S0528 Lapatinib and Everolimus in Treating Patients With Advanced Solid Tumors or Non-Hodgkin's Lymphoma

Sponsor

Southwest Oncology Group (Other)

Overall Status

Completed

CT.gov ID

NCT00352443

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Lapatinib and everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Everolimus may also stop the growth of cancer cells by blocking blood flow to the cancer. Giving lapatinib together with everolimus may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of lapatinib and everolimus in treating patients with advanced solid tumors or non-Hodgkin's lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma Unspecified Adult Solid Tumor, Protocol Specific	Drug: everolimus Drug: lapatinib ditosylate	Phase 1

Detailed Description

OBJECTIVES:

Estimate the maximum tolerated dose (MTD) of lapatinib and everolimus in patients with advanced solid tumors or non-Hodgkin's lymphoma. (Part I)
Investigate the pharmacokinetics of everolimus and lapatinib (when given alone and in combination) at the MTD determined in Part I. (Part II)
Investigate the effects of everolimus and lapatinib (when given alone and in combination) on serum levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), matrix metalloproteinase (MMP)-2 and MMP-9, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). (Part II)

OUTLINE: This is a multicenter, dose-escalation study followed by a randomized study. Initial patients enrolled on the study are treated in part I. After the maximum tolerated dose (MTD) is determined in part I, subsequent patients are enrolled and treated in part II.

Part I: Patients receive oral everolimus and oral lapatinib once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of everolimus and lapatinib until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

Part II: Patients are randomized to 1 of 2 treatment arms. Everolimus and lapatinib are administered at the MTD determined in part I.
Arm I: Patients receive oral everolimus once daily on days 1-28. Patients also receive oral lapatinib once daily on days 8-28 during the first course and on days 1-28 during all subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm II: Patients receive oral lapatinib once daily on days 1-28. Patients also receive oral everolimus once daily on days 8-28 during the first course and on days 1-28 during all subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients in part II undergo blood collection periodically for correlative biomarker and pharmacokinetic studies.

After finishing treatment, patients are followed periodically for 28 days.

PROJECTED ACCRUAL: A total of 48 patients will be accrued for this study.

Study Design

Study Type:

Interventional

Actual Enrollment :

66 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study Evaluating the Combination of Lapatinib (GW572016; NSC-727989) and Everolimus (RAD001) in Patients With Advanced Solid Tumors

Study Start Date :

Sep 1, 2006

Actual Primary Completion Date :

Aug 1, 2007

Actual Study Completion Date :

Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: everolimus/lapatinib Part 1, dose finding: everolimus and lapatinib at assigned dose daily Part 2, cohort A: Everolimus MTD from Part I: 5 mg PO 1-28 Daily Lapatinib MTD from Part I: 1,250 mg PO Cycle 1, Daily Days 8-28 Subsequent Cycles, Days 1-28 Part 2, cohort B: Lapatinib MTD from Part I: 1,250 mg PO 1-28 Daily Everolimus MTD from Part I: 5 mg PO Cycle 1, Daily Days 8-28 Subsequent Cycles, Days 1-28	Drug: everolimus part 1: dose assigned by ETx online system PO days 1-28 daily part 2: cohort a: 5 mg PO days 1-28 part 2: cohort a: 1250 mg PO days 8-28 (cycle 1) days 1-28 (subsequent cycles) Drug: lapatinib ditosylate dose assigned by ETx online system PO days 1-28 daily part 2 cohort a: 1250 mg PO d 8-28 (cycle 1) days 1-28 (subsequent cycles) part 2 cohort b: 120 mg PO days 1-28 daily

Arm

Intervention/Treatment

Experimental: everolimus/lapatinib

Part 1, dose finding: everolimus and lapatinib at assigned dose daily Part 2, cohort A: Everolimus MTD from Part I: 5 mg PO 1-28 Daily Lapatinib MTD from Part I: 1,250 mg PO Cycle 1, Daily Days 8-28** Subsequent Cycles, Days 1-28 Part 2, cohort B: Lapatinib MTD from Part I: 1,250 mg PO 1-28 Daily Everolimus MTD from Part I: 5 mg PO Cycle 1, Daily Days 8-28** Subsequent Cycles, Days 1-28

Drug: everolimus

part 1: dose assigned by ETx online system PO days 1-28 daily part 2: cohort a: 5 mg PO days 1-28 part 2: cohort a: 1250 mg PO days 8-28 (cycle 1) days 1-28 (subsequent cycles)

Drug: lapatinib ditosylate

dose assigned by ETx online system PO days 1-28 daily part 2 cohort a: 1250 mg PO d 8-28 (cycle 1) days 1-28 (subsequent cycles) part 2 cohort b: 120 mg PO days 1-28 daily

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of lapatinib and everolimus (Part I) [1 month]

Secondary Outcome Measures

Pharmacokinetics (Part II) [1 month]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed advanced solid tumor or non-Hodgkin's lymphoma for which no curative options exist
Measurable or nonmeasurable disease
Patients with brain metastases who require corticosteroids or anticonvulsants must be on a stable or decreasing dose of corticosteroids and seizure free for 30 days prior to study entry
Patients with known brain metastases must have had brain irradiation (whole brain or gamma knife)
No untreated (non-irradiated) brain metastases

PATIENT CHARACTERISTICS:

Zubrod performance status 0-2
Absolute neutrophil count ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
SGOT or SGPT ≤ 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases are present)
Bilirubin normal
Creatinine normal OR creatinine clearance > 60 mL/min
Cardiac ejection fraction normal by echocardiogram or MUGA
Able to swallow enteral medications
No feeding tubes
No intractable nausea or vomiting
No gastrointestinal (GI) tract disease resulting in an inability to take oral medication
No current active hepatic or biliary disease with the exception of Gilbert's syndrome or asymptomatic gallstones
No malabsorption syndrome
No requirement for IV alimentation
No uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib or everolimus, including other quinazoline compounds, such as gefitinib and erlotinib, or other rapamycins, such as sirolimus and temsirolimus
No known HIV positivity
No concurrent uncontrolled illness, including, but not limited to, any of the following:
Ongoing or active infection
Symptomatic congestive heart failure
Unstable angina pectoris
Cardiac arrhythmia
Myocardial infarction or cerebrovascular accident within the past 3 months
Uncontrolled diarrhea
Psychiatric illness or social situation that would preclude compliance with study requirements
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Willing to undergo pharmacokinetic (PK) sampling and blood collection for PK and correlative studies (for patients enrolled in part II)

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Recovered from prior therapy
No prior lapatinib or everolimus
No prior surgical procedures affecting absorption
More than 14 days since prior major surgery, chemotherapy (42 days for nitrosoureas or mitomycin C), or radiotherapy
More than 28 days since prior investigational agents
At least 7 days since prior and no concurrent CYP3A4 inhibitors
At least 14 days since prior and no concurrent CYP3A4 inducers
At least 14 days since prior and no concurrent herbal or dietary supplements
No concurrent chemotherapy, hormone therapy, radiotherapy, immunotherapy, live vaccines or any other anticancer therapy
Concurrent luteinizing hormone-releasing hormone agonists allowed
Concurrent bisphosphonates or epoetin alfa or its analogue allowed
No concurrent gastric H2 blockers (e.g., cimetidine, ranitidine, nizatidine, famotidine) or proton pump inhibitors (e.g., omeprazole, esomeprazole, rabeprazole, pantoprazole, or lansoprazole)
Antacids allowed provided they are not administered within 1 hour before and after lapatinib
No concurrent glucocorticoids or immunosuppressants

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California	United States	90089-9181
2	University of California Davis Cancer Center	Sacramento	California	United States	95817
3	University of Colorado Cancer Center at UC Health Sciences Center	Aurora	Colorado	United States	80045
4	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
5	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109-0942
6	University Cancer Center at University of Washington Medical Center	Seattle	Washington	United States	98195-6043

Sponsors and Collaborators

Southwest Oncology Group
National Cancer Institute (NCI)

Investigators

Study Chair: Shirish M. Gadgeel, MD, Barbara Ann Karmanos Cancer Institute
Principal Investigator: Patricia M. LoRusso, DO, Barbara Ann Karmanos Cancer Institute