ANTELOPE: Pemetrexed-free vs. Pemetrexed-based Immunochemotherapy in Metastatic TTF-1 Negative Lung Adenocarcinoma

Sponsor

Nikolaj Frost MD (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05689671

Collaborator

Roche Pharma AG (Industry), Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest (Other)

136

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This is an open-label randomized, controlled, multicenter, phase II trial with two arms. Patients with metastatic TTF-1 negative, treatment-naive lung adenocarcinoma without actionable genomic alterations are randomized in a 1:1 manner to investigate the efficiency of atezolizumab, carboplatin and nab-paclitaxel (Arm A) versus pembrolizumab, cis-/carboplatin and pemetrexed (Arm B) as first-line treatment.

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer Metastatic	Drug: Atezolizumab Drug: Nab paclitaxel Drug: Carboplatin Drug: Pembrolizumab Drug: Cisplatin Drug: Carboplatin Drug: Pemetrexed	Phase 2

Detailed Description

Thyroid transcription factor 1 (TTF-1) is expressed in the majority of lung adenocarcinoma and has a clear prognostic value. Pemetrexed-based immunochemotherapy is a standard of care for advanced lung adenocarcinoma. However, real-world data suggest that TTF-1 negative patients might derive superior outcome using pemetrexed-free regimens. The aim of this study is to compare a pemetrexed-free (Arm A) vs. a pemetrexed-based immunochemotherapy (Arm B) as first-line treatment for metastatic TTF-1 negative lung adenocarcinoma without actionable genomic alterations.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

136 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Atezolizumab/Carboplatin/Nab-Paclitaxel vs. Pembrolizumab/Platinum/Pemetrexed in Metastatic TTF-1 Negative Lung Adenocarcinoma

Anticipated Study Start Date :

Apr 1, 2023

Anticipated Primary Completion Date :

Oct 1, 2025

Anticipated Study Completion Date :

Oct 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pemetrexed-free Immunochemotherapy (Arm A) Atezolizumab 1200 mg q3w, carboplatin AUC 5-6 q3w, nab-paclitaxel 100 mg/m2 qw (administered for 4 cycles with subsequent maintenance with atezolizumab monotherapy 1200 mg q3w until loss of clinical benefit or occurrence of unacceptable toxicity)	Drug: Atezolizumab 1200 mg i.v. q3w Other Names: Tecentriq Drug: Nab paclitaxel 100 mg/m² i.v. qw Other Names: Abraxane Drug: Carboplatin AUC 5-6 i.v. q3w
Active Comparator: Pemetrexed-based Immunochemotherapy (Arm B) Pembrolizumab 200 mg q3w, cisplatin 75 mg/m2 q3w OR carboplatin AUC 5-6 (each) q3w, pemetrexed 500 mg/m2 q3w (administered for 4 cycles with subsequent maintenance with pembrolizumab 200 mg AND pemetrexed 500 mg/m2 (each) q3w until loss of clinical benefit or occurrence of unacceptable toxicity)	Drug: Pembrolizumab 200 mg i.v. q3w Other Names: Keytruda Drug: Cisplatin 75 mg/m² i.v. q3w Drug: Carboplatin AUC 5-6 i.v. q3w Drug: Pemetrexed 500 mg/m² i.v. q3w

Arm

Intervention/Treatment

Experimental: Pemetrexed-free Immunochemotherapy (Arm A)

Atezolizumab 1200 mg q3w, carboplatin AUC 5-6 q3w, nab-paclitaxel 100 mg/m2 qw (administered for 4 cycles with subsequent maintenance with atezolizumab monotherapy 1200 mg q3w until loss of clinical benefit or occurrence of unacceptable toxicity)

Drug: Atezolizumab

1200 mg i.v. q3w

Other Names:

Tecentriq

Drug: Nab paclitaxel

100 mg/m² i.v. qw

Other Names:

Abraxane

Drug: Carboplatin

AUC 5-6 i.v. q3w

Active Comparator: Pemetrexed-based Immunochemotherapy (Arm B)

Pembrolizumab 200 mg q3w, cisplatin 75 mg/m2 q3w OR carboplatin AUC 5-6 (each) q3w, pemetrexed 500 mg/m2 q3w (administered for 4 cycles with subsequent maintenance with pembrolizumab 200 mg AND pemetrexed 500 mg/m2 (each) q3w until loss of clinical benefit or occurrence of unacceptable toxicity)

Drug: Pembrolizumab

200 mg i.v. q3w

Other Names:

Keytruda

Drug: Cisplatin

75 mg/m² i.v. q3w

Drug: Carboplatin

AUC 5-6 i.v. q3w

Drug: Pemetrexed

500 mg/m² i.v. q3w

Outcome Measures

Primary Outcome Measures

Overall Survival (OS) [30 months]
time from randomization to the date of death due to any case

Secondary Outcome Measures

Objectice Response Rate (ORR) [30 months]
proportion of subjects with best response of complete or partial response (CR & PR) according to RECIST v1.1
Progression-Free Survival (PFS) [30 months]
time from randomization until progression defined by RECIST v1.1 or death due to any cause
One-Year Overall Survival Rate [30 months]
percentage of patients alive at 12 months after randomization
Time to Next Treatment or Death (TNTD) [30 months]
time from initial study randomization to the start of next subsequent treatment or death, whichever occurs first
Progression-Free Survival 2 (PFS2) [30 months]
time from initial study randomization to second disease progression or death from any cause to assess efficacy post-trial-treatment anti-cancer therapy
Health-related quality of life 1 (HRQoL) [Assessed after randomization at cycle 1 day 1, after completion of cycle 4 (each cycle is 21 days) of the chemoimmunotherapy and at progressive disease (if occurring within the maximum time frame of 30 months)]
assessed with the QoL questionnaire QLQ-C30 on general health conditions in lung cancer patients using numeric scales ranging from 1-4. Lower numbers indicate no, higher numbers high agreement.
Health-related quality of life 2 (HRQoL) [Assessed after randomization at cycle 1 day 1, after completion of cycle 4 (each cycle is 21 days) of the chemoimmunotherapy and at progressive disease (if occurring within the maximum time frame of 30 months)]
assessed with the lung cancer symptom-specific QoL questionnaire QLQ-LC13 using numeric scales ranging from 1-4. Lower numbers indicate no, higher numbers high agreement.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient has provided written informed consent
Patient* 18 years or older at time of signing the informed consent form
Histologically or cytologically confirmed metastatic stage IV non-squamous NSCLC
Negative local testing for TTF-1
Negative molecular testing for EGFR mutations and ALK rearrangements (tested locally)
PD-L1 tumor proportion score (TPS) < 50%, tested locally by QUiP®-certified immunohistochemistry
ECOG performance status ≤ 1
Measurable lesions according to RECIST v1.1
Life expectancy ≥ 12 weeks
Adequate hepatic, renal and bone marrow function
Hemoglobin ≥ 8.0 g/dL
Absolute neutrophil count ≥ 1.5 x 109/L
Platelets ≥ 100 x 109/L
Calculated creatine clearance ≥ 50 mL/min as determined by the Cockcroft-Gault equation and/or creatinin ≤ 1,5x upper limit of normal (ULN)
Serum bilirubin ≤ 1.5 x institutional ULN
AST/ ALT and alkaline phosphatase ≤ 2.5 x ULN
International normalized ratio (INR)/ Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PTT is within therapeutic range of intended use of anticoagulants
The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
Female patients who are considered as woman of childbearing potential (WOCBP) must use any contraceptive method with a failure rate of less than 1% per year during the treatment as well as up to 6 months after the last dose of study treatment. Male patients who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year during the treatment as well as at least 6 months after the last dose of IMP. Female patients who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic male patients do not require contraception

Exclusion Criteria:

Mixed histologies (small-cell and non-small cell or non-squamous and squamous; patients exhibiting the latter expression pattern may be eligible if the non-squamous part predominates)
Patients having received:
Systemic treatment for metastatic or locally advanced disease
prior PD-1/PD-L1 immunotherapies (prior treatment with CD137 agonists or immune checkpoint blockade therapies, including, but not limited to, anti-cytotoxic T lymphocyte associated protein 4 [anti-CTLA-4], anti T cell immunoreceptor with Ig and tyrosine-based inhibition motif domains [anti-TIGIT], anti-PD-1 and anti-PD-L1 therapeutic antibodies)
Symptomatic, neurologically unstable central nervous system (CNS) metastases or requiring increasing doses of steroids to manage CNS symptoms within 2 weeks prior to study entry (maximal acceptable dose must be ≤ 10 mg of prednisolone)
Leptomeningeal disease
History of interstitial lung disease
Severe infection within 2 weeks prior to study entry. Clinical signs must have been resolved to CTCAE grade ≤ 1
Active infection with hepatitis B or C virus (HBV, HCV), human immunodeficiency virus (HIV) or Mycobacterium tuberculosis
Known additional malignancies other than NSCLC, either untreated or having required active treatment within the past 3 years
Significant cardiovascular disease (≥ NYHA 3)
Active or prior documented autoimmune or inflammatory disorders (including but not limited to diverticulitis [with the exception of diverticulosis], celiac disease, systemic lupus erythematosus, Sarcoidosis, or Wegener's syndrome [granulomatosis with polyangiitis], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis). The following are exceptions to this criterion:
Patients with vitiligo or alopecia
Patients with hypothyroidism (e.g., following Hashimoto's disease) stable on hormone replacement
Patients with controlled Type I diabetes mellitus on an insulin regimen
Any chronic skin condition that does not require systemic therapy
Patients without active disease in the last 5 years may be included but only after consultation with the study physician
Current or prior use of immunosuppressive medication within 14 days before the first dose of atezolizumab/pembrolizumab. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection)
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
Live vaccine within 30 days prior to first dose of trial treatment
Known allergy or hypersensitivity to any component of the chemotherapy regimen or to atezolizumab or pembrolizumab or any constituents of the products
Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study.
Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.