Erlotinib Hydrochloride and Quinacrine Dihydrochloride in Stage IIIB-IV Non-Small Cell Lung Cancer

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified July 2013 by Case Comprehensive Cancer Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Neelesh Sharma MD PhD, Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01839955
First received: April 23, 2013
Last updated: July 18, 2013
Last verified: July 2013
  Purpose

This phase I/II trial studies the side effects and best dose of quinacrine dihydrochloride when given together with erlotinib hydrochloride and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as quinacrine dihydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving erlotinib hydrochloride together with quinacrine dihydrochloride may kill more tumor cells


Condition Intervention Phase
Recurrent Non-small Cell Lung Cancer
Stage IIIB Non-small Cell Lung Cancer
Stage IV Non-small Cell Lung Cancer
Drug: erlotinib hydrochloride
Drug: quinacrine dihydrochloride
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Erlotinib in Combination With Quinacrine in Patients With Advanced Non-Small-Cell Lung Cancer

Resource links provided by NLM:


Further study details as provided by Case Comprehensive Cancer Center:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of quinacrine dihydrochloride in combination of erlotinib hydrochloride determined by dose-limiting toxicities: Phase I [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Progression Free Survival (PFS): Phase II [ Time Frame: Date of randomization to the date of disease progression or the date of death, assessed up to 2 years ] [ Designated as safety issue: No ]
    Estimated by Kaplan-Meier method and the difference between two treatment arms will be evaluated by log-rank test.


Secondary Outcome Measures:
  • Pharmacokinetic parameters [ Time Frame: after 2 months (2 cycles) ] [ Designated as safety issue: No ]
  • Objective tumor response rate (ORR) (complete response and partial response) evaluated by revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Estimated based on the number of responses by excluding the dropouts who are not evaluable for response using a binomial distribution.

  • Disease stabilization rate (complete response, partial response and stable disease) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    The confidence intervals for them will be estimated using Wilson's method.

  • Baseline expression of intracellular inhibitor of the nuclear factor kappa B (IkappaB) or NFkappaB gene signature in determining survival or response [ Time Frame: Baseline up to 2 years ] [ Designated as safety issue: No ]
  • Overall survival (OS) [ Time Frame: Date of randomization to the date of death, assessed up to 2 years ] [ Designated as safety issue: No ]
    Estimated by Kaplan-Meier method and the difference between two treatment arms will be evaluated by log-rank test. Identified by Cox model or extended Cox model. Chi-square test or Fisher's exact test will be used to examine the difference of response rate between two treatment arms.


Estimated Enrollment: 70
Study Start Date: August 2013
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (erlotinib hydrochloride)
Patients receive erlotinib hydrochloride PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: erlotinib hydrochloride
Given PO
Other Names:
  • CP-358,774
  • erlotinib
  • OSI-774
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Experimental: Arm II (erlotinib hydrochloride, quinacrine dihydrochloride)
Patients receive erlotinib hydrochloride PO daily and quinacrine dihydrochloride PO thrice daily (TID) on days, 1-7 and PO daily from days 8-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: erlotinib hydrochloride
Given PO
Other Names:
  • CP-358,774
  • erlotinib
  • OSI-774
Drug: quinacrine dihydrochloride
Given PO
Other Names:
  • atabrine dihydrochloride
  • mepacrine dihydrochoride
  • SN 390
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of the combination of erlotinib (erlotinib hydrochloride) and quinacrine (quinacrine dihydrochloride) in patients with advanced non-small-cell lung cancer. (Phase I) II. To determine the recommended phase II doses of the combination of erlotinib and quinacrine in patients with advanced non-small-cell lung cancer. (Phase I) III. To determine the progression free survival (PFS) of erlotinib and quinacrine combination or erlotinib alone in patients with advanced non-small-cell lung cancer. (Phase II)

SECONDARY OBJECTIVES:

I. To describe the dose limiting toxicity of the erlotinib and quinacrine combination.

II. To determine the pharmacokinetic profile of the erlotinib and quinacrine combination.

III. To determine objective response rate (complete response [CR]+partial response [PR]) and clinical benefit rate (CR+PR+ stable disease [SD]) of the erlotinib and quinacrine combination and erlotinib alone.

IV. To estimate overall survival (OS).

TERTIARY OBJECTIVES:

I. To examine change in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) related genes in the pre and post treatment biopsy samples as a pharmacodynamic marker of treatment with quinacrine.

II. To correlate expression of NF-κB related proteins in the pre-treatment tissue with clinical activity of quinacrine and erlotinib combination.

III. To measure circulating tumor cells and correlate with response and survival.

OUTLINE: This is a phase I, dose escalation study of quinacrine dihydrochloride followed by a phase II study.

PHASE I: Patients receive erlotinib hydrochloride orally (PO)daily on days 1-28 and quinacrine dihydrochloride PO thrice daily (TID) on days, 1-7 and PO daily from days 8-28.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive erlotinib hydrochloride PO daily on days 1-28.

ARM II: Patients receive erlotinib hydrochloride PO and quinacrine dihydrochloride PO thrice daily (TID) on days, 1-7 and PO daily from days 8-28.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed incurable malignancy that is surgically unresectable locally advanced or metastatic (stage IIIB/IV) non-small cell lung cancer (NSCLC)
  • Patients with wild type epidermal growth factor receptor (EGFR), who have received one or two regimens of systemic chemotherapy for advanced or metastatic disease, one of which must be a platinum-containing regimen. Prior maintenance therapy is allowed and will be considered as the same line of therapy when continued without discontinuation after initiation of a treatment regimen. NSCLC with documented EGFR mutation or documented fusion gene involving the anaplastic lymphoma kinase (ALK) gene (such as echinoderm microtubule associated protein like 4 [EML4]-ALK) will be eligible if they have progressed on erlotinib or crizotinib and chemotherapy. Adjuvant/neoadjuvant chemotherapy or chemoradiation is considered a line of therapy if < 12 months have elapsed between the last dose and the date of recurrence. Combined treatment with chemotherapy and radiation constitutes a single regimen.
  • Eastern Cooperative Oncology Group (ECOG) performance status >= 2
  • Life expectancy of >= 12 weeks, in the opinion of and as documented by the investigator
  • Hemoglobin >= 9.0 g/dl (transfusion and/or growth factor support allowed)
  • Absolute neutrophil count (ANC) >= 1,500/mcL
  • Platelet count >= 100 x 10^9 L
  • Alkaline phosphatase < 2.5 X institutional upper limit of normal (in subjects with no liver metastasis and < 5.0 upper limit of normal [ULN] in subjects with liver metastasis)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal (in subjects with no liver metastasis and < 5.0 ULN in subjects with liver metastasis)
  • Serum creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min
  • Serum total bilirubin =< 1.5 x ULN OR total bilirubin =< 4.0 ULN with direct bilirubin =< 1.5 x ULN in patients with well documented Gilbert syndrome
  • Patients who are receiving therapeutic anticoagulation with heparin are allowed to participate provided that no prior evidence of underlying abnormality exists in these parameters. Patients on warfarin are eligible provided they are on stable doses of warfarin and there is close monitoring of INR.
  • Resolution of any toxic effects of prior therapy (including radiotherapy) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0, grade < 1 (with the exception of alopecia and < grade 2 neuropathy); subject must have recovered from significant surgery-related complications
  • Women of childbearing potential must have a negative pregnancy test performed within 48 hours prior to the start of the study drug
  • The effects of quinacrine on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) prior to study entry, for the duration of study participation and for 90 days after completing the last investigational drug dose; should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately
  • Subjects must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients with previous anti-cancer chemotherapy, immunotherapy or investigational agents < 3 weeks prior to the first day of study defined treatment. Palliative radiation < 1 week before the start of treatment (lesions subjected to radiotherapy may not be used as target lesions). Patients who receive gamma knife radiosurgery for brain metastases within 1 week prior to treatment start.
  • Patients with unknown status of EGFR mutation
  • Patients that have had major surgery < 3 weeks or minor surgery (e.g. talc pleurodesis, excisional biopsy, etc) < 1 week prior to the first day of study defined treatment.
  • History of cardiac disease: congestive heart failure defined as class II to IV per New York Heart Association (NYHA) classification; active coronary artery disease (CAD); previously diagnosed bradycardia or other cardiac arrhythmia defined as >= grade 2 according to NCI-CTCAE (version 4.0), or uncontrolled hypertension; myocardial infarction occurred within 6 months prior to study entry (myocardial infarction occurred > 6 months prior to study entry is permitted)
  • Patients with clinically unstable central nervous system (CNS) metastasis (to be enrolled in the study, subjects must have confirmation of stable disease by magnetic resonance imaging [MRI] or computed tomography [CT] scan within 4 weeks of the first day of study defined treatment and have CNS metastases well controlled by steroids, anti-epileptics or other symptom-relieving medications)
  • Patients with significant gastrointestinal disorder that, in the opinion of the investigator, could interfere with absorption of quinacrine and/or erlotinib (eg, Crohn's disease, small or large bowel resection, malabsorption syndrome)
  • Patients with any known contraindication to treatment with, including hypersensitivity to quinacrine or erlotinib
  • Patients with active clinically serious infections defined as >= grade 2 according to NCI CTCAE, version 4.0
  • Patients with substance abuse, medical, psychological or social conditions that may, in the opinion of the Investigator, interfere with the patient's participation in the study or evaluation of the study results
  • Any other condition that is unstable or which could jeopardize the safety of the patient and his/her protocol compliance
  • History of incurable malignancy other than NSCLC within the 5 years prior to start of treatment, with the exceptions of adequately treated intraepithelial carcinoma of the cervix uteri; prostate carcinoma with a prostate-specific antigen value <0.2 ng/mL; or basal or squamous-cell carcinoma of the skin.
  • Pregnant or breastfeeding women and adults of reproductive potential not employing an effective method of birth control are excluded from this study because quinacrine is category N agent with the potential for teratogenic or abortifacient effects; these potential risks may also apply to other agents used in this study
  • Patients with previously known infection with human immunodeficiency virus (HIV) or hepatitis B and C are ineligible because of the potential for pharmacokinetic interactions with quinacrine; (diagnostic testing for these infections will be done only if clinically indicated)
  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: NCT01839955

Locations
United States, Ohio
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center Not yet recruiting
Cleveland, Ohio, United States, 44106
Contact: Neelesh Sharma    800-641-2422    neelesh.sharma@uhhospitals.org   
Principal Investigator: Neelesh Sharma, MD PhD         
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Patrick Ma, MD    216-445-5545    map@ccf.org   
Principal Investigator: Patrick Ma, MD         
Sponsors and Collaborators
Neelesh Sharma MD PhD
Investigators
Principal Investigator: Neelesh Sharma, MD PhD Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: Neelesh Sharma MD PhD, Principal Investigator, Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01839955     History of Changes
Other Study ID Numbers: CASE8512, NCI-2013-00599
Study First Received: April 23, 2013
Last Updated: July 18, 2013
Health Authority: United States: Food and Drug Administration

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
Quinacrine
Erlotinib
Anticestodal Agents
Antiplatyhelmintic Agents
Anthelmintics
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antimalarials
Antiprotozoal Agents
Antinematodal Agents
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on August 28, 2014