Study of Everolimus, Pemetrexed, Carboplatin, and Bevacizumab to Treat Stage IV Lung Cancer

This study is currently recruiting participants.
Verified December 2013 by Cancer Research and Biostatistics Clinical Trials Consortium
Sponsor:
Collaborators:
University of Arizona
Providence Cancer Center, Earle A. Chiles Research Institute
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Cancer Research and Biostatistics Clinical Trials Consortium
ClinicalTrials.gov Identifier:
NCT01700400
First received: September 21, 2012
Last updated: December 3, 2013
Last verified: December 2013
  Purpose

The purpose of this study is to identify a well-tolerated dose of everolimus in combination with chemotherapy treatment for patients with advanced lung cancer.


Condition Intervention Phase
Non Small Cell Lung Cancer
Drug: Everolimus
Drug: Pemetrexed
Drug: Carboplatin
Drug: Bevacizumab
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Dose Escalation Study of Everolimus, Pemetrexed, Carboplatin, and Bevacizumab in Stage IV Non-Squamous Non-Small Cell Lung Cancer

Resource links provided by NLM:


Further study details as provided by Cancer Research and Biostatistics Clinical Trials Consortium:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) and Recommended Phase Two Dose (RPTD) of the combination of everolimus with pemetrexed, carboplatin, and bevacizumab in patients with Stage IV non-squamous NSCLC. [ Time Frame: up to 2 years ] [ Designated as safety issue: Yes ]
    Measured by adverse event profile at the end of Cycle 1. MTD is the highest dose level where less than one third of 12 evaluable patients experience a dose limiting toxicity as defined by the protocol.


Secondary Outcome Measures:
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: up to 2 years ] [ Designated as safety issue: Yes ]

    Dose Limiting Toxicity (DLT) adverse events related to everolimus/pemetrexed/carboplatin/bevacizumab administration in patients with Stage IV non-squamous NSCLC. DLTs will be defined during cycle 1 only. Grading of adverse events will be according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.

    Hematologic Adverse Events are defined as:

    Grade 4 neutropenia lasting greater than 5 days; Grade 3 or 4 febrile neutropenia; and/or Grade 4 thrombocytopenia

    Non-hematologic Adverse Events are defined as:

    Grade 3 or greater non-hematologic excluding the following:

    Hypersensitivity reaction grade 3 or 4 occurring on day 1 or day 15; Nausea/vomiting grade 3 or 4 in the absence of optimal antiemetics; Diarrhea grade 3 or 4 in the absence of optimal anti-diarrheal therapy; Asthenia grade 3 or 4 of less than 2 weeks duration; and/or Hyperglycemia grade 3 or 4 temporally related to corticosteroid pre-or post-medication


  • Antitumor efficacy associated with administration of everolimus/pemetrexed/carboplatin/bevacizumab administration in patients with Stage IV non-squamous NSCLC. [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]
    number of patients with a response according to the Response Evaluation Criteria in Solid Tumors (RECIST)

  • Progression-free survival (PFS) [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]
    time from start of treatment to time of progression or death (overall PFS)

  • Overall Survival (OS) [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]
    measured from the start of treatment to time of death.


Estimated Enrollment: 24
Study Start Date: September 2012
Estimated Study Completion Date: March 2014
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Experimental Phase I Dose Escalation

Pemetrexed: intravenous; 500 mg/m² for Dose Levels 1, 2 and 3

Carboplatin: intravenous; 5 AUC for Dose Level 1; 6 AUC for Dose Levels 2 and 3

Bevacizumab: intravenous; 15 mg/kg for Dose Levels 1, 2, and 3

Everolimus: oral, 2.5 mg/day for Dose Levels 1 and 2; 5.0 mg/day for Dose Level 3

Drug: Everolimus
Other Names:
  • Afinitor
  • Zortress
  • RAD001
Drug: Pemetrexed
Other Name: Alimta
Drug: Carboplatin
Other Names:
  • Paraplatin
  • CBDCA
Drug: Bevacizumab
Other Name: Avastin

Detailed Description:

The AKT/mTOR pathway is a relevant target in NSCLC based on preclinical data showing aberrant pathway activation in human NSCLC tumors. Everolimus as a single agent has produced some responses as well as prolonged stable disease in both chemonaive and pre-treated NSCLC (Gridelli et al, 2008). There is interest in augmenting tumor responses to chemotherapy by the addition of mTOR inhibition. Additionally, preclinically, everolimus has shown antiangiogenic activity that appears to have different targets than direct VEGF inhibiting strategies and therefore may augment the activity of targeted VEGF inhibitors (Lane et al, 2009). Therefore, we propose to study in a Phase 1 dose escalation design the addition of everolimus in escalating doses in combination with Pem/Carbo/Bev in non-squamous histology NSCLC.

Patients will be entered onto dosing cohorts of 3 patients according to the following dose escalation scheme. The first cohort will begin at dose level 1. At least three patients on each dose level must have completed cycle one before the study leadership (principal investigators, study statisticians) will allow patients to be enrolled onto the successive dose level.

Dose Level (K): 1, 2, 3

Pemetrexed (mg/m²): 500, 500, 500

Carboplatin (AUC): 5, 6, 6

Bevacizumab (mg/kg): 15, 15, 15

Everolimus (mg/day): 2.5, 2.5, 5.0

Dose-limiting toxicities (DLTs) will be defined according to the National Cancer Institute's CTCAE v.4.0 toxicity scale (see Section 3.3 below). The traditional "3+3" dosing scheme will be used for dose escalation.

When the potential MTD has been identified, it will be expanded to a total of 12 patients.

  Eligibility

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

    1. Signed informed consent
    2. Histological or cytological diagnosis of non-squamous non-small cell lung cancer
    3. Stage IV disease
    4. At least one measurable site of disease according to RECIST criteria that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation.
    5. Age ≥ 18 years
    6. Zubrod performance status of 0 or 1
    7. Normal hematologic function as evidenced the following laboratory parameters collected ≤ 14 days prior to enrollment:

      • ANC ≥ 1,500/mm³,
      • Hb ≥ 9.0 g/dL, and
      • Platelet count ≥ 100,000/mm³
    8. Adequate hepatic, renal, and chemistry function as evidenced by the following laboratory parameters collected ≤ 14 days prior to enrollment:

      • serum bilirubin ≤1.5 IULN,
      • AST (SGOT) or ALT (SGPT) ≤ 2.5 IULN, and
      • Calculated or measured creatinine clearance ≥ 50 ml/min
    9. INR ≤ 1.5 within 14 days prior to enrollment. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of low molecular weight heparin for >2 weeks at time of study entry). aPTT no greater than IULN
    10. Urine dipstick for proteinuria 0-1+.
    11. Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x IULN. Testing must be performed within 14 days prior to enrollment.
    12. The ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of pemetrexed.
    13. No prior treatment with everolimus. Prior treatment with pemetrexed or carboplatin is allowed, provided no disease progression with prior exposure to drugs. Prior treatment with bevacizumab allowed.
  2. Exclusion Criteria:

    1. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol
    2. Clinically significant cardiac event such as Myocardial infarction; New York Heart Association (NYHA) classification of heart disease ≥ 2 within 3 months before study enrollment; or presence of cardiac disease that in the opinion of the Investigator increase the risk of ventricular arrhythmia.
    3. Inadequately controlled hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg)
    4. Active gastrointestinal disease resulting in an inability to take oral or enteral medication via a feeding tube or a requirement for IV alimentation; prior surgical procedures affecting absorption; or active peptic ulcer disease
    5. Presence of third space fluid which cannot be controlled by drainage
    6. Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to enrollment
    7. History of stroke within 6 months prior to enrollment
    8. Symptomatic peripheral vascular disease within 6 months prior to enrollment, or history of significant vascular disease (i.e., aortic aneurysm)
    9. Bleeding diathesis or significant coagulopathy (assuming not on anti-coagulation); patients with a history of DVT and/pr pulmonary embolism are excluded
    10. Serious non-healing wound, ulcer, or bone fracture
    11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment, or anticipation of need for major surgical procedure during the course of the study. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1.
    12. Untreated brain metastases (treated brain metastases allowed if stable clinically and radiographically by post-treatment MRI or CT brain at least 14 days after completion of radiotherapy). Resolution of radiation-related toxicity to ≤ gr 1, and not requiring glucocorticoids for symptom management
    13. Radiotherapy to systemic disease less than 28 days prior to registration. Side effects due to radiotherapy must have resolved to ≤ gr 1
    14. Gross hemoptysis of ≥ 5 ml within 3 months prior to enrollment
    15. ≥ Grade 2 proteinuria
    16. Significant hyperlipidemia
    17. Previous or current malignancies of other histologies within the last 3 years, with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin
    18. Prior treatment with any investigational drug within the preceding 4 weeks prior to enrollment
    19. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
    20. Patients must not receive immunization with attenuated live vaccines within one week prior to study enrollment or during study period.
    21. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

      • symptomatic congestive heart failure of New York heart Association Class III or IV
      • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
      • severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air
      • uncontrolled diabetes as defined by fasting serum glucose >1.5 x IULN
      • active (acute or chronic) or uncontrolled severe infections
      • liver disease such as cirrhosis, or severe hepatic impairment (Child-Pugh class C).
      • Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.
    22. A known history of HIV seropositivity
    23. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
    24. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of everolimus.
    25. Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus)
    26. Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients aa. History of noncompliance to medical regimens ab. Patients unwilling to or unable to comply with the protocol
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01700400

Contacts
Contact: Jennifer Newman, CTC Operations (206) 839-1738 jennifern@crab.org

Locations
United States, Arizona
University of Arizona Cancer Center Recruiting
Tuscon, Arizona, United States, 85724
Contact: Linda L. Garland, MD    520-626-3434    lgarland@azcc.arizona.edu   
Contact: Jeanette Cardenas    520-694-9082    jcardenas@azcc.arizona.edu   
Principal Investigator: Linda L. Garland, MD         
United States, Kentucky
University of Kentucky Markey Cancer Center Not yet recruiting
Lexington, Kentucky, United States, 40536
Contact: Dennie V. Jones, MD    859-257-2014    dennie.jones@uky.edu   
Principal Investigator: Dennie V. Jones, MD         
United States, Oregon
Providence Cancer Center Recruiting
Portland, Oregon, United States, 97213
Contact: Rachel Sanborn, MD    503-215-5396    Rachel.Sanborn@providence.org   
Contact: Brenda Fisher, RN    (503) 215-2613    Brenda.Fisher@providence.org   
Principal Investigator: Rachel Sanborn, MD         
United States, Washington
Cancer Research And Biostatistics Clinical Trials Consortium Recruiting
Seattle, Washington, United States, 98101
Contact: CTC Operations Office    206-839-1738    jennifern@crab.org   
Sponsors and Collaborators
Cancer Research and Biostatistics Clinical Trials Consortium
University of Arizona
Providence Cancer Center, Earle A. Chiles Research Institute
Novartis Pharmaceuticals
Investigators
Principal Investigator: Linda L. Garland, MD University of Arizona
Study Chair: John Crowley, PhD Cancer Research And Bioststistics
  More Information

Additional Information:
No publications provided

Responsible Party: Cancer Research and Biostatistics Clinical Trials Consortium
ClinicalTrials.gov Identifier: NCT01700400     History of Changes
Other Study ID Numbers: CRAB CTC 10-001
Study First Received: September 21, 2012
Last Updated: December 3, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Cancer Research and Biostatistics Clinical Trials Consortium:
Lung Cancer
Non Small Cell Lung Cancer
Advanced Lung Cancer

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Everolimus
Sirolimus
Pemetrexed
Bevacizumab
Carboplatin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on April 17, 2014