| Eligibility |
Inclusion Criteria:
1. Provision to sign and date the consent form.
2. Stated willingness to comply with all study procedures and be available for the
duration of the study.
3. Male or female subject = 18 years old
4. ECOG performance status 0-2
5. 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
6. Evaluable CNS disease is required, measurable CNS disease is not required
7. Patients who are on corticosteroids must be on stable or decreasing doses of
corticosteroids for at least 14 days.
8. Adequate hematologic function defined as:
- ANC = 1.5 x 10^9/L
- Hemoglobin = 9 g/dL
- Platelets = 150 x 10^9/L
9. Adequate hepatic function defined as:
- Total bilirubin =1.5 x upper limit of normal (ULN). For subjects with Gilbert's
Disease, Total bilirubin =3 x ULN
- ALT and AST =3 x ULN. For subjects with documented liver metastases, ALT and AST
=5×ULN
10. Adequate renal function defined as:
- Estimated glomerular filtration rate (eGFR) = 40 mL/minute as determined using
the Cockcroft-Gault formula
11. Patients must be capable of taking oral medication and have no known gastrointestinal
malabsorption disorder.
12. 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.
13. Brain MRI with contrast is required to have demonstrated progressive CNS disease or an
LP with cytology is required to have demonstrated progressive leptomeningeal disease
on osimertinib or lorlatinib within 21 days of starting study drugs. 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).
14. 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" (see section 6.6 for list of
effective contraceptive methods) also includes heterosexual celibacy and surgery
intended to prevent pregnancy (or with a sideeffect 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.
15. 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.
Exclusion Criteria:
1. 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:
1. C797S and EGFR exon 19 deletion or EGFR exon 21 point mutation and
2. T790M mutation and EGFR exon 19 deletion or EGFR exon 21 point mutation.
2. Prior therapy with temozolomide.
3. 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.
4. 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).
5. 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.
6. Patients with a history of baseline QTcF interval greater than 470 msec on
electrocardiogram for the osimertinib plus temozolomide arm only.
7. 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.
8. Clinically significant acute infection requiring systemic antibacterial, antifungal,
or antiviral therapy. Suppressive therapy for chronic infections allowed, for example:
Subjects with HIV/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.
9. Treated with any investigational drug or chemotherapy within 3 weeks or = 5 half-lives
of first dose of study treatment.
10. 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.
11. Patient is not taking any prohibited medications listed in section 6.4. (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.)
|
