A Randomized Phase II Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Adenocarcinoma. (NA_00052073)

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2013 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01578551
First received: April 13, 2012
Last updated: October 10, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
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).
Drug: Paclitaxel, Carboplatin, Bevacizumab, and Metformin
Drug: Paclictaxl, Carboplatin, and Bevcizumab.
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Previously Untreated Advanced/Metastatic Pulmonary Adenocarcinoma

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • PFS [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Response to therapy and overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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.

  • LKB1 [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To determine whether LKB1 gene status in tumors is a significant determinant of response when metformin is added to the therapy

  • Uptake of fluorodeoxyglucose [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To acquire preliminary data regarding the effects of metformin on uptake of fluorodeoxyglucose in tumor and normal tissues.


Estimated Enrollment: 60
Study Start Date: April 2012
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A
Paclitaxel, Carboplatin, Bevacizumab, and Metformin. 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.
Drug: Paclitaxel, Carboplatin, Bevacizumab, and Metformin
Paclitaxel + Carboplatin + Bevacizumab will be administered once every 21 days (Day 1) for up to 6 cycles. If subject has complete response, partial response, stable disease, or unacceptable toxicity. Bevacizumab with Metformin (Arm A) or Bevacizumab alone (Arm B) may continue as maintenance therap
Active Comparator: Arm B
Paclictaxl, Carboplatin, and Bevcizumab
Drug: Paclictaxl, Carboplatin, and Bevcizumab.
Paclitaxel + Carboplatin + Bevacizumab will be administered once every 21 days (Day 1) for up to 6 cycles. If subject has complete response, partial response, stable disease, or unacceptable toxicity. Bevacizumab with Metformin (Arm A) or Bevacizumab alone (Arm B) may continue as maintenance therap

Detailed Description:

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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01578551

Locations
United States, Maryland
Johns Hopkins University SKCCC Recruiting
Baltimore, Maryland, United States, 21231
Contact: David Ettinger, M.D.    410-955-8847    ETTINDA@jhmi.edu   
Contact: Charles P. Raines, CRNP, MSN    410-502-3696    craines1@jhmi.edu   
Principal Investigator: David Ettinger, MD         
Johns Hopkins Bayview Medical Center Recruiting
Baltimore, Maryland, United States, 21224
Contact: Phillip Dennis, MD PhD    410-550-9250    pdennis1@jhmi.edu   
Principal Investigator: Phillip Dennis, MD PhD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01578551     History of Changes
Other Study ID Numbers: J1188, NA_00052073, 2 P50 CA058184-16
Study First Received: April 13, 2012
Last Updated: October 10, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
Previously Untreated Advanced/Metastatic Pulmonary Adenocarcinoma.

Additional relevant MeSH terms:
Adenocarcinoma
Carcinoma
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Metformin
Bevacizumab
Carboplatin
Paclitaxel
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Angiogenesis Inhibitors
Angiogenesis Modulating Agents

ClinicalTrials.gov processed this record on August 01, 2014