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JOURNAL ONKOLOGIE – STUDIE

ABC-lung ABC-lung: Atezolizumab, Bevacizumab and Chemotherapy in EGFR-mutant Non-small Cell Lung Carcinoma

Rekrutierend

NCT-Nummer:
NCT04245085

Studienbeginn:
Juli 2020

Letztes Update:
15.02.2021

Wirkstoff:
Atezolizumab, Bevacizumab, Carboplatin, Paclitaxel, Pemetrexed

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

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
European Thoracic Oncology Platform

Collaborator:
Roche Pharma AG

Kontakt

Studienlocations (3 von 23)

Lungenkrebszentrum des NCT Heidelberg; Thoraxklinik Heidelberg
Im Neuenheimer Feld 672
69126 Heidelberg
DeutschlandNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Farastuk Bozorgmehr, MD
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Studien-Informationen

Brief Summary:

ETOP 15-19 ABC-lung is an international, multi-centre open-label, randomized phase II trial

with two non-comparative parallel arms of atezolizumab plus bevacizumab with

carboplatin-paclitaxel (Arm A) or atezolizumab, bevacizumab and pemetrexed (Arm B) in

patients with stage IIIB-IV non-squamous non-small cell lung cancer (NSCLC) harbouring EGFR

mutations after failure of standard EGFR tyrosine kinase inhibitors (TKIs).

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Patients (male/female) must be ≥18 years of age.

2. Chemotherapy naïve, non-squamous NSCLC, stage IIIB/C (not amenable to radical therapy)

or IV. Patients who have received previous adjuvant or neoadjuvant chemotherapy are

eligible if the date of last dose of treatment was at least 12 months before

randomisation.

3. Known EGFR mutations genotypes by tissue or ctDNA, patients with common mutations

(L858R or Del19) and other rare mutations (e.g. S768I, G719X) are eligible.

4. Measurable or evaluable disease by RECIST v1.1.

5. Disease progression (during or after) or unacceptable side effects from prior

treatment with at least one EGFR TKI (washout period = 7 days).

If most recent line of treatment (1st or 2nd line) was a third-generation EGFR TKI

(e.g. osimertinib):

- Patient must be known to be EGFR mutation positive, either on fresh tumour biopsy

taken >7 days prior to protocol treatment start or by recent ctDNA analysis

(informative ctDNA test, local test).

- T790M genotype is allowed

If most recent line of treatment (1st or 2nd line) was a first- or second-generation

EGFR TKI (e.g. afatinib, dacomitinib, erlotinib, gefitinib):

- Patient must be known to be tissue EGFR T790M wild type (local test) on most recent

line of EGFR TKI or if no tissue re-biopsy, no evidence of T790M on ctDNA but

identified L858R, del19, S768I or G719X genotypes (informative ctDNA test, local test)

6. Treatment with an EGFR TKI therapy for at least 10 days

7. Adequate haematological function:

- Haemoglobin greater or equal 90 g/L

- Absolute neutrophils count (ANC) greater or equal 1.5× 109/L

- Platelet count greater or equal 100× 109/L

8. Adequate renal function:

- Creatinine less or equal 1.5× ULN OR

- Creatinine clearance greater or equal 45 mL/min (using the Cockcroft-Gault

formula)

9. Adequate liver function:

- ALT and AST less or equal 2.5× ULN. If the patient has liver metastases, ALT and

AST must be less or equal 5× ULN

- Total bilirubin less or equal 1.5x ULN.

10. Willingness to provide any surplus tumour sample obtained at the time of acquired

resistance to prior EGFR TKI

11. Men and women of childbearing potential must agree to use adequate contraception

12. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

13. Life expectancy greater or equal 12 weeks

14. Women of childbearing potential, including women who had their last menstrual period

in the last 2 years, must have a negative serum or urine pregnancy test within 7 days

before randomisation.

15. Patient is willing and able to comply with the protocol for the duration of the trial

including undergoing treatment and scheduled visits and examinations including follow

up.

Exclusion Criteria:

1. Prior systemic cytotoxic chemotherapy for advanced stage NSCLC Patients who had

received previous adjuvant or neoadjuvant chemotherapy are eligible if the last dose

of treatment was at least 12 months before randomisation.

2. Prior therapy with bevacizumab or other anti-angiogenic agent

3. Prior immune checkpoint inhibitor therapy

4. More than two lines of EGFR TKI therapy

5. Known small-cell lung carcinoma (SCLC) or high grade neuroendocrine carcinoma (if

progression biopsy has been performed locally).

6. Squamous cell histologic subtype

7. Known EGFR T790M positive genotype by tissue on most recent EGFR TKI progression or

ctDNA and have not received an approved EGFR TKI targeting T790M (e.g. a

third-generation EGFR TKI such as osimertinib).

8. Active or untreated CNS metastases as determined by brain MRI

- Patients with CNS metastases must be non-progressive by RECIST and symptomatically

stable with no ongoing requirement for corticosteroids as therapy for CNS disease;

anticonvulsants at a stable dose allowed

9. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of

radiation within 4 weeks of randomization.

10. Presence or history of a malignant disease that has been diagnosed and/or required

therapy within the past 3 years. Exceptions to this exclusion include the following:

completely resected basal cell and squamous cell skin cancers, and completely resected

carcinoma in situ of any type.

11. Clear tumour infiltration into the thoracic great vessels (seen on imaging)

12. QTc of grade ≥3 according to CTCAE v5.0

13. Active autoimmune disease that has required systemic treatment in past 2 years.

Patients with vitiligo, controlled type I diabetes mellitus on stable insulin, or

residual autoimmune-related hypothyroidism only requiring hormone replacement or

psoriasis not requiring systemic treatment are permitted

14. Active or uncontrolled HIV, tuberculosis, hepatitis B or C infection

15. Live attenuated vaccination within 4 weeks prior to randomisation.

16. Subject receiving any biologic drugs targeting the immune system (for example, TNF

blockers, anakinra, rituximab, abatacept, or tocilizumab).

17. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced

pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening

chest computed tomography scan. History of radiation pneumonitis in the radiation

field (fibrosis) is permitted

18. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg

and/or diastolic blood pressure >100 mmHg)

- Anti-hypertensive therapy to achieve these parameters is allowable.

19. Prior history of hypertensive crisis or hypertensive encephalopathy

20. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent

peripheral arterial thrombosis) within 6 months prior to randomization

21. History of haemoptysis (greater or equal 2.5mL of bright red blood per episode) within

1 month prior to randomization

22. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic

anticoagulation)

23. Current or recent (within 10 days of randomization) use of aspirin (>325 mg/day) or

treatment with dipyramidole, ticlopidine, clopidogrel, and clostazol

24. Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for

therapeutic purposes that has not been stable for >2 weeks prior to randomization

- The use of full-dose oral or parenteral anticoagulants is permitted as long as

the INR or aPTT is within therapeutic limits (according to the medical standard

of the enrolling institution) and the patient has been on a stable dose of

anticoagulants for at least 2 weeks prior to randomization.

- Prophylactic anticoagulation for the patency of venous access devices is allowed,

provided the activity of the agent results in an INR <1.5× ULN and aPTT is within

normal limits within 14 days prior to randomization.

- Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is

permitted.

25. Core biopsy or other minor surgical procedure, excluding placement of a vascular

access device, within 7 days prior to the first dose of bevacizumab

26. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation

within 6 months prior to randomization

27. Clinical signs of gastrointestinal obstruction or requirement for routine parenteral

hydration, parenteral nutrition, or tube feeding

28. Evidence of abdominal free air not explained by paracentesis or recent surgical

procedure

29. Serious, non-healing wound, active ulcer, or untreated bone fracture

30. Proteinuria, as demonstrated by urine dipstick or >1.0 g of protein in a 24-hour urine

collection

- All patients with greater or equal 2+ protein on dipstick urine alysis at baseline

must undergo a 24 hour urine collection and must demonstrate lesser or equal 1 g of

protein in 24 hours.

31. Any unresolved toxicities from prior therapy greater than CTCAE v5.0 grade 1 at the

time of starting trial treatment with the exception of alopecia

32. History of hypersensitivity to the known active substances (atezolizumab, bevacizumab

and chemotherapy drugs) or to any of the excipients.

33. History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other

recombinant human or humanised antibodies.

34. Judgment by the Investigator that the patient should not participate in the study if

the patient is unlikely to comply with study procedures, restrictions and

requirements.

35. Women who are pregnant or in the period of lactation.

36. Sexually active men and women of childbearing potential who are not willing to use an

effective contraceptive method during the trial and up to 6 months after discontinuing

trial treatment

Studien-Rationale

Primary outcome:

1. Progression-free survival (PFS) rate at 12 months according to RECIST v1.1 (Time Frame - 12 months from randomisation):
The primary objective of this study is to explore the clinical efficacy of atezolizumab and bevacizumab combined with chemotherapy in patients with EGFR-mutant advanced NSCLC after failure of standard EGFR TKIs.



Secondary outcome:

1. Adverse events according to CTCAE v5.0 (Time Frame - from the date of randomisation until 90 days after the last dose of protocol treatment):
To assess the safety and tolerability of the treatment.

2. Overall survival (Time Frame - through study completion, from the date of randomisation until death, including OS rate at 12 months.):
OS is defined as the time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.

3. Objective response (Time Frame - From date of randomisation until date of treatment completion (until documented disease progression, death or any other causes), assessed up to 2 years.):
Objective response is defined as best overall response (CR or PR) across all assessment time-points according to RECIST criteria v1.1, from randomisation until the end of protocol treatment.

4. Quality of Life Core Questionnaire (EORTC QLQ-C30) (Time Frame - from baseline up to 12 months or until disease progression, whatever is first.):
Quality of life will be assessed by the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30). The key QoL outcome is the time to deterioration (TTD) in the QLQ-C30 global health status/global QoL.

5. Quality of Life lung cancer-specific module (QLQ-LC13) (Time Frame - from baseline up to 12 months or until disease progression, whatever is first.):
Lung cancer associated symptoms will be measured by the lung cancer-specific module (QLQ-LC13).

6. Extra-cranial PFS (Time Frame - through study completion, from date of randomisation to documentation of PD outside the CNS, assessed up to 2 years):
Extra-cranial progression-free-survival is the time from randomisation to documentation of disease progression outside the central nervous system (CNS) as per RECIST criteria or death, whichever occurred first.

7. Intracranial PFS (Time Frame - through study completion, from date of randomisation to first documented radiographic evidence of CNS progression, assessed up to 2 years.):
Intracranial progression-free-survival is defined as the time from randomisation to first documented radiographic evidence of CNS progression. CNS progression is defined as progression due to newly developed CNS lesions and/or progression of pre-existing baseline CNS lesions.

Studien-Arme

  • Active Comparator: Arm A
    Atezolizumab (1200 mg) Q3W, until PD Bevacizumab (15 mg/kg), Q3W, until PD Carboplatin (AUC5) Q3W, 4-6 cycles Paclitaxel (200 mg/m2), Q3W, 4-6 cycles
  • Active Comparator: Arm B
    Atezolizumab (1200 mg), Q3W, until PD Bevacizumab (15 mg/kg), Q3W, until PD Pemetrexed (500 mg/m2), Q3W, until PD

Geprüfte Regime

  • Atezolizumab (Tecentriq):
    Patients in both treatment arms will receive atezolizumab at a fixed dose of 1200 mg i.v. on day one of every 3-week (3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Treatment beyond RECIST-defined progression will be allowed if patient is continuing to derive clinical benefit.
  • Bevacizumab (Avastin):
    Patients in both treatment arms will receive bevacizumab at a dose of 15 mg/kg i.v. on day one of every 3-week (+/- 3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment.
  • Carboplatin:
    Patients in treatment Arm A will receive carboplatin, AUC5 every 3 weeks for 4-6 cycles.
  • Paclitaxel:
    Patients in treatment Arm A will receive paclitaxel, 200 mg/m2, every 3 weeks for 4-6 cycles.
  • Pemetrexed (Alimta):
    Patients in treatment Arm B will receive Pemetrexed, 500 mg/m2 every 3 weeks until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment.

Quelle: ClinicalTrials.gov


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