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Alectinib and Bevacizumab in Treating Patients with ALK-positive Stage IIIB-IV Non-small Cell Lung Cancer

Trial Status: Active

This phase I / II trial studies the side effects and best dose of alectinib and bevacizumab when given together in treating patients with anaplastic lymphoma kinase (ALK) positive stage IIIB-IV non-small cell lung cancer. Alectinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab may stop the growth of non-small cell lung cancer by blocking the growth of new blood vessels necessary for tumor growth. Giving alectinib together with bevacizumab may be a better treatment for non-small cell lung cancer.

Inclusion Criteria

  • Histologically or cytologically confirmed advanced (stage IIIB or IV) non-squamous, non-small cell lung cancer
  • Molecular confirmation of an anaplastic lymphoma kinase (ALK) rearrangement using ALK fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) or next-generation sequencing (NGS); for ALK FISH, rearrangements must be detected in > 15% of tumor cells; if an ALK rearrangement has been detected by IHC or NGS, archival tissue must be available to confirm ALK positivity by FISH
  • Life expectancy > 12 weeks
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Absolute neutrophil count (ANC) >= 1500 cells/uL
  • Platelet count >= 100 x 100^9/L
  • Hemoglobin >= 8 g/dL
  • An estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) equation of at least 45 mL/min/1.73 m^2
  • International normalized ratio (INR) =< 1.5
  • Partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN)
  • For all females of childbearing potential, a negative pregnancy test must be obtained within 3 days before starting study treatment
  • For women who are not postmenopausal (>= 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of study drug; abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception; examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices; alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year; barrier methods must always be supplemented with the use of a spermicide
  • For men: agreement to remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of study drug; abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
  • Able and willing to provide written informed consent prior to performing any study-related procedures and to comply with the study protocol, including patients must be willing and able to use the electronic patient-reported outcome (ePRO) device
  • At least one measurable lesion based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Exclusion Criteria

  • Squamous cell histology or mixed, predominantly squamous adenosquamous carcinoma
  • Previous history of hemoptysis (expectoration of more than 2.5 mL of blood), within three months prior to enrollment
  • Tumor infiltrating into large vessels or infiltrating into the proximal tracheobronchial network, visible on medical imaging; the investigator or radiologist must rule out tumors that conjoin, surround or extend into the immediate area of a large vessel (e.g.: pulmonary artery, superior vena cava)
  • Unstable, symptomatic brain metastases; asymptomatic CNS metastasis noted on baseline scans are acceptable after discussion and approval from the overall principal investigator (PI) of the study
  • History of hemorrhagic CNS metastases
  • History of intracranial hemorrhage (either by clinical history or neuroimaging)
  • History of or genetic predisposition to a bleeding diathesis or coagulopathy
  • Therapeutic anticoagulation, including but not limited to: low-molecular weight heparin (LMWH), heparin, or warfarin; anticoagulants must be discontinued 10 days prior to the first administration of bevacizumab; prophylactic use of anticoagulants is allowed
  • Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 325 mg/day) or other nonsteroidal anti-inflammatories known to inhibit platelet function; prophylactic use of anticoagulants is allowed
  • Clinically significant heart disease (i.e., active), stroke or myocardial infarction within 6 months prior to enrollment, unstable angina pectoris, congestive heart failure of grade > II according to the New York Heart Association (NYHA), or cardiac arrhythmia requiring specific treatment during the study and that may interfere with the follow-up of the study treatment or poorly controlled by treatment
  • Arterial or venous thromboembolic events within 6 months of study enrollment
  • Poorly controlled arterial hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg), with or without antihypertensive medication; patients presenting with high blood pressure are eligible if the dose or adjustment of anti-hypertensive lowers blood pressure to meet the inclusion criteria of the study
  • Invasive surgical intervention (including biopsy by surgical route), major traumatic injury during the 28 days prior to the start of treatment, or scheduled invasive surgical intervention during the study treatment
  • Minor surgical intervention, including placement of a permanent catheter within 24 hours prior to the first infusion of bevacizumab
  • Non-healing wound, active peptic ulcer or bone fracture
  • Previous history of abdominal fistula, tracheoesophageal fistula or other fistula with grade 4 severity, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to enrollment
  • Proteinuria at baseline; subjects unexpectedly found to have >= 2+ proteinuria on a urine dipstick at baseline should undergo a 24-hour urine which must be an adequate collection and must demonstrate < 2 g of protein/24 hour (hr) to allow participation in the study
  • Patients who have received previous anti-angiogenic treatment (experimental or marketed: bevacizumab, thalidomide, CP-547632, sunitinib, sorafenib or others)
  • Patients previously treated with alectinib
  • Radical radiotherapy to the thorax with curative intent within 28 days of initiation of study drug treatment; palliative radiotherapy for bone lesions outside of the thorax or brain within 14 days of the first dose of study treatment; palliative radiotherapy to the brain or thorax within 28 days of the first dose of study drug treatment
  • Cytotoxic chemotherapy within 21 days prior to enrollment
  • Treatment with crizotinib within 7 days prior to enrollment; for all other ALK tyrosine-kinase inhibitors (TKIs), the washout period should 3 days prior to enrollment; a shorter washout period may be considered after discussion with the overall investigator
  • Any gastrointestinal (GI) disorder that may affect absorption of oral medications, such as mal-absorption syndrome or status post major bowel resection
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × ULN (>= 5 × ULN for patients with concurrent liver metastasis); OR impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices; OR acute viral or active autoimmune, alcoholic, or other types of hepatitis
  • National Cancer Institute (NCI) CTCAE (version 4.0) grade 3 or higher toxicities due to any prior therapy (e.g. radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication
  • History of organ transplant
  • Co-administration of anti-cancer therapies other than those administered in this study
  • Patients with baseline corrected QT (QTc) > 470 ms or patients with symptomatic bradycardia
  • History of hypersensitivity to any of the additives in the alectinib drug formulation (lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, sodium lauryl sulfate [SLS], magnesium stearate)
  • Documented allergy or hypersensitivity to monoclonal antibodies (bevacizumab), to Chinese hamster ovarian cells of the or to any other humanized or recombinant antibodies
  • A history of drug-induced pneumonitis or hypersensitivity pneumonitis from prior ALK TKI therapy
  • Pregnant or lactating women
  • Known human immunodeficiency virus (HIV) positivity or acquired immune deficiency syndrome (AIDS)-related illness
  • Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the patient in this study

Massachusetts

Boston
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Justin F. Gainor
Phone: 617-724-4000

PRIMARY OBJECTIVES:

I. To determine the recommended phase II doses (RP2Ds) of the combination of alectinib and bevacizumab. (Phase I)

II. To evaluate the safety and tolerability of alectinib and bevacizumab at the RP2Ds as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. (Phase II)

SECONDARY OBJECTIVES:

I. Safety, tolerability and dose-limited toxicities. (Phase I)

II. Central nervous system (CNS) objective response rate. (Phase II)

III. CNS disease control rate. (Phase II)

IV. Time to CNS progression. (Phase II)

V. Overall (intra- and extra-CNS) objective response rate. (Phase II)

VI. Overall (intra- and extra-CNS) disease control rate. (Phase II)

VII. Progression-free survival (PFS). (Phase II)

VIII. Patient reported functioning and impact on disease/treatment-related symptoms of brain metastases and global quality of life (QOL). (Phase II)

IX. Select tumor genotyping of pre- and post-alectinib/bevacizumab biopsies (optional). (Phase II)

OUTLINE: This is a phase I, dose de-escalation study followed by a phase II study.

Patients receive alectinib orally (PO) twice daily (BID) on days 1-21 and bevacizumab intravenously (IV) over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Justin F. Gainor

  • Primary ID 15-055
  • Secondary IDs NCI-2015-01704
  • Clinicaltrials.gov ID NCT02521051