Erlotinib and Temozolomide in Treating Young Patients With Recurrent or Refractory Solid Tumors

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of erlotinib when given with temozolomide in treating young patients with recurrent or refractory solid tumors. Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop tumor cells from dividing so they stop growing or die. Giving erlotinib with temozolomide may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of erlotinib in children with recurrent or refractory solid tumors. II. Determine the dose-limiting toxic effects of this drug alone and with temozolomide in these patients. III. Determine the tolerability of this regimen in these patients. IV. Determine the pharmacokinetics of this regimen in these patients. SECONDARY OBJECTIVES: I. Determine, preliminarily, the antitumor activity of this regimen in these patients. OUTLINE: This is a 2-part, multicenter, dose-escalation study of erlotinib. Patients are stratified according to pretreatment (heavily pretreated [received more than 2 prior multiagent myelosuppressive chemotherapy regimens OR received prior craniospinal or pelvic radiotherapy or bone marrow transplantation OR has bone marrow involvement] vs less heavily pretreated).Part 1: Patients receive oral erlotinib once daily on days 1-28. Beginning with course 2, patients also receive oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for up to 23 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of erlotinib during course 1 only until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Part 2: Patients receive erlotinib (at the MTD) and temozolomide as in part 1. PROJECTED ACCRUAL: A total of 9-45 patients (9-24 for part 1 and up to 21 for part 2) will be accrued for this study.

Official Title
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A Phase I Study of Single Agent OSI-774 (Tarceva) (NSC# 718781, IND# 63383) Followed by OSI-774 With Temozolomide for Patients With Selected Recurrent/Refractory Solid Tumors, Including Brain Tumors

Conditions
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Previously Treated Childhood Rhabdomyosarcoma, Recurrent Childhood Brain Tumor, Recurrent Childhood Cerebellar Astrocytoma, Recurrent Childhood Cerebral Astrocytoma, Recurrent Childhood Ependymoma, Recurrent Childhood Malignant Germ Cell Tumor, Recurrent Childhood Medulloblastoma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor, Recurrent Neuroblastoma, Recurrent Osteosarcoma

Intervention / Treatment
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* Drug: erlotinib hydrochloride
* Drug: temozolomide
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: One of the following histologically confirmed solid tumors: Brain tumors Osteogenic sarcoma Rhabdomyosarcoma Soft tissue sarcoma (excluding Ewing's sarcoma) Neuroblastoma Germ cell tumors Recurrent or refractory disease No known curative therapy exists Performance status - Karnofsky 50-100% (for patients age 11 to 21) Performance status - Lansky 50-100% (for patients age 10 and under) At least 8 weeks Absolute neutrophil count > 1,000/mm^3 Platelet count > 100,000/mm^3 (transfusion independent*) Hemoglobin > 8.0 g/dL (transfusion allowed) Bilirubin < 1.5 times upper limit of normal (ULN) ALT < 2.5 times ULN Albumin ≥ 2 g/dL Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min Creatinine based on age as follows: ≤ 0.8 mg/dL for patients age 5 and under ≤ 1.0 mg/dL for patients 6 to 10 ≤ 1.2 mg/dL for patients 11 to 15 ≤ 1.5 mg/dL for patients age 15 to 21 Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Able to swallow tablets (for patients in part 2 only) No uncontrolled infection Recovered from all prior immunotherapy At least 7 days since prior biologic therapy At least 3 months since prior stem cell transplantation and no evidence of active graft-versus-host disease More than 1 week since prior growth factors No concurrent prophylactic growth factor therapy No concurrent immunotherapy No concurrent biologic therapy More than 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered No other concurrent chemotherapy No concurrent systemic corticosteroids except for treatment of increased intracranial pressure or symptomatic tumor edema in patients with CNS tumors No concurrent steroids as an antiemetic Concurrent dexamethasone for patients with CNS tumors allowed provided patient has been on a stable or decreasing dose for at least 1 week before study entry Recovered from all prior radiotherapy At least 2 weeks since prior local palliative radiotherapy (small port) At least 6 weeks since prior substantial bone marrow irradiation At least 6 months since prior craniospinal radiotherapy At least 6 months since prior radiotherapy to 50% or more of the pelvis At least 8 weeks since prior standard-fraction radiotherapy for patients with recurrent brain tumors unless there is biopsy proof of recurrent tumor Prior radiosurgery within the past 9 months allowed provided there is documentation of progressive disease by biopsy, positron-emission tomography (PET) scan, or MR spectroscopy No concurrent radiotherapy More than 1 week since prior CYP3A4 inhibitors More than 4 weeks since prior CYP3A4 inducers More than 5 days since prior proton-pump inhibitors More than 2 days since prior H_2 blockers No prior erlotinib No concurrent enzyme-inducing anticonvulsants No concurrent proton-pump inhibitors No concurrent H2 blockers No other concurrent investigational agents Concurrent antacids allowed provided the antacid is not administered 2 hours before, during, and 2 hours after erlotinib administration

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (erlotinib hydrochloride, temozolomide)<br>Patients receive oral erlotinib once daily on days 1-28. Beginning with course 2, patients also receive oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for up to 23 courses in the absence of disease progression or unacceptable toxicity. | Drug: erlotinib hydrochloride<br>* Given orally (PO)<br>* Other names: OSI-774;Drug: temozolomide<br>* Given PO<br>* Other names: TMZ;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 |  | 56 days (2 courses) | 
| Maximum-tolerated dose (MTD) based on the incidence of DLT as assessed by NCI CTCAE version 3.0 |  | 56 days (2 courses) | 
| Pharmacokinetics of erlotinib hydrochloride |  | At baseline and at 0.5, 1, 2, 4, 6, 8, and 24 hours of course 1 |