Radiolabeled Octreotide in Treating Children With Advanced or Refractory Solid Tumors

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Radiolabeled octreotide can locate tumor cells and deliver radioactive tumor-killing substances to them without harming normal cells. PURPOSE: This phase I trial is to study the safety and effectiveness of radiolabeled octreotide in treating children who have advanced or refractory solid tumors.

Detailed Description
-----------------
OBJECTIVES: Determine the maximum tolerated dose of yttrium Y 90-DOTA-tyr3-octreotide in children with advanced or refractory somatostatin receptor-positive tumors. Determine the short-term and long-term safety and the serious adverse-event profiles of this drug in these patients. Determine any potential antitumor effect of this drug in these patients. Correlate level of somatostatin receptor type 2 expression with response in patients treated with this drug. OUTLINE: This is a dose-escalation study. Patients receive yttrium Y 90-DOTA-tyr3-octreotide IV over 5-10 minutes on day 1. Treatment repeats every 6 weeks for up to 3 courses in the absence of unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of yttrium Y 90-DOTA-tyr3-octreotide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity. Patients are followed weekly after each treatment course, 6 weeks after the last course, and then every 6 months thereafter for life. PROJECTED ACCRUAL: Approximately 25-35 patients will be accrued for this study.

Official Title
-----------------
A Phase I, Open Label, Maximum Tolerated Dose-Finding Study to Evaluate the Safety and Tolerability of 90Y-DOTA-tyr3-Octreotide Administered by Intravenous Infusion to Children With Refractory Somatostatin-Receptor Positive Tumors

Conditions
-----------------
Brain and Central Nervous System Tumors, Gastrointestinal Carcinoid Tumor, Islet Cell Tumor, Neuroblastoma, Pheochromocytoma, Sarcoma, Unspecified Childhood Solid Tumor, Protocol Specific

Intervention / Treatment
-----------------
* Radiation: 90Y-DOTA-tyr3-OCTREOTIDE


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically or cytologically confirmed malignant neoplasm Not amenable to standard therapy or has failed existing first- and second-line therapies Tumor positive for somatostatin receptors by OctreoScan within the past 4 weeks At least 1 measurable lesion Lesions that have been previously irradiated must demonstrate progression since radiation At least 1 measurable somatostatin receptor-positive lesion that has not been irradiated within the past 4 weeks AND has not had full craniospinal radiation within the past 3 months Bone marrow with at least 40% cellularity OR at least 20% cellularity with one million CD34+ stem cells/kg stored No diffuse bone marrow involvement by OctreoScan scintigraphy PATIENT CHARACTERISTICS: Age 2 to 25 Performance status COG 0-2 OR Karnofsky 60-100% OR Lansky 60-100% Life expectancy 2-12 months Hematopoietic See Disease Characteristics Absolute neutrophil count at least 1,000/mm^3 Platelet count at least 100,000/mm^3 Hepatic Bilirubin less than 1.5 times normal AST and ALT less than 2.5 times upper limit of normal Renal Creatinine no greater than 1 mg/dL (children less than 5 years of age) Creatinine less than 1.2 mg/dL (children 5 to 10 years of age) Creatinine less than 1.7 mg/dL (children over 10 years of age) AND Glomerular filtration rate at least 80 mL/min/m^2 Cardiovascular Shortening fraction at least 28% by echocardiogram Ejection fraction at least 50% by bi-plane method of echocardiogram No prior congestive heart failure unless ejection fraction at least 40% No unstable angina pectoris No cardiac arrhythmia No symptomatic congestive heart failure Other No other concurrent malignancy No other significant uncontrolled medical, psychiatric, or surgical condition that would preclude study compliance No antibodies to yttrium Y 90-DOTA-tyr3-octreotide or octreotide No prior allergic reactions to compounds of similar chemical or biologic composition to yttrium Y 90-DOTA-tyr3-octreotide No ongoing or active infection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after study participation PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) Endocrine therapy More than 28 days since prior long-acting somatostatin analogues No concurrent somatostatin analogues 12 hours before or 12 hours after study drug administration Concurrent hormonal therapy (other than somatostatin analogue) allowed provided patient received hormonal therapy for at least 2 months and has stable disease or progressive disease Radiotherapy See Disease Characteristics At least 4 weeks since prior radiotherapy No prior radiotherapy to 25% or more of bone marrow No prior external beam radiotherapy to both kidneys (scatter doses of less than 500 cGy to a single kidney or radiation to less than 50% of a single kidney is allowed) Surgery At least 4 weeks since prior surgery Other Recovered from prior therapy At least 4 weeks since prior investigational drugs No other concurrent approved or investigational anti-neoplastic therapies except for bisphosphonates No concurrent combination antiretroviral therapy for HIV-positive patients

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 25 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 90Y-DOTA-tyr3-OCTREOTIDE<br>Dose escalation will proceed so that the single-cycle and three-cycle maximum tolerated doses of 90Y-DOTA-tyr3-Octreotide can be determined. The initial dose of 90Y-DOTA-tyr3-Octreotide to be administered is 30 mCi/m2 in each of three cycles. Dose escalation will proceed in 10 mCi/m2 intervals and will be permitted for the next cohort of subjects pending completion of Cycle 3 by 2 members of the previous cohort with no DLTs. A DLT is defined as a Grade 3 renal toxicity, Grade 4 bone marrow toxicity, or any other Grade 3 toxicity whether or not related to study drug and regardless of duration. Lymphopenia will not be used to define a DLT. | Radiation: 90Y-DOTA-tyr3-OCTREOTIDE<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establish the three-cycle maximum-tolerated dose of 90Y-DOTA-tyr3-Octreotide | Establish the three-cycle maximum-tolerated dose of 90Y-DOTA-tyr3-Octreotide administered by intravenous infusion to children with refractory somatostatin-receptor positive tumors based upon the 6 week/cycle dose-limiting-toxicity profile. | 6 weeks per cycle | 
| Evaluate the short term and long term safety (mild/moderate/severe/life-threatening adverse events, premature discontinuations and serious adverse events) | 2. Evaluate the short-term (6 weeks/cycle) and long term (4-6 months) safety (mild/moderate/severe/life-threatening adverse events, premature discontinuations and serious adverse events) serious adverse event profile of three-cycles of 90Y-DOTA-tyr3-Octreotide administered by intravenous infusion to children with refractory somatostatin-receptor positive tumors. | short term (6 weeks/cycle); long term (4-6 mos./cycle) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
childhood grade III meningioma, disseminated neuroblastoma, localized unresectable neuroblastoma, metastatic pheochromocytoma, metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor, recurrent childhood brain tumor, recurrent childhood medulloblastoma, recurrent neuroblastoma, recurrent pheochromocytoma, recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor, regional neuroblastoma, regional pheochromocytoma, unspecified childhood solid tumor, protocol specific, recurrent childhood ependymoma, childhood infratentorial ependymoma, childhood supratentorial ependymoma, recurrent islet cell carcinoma, gastrinoma, insulinoma, metastatic gastrointestinal carcinoid tumor, recurrent gastrointestinal carcinoid tumor, regional gastrointestinal carcinoid tumor