Alisertib in Combination With Osimertinib in Metastatic EGFR-mutant Lung Cancer

  • STATUS
    Recruiting
  • End date
    May 31, 2023
  • participants needed
    38
  • sponsor
    Collin Blakely
Updated on 31 May 2021
ct scan
cancer
measurable disease
lung cancer
neutrophil count
EGFR

Summary

This phase I/Ib trial studies the side effects and best dose of alisertib when given together with osimertinib in treating patients with EGFR-mutated stage IV lung cancer. Alisertib may stop the growth of tumor cells by blocking a specific protein (Aurora Kinase A) that researchers believe may be important for the growth of lung cancer. Osimertinib may reduce tumor growth by blocking the action of a certain mutant protein (EGFR). This study may help researchers test the safety of alisertib at different dose levels in combination with osimertinib, and to find out what effects, good and/or bad, it has on EGFR-mutated lung cancer.

Description

PRIMARY OBJECTIVE:

I. To determine the safety and tolerability of combination treatment with alisertib and osimertinib in patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) who have progressed on osimertinib monotherapy and to identify a recommended phase 2 dose for the combination.

SECONDARY OBJECTIVES:

I. To provide preliminary efficacy data for the combination of alisertib and osimertinib in metastatic EGFR-mutant lung cancer patients who have progressed on osimertinib monotherapy.

PRIMARY OBJECTIVE:

I. To determine the safety and tolerability of combination treatment with alisertib and osimertinib in patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) who have progressed on osimertinib monotherapy and to identify a recommended phase 2 dose for the combination.

SECONDARY OBJECTIVES:

I. To provide preliminary efficacy data for the combination of alisertib and osimertinib in metastatic EGFR-mutant lung cancer patients who have progressed on osimertinib monotherapy.

II. To determine whether pre-treatment TPX2 positivity by immunohistochemistry (IHC) correlates with response to alisertib + osimertinib combination therapy.

III. To evaluate the pharmacokinetics of alisertib in combination with osimertinib.

IV. To evaluate the central nervous system (CNS) response rate of alisertib + osimertinib.

EXPLORATORY (CORRELATIVE) OBJECTIVES:

I. To identify tumor co-occurring genomic alterations that correlate with response to alisertib + osimertinib treatment.

II. To determine whether phosphorylated (phospho)-aurora kinase A (AURKA) levels correlate with response to alisertib + osimertinib treatment.

III. To determine whether tumor NF-kappaB activity correlates with response to alisertib + osimertinib treatment.

IV. To evaluate for changes in circulating tumor deoxyribonucleic acid (ctDNA) during treatment with combination alisertib + osimertinib.

V. To identify mechanisms of resistance to alisertib + osimertinib. VI. Safety in East Asian vs. Non-East Asian population. VII. Pharmacokinetics in East Asian vs. Non-East Asian.

OUTLINE: This is a dose-escalation study of alisertib.

Patients receive alisertib orally (PO) twice daily (BID) on days 1-3, 8-10, and 15-17. Patients also receive osimertinib PO once daily (QD) on days 1-28. Cycles repeat every 28 days the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 to 6 months for up to 2 years.

Details
Condition EGFR Gene Mutation, Lung Metastases, Pulmonary Metastasis, Lung Cancer Metastatic, Lung Metastasis
Treatment alisertib, Osimertinib
Clinical Study IdentifierNCT04085315
SponsorCollin Blakely
Last Modified on31 May 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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)
Male or female patients >=18 years of age
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
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
Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
Clinical laboratory values as specified below within 7 days before the first dose of study drug (if applicable)
Absolute neutrophil count (ANC) > 1500/mm
Absolute lymphocyte count > 500 mm3
Platelets > 100,000/mm
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
Total bilirubin <=1.5 x upper limit of normal (ULN), or direct bilirubin <= 1.5 x ULN for patients with Gilbert's syndrome
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
Renal function as defined by calculated creatinine clearance >=30 ml/min (Cockcroft-Gault Formula)
Willing to provide blood and tissue for correlative research purposes
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
Female patients who
Are postmenopausal (see Appendix 6) 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 (see Appendix 6), 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, post-ovulation 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 post-vasectomy), who
Agree to practice effective barrier contraception during the entire study treatment period and through 120 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, post-ovulation 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
Currently receiving and tolerating osimertinib 80 mg PO daily with no current grade 2 or greater AE attributable to osimertinib
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
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
\. The following inclusion criteria must also be met: Patients must be nave
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
\. Patients must be currently receiving osimertinib 80 mg as either 1st or
nd 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
\. 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
\. Meet RECIST 1.1 criteria for partial response (PR) or stable disease (SD)
to osimertinib, including a confirmation scan
\. Have received osimertinib 80 mg for a minimum of 90 days, but no more
than 180 days

Exclusion Criteria

Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is considered to be over 25%
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
H2 antagonists until Day -1 and after the dosing of alisertib is done
Antacid formulations until 2 hours before dosing and after 2 hours following dosing
Proton Pump Inhibitor (PPI) is allowed until Day -5 of first alisertib dose. PPIs are prohibited throughout the study
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
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)
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
Prior allogeneic bone marrow or organ transplantation
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
Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to alisertib
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
QT interval corrected (QTc) using Fridericia's method (QTCF) > 470 milliseconds (msec)
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 4 months after receiving their last dose of study drug(s)
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
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
Patients with central nervous system (CNS) metastases who are neurologically unstable (as defined by need for steroids in last 14 days)
Known leptomeningeal carcinomatosis
Exclusion Criteria (Cohort A): Must meet exclusion criteria 1-16 above in
addition to the following
\. Known small cell lung cancer transformation on osimertinib resistance
biopsy
\. 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
\. 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
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