Study of Lenalidomide With Vorinostat in Pediatric Patients With High Grade or Progressive CNS Tumors

Study Overview
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Brief Summary
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Independently, both lenalidomide and vorinostat have shown promising activity in pediatric central nervous system (CNS) tumors. These are both agents that are not typically part of first-line studies, although both agents are of serious interest and are currently in clinical trials for further investigation. This study is to evaluate the combination of lenalidomide and vorinostat in high grade or progressive central nervous system tumors in children.

Detailed Description
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Brain tumors are the second most common cause of cancer in pediatrics and the leading cause of cancer death in children. For children with relapsed, refractory, or recurrent brain tumors, new agents in new combinations are needed. This study is a phase I study designed to provide an objective observation of toxicity and establish a maximum tolerated dose of this combination. In addition, this study will observe the response of children with relapsed or refractory central nervous system tumors. Lenalidomide will be dosed orally once daily days 1-21 consecutive days of a 28 day cycle. Vorinostat will be dosed orally once daily days 1-7 and 15-21 of a 28-day cycle.Doses will be escalated according to standard phase 1 dose escalation criteria. In the absence of treatment delays due to adverse event(s), treatment may continue for 24 cycles.

Official Title
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A Phase 1 Study of Lenalidomide in Combination With Vorinostat in Pediatric Patients With High Grade or Progressive Central Nervous System Tumors

Conditions
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Central Nervous System Tumors

Intervention / Treatment
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* Drug: 25 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®)
* Drug: 50 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®)
* Drug: 100 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®)
* Drug: 150 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®)
* Drug: 150 mg/m2 Lenalidomide (Revlimid®) and 230 mg/m2 Vorinostat (Zolinza®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have histologically confirmed central nervous system malignancy for which standard curative measures do not exist or are not loner effective Must have measurable disease may not have received vorinostat and lenalidomide in combination At least 3 weeks since prior chemotherapy At least 6 weeks from last nitrosurea At least 6 weeks from autologous transplant At least 3 months from bone marrow donor transplant At least 3 weeks from focal radiation At least 6 weeks from craniospinal radiation Must have not received growth factors within 1 week of study entry Must be on a stable or decreasing dose of steroids for 1 week prior Must not be receiving any chemo, biologic, or radiation therapy Must not be receiving enzyme inducing anticonvulsants or valproic acid Must not be receiving pro-thrombotic agents Karnofsky or Lansky performance status ≥50% Life expectancy of greater than 8 weeks Patients must have normal organ and marrow function, including Absolute neutrophil count ≥1,000/mcL Platelets ≥100,000/mcL Pulse oximetry >93% Total bilirubin ≤ 1.5 x upper limit of normal (ULN) aspartate aminotransferase (AST)(SGOT)/Alanine transaminase (ALT)(SGPT) ≤2.5 × institutional upper limit of normal Creatinine within normal institutional limits OR Creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal The effects of vorinostat and lenalidomide on the developing human fetus are unknown. For this reason and because agents used in this trial are known to be teratogenic, women of child-bearing potential must commit to complete abstinence or use TWO methods of birth control (one highly effective (i.e. intrauterine device (IUD), birth control pills, injections, implants, tubal ligation, partner's vasectomy), and one additional method (i.e. male condom, diaphragm, cervical cap) for the duration of study participation and at least 28 days after completion. Females of childbearing potential must agree to ongoing pregnancy testing and counseling every 28 days about pregnancy precautions. If a female has not had a menstrual period in the preceding 24 consecutive months or has had a hysterectomy, the two methods of birth control requirement does not apply. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must agree to use condoms for the duration of study participation, and 28 days after completion. Exclusion Criteria: Patient has not recovered from acute toxic effects of all prior therapies Patients who are receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or lenalidomide Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, dyspnea at rest, symptomatic congestive heart failure, history of thromboembolism unrelated to central line, patients with known predisposition syndrome for thromboembolism, patients receiving anticoagulation therapy, unstable angina pectoris, cardiac arrhythmia, patients receiving enzyme inducing anticonvulsants, patients receiving valproic acid, patients receiving antiplatelet agents (aspirin, anti-inflammatory drugs), or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study due to the potential for teratogenic effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is being treated and not resumed until 28 days after completing therapy. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with these agents. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dose level 1<br>25 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®) | Drug: 25 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®)<br>* Drug: Lenalidomide 25 mg/m2 days 1-21 of a 28 days cycle Drug: Vorinostat 180 mg/m2 days 1-7 and 15-21 of a 28 day cycle<br>* Other names: Zolinza®;|
| Experimental: dose level 2<br>50 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®) | Drug: 50 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®)<br>* Drug: Lenalidomide 50 mg/m2 days 1-21 of a 28 days cycle Drug: Vorinostat 180 mg/m2 days 1-7 and 15-21 of a 28 day cycle<br>* Other names: Zolinza®;|
| Experimental: dose level 3<br>100 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®) | Drug: 100 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®)<br>* Drug: Lenalidomide 100 mg/m2 days 1-21 of a 28 days cycle Drug: Vorinostat 180 mg/m2 days 1-7 and 15-21 of a 28 day cycle<br>* Other names: Zolinza®;|
| Experimental: dose level 4<br>150 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®) | Drug: 150 mg/m2 Lenalidomide (Revlimid®) and 180 mg/m2 Vorinostat (Zolinza®)<br>* Drug: Lenalidomide 150 mg/m2 days 1-21 of a 28 days cycle Drug: Vorinostat 180 mg/m2 days 1-7 and 15-21 of a 28 day cycle<br>* Other names: Zolinza®;|
| Experimental: dose level 5<br>150 mg/m2 Lenalidomide (Revlimid®) and 230 mg/m2 Vorinostat (Zolinza®) | Drug: 150 mg/m2 Lenalidomide (Revlimid®) and 230 mg/m2 Vorinostat (Zolinza®)<br>* Drug: Lenalidomide 150 mg/m2 days 1-21 of a 28 days cycle Drug: Vorinostat 230 mg/m2 days 1-7 and 15-21 of a 28 day cycle<br>* Other names: Zolinza®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Adverse Events | Collect and grade all of the adverse events to evaluate for safety. This data was collected for the first 2 cycles for each participant. | Two 28 day cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response of Children With Recurrent or Refractory Central Nervous System Tumors | Best response by MRIs per definitions in the protocol (complete response, partial response, stable disease, progressive disease). MRI's were obtained every 2 cycles and the best response was reported. | Every 2 cycles up to 24 cycles | 
| 2 Year Event Free Survival With Children Treated With This Regimen. | 2 year actual event free survival with children treated with this protocol. | 2 year | 
| Number Participants With Hematologic and Non-hematologic Toxicities | Number participants with grades 3 to 5 hematologic and non-hematologic toxicities. All toxicities are for end of cycle 2. | Two 28 day cycles |