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


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

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Trial Information

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


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.

Inclusion Criteria


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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum tolerated dose of lapatinib and everolimus (Part I)

Outcome Time Frame:

1 month

Safety Issue:

Yes

Principal Investigator

Shirish M. Gadgeel, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Barbara Ann Karmanos Cancer Institute

Authority:

United States: Federal Government

Study ID:

CDR0000486867

NCT ID:

NCT00352443

Start Date:

September 2006

Completion Date:

October 2013

Related Keywords:

  • Lymphoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • adult grade III lymphomatoid granulomatosis
  • recurrent adult grade III lymphomatoid granulomatosis
  • Waldenstrom macroglobulinemia
  • recurrent adult Burkitt lymphoma
  • stage IV adult Burkitt lymphoma
  • recurrent adult diffuse large cell lymphoma
  • recurrent adult diffuse mixed cell lymphoma
  • recurrent adult diffuse small cleaved cell lymphoma
  • recurrent adult immunoblastic large cell lymphoma
  • recurrent adult lymphoblastic lymphoma
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent grade 3 follicular lymphoma
  • recurrent mantle cell lymphoma
  • recurrent marginal zone lymphoma
  • recurrent small lymphocytic lymphoma
  • stage IV adult diffuse large cell lymphoma
  • stage IV adult diffuse mixed cell lymphoma
  • stage IV adult diffuse small cleaved cell lymphoma
  • stage IV adult immunoblastic large cell lymphoma
  • stage IV adult lymphoblastic lymphoma
  • stage IV grade 1 follicular lymphoma
  • stage IV grade 2 follicular lymphoma
  • stage IV grade 3 follicular lymphoma
  • stage IV mantle cell lymphoma
  • stage IV marginal zone lymphoma
  • stage IV small lymphocytic lymphoma
  • extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
  • nodal marginal zone B-cell lymphoma
  • splenic marginal zone lymphoma
  • unspecified adult solid tumor, protocol specific
  • anaplastic large cell lymphoma
  • angioimmunoblastic T-cell lymphoma
  • adult nasal type extranodal NK/T-cell lymphoma
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Lymphoma, Large-Cell, Immunoblastic
  • Neoplasms

Name

Location

University of Michigan Comprehensive Cancer CenterAnn Arbor, Michigan  48109-0752
USC/Norris Comprehensive Cancer Center and HospitalLos Angeles, California  90033-0804
University of California Davis Cancer CenterSacramento, California  95817
University Cancer Center at University of Washington Medical CenterSeattle, Washington  98195
Lucille P. Markey Cancer Center at University of KentuckyLexington, Kentucky  40536-0093
University of Colorado Cancer Center at UC Health Sciences CenterAurora, Colorado  80045