Histologically or cytologically confirmed diagnosis of extensive or limited SCLC. Progression to first-line platinum-based chemotherapy. Measurable disease according to RECIST v.1.1.
Conditions
Sponsors
Fundacion ONCOSUR
Eligibility
Sex/Gender
All
Inclusion criteria
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: a chemotherapy-free interval (CTFI, time from the last dose of first-line chemotherapy to the occurrence of progressive disease)=30 days. -Available tumor tissue blocks or slides from a previous surgery or biopsy. -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): a.Platelet count=100 x 109/L, hemoglobin=9.0g/dL and absolute neutrophil count (ANC)=1.5x109/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) =65 years) yes F.1.3.1 Number of subjects for this age range 25
Exclusion criteria
Exclusion criteria: -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 -More than one prior chemotherapy-containing line (re-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 -Impending need for RT (e.g., painful bone metastasis and/or risk of spinal cord compression). -History of allergy or hypersensitivity to any of the study drugs or their excipients -Prior therapy with PM01183, antibodies against PD-1, PD-L1, PD-L2, CD137, or cytotoxic T lymphocyte associated antigen-4 (CTLA-4) -Live vaccines within 30 days prior to start of study treatment and while on treatment -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 -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 positiv
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I • To determine the maximum tolerated dose (MTD) and the recommended dose for phase II studies (RD) of PM01183 in combination with atezolizumab in advanced SCLC patients progressing after platinum doublet chemotherapy. Phase II • To assess the efficacy of PM01183 in combination with atezolizumab in terms of confirmed tumor response rate according to Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1 in patients with SCLC progressing after platinum doublet chemotherapy. ; Secondary Objective: Ph.I-Characterize comb safety profile&feasibility-Characterize PM01183 PK&detect major drug-drug PK interactions-Obtain preliminary inform on comb clinical antitumor activity-If DLTs being exclusively related to neutropenia,determine PM01183 in comb w/atezolizumab MTD&RD in patients w/advanced SCLC w/compulsory primary G-CSF prophylaxis-Evaluate PGt in germline DNA to identify factors that explain individual variability in main PK parameters-Evaluate PGx in tumor&blood samples to identify response &/or resistance potential markers Ph.II-Confirm comb safety profile&tolerability-Characterize comb antitumor activity in terms of DoR,clinical benefit[ORR/stable disease lasting=3mos]PFS,OS&mid/long-term survival(12,18,24mos)-Characterize plasma PK of comb&detect major drug-drug PK interactions-Evaluate PGt in germline DNA to identify factors that explain individual variability in main PK parameters-Evaluate PGx in tumor&blood samples to identify response &/or resistance potential markers ; Primary end point(s): Phase I Determination of MTD and RD: • The MTD will be the lowest dose level explored during dose escalation at which more than one third of evaluable patients experience a DLT during Cycle 1. • The RD will be the highest dose level explored during dose escalation at which less tha | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: see Protocol; Secondary end point(s): Both phases • Safety: patients will be evaluable for safety if they have received at least one partial infusion of atezolizumab and PM01183. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5. • Efficacy: antitumor activity of the combination will be evaluated in terms of: -Progression-free survival defined as the time from the date of registration to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy. -Duration of response (DoR) will be calculated from the date of first documentation of response per RECIST v.1.1 (complete or partial response, whichever comes first) to the date of documented PD or death. The censoring rules defined above for PFS will be used for DoR. -Clinical benefit defined as percentage of evaluable patient with complete response, partial response or stable disease lasting =3 months, as defined by RECIST v1.1. -Overall survival (OS): calculated from the date of registration to the date of death (death event) or last contact (in this case, survival will be censored on that date). -Mid- and long-term survival (OS at 12, 18 and 24 months) will be the Kaplan-Meier estimates of the probability of being alive at these time points. • Pharmacokinetics: PK parameters will be evaluated in plasma by standard non-compartmental methods (compartmental modeling may be performed if appropriate). • Pharmacogenetics: factors that may help to explain individual variability in main PK parameters, the presence or absence o | — |
Countries
Spain
Contacts
Public ContactFundación ONCOSUR
Fundación ONCOSUR
Outcome results
None listed