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A Sequential Phase I Study Of The Combination Of Everolimus (Rad001) With 5-Fu/Lv (De Gramont), Folfox6, And Folfox6/Panitumumab In Patients With Refractory Solid Malignancies


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Sequential Phase I Study Of The Combination Of Everolimus (Rad001) With 5-Fu/Lv (De Gramont), Folfox6, And Folfox6/Panitumumab In Patients With Refractory Solid Malignancies


OBJECTIVES:

Primary

- To determine the maximum tolerated dose of everolimus in combination with sequential
fluorouracil (5-FU) and leucovorin calcium, panitumumab, modified 5-FU, leucovorin
calcium, and oxaliplatin (mFOLFOX6), and mFOLFOX6 with panitumumab in patients with
refractory solid tumors.

Secondary

- To determine the adverse event profile of these regimens.

- To correlate response with S6-phosphorylation and AKT-phosphorylation in available
archived tumor samples.

- To evaluate preliminary evidence of antitumor activity of these regimens using RECIST
criteria for a subset of patients with measurable disease.

OUTLINE: This is a dose-escalation study. Cohorts of patients are enrolled into treatment
groups 1 or 2. If a final cohort of patients is reached in groups 1 and/or 2, additional
cohorts of patients are enrolled into treatment group 3.

- Group 1: Patients receive oral everolimus once daily on days 1-28. Patients also
receive leucovorin calcium IV followed by fluorouracil IV continuously over 46 hours
beginning on day 1. Treatment repeats every 28 days in the absence of disease
progression or unacceptable toxicity.

- Group 2: Patients receive oral everolimus once daily on days 1-28 and panitumumab IV
over 30-90 minutes on day 1. Treatment repeats every 28 days in the absence of disease
progression or unacceptable toxicity.

- Group 3: Patients receive oral everolimus once daily on days 1-28, leucovorin calcium
IV followed by fluorouracil IV continuously over 46 hours beginning on day 1, and
oxaliplatin IV over 2-4 hours on day 1. Some patients may also receive panitumumab IV
over 30-90 minutes on day 1. Treatment repeats every 28 days in the absence of disease
progression or unacceptable toxicity.

Archived tumor samples are assessed for phospho-AKT, phospho-S6K, and phospho-S6 by
immunohistochemistry.

After completion of study treatment, patients are followed every 3 months for 1 year.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed malignant solid tumor

- Advanced or unresectable disease

- No standard therapeutic option available

- Evaluable disease (according to RECIST criteria) that has not been previously
irradiated

- Prior radiotherapy to the marker lesion(s) allowed provided there is evidence of
progression since radiotherapy

- Brain metastases allowed provided the following criteria are met:

- CNS-directed treatment was given and was completed > 3 months ago

- CNS disease has been clinically and radiographically stable for ≥ 8 weeks

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Absolute neutrophil count ≥ 1,500/µL

- Platelet count ≥ 100,000/µL

- Creatinine clearance ≥ 60 mL/min

- Total bilirubin ≤ 1.2 mg/dL

- Transaminases ≤ 5 times upper limit of normal (ULN)

- Magnesium ≥ lower limit of normal

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 24 weeks (females)
or for 4 weeks (males) after completion of study therapy

- Willing to avoid pregnancy for 3 months after completion of study therapy

- No neuropathy ≥ grade 2

- No concurrent life-threatening acute medical illness

- No 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)

- No active bleeding diathesis

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 3 weeks since prior major surgery, radiotherapy (including radiotherapy
involving the abdomen or spine), chemotherapy, or other systemic anticancer therapy
and recovered

- At least 4 weeks since prior investigational drugs

- No concurrent CYP3A4 inducers or inhibitors that cannot be substituted by a different
agent

- No concurrent oral anti-vitamin K medication (except for low-dose warfarin)

- No concurrent colony stimulating factors during the first course of treatment

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of everolimus in combination with sequential fluorouracil (5-FU) and leucovorin calcium, panitumumab, modified 5-FU, leucovorin calcium, and oxaliplatin (mFOLFOX6), and mFOLFOX6 with panitumumab

Outcome Description:

Patients will be assessed for toxicity at the commencement of each cycle

Outcome Time Frame:

after the first 28 day cycle

Safety Issue:

Yes

Principal Investigator

Bert H. O'Neil, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UNC Lineberger Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

LCCC 0621

NCT ID:

NCT00610948

Start Date:

March 2008

Completion Date:

December 2014

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific

Name

Location

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570