A Phase 1 Study of Temozolomide in Combination With Targeted Therapy for NSCLC Patients With CNS Progression on Either Osimertinib or Lorlatinib
Overview
- Phase
- Phase 1
- Intervention
- Temozolomide plus Osimertinib
- Conditions
- Non Small Cell Lung Cancer
- Sponsor
- University of Colorado, Denver
- Enrollment
- 1
- Locations
- 1
- Primary Endpoint
- Adverse events
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This trial is testing two novel combinations (temozolomide plus osimertinib OR temozolomide plus lorlatinib) which have not been evaluated in clinical trials. Thus, the exact benefits of these novel combinations are unclear. However, based on the mechanism of action of temozolomide and CNS(Central Nervous System) penetration/activity in other tumor types, it is hypothesized that adding temozolomide to osimertinib or temozolomide to lorlatinib may provide improvement in CNS disease control in patients with CNS progression on either of these latter two TKIs (Tyrosine kinase inhibitors).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision to sign and date the consent form.
- •Stated willingness to comply with all study procedures and be available for the duration of the study.
- •Male or female subject ≥ 18 years old
- •ECOG performance status 0-2
- •Stage IV NSCLC with progression of disease in the CNS on osimertinib 80 mg daily for patients with EGFR activating mutations (EGFR exon 19 deletions or EGFR L858R exon 21 point mutations) -OR- Stage IV NSCLC with progression of disease in the CNS on lorlatinib 100 mg daily for patients with ALK fusions
- •Evaluable CNS disease is required, measurable CNS disease is not required
- •Patients who are on corticosteroids must be on stable or decreasing doses of corticosteroids for at least 14 days.
- •Adequate hematologic function defined as:
- •ANC ≥ 1.5 x 10\^9/L
- •Hemoglobin ≥ 9 g/dL
Exclusion Criteria
- •Patients with compound mutations in EGFR will be excluded from this study. Compound mutations are defined as 2 or more mutations in the EGFR tyrosine kinase domain with the following exceptions:
- •C797S and EGFR exon 19 deletion or EGFR exon 21 point mutation and
- •T790M mutation and EGFR exon 19 deletion or EGFR exon 21 point mutation.
- •Prior therapy with temozolomide.
- •Patients must not receive surgery or radiation as local therapies for the progressing CNS disease for which they are being enrolled on this trial. Ventriculoperitoneal shunt placement will be allowed for leptomeningeal disease with symptomatic hydrocephalis. Radiation or surgery for progressing extra-CNS disease is allowed.
- •Patients with a history of an allergic/hypersensitivity reaction to any component of temozolomide, dacarbazine, osimertinib (for temozolomide plus osimertinib arm) or lorlatinib (for temozolomide plus lorlatinib arm).
- •Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia.
- •Patients with a history of baseline QTcF interval greater than 470 msec on electrocardiogram for the osimertinib plus temozolomide arm only.
- •Unstable or clinically significant concurrent medical condition, psychiatric illness or social situation that would, in the opinion of the investigator, jeopardize the safety of a subject and/or their compliance with the protocol.
- •Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy. Suppressive therapy for chronic infections allowed, for example:
Arms & Interventions
Exon 19 deletions or L858R point mutations in exon 21
Will include patients with exon 19 deletions or L858R point mutations in exon 21 of the epidermal growth factor receptor (EGFR) gene. Temozolomide plus Osimertinib will be the study drug combination administered. Osimertinib will be given at a fixed dose of 80 mg daily for dose level 1, with a potential to increase to 160 mg daily for dose level 2. Temozolomide will be started at a dose of 150 mg/m2 on days 1-5 of a 28 day cycle for cycle 1 and if tolerated will be increased to 200 mg/m2 on days 1-5 of a 28 day cycle for cycles 2+. There will be a -1 dose level.
Intervention: Temozolomide plus Osimertinib
Patients with anaplastic lymphoma kinase (ALK) fusions
Will include patients with anaplastic lymphoma kinase (ALK) fusions. Temozolomide plus Lorlatinib will be the study drug combination administered. Lorlatinib will be given at a fixed dose of 100 mg daily. Temozolomide will be started at a dose of 150 mg/m2 on days 1-5 of a 28 day cycle for cycle 1 and if tolerated will be increased to 200 mg/m2 on days 1-5 of a 28 day cycle for cycles 2+. There will be a -1 dose level depending on tolerability.
Intervention: Temozolomide plus Lorlatinib
Outcomes
Primary Outcomes
Adverse events
Time Frame: Up to 3.5 years
Adverse events will be determined by the common terminology criteria for adverse events version 5.0
Secondary Outcomes
- Overall response rate(Up to 3.5 years)
- CNS PFS(Up to 3.5 years)
- Extra-CNS PFS(Up to 3.5 years)
- Overall Survival(Up to 3.5 years)
- CNS response rate(Up to 3.5 years)
- Extra-CNS response rate(Up to 3.5 years)
- Incidence of improvement in neurological function(Up to 3.5 years)
- Progression free survival (PFS)(Up to 3.5 years)