SAKK 17/18 (ORIGIN) MPM & NSCLC >1st Line Gemci & Atezo Ph II

The trial combines two (Gemcitabine and Atezolizumab). Gemcitabine, alone or in combination regimens is a standard of care for several solid tumors, such as advanced or metastatic NSCLC. It is also used in an off-label setting for pre-treated MPM or naïve MPM in combination with platin-chemotherapy.

Atezolizumab is approved in the United States, European Union and in Switzerland for the treatment of NSCLC, urothelial carcinoma, small cell lung cancer (SCLC), triple-negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) patients.

A significant number of patients with malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC) are not cured with available treatments and will eventually relapse. After relapse treatment options are limited. Preclinical in vitro studies have demonstrated a synergism of immunotherapy with PD(L)1-targeting monoclonal antibodies and gemcitabine administered in different tumors models and ongoing clinical studies showed encouraging results. This may represent a safe and effective therapy for patients who relapsed or did not respond to standard therapies.

Patients will be treated with gemcitabine (1000 mg/m2 i.v. on day 1 and day 8 of each cycle, (every 3 weeks) and with atezolizumab (1200 mg i.v. on day 1 of each cycle, (every 3 weeks). The trial treatments will be continued for max. 2 years or until discontinuation criteria are met. The follow-up phase will last up to 5 years from treatment start.

The main objective of this trial is to determine the efficacy of chemotherapy (gemcitabine) combined with immunotherapy (atezolizumab) in patients with progressive NSCLC and MPM.

Inclusion criteria

• Written informed consent according to Swiss law and ICH/GCP regulations before registration and prior to any trial specific procedures including screening procedures.
• For Cohort 1 (NSCLC): Patients with histologically- or cytologically- confirmed squamous or non-squamous metastatic NSCLC stage IIIB-IV (based on TNM classification). Patients must have experienced disease recurrence or progression during or after one or more prior immunotherapy or chemo-immunotherapy regimen for metastatic disease.
• For Cohort 2 (MPM): Patients with histologically confirmed inoperable malignant pleural mesothelioma (MPM; with or without metastasis; all histological subtypes are eligible). Participants must have experienced disease recurrence or progression during or after one or more prior systemic therapy regimen for advanced or metastatic disease.
• Patients with treated and stable CNS metastases are eligible, if:

• Previous CNS-directed therapy has been completed at least 4 weeks prior to treatment start
• No evidence of progression after completion of CNS-directed therapy as ascertained by clinical examination and brain imaging (MRI or CT).
• Patients with known HIV-infection are eligible, if:

• CD4+ T-cell counts are ≥ 350 cells/ųl
• No history of AIDS-defining opportunistic infection within past 12 months
• Patient agrees to concomitant antiretroviral therapy (ART) if not currently on ART, or is on ART for ˃ 4 weeks and has a HIV viral load ˂ 400 copies/ml.
• Patients with a previously treated malignancy are eligible if this is clinically stable and does not require concurrent tumor-directed treatment.

Exception: patients suffering from prostate cancer under hormonal ablation therapy (hormone sensitive disease) are eligible.

• Patients with measurable disease according to RECIST 1.1 or mRECIST 1.1.
• Availability of samples for translational research prior to treatment start. For the tumor samples either archival or freshly prepared biopsy samples (cytology is not allowed) are acceptable. Acceptable samples include core needle biopsies for deep tumor tissue (three cores; or in case only two cores can be obtained, there has to be tissue available in order to send 10 unstained slides considered by the local pathologist to be representative of the tumor) or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.
• Age ≥ 18 years.
• ECOG performance status 0-2.
• Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, hemoglobin ≥ 90 g/L or ≥ 5.6 mmol/L.
• Adequate hepatic function: total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's disease ≤ 3.0 x ULN), AST and ALT ≤ 2.5 x ULN, or ≤ 5 x ULN for patients with hepatic metastasis.
• Adequate renal function: estimated glomerular filtration rate (eGFR) ≥ 40 ml/min/1.73 m2 (according to the Chronic Kidney Disease Epidemiology Collaboration) abbreviated formula CKD-EPI formula).
• Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must use highly effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and until 5 months after the last dose of investigational drug. A negative serum or urine pregnancy test before starting of trial treatment is required for all women of childbearing potential.
• Men agree not to donate sperm or to father a child during trial treatment and until 5 months after the last dose of investigational drug (www.swissmedicinfo.ch).
• Patients consent to the mandatory translational research projects providing the required samples.

Exclusion criteria

The presence of any one of the following exclusion criteria will lead to exclusion of the participant:

• Symptomatic brain metastases indicative of active disease (defined as new and/or progressive brain metastases at the time of treatment start [38]) or leptomeningeal disease.
• Prior treatment with gemcitabine in combination with atezolizumab.
• NSCLC patients who progressed within the first 8 weeks from start of first line treatment.
• NSCLC patients with activating EGFR or ALK mutations.
• Known unstable or unresolved surgical or chemotherapy-related toxicity that would compromise trial treatment' duration.
• Concomitant or recent anti-cancer treatment (within 14 days prior to trial treatment start) with any other experimental drug (enrollment in another clinical trial).
• Concomitant use of other anti-cancer drugs or radiotherapy (except for local pain control).
• Cardiac disease NYHA 2 or greater.
• Major surgery within 1 month prior to trial treatment start.
• Known history of any uncontrolled active systemic infection requiring intravenous (i.v.) antimicrobial treatment.
• Known history of tuberculosis, of primary immunodeficiency, of allogeneic tissue/solid organ transplant, of receipt of live attenuated vaccine within 28 days prior to treatment start.
• History of interstitial lung disease (ILD) or severe pneumonitis (other than chronic obstructive pulmonary disease -COPD- exacerbation) that have required oral or i.v. steroids, or uncontrolled pleural effusion.
• Concomitant use of systemic corticosteroids as premedication for chemotherapy.
• Concomitant or prior use of systemic immunosuppressive medication (such as interferon, methotrexate) within 28 days prior to trial treatment start, with the exceptions local (i.e. intranasal, inhaled and topical) corticosteroids.
• Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information or to the Investigator' Brochure.
• Known or suspected hypersensitivity to trial drug(s) or to any component of the trial drug(s).
• Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.