 1.5 times ULN.
6. Life expectancy of at least 12 weeks.

Exclusion Criteria:

1. Presence of untreated, active, or symptomatic CNS metastases. Patients who have received treatment for CNS metastases and are stable may be considered for inclusion.
2. Diagnosis of leptomeningeal disease or carcinomatous meningitis.
3. Active autoimmune disease or any condition requiring systemic immunosuppression that would interfere with the study treatment.
4. Insufficient washout time from prior anticancer therapy (i.e., approximately 3-4 weeks or 5 half-lives, depending on the agent).
5. Uncontrolled intercurrent illness or active infection.
6. Presence of a second malignancy that requires active treatment.
7. Any active CNS disease or condition (seizure disorders, active CNS autoimmune conditions) that may heighten the risk of ICANS.
8. Insufficient cardiac reserve, including recent myocardial infarction or NYHA III/IV congestive heart failure, as CRS may induce hemodynamic stress.
9. Significant baseline hypoxia or poor pulmonary reserve.

Notes:

• Due to the risks associated with cytokine release syndrome (CRS) and ICANS, patients will require close monitoring, particularly during the initial cycle of therapy, which may involve inpatient observation during dose escalation.
• Recruitment may also emphasize the need for immediate access to CRS management resources, including tocilizumab and corticosteroids.
• All patients will undergo a baseline neurological assessment and continuous evaluation for signs of ICANS post-treatment. Regular monitoring of vital signs and relevant lab parameters will be mandated during the trial.

This criteria set aims to optimize participant safety while maintaining the feasibility of enrollment for advancing the research into DLL3 T-cell engagers in extensive-stage SCLC.