Safety and Clinical Activity of Nivatrotamab in Relapsed/Recurrent Metastatic Small-cell Lung Cancer

Adult patients with small-cell lung cancer (SCLC) will be treated with nivatrotamab a monoclonal anti GD2×CD3 bispecific antibody to investigate the safety and tolerability of the drug.

The study will include a phase 1 dose escalation part to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). This will be conducted following a modified Bayesian Optimal Interval Design (mBOIN) design. For the purpose of dose escalation, dose-limiting toxicities (DLTs) will be collected and assessed for a period of 28 days (the DLT evaluation period).

A phase 2 dose expansion part will follow the phase 1 dose escalation. In phase 2, patients will be stratified according to whether they have platinum sensitive or platinum-resistant SCLC. Phase 2 will assess the long term safety and tolerability of nivatrotamab as well as the clinical activity of nivatrotamab when administered at the obtained MTD/RP2D in phase 1.

Eligibility Criteria:
Inclusion Criteria:

* Signed and dated informed consent has been provided prior to any trial-related procedures.
* Patient willing and able to comply with the trial protocol
* Age ≥18 years at the time of informed consent
* Histologically or cytologically proven SCLC. Radiographical relapse/progression after minimum 1 line of platinum-containing chemotherapy with partial response or complete response as the best response (only applicable for phase 2) and not more than 3 prior lines of therapy
* Measurable disease according to RECIST v1.1
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Expected survival \>3 months
* Platelet counts ≥100,000 cells/mm3
* Hemoglobin ≥9 g/dL
* Absolute neutrophil count (ANC) ≥1000 cells/mm3
* Adequate liver function defined by aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) ≤3 × upper limit of normal (ULN), and serum bilirubin ≤1.5 × ULN with the following exceptions
* In patients with documented liver metastases, AST, ALT, and ALP ≤5 × ULN and serum bilirubin ≤1.5 × ULN
* Adequate renal function with serum creatinine ≤1.5 mg/dL or creatinine clearance ≥50 mL/min as calculated using the Cockcroft Gault equation
* Serum albumin \>3.0 g/dL
* Women of child-bearing potential must agree to appropriate contraception during treatment and for a period of 30 days after the last dose of study drug.

Exclusion Criteria:

* Systemic chemotherapy, radiotherapy, immunotherapy, or major surgery administered within 3 weeks prior to the first planned dosing of the investigational Medicinal Product (IMP) per protocol
* Patients receiving any other investigational therapy for their cancer within 3 weeks prior to the first planned dosing of the IMP per protocol
* Patients who never received platinum-containing regimen for SCLC (defined as less than 2 cycles of platinum doublet)
* Persistent \> grade 1 toxicity from previous treatment with checkpoint inhibitors
* Any immunosuppressive concomitant medication (i.e., salazopyrine, methotrexate, steroids etc.)
* Inability to wean off steroid, unless tapered to 0 mg/day minimum 10 days prior to the first treatment in case of prior use
* Any active, uncontrolled viral, fungal, or bacterial infection
* Any medical history within 3 months prior to enrolment with need for anticonvulsant therapy
* Patients with diagnosis of autoimmune diseases or immunodeficiencies or documented infection with human immunodeficiency virus (HIV) or hepatitis B or C virus (active)
* Previous autologous stem cell transplantation or solid organ transplantation
* Active heart disease including myocardial infarction within the last 6 months before first dose. This includes cardiac insufficiency with left ventricular ejection fraction (LVEF) \<50%
* Active CNS metastases. Patients with treated central nervous system (CNS) metastases are eligible if they are clinically stable without any new neurological symptoms and if there is no radiological evidence of new or enlarging CNS metastases. CNS-directed treatment (surgery, radiation) must be completed 4 weeks prior to the first IMP administration.

Furthermore, patients are excluded if they have:

Leptomeningeal carcinomatosis Uncontrolled seizures. Patients with known seizure are eligible if they are stable and have been without seizure 4 weeks prior to the first IMP administration

* Patients who experienced severe or recurrent (\>grade 2) immune mediated adverse events (AEs) or infusion related reactions (IRRs), including those that lead to permanent discontinuation while on treatment with immune oncology agents
* Prior treatment with anti-GD2 antibody or bispecific antibodies
* Patients with Limited Disease (LD), who are candidates for local or regional therapy.
* Impending need for palliative radiotherapy or surgery for pathological fractures and/or for medullary compression up to 3 weeks prior to the first planned dosing of the IMP per protocol (palliative radiation for other reasons within 2 weeks)
* History of other active malignancy within the past 3 years prior to the first planned dosing of the IMP per protocol (excluding non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, incidental prostate cancer (T1a, Gleason score ≤ 6, prostate specific antigen (PSA) less than 0.5 ng/ml)
* Patients with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of the trial IMP or significantly increase the severity of the toxicities experienced from trial treatment
* Patients who are pregnant or breastfeeding
* Patients with a body weight of \< 45 kg
* Patients with prior orthostatic hypotension