Study to Assess Safety,Tolerability,Efficacy of PM01183 and Atezolizumab in Patients w/ Advanced Small Cell Lung Cancer.

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.

Prospective, open-label, uncontrolled and multicenter phase I-II study in SCLC patients with ECOG PS 0-1 who have failed one prior platinum-containing line but no more than one chemotherapy-containing line. The study will be divided into two parts: a dose-ranging phase I with escalating doses of PM01183 in combination with a fixed dose of atezolizumab, followed by a single-arm phase II part with expansion at the RD determined during the phase I.

Phase I Patients will receive atezolizumab at a fixed dose of 1200 mg intravenously (i.v.) followed by PM01183 at a starting dose of 2.5 mg/m2 i.v. as a 1-hour infusion on Day 1 every three weeks (q3wk). PM01183 doses will be escalated in successive cohorts of patients following a modified Fibonacci scheme and a classical 3+3 design, and according to observed tolerance and safety.

Phase II Patients will receive atezolizumab i.v. as a 60-minute infusion (the second and subsequent infusions may be administered over 30 minutes) followed by PM01183 i.v. as a 1-hour infusion on Day 1 q3wk, at the RD determined during the phase I part.

It is expected that approximately 50% of patients included were previously treated with chemotherapy and the other 50% with immunotherapy and chemotherapy. In case one of the groups reaches 50% of the total number of patients expected to be recruited, no further patient will be included in this group and accrual will be limited to patients with the other group.

It is expected that approximately 50% of the patients included in the phase II part will be platinum-resistant [i.e., chemotherapy-free interval (CTFI) 30 to < 90 days from the end of first-line platinum-based chemotherapy] and 50% will be platinum-sensitive (i.e., CTFI ≥ 90 days), so as to assess efficacy in both settings. However in case that one of the CTFI groups reaches 60% of the total number of patients expected to be recruited, no further patient will be included in this group and accrual will be limited to patients with the other CTFI group.

Inclusion Criteria:

• 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 platinum-based chemotherapy or first- line platinum- based chemotherapy and immunoterapy (anti PD1/ PDL1). 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 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):
• Platelet count ≥100 x 109/L, hemoglobin ≥9.0 g/dL and absolute neutrophil count (ANC) ≥1.5 x 109/L.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x the upper limit of normal (ULN), independently of the presence of liver metastases.
• Alkaline phosphatase (AP) ≤2.5 x ULN.
• Total bilirubin ≤1.5 x ULN or direct bilirubin ≤ULN
• International Normalized Ratio (INR) <1.5 (except if patient is on oral anticoagulation therapy).
• Calculated creatinine clearance (CrCL) ≥30 mL/minute (using Cockcroft and Gault´s formula).
• Creatine phosphokinase (CPK) ≤2.5 x ULN.
• Albumin ≥3.0 g/dL. Albumin infusion to fulfill the inclusion criterion is forbidden.
• 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.

Exclusion Criteria:

1. 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 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.

2. More than one prior chemotherapy-containing line (re-challenge with the same initial regimen is not allowed).

3. Patients with radiation therapy (RT) in more than 35% of the bone marrow.

4. History of previous bone marrow and/or stem cell transplantation.

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

6. History of allergy or hypersensitivity to any of the study drugs or their excipients.

7. Prior therapy with PM01183, antibodies against PD-1, PD-L1, 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).

8. Live vaccines within 30 days prior to start of study treatment and while on treatment.

9. 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.

10. Concomitant diseases/conditions:

    1. 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.

    2. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment.

    3. Ongoing chronic alcohol consumption, or cirrhosis with Child-Pugh score B or C.

    4. Active uncontrolled infection. Serious non-healing wound, ulcer or bone fracture.

    5. 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.

    6. 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 hypothyroidism stable on hormone replacement, patients with insulin-treated controlled type 1 diabetes or Sjogren's syndrome.

    7. 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.

    8. Known history of active tuberculosis (Mycobacterium tuberculosis).

    9. 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.

    10. Known human immunodeficiency virus (HIV) infection.

    11. 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).

    12. Limitation of the patient's ability to comply with the treatment or follow-up procedures.

    13. Patiens who have previously experienced pericarditis, pericardial effusion and cardiac tamponade) on prior treatment with other immune- stimulatory anticancer agents.

    14. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.

11. Active COVID19 infection determined by PCR (positive result of SARS-CoV-2 virus), not mandatory if fully vaccinated.