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A Phase I/II Study of Erlotinib in Combination With Quinacrine in Patients With Advanced Non-Small-Cell Lung Cancer


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
Recurrent Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

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Trial Information

A Phase I/II Study of Erlotinib in Combination With Quinacrine in Patients With Advanced Non-Small-Cell Lung Cancer


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.


Inclusion Criteria:



- Patients must have histologically or cytologically confirmed 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

- 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

- International normalized ratio (INR) =< 1.5 x ULN AND activated partial
thromboplastin time (APTT) =< 1.5 ULN if not on anti-coagulants; 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 should have stable doses with INR between 2-3 in the 2 months
prior to study registration

- 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 < 2 weeks before the start of treatment (lesions subjected to radiotherapy
within 2 weeks prior to start of treatment may not be used as target lesions);
patients who receive gamma knife radiosurgery for brain metastases within 2 weeks
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) =< 2 weeks 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 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)

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) of quinacrine dihydrochloride in combination of erlotinib hydrochloride determined by dose-limiting toxicities: Phase I

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Neelesh Sharma, MD PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

CASE8512

NCT ID:

NCT01839955

Start Date:

June 2013

Completion Date:

Related Keywords:

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

Name

Location

Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer CenterCleveland, Ohio  44106-5065
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer CenterCleveland, Ohio  44195