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A Randomized Phase II Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Previously Untreated Advanced/Metastatic Pulmonary Adenocarcinoma


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Patients Must Have Histologically or Cytologically Confirmed Non-squamous Cell, Non Small Cell Carcinoma of the Lung., Patient Must Have Measurable Stage IV Disease (Includes M1a, M1b Stages or Recurrent Disease).

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Trial Information

A Randomized Phase II Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Previously Untreated Advanced/Metastatic Pulmonary Adenocarcinoma


Primary Objectives

To determine the 1 year progression-free survival (PFS) of the combination of metformin and
standard chemotherapy in patients with previously untreated advanced or metastatic pulmonary
adenocarcinoma.

Secondary Objectives

A. To evaluate the response to therapy and overall survival of the combination of metformin
with standard chemotherapy in patients with previously untreated advanced or metastatic
pulmonary adenocarcinoma.

B. To determine whether LKB1 gene status in tumors is a significant determinant of response
when metformin is added to the therapy C. To acquire preliminary data regarding the effects
of metformin on uptake of fluorodeoxyglucose in tumor and normal tissues.

Treatment will be administered on an outpatient basis.

Induction Therapy (Step 1, Cycles 1-4)

Metformin starting at a dose of 500 mg twice a day, orally with meals. After one week,
increase the dose of metformin to 1000 mg as the first dose of the day and 500 mg as the
second dose. After another week, increase to 1000 mg of metformin two times a day. Metformin
treatment will be initiated one week before beginning chemotherapy, if possible, but
chemotherapy will not be delayed for metformin loading.

Paclitaxel 200 mg/m2 IV over 3 hours. For Paclitaxel pre-medication information

Carboplatin AUC = 6 mg/ml IV over 15 - 30 minutes, immediately following paclitaxel infusion

Bevacizumab 15 mg/kg IV infusion over 30 - 90 minutes

Metformin will be administered continuously, beginning one week before beginning
chemotherapy, if possible, but chemotherapy will not be delayed for metformin loading. The
other three drugs (paclitaxel, carboplatin, and bevacizumab) will be administered on day 1
of each 21 day cycle.

Maintenance Therapy

Patients responding to this therapy will be maintained with metformin (1000 mg twice daily)
and bevacizumab (15 mg/kg IV over 30-90 minutes on day 1 of each 21-day cycle).

Duration of Therapy

In the absence of treatment delays due to adverse events, treatment may continue until one
of the following criteria applies:

1. Disease progression,

2. Intercurrent illness that prevents further administration of treatment,

3. Unacceptable adverse events(s),

4. Patient decides to withdraw from the study, or

5. General or specific changes in the patient's condition render the patient unacceptable
for further treatment in the judgment of the investigator.


Inclusion Criteria:



Patients must have Histologically or cytologically confirmed non-squamous cell, non small
cell carcinoma of the lung.

Patient must have measurable stage IV disease (includes M1a, M1b stages or recurrent
disease) (according to the 7th edition of the TNM classification system). However,
patients with T4NX disease (stage III B) with nodule(s) in ipsilateral lung lobe are not
eligible, because such patients were not included in historical controls.

Patients be age >18 years.

Patients must have a Life Expectancy of greater than 12 weeks.

Patients must have an ECOG performance status 0 or 1 (Karnofsky > 70%; see Appendix A).

Patients must have normal organ and marrow function as defined below, within one week
prior to randomization:

- absolute neutrophil count >1,500/mcL

- platelets > 100,000/mcL

- total bilirubin: within normal institutional limits

- AST(SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal

- creatinine ≤ 1.5 X institutional upper limit of normal

- urine dipstick for proteinuria of < less than 1+. If urine dipstick is > 1+ then a 24
hour urine for protein must demonstrate < 500 mg of protein in 24 hours to allow
participation in the study.

Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician immediately.

Patients must have an INR < 1.5 and a PTT no greater than upper limits of normal within 1
week prior to randomization.

Patients with a history of hypertension must be well-controlled
(<150sytolic/<100diastolic) on a stable regimen of anti-hypertensive therapy.

Patients must have the ability to understand and the willingness to sign a written
informed consent document.

Exclusion Criteria:

Patients with a history of gross hemoptysis (defined as bright red blood of ½ teaspoon or
more) will be excluded from this trial.

Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situation that would limit compliance with study
requirements.

Patients with a history of thrombotic or hemorrhagic disorders.

Patients receiving chronic daily treatment with aspirin (> 325 mg/day) or nonsteroidal
anti-inflammatory agents known to inhibit platelet function. Treatment with dipyridamole
(Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and/or cilostazol (Pletal)is also
not allowed.

Patients receiving therapeutic anticoagulation. Prophylactic anticoagulation of venous
access devices is allowed provided Section 3.10 is met. Caution should be taken on
treating patients with low dose heparin or low molecular weight heparin for DVT
prophylaxis during treatment with bevacizumab as there may be an increased risk of
bleeding.

Prior use of chemotherapy.

Patients receiving immunotherapy, hormonal-therapy and or radiotherapy within 2 weeks
prior to entering the study. Note: Those who have not recovered from adverse events due to
these agents administered will be considered ineligible.

Patients receiving any other investigational agents.

Patients with a serious non-healing wound ulcer, or bone fracture, or major surgical
procedure within 21 days prior to starting treatment.

Patients with uncontrolled brain metastasis. Note: Patients with brain metastases must
have stable neurologic status following local therapy (surgery or radiation) for at least
2 weeks, and must be without neurologic dysfunction that would confound the evaluation of
neurologic and other adverse events.

Patients with a history of allergic reactions attributed to compounds of similar chemical
or biologic composition to metformin and paclitaxel or other agents used in the study are
excluded.

Women that are pregnant or breastfeeding Note: Pregnant women are excluded from this study
because the agents used in this study may be teratogenic to a fetus. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to treatment of
the mother with paclitaxel, breastfeeding women are also excluded from this study.

Patients that are HIV-positive on combination antiretroviral therapy due to the potential
for lethal infections when treated with marrow-suppressive therapy.

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:

PFS

Outcome Description:

To determine the 1 year progression-free survival (PFS) of the combination of metformin and standard chemotherapy in patients with previously untreated advanced or metastatic pulmonary adenocarcinoma.

Outcome Time Frame:

1 year

Safety Issue:

No

Authority:

United States: Food and Drug Administration

Study ID:

J1188

NCT ID:

NCT01578551

Start Date:

April 2012

Completion Date:

April 2015

Related Keywords:

  • Patients Must Have Histologically or Cytologically Confirmed Non-squamous Cell, Non Small Cell Carcinoma of the Lung.
  • Patient Must Have Measurable Stage IV Disease (Includes M1a, M1b Stages or Recurrent Disease).
  • Previously Untreated Advanced/Metastatic Pulmonary Adenocarcinoma.
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Carcinoma
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms

Name

Location

Johns Hopkins University SKCCCBaltimore, Maryland  21231