Palbociclib + Ganitumab In Ewing Sarcoma

Status: Recruiting
DFCI Protocol ID: 19-373

This research study is designed to study the combination of two drugs, palbociclib and ganitumab, as a potential treatment for Ewing sarcoma. The names of the study drugs involved in this study are: - Palbociclib - Ganitumab

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Site-responsible Investigators:


Eligibility Criteria

Inclusion Criteria:

  -  Age ≥ 12 years and ≤ 50 years at time of enrollment.

  -  Karnofsky performance status ≥ 50% for patients ≥16 years of age and Lansky ≥ 50% for
     patients <16 years of age (see Appendix A)

  -  Disease Requirement: Participants must have relapsed or refractory Ewing sarcoma with:

       -  RECIST measurable disease at study entry, including at least one RECIST
  measurable site that has either not been previously radiated or that has had
  progression after prior radiotherapy;

       -  Histologic diagnosis consistent with Ewing sarcoma or PNET; and

       -  Molecular evidence of translocation involving EWSR1 or FUS (also known as TLS),
  such as FISH, RT-PCR, or next generation sequencing. If the translocation partner
  is known it must be of the ETS family (i.e. FLI1 or ERG).

  -  Participants must have disease for which standard curative or palliative measures do
     not exist or are no longer effective.

  -  Patients must have fully recovered (Common Terminology Criteria for Adverse Events
     [CTCAE] version 5 Grade ≤1) from the acute toxic effects of all prior anti-cancer
     therapy except organ function as noted in Section 3.1.6. Patients must meet the
     following minimum washout periods prior to enrollment:

  -  Myelosuppressive chemotherapy: At least 14 days after the last dose of
     myelosuppressive chemotherapy (42 days for nitrosourea or mitomycin C).

  -  Radiotherapy:

       -  At least 14 days after local palliative XRT (small port);

       -  At least 90 days must have elapsed after craniospinal XRT or if >50% radiation of

       -  At least 6-months must have elapsed following TBI or thoracic radiation involving
  the lungs;

       -  At least 42 days must have elapsed if other substantial bone marrow radiation;

  -  Small molecule biologic therapy: At least 7 days following the last dose of a biologic
     agent. For agents with known adverse events occurring beyond 7 days, this duration
     must be extended beyond the time in which adverse events are known to occur. If
     extended duration is required, this should be discussed and approved by the study

  -  Monoclonal antibody: At least 21 days must have elapsed after the last dose of

  -  Myeloid growth factors: At least 14 days following the last dose of long-acting growth
     factor (e.g. Neulasta®) or 7 days following short-acting growth factor.

  -  Immunotherapy: At least 4 weeks since the completion of immunotherapy (e.g. tumor
     vaccines) aside from monoclonal antibodies with immune effects covered under Section

  -  Stem Cell Infusion or Cellular Therapies: The patient must have no evidence of graft
     versus host disease and at least 42 days must have elapsed after transplant, stem cell
     infusion, or cellular therapy.

  -  Major Surgery: At least 2 weeks from prior major surgical procedure. Note: Biopsy and
     central line placement/removal are not considered major surgery.

  -  CDK4/6 and IGF-1R inhibitors: The participant must not have received a prior CDK4/6
     inhibitor. Prior therapy with IGF-1R inhibitor is allowed if the patient did not
     relapse while on IGF-1R therapy. Patients must not have received prior therapy with a
     combination of CDK4/6 inhibitor and IGF-1R inhibitor.

  -  Participants must have normal organ function as defined below.

  -  Hematologic Requirements for Subjects without Known Bone Marrow Involvement by

       -  Absolute neutrophil count ≥ 1000 /uL

       -  Hemoglobin ≥ 8 g/dL (transfusion allowed)

       -  Platelets ≥100,000 /uL and transfusion independent, defined as not receiving a
  platelet transfusion for at least 7 days prior to CBC documenting eligibility.

  -  Hematologic Requirements for Subjects with Bone Marrow Involvement by Disease as
     Demonstrated on Clinically-Indicated Bone Marrow Biopsy:

       -  Absolute neutrophil count >750 /uL

       -  Hemoglobin ≥ 8 g/dL (transfusion allowed)

       -  Platelets ≥50,000 /uL and transfusion independent, defined as not receiving a
  platelet transfusion for at least 7 days prior to CBC documenting eligibility.

       -  Not known to be refractory to platelet or red cell transfusions.

  -  Hepatic Function:

       -  Total bilirubin ≤ 1.5 x upper limit of normal for age Patients with Gilbert's
  syndrome with a total bilirubin < 2 x upper limit of normal for age and a direct
  bilirubin within normal limits are permitted.

       -  ALT (SGPT) ≤ 135 U/L For the purpose of this study, the ULN for ALT is 45 U/L

       -  AST (SGOT)≤ 90 U/L For the purpose of this study, the ULN for AST is 90 U/L

       -  Serum albumin ≥ 2 g/dL

  -  Renal Function:

     -- A serum creatinine based on age/gender as follows: Maximum Serum Creatinine (mg/dL)
     Male Female

       -  12 to < 13 years 1.2 1.2

       -  13 to < 16 years 1.5 1.4

       -  ≥ 16 years 1.7 1.4 Or

  -  Creatinine clearance ≥ 70 mL/min/1.73 m2 for participants with creatinine levels above
     institutional normal.

  -  Adequate Cardiac Function: QTc ≤ 480 msec on ECG

  -  Adequate GI Function: Diarrhea < grade 2 by CTCAE version 5

  -  Adequate Metabolic Function: Fasting glucose ≤ 160 mg/dL (or < 8.9 mmol/L) without the
     use of antihyperglycemic agents. If random glucose ≤ 160 mg/dL (or ≤ 8.9 mmol/L),
     fasting value does not need to be obtained.

  -  Additional Agent-Specific Requirements

       -  Patients must be able to swallow capsules.

       -  For patients with CNS metastatic disease, any baseline neurologic deficits
  (including seizure) must be stable for at least one week prior to study

  -  Ability to understand and/or the willingness of the patient (or parent or legally
     authorized representative, if minor) to provide informed consent, using an
     institutionally approved informed consent procedure.

Exclusion Criteria:

  -  Patients must not be receiving any of the following concomitant medications:

     -- Pharmacologic doses of systemic corticosteroids unless for CNS metastatic disease.
     For patients with CNS metastatic disease receiving corticosteroids, they should be on
     a stable or decreasing dose over the 7 days prior to registration Section of
     protocol document. For all patients, receipt of systemic physiologic replacement
     steroids, topical and/or inhaled corticosteroids is acceptable.

  -  Patients receiving medications that are strong inhibitors or inducers of CYP3A4 within
     7 days of enrollment (refer to Appendix B, Table 10 for prohibited medications)

  -  Patients receiving medications that cause significant QTc prolongation as outlined in
     Table 12 of Appendix B.

  -  Patients who have had tumor molecular testing with sequencing of the RB1 gene and were
     found to have RB1 mutation or loss will be excluded.

  -  Patients with a history of pneumonitis will be excluded.

  -  Pregnant participants will not be entered on this study given that the effects of
     palbociclib and ganitumab on the developing human fetus are unknown.

  -  Because there is an unknown but potential risk for adverse events in nursing infants
     secondary to treatment of the mother with palbociclib and ganitumab, breastfeeding
     mothers are not eligible.

  -  Participants of child-bearing or child-fathering potential must agree to use adequate
     contraception (hormonal birth control; intrauterine device; double barrier method; or
     total abstinence) throughout their participation, including up until 30 days after
     last dose of palbociclib or ganitumab, whichever was administered last.

  -  History of allergic reactions attributed to compounds of similar chemical or biologic
     composition to palbociclib or ganitumab.

  -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
     infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
     arrhythmia, or psychiatric illness/social situations that would limit compliance with
     study requirements.

  -  Participants with a personal history of any of the following: syncope due to an
     intrinsic cardiac etiology (note that syncope due to vasovagal episodes or
     dehydration/orthostasis would NOT exclude a participant), pathologic ventricular
     arrhythmias (including, but not limited to, ventricular tachycardia and ventricular
     fibrillation), or sudden cardiac arrest.

  -  Patients with known HIV, hepatitis B, and/or hepatitis C (testing not required as part
     of screening).

  -  Patients with a known history of type 1 or type 2 diabetes mellitus.

  -  Patients with gastrointestinal disease or disorder that could interfere with
     absorption of palbociclib, such as bowel obstruction or inflammatory bowel disease.

  -  Patients < 40 kg will be excluded given use of palbociclib at non-weight / non-BSA
     based flat dosing.

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