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A Phase I Study of Bevacizumab, Everolimus, and Panitumumab for Patients With Advanced Solid Tumors

Phase 1
18 Years
Open (Enrolling)
Solid Tumors

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Trial Information

A Phase I Study of Bevacizumab, Everolimus, and Panitumumab for Patients With Advanced Solid Tumors

EGFr inhibition has been shown to have down-regulatory effects on VEGF expression and
angiogenesis. The combination of anti-VEGF and anti-EGFr targeting is clinically rational,
and preliminarily has shown at least additive, if not synergistic effects [12, 13].
Further, preclinical data has shown that constitutive activation of the AKT pathway is a
mechanism of resistance to EGFr inhibitors [14]. Therefore, inhibition of both EGFr and AKT
pathways by panitumumab and RAD001 may create a synergistic antitumor effect. There is also
rationale that RAD001 and anti-VEGF therapies may be synergistic. Preliminary results from
a Phase I dose escalation study of bevacizumab in combination with RAD001 has reported a
recommended Phase II dose of this combination, and has described a minor response in a
colorectal cancer patient previously refractory to bevacizumab-based therapy, and over 10
months of stable disease in another colorectal cancer patient previous refractory to
bevacizumab-based therapy [15].

Bevicizumab (Avatstin) is a humanized monoclonal antibody to VEGF. VEGF is known to play a
pivotal role in tumor angiogenesis and is a significant mitogenic stimulus for arterial,
venous and lymphatic endothelial cells. The addition of bevacizumab to chemotherapy has
been shown to increase overall response rate, duration of response and survival for patients
with metastatic colon cancer (4) and is beneficial in first line non-small cell lung cancer
and metastatic breast cancer [1, 2], and second line metastatic colorectal cancer (7). VEGF
signals through phosphoatidylinositol 3-kinase (PI3K) and Akt as well as through the
extracellular regulated kinase (ERK 1/2), a mitogen activated protein kinase (MAPK). VEGF's
multiple biologic actions may be mediated by different pathways. Erikkson demonstrated that
VEGF induced hyperpermeability was highly dependent on activation of the AKT pathway, while
the angiogenic effect was largely unaffected by blocking this pathway and likely depended on
ERK activation [3].

RAD001 (Everolimus), an oral derivative of rapamycin, selectively inhibits mTOR (mammalian
target of rapamycin), an intracellular protein kinase implicated in the control of cellular
proliferation of activated T-lymphocytes or neoplastic cells. mTOR is considered to be a
downstream component of the PI3K/AKT/TSC pathway, a signalling module known to be heavily
deregulated in many human cancers[4, 5]. In this context, there is an increasing body of
evidence suggesting that AKT regulates mTOR activity[5-7], and that the activation status of
the PI3K/AKT pathway may be indicative of responsiveness to rapamycins such as RAD001.
Specifically, loss of PTEN or constitutive/hyper-activation of AKT has been suggested to
sensitize tumors to the effects of inhibition of mTOR[6-8]. Indeed, RAD001 preferentially
inhibits the proliferation of tumor cells displaying high AKT activity and totally reverses
AKT-driven prostate intraepithelial neoplasia in a mouse transgenic model[7]. Rapamycins
also inhibit downstream signaling pathways of VEGF. The rapamycin-regulated PI3K and p70s6
pathways are known to be involved in mediating VEGF's effects on endothelial cells [9]. In
animal models, rapamycins modestly decrease tumor VEGF expression, and significantly blunt
typical angiogenic responses to VEGF. Everolimus has been shown to inhibit tumor growth and
reduce number of blood vessels in a murine melanoma model, indicating that RAD001 has direct
antiangiogenic effects [10].

Panitumumab (Vectibix) is a fully humanized monoclonal antibody directed against epidermal
growth factor receptor (EGFr), which is a 170-kD transmembrane glycoprotein with a
cytoplasmic protein kinase domain essential for tumor growth and division. The receptor
binds multiple ligands including epidermal growth factor and transforming growth
factor-alpha (TGF-alpha). The tyrosine kinase intracellular domain of the receptor is
activated via binding of a ligand to EGFr, which in turn initiates a cascade of
intracellular signals. These downstream signaling pathways again include the phosphorylation
of mitogen-activated protein kinase (MAPK) through the ras/raf pathway. Inhibition of these
signaling pathways can result in cell growth arrest and apoptosis, respectively[11].

1. Sandler, A.B., et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin
(C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous
non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG)
Trial- E4599. in Proc Am Soc Clin Oncol. 2005.

2. Miller, K.D., et al. E2100: A randomized phase III trial of paclitaxel versus
paclitaxel plus bevacizumab as first line threapy for locally recurrent or metastatic
breast cancer. in American Society for Clinical Oncology. 2005. Orlando, FL.

3. Eriksson, A., et al., Small GTP-binding protein Rac is an essential mediator of
vascular endothelial growth factor-induced endothelial fenestrations and vascular
permeability. Circulation, 2003. 107(11): p. 1532-8.

4. Vivanco, I. and C.L. Sawyers, The phosphatidylinositol 3-kinase-akt pathway in human
cancer. Nature Cancer, 2002. 2: p. 489-501.

5. Krymskaya, V.P., Tumor suppressors hamartin and tuberin: intracellular signaling. Cell
Signal, 2003. 15: p. 729-739.

6. Bjornsti, M.-A. and P.J. Houghton, The TOR pathway: A target for cancer chemotherapy.
Nat Rev Cancer, 2004. 4: p. 335-348.

7. Majumder, P.K., et al., mTOR inhibition reverses Akt-dependent prostate intraepithelial
neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med, 2004.
10: p. 594-601.

8. Noh, W.C., et al., Determinants of rapamycin in breast cancer cells. Clin Cancer Res,
2004. 10: p. 1013-1023.

9. Yu, Y. and J.D. Sato, MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase
mediate the mitogenic response of human endothelial cells to vascular endothelial
growth factor. J Cell Physiol, 1999. 178(2): p. 235-46.

10. Lane, H., et al. Antiangiogenic activity of RAD001, an orally active anticancer agent.
in Proc AACR. 2002.

11. Ciardiello, F. and G. Tortora, A novel approach in the treatment of cancer: Targeting
the epidermal growth factor receptor. Clin Cancer Res, 2001. 7: p. 2958-2970.

12. Spigel, D.R., et al. Bevacizumab and erlotinib in the treatment of patients with
metastatic renal cell cancer (RCC): Update of a phase II multicenter trial. in Proc Am
Soc Clin Oncol. 2005.

13. Saltz, L.B., et al. Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI)
versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. in Proc
Am Soc Clin Oncol. 2005.

14. She, Q.B., et al., Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells
can be overcome through restoration of PTEN function or pharmacologic modulation of
constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling. Clin Cancer Res,
2003. 9(12): p. 4340-6.

15. Zafar, Y., et al. Preliminary results of a phase I study of bevacizumab (BV) in
combination with everolimus (E) in patients with advanced solid tumors. in Proc Am Soc
Clin Oncol. 2006.

Inclusion Criteria:

- Patients must have histologically confirmed malignancy that is metastatic or
unresectable and for which standard curative or palliative measures do not exist or
are no longer effective. Disease must be measurable or evaluable by RECIST criteria.

- Patients must not have had radiation therapy, hormonal therapy, biologic therapy or
chemotherapy for cancer within the 28 days prior to study day 1. Patients must not
have had major surgery within the 28 days prior to study day 1 or minor surgical
procedures within the 7 days prior to study day 1.

- Age >18 years.

- Karnofsky performance status > 70%.

- Life expectancy of at least 3 months.

- Patients must have normal organ and marrow function as defined below:

**Absolute neutrophil count greater or equal to 1,500/μl; Platelets greater or equal
to 100,000/μl; Total bilirubin, less or equal to 1.5 X upper limit of normal
(ULN)AST(SGOT)/ALT(SGPT)less or equal to 2.5 X ULN less or equal to 5 X ULN if
known hepatic metastases; Creatinine clearance greater or equal to 50 mL/min/m2 for
patients with creatinine levels (by Cockroft-Gault equation or 24 hour urine;
Hemoglobin > 9 g/dL; Magnesium > 1.2 mg/dL; Calcium (corrected for albumin)> 8.7

- The effect of the investigational drugs on the developing human fetus is not known,
but these drugs are likely to be embryo- and feto- toxic. 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
she or her partner are participating in this study, she should inform her treating
physician and study PI immediately. Oral, implantable, or injectable contraceptives
may be affected by cytochrome P450 interactions, and are therefore not considered
effective for this study.

- Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

- Patients who have had radiation therapy, hormonal therapy, biologic therapy, or
chemotherapy for cancer within the 28 days prior to day 1 of the study.

- Patients who have received any other investigational agents within the 28 days prior
to day 1 of the study.

- Patients with known CNS metastases or centrally-located non-small cell lung cancer.

- Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or
diastolic blood pressure > 100 mmHg)

- Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

- Symptomatic peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy. Patients on full dose
anticoagulation are excluded from this trial.

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to study enrollment (56 days for hepatectomy, thoracotomy, neurosurgery) 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 study enrollment

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to study enrollment

- Serious, non-healing wound, ulcer, or bone fracture

- Proteinuria at screening as demonstrated by Urine protein:creatinine (UPC) ratio
greater than 1.0

- Any prior history of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) Grade II or greater congestive heart failure

- History of myocardial infarction or unstable angina within 6 months prior to study

- History of stroke or transient ischemic attack within 6 months prior to study

- History of intolerance or hypersensitivity to prior treatment with bevacizumab,
RAD001, or panitumumab. Prior treatment with these agents is otherwise permitted.

- Chronic treatment with systemic steroids or another immunosuppressive agent, though
steroids may be used on an as-needed basis - ie - for treatment of nausea. Treatment
with megace is permitted for treatment of anorexia.

- Other concurrent severe and/or uncontrolled medical disease which could compromise
safety of treatment (i.e., severely impaired lung function, uncontrolled diabetes,
uncontrolled hypertension, severe infection, severe malnutrition, ventricular
arrhythmias, active ischemic heart disease, chronic liver or renal disease, active
upper GI tract ulceration)

- A known history of HIV seropositivity, hepatitis C virus, acute or chronic active
hepatitis B infection.

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter drug absorption (e.g., inflammatory bowel disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome or significant small bowel

- Patients with an active, bleeding diathesis or on oral anti-vitamin K medication
(except low dose coumarin)

- Patients unwilling to or unable to comply with the protocol

- Medical need for the continued administration of any of the following drugs which
affect CYP3A. (see Appendix A ifor a list of common medications).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, or psychiatric illness/social situations that would limit safety or
compliance with study requirements or may interfere with the interpretation of the

- History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or any
evidence of interstitial lung disease on baseline chest CT scan

Type of Study:


Study Design:

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

Outcome Measure:

To determine the MTD/recommended phase II regimen and evaluate safety of panitumumab added to RAD001 plus bevacizumab in adult patients with advanced solid tumors.

Outcome Time Frame:

Every cycle (28-days)

Safety Issue:


Principal Investigator

Herbert I Hurwitz, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Institutional Review Board

Study ID:




Start Date:

November 2007

Completion Date:

November 2013

Related Keywords:

  • Solid Tumors
  • solid tumors
  • avastin
  • Phase I
  • Phase 1
  • combination therapy
  • bevacizumab
  • RAD001
  • everolimus
  • pantitumumab
  • Neoplasms



Duke University Medical Center Durham, North Carolina  27710