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Clinical Trial 18915

Cancer Type: Thoracic
Study Type: Treatment
NCT#: NCT02503722

Phase: Phase I
Prinicipal Investigator:

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Study Title

A Phase 1 Trial of MLN0128 (TAK-228) in Combination with Osimertinib (AZD9291) in Advanced EGFR Mutation Positive Non-Small Cell Lung Cancer (NSCLC) After Progression on a Previous EGFR Tyrosine Kinase Inhibitor


The purpose of this study is to test the safety of two investigational drugs, MLN0128 (TAK-228) and AZD9291 when given together. MLN0128 (TAK-228) is experimental and AZD9291(osimertinib) is approved by the FDA for lung cancer treatment by itself. Both drugs have been tested in humans but combining MLN0128 (TAK-228) and AZD9291 together has not been tested in humans. This study tests different doses of the drugs to see which dose is safer in people with lung cancer.


Primary Objectives: - Dose Escalation Phase: To determine the safety and recommended phase II dose (RP2D) of MLN0128 (TAK-228) in combination with osimertinib (AZD9291) in patients with advanced EGFRm NSCLC and who are resistant to previous EGFR-TKI therapy. - Dose Expansion Phase: To evaluate the safety and preliminary efficacy of MLN0128 (TAK-228) in combination with osimertinib (AZD9291) in patients with advanced EGFRm NSCLC that is negative for the resistance mutation T790M (T790M-) and who are resistant to previous EGFR-TKI therapy. Secondary Objectives: - To evaluate pharmacokinetic profiles of MLN0128 (TAK-228) in combination with osimertinib (AZD9291). - To evaluate the response rate, disease control rate and progression free survival of the combination. - To explore biomarkers of response and resistance to the combination by studying baseline biopsies, resistance biopsies, and serial plasma DNA specimens.




AZD9291 (Osimertinib); MLN0128 (); Osimertinib (); TAK-228 (MLN0128)

Inclusion Criteria

Inclusion Criteria

  • Stage IV or recurrent/metastatic histologically or cytologically confirmed non-squamous NSCLC
  • NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion)
  • Progressive disease on osimertinib (AZD9291) given first line.
  • For the dose expansion portion ONLY, patient must: 1) have progression of disease with first line osimertinib administered for advanced or metastatic disease as the last previous systemic treatment., 2) be treatment naïve for other 3rd generation EGFR-TKI (CO-1686) and mTOR inhibitors
  • Must have measurable disease by RECIST 1.1, defined as at least one lesion that can be accurately measured in at least one dimension ≥ 10mm (≥ 1cm) by CT imaging or MRI within 28 days prior to start of protocol therapy. The CT from a combined PET/CT may be used if it is of diagnostic quality as defined in Section 11. Laboratory parameters are not acceptable as the only evidence of disease.
  • For the dose expansion, no other systemic therapies for advanced/metastatic disease is permissible after first line osimertinib
  • Prior history of brain metastases are eligible provided: (a) The brain metastases have been treated. Patients with small brain metastases for which radiation or surgery is not indicated, may be eligible on discussion with the study chair. Brain metastases that were managed with first line osimertinib is permissible, provided that the brain metastases are stable on a baseline MRI and for whom radiation or surgical resection is not indicated. (b) The patient is asymptomatic from the brain metastases (c) Corticosteroids and anti-epileptic drugs prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration (d) The brain metastases are stable on pre-registration imaging
  • Adequate organ and marrow function as defined per protocol.
  • 18 years of age or older. Because no dosing or adverse event data are currently available on the use of MLN0128 (TAK-228) in patients > Must have had sufficient time between a prior therapy and resolution of toxicities from the prior therapies prior to registration as follows: (a) Prior EGFR inhibitor: A minimum of 7 days must have elapsed from the last dose of the prior EGFR inhibitor and resolution of any drug-related toxicity to > Available for follow-up of their disease after treatment until progressive disease is documented and resolution of related adverse events until < grade 2

  • Exclusion Criteria

  • Intercurrent illness that would prevent the protocol being followed, including but not limited to: Uncontrolled diabetes mellitus (HbA1c > 7%); Prior history of pneumonitis; Active infections; Gastrointestinal disease limiting the ability to swallow oral medications or absorb oral medications including inflammatory bowel disease; malabsorption syndromes
  • Active other malignancy or prior curatively treated malignancy within the last 3 years
  • Concurrent anti-cancer therapy
  • History of hypersensitivity attributed to compounds of similar chemical or biologic composition to MLN0128 or AZD9291
  • Pregnant women or women who are breast feeding are not eligible for the study; women of child bearing potential must have a negative serum or urine pregnancy test within 7 days of registration
  • Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months following the date of last dose of MLN0128 and AZD9291
  • Congestive heart failure (even if medically controlled), unstable angina, active cardiomyopathy or a family history of prolonged QTc syndrome
  • Inability to discontinue drugs that are strong cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2C19 (CYP2C19) inhibitors and/or inducers
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy

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