A Study of Pomalidomide Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors
Condition: Central Nervous System Neoplasms; Medulloblastoma
MeSH terms: Brain Neoplasms; Medulloblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms
Intervention: Pomalidomide; Pomalidomide
Intervention description: : Subjects will be administered pomalidomide on Days 1 to 21, followed by a 7-day rest period, of each 28-day treatment cycle and will continue treatment for up to 24 cycles or until disease progression, withdrawal of consent/assent or unresolved toxicities as described in the protocol.; Pomalidomide will be provided as gelatin capsules and as an oral suspension. The starting dose will be 2.6 mg/m²/day, administered on Days 1 to 21, followed by a 7-day rest period, of each 28-day treatment cycle.
Intervention MeSH terms: Thalidomide; Pomalidomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 53.0
Sex: All
Minimum age: 1 Year
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Pediatric; Brain Tumor; Central Nervous System Neoplasms; Glioma; High-grade glioma; HGG; Ependymoma; Medulloblastoma; DIPG; Diffuse intrinsic pontine gliomaProgressive; RecurrentPomalidomide; PomalystImnovid; CC-4047; Children

Summary:

      This study will assess the efficacy, safety and tolerability of pomalidomide in children and
      young adults aged 1 to < 21 years with recurrent or progressive primary brain tumors in one
      of four primary brain tumor types: high-grade glioma (HGG), medulloblastoma, ependymoma and
      diffuse intrinsic pontine glioma (DIPG).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subject is 1 to < 21 years of age at the time of signing the Informed Consent
             Form/Informed Assent Form (ICF/IAF).

          2. Subject (when applicable, parental/legal representative) must understand and
             voluntarily sign an ICF/IAF prior to any study-related assessments/procedures being
             conducted.

          3. Subject has received at least one prior standard therapy (or generally accepted
             upfront therapy if no standard exists) and have no known curative therapy.

          4. Subject has a diagnosis of high-grade glioma, medulloblastoma, ependymoma or diffuse
             intrinsic pontine glioma (DIPG) that is recurrent or progressive. Subjects with
             neurofibromatosis type 1 (NF-1) associated tumors are eligible if they meet all other
             eligibility criteria.

          5. Subject has histological verification of tumor either at the time of diagnosis or
             recurrence. Subjects with DIPG are exempt from histologic verification if they have
             typical magnetic resonance imaging (MRI) findings of DIPG

          6. Subject has measurable disease defined as a tumor that is measurable in 2
             perpendicular diameters on MRI. For a lesion to be considered measurable, it must be
             at least twice the slice thickness on MRI (ie, visible on 2 or more axial slices)

          7. To document the degree of tumor at study baseline, the following scan(s) must be
             obtained:

               -  A brain MRI with and without contrast (ie, gadolinium) and a spine MRI with
                  contrast within 21 days prior to first dose of study treatment. For subjects on
                  steroids, baseline MRI scans must be performed while on stable or decreasing dose
                  of steroids for at least 5 days.

          8. Subject has Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status
             score ≥ 50 at screening

          9. Subject has adequate bone marrow function defined as:

               -  Peripheral absolute neutrophil count (ANC) ≥ 1000/mm³

               -  Platelet count ≥ 100,000/mm³ (transfusion independent defined as no platelet
                  transfusion within 7 days and recovery from nadir)

               -  Hemoglobin ≥ 8 g/dL (red blood cell [RBC] transfusion is allowed)

         10. Subject has adequate renal function defined as:

               -  Serum creatinine based on age/gender calculated using the Schwartz formula, or a
                  24-hour creatinine clearance or radioisotope glomerular filtration rate (GFR)
                  (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m².

         11. Subject has adequate liver function defined as:

               -  Total bilirubin ≤ 1.5 X upper limit of normal (ULN) for current age (≤ 3 X ULN if
                  increase in bilirubin is attributable to Gilbert's Syndrome)

               -  Alanine aminotransferase (ALT) (SPGT) is ≤ 3 X ULN for age

               -  Serum albumin ≥ 3 g/dL

         12. Subject has adequate pulmonary function defined as:

               -  No evidence of dyspnea at rest

               -  A pulse oximetry ≥ 93%

         13. Subject has recovered from clinically significant acute treatment related toxicities
             from all prior therapies. Recovery is defined as a toxicity Grade ≤ 2 (common
             terminology criteria for adverse events [CTCAE] v. 4.03).

         14. Subject has no significant worsening in clinical status for a minimum of 7 days prior
             to first dose of study drug.

         15. Subject (and when applicable, with parental/legal representative) is willing and able
             to adhere to the study visit schedule and other protocol requirements.

         16. Females of Childbearing Potential (FCBP) and male subjects who have reached puberty
             (and when applicable, with parental/legal representative) must agree to undergo
             physician-approved reproductive education and discuss the side effects of the study
             therapy on reproduction.

         17. Females of childbearing potential must agree and meet the following conditions below:

               -  Medically supervised (ie, performed in a clinic) pregnancy testing, including
                  those who commit to true abstinence. Two pregnancy tests must be conducted prior
                  to starting pomalidomide. The first pregnancy test must be performed 10 to 14
                  days prior to the start of pomalidomide and the second pregnancy test must be
                  performed within 24 hours prior to starting pomalidomide. Females of childbearing
                  potential with regular or no menstrual cycles must also agree to have pregnancy
                  tests weekly for the first 28 days study participation, every 28 days while on
                  study, at study treatment discontinuation, and at Day 28 following pomalidomide
                  discontinuation. If menstrual cycles are irregular, the pregnancy testing must
                  occur weekly for the first 28 days of study participation and then every 14 days
                  while on study, at study treatment discontinuation visit, and at Days 14 and 28
                  following pomalidomide discontinuation.

               -  Female subjects must, as appropriate to age and at the discretion of the study
                  Investigator, either commit to true abstinence from heterosexual contact and/or
                  agree to the use of two reliable forms of approved and effective contraceptive
                  methods simultaneously. The two methods of reliable contraception must include
                  one highly effective method (ie, oral, injectable, or implantable hormonal
                  contraceptive; tubal ligation; intra-uterine device; vasectomized partner) and
                  one additional effective barrier method (ie, male condom, diaphragm, cervical
                  cap) 28 days prior to starting pomalidomide, throughout the entire duration of
                  study treatment including dose interruptions and 28 days after discontinuation of
                  pomalidomide.

               -  All male and female subjects must follow all requirements defined in the
                  pomalidomide Pregnancy Prevention Program.

         18. Male subjects must, as appropriate to age and the discretion of the study physician:

               -  Practice true abstinence or agree to use a condom during sexual contact with a
                  pregnant female or a female of child bearing potential while participating in the
                  study, during dose interruptions and for at least 28 days following pomalidomide
                  discontinuation, even if he has undergone a successful vasectomy or practices
                  complete abstinence.

        Exclusion Criteria:

          1. Subject has a history of non-central line related thrombosis (arterial or venous),
             more than one prior central-line related thrombosis or known coagulopathy.

          2. Subject has first degree family member with a known hereditary coagulopathy.

          3. Subject is actively on anticoagulation therapy.

          4. Subject has had major (per Investigator discretion) surgery, with the exception of
             tumor resection, within 21 days from first dose of study drug.

          5. Subject has previously received (presence of any of the following will exclude a
             subject from enrollment):

               -  Any prior treatment with pomalidomide. Subjects who have prior treatment with
                  other immunomodulatory compounds (thalidomide, lenalidomide) are eligible if they
                  meet all other eligibility criteria and did not have allergic reactions or other
                  "significant toxicity" per Investigator discretion associated with lenalidomide
                  or thalidomide use.

               -  Myelosuppressive chemotherapy, immunotherapy, or any investigational agent: ≤ 21
                  days (≤ 42 days if a nitrosourea) prior to screening.

               -  Biological (anti-neoplastic) therapy: ≤ 7 days prior to screening.

               -  Immunomodulatory therapy: ≤ 28 days prior to screening.

               -  Monoclonal antibody treatment and agents with known prolonged half-lives: < 3
                  halflives have elapsed or ≤ 28 days prior to screening, whichever is longer.

               -  Prior radiation:

                    -  Cranial irradiation, total body irradiation (TBI), or ≥ 50% radiation of
                       pelvis ≤ 3 months prior to screening.

                    -  Focal irradiation: ≤ 3 weeks prior to screening if radiation field involved
                       a nontarget lesion; ≤ 6 weeks prior to screening if radiation field involved
                       a target lesion.

             Note: True disease progression following prior irradiation therapy must be confirmed
             by Investigator prior to screening.

               -  Bone marrow transplant:

                    -  Presence of graft versus host disease (GVHD).

                    -  < 6 months since allogeneic bone marrow transplant prior to screening.

                    -  < 3 months since autologous bone marrow/stem cell transplant prior to
                       screening.

                    -  < 3 months since stem cell transplant (SCT) or Rescue without TBI with no
                       evidence of GVHD prior to screening.

               -  Radioisotopes: fluorothymidine (18FLT) ≤ 72 hours prior to first dose of study
                  drug

          6. Subject has received therapy with a known moderate to potent CYP1A2 inhibitor within
             14 days or 5 half-lives of first dose of study treatment (whichever is longer).

          7. Subject has received colony-stimulating growth factor(s) within 7 days prior to
             screening (or within 14 days if subject received polyethylene glycol formulations).

          8. Subject is pregnant, breast-feeding or lactating.

          9. Subject has an untreated or uncontrolled infection defined as ongoing signs/symptoms
             related to the infection without improvement despite appropriate antibiotics,
             antiviral therapy and/or other treatment.

         10. Subject has active infectious hepatitis, type A, B, or C, or chronic carriers of
             hepatitis C.

         11. Subject has any prior history of malignancies, other than high-grade glioma,
             medulloblastoma, ependymoma or DIPG (Note: radiation-associated gliomas are excluded
             from enrollment)

         12. Subject who, in the opinion of the Investigator, has any significant medical
             condition, laboratory abnormality, or psychiatric illness that would prevent the
             subject from participating in the study.

         13. Subject has any condition including the presence of laboratory abnormalities which, in
             the opinion of the Investigator, places the subject at unacceptable risk if he/she
             were to participate in the study.

         14. Subject has any condition that confounds the ability to interpret data from the study.

         15. Subject has symptomatic cardiac disorders (CTCAE v. 4.03 Grade 3 and 4).