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

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ClinicalTrials.gov Identifier: NCT04085315
Recruitment Status : Recruiting
First Posted : September 11, 2019
Last Update Posted : September 4, 2020
Sponsor:
Collaborator:
Takeda
Information provided by (Responsible Party):
Collin Blakely, University of California, San Francisco

Brief Summary:
This is a phase I/Ib, open-label, single-center, single-arm study of alisertib and osimertinib for patients with stage IV EGFR-mutated lung cancer, incorporating both a dose escalation and dose-expansion phase

Condition or disease Intervention/treatment Phase
Lung Cancer Metastatic EGFR Gene Mutation Drug: Osimertinib Drug: Alisertib Phase 1

Detailed Description:

The dose-escalation phase will consist of a modified 3+3 dose escalation and will be open to patients with metastatic lung cancer with an activating EGFR mutation who have progressed on and are currently receiving osimertinib therapy. The dose-escalation and expansion phases will be open to patients who have received any number of therapies as long as they are currently being treated with and tolerating osimertinib 80 mg orally once per day, and who have demonstrated radiographic progression by RECIST 1.1 criteria on their most recent scan.

Primary Objective:

To determine the safety and tolerability of the combination osimertinib + alisertib in patients with advanced EGFR-mutant NSCLC and identify a recommended phase II dose.

Secondary Objectives:

  1. To evaluate the clinical efficacy of adding alisertib to osimertinib compared to "historical" data of platinum doublet chemotherapy in patients who have progressed on osimertinib monotherapy.
  2. To explore tumor biomarkers, including TPX2, that predict response to osimertinib + alisertib.
  3. To evaluate alisertib and osimertinib pharmacokinetics
  4. To evaluate the CNS response rate of alisertib + osimertinib

Patients may continue treatment indefinitely until disease progression, intolerance, or other contraindication to study treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/Ib Study of Alisertib in Combination With Osimertinib in Metastatic EGFR-mutant Lung Cancer
Actual Study Start Date : November 12, 2019
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : September 30, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: Dose Escalation: Cohort 1
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
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.
Other Name: Tagrisso

Drug: Alisertib
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).
Other Name: MLN8237




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: First 28 days of study treatment ]
    ≤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.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: Up to 2 years ]
    defined as the best overall response recorded from the start of the treatment until disease progression from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined based on RECIST 1.1 criteria. We will compute a 95% confidence interval using a binomial distribution.

  2. Duration of Response (DR) [ Time Frame: Up to 2 years ]
    The DR for CR and PR will be measured from the date that the best response if first recorded until the date that PD is documented over the period of 2 years. For patients who continue treatment post-progression, the date of PD documentation will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum)

  3. Depth of response (DOR) [ Time Frame: Up to 2 years ]
    The depth of response will be assessed by RECIST 1.1 criteria. The DOR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

  4. Disease Control Rate (DCR) [ Time Frame: Up to 2 years ]
    Defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

  5. Progression Free Survival (PFS) [ Time Frame: Up to 2 years ]
    PFS will be calculated as 1+ the number of days from the first dose of alisertib to documented radiographic progression or death due to any cause over a period of 2 years. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the mean PFS with 95% confidence interval.

  6. Overall Survival (OS) [ Time Frame: Up to 2 years ]
    OS will be calculated as 1+ the number of days from the first dose of alisertib to death due to any cause over a period of 2 years. The Kaplan-Meier analysis will be used to calculate the mean OS with 95% confidence interval.

  7. Central Nervous System (CNS) disease control rate [ Time Frame: Up to 2 years ]
    Defined as the percentage of patients who have achieved CR, PR, or SD in the CNS for at least 12 weeks. The CNS disease control rate will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

  8. Intratumoral TPX2 expression by Immunohistochemistry (IHC) [ Time Frame: From pretreatment biopsy to time of response, up to 2 years ]
    Pre-treatment tumor biopsy formalin-fixed paraffin-embedded (FFPE) samples will be stained for TPX2 expression by IHC. TPX2 IHC staining will be scored using the following scale: 0, 0-10% of tissue stained positive; 1, 10-20% stained positive; 2, 20-40% stained positive; 3, 40-70% stained positive; and 4, > 70% positive cells. The sum of staining score index (intensity + extent) will be designated as follows: 0-2, negative expression; 3-4, strong expression. The IHC score will be generated from three different areas of the slides and an average score will be calculated for each sample. We will determine whether there is a difference in TPX2 staining between responders and non-responders to alisertib + osimertinib treatment by the Fisher's exact test.

  9. Area Under Curve (AUC) [ Time Frame: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days ]
    Plasma will be collected to measure the drug concentrations at the indicated time points and area under curve (AUC) 0-24 hours. The area under the curve (AUC) is the definite integral in a plot of drug concentration in blood plasma vs. time

  10. Maximum (or peak) serum concentration (Cmax) [ Time Frame: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days ]
    Plasma will be collected to measure the drug concentrations at the indicated time points and Cmax will be calculated. It is a standard measurement in pharmacokinetics

  11. Amount of time (maximum) drug concentration in serum (Tmax) [ Time Frame: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days ]
    Plasma will be collected to measure the drug concentrations at the indicated time points and Tmax will be calculated. It is a standard measurement in pharmacokinetics



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 (see Appendix 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. 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.

    • 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 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04085315


Contacts
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Contact: Collin Blakely, MD, PhD 877-827-3222 cancertrials@ucsf.edu

Locations
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United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Collin Blakely, MD, PhD    877-827-3222    cancertrials@ucsf.edu   
Principal Investigator: Collin Blakely, MD, PhD         
Sponsors and Collaborators
Collin Blakely
Takeda
Investigators
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Principal Investigator: Collin Blakely, MD, PhD University of California, San Francisco
Publications:
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Responsible Party: Collin Blakely, Assistant Professor, Medicine, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT04085315    
Other Study ID Numbers: 19655
NCI-2019-05913 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
First Posted: September 11, 2019    Key Record Dates
Last Update Posted: September 4, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Osimertinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action