Temozolomide with Osimertinib or Lorlatinib for the Treatment of Stage IV Non-small Cell Lung Cancer in Patients with CNS Progression on Either Osimertinib or Lorlatinib
- 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
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Stage IV non-small cell lung cancer (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
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- Hemoglobin >= 9 g/dL
- Platelets >= 150 x 10^9/L
- Total bilirubin =< 1.5 x upper limit of normal (ULN). For subjects with Gilbert’s disease, total bilirubin =< 3 x ULN
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN. For subjects with documented liver metastases, ALT and AST =< 5 x ULN
- Estimated glomerular filtration rate (eGFR) >= 40 mL/minute as determined using the Cockcroft-Gault formula
- Patients must be capable of taking oral medication and have no known gastrointestinal malabsorption disorder
- Patients must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable
- Brain magnetic resonance imaging (MRI) with contrast is required to have demonstrated progressive CNS disease or a lumbar puncture (LP) with cytology is required to have demonstrated progressive leptomeningeal disease on osimertinib or lorlatinib within 21 days of starting study drugs. Computed tomography (CT) of brain with contrast can be used to demonstrate progressive disease if patients have a documented anaphylaxis to gadolinium contrast and/or other contraindication to MRI (e.g., severe claustrophobia that cannot be managed with anxiolytics)
- Patients must not be pregnant. Women/men of reproductive potential must have agreed to use an effective contraceptive method (see section 6.6 for list of effective methods). Women must use an effective contraceptive method during the study and for 6 months following the last dose. Men having sex with women of reproductive potential are required to use effective contraception during the study and for 6 months following the last dose. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. Women of reproductive potential are not to be nursing during the study and for six months following the last dose of all study drugs
- Women on the lorlatinib arm who are of reproductive potential agree to use a non-hormonal method of contraception during the study and for the time periods outlined above
- 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 corrected QT interval by Fridericia's formula (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: Subjects with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) with adequate antiviral therapy to control viral load would be allowed. Subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy
- Treated with any investigational drug or chemotherapy within 3 weeks or =< 5 half-lives of first dose of study treatment
- No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years
- Patient is not taking any prohibited medications. (Strong CYP3A inducers should be stopped greater than 3 half-lives prior to starting study drugs for patients on either study drug combination. Moderate inducers of CYP3A should be stopped greater than 3 half-lives prior to starting study drugs for patients receiving lorlatinib plus temozolomide. Strong CYP3A inhibitors should be stopped greater than 3 half-lives prior to starting study drugs for patients receiving lorlatinib plus temozolomide.)
I. Determination of the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of temozolomide and osimertinib.
II. Determination of the MTD and RP2D of temozolomide and lorlatinib.
I. Central nervous system (CNS) response rate per investigator assessment.
II. Extra-CNS response rate per investigator assessment.
III. Overall response rate including both CNS and extra-CNS sites per investigator assessment.
IV. Improvement in neurological function.
V. Progression free survival (PFS) per investigator assessment.
VI. CNS PFS per investigator assessment.
VII. Extra-CNS PFS per investigator assessment.
VIII. Overall survival (OS).
I. Assess for MGMT promotor methylation status in patients with available tumor tissue (CNS or extra-CNS, archival or fresh).
OUTLINE: This is a dose-escalation study of temozolomide. Patients are assigned to 1 of 2 arms.
ARM I: Patients receive osimertinib orally (PO) once daily (QD) and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive lorlatinib PO QD temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Trial Phase Phase I
Trial Type Treatment
University of Colorado Hospital
Jose Maria Pacheco
- Primary ID 20-0138.cc
- Secondary IDs NCI-2020-13878
- Clinicaltrials.gov ID NCT04541407