Status:Not yet recruiting
Keywords:Ipilimumab
, T-cells
, Melanoma
, Tumor
, Pediatric
IRB Number:00059293
Specialty:Oncology
Sub Specialty:
To estimate the survival rate at 1 year in adolescent patients (12 to < 18 years) with previously treated
or untreated, unresectable Stage III or Stage IV malignant melanoma
• To assess safety and tolerability, specifically the frequency of severe (grade 3 - 5) immune-mediated
adverse reactions of ipilimumab in adolescent patients (12 to < 18 years) at the 10 mg/kg dose level
Ipilimumab is a fully human monoclonal immunoglobulin (IgG1κ) specific for human cytotoxic T lymphocyte antigen γ 4 (CTLA-4, CD152), which is expressed on a subset of activated T cells. The proposed mechanism of action for ipilimumab is T-cell potentiation through interference of the interaction of CTLA-4 with B7 (CD80 or CD86) molecules on antigen presenting cells, with subsequent blockade of the inhibitory function of CTLA-4. Ipilimumab is approved for use in the US (metastatic melanoma) and in the EU (previously treated metastatic melanoma) in the adult patient population. The current study is designed to determine the efficacy and safety of ipilimumab monotherapy in adolescents (12 to < 18 years) with previously treated or untreated, unresectable Stage III or Stage IV malignant melanoma. Melanoma in children Melanoma in childhood is rare but the incidence is rising rapidly (1.1% per year in children < 20 years). In Australia, where melanoma is most common, the estimated incidence reported in 2008 among children age 0 - 14 years was five cases per million compared to an incidence of 2 cases per million in Western Europe and Northern America. The incidence, as in adults, increases with age and there is a sharp rise following puberty. Fifteen to nineteen year old adolescents account for between 70 and 85% of all melanoma cases diagnosed in individuals under 20 years of age. Risk factors for the development of pediatric melanoma based on the Surveillance, Epidemiology and End Results (SEER) database (1973-2001) include white ethnicity, female gender, increasing age, and environmental UV radiation. The increased incidence of melanoma in children, particularly adolescents, may be attributed to increased UV exposure during childhood and adolescence, as well as an increased awareness of physicians and patients leading to an improvement in the timing of diagnosis. Histologically, melanoma has the same pathologic characteristics in children and in adults, with the most common type being superficial spreading melanoma. Prognostic factors are not as clearly defined for children as for adults. Primary tumor thickness, age and stage at presentation are considered the most important prognostic factors for pediatric melanoma. Studies conducted in children with melanoma have been of small size, from single institutions, and have shown high levels of variability in staging criteria and outcome. Although some reports indicate that pediatric patients may have a higher probability of survival compared to adults, a number of children will develop metastasis and die of their disease, particularly when melanoma is diagnosed after puberty. Some studies which include younger children suggest a more favorable outcome compared to adults. Studies which exclude children younger than 12 years have reported survival similar to that seen among adults. In one series, age greater than 10 years and detection of metastases at the time of diagnosis were significantly related to a higher mortality risk. Another study reported that patients < 20 years of age with regional or distant metastases at diagnosis had 10 year survival rates of approximately 60 and 25% respectively. Livestro et al, when comparing melanomas in children and adults after matching by thickness and year of diagnosis, reported no significant differences in 5 year and 10 year disease free and overall survivals. More recent data show that overall survival for all patients with pediatric melanoma appears similar to that of adults, with no apparent difference in survival between patients < 13 years of age and those 13 to 20 years of age. Treatment of pediatric melanoma There is no established standard treatment for pediatric patients with advanced melanoma. Because of the rarity of pediatric melanoma, accruing adequate numbers of patients for clinical trials to evaluate adjuvant therapy is very difficult. Therefore, treatment of children is often based on information from adult studies. Biologic agents such as interferon α2b (IFNα2b) and interleukin-2 (IL-2) are currently used as adjuvant treatment for high-risk melanoma after surgical resection. The basis of this immunological approach came from the observations that tumors with lymphoid infiltration had a better prognosis than tumors without. In addition, the host response is assumed to be involved in the spontaneous regression of some tumors. There is no approved therapy for metastatic melanoma in children. A few small studies published promising results with the use of chemotherapy. In studies of 10 pediatric patients with metastatic disease treated with cyclophosphamide, vincristine, and dactinomycin, half were in remission for > 5 years. The results of studies with single agent dacarbazine, an agent commonly used in adult melanoma, showed positive activity in 4 children with melanoma treated between 1975 and 1984. In a trial using a combination of vincristine, NCT01519323). In summary, there is a high need for new therapeutic modalities for pediatric melanoma given the limited options and equally poor outcome of treatment in children compared to adults, especially in the advanced disease setting.
Principle Investigator: Richard Lemons
Principle Department: Pediatric Administration
Co Investigator: Phillip Barnette
Name:Stefanie Bjerregaard
Phone:801-587-7484
Email:stefanie.bjerregaard@hsc.utah.edu
1) Signed Written Informed Consent
a) This study will be conducted in adolescent patients (12 to < 18 years). Therefore,
for all minors, according to local legislation, one or both parents or a legally
acceptable representative must be informed of the study procedures and must sign
the informed consent form approved for the study prior to clinical study
participation. The explicit wish of a minor, who is capable of forming an opinion
and assessing this information to refuse participation in, or to be withdrawn from
the clinical study at any time should be considered by the Investigator. Following our local IRB guidlines and the study inclusion criteria, study participant minors who are between the ages of 12 to <18 will be asked for written assent.
2) Target Population
a) Histologically or cytologically confirmed diagnosis of malignant melanoma
b) Previously treated or untreated, unresectable Stage III or Stage IV malignant
melanoma (AJCC 2010) (regardless of B-Raf mutation status or HLA type)
c) Prior adjuvant melanoma therapy is permitted; any number of previous treatments
for melanoma are permitted
d) Measurable and/or evaluable disease, within 28 days prior to first dose of study
drug
e) Subjects with brain metastases who are free of neurologic symptoms related to
metastatic brain lesions and who do not require or receive systemic corticosteroid
therapy in the 10 days prior to beginning ipilimumab therapy are eligible
f) Karnofsky or Lansky Score ≥ 50
g) Subjects must have a complete set of baseline (ie, screening) digital radiographic
images of lesions and from the following anatomic regions: brain, chest, and
abdomen (obtained within 28 days of first dose of study drug)
h) Adequate hematologic, renal and hepatic function, specifically:
i) WBC ≥ 2500/uL, ANC ≥ 1000/uL,
ii) Platelets ≥ 75 x 10^3/uL,
iii) Hemoglobin ≥ 9 g/dL,
iv) Creatinine ≤ 2.5 x ULN,
v) AST/ALT ≤ 3 x ULN for subjects without liver metastasis; ≤ 5 x ULN for
subjects with liver metastasis,
vi) Total bilirubin ≤ 3 x ULN (except subjects with documented Gilbert’s
Syndrome);
i) Life expectancy ≥ 4 months
j) Accessible for treatment and Follow-up
3) Age and Reproductive Status
a) Male and female age 12 to < 18 years
b) Female adolescents of childbearing potential (WOCBP) and male adolescents (if
their partners are WOCBP) must be using an acceptable method of contraception
(double barrier, eg, condom or diaphragm or cervical cap associated with
spermicide or intrauterine device combined with another form of birth control) to
avoid pregnancy throughout the study and for up to 12 weeks after the last dose of
investigational product in such a manner that the risk of pregnancy is minimized.
See Section 3.3.4 for the definition of WOCBP.
c) Female adolescents of childbearing potential must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at
screening and within 24 hours prior to the start of investigational product.
d) Female adolescents must not be breastfeeding
Retreatment Inclusion Criteria
subjects who enter the Re-Treatment phase must have an adequate
hematologic, renal and hepatic function within 14 days of re-treatment to be eligible:
1) WBC ≥ 2500/uL, ANC ≥ 1000/uL,
2) Platelets ≥ 75 x 10^3/uL,
3) Hemoglobin ≥ 9 g/dL,
4) Creatinine ≤ 2.5 x ULN,
5) AST/ALT ≤ 3 x ULN for subjects without liver metastasis; ≤ 5 x ULN for subjects
with liver metastasis,
6) Total bilirubin ≤ 3 x ULN (except subjects with documented Gilbert’s Syndrome)
1) Target Disease Exceptions
a) Primary ocular melanoma
b) Active brain metastases with symptoms or requiring corticosteroid treatment
2) Medical History and Concurrent Diseases
a) Any other malignancy from which the subject has been disease-free for less than
2 years, with the exception of adequately treated and cured basal or squamous cell
skin cancer;
b) History of or current active autoimmune diseases, including but not limited to
inflammatory bowel diseases, rheumatoid arthritis, autoimmune thyroiditis
(subjects under stable thyroid hormone substitution are eligible), autoimmune
hepatitis, systemic sclerosis (scleroderma and variants), systemic lupus
erythematosus, autoimmune vasculitis, autoimmune neuropathies (eg, Guillain-
Barre syndrome). Vitiligo is NOT excluded;
c) Uncontrolled infectious diseases – requires negative tests for clinically suspected
HIV, HBV and HCV. If positive results are not indicative of true active or chronic
infection, the subject may enter the study after discussion and agreement between
the Investigator and the Medical Monitor;
d) History of or current immunodeficiency disease, splenectomy or splenic
irradiation;
e) Prior allogeneic stem cell transplantation;
f) Any underlying medical or psychiatric condition, which in the opinion of the
Investigator, will make the administration of study drug hazardous or obscure the
interpretation of AEs, such as a condition associated with frequent diarrhea.
3) Physical and Laboratory Test Findings
a) Defined in Inclusion criteria
4) Prohibited Therapies and/or Medications
a) Prior therapy with a CTLA-4 or PD-1 antagonist, or PD-L1 or CD137 agonists;
b) Concomitant therapy with any anti-cancer agent, potent immunosuppressive
agents, surgery or radiotherapy or other investigational anti-cancer therapies or
chronic use of systemic corticosteroids (used in the management of cancer or noncancer-
related illnesses);
c) Prior anti-cancer therapy < 4 weeks prior to treatment (subjects with prior anticancer
therapy < 4 weeks prior to treatment might be eligible after discussion
between investigator and sponsor, if toxicities from the prior treatment have been
resolved to CTC grade 1 level);
d) Prior therapies with systemic immunosuppressive agents such as cyclosporine or
high dose steroid treatment within 4 weeks (excluding episodic low dose
corticosteroids, eg, for treatment of allergic dermatologic conditions);
e) Treatment with a cytotoxic or any other investigational products within 4 weeks
prior to entry into this study (subjects with prior cytotoxic or investigational
products < 4 weeks prior to treatment might be eligible after discussion between
investigator and sponsor, if toxicities from the prior treatment have been resolved
to CTC grade 1 level);
f) Any psychological or medical condition which may interfere with the ability to
provide informed consent;
g) Any psychological, familial, cultural/sociological or geographical condition
which could potentially hamper compliance with study schedule, procedures and
testing;
5) Allergies and Adverse Drug Reaction
a) History of allergic reaction to parenteral administered recombinant protein
6) Sex and Reproductive Status
a) Sexually active fertile female adolescents not using highly effective birth control.
b) Sexually active fertile male adolescents not using highly effective birth control if
their partners are WOCBP
7) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
