Clinical Trials /

Phase I Trial of Afatinib (BIBW 2992) and Dasatinib in Non-small Cell Lung Cancer (NSCLC)

NCT01999985

Description:

The purpose of this study is to: - Find out if the study drugs Afatinib and Dasatinib can be safely given together to patients with lung cancer - Learn how these two drugs work in cancer cells when they are combined - Learn more about the side effects of these two drugs when combined - Find the highest doses of the study drugs Afatinib and Dasatinib that can be given safely without causing serious side effects

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

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I Trial of Afatinib (BIBW 2992) and Dasatinib in Non-small Cell Lung Cancer (NSCLC)
  • Official Title: Phase I Trial Evaluating Safety and Tolerability of the Irreversible Epidermal Growth Factor Receptor Inhibitor Afatinib (BIBW 2992) in Combination With the SRC Kinase Inhibitor Dasatinib for Patients With Non-small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: MCC-17176
  • SECONDARY ID: BI 1200.166
  • SECONDARY ID: BMS CA180-379
  • NCT ID: NCT01999985

Conditions

  • Lung Cancer
  • Non-small Cell Lung Cancer (NSCLC)

Interventions

DrugSynonymsArms
Dasatinib - 1ASPRYCEL®, BMS-354825, tyrosine kinase inhibitor, SRC Kinase Inhibitor1A - Dose Escalation Group
Afatinib - 1ABIBW 2992, EGFR Inhibitor1A - Dose Escalation Group
Dasatinib - 1B1B - Extension Group
Afatinib - 1B1B - Extension Group

Purpose

The purpose of this study is to: - Find out if the study drugs Afatinib and Dasatinib can be safely given together to patients with lung cancer - Learn how these two drugs work in cancer cells when they are combined - Learn more about the side effects of these two drugs when combined - Find the highest doses of the study drugs Afatinib and Dasatinib that can be given safely without causing serious side effects

Trial Arms

NameTypeDescriptionInterventions
1A - Dose Escalation GroupExperimentalDose escalation: Afatinib and Dasatinib. This study is divided into two parts. The first 8 - 18 people will be entered in the first part, called Phase 1A. Then this part will end.
  • Dasatinib - 1A
  • Afatinib - 1A
1B - Extension GroupExperimentalExtension: Afatinib and Dasatinib. The next 20 people will enter into the second part, called Phase 1B.
  • Dasatinib - 1B
  • Afatinib - 1B

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically or cytologically documented Stage IIIB/IV non-small cell lung cancer,
             or unresectable recurrent disease following locoregional treatment.

          -  For Phase 1B Extension Only:

               -  Either or both of the following: A tumor which harbors an activating Epidermal
                  Growth Factor Receptor (EGFR) - mutation; History of objective response, or
                  stable disease for at least 6 months, after treatment with erlotinib, afatinib,
                  or gefitinib.

               -  Either or both of the following: Progression or recurrence of disease after
                  receiving prior continuous gefitinib, afatinib, or erlotinib; A tumor known to
                  harbor a de novo T790M mutation, which is known to confer EGFR TKI resistance.

               -  Participants are allowed to have received systemic chemotherapy or
                  investigational therapy in the intervening period prior to trial enrollment

          -  Capable of giving written informed consent.

          -  Evaluable disease, as follows: For Phase 1A Dose Escalation: Have the presence of any
             evaluable disease, including bone metastases, effusion, or cystic metastases. For
             Phase 1B Extension Only: Have progressive and measurable disease as defined by the
             Response Evaluation Criteria in Solid Tumors (RECIST v 1.1).

          -  Reproductive potential must be either terminated (by surgery, radiation, or menopause)
             or attenuated by the use of an approved contraceptive method during and for 3 to 6
             months following the study.

          -  Participant agrees that IV bisphosphonates will be withheld during the first 8 weeks
             of dasatinib therapy due to risk of hypocalcemia.

          -  Have recovered from prior drug-related toxicity to Grade ≤ 1 Common Terminology
             Criteria for Adverse Events (CTCAE) v4, within 21 days of initiation of on-study
             treatment.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at initial
             enrollment, as assessed by clinician or investigator.

        Exclusion Criteria:

          -  Have previously completed or withdrawn from this study or any other study
             investigating dasatinib. Prior treatment with other tyrosine kinases, including
             afatinib, is acceptable.

          -  Prior recent systemic or investigational therapy within 21 days of initiation of study
             treatment. An exception is that epidermal growth factor receptor (EGFR) inhibitor may
             be continued up until 3 days of initiation of study treatment.

          -  Women who are pregnant or breastfeeding. Women of childbearing potential must have a
             negative pregnancy test (β-HCG test in urine or serum) prior to commencing study
             treatment.

          -  Patients with documented central nervous system or leptomeningeal metastasis (brain
             metastasis) at the time of study entry. Patients with prior brain metastasis may be
             considered if they have completed their treatment for brain metastasis and no longer
             require corticosteroids.

          -  Patients with disease progression in the central nervous system (CNS) only.

          -  Serious concomitant disorder, including active bacterial, fungal, or viral infection,
             incompatible with the study (at the discretion of the principal investigator).

          -  Uncorrected severe electrolyte disorder, including severe potassium (<3.0 mEq/L) or
             magnesium ( < 1.0 mEq/L) deficiency.

          -  Any gastrointestinal disorder with diarrhea as a major symptom, such as Crohn's, or
             pre-existing chronic diarrhea Common Toxicity Criteria (CTC) Grade ≥ 2 of any
             etiology. Included are malabsorption disorders that in the opinion of the study
             physician may affect absorption of either afatinib or dasatinib.

          -  Prior major surgery or radiation therapy within 14 days of initiation of treatment.

          -  Electrocardiogram (ECG) abnormalities indicative of arrhythmia (at the discretion of
             the investigator).

          -  History or presence of clinically relevant cardiovascular abnormalities such as
             uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA)
             classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial
             infarction within 6 months prior to enrollment.

          -  Baseline (< 1 month before treatment) cardiac left ventricular function with resting
             ejection fraction of less than 50% measured by multigated blood pool imaging of the
             heart (MUGA scan) or echocardiogram.

          -  Any history of clinically significant ventricular arrhythmias (such as ventricular
             tachycardia, ventricular fibrillation, congenital long QT syndrome, or Torsades de
             pointes).

          -  Prolonged QTc interval on pre-entry electrocardiogram (> 470 msec for men and >480
             msec for women per American College of Cardiology/American Heart Association [AHA/ACC]
             2011 scientific statement).

          -  History of significant bleeding disorder unrelated to cancer, including diagnosed
             congenital bleeding disorders (e.g., von Willebrand's disease).

          -  Patients currently taking drugs that are generally accepted to have a high risk of
             causing Torsades de Pointes.

          -  Patients with pre-existing interstitial lung disease (ILD), or pericardial / pleural
             effusion of grade 2 or higher. Trace pericardial or pleural effusion is acceptable.

          -  Patients who require chronic oxygen therapy for chronic obstructive pulmonary disease
             or pleural effusions (malignant or benign).

          -  Patients requiring comedication with potent P-gp inhibitors (including cyclosporin,
             azithromycin, erythromycin, ketoconazole, itraconazole, quinidine, phenobarbital salt
             with quinidine, ritonavir, valspodar, verapamil) or inducers (including rifampicin).

          -  Known active hepatitis B infection, known active hepatitis C infection, or known HIV
             carrier.

          -  Known or suspected active drug or alcohol abuse.

          -  Known hypersensitivity to afatinib, dasatinib, or the excipients of any of the trial
             drugs.

          -  Laboratory exclusion criteria: Absolute neutrophil count (ANC) < 1000 / mm^3, Platelet
             count < 100,000 / mm^3, Serum creatinine ≥1.5 times the upper normal limit or
             calculated/measured creatinine Clearance ≤60 mL/min., Total bilirubin ≥1.5 mg/dL (>26
             mol/L, SI unit equivalent), Aspartate amino transferase (AST) or Alanine amino
             transferase (ALT) ≥ 2.5 times the upper limit of normal (if related to liver
             metastases ≥ five times the upper limit of normal).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of BIBW 2992 in Combination with Dasatinib
Time Frame:Up to 6 Months
Safety Issue:
Description:1A - The MTD for this combined treatment will be defined as either: The highest dosage cohort in which six patients had been treated and there were less than two dose limiting toxicities (DLTs) or, Afatinib at the highest tolerated dose investigated (40 mg by mouth [PO] daily) plus dasatinib at the highest tolerated dose investigated (cohort 3, 140 mg PO daily).

Secondary Outcome Measures

Measure:Objective Response Rate
Time Frame:Up to 6 Months
Safety Issue:
Description:Estimate the objective response rate (complete response [CR] and partial response [PR]), and clinical benefit rate, in participants with acquired EGFR resistance. Response Criteria for Phase 1B will follow RECIST v.1.1: Complete Response (CR is defined as disappearance of all target lesions; Partial Response (PR) is defined as at least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD.
Measure:Progression Free Survival Rate
Time Frame:Up to 6 Months
Safety Issue:
Description:Estimate the 6-month progression free survival (PFS) rate in participants with acquired EGFR resistance. Response Criteria for Phase 1B will follow RECIST v.1.1: Progressive Disease (PD) is defined as at least a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:H. Lee Moffitt Cancer Center and Research Institute

Trial Keywords

  • Epidermal Growth Factor Receptor (EGFR)
  • Tyrosine kinase inhibitors
  • Neoplasms
  • Lung Diseases
  • Respiratory Tract Diseases
  • Pleural Diseases
  • Pleural Neoplasms
  • Lung Neoplasms
  • Pleural Effusion
  • Pleural Effusion, Malignant
  • Respiratory Tract Neoplasms
  • Thoracic Neoplasms
  • Neoplasms by Site
  • EGFR mutation
  • Afatinib
  • Dasatinib
  • Carcinoma, Bronchogenic
  • Gene Mutation
  • T790M mutation.
  • Non-small cell lung cancer

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