Status and phase
Conditions
Treatments
About
PACE is a prospective multicenter single-arm investigator-initiated phase II trial that examines the value of a treatment escalation strategy by the addition of platinum-based doublet chemotherapy to osimertinib in patients with treatment-naïve NSCLC harboring L858R or del19 EGFR mutation who are suspected to have poor response upon single-agent TKI treatment.
Full description
Hypothesize, that in patients with on-label osimertinib 1st-line treatment of stage IIIB or IV NSCLC, a biomarker-driven escalation of osimertinib therapy with a platinum-based chemotherapy regimen will effectively enhance PFS and subsequently OS. Lack of EGFRm clearance after an osimertinib treatment period of 3 weeks as assessed by liquid biopsy will be used to predict sub-optimal response. In these patients, treatment will be escalated after approx. 7 weeks of on-label osimertinib monotherapy by adding up to 4 cycles of a combination regimen of pemetrexed and cisplatin or carboplatin. Patients with complete EGFR plasma clearance will continue to receive standard of care osimertinib and will not be eligible for the study. Primary outcome measure will be PFS, which will be compared to historical data on TKI monotherapy from persistent EGFR shedder from the FLAURA trial.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Pre-Screening Phase
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:
Treatment Phase
Exclusion criteria
Pre-Screening Phase
History of another primary malignancy. Exceptions are:
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.
Treatment Phase
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:
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.
Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
Absolute neutrophil count below lower limit of normal (<LLN) *
Platelet count below lower limit of normal (<LLN) *
Hemoglobin <90 g/L *
* The use of granulocyte colony stimulating factor support, platelet transfusion and blood transfusions to meet these criteria is not permitted.
Alanine aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases;
Aspartate aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases;
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;
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.
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
Primary purpose
Allocation
Interventional model
Masking
50 participants in 1 patient group
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Central trial contact
Martin Sebastian, MD; Jan Stratmann, MD
Data sourced from clinicaltrials.gov
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