| Eligibility |
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed non-small cell lung
cancer
- Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to
curative intent therapy
- EGFR exon 21 L858R or exon 19 deletion mutation, or T790M mutation that was acquired
following treatment with first or second generation tyrosine kinase inhibitor (TKI).
Eligible EGFR mutation must be confirmed by Clinical Laboratory Improvement Amendments
(CLIA) certified test
- Patients must have either a) disease progression on osimertinib within 30 days prior
to study enrollment. Patients who continued osimertinib beyond disease progression
(e.g. patients with oligo-progression who had radiation) may be eligible on further
disease progression after discussion with principal investigator OR b) disease
progression on osimertinib and one other line of systemic therapy (if the other
systemic therapy line included PD-L1 blockade then the last dose of the latter must be
more than 3 months prior to study enrollment). The number of patients who had prior
osimertinib and other line of systemic therapy will be capped at 25% in each study arm
- Local ablative therapy (e.g. stereotactic radiosurgery [SRS], stereotactic body
radiation therapy [SBRT], or surgery) for brain or systemic metastases prior to
enrollment is allowed
- Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Absolute neutrophil count (ANC) > 1500/ mm^3 (within 28 days before the first dose of
study drug)
- Platelets > 100,000/mm^3 (within 28 days before the first dose of study drug)
- Hemoglobin > 9 g/dL. Values must be obtained without need for myeloid growth factor or
transfusion support within 14 days, however, erythrocyte growth factor is allowed as
per published American Society of Clinical Oncology (ASCO) guidelines (within 28 days
before the first dose of study drug)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 28 days before the first
dose of study drug)
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
ULN (may be up to 5 x ULN if with known liver metastases [mets]) (within 28 days
before the first dose of study drug)
- ALISERTIB ARM: Creatinine clearance (Cockcroft-Gault Formula) >= 30 ml/min (within 28
days before the first dose of study drug)
- SAPANISERTIB ARM: Creatinine clearance (Cockcroft-Gault Formula) >= 60 ml/min (within
28 days before the first dose of study drug)
- SAPANISERTIB ARM: Glycosylated hemoglobin (HbA1c) < 7.0% (within 28 days before the
first dose of study drug)
- SAPANISERTIB ARM: Fasting serum glucose (FSG) =< 130 mg/dL (within 28 days before the
first dose of study drug)
- SAPANISERTIB ARM: Fasting triglycerides (TG) =< 300 mg/dL (within 28 days before the
first dose of study drug)
- Willing to provide blood and tissue for correlative research purposes
- Female patients who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- 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, from the time of signing the informed consent through 180 days after the
last dose of study drug, OR
- 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, postovulation methods], withdrawal, spermicides
only, and lactational amenorrhea are not acceptable methods of
contraception. Female and male condoms should not be used together.)
- Male patients, even if surgically sterilized (i.e., status postvasectomy), who:
- Agree to practice effective barrier contraception during the entire study
treatment period and through 120 days after the last dose of study drug, OR
- 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, postovulation methods], withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception. Female and
male condoms should not be used together.)
- 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
- Ability to swallow oral medications
- Resolution of all acute toxic effects of prior treatments (chemotherapy,
immunotherapy, radiotherapy, surgical procedures) to grade 1 or less (National Cancer
Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 5.0).
Patients should have tolerated osimertinib 80 mg PO daily with no current grade 2 or
greater adverse events (AE) attributable to osimertinib
Exclusion Criteria:
- ALISERTIB ARM: Radiation therapy to more than 25% of the bone marrow. Whole pelvic
radiation is considered to be over 25%
- ALISERTIB ARM: Prior allogeneic bone marrow or organ transplantation
- Known gastrointestinal (GI) disease or GI procedures that could interfere with the
oral absorption or tolerance of study drugs. Examples include, but are not limited to
partial gastrectomy, history of small intestine surgery, and celiac disease. In
addition, patients with enteric stomata are also excluded
- Inability to swallow oral medication or inability or unwillingness to comply with the
administration requirements related to study drugs
- ALISERTIB ARM: 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
- Requirement for constant administration of proton pump inhibitor, H2 antagonist, or
pancreatic enzymes throughout the study. The intermittent use of proton pump inhibitor
(PPI), H2-antagonists and antacids (including carafate) is only allowed within the
following guidelines:
- H2 receptor antagonists until 24 hours (h) of the first dose of study drug
- Antacid formulations until 2 hours before dosing and after 2 hours following
dosing.
- PPI is allowed until 5 days before the first study treatment dose. PPIs are
prohibited throughout the study
- SAPANISERTIB ARM: Patients receiving systemic corticosteroids (either intravenous [IV]
or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1
week before administration of the first dose of study drug
- History of any of the following within the last 6 months before administration of the
first dose of the drug:
- New York Heart Association (NYHA) class III or IV heart failure, ischemic
myocardial event, including angina requiring therapy and artery revascularization
procedures
- Ischemic cerebrovascular event, including transient ischemic attack and artery
revascularization procedures
- Pulmonary embolism
- Any of the following cardiac criteria
- Mean resting corrected QT interval (QTc using Fridericia's formula) > 470 msec or
torsades de pointes
- Any clinically important abnormalities in rhythm, conduction or morphology of
resting electrocardiogram (ECG) e.g., complete left bundle branch block, third
degree heart block, second degree heart block, PR interval > 250 msec. Prior to
study entry, any ECG abnormality at Screening has to be documented by the
investigator as not medically relevant.
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years of age in
first degree relatives or any concomitant medication known to prolong the QT
interval
- SAPANISERTIB ARM: Significant active cardiovascular or pulmonary disease including:
- Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg, diastolic
blood pressure > 95 mm Hg). Use of anti-hypertensive agents to control
hypertension before cycle 1 day 1 is allowed
- Pulmonary hypertension
- Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gas
analysis or pulse oximetry on room air
- Significant valvular disease; severe regurgitation or stenosis by imaging
independent of symptom control with medical intervention, or history of valve
replacement
- Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation
pneumonitis which required steroid treatment, or any evidence of clinically active
interstitial lung disease
- Patients with uncharacterized eye disorders
- Unstable central nervous system (CNS) metastasis (as defined by need for steroids in
last 14 days)
- Patients who are currently receiving treatment with contraindicated QTc prolonging
medications (list provided https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf) or
potent CYP3A4 inducers/inhibitors (list provided
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interac
tions-table-substrates-inhibitors-and-inducers), if that treatment cannot be either
discontinued or switched to a different medication prior to first day of study
treatment
- Known leptomeningeal carcinomatosis
- SAPANISERTIB ARM: Known hepatitis B surface antigen-positive, or known or suspected
active hepatitis C infection
- ALISERTIB ARM: Known human immunodeficiency virus (HIV) positive patients who meet the
following criteria will be considered eligible:
- CD4 count > 350 cells/mm^3
- Undetectable viral load
- Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents
- No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic
infections
- SAPANISERTIB ARM: Known HIV positive patients
- Use of investigational drugs within 30 days or 5 half-lives of enrollment (whichever
was greater)
- ALISERTIB ARM: Previous treatment with aurora kinase inhibitors
- SAPANISERTIB ARM: Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors,
TORC1/2 inhibitors or TORC1 inhibitors
- Diagnosed or treated for another malignancy within 2 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 after curative therapy
- Other severe acute or chronic medical or psychiatric condition, 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
- 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.
- Female patient who intend to donate eggs (ova) during the course of this study or 180
days after receiving their last dose of study drug(s)
- 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)
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