Everolimus, Fluorouracil, Leucovorin, Panitumumab, and Oxaliplatin in Treating Patients With Tumors That Did Not Respond to Treatment

Sponsor

UNC Lineberger Comprehensive Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00610948

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arms

Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as fluorouracil, leucovorin, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving everolimus together with combination chemotherapy and/or panitumumab may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of everolimus when given together with fluorouracil, leucovorin, panitumumab, and oxaliplatin in treating patients with solid tumors that did not respond to previous treatment.

Condition or Disease	Intervention/Treatment	Phase
Unspecified Adult Solid Tumor, Protocol Specific	Biological: panitumumab Drug: everolimus Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

74 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Mar 1, 2008

Actual Primary Completion Date :

May 1, 2013

Actual Study Completion Date :

Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: everolimus Given orally Other Names: Afinitor Drug: fluorouracil Given IV Other Names: 5FU Drug: leucovorin calcium Given IV
Experimental: 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.	Biological: panitumumab Given IV Other Names: Vectibix Drug: everolimus Given orally Other Names: Afinitor
Experimental: 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.	Biological: panitumumab Given IV Other Names: Vectibix Drug: everolimus Given orally Other Names: Afinitor Drug: fluorouracil Given IV Other Names: 5FU Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV Other Names: Eloxatin

Arm

Intervention/Treatment

Experimental: 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.

Drug: everolimus

Given orally

Other Names:

Afinitor

Drug: fluorouracil

Given IV

Other Names:

5FU

Drug: leucovorin calcium

Given IV

Experimental: 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.

Biological: panitumumab

Given IV

Other Names:

Vectibix

Drug: everolimus

Given orally

Other Names:

Afinitor

Experimental: 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.

Biological: panitumumab

Given IV

Other Names:

Vectibix

Drug: everolimus

Given orally

Other Names:

Afinitor

Drug: fluorouracil

Given IV

Other Names:

5FU

Drug: leucovorin calcium

Given IV

Drug: oxaliplatin

Given IV

Other Names:

Eloxatin

Outcome Measures

Primary Outcome Measures

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 [after the first 28 day cycle]
Patients will be assessed for toxicity at the commencement of each cycle
Toxicity as assessed by CTC version 3.0 at the beginning of each treatment course [first 28 day cycle]
Dose Limiting Toxicities (DLT) are defined during the first cycle (28 days).
Tumor response [Every 8 weeks during treatment]
Tumor response will be assessed by RECIST criteria
Correlation of response with S6-phosphorylation and AKT-phosphorylation in archived tumor samples [3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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