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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by H. Lee Moffitt Cancer Center and Research Institute
Sponsor:
Collaborators:
Boehringer Ingelheim
Bristol-Myers Squibb
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT01999985
First received: November 26, 2013
Last updated: August 21, 2014
Last verified: August 2014
  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

Condition Intervention Phase
Lung Cancer
Non-small Cell Lung Cancer (NSCLC)
Drug: Dasatinib - 1A
Drug: Afatinib - 1A
Drug: Dasatinib - 1B
Drug: Afatinib - 1B
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of BIBW 2992 in Combination with Dasatinib [ Time Frame: Up to 6 Months ] [ Designated as safety issue: Yes ]

    1A - The MTD for this combined treatment will be defined as either:

    1. The highest dosage cohort in which six patients had been treated and there were less than two dose limiting toxicities (DLTs) or,
    2. 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:
  • Objective Response Rate [ Time Frame: Up to 6 Months ] [ Designated as safety issue: No ]
    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.

  • Progression Free Survival Rate [ Time Frame: Up to 6 Months ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 38
Study Start Date: December 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1A - Dose Escalation Group
Dose 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.
Drug: Dasatinib - 1A
1A: Begins Day 8. Level 1 - 100 mg, Level 2 - 100 mg, Level 3 - 140 mg.
Other Names:
  • SPRYCEL®
  • BMS-354825
  • tyrosine kinase inhibitor
  • SRC Kinase Inhibitor
Drug: Afatinib - 1A
1A: Begins Day 1. Level 1 - 30 mg, Level 2 - 40 mg, Level 3 - 40 mg.
Other Names:
  • BIBW 2992
  • EGFR Inhibitor
Experimental: 1B - Extension Group
Extension: Afatinib and Dasatinib. The next 20 people will enter into the second part, called Phase 1B.
Drug: Dasatinib - 1B
In Phase 1B, a mutationally selected 20 participants (total) will be treated at the recommended dose to confirm tolerability and evaluate for early response signal.
Drug: Afatinib - 1B
In Phase 1B, a mutationally selected 20 participants (total) will be treated at the recommended dose to confirm tolerability and evaluate for early response signal.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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.
  • 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 cyclosporine, diltiazem, felodipine, ketoconazole, itraconazole, quinidine, verapamil, tacrolimus, conivaptan, carvedilol, dronedarone, ticagrelor, lopinavir, nelfinavir, ritonavir, saquinavir) or inducers (phenobarbital, phenytoin, carbamazepine, rifampicin, tipranavir).
  • 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) < 1500 / 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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01999985

Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute Recruiting
Tampa, Florida, United States, 33612
Contact: Amanda Carpenter    813-745-3905    amanda.carpenter@moffitt.org   
Principal Investigator: Ben Creelan, M.D.         
Sub-Investigator: Scott Antonia, M.D., Ph.D.         
Sub-Investigator: Alberto Chiappori, M.D.         
Sub-Investigator: Jhanelle Gray, M.D.         
Sub-Investigator: Eric Haura, M.D.         
Sub-Investigator: Mary Pinder, M.D.         
Sub-Investigator: Tawee Tanvetyanon, M.D.         
Sub-Investigator: Charles Williams, M.D.         
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Boehringer Ingelheim
Bristol-Myers Squibb
Investigators
Principal Investigator: Ben Creelan, M.D. H. Lee Moffitt Cancer Center and Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT01999985     History of Changes
Other Study ID Numbers: MCC-17176, BI 1200.166, BMS CA180-379
Study First Received: November 26, 2013
Last Updated: August 21, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
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

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Mitogens
Dasatinib
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 28, 2014