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Phase I Dose Escalation Study of Everolimus, Pemetrexed, Carboplatin, and Bevacizumab in Stage IV Non-Squamous Non-Small Cell Lung Cancer

Phase 1
18 Years
Open (Enrolling)
Non Small Cell Lung Cancer

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Trial Information

Phase I Dose Escalation Study of Everolimus, Pemetrexed, Carboplatin, and Bevacizumab in Stage IV Non-Squamous Non-Small Cell Lung Cancer

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

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.


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

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

- 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

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

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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Outcome Description:

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.

Outcome Time Frame:

up to 2 years

Safety Issue:


Principal Investigator

Linda L. Garland, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Arizona


United States: Institutional Review Board

Study ID:

CRAB CTC 10-001



Start Date:

September 2012

Completion Date:

March 2014

Related Keywords:

  • Non Small Cell Lung Cancer
  • Lung Cancer
  • Non Small Cell Lung Cancer
  • Advanced Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



University of Arizona Cancer Center Tucson, Arizona  85724
Providence Cancer Center Portland, Oregon  97213-2933
Cancer Research And Biostatistics Clinical Trials Consortium Seattle, Washington  98101