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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Childhood Medulloblastoma; Recurrent Childhood Ependymoma; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Childhood Rhabdomyosarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Brain Tumor
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Drug: temozolomide; Drug: erlotinib hydrochloride

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Arcadia, California, United States, 91006-3776
      • COG Phase I Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (erlotinib hydrochloride, temozolomide); 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.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; TMZ; Drug: erlotinib hydrochloride; Given orally (PO); Other Names: OSI-774; erlotinib; CP-358,774

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Regina Jakacki, COG Phase I Consortium

Study record dates

Study Major Dates

• Study Start: February 1, 2004
• Primary Completion (Actual): September 1, 2007

Study Registration Dates

• First Submitted: February 10, 2004
• First Submitted That Met QC Criteria: February 11, 2004
• First Posted (Estimate): February 12, 2004

Study Record Updates

• Last Update Posted (Estimate): June 5, 2013
• Last Update Submitted That Met QC Criteria: June 4, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Glioma; Neoplasms, Neuroepithelial; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Muscle Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Myosarcoma; Neoplasms; Sarcoma; Recurrence; Brain Neoplasms; Ependymoma; Medulloblastoma; Osteosarcoma; Astrocytoma; Neuroblastoma; Rhabdomyosarcoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Rhabdomyosarcoma, Embryonal; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Temozolomide
• Other Study ID Numbers: NCI-2012-01808; U01CA097452 (U.S. NIH Grant/Contract); ADVL0214; CDR0000350336; COG-ADVL0214; NCI-04-C-0256