Clinical Trials /

Sapanisertib and Osimertinib in Treating Patients With Stage IV EGFR Mutation Positive Non-small Cell Lung Cancer After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

NCT02503722

Description:

This phase I trial studies the side effects and best dose of sapanisertib when given together with osimertinib in treating patients with stage IV EGFR mutation positive non-small cell lung cancer that has progressed after treatment with an EGFR tyrosine kinase inhibitor. Sapanisertib and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: TORC1/2 Inhibitor INK128 and EGFR Inhibitor AZD9291 in Treating Patients With Advanced EGFR Mutation Positive Non-small Cell Lung Cancer After Progression on a Previous EGFR Tyrosine Kinase Inhibitor
  • Official Title: A Phase 1 Trial of MLN0128 in Combination With AZD9291 in Advanced EGFR Mutation Positive Non-small Cell Lung Cancer (NSCLC) After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01139
  • SECONDARY ID: NCI-2015-01139
  • SECONDARY ID: 9910/PJC-020
  • SECONDARY ID: PJC-020
  • SECONDARY ID: 9910
  • SECONDARY ID: PJC-020
  • SECONDARY ID: 9910
  • SECONDARY ID: UM1CA186644
  • NCT ID: NCT02503722

Conditions

  • Recurrent Non-Small Cell Lung Carcinoma
  • Stage IIIA Non-Small Cell Lung Cancer
  • Stage IIIB Non-Small Cell Lung Cancer
  • Stage IV Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoTreatment (TORC1/2 inhibitor INK128, EGFR inhibitor AZD9291)
SapanisertibINK-128, INK128, MLN-0128, MLN0128, TAK-228Treatment (TORC1/2 inhibitor INK128, EGFR inhibitor AZD9291)

Purpose

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.

Detailed Description

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.

Trial Arms

NameTypeDescriptionInterventions
Treatment (TORC1/2 inhibitor INK128, EGFR inhibitor AZD9291)ExperimentalPatients receive TORC1/2 inhibitor INK128 PO 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.
    • Osimertinib
      • Sapanisertib

Eligibility Criteria

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

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

Primary Outcome Measures

Measure:Dose-limiting toxicity (DLT) of TORC1/2 inhibitor INK128 in combination with EGFR inhibitor AZD9291 in patients with EGFRm NSCLC
Time Frame:28 days
Safety Issue:
Description:Toxicities will be graded according to the NCI CTCAE v4.

Secondary Outcome Measures

Measure:Biomarkers of response and resistance to the combination, explored by studying baseline biopsies, resistance biopsies, and serial plasma DNA specimens
Time Frame:Up to 2 years
Safety Issue:
Description:Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional hazards regression and or generalized estimating equations as appropriate. Potential predictors include clinical predictors and molecular correlates analyzed in tumor and blood. Descriptive statistics and plotting of data will also be used to better understand potential relationships.
Measure:Disease control rate
Time Frame:Up to 2 years
Safety Issue:
Description:Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.
Measure:Disease control rate of patients with T790M- NSCLC in an expansion cohort
Time Frame:Up to 2 years
Safety Issue:
Description:Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.
Measure:Non-DLTs associated with the administration of TORC1/2 inhibitor INK128 and EGFR inhibitor AZD9291
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.
Measure:Pharmacokinetic (PK) profiles of TORC1/2 inhibitor INK128 in combination with EGFR inhibitor AZD9291
Time Frame:Baseline, and at 1, 2, 4, 6, 8, and 24 hours post-TORC1/2 administration, before administration and at 1, 2, 4, 6, 8, and 24 hours post-TORC1/2 on day 26 of course 1; and day 1 of course 2
Safety Issue:
Description:PK analyses will be descriptive and will permit the evaluation of the PK profile of TORC1/2 inhibitor INK128 when combined with EGFR inhibitor AZD9291.
Measure:Progression free survival
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.
Measure:Progression free survival of patients with T790M- NSCLC in an expansion cohort
Time Frame:At 6 months
Safety Issue:
Description:Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.
Measure:Response rate of patients with T790M- NSCLC in an expansion cohort, assessed using RECIST 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.
Measure:Response rate, assessed using RECIST 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

    Last Updated

    December 21, 2016