Modulation of Autophagy With Hydroxychloroquine in Combination With Carboplatin, Paclitaxel and Bevacizumab in Patients With Advanced/Recurrent Non-Small Cell Lung Cancer - A Phase I/II Study
- Signed a protocol-specific informed consent.
- 18 years of age or older.
- ECOG Performance Status 0 or 1.
- Histologically or cytologically confirmed non-small cell lung cancer EXCEPT squamous
cell carcinoma. Mixed tumors will be categorized by the predominant cell type unless
small cell elements are present, in which case the patient is ineligible. Cytologic
or histologic elements can be established on metastatic tumor aspirate or biopsy.
Sputum cytology alone is not sufficient.
- Advanced stage NSCLC (stage IIIB with malignant pleural effusion, or stage IV, or
- Measurable disease according to RECIST criteria.
- No known CNS metastases. A head CT or brain MRI is required within 28 days of
- No prior cytotoxic chemotherapy or targeted therapy in the advanced or metastatic
setting. Post-operative adjuvant therapy for previously resected NSCLC is allowed as
long as the last dose was given greater than 1 year before study entry, and there is
current evidence of disease progression.
- Prior radiation to sites other than the brain is allowed, if completed at least 2
weeks prior to treatment and provided that all radiation-related toxicities have
resolved to ≤ Grade 1.
- No active malignancy other than NSCLC. Patients with a history of basal cell or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, or ductal or
lobular carcinoma in situ of the breast within the past 3 years must have been
treated with curative intent. Patients with a history of prior malignancy are
eligible provided they were treated with curative intent and have been free of
disease for > 3 years.
- Adequate organ function
- No history of gross hemoptysis (defined as bright red blood of a half-teaspoon or
more) within 3 months prior to enrollment.
- None of the following conditions within 6 months prior to enrollment: myocardial
infarction, stroke or symptomatic peripheral vascular disease.
- No major surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to enrollment, or anticipate the need for such while on active treatment.
Placement of vascular access device is not considered major surgery, but the incision
must have healed before initiation of treatment.
- No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to enrollment.
- No serious non-healing wound, ulcer or bone fracture.
- Patients must have a systolic blood pressure ≤ 150 mm Hg and diastolic blood pressure
≤ 100 mm Hg (the use of antihypertensive medications to achieve these goals is
- Patients must not have unstable angina or NYHA classification of congestive heart
failure of Grade ≥ 2 (see Appendix C).
- No history of significant vascular disease (eg aortic aneurysm).
- Patients must not have psoriasis or porphyria.
- No known hypersensitivity to 4-aminoquinoline compound.
- Patients must not have retinal or visual field changes from prior 4-aminoquinoline
- Patients must not have known G-6P deficiency.
- No current or recent (within 28 days of enrollment) full dose anticoagulants or
- No know bleeding diathesis or coagulopathy.
- No known GI pathology that would interfere with drug bioavailability.
- No peripheral or sensory neuropathy > Grade 1 at study entry.
- No known prior hypersensitivity to carboplatin, paclitaxel, bevacizumab or
hydroxychloroquine or any of their components.
- No ongoing or active infection at study entry.
- Patients must not be receiving treatment for rheumatoid arthritis or systemic lupus
- Patients must not have HIV or be taking HAART therapy.
- Patients must not have a history of any condition (social or medical) that, in the
opinion of the Investigator, might interfere with the patient's ability to comply
with the protocol or pose additional or unacceptable risk to the patient.
- Women must NOT be pregnant or breastfeeding.
- Women must :
- Have a negative serum or urine pregnancy test within 7 days prior to study entry
if she is a woman of child-bearing potential
- Be at least one year post-menopausal
- Be surgically sterile
- Patients of childbearing or child fathering potential must be willing to use an
acceptable method of birth control prior to study entry and for the duration of the
study. Acceptable methods of contraception include hormonal, barrier methods,
intrauterine device, tubal ligation/vasectomy or abstinence.
- Must not be taking hydroxychloroquine for treatment or prophylaxis of malaria.