90Y-DOTA-tyr3-Octreotide With or Without Retinoic Acid for the Treatment of Neuroblastoma and Neuroendocrine Tumors in Children and Young Adults. A Randomized, Placebo Controlled Phase II Trial With Dosimetry Guided Dosing
1. Disease Criteria
1. A pathologically confirmed (histology or cytology) malignant neoplasm that is
determined to be neuroblastoma or neuroendocrine tumor. The subject's neoplastic
disease must have been (positively) imaged by OctreoScan® or
111In-DOTA-tyr3-Octreotide within 4 weeks prior to ordering study drug.
2. b) Disease not amenable to standard treatment (disease present after surgery
and/or Sandostatin treatment) or subject has failed existing first line therapy
(surgery and chemotherapy/radiation therapy).
3. c) Upon baseline disease assessment, all subjects must have at least 1
measurable, evaluable, site of disease that either has never been irradiated or
has been previously irradiated and has since demonstrated progression based on
COG response criteria. Children's Oncology Group response criteria include: 1)
Complete response (CR) is defined as no measureable disease; 2) partial response
(PR) as >50% decrease in longest X widest perpendicular diameter of target
lesions with no increase in any lesions and no new lesions; 3) minor response
(MR) as >25%<50% decrease in target lesions with no increase in any lesion and
no new lesions; 4) stable disease as <25% increase or decrease in any target
lesion and no new lesions; 5) Progressive disease (PD) as an increase >25% in
any measureable lesion or the presence of any new lesion was considered
progressive disease (PD). Response will be assessed based on intent to treat for
all subjects who receive at least one dose of 90Y-DOTA-tyr3-Octreotide.
4. Each subject must have at least one measurable somatostatin receptor positive
lesion that has not had local irradiation via external beam, conformal or
stereotactic radiation treatments within 4 weeks prior to study drug
administration and no full craniospinal radiation within 3 months prior to study
5. Bone marrow with >/= 40% cellularity or with 1 million CD34+ stem cells/kg
6. Life expectancy > 2 months and < 12 months.
7. Biopsy of at least one lesion or bone marrow that has been identified as
progressive malignancy within four weeks prior to the first dose of Onalta® is
encouraged but not required. If no biopsy can be performed for clinical reasons,
available tissue from a previous biopsy will be required.
2. Age 6 months-30 years.
3. COG performance status /= 60% or Lansky Play Scale >/= 60%).
4. Patients must have normal organ and marrow function as defined below:
- absolute neutrophil count >1000/mm3
- platelets >100,000/mm3
- total bilirubin <1.5 x nl for age and weight
- AST(SGOT) & ALT(SGPT) <2.5 X institutional upper limit of normal for age
- creatinine <1.0 for children <5 years of age; <1.2 for children 5-10 years of
age; <1.7 for >10 years AND
- GFR >80 mL/min/1.73 m2
- urinalysis with no greater than 1+ hematuria or proteinuria
5. Cardiac function must be adequate
- shortening fraction of > 28% by echo
- ejection fraction > 50% by bi-plane method of echo
6. The effects of 90Y-DOTA-tyr3-Octreotide on the developing human fetus are unknown.
Retinoic acid is known to be harmful to the developing human fetus. For these reasons
and because Class C agents are known to be teratogenic, women and men of
child-bearing potential must agree to use adequate contraception (hormonal or barrier
method of birth control) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.
7. Ability to understand and the willingness to sign a written informed consent
8. Serum triglycerides <300 mg/dL.
9. Concomitant Therapy - The subject may not receive any other approved or
investigational anti-neoplastic therapies for the treatment of the refractory
somatostatin-receptor positive tumor during the course of the study, excluding
somatostatin analogues and bisphosphonates. However, all subjects on somatostatin
analogue therapy will discontinue therapy from 12 hours prior to a) injection with
OctreoScan® or 111In-DOTA-tyr3-Octreotide, and b) infusion with
90Y-DOTA-tyr3-Octreotide until 12 hours post administration. Subjects who have been
on hormonal therapy (other than somatostatin analogues) for > 2 months with SD or PD
may continue to receive hormonal therapy during this study. Subjects who initiate
another tumor-specific therapy will be discontinued from further treatment with
90YDOTA-tyr3-Octreotide. Disease progression alone does not mandate discontinuation
of a subject from treatment.
All subjects who have received at least one dose of 90Y-DOTA-tyr3-Octreotide must continue
into the Long-Term Follow-up Study Period at the point of treatment discontinuation. This
is necessary to determine any long-term effects of treatment with
90Y-DOTA-tyr3-Octreotide. Subjects may receive, at the discretion of the investigator,
appropriate medical treatment for medical problems that arise while on study.
Exclusion Criteria for enrollment and Cycle One study period:
1. Age less than 6 months or greater than 30 years.
2. Pregnancy or breast feeding.
3. Surgery, radiation or chemotherapy within 4 weeks of study drug administration.
4. Another investigational drug within 4 weeks of study drug administration.
5. More than one, concurrent, malignant disease.
6. History of congestive heart failure, unless cardiac ejection fraction ≥ 40%.
7. Another significant medical, psychiatric, or surgical condition which is currently
uncontrolled by treatment and which would likely affect the subject's ability to
complete this protocol.
8. Any subject for whom, in the opinion of their physician, a 24-hour discontinuation of
somatostatin analogue therapy represents a health risk. Also subjects who have
received long-acting somatostatin analogue in the past 21 days are excluded.
9. Bone marrow cellularity <40% without >/= 1 million CD34+ stem cells/kg stored.
10. External beam radiation to both kidneys (scatter doses of < 500 cGy to a single
kidney or radiation to < 50% of a single kidney is acceptable).
11. Antibodies to 90Y-DOTA-tyr3-Octreotide or Octreotide.
12. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) of study drug administration or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.
13. Patients may not be receiving any other investigational agents.
14. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to 90YDOTA-tyr3-Octreotide.
15. Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
16. Pregnant women are excluded from this study because 90Y-DOTA-tyr3-Octreotide is a
Class C agent with the potential for teratogenic or abortifacient effects. Because
there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with 90Y-DOTA-tyr3-Octreotide, breastfeeding
should be discontinued if the mother is treated with 90Y-DOTA-tyr3-Octreotide.
17. Because patients with immune deficiency are at increased risk of lethal infections
when treated with marrow-suppressive therapy, HIV-positive patients receiving
combination anti-retroviral therapy are excluded from the study because of possible
pharmacokinetic interactions with 90Y-DOTA-tyr3-Octreotide. Appropriate studies will
be undertaken in patients receiving combination anti-retroviral therapy when