Ipilimumab in Children and Adolescents with Malignant Melanoma

Overview

Status: Not yet recruiting
Keywords: Ipilimumab , T-cells , Melanoma , Tumor , Pediatric
IRB Number: 00059293
Specialty: Oncology
Sub Specialties:

Brief Summary

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 at the 3 mg/kg dose level

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 3 mg/kg dose level.

 

This is a non randomized, multicenter, open label Phase 2 study in adolescent patients
(12 to < 18 years of age) with previously treated or untreated, unresectable Stage III or Stage IV malignant melanoma. The study will enroll approximately 40 subjects in order to treat at least 30 subjects.approximately 30 subjects with the expectation that 20-25 subjects would be treated at the 3 mg/kg dose level, and the rest of the subjects at the 10 mg/kg dose level. The patient accrual is expected to be completed in approximately 3.5 years with an additional follow up time of 1 year to assess the primary endpoint of overall survival rate at 1 year for patients treated with ipilimumab 3 mg/kg.

Detailed Description

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.

Principal Investigator: Richard Lemons
Department: Pediatric Administration
Co Investigator: Phillip Barnette

Contact Information

Name:Stefanie Bjerregaard
Phone: 801-587-7484
Email: stefanie.bjerregaard@hsc.utah.edu

Inclusion Criteria

1) Signed Written Informed Consent

a) This study will be conducted in adolescent patients (12 to < 18 years). Prior to study participation, written informed consent from subjects, or in the case of minors,
written permission (informed consent) from parents, guardians, or legally acceptable
representatives must be obtained according to local laws and regulations.
  Assent from minor subjects should be obtained per local laws and regulations and should
be documented in accordance with local requirements.

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

k) Subject Re-enrollment: This study permits the re-enrollment of a subject that has
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / has
not been treated). If re-enrolled, the subject must be re-consented.

3) Age and Reproductive Status

a) Males and females ages 12 to < 18 years

b) Female of childbearing potential (FOCBP) must have a negative serum or urine

pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG)  within 24 hours prior to the start of study drug.

d) Female must not be breastfeeding

d) FOCBP must agree to follow instructions for method(s) of contraception for the duration
of treatment with ipilimumab plus 5 half-lives of ipilimumab (75 days) plus 30 days
(duration of ovulatory cycle) for a total of 105 days post-treatment completion.
e) Males who are sexually active with FOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with ipilimumab plus 5 half-lives
of ipilimumab (75 days) plus 90 days (duration of sperm turnover) for a total of 165 days
post-treatment completion.
f) Azoospermic males and FOCBP who are continuously not heterosexually active
are exempt from contraceptive requirements. However FOCBP must still undergo pregnancy
testing as described in this section.

Investigators shall counsel FOCBP and male subjects who are sexually active with FOCBP on
the importance of pregnancy prevention and the implications of an unexpected pregnancy
Investigators shall advise FOCBP and male subjects who are sexually active with FOCBP on the
use of highly effective methods of contraception. Highly effective methods of contraception have
a failure rate of < 1% when used consistently and correctly. At a minimum, contraceptive
counseling should be provided at the time of assent or consent.
The individual acceptable and unacceptable methods of contraception can be found in the subject informed consent form.

Retreatment Inclusion Criteria

For general eligibility criteria to enter the Retreatment phase please refer to Section 3.1.1.3. In
addition, subjects who enter the Retreatment phase must have an adequate hematologic, renal
and hepatic function within 14 days of retreatment 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)
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.

 

Exclusion Criteria

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, PD-1, PD-L1 or CD137 targeted agents;

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 FOCBP

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