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

NCT04085315 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 19655NCI-2019-05913
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Lung Cancer Metastatic; EGFR Gene Mutation

Outcome Measures

Primary Outcomes (3)

• Determination of Maximum Tolerated Dose (MTD) (Cohort A)

  The MTD is the highest dose at which no more than one instance of a dose-limiting toxicity is observed among the 6 participants treated.

  First 28 days of study treatment (1 cycle is 28 days)

• Proportion of patients experiencing dose limiting toxicity (DLT) (Cohort A)

  Less than or at least 1 out of 6 at highest dose level below the maximal administered dose. If 0 of these 3 additional participants experience a dose limiting toxicity (DLT) (1 of 6), proceed to the next dose level. If 1 or more of the 3 additional participants experience DLT (2 of 6), then dose escalation is stopped, and this dose is declared the maximal administered dose (highest dose administered). Three (3) additional participants will be entered at the next lowest dose level if only 3 participants were treated previously at that dose.

  First 28 days of study treatment (1 cycle is 28 days)

• Proportion of patients experiencing serious adverse event (SAE)

  The proportion of participants experiencing an adverse event classified as an SAE will be reported by grade and type according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5, with exact 95% confidence intervals

  Up to 2 years

Secondary Outcomes (11)

• Overall Response Rate (ORR)

  Up to 2 years

• Median Duration of Response (DR)

  Up to 2 years

• Percentage of tumor shrinkage

  Up to 2 years

• Disease Control Rate (DCR)

  Up to 2 years

• Median Progression Free Survival (PFS)

  Up to 2 years

Study Arms (4)

Dose Escalation (Closed to Enrollment)

EXPERIMENTAL

Patients will continue to receive osimertinib 80 mg PO daily as part of standard of care therapy during screening and study treatments. Alisertib will be administered to eligible patients in combination with osimertinib at doses ranging from 20 mg to 50 mg PO twice daily on days 1-3, 8-10, and 15-17 of a 28-day cycle. The starting alisertib dose will be 30 mg twice daily (dose level 1). All patients at a given dose level must complete the DLT period before any additional cohorts can be opened.

Drug: Osimertinib; Drug: Alisertib

Dose Expansion: Cohort A

EXPERIMENTAL

Stage IV EGFR-mutant NSCLC currently receiving and progressing on osimertinib who have received no more than one additional line of systemic cancer therapy other than osimertinib (e.g., chemotherapy +/- immunotherapy, amivantamab +/- Lazertinib) for metastatic disease. Patients may receive alisertib therapy until lack of clinical benefit or intolerable toxicity.

Drug: Osimertinib; Drug: Alisertib

Dose Expansion: Cohort B

EXPERIMENTAL

Stage IV EGFR-mutant NSCLC patients who are currently receiving first line osimertinib treatment and have received at least 3 months, but no more than 6 months, of osimertinib with a best response of PR or SD. Patients may receive alisertib therapy until lack of clinical benefit or intolerable toxicity.

Drug: Osimertinib; Drug: Alisertib

Dose Expansion: Cohort C

EXPERIMENTAL

Stage IV EGFR-mutant NSCLC patients with no known tumor non-synonymous TP53 genomic alteration who are currently receiving first line osimertinib treatment and have received at least 3 months, but no more than 6 months, of osimertinib with a best response of PR or SD. Patients may receive alisertib therapy until lack of clinical benefit or intolerable toxicity.

Drug: Osimertinib; Drug: Alisertib

Interventions

Osimertinib DRUG

Osimertinib is a medication used to treat non-small-cell lung carcinomas with a specific mutation. It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor. Patients will be receiving full dose osimertinib (80 mg PO daily) as part of the patient's current standard of care.

Also known as: Tagrisso

Dose Escalation (Closed to Enrollment); Dose Expansion: Cohort A; Dose Expansion: Cohort B; Dose Expansion: Cohort C

Alisertib DRUG

Alisertib is an orally available selective aurora A kinase inhibitor. Alisertib will be administered to eligible patients in combination with osimertinib at doses ranging from 20 mg to 50 mg PO twice daily on days 1-3, 8-10, and 15-17 of a 28-day cycle. The starting alisertib dose for Cohort 1 will be 30 mg twice daily (dose level 1).

Also known as: MLN8237

Dose Escalation (Closed to Enrollment); Dose Expansion: Cohort A; Dose Expansion: Cohort B; Dose Expansion: Cohort C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed stage IV non-small cell lung cancer.
• 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\^3
• Absolute lymphocyte count \> 500 mm\^3
• Platelets \> 100,000/mm\^3
• 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). Patients with Gilbert's syndrome may be allowed on study if total bilirubin is \<= 3 x upper limit of normal (ULN) if direct bilirubin is \<= 1.5 x upper limit of normal (ULN).
• 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 60 days of the first dose of study drug is available.

You may not qualify if:

• Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is considered to be over 25%.
• 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.
• 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, 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:
• 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.
• QT interval corrected (QTc) using Fridericia's method (QTCF) \> 470 milliseconds (msec). The following formula can be used to calculate QTcF for subjects with a wide QRS complex caused by the bundle branch block, QTcF = measured QTcF - (QRS - 100msec).
• 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).
• 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.

Sponsors & Collaborators

• Collin Blakely: lead
• Puma Biotechnology, Inc.: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

RECRUITING

Related Publications (1)

• Shah KN, Bhatt R, Rotow J, Rohrberg J, Olivas V, Wang VE, Hemmati G, Martins MM, Maynard A, Kuhn J, Galeas J, Donnella HJ, Kaushik S, Ku A, Dumont S, Krings G, Haringsma HJ, Robillard L, Simmons AD, Harding TC, McCormick F, Goga A, Blakely CM, Bivona TG, Bandyopadhyay S. Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer. Nat Med. 2019 Jan;25(1):111-118. doi: 10.1038/s41591-018-0264-7. Epub 2018 Nov 26.

  PMID: 30478424 BACKGROUND

MeSH Terms

Interventions

osimertinib; MLN 8237

Study Officials

• Collin Blakely, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lisa Tan

CONTACT

(415) 353-7710; Lisa.Tan@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor, Medicine

Study Record Dates

• First Submitted: September 6, 2019
• First Posted: September 11, 2019
• Study Start: November 12, 2019
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: June 10, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)