PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of
pomalidomide, in children from >= 3 years to < 21 years of age with recurrent, progressive or
refractory central nervous system (CNS) tumors when given once daily for 21 consecutive days
of a 28-day course.
II. To describe the toxicity profile and dose-limiting toxicities of pomalidomide in children
from >= 3 years to < 21 years of age with recurrent, progressive or refractory CNS tumors.
III. To characterize the pharmacokinetics of pomalidomide when administered orally in
children from >= 3 years old to < 21 years of age with recurrent, progressive or refractory
CNS tumors and study the association of pharmacokinetic (PK) parameters with age and steroid
use.
SECONDARY OBJECTIVES:
I. To explore the preliminary efficacy of pomalidomide in this patient population as defined
by radiographic response rate, duration of response, and event-free survival (EFS) within the
confines of a Phase 1 study. *For the purposes of this study, long-term stable disease will
be considered a response (defined as stable disease for >= 6 courses).
II. To investigate a relationship between pomalidomide dose and exposure with radiographic
response and changes in immune function (for example, T-cell subsets, natural killer [NK]
cell activity, granzyme B and circulating levels of IL-12, IL-2, IL-15, GM-CSF).
OUTLINE: This is a dose-escalation study.
Patients receive pomalidomide orally (PO) once daily (QD) on days 1-21. Treatment repeats
every 28 days for up to 26 courses in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up for 2 years.
Inclusion Criteria:
- Patients must have received standard therapy (or generally accepted upfront therapy if
no standard exists) and have no known curative therapy
- Patients with a histologically confirmed diagnosis of a primary CNS tumor that is
recurrent, progressive or refractory to standard therapy; refractory disease will be
defined as the presence of persistent abnormality on conventional magnetic resonance
imaging (MRI) imaging that is further distinguished by histology (biopsy or sample of
lesion) or advanced imaging, OR as determined by the treating physician and discussed
with the primary investigator prior to enrollment; all tumors must have histological
verification at either the time of diagnosis or recurrence except for patients with
diffuse intrinsic brain stem tumors or optic pathway gliomas; patients with
neurofibromatosis type-I (NF-1) associated CNS tumors are eligible if they meet all
other eligibility criteria
- Patients must have evaluable disease on MRI imaging
- Patients must have body surface area (BSA) > 0.55 m^2 at the time of enrollment
- In the event of de-escalation from dose level 1 to dose level 0, patients with
BSAs < 0.67 m^2 are not eligible
- Patients must have recovered from clinically significant, acute, treatment-related
toxicities of prior therapies; for those acute baseline adverse events attributable to
prior therapy, recovery is defined as a toxicity grade =< 2, using Common Terminology
Criteria for Adverse Events (CTCAE) version (v) 4.0, unless otherwise specified in the
inclusion and exclusion criteria
- Agents that potentially fit into more than one category or do not clearly fit
into any category listed above should be discussed with the study principal
investigator (PI) prior to enrollment
- Patients must have received their last dose of known myelosuppressive anticancer
therapy greater than 28 days prior to study enrollment or > 42 days if nitrosourea
- Patients must have received their last dose of any other investigational agent greater
than 28 days prior to enrollment (with exception of fluorothymidine F-18 [FLT])
- Patients must have received their last dose of any other biologic agent greater
than 7 days prior to enrollment
- Patients must have received their last dose of any other biologic agent greater than 7
days prior to enrollment
- For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur and discussed with the PI
- Monoclonal antibody treatment and agents with known prolonged half-lives: at least
three half-lives must have elapsed prior to enrollment
- Immunomodulatory therapy: greater than 28 days must have elapsed since last dose of an
immune modulating agent, including vaccine therapy
- Administration of the radioisotope, 18-FLT, which is being concurrently investigated
on an imaging study within the Pediatric Brain Tumor Consortium (PBTC), is allowed >
72 hours prior to initiation of pomalidomide on this study; any adverse events related
to the FLT must have resolved completely
- Patients must have had their last fraction of:
- Craniospinal irradiation, total body irradiation (TBI), or >= 50% radiation of
pelvis > 3 months prior to enrollment
- Focal irradiation > 6 weeks prior to enrollment
- Local palliative radiation therapy (XRT) (small port) >= 4 weeks
- Patient must be:
- >= 6 months since allogeneic bone marrow transplant prior to enrollment
- >= 3 months since autologous bone marrow/stem cell prior to enrollment
- >= 3 months since stem cell transplant or rescue without TBI with no graft vs.
host disease prior to enrollment
- No graft versus host disease
- Patients on anticonvulsant therapy may continue these at the discretion of their
treating physician; however, it is recommended that anticonvulsant levels be checked
periodically as clinically indicated if possible
- Patients on alternative supplements should strongly be encouraged to discontinue them
prior to enrollment; if they opt to continue, they may enroll on study as long as they
have been receiving the supplement for at least 30 days, there is NO evidence of
hepatic, renal or other organ dysfunction, administration is approved by the PI, and
administration is documented in the study diary
- Patients must be on a stable or decreasing dose of corticosteroids for 5 days prior to
enrollment; patient may be taking therapeutic doses of steroids during the initial
dose escalations and prior to defining an RP2D; this should be recorded in the
database; once the RP2D has been established, enrollment may be limited based on
steroid use;*physiologic replacement doses will be defined on this protocol as no more
than 0.75 mg/m^2/day of dexamethasone or equivalent of steroids; doses higher than
this will be considered therapeutic
- All races and ethnic groups are eligible for this study
- Patients should have no significant worsening in clinical status for a minimum of 2
days prior to enrollment
- Patients must be able to swallow whole capsules
- Patients should undergo a repeat MRI prior to enrollment if there is a significant
worsening or new neurologic symptoms in the interval between the eligibility scan and
start of protocol therapy
- The repeat scan will act as a new baseline and the eligibility scan for these
patients
- Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score
(LPS for =< 16 years of age) assessed within 14 days of enrollment must be >= 50
- Absolute neutrophil count >= 1,000/mm^3
- Platelets >= 100,000/mm^3 (unsupported, defined as no platelet transfusion within 7
days and recovery from nadir)
- Hemoglobin >= 8 g/dL (may receive transfusions)
- Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
institutional upper limit of normal
- Albumin >= 3 g/dL
- Serum creatinine based on age/gender as noted; patients that do not meet the criteria
below but who have a 24-hour creatinine clearance or glomerular filtration rate (GFR)
(radioisotope or iothalamate) >= 70 ml/min/1.73 m^2 are eligible
- Serum creatinine for age/gender
- 3 to < 6 years: 0.8 mg/dL
- 6 to < 10 years: 1 mg/dL
- 10 to < 13 years: 1.2 mg/dL
- 13 to < 16 years: 1.5 mg/dL (male) and 1.4 mg/dL (female)
- >= 16 years: 1.7 mg/dL (male) and 1.4 mg/dL (female)
- Oxygen saturation as measured by pulse oximetry must be >= 93% on room air
- Patients must be off all colony-forming growth factor(s) for at least 1 week prior to
enrollment (i.e. filgrastim, sargramostim); two weeks must have elapsed if patients
received polyethylene glycol (PEG) formulations
- Pregnant or breast-feeding patients are excluded; female patients of childbearing
potential must have a negative serum or urine pregnancy test at the time of
enrollment; in addition, female patients of childbearing potential must have negative
pregnancy tests within 10 - 14 days prior to starting pomalidomide (can use enrollment
pregnancy test if within the 10-14 day limit) AND again within 24 hours prior to
initiation of pomalidomide; this protocol defines the following childbearing potential
risk categories as:
- Female child/young adult of childbearing potential as a female who has:
- Achieved menarche and/or breast development, in Tanner stage 2 or greater
- Has not undergone a hysterectomy or bilateral oophorectomy, or has not been
naturally postmenopausal for at least 24 consecutive months (i.e., has had
menses at any time in the preceding 24 consecutive months)
- Note: amenorrhea following cancer therapy does not rule out childbearing
potential
- Patients of childbearing or child fathering potential must use medically acceptable
form(s) of birth control as stated within the pomalidomide Pregnancy Risk Minimization
Plan, which includes abstinence, while being treated on this study; true abstinence is
acceptable when this is in line with the preferred and usual lifestyle of the patient;
periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods)
and withdrawal are not acceptable methods of contraception
- Female patients of childbearing potential agree to and will have had effective
contraception without interruption for 28 days before starting pomalidomide
- The patient or parent/guardian is able to understand the consent and is willing to
sign a written informed consent document according to institutional guidelines
Exclusion Criteria:
- Patients with any clinically significant unrelated systemic illness (e.g., serious
infections or significant cardiac, pulmonary, hepatic or other organ dysfunction),
that in the opinion of the investigator would compromise the patient's ability to
tolerate protocol therapy, put them at additional risk for toxicity or would interfere
with the study procedures or results
- Patients with a history of any other malignancy will not be eligible
- Patients with radiation-associated gliomas will not be eligible
- Patients with a history of non-central line related thrombosis, more than one prior
central-line related thrombosis, or known coagulopathy will not be eligible; patients
with a first degree family member with a known coagulopathy will be excluded, and
therefore, obtaining a family history is essential when possible; patients actively on
anticoagulation therapy are not eligible
- Patients with a prior history of serious allergic reactions associated with
thalidomide or lenalidomide
- Patients who are receiving any other anti-cancer or investigational drug therapy are
excluded
- Patients taking a known moderate to potent inhibitor of CYP1A2 are excluded;
pomalidomide is primarily metabolized by CYP1A2 and CYP3A; pomalidomide is also a
substrate for permeability (P)-glycoprotein (P-gp)
- Patients who in the opinion of the investigator are unwilling or unable to return for
required follow-up visits or obtain follow-up studies required to assess toxicity to
therapy or to adhere to drug administration plan, other study procedures, and study
restrictions
- Patients who have received pomalidomide in the past are not eligible; patients who
have prior treatment with other immunomodulatory drugs (IMiDs) (thalidomide,
lenalidomide) ARE eligible if they meet all other eligibility criteria and did not
have "significant toxicity" associated with lenalidomide or thalidomide use; a
"significant" toxicity will be defined as one that required a dose reduction or
discontinuation due to toxicity; please discuss any questions with the PI
