Inclusion Criteria:
1. Patients must have histologically confirmed stage IV lung cancer (patients with both
non-small cell lung cancer and cancer that has transformed to small cell lung cancer
at osimertinib progression will also be considered eligible if osimertinib treatment
is planned to continue post-progression).
2. Male or female patients >=18 years of age
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
4. Documented activating EGFR mutation (Exon 19 deletion, Exon 19 insertion, E709K,
G719X, S768I, V769L, T790M, L833F, L833V, V834L, H835L, L858R, A859S, K860I, L861Q,
A871E, V843I, or H870R) on tumor sample or cell-free DNA sample performed in Clinical
Laboratory Improvement Amendments (CLIA)-approved laboratory.
5. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria.
6. Clinical laboratory values as specified below within 7 days before the first dose of
study drug (if applicable):
1. Absolute neutrophil count (ANC) > 1500/mm³
2. Absolute lymphocyte count > 500 mm3
3. Platelets > 100,000/mm³
4. Hemoglobin (Hgb) > 9 g/dL. Values must be obtained without need for red blood
cell transfusion support within 14 days. However, erythrocyte growth factor is
allowed as per published American Society of Clinical Oncology (ASCO) guidelines.
5. Total bilirubin <=1.5 x upper limit of normal (ULN), or direct bilirubin <= 1.5 x
ULN for patients with Gilbert's syndrome.
6. Serum glutamic-oxaloacetic transaminase (SGOT) / aspartate aminotransferase (AST)
and serum glutamic-pyruvic transaminase (SGPT) / alanine aminotransferase (ALT) <
2.5 x ULN. AST and/or ALT may be up to 5 x ULN if with known liver metastases.
7. Renal function as defined by calculated creatinine clearance >=30 ml/min
(Cockcroft-Gault Formula).
7. Willing to provide blood and tissue for correlative research purposes
8. Willing to undergo pre-treatment research biopsy, OR donate archived tissue from a
biopsy performed within 30 days of the first dose of study drug is available
9. Female patients who:
1. Are postmenopausal (see Appendix 6) for at least 1 year before the screening
visit, OR
2. Are surgically sterile, OR
3. If they are of childbearing potential, agree to practice 1 highly effective
method of contraception and 1 additional effective (barrier) method at the same
time (see Appendix 6), from the time of signing the informed consent through 180
days after the last dose of study drug, OR
4. Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
symptothermal, post-ovulation methods], withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception. Female and
male condoms should not be used together.)
10. Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:
1. Agree to practice effective barrier contraception during the entire study
treatment period and through 120 after the last dose of study drug, OR
2. Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
symptothermal, post-ovulation methods], withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception. Female and
male condoms should not be used together.)
11. Voluntary written consent must be given before performance of any study-related
procedure not part of standard of care, with the understanding that consent may be
withdrawn by the patient at any time without prejudice to future medical care.
12. Currently receiving and tolerating osimertinib 80 mg PO daily with no current grade 2
or greater AE attributable to osimertinib.
13. Evidence of disease progression on imaging (computerized tomography (CT) scan,
magnetic resonance imaging (MRI), or Positron Emission Tomography (PET) CT within the
last 30 days.
14. Resolution of all acute toxic effects of prior chemotherapy, immunotherapy,
radiotherapy or surgical procedures to less than or equal to grade 2 per the National
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version
5.0.
Inclusion Criteria (Cohort A): Must meet inclusion criteria below in addition to 1-14
above, however, patients with evidence of small cell transformation will not be
allowed.
15. The following inclusion criteria must also be met: Patients must be naïve to
chemotherapy or immunotherapy for treatment of metastatic NSCLC. Patients who have
received adjuvant or neoadjuvant chemotherapy for surgically resectable NSCLC, or
chemotherapy + radiation for locally advanced NSCLC, will be allowed if it is equal to
or greater than 12 months since completing their treatment.
16. Patients must be currently receiving osimertinib 80 mg as either 1st or 2nd line
therapy for the treatment of metastatic disease or have evidence of metastatic disease
recurrence while receiving adjuvant osimertinib therapy.
Inclusion Criteria (Cohort B): Must meet inclusion criteria below in addition to 1-7, 9-12,
and 14. Inclusion criteria 8 and 13 are not required.
15. The following inclusion criteria must also be met: Currently receiving osimertinib 80
mg as 1st line therapy for metastatic NSCLC. Patients who have received adjuvant or
neoadjuvant chemotherapy for surgically resectable NSCLC, or chemotherapy + radiation for
locally advanced NSCLC, will be allowed if it is equal to or greater than 12 months since
completing their treatment.
16. Meet RECIST 1.1 criteria for partial response (PR) or stable disease (SD) to
osimertinib, including a confirmation scan.
17. Have received osimertinib 80 mg for a minimum of 90 days, but no more than 180 days.
Exclusion Criteria
1. Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is
considered to be over 25%.
2. Prior allogeneic bone marrow or organ transplantation
3. Known Gastrointestinal (GI) disease or GI procedures that could interfere with the
oral absorption or tolerance of alisertib. Examples include, but are not limited to
partial gastrectomy, history of small intestine surgery, and celiac disease
4. Inability to swallow oral medication or inability or unwillingness to comply with the
administration requirements related to alisertib.
5. Known history of uncontrolled sleep apnea syndrome and other conditions that could
result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary
disease; requirement for supplemental oxygen.
6. Requirement for constant administration of proton pump inhibitor, Histamine 2 (H2)
antagonist, or pancreatic enzymes throughout the study. The intermittent use of
H2-antagonists and antacids (including carafate) is only allowed within these
guidelines:
1. H2 antagonists until Day -1 and after the dosing of alisertib is done
2. Antacid formulations until 2 hours before dosing and after 2 hours following
dosing.
3. Proton Pump Inhibitor (PPI) is allowed until Day -5 of first alisertib dose. PPIs
are prohibited throughout the study.
7. Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities. Prior to study entry, any
electrocardiogram (ECG) abnormality at Screening has to be documented by the
investigator as not medically relevant.
8. QT interval corrected (QTc) using Fridericia's method (QTCF) > 470 milliseconds (msec)
9. Female subject who is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum beta-human chorionic gonadotropin
(Beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not
required for post-menopausal or surgically sterilized women.
10. Female patient who intend to donate eggs (ova) during the course of this study or 4
months after receiving their last dose of study drug(s).
11. Male patients who intend to donate sperm during the course of this study or 4 months
after receiving their last dose of study drug(s).
12. Other severe acute or chronic medical or psychiatric condition, including uncontrolled
diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement
for pancreatic enzymes, any condition that would modify small bowel absorption of oral
medications, or laboratory abnormality that may increase the risk associated with
study participation or investigational product administration or may interfere with
the interpretation of study results and, in the judgment of the investigator, would
make the patient inappropriate for enrollment in this study.
13. Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer or breast cancer, or
thyroid cancer after curative therapy
14. Patients who are currently receiving treatment with contraindicated QTc prolonging
medications or potent CYP3A4 inducers/inhibitors, as listed in the protocol, if that
treatment cannot be either discontinued or switched to a different medication prior to
first day of study treatment. The washout period for the medication is provided in the
protocol
15. Patients with central nervous system (CNS) metastases who are neurologically unstable
(as defined by need for steroids in last 14 days).
16. Known leptomeningeal carcinomatosis.
Exclusion Criteria (Cohort A): Must meet exclusion criteria 1-16 above in addition to
the following:
17. Known small cell lung cancer transformation on osimertinib resistance biopsy.
18. Known EGFR C797S osimertinib resistance mutation, MET amplification, oncogenic fusion
involving NTRK, RET, ALK, ROS-1, or BRAF, BRAF V600E, or oncogenic KRAS mutation
determined by CLIA-approved test on osimertinib resistance biopsy or cell-free DNA
test performed at osimertinib resistance.
Exclusion Criteria (Cohort B): Must meet exclusion criteria 1-16 above in addition to the
following:
17. Evidence of complete response (CR) or progressive disease (PD) to osimertinib by RECIST
1.1 criteria on imaging within 30 days prior to starting alisertib.
18. Prior treatment with adjuvant osimertinib. 19. Prior treatment with an EGFR TKI other
than osimertinib.
