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Clinical Trial 18915

Cancer Type: Thoracic
Interventions:AZD9291 (Osimertinib); MLN0128 (); Osimertinib (); TAK-228 (MLN0128)

Study Type: Treatment
Phase of Study: Phase I

  • Eric Haura

Call 813-745-6100
or 1-800-679-0775

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.

Inclusion Criteria

  • Histologically or cytologically confirmed diagnosis of non-squamous EGFR mutation (L858R, G719X, exon 19 deletion, L861Q) positive Non-small Cell Lung Cancer (NSCLC)
  • Advanced or metastatic disease that is incurable
  • Availability of tissue for correlative analyses collected after progression on the most recent epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI); if tissue is not available at that time point, a re-biopsy is required prior to registration
  • Have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky more than or equal to 70%)
  • Patients with a prior history of brain metastases are eligible provided: The brain metastases have been treated; The patient is asymptomatic from the brain metastases; Corticosteroids prescribed for the management of brain metastases have been discontinued at least 2 weeks prior to registration; The brain metastases are stable on pre-registration imaging.
  • Adequate biochemistry, bone marrow and cardiac function DOSE ESCALATION PHASE:
  • Progressive disease on at least one prior EGFR TKI administered for advanced/ metastatic disease
  • May have had more than one prior EGFR TKI therapy and previous 3rd generation EGFR-TKIs are permissible (for example CO-1686 [EGFR inhibitor CO-1686], AZD9291) DOSE EXPANSION PHASE:
  • Progressive disease on one prior EGFR TKI (erlotinib or gefitinib or afatinib), which must be the last prior therapy and tumor must be EGFR negative for T790M based on tissue collected after progression on the prior EGFR TKI and T790M status confirmed by central testing prior to registration
  • Prior therapy with 3rd generation TKI including CO-1686, AZD9291 is not permissible DOSE ESCALATION AND DOSE EXPANSION PHASE:
  • 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 equal to or less than grade 2 except for alopecia
  • Prior chemotherapy, radiation therapy and surgery are permissible as follows: Chemotherapy- a minimum of 21 days must have elapsed from the last dose and resolution of toxicity excluding equal to or less than grade 2 peripheral neuropathy or alopecia; Surgery- a minimum of 21 days must have elapsed following major surgery and complete wound healing must have occurred; Radiation- minimum of 14 days must have elapsed following radiation therapy and resolution of all radiation induced toxicity.
  • Ability to understand and the willingness to sign a written informed consent document
  • Available for long-term follow-up of their disease after treatment

  • 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