Clinical Trials /

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

NCT04085315

Description:

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

Related Conditions:
  • Non-Small Cell Lung Carcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Alisertib in Combination With Osimertinib in Metastatic EGFR-mutant Lung Cancer
  • Official Title: A Phase I/Ib Study of Alisertib in Combination With Osimertinib in Metastatic EGFR-mutant Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 19655
  • NCT ID: NCT04085315

Conditions

  • Lung Cancer Metastatic
  • EGFR Gene Mutation

Interventions

DrugSynonymsArms
OsimertinibTagrissoDose Escalation: Cohort 1
AlisertibMLN8237Dose Escalation: Cohort 1

Purpose

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

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.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation: Cohort 1ExperimentalPatients 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 befor any additional cohorts can be opened.
  • Osimertinib
  • Alisertib

Eligibility 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 Epithelial Growth Factor Receptor (EGFR) mutation (Exon 19
             deletion, G719X, S768I, V769L,T790M, L833F, L858R, or L861Q) 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

          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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:First 28 days of study treatment
Safety Issue:
Description:≤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

Measure:Overall Response Rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Duration of Response (DR)
Time Frame:Up to 2 years
Safety Issue:
Description: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)
Measure:Depth of response (DOR)
Time Frame:Up to 2 years
Safety Issue:
Description: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).
Measure:Disease Control Rate (DCR)
Time Frame:Up to 2 years
Safety Issue:
Description: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).
Measure:Progression Free Survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Central Nervous System (CNS) disease control rate
Time Frame:Up to 2 years
Safety Issue:
Description: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).
Measure:Intratumoral TPX2 expression by Immunohistochemistry (IHC)
Time Frame:From pretreatment biopsy to time of response, up to 2 years
Safety Issue:
Description: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.
Measure:Area Under Curve (AUC)
Time Frame:1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days
Safety Issue:
Description: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
Measure:Maximum (or peak) serum concentration (Cmax)
Time Frame:1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description: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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Collin Blakely

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