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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT04480372

Studienbeginn:
März 2021

Letztes Update:
19.05.2021

Wirkstoff:
Gemcitabine, Atezolizumab

Indikation (Clinical Trials):
Carcinoma, Non-Small-Cell Lung, Mesothelioma

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Swiss Group for Clinical Cancer Research

Collaborator:
-

Studienleiter

Alessandra Curioni Fontecedro, MD
Study Chair
University of Zurich

Kontakt

Studienlocations
(3 von 12)

Alle anzeigen

Studien-Informationen

Detailed Description:

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) and triple-negative

breast cancer (TNBC) 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.

Ein-/Ausschlusskriterien

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 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 (minimum three cores) or excisional, incisional, punch, or forceps

biopsies for cutaneous, subcutaneous, or mucosal lesions. See Ch. 12 and 17 for

further details.

- 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 treatment (within 30 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 corticosteroids as premedication for chemotherapy.

- Concomitant or prior use of immunosuppressive medication (such as interferon,

methotrexate) within 28 days prior to trial treatment start, with the exceptions of

intranasal and inhaled 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.

Studien-Rationale

Primary outcome:

1. Primary endpoint for cohort 1: Objective response rate (ORR) according to RECIST 1.1 (Time Frame - At the date of tumor assessment according to RECIST 1.1, assessed up to 2 years after registration):
ORR according to RECIST 1.1 is defined as the proportion of patients, whose best overall response is either complete response (CR) or partial response (PR) achieved during trial treatment until disease progression according to RECIST 1.1. Patients with CR or PR as best observed response during trial treatment will be considered as success; otherwise as failures for this endpoint. Patients without any tumor assessment or with non-evaluable response (NE) during trial treatment will be considered as failures for this endpoint.

2. Primary endpoint for cohort 2: ORR according to mRECIST (Time Frame - At the date of tumor assessment according to mRECIST, assessed up to 2 years after registration):
ORR according to mRECIST is defined as the proportion of patients, whose best overall response is either complete response (CR) or partial response (PR) achieved during trial treatment until disease progression according to mRECIST. Patients with CR or PR as best observed response during trial treatment will be considered as success; otherwise as failures for this endpoint. Patients without any tumor assessment or with non-evaluable response (NE) during trial treatment will be considered as failures for this endpoint.

Secondary outcome:

1. For cohort 1 (NSCLC): Duration of response (DoR) according to RECIST 1.1 (Time Frame - From the time from the first documentation of CR or PR (whichever occurs first) until disease progression according to RECIST 1.1 or death due to any cause, assessed up to 5 years after registration):
DoR according to RECIST 1.1 is defined as the time from the first documentation of CR or PR (whichever occurs first) until disease progression according to RECIST 1.1 or death due to any cause. Patients not experiencing an event at the time of analysis and those starting a subsequent treatment without an event will be censored at the date of their last available tumor assessment before starting subsequent treatment, if any. This endpoint will be calculated for the subgroup of patients achieving CR or PR.

2. For cohort 1 (NSCLC): Progression-free survival (PFS) according to RECIST 1.1 (Time Frame - From the date of first dose of atezolizumab/gemcitabine until the date of progressive disease according to RECIST 1.1 or death due to any cause, whichever occurs first, assessed up to 5 years after the first registration):
PFS according to RECIST 1.1 is measured as the time from the first dose of atezolizumab/gemcitabine until disease progression according to RECIST 1.1 or death due to any cause. Patients not experiencing an event at the time of analysis and those receiving a subsequent treatment without an event will be censored at the date of their last available tumor assessment before starting subsequent treatment, if any.

3. For cohort 1 (NSCLC): Disease control rate (DCR) at 18 weeks according to RECIST 1.1 (Time Frame - At the date of tumor assessment according to RECIST 1.1, assessed up to 2 years after registration):
DCR at 18 weeks according to RECIST 1.1 is defined as the proportion of patients, whose best overall response is either CR, PR or stable disease maintained for at least 18 weeks (SD≥18weeks) during trial treatment until disease progression according to RECIST 1.1. Patients with CR, PR, SD≥18weeks as best observed response during the trial treatment until disease progression according to RECIST 1.1 will be considered as success; otherwise as failures for this endpoint. Patients without any tumor assessment or with non-evaluable response (NE) during trial treatment will be considered as failures for this endpoint.

4. For cohort 2 (MPM): ORR according to mRECIST 1.1 (Time Frame - At the date of tumor assessment according to mRECIST 1.1, assessed up to 2 years after registration):
ORR according to mRECIST 1.1 is defined as the proportion of patients whose best overall response is either CR or PR achieved during trial treatment until disease progression according to mRECIST 1.1. Patients with CR or PR as best observed response will be considered as success; otherwise as failures for this endpoint. Patients without any tumor assessment or with non-evaluable response (NE) during trial treatment will be considered as failures for this endpoint.

5. For cohort 2 (MPM): DoR according to mRECIST 1.1 (Time Frame - From the time from the first documentation of CR or PR (whichever occurs first) until disease progression according to mRECIST 1.1 or death due to any cause, assessed up to 5 years after registration):
DoR according to mRECIST 1.1 is defined as the time from the first documentation of CR or PR (whichever occurs first) until disease progression according to mRECIST 1.1 or death due to any cause, whichever occurs first. Patients not experiencing an event at the time of analysis and those starting a subsequent treatment without an event will be censored at the date of their last available tumor assessment before starting subsequent treatment, if any. This endpoint will be calculated for the subgroup of patients achieving CR or PR.

6. For cohort 2 (MPM): PFS according to mRECIST 1.1 (Time Frame - From the date of first dose of atezolizumab/gemcitabine until the date of progressive disease according to mRECIST 1.1 or death due to any cause, whichever occurs first, assessed up to 5 years after registration):
PFS is defined as the time from the first dose of atezolizumab/gemcitabine until disease progression according to mRECIST 1.1 or death due to any cause. Patients not experiencing an event at the time of analysis and those receiving a subsequent treatment without an event will be censored at the date of their last available tumor assessment before starting subsequent treatment, if any.

7. For cohort 2 (MPM): DCR at 18 weeks according to mRECIST 1.1 (Time Frame - At the date of tumor assessment according to mRECIST 1.1, assessed up to 2 years after registration):
DCR at 18 weeks according to mRECIST 1.1 is defined as the proportion of patients whose confirmed best overall response is either CR, PR or stable disease maintained for at least 18 weeks (SD≥18weeks) during trial treatment until disease progression according to mRECIST 1.1. Patients with CR, PR, SD18weeks as best observed response will be considered as success; otherwise as failures for this endpoint. Patients without any tumor assessment or with non-evaluable response (NE) during trial treatment will be considered as failures for this endpoint.

8. For cohort 1 and cohort 2: Objective response rate according to iRECIST (iORR) (Time Frame - At the date of tumor assessment according to iRECIST, assessed up to 2 years after registration):
iORR is defined as the proportion of patients whose best overall response is either (CR/iCR) or (PR/iPR) according to RECIST 1.1, modified RECIST 1.1 or iRECIST achieved during trial treatment until disease progression according to iRECIST. Patients with CR/iCR or PR/iPR as best observed response during trial treatment until disease progression according to iRECIST will be considered as a success; otherwise as failures for this endpoint. Patients without any tumor assessment or with non-evaluable response (NE) during trial treatment will be considered as failures for this endpoint.

9. For cohort 1 and cohort 2: DoR according to iRECIST (iDoR) (Time Frame - From the time of documentation of CR or PR (whichever occurs first) until disease progression according to iRECIST or death due to any cause, assessed up to 5 years after registration):
iDoR is defined as the time from the first documentation of CR/iCR or PR/iPR (whichever occurs first) according to RECIST 1.1, modified RECIST 1.1 or iRECIST achieved during trial treatment until disease progression according to iRECIST or death due to any cause. Patients not experiencing an event at the time of analysis and those starting a subsequent treatment without an event will be censored at the date of their last available tumor assessment before starting subsequent treatment, if any. This endpoint will be calculated for the subgroup of patients achieving CR/iCR or PR/iPR.

10. For cohort 1 and cohort 2: PFS according to iRECIST (iPFS) (Time Frame - From the date of first dose of treatment until the date of progressive disease according to iRECIST or death due to any cause, whichever occurs first, assessed up to 5 years after registration):
iPFS is defined as the time from the first dose of atezolizumab/gemcitabine until disease progression according to iRECIST or death due to any cause. Patients not experiencing an event at the time of analysis and those receiving a subsequent treatment without an event will be censored at the date of their last available tumor assessment before starting subsequent treatment, if any.

11. For cohort 1 and cohort 2: Overall Survival (OS) (Time Frame - From the date of from the first dose of atezolizumab/gemcitabine until the date of death from any cause, assessed up to 5 years after registration):
OS is defined as the time from the first dose of atezolizumab/gemcitabine until death due to any cause. Patients alive or lost to follow-up will be censored at the last date where they will be known to be alive.

12. For cohort 1 and cohort 2: Adverse events (AEs) will be assessed according to CTCAE v5.0. (Time Frame - Up to 5 years after registration):
AEs will be assessed according to CTCAE v5.0.

Geprüfte Regime

  • Gemcitabine:
    Gemcitabine is administered at the dose of 1000 mg/m2 intravenously (i.v.) on day 1 and day 8 of each cycle (every 3 weeks).
  • Atezolizumab:
    Atezolizumab is administered at the dose of 1200 mg i.v. on day 1 of each cycle (every 3 weeks).

Quelle: ClinicalTrials.gov


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