A Phase I Study of Erlotinib in Combination With Quinacrine in Patients With Advanced Non-Small-Cell Lung Cancer
Overview
- Phase
- Phase 1
- Intervention
- erlotinib hydrochloride
- Conditions
- Recurrent Non-small Cell Lung Cancer
- Sponsor
- Neelesh Sharma MD PhD
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose (MTD) of quinacrine dihydrochloride in combination of erlotinib hydrochloride determined by dose-limiting toxicities
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
This phase I 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
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. II. To determine the recommended Maximum Tolerated Dose (MTD) of the combination of erlotinib and quinacrine in patients with advanced non-small-cell lung cancer. 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. IV. To estimate overall survival (OS) OUTLINE: This is a phase I, dose escalation study of quinacrine dihydrochloride Escalation Portion: 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. After Maximum Tolerated Dose is established: 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 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.
Investigators
Neelesh Sharma MD PhD
Principal Investigator
Case Comprehensive Cancer Center
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically or cytologically confirmed incurable malignancy that is surgically unresectable locally advanced, recurrent, or metastatic (stage IIIB/IV) non-small cell lung cancer (NSCLC). Patients with adenocarcinoma, squamous cell carcinoma, large cell carcinoma and sarcomatoid carcinoma will be eligible.
- •Patients must have received at least one platinum-containing regimen for the treatment of advanced or metastatic disease (except for EGFR-mutant patients). 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 will be eligible after progression on an EGFR-TKI alone. NSCLC with other molecular targets, such as fusion gene involving the anaplastic lymphoma kinase (ALK) gene (such as echinoderm microtubule associated protein like 4 \[EML4\]-ALK) or ROS-1 will be eligible if they have progressed on targeted agents (ALK inhibitor) and chemotherapy or are not a candidate for 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
Exclusion Criteria
- •Patients with previous anti-cancer chemotherapy, immunotherapy or investigational agents ≤ 3 weeks prior to the first day of study defined treatment. NSCLC patients with EGFR mutation can enroll within 7 days of discontinuing EGFR-TKI. 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 (only for patients with adenocarcinoma histology)
- •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
Arms & Interventions
Arm I (Dose Escalation Group)
Erlotinib hydrochloride and quinacrine dihydrochloride. The first three or six patients will be entered in this part of the study. Then this part will end.
Intervention: erlotinib hydrochloride
Arm I (Dose Escalation Group)
Erlotinib hydrochloride and quinacrine dihydrochloride. The first three or six patients will be entered in this part of the study. Then this part will end.
Intervention: quinacrine dihydrochloride - Escalation dose
Arm I (Dose Escalation Group)
Erlotinib hydrochloride and quinacrine dihydrochloride. The first three or six patients will be entered in this part of the study. Then this part will end.
Intervention: laboratory biomarker analysis
Arm I (Dose Escalation Group)
Erlotinib hydrochloride and quinacrine dihydrochloride. The first three or six patients will be entered in this part of the study. Then this part will end.
Intervention: pharmacological study
Arm II (Extension Group)
Erlotinib hydrochloride and quinacrine dihydrochloride. The next 12 patients will enter into the second part of this study.
Intervention: erlotinib hydrochloride
Arm II (Extension Group)
Erlotinib hydrochloride and quinacrine dihydrochloride. The next 12 patients will enter into the second part of this study.
Intervention: laboratory biomarker analysis
Arm II (Extension Group)
Erlotinib hydrochloride and quinacrine dihydrochloride. The next 12 patients will enter into the second part of this study.
Intervention: pharmacological study
Arm II (Extension Group)
Erlotinib hydrochloride and quinacrine dihydrochloride. The next 12 patients will enter into the second part of this study.
Intervention: quinacrine dihydrochloride - Extension dose
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD) of quinacrine dihydrochloride in combination of erlotinib hydrochloride determined by dose-limiting toxicities
Time Frame: 28 days
Progression Free Survival (PFS)
Time Frame: Date of randomization to the date of disease progression or the date of death, assessed up to 2 years
Estimated by Kaplan-Meier method and the difference between two treatment arms will be evaluated by log-rank test.
Secondary Outcomes
- Pharmacokinetic parameters(after 2 months (2 cycles))
- Disease stabilization rate (complete response, partial response and stable disease)(Up to 2 years)
- Baseline expression of intracellular inhibitor of the nuclear factor kappa B (IkappaB) or NFkappaB gene signature in determining survival or response(Baseline up to 2 years)
- Objective tumor response rate (ORR) (complete response and partial response) evaluated by revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria(Up to 2 years)
- Overall survival (OS)(Date of randomization to the date of death, assessed up to 2 years)