PHASE 1/2 STUDY TO EVALUATE PALBOCICLIB (IBRANCE® ) IN
COMBINATION WITH IRINOTECAN AND TEMOZOLOMIDE AND/OR IN COMBINATION WITH TOPOTECAN AND CYCLOPHOSPHAMIDE IN
PEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY SOLID
TUMORS

1. Histologically confirmed relapsed or refractory solid tumor as follows:
• For randomized Phase 2 part: Histologically confirmed Ewing sarcoma at
diagnosis or at relapse, with presence of EWSR1-ETS or FUS-ETS rearrangement.
Histopathology confirmation of both EWSR1-ETS or FUSETS rearrangement partners
is required OR availability of formalin fixed paraffin embedded (FFPE) tumor
tissue sample for central testing. Patient must have relapsed or have
refractory disease and at least evaluable disease in at least one site other
than bone marrow that can be followed by imaging.
2. Age >=2 and <21 years at the time of study entry. Refer to Section 4.3 for
reproductive criteria for male and female participants.
3. Lansky performance status >=50% for patients <=16 years of age, or Eastern
Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age.
4. Adequate bone marrow function.
• Absolute neutrophil count >=1000/mm3;
• Platelet count >=75,000/mm3 (transfusion independent, no platelet transfusion
in past 7 days prior study entry);
• Hemoglobin >=8.5 g/dL (transfusion allowed).
5. Adequate renal function: Serum creatinine level based on age/gender must be
less than or equal to the following maximum upper limits
6. Adequate liver function, including:
•Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5 ×
upper limit of normal (ULN) or <=5 × ULN for age, if attributable to disease
involvement of the liver;
•Total bilirubin <=1.5 × ULN for age unless the patient has documented
Gilbert's syndrome. Patients with documented Gilbert's syndrome are eligible
if direct bilirubin is within normal ranges (<=ULN).
7. Patients enrolled to Phase 1 portion of the study and tumor specific
cohorts must have measurable disease as defined by RECIST version 1.1 or
modified RANO criteria for CNS disease or at least evaluable disease by INRC
for neuroblastoma.
The eligible patients with neuroblastoma must have at least one of the
following at the time of study entry:
•Measurable tumor by CT or MRI that is avid on MIBG scan or demonstrates
increased FDG uptake on PET scan;
•Avid lesion on MIBG scan with positive uptake at a minimum of one site;
•For disease that is not avid by MIBG-scan, at least one lesion that
demonstrates increased FDG uptake on PET scan AND viable neuroblastoma
confirmed by current or prior biopsy;
•bone marrow involvement with more than 5% neuroblastoma cells in at least one
sample from bilateral bone marrow biopsies;
•In non MIBG-avid refractory soft tissue disease that does not demonstrate
increased FDG uptake; lesion biopsy is required to document the presence of
viable neuroblastoma, unless patient has a
new soft tissue lesion (radiographic evidence of disease progression). Patients
with EWS enrolled to Phase 2 portion of the study are eligible with at least
evaluable disease (eg, bone only disease with no soft tissue component).
8. Recovered to CTCAE Grade <=1, or to baseline, from any non-hematological
acute toxicities of prior surgery, chemotherapy,
immunotherapy, radiotherapy, differentiation therapy or biologic
therapy, with the exception of alopecia.
9. Serum/urine pregnancy test (for all girls >=8 years of age) negative at
screening and at the baseline visit.

1. Phase 2 portion: prior treatment with a CDK4/6 inhibitor or progression
while on treatment with an IRN-containing or TMZcontaining regimen. Patients
who have received IRN and/or TMZ and did
not progress while on these medications are eligible.
2. Prior intolerability to IRN and/or TMZ for IRN and TMZ plus/minus
palbociclib combinations and prior intolerability to TOPO and/or CTX for TOPO
and CTX combination. For patients enrolled in the UK, any contraindication for
IRN and/or TMZ treatment, as per the local SmPC.
3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers within 12 days
of study entry. Patients who are receiving strong uridine
diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of
C1D1 are not eligible for the palbociclib with IRN and TMZ combination.
Patients who are receiving strong UGT1A1 inhibitors within 12 days of C1D1 are
eligible for the palbociclib with TOPO and CTX combination
4. Systemic anticancer therapy within 2 weeks prior to study entry and 6 weeks
for nitrosoureas.
5. Prior irradiation to >50% of the bone marrow (see ATTACHMENTS).
6. Participation in other studies involving investigational drug(s) within 2
weeks or 5 halflives, whichever is longer, prior to study entry.
7. Major surgery within 4 weeks prior to study entry. Surgical biopsies or
central line placement are not considered major surgeries.
8. For IRN and TMZ with/without palbociclib combinations: known or suspected
hypersensitivity to palbociclib, dacarbazine, IRN and/or TMZ. For combination
of palbociclib with TOPO and CTX: known or suspected hypersensitivity to
palbociclib, TOPO and/or CTX
9. Patients with known symptomatic brain tumors or brain metastases and require
steroids, unless they have been on a stable or on a decreasing steroid dose for
>14 days.
10. Patients with previously diagnosed brain metastases are eligible if they
have completed their prior treatment and have recovered from the acute effects
of radiation therapy or surgery prior to study entry for these metastases for
at least 14 days postradiation and 4 weeks postsurgery
and are neurologically stable.
11. Hereditary bone marrow failure disorder.
12. QTc >470 msec.
13. History of clinically significant or uncontrolled cardiac disease,
including:
• History of or active congestive heart failure; if patient had congestive
heart failure resolve and >1 year from resolution, patient will be considered
eligible;
• Clinically significant ventricular arrhythmia (such as ventricular
tachycardia, ventricular fibrillation or Torsades de Pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• Need for medications known to prolong the QT interval;
• Uncorrected hypomagnesemia or hypokalemia because of potential effects on the
QT interval;
• Left ventricular ejection fraction <50% or shortening fraction <28%.
14. Recent or ongoing clinically significant gastrointestinal disorder that may
interfere with absorption of orally administered drugs (eg, gastrectomy).
15. Evidence of serious active or uncontrolled bacterial, fungal or viral
infection or known history of hepatitis B virus, hepatitis C virus, or human
immunodeficiency virus infection or acquired immunodeficiency syndrome-related
illness. Screening for viral hepatitis and HIV is under
discretion of investigator unless required by local regulation.
16. Severe acute or chronic medical or laboratory test abnormality that may
increase the risk associated with study participation or investigational
product administration or may interfere with the
interpretation of study results, and in the judgment of the Investigator, would
make the patient inappropriate for entry into this study.
17. Investigator site staff members directly involved in the conduct of the
study and their family members, site staff members otherwise supervised by the
investigator, or patients who are Pfizer employees, including their family
members, directly involved in the conduct of the study.
18. Fertile male patients or female patients of childbearing potential who are
unwilling or unable to follow contraceptive requirements as detailed in
Section 4.3.
19. Pregnant or breastfeeding women.