Phase I-II Study to Assess the Safety, Tolerability and Efficacy of PM01183 and Atezolizumab in Patients with Advanced Small Cell Lung Cancer that Progressed Following Prior Therapy with Platinum-Based Chemotherapy

Prior treatment

• Active or untreated central nervous system (CNS) involvement. Treated CNS metastases have to show radiographic stability (defined as no CNS progression for at least three weeks from pre or post-radiotherapy brain scan to brain scan performed prior study entry), and patients should not have neurologic sign/symptoms secondary to the brain metastases or RT. Any steroid treatment must be completed ≥ 14 days before first dose of study treatment.
• More than one prior chemotherapy-containing line (reProtocol version 4.0 – 27 Feb 2023 Page 11/131 challenge with the same initial regimen is not allowed).
• Patients with radiation therapy (RT) in more than 35% of the bone marrow.
• History of previous bone marrow and/or stem cell transplantation.
• Live vaccines within 30 days prior to start of study treatment and while on treatment.

Other illness

• Active COVID19 infection determined by PCR (positive result of SARS-CoV-2 virus), not mandatory if fully vaccinated.
• History of allergy or hypersensitivity to any of the study drugs or their excipients.
• History of other prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer. Patients with other prior malignancies and no disease recurrence for 3 years are eligible.

Lab values

• Concomitant diseases/conditions: a) History or presence of unstable angina, myocardial infarction, congestive heart failure defined as abnormal left ventricular ejection fraction (LVEF) < 50% assessed by multiple-gated acquisition scan (MUGA) or equivalent by ultrasound (US), or clinically significant valvular heart disease within 12 months prior first study dose. b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. c) Ongoing chronic alcohol consumption, or cirrhosis with Child-Pugh score B or C. d) Active uncontrolled infection. Serious non-healing wound, ulcer or bone fracture. e) Diagnose of immunodeficiency or receiving systemic steroids therapy (more than a daily dose of 10 mg of prednisone or equivalent per day) or any other form of immunosuppressive therapy within 14 days prior to the first study dose. f) Active autoimmune disease that required systemic treatment in the past two years (i.e., with disease-modifying agents, corticosteroids and immunosuppressive drugs). Patients with vitiligo or resolved childhood asthma/atopy are eligible, as well as patients who require intermittent use of bronchodilators or local steroid injections, patients with Protocol version 4.0 – 27 Feb 2023 Page 12/131 hypothyroidism stable on hormone replacement, patients with insulin-treated controlled type 1 diabetes or Sjogren's syndrome. g) History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis or evidence of active pneumonitis on screening chest computed tomography (CT) scans. A history of radiation pneumonitis in radiation field (fibrosis) will be allowed if asymptomatic and not requiring steroids. h) Known history of active tuberculosis (Mycobacterium tuberculosis). i) Ongoing treatment-requiring, non-neoplastic chronic liver disease of any origin. For hepatitis B, this includes positive tests for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR). For hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR. Patients taking hepatitis-related antiviral therapy within 6 months prior to the first study dose will also be excluded. j) Known human immunodeficiency virus (HIV) infection. k) Myopathy or any clinical situation that causes significant and persistent elevation of CPK (>2.5 x ULN in two different determinations performed one week apart). l) Limitation of the patient’s ability to comply with the treatment or follow-up procedures. m) Patients who have previously experienced pericarditis, pericardial effusion and cardiac tamponade) on prior treatment with other immune-stimulatory anticancer agents. n) Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study.
• Prior therapy with PM01183, antibodies against PD-1, PDL1, PD-L2, CD137, or cytotoxic T lymphocyte associated antigen-4 (CTLA-4). For phase II part: Prior therapy with PM01183, PD-L2, CD137, or cytotoxic T lymphocyte associated antigen-4 (CTLA-4).

Other

• Impending need for RT (e.g., painful bone metastasis and/or risk of spinal cord compression).

• Voluntarily signed and dated written informed consent prior to any specific study procedure.
• Age >18 years.
• Histologically or cytologically confirmed diagnosis of extensive or limited SCLC.
• Progression to first-line platinum-based chemotherapy. For phase II part: Progression to first-line platinumbased chemotherapy or first-line platinum-based chemotherapy and immunotherapy (anti PD1/PDL-1). A chemotherapy and/or immunotherapy -free interval (CTFI, time from the last dose of first-line chemotherapy to the occurrence of progressive disease) ≥ 30 days.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤1.
• Measurable disease according to RECIST v.1.1. Note: irradiated lesions may qualify as target if progression has been documented.
• At least three weeks since last prior anticancer treatment (including radiotherapy) and recovery to grade ≤ 1 from any adverse event (AE) related to previous anticancer treatment (excluding sensory neuropathy, anemia, asthenia and alopecia, all grade ≤ 2) according to the National Protocol version 4.0 – 27 Feb 2023 Page 10/131 Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, v.5).
• Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤7 days before inclusion in the study): a) Platelet count ≥100 x 109/L, hemoglobin ≥9.0 g/dL and absolute neutrophil count (ANC) ≥1.5 x 109/L. b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x the upper limit of normal (ULN), independently of the presence of liver metastases. c) Alkaline phosphatase (AP) ≤2.5 x ULN. d) Total bilirubin ≤1.5 x ULN or direct bilirubin ≤ULN. e) International Normalized Ratio (INR) <1.5 (except if patient is on oral anticoagulation therapy). f) Calculated creatinine clearance (CrCL) ≥30 mL/minute (using Cockcroft and Gault´s formula). g) Creatine phosphokinase (CPK) ≤2.5 x ULN. h) Albumin ≥3.0 g/dL. Albumin infusion to fulfill the inclusion criterion is forbidden. i) Thyroid stimulating hormone (TSH) within institutional normal limits. If TSH is above the ULN, then a free T4 within institutional normal limits is acceptable.
• Evidence of non-childbearing status for women of childbearing potential (WOCBP). Both women and men must agree to use a highly effective contraceptive measure during the trial, for at least five months after last atezolizumab dose, and for at least six weeks (women) or 4 months (men) after last PM01183 dose. Fertile male patients with WOCBP partners must agree to refrain from fathering a child or donating sperm during the trial and up to five months after treatment discontinuation. Acceptable methods of contraception include abstinence, intrauterine device (IUD), oral contraceptive, subdermal implant and/or double barrier.