Tampa, Florida 33612


This phase I trial studies the side effects and best dose of transducer of regulated CREB activity 1/2 (TORC1/2) inhibitor INK128 when given together with epidermal growth factor receptor (EGFR) inhibitor AZD9291in treating patients with advanced EGFR mutation positive non-small cell lung cancer that has spread to other places in the body (advanced) and has progressed after treatment with an EGFR tyrosine kinase inhibitor. TORC1/2 inhibitor INK128 and EGFR inhibitor AZD9291 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Study summary:

PRIMARY OBJECTIVES: I. To determine the safety and recommended phase II dose (RP2D) of MLN0128 (TORC1/2 inhibitor INK128) in combination with AZD9291 (EGFR inhibitor AZD9291) in patients with advanced epidermal growth factor receptor mutation positive (EGFRm) non-small cell lung cancer (NSCLC). (Dose escalation phase) II. To evaluate the safety and preliminary efficacy of MLN0128 in combination with AZD9291 in patients with advanced EGFRm NSCLC that is negative for the resistance mutation T790M (T790M negative [-]). (Dose expansion phase) SECONDARY OBJECTIVES: I. To evaluate pharmacokinetic profiles of MLN0128 in combination with AZD9291. II. To evaluate the response rate, disease control rate and progression free survival of the combination. III. To explore biomarkers of response and resistance to the combination by studying baseline biopsies, resistance biopsies, and serial plasma deoxyribonucleic acid (DNA) specimens. OUTLINE: This is a dose-escalation study of TORC1/2 inhibitor INK128. Patients receive TORC1/2 inhibitor INK128 orally (PO) once daily (QD) on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 (day 1 is omitted in course 1). Patients also receive EGFR inhibitor AZD9291 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, and then every 8 weeks thereafter.


Inclusion Criteria: - Patients must have histologically or cytologically confirmed diagnosis of non squamous EGFR mutation (L858R, G719X, exon 19 deletion, L861Q) positive 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 - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 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 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 90 g/L (or >= 9 g/dL) - Platelets >= 100 x 10^9/L - Calculated creatinine clearance of > 50 mL/min using Cockcroft Gault equation - Total bilirubin =< 1.5 institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Glycosylated hemoglobin (Hb A1c) =< 7% - Fasting triglycerides =< 300mg/dL - Fridericia's correction formula (QTcF) =< 470 msec - DOSE ESCALATION PHASE: - Progressive disease on at least one prior EGFR TKI administered for advanced/ metastatic disease - Patients 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 =< 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 =< 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 (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; 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 are ineligible because of the potential for pharmacokinetic interactions with MLN0128 and AZD9291; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated



Primary Contact:

Principal Investigator
Penelope Bradbury
University Health Network Princess Margaret Cancer Center LAO

Backup Contact:


Location Contact:

Tampa, Florida 33612
United States

Eric B. Haura
Phone: 800-456-7121
Email: canceranswers@moffitt.org

Site Status: Recruiting

Data Source: ClinicalTrials.gov

Date Processed: November 17, 2017

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