A Study of Pomalidomide (CC-4047) Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors

Status: Recruiting
Phase:
DFCI Protocol ID: 17-227

A Phase 2 study that 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. The study will consist of 4 parallel groups, one for each of the following primary brain tumor types: high-grade glioma, medulloblastoma, ependymoma and DIPG. A Simon's Optimal two-stage study design will be applied to each group.

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Mark Kieran, MD, Dana-Farber Cancer Institute

Site-responsible Investigators:

Contacts:

Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org

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 the 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/mm33

       -  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:

     Adequate real function with Sserum creatinine based on age/gender calculated using the
     Schwartz formula as described in protocol, 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:
     to

       -  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: < 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)

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