| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced NSCLC with common EGFR-Mutation |
| fortgeschrittenes nicht-kleinzelliges Lungenkarzinom mit EGFR-Mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced NSCLC with common EGFR-Mutation |
| fortgeschrittenes nicht-kleinzelliges Lungenkarzinom mit EGFR-Mutation |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of biomarker-driven escalation of osimertinib therapy with a combination platinum-based regimen by assessment of progression-free survival (PFS). |
|
| E.2.2 | Secondary objectives of the trial |
| To further assess efficacy such as tumor response, overall survival of biomarker-driven escalation of osimertinib therapy, and to investigate safety, quality of life and patient reported outcomes. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Pre-Screening Phase:
1. Provision of written informed consent for the pre-screening phase.
2. Age ≥ 18 years
3. Histologically confirmed stage IIIB or IV NSCLC
4. Tumor positive for Ex19del or L858R EGFR mutation assessed according to local standard.
5. Planned treatment with osimertinib 80mg/d 1st-line as SoC or ongoing treatment for a maximum of 28 days
6. Available radiographic chest and abdominal CT or MRI scans performed up to 42 days before initial osimertinib treatment
7. Previously untreated with systemic treatment given as primary therapy for advanced or metastatic disease, except for osimertinib for a maximum of 28 days (see above)
8. At least one measurable site of disease as defined by RECISTv1.1 criteria
9. Female subjects of childbearing potential (WOCBP) should be using highly effective contraceptive measures and must have a negative urine or serum pregnancy test within 7 days prior to start of study treatment and must not be breast-feeding prior to start of trial.
10. Non-child-bearing potential must be evidenced by fulfilling one of the following criteria at screening:
• Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments
• Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution.
• Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
Treatment Phase:
1. Provision of informed consent for the screening and treatment phase prior to any study specific procedures, including screening evaluations that are not SoC.
2. Persistent mEGFR ctDNA signal 21 to 28 days after osimertinib initiation for advanced of metastatic ex19del or L858R EGFR mutation positive NSCLC as assessed by a liquid biopsy during the pre-screening phase of the trial in the central laboratory.
3. ECOG performance status 0-2.
4. 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.
5. Osimertinib no longer than 10 weeks before start of chemotherapy in the treatment phase |
|
| E.4 | Principal exclusion criteria |
Pre-Screening Phase
1. History of another primary malignancy. Exceptions are:
• Malignancy treated with curative intent and with no known active disease ≥6 months before the first dose of IMP, and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease
2. History of leptomeningeal carcinomatosis
3. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the follow-up period of an interventional study
4. Previous enrolment in the present study.
Treatment Phase
1. Symptomatic CNS metastases. [Patients with asymptomatic brain metastases may be included.]
2. Currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (at least 3 weeks prior) ). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.
3. Osimertinib had to be withheld or administered at reduced dosage for toxicity management for more than 7 days or persistent unresolved toxicities which preclude study treatment.
4. Any unresolved toxicities other than osimertinib from prior therapy greater than CTCAE grade 1 at the time of starting study treatment, with the exception of alopecia and grade 2 prior platinum-therapy–related neuropathy.
5. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib. History of hypersensitivity to any of the chemotherapy drugs used.
6. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
7. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.
8. Any of the following cardiac criteria:
a. Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value
b. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block.
c. Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: Serum/plasma potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < LLN), congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes. [Note: Electrolyte abnormalities (hypokalaemia, hypomagnesaemia, hypocalcaemia) can be corrected to be within normal ranges prior to first dose. No more than two re-tests may be performed in order to meet this criterion.]
9. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
10. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
a. Absolute neutrophil count below lower limit of normal (<LLN) *
b. Platelet count below lower limit of normal (<LLN) *
c. Hemoglobin <90 g/L *
* The use of granulocyte colony stimulating factor support, platelet transfusion and blood transfusions to meet these criteria is not permitted.
d. Alanine aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases;
e. Aspartate aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases;
f. Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of documented Gilbert’s Syndrome [unconjugated hyperbilirubinaemia] or liver metastases;
g. Serum creatinine >1.5 times ULN concurrent with creatinine clearance <60 mL/min [calculated by Cockcroft and Gault equation]—confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN.
h. INR ≤ 1.4 or aPTT ≤ 40 sec during the last 7 days before chemotherapy [Subjects under therapeutic anticoagulation are permitted.]
11. Women who are pregnant or breast-feeding |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival (PFS1) using investigator assessments according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1) defined as number of months from first dose of chemotherapy until last follow-up, PD, death or withdrawal of consent. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Radiologic assessments (CT or MRI scans) according to standard of care until progressive disease. During chemotherapy imaging is performed every 6 weeks and during maintenance/follow-up every 12 weeks.
Until last follow-up (until the end of trial but for a minimum of 24 months from study inclusion), progressive disease, death or withdrawal of consent. |
|
| E.5.2 | Secondary end point(s) |
Efficacy endpoints:
• PFS0 measured from first dose of Osimertinib
• Overall Survival (OS1), measured from cycle 1 day 1 of chemotherapy.
• Overall Survival (OS0), measured from first dose of osimertinib
• Overall Response Rate (ORR1) (base line before initiation of chemotherapy)
• Overall Response Rate (ORR0) (base line before first dose of osimertinib)
• Disease Control Rate (DCR1) accordingly
• Subject disposition
Safety and tolerability: Frequency and severity of Adverse Events, grading according to CTCAE V5.0
Quality of Life: PRO-CTCAE, EORTC QLQ-30 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy
At least 24 months from inclusion; every 9-12 weeks or more frequently until death, loss to follow-up, or study termination by the Sponsor, whichever occurs first.
Safety and tolerability
- Continuously until End of Treatment (approx. 30 days after the last dose of study drug treatment)
Quality of Life
- pre-dose at cycle 1, day 1
- at the start of each treatment cycle, i.e. at intervals of approximately 3 weeks
- End of Treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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