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A Phase I Trial of the IGF-1R Antibody AMG 479 in Combination With Everolimus (RAD001) and Panitumumab in Patients With Advanced Cancer (The RAP Trial)


Phase 1
18 Years
90 Years
Open (Enrolling)
Both
Advanced Solid Tumors

Thank you

Trial Information

A Phase I Trial of the IGF-1R Antibody AMG 479 in Combination With Everolimus (RAD001) and Panitumumab in Patients With Advanced Cancer (The RAP Trial)


The purpose of this study is to find the safest dose of the drugs AMG 479 and everolimus in
combination and then with panitumumab added. This study will consist of two parts. If you
are enrolled in Part One of the study, you will receive AMG 479 and everolimus. If you are
enrolled in Part Two of the study, you will receive AMG 479, everolimus, and panitumumab.
The study will also look at how the drugs work in the body, and will see if there is any
effect on your cancer.

The study will have two parts: The first part will be to define the MTD/RPTD of the doublet
combination of AMG 479 + everolimus using a standard 3-6 subjects per dose level. Since
each agent is known to be well tolerated as monotherapy, we will start with the full dose of
AMG 479 and escalate the dose of everolimus. Once the RPTD is established, an additional 20
subjects will be added to confirm the tolerability of this regimen and to allow more
detailed biomarker assessment for the effect of each agent alone in the doublet combination.
In this biomarker expanded cohort, subjects will start treatment with 2 weeks of AMG 479
monotherapy (a single dose of AMG 479), followed by the combination of AMG 479 + everolimus
on day 15.

The second part of the study will assess tolerability of the triplet therapy, with
panitumumab added to the RPTD of AMG 479 + everolimus, again using a standard cohort size of
3-6 subjects. Finally, at the recommended phase II dose of the triplet therapy, 20 subjects
will be added to an expanded safety and biomarker cohort. In this biomarker expanded cohort,
10 subjects will start treatment with two weeks of AMG 479 monotherapy (a single dose of AMG
479), and 10 subjects will start treatment with two weeks of everolimus monotherapy, with
all subjects starting the triplet combination therapy with panitumumab on day 15.

ABOUT THE STUDY DRUGS:

AMG 479 is an intravenous (I.V., meaning through a vein) medication made from a special type
of human protein called antibodies. AMG 479 blocks the activity of another protein called
IGF-1R which is important for tumors to grow. Blocking IGFR-1 activity has been shown to
slow or kill cancer cells in laboratory studies. AMG 479 is currently being evaluated in
clinical research studies in a variety of cancers. AMG 479 is not approved by the U.S. Food
and Drug Administration (FDA) for the treatment of cancer and is therefore considered an
investigational drug.

Everolimus is a pill that works by blocking the activity of a substance in the body known as
mTOR (mammalian target of rapamycin). mTOR is important for helping the growth and survival
in normal and cancer cells. Blocking mTOR activity has been shown to slow or kill cancer
cells in laboratory studies. Everolimus is currently being evaluated in clinical research
studies in a variety of cancers. Everolimus (AfinitorTM) is approved by the FDA for the
treatment of advanced renal cell carcinoma (kidney cancer). Besides cancer, everolimus also
has been tested for its ability to help block the rejection of solid organs transplants
(such as liver or kidney transplants). Everolimus is approved for this purpose in Europe
but not in the United States.

Panitumumab is another intravenous (I.V.) medication made from a special type of human
protein called antibodies. Panitumumab blocks the activity of a protein called EGFr which is
also important for tumors to grow. Blocking EGFr activity has been shown to slow or kill
cancer cells in laboratory studies. Panitumumab is currently being evaluated in clinical
research studies in a variety of cancers. Panitumumab (Vectibix™) is approved by the FDA
for the treatment of advanced colorectal cancer following 5'FU, oxaliplatin and irinotecan
chemotherapy regimens.


Inclusion Criteria:



1. Histologically and/or cytologically confirmed malignant solid tumor that is
refractory to standard therapies, or for which no standard therapies exist. Disease
must be measurable by RECIST criteria.

2. Age >18 years.

3. ECOG performance status 0-2.

4. Life expectancy of at least 3 months.

5. Subjects must have adequate organ and marrow function as defined below:

- Absolute neutrophil count >/=1,500/μl

- Platelets >/=100,000/μl

- Magnesium > 1.8 mg/dL

- Phosphorus > 2.3 mg/dL

- Total bilirubin
- AST(SGOT)/ALT(SGPT) PTT
- Creatinine clearance >/=40 mL/min/m2 by Cockroft-Gault or MDRD equation

- Hemoglobin >9 g/dL

- Continuation of erythropoietin products is permitted. Hemoglobin must be stable
above 9 g/dL for at least 2 weeks without blood transfusion to maintain
hemoglobin level.

- Fasting blood sugar
- Patient may be on diabetic medication to achieve glucose control:

- Documented fasting blood sugars
- Diabetic subjects who have recently had their glycemic control regimens
adjusted and have documented fasting blood glucose concentrations ≤ 160
mg/dL may be considered regardless of HgbA1c value, if per investigator
discretion the subject is considered to have adequate glycemic function

6. Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

1. Radiation therapy, hormonal therapy, biologic therapy or chemotherapy for cancer
within the 28 days prior to day 1 of study drug.

2. Active CNS metastases. MRI (or CT) required within 3 months of starting treatment for
all tumor types known to commonly metastasize to the brain (i.e. all tumors except
pancreas, colorectal, ovarian) and for all patients with CNS symptoms that may
represent CNS metastases. Metastases which have been treated with radiotherapy > 2
months prior to start of protocol therapy and are asymptomatic (off steroid therapy
for at least 1 month) may be included. Patients must have had normal or stable (if
treated, no new lesions) brain imaging (CT or MRI) within the two months prior to day
1 of study drug.

3. Inadequately controlled hypertension (defined as systolic blood pressure 140 and/or
diastolic blood pressure > 90 mmHg). Initiation of antihypertensive is permitted
provided adequate control is documented over at least 1 week prior to day 1 of study
drug.

4. Evidence of active bleeding diathesis or coagulopathy.

5. No warfarin therapy. Low molecular weight heparin anticoagulation is permitted
provided that patients have been clinically stable on anti-coagulation for at least 2
weeks prior to day 1 of study drug and meet platelet inclusion criteria. No history
of active GI bleeding or other major bleeding within previous 6 months prior to day 1
of study drug.

6. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to day 1 of study drug (56 days for hepatectomy, open thoracotomy, major
neurosurgery) or anticipation of need for major surgical procedure during the course
of the study.

7. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to day 1 of study drug.

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

9. Any prior history of hypertensive crisis or hypertensive encephalopathy.

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

11. History of clinically significant vascular disease, including any of the following
within 6 months prior to day 1 of study drug: myocardial infarction or unstable
angina, percutaneous coronary intervention, bypass grafting, ventricular arrhythmia
requiring medication, stroke or transient ischemic attack, symptomatic peripheral
arterial disease and/or involvement of great vessels by tumor with or without
vascular grafting.

12. Chronic treatment with systemic steroids or another immunosuppressive agent with the
following exceptions:

Intermittent steroids may be used on an as-needed basis (e.g. treatment for
chemotherapy-related nausea.) Patients on physiologic replacement doses of steroids
due to adrenal insufficiency for any reason may remain on these medications.

13. A known history of HIV seropositivity, hepatitis C virus, acute or chronic active
hepatitis B infection, or other serious chronic infection requiring ongoing
treatment.

14. 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
resection).

15. Patient unwilling to or unable to comply with the protocol.

16. Medical need for the continuous administration of any drugs which affect CYP3A4
though the use of low dose glucocorticoids (e.g. Dexamethasone equivalent) for anorexia and /or nausea is permitted.

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

18. Patients who are pregnant and/or lactating are excluded from this study. (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 two forms of adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to day 1 of study drug, the duration of study
participation and 6 months after the last dose of study drug. 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. )

19. Other concurrent severe and/or uncontrolled medical, psychiatric or social conditions
that could compromise the safety or compliance of treatment as so judged by treating
physician. Examples include but are not limited to:

History of severely impaired lung function defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is room air.

Uncontrolled diabetes mellitus consistent fasting blood glucose readings > 160 mg/dL
or < 50 mg/dL). Use of diabetic medications is permitted.

Hyperlipidemia (>CTC Grade 2: Total Cholesterol > 300-400; Triglycerides > 2.5 ULN).
Use of lipid lowering agents is permitted.

Other: e.g. severe infection, severe malnutrition, ventricular arrhythmias, known
active vasculitis of any cause, tumor invasion of any major blood vessel, severe
chronic liver or renal disease, active upper GI tract ulceration.

20. No immunizations with attenuated live vaccines within one week of study entry or
during study period.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

To define the maximal tolerated dose (MTD) and/or recommended phase II dose (RPTD) for the doublet AMG 479 in combination with everolimus in subjects with advanced solid tumors.

Outcome Time Frame:

3 years

Safety Issue:

Yes

Principal Investigator

Gordana Vlahovic, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University

Authority:

United States: Food and Drug Administration

Study ID:

Pro00021317

NCT ID:

NCT01061788

Start Date:

April 2010

Completion Date:

April 2014

Related Keywords:

  • Advanced Solid Tumors
  • Phase I
  • Solid Tumor
  • AMG 479
  • Panitumumab
  • Everolimus
  • RAD001
  • Duke
  • Subjects with refractory advanced solid tumors

Name

Location

Duke University Medical Center Durham, North Carolina  27710