Evaluation of Chemotherapy Addition in EGFR-Mutant Advanced NSCLC with Persistent Plasma ctDNA EGFR Mutation Post-Osimertinib Therapy
- Trial ID
- 2024-517965-18-00
- Protocol
- PACE-LUNG
- Sponsor
- Goethe University Frankfurt
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the efficacy of **biomarker-driven** escalation of osimertinib therapy with a combination platinum-based regimen by evaluating progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) harboring common EGFR mutations. This objective is clinically relevant as it aims to determine whether the addition of chemotherapy can improve outcomes in patients who continue to exhibit plasma ctDNA EGFR mutations after three weeks of first-line treatment with osimertinib. The study focuses on the potential benefits of combining osimertinib with platinum-based chemotherapy agents such as carboplatin, cisplatin, and pemetrexed, which are administered intravenously, to enhance treatment efficacy and delay disease progression.
Participants
The clinical trial involves participants diagnosed with **advanced non-small cell lung cancer (NSCLC)** characterized by common EGFR mutations. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically confirmed stage IIIB or IV NSCLC with tumors positive for Ex19del or L858R EGFR mutations. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are in relatively good health despite their condition. The trial population was selected based on specific inclusion criteria, such as the presence of a persistent mEGFR ctDNA signal after osimertinib initiation and the availability of radiographic imaging. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **osimertinib** therapy escalation with a platinum-based chemotherapy regimen in patients with advanced non-small cell lung cancer (NSCLC) harboring common EGFR mutations. This study is a randomized, double-blind, controlled trial, conducted over an estimated duration from November 2021 to September 2026. Participants will be randomly assigned to receive either the standard osimertinib treatment or an escalated regimen including **carboplatin**, **cisplatin**, and **pemetrexed**. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with evaluations based on the Response Evaluation Criteria in Solid Tumours (RECIST 1.1).
Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening phase, involves obtaining informed consent and verifying eligibility criteria, such as the presence of persistent mEGFR ctDNA signal and a histologically confirmed diagnosis of stage IIIB or IV NSCLC. Participants must also demonstrate an ECOG performance status of 0-2 and have not received systemic treatment for advanced disease, except for a maximum of 28 days of osimertinib. Follow-up visits are scheduled to monitor treatment response and adverse events, with assessments conducted at regular intervals. The end-of-study visit will conclude the participant's involvement, with final evaluations of treatment efficacy and safety.
Participant involvement is expected to last up to four treatment cycles, with each cycle corresponding to the maximum treatment period of four weeks. Conditions that may lead to early termination from the study include disease progression, withdrawal of consent, or the occurrence of unacceptable adverse events. The trial is conducted in accordance with ethical standards, ensuring that all participants provide informed consent and are fully aware of the study's requirements and potential risks.
Treatment
The clinical trial involves the administration of several **chemotherapy** agents, including **carboplatin**, **cisplatin**, **pemetrexed**, and **osimertinib**. **Carboplatin** is provided as a concentrate for solution for infusion, with a maximum daily dose of 750 mg and a total dose not exceeding 3000 mg over a treatment period of up to 4 weeks. The administration route is intravenous, and the dosing schedule is determined based on the specific protocol requirements. Participant compliance is monitored through regular assessments and documentation of infusion sessions.
**Cisplatin** is also administered as a concentrate for solution for infusion, with a maximum daily dose of 75 mg/m² and a total dose not exceeding 300 mg/m² over a 4-week treatment period. The administration is intravenous, and dosing is adjusted according to the participant's body surface area. Compliance is ensured through scheduled visits and infusion records.
**Pemetrexed** is provided in the form of a powder for solution for infusion, with a maximum daily dose of 500 mg/m² and a total dose not exceeding 2000 mg/m² over a 4-week period. The administration route is intravenous, and dosing is based on body surface area calculations. Participant adherence is monitored through infusion logs and follow-up appointments.
**Osimertinib** is administered orally in the form of film-coated tablets, available in 40 mg and 80 mg strengths. The maximum daily dose is 80 mg, with a total dose not exceeding 6720 mg over a 4-week treatment period. Compliance is monitored through pill counts and patient diaries, ensuring adherence to the prescribed dosing schedule.
Throughout the trial, all medications are administered according to the study protocol, with careful monitoring of participant compliance and adverse events. The trial aims to assess the efficacy of biomarker-driven escalation of osimertinib therapy in combination with a platinum-based regimen, focusing on progression-free survival as the primary endpoint.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)**. This primary endpoint will be measured using investigator assessments according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). PFS is defined as the number of months from the first dose of chemotherapy until the last follow-up, progression of disease (PD), death, or withdrawal of consent. The trial aims to assess the efficacy of biomarker-driven escalation of osimertinib therapy with a combination platinum-based regimen by evaluating PFS.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Provision of written informed consent for the pre-screening phase.
- Age ≥ 18 years
- Histologically confirmed stage IIIB or IV NSCLC
- Tumor positive for Ex19del or L858R EGFR mutation assessed according to local standard
- Planned treatment with osimertinib 80mg/d 1st-line as SoC or ongoing treatment for a maximum of 28 days
- Available radiographic chest and abdominal CT or MRI scans performed up to 42 days before initial osimertinib treatment
- 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)
- At least one measurable site of disease as defined by RECISTv1.1 criteria
- 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. Further information in Appendix 20.7 (Definition of Women of Childbearing Potential and Acceptable Contraceptive Methods)
- 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
- Provision of informed consent for the screening and treatment phase prior to any study specific procedures, including screening evaluations that are not SoC
- 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.
- ECOG performance status 0-2
- 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.
- Osimertinib no longer than 10 weeks before start of chemotherapy in the treatment phase
Exclusion Criteria
- 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
- History of leptomeningeal carcinomatosis
- 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
- Previous enrolment in the present study.
- Symptomatic CNS metastases. [Patients with asymptomatic brain metastases may be included.]
- History of leptomeningeal carcinomatosis
- 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) (Appendix 20.5). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4
- 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.
- 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.
- 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
- 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
- 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.
- 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.]
- 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
- nadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: a. Absolute neutrophil count below lower limit of normal (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.]
- Judgement 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.
- Women who are pregnant or breast-feeding
- Male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 4 months (male patients) or 6 weeks (female patients) after the last dose of osimertinib and 6 months after the last dose of chemotherapy
- Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
- Treatment with an investigational drug within five half-lives of the compound or 3 months, whichever is greater
- Any chemotherapy, biologic, or hormonal therapy for cancer treatment used concurrently or within 6 months prior to first dose of study treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
- Major surgery (as defined by the Investigator) within 4 weeks prior to starting the study; patients must have recovered from effects of preceding major surgery. Note: Local non-major surgery for palliative intent (e.g., surgery of isolated lesions) is acceptable
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 12 Nov 2021 | 400 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TAGRISSO 80 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 80 | 4 | PRD3702398 |
CISPLATIN | Test | — | INTRAVENOUS USE | 75 | 4 | SUB07483MIG |
PEMETREXED | Test | — | INTRAVENOUS USE | 500 | 4 | SUB09655MIG |
CARBOPLATIN | Test | — | INTRAVENOUS USE | 750 | 4 | SUB06614MIG |
TAGRISSO 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 80 | 4 | PRD3702399 |