Clinical Trials /

Osimertinib With Alisertib or Sapanisertib for the Treatment of Osimertinib-Resistant EGFR Mutant Stage IIIB or IV Non-Small Cell Lung Cancer

NCT04479306

Description:

This phase Ib trial studies the side effects and best dose of alisertib or sapanisertib, in combination with osimertinib, in treating patients with EGFR mutated stage IIIB or IV non-small cell lung cancer that remains despite treatment with osimertinib (osimertinib resistant). Osimertinib, alisertib, and sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The goal of part 1 of this trial is to find the highest tolerable dose of alisertib or sapanisertib in combination with osimertinib that can be given to patients with EGFR mutated non-small cell lung cancer. The goal of part 2 of this trial is to learn if the dose of alisertib or sapanisertib found in part 1 can help control EGFR mutated non-small cell lung cancer when given in combination with osimertinib.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Osimertinib With Alisertib or Sapanisertib for the Treatment of Osimertinib-Resistant EGFR Mutant Stage IIIB or IV Non-Small Cell Lung Cancer
  • Official Title: A Ph1b Study of Osimertinib + Alisertib or Sapanisertib for Osimertinib-Resistant EGFR Mutant Non-Small Cell Lung Cancer (NSCLC) (Crossover Study)

Clinical Trial IDs

  • ORG STUDY ID: 2019-1196
  • SECONDARY ID: NCI-2020-05282
  • SECONDARY ID: 2019-1196
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04479306

Conditions

  • EGFR T790M Mutation Positive Non-Small Cell Lung Carcinoma
  • Recurrent Lung Non-Small Cell Carcinoma
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IV Lung Cancer AJCC v8
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVB Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
AlisertibAurora A Kinase Inhibitor MLN8237, MLN-8237, MLN8237Arm A (osimertinib, alisertib)
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoArm A (osimertinib, alisertib)
SapanisertibINK-128, INK128, MLN-0128, MLN0128, TAK-228Arm B (osimertinib, sapanisertib)

Purpose

This phase Ib trial studies the side effects and best dose of alisertib or sapanisertib, in combination with osimertinib, in treating patients with EGFR mutated stage IIIB or IV non-small cell lung cancer that remains despite treatment with osimertinib (osimertinib resistant). Osimertinib, alisertib, and sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The goal of part 1 of this trial is to find the highest tolerable dose of alisertib or sapanisertib in combination with osimertinib that can be given to patients with EGFR mutated non-small cell lung cancer. The goal of part 2 of this trial is to learn if the dose of alisertib or sapanisertib found in part 1 can help control EGFR mutated non-small cell lung cancer when given in combination with osimertinib.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the safety and the recommended phase 2 dose (RP2D) of osimertinib plus alisertib
      II. Determine the safety and the recommended phase 2 dose (RP2D) of osimertinib plus
      sapanisertib.

      SECONDARY OBJECTIVES:

      I. Determine the objective response rate (ORR) to the study combinations
      (osimertinib+alisertib and osimertinib+sapanisertib) in osimertinib-resistant EGFR mutant
      non-small cell lung cancer (NSCLC).

      II. Determine the progression free survival of the study combinations (osimertinib+alisertib
      and osimertinib+sapanisertib) in osimertinib-resistant EGFR mutant NSCLC.

      III. Determine the disease control rate (DCR) of the study combinations
      (osimertinib+alisertib and osimertinib+sapanisertib) in osimertinib-resistant EGFR mutant
      NSCLC.

      IV. Explore biomarkers associated with response/resistance of the study combinations
      (osimertinib+aliertib and osimertinib+sapanisertib) in osimertinib-resistant EGFR mutant
      NSCLC.

      OUTLINE: This is a dose-escalation study of alisertib and sapanisertib. Patients are assigned
      to 1 of 2 arms.

      ARM A: Patients receive osimertinib orally (PO) once daily (QD) on days 1-28 and alisertib PO
      QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or
      unacceptable toxicity. Patients who develop progressive disease may crossover to Arm B.

      ARM B: Patients receive osimertinib PO QD on days 1-28 and sapanisertib PO QD on days 1-28.
      Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
      Patients who develop progressive disease may crossover to Arm A.

      After completion of study treatment, patients are followed up at 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (osimertinib, alisertib)ExperimentalPatients receive osimertinib PO QD on days 1-28 and alisertib PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who develop progressive disease may crossover to Arm B.
  • Alisertib
  • Osimertinib
Arm B (osimertinib, sapanisertib)ExperimentalPatients receive osimertinib PO QD on days 1-28 and sapanisertib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who develop progressive disease may crossover to Arm A.
  • Osimertinib
  • Sapanisertib

Eligibility Criteria

        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 (ie, 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose (RP2D) of osimertinib and alisertib combination (Arm A)
Time Frame:Up to 30 days
Safety Issue:
Description:Will employ the Bayesian optimal interval (BOIN) design to find the maximum tolerated dose (MTD) in each treatment arm. RP2D will be the same as the MTD or a lower dose level if pharmacokinetic/pharmacodynamics data indicate that the lower dose level can be as efficacious with possible lower toxicities

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:At end of 4th cycle (1 cycle = 28 days)
Safety Issue:
Description:Will be estimated with 95% confidence intervals.
Measure:Progression-free survival
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Estimated using the method of Kaplan and Meier.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

July 16, 2020