Palbociclib + Ganitumab In Ewing Sarcoma

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 sarcomawith:

• RECIST measurable disease at study entry, including at least one RECISTmeasurable site that has either not been previously radiated or that has hadprogression 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 translocationpartner 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 donot 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-cancertherapy except organ function as noted in Section 3.1.6. Patients must meet thefollowing minimum washout periods prior to enrollment:

• Myelosuppressive chemotherapy: At least 14 days after the last dose ofmyelosuppressive 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% radiationof pelvis;

• At least 6-months must have elapsed following TBI or thoracic radiationinvolving 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 abiologic agent. For agents with known adverse events occurring beyond 7 days, thisduration must be extended beyond the time in which adverse events are known tooccur. If extended duration is required, this should be discussed and approved bythe study chair.

• Monoclonal antibody: At least 21 days must have elapsed after the last dose ofantibody.

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

• Immunotherapy: At least 4 weeks since the completion of immunotherapy (e.g. tumorvaccines) aside from monoclonal antibodies with immune effects covered under Section 3.1.5.4.

• Stem Cell Infusion or Cellular Therapies: The patient must have no evidence of graftversus host disease and at least 42 days must have elapsed after transplant, stemcell infusion, or cellular therapy.

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

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

• Absolute neutrophil count ≥ 1000 /uL

• Hemoglobin ≥ 8 g/dL (transfusion allowed)

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

• Hematologic Requirements for Subjects with Bone Marrow Involvement by Disease asDemonstrated 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 aplatelet 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'ssyndrome with a total bilirubin < 2 x upper limit of normal for age and adirect 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 levelsabove 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) withoutthe use of antihyperglycemic agents. If random glucose ≤ 160 mg/dL (or ≤ 8.9mmol/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 studyenrollment.

• Ability to understand and/or the willingness of the patient (or parent or legallyauthorized representative, if minor) to provide informed consent, using aninstitutionally 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 metastaticdisease. For patients with CNS metastatic disease receiving corticosteroids, theyshould be on a stable or decreasing dose over the 7 days prior to registrationSection 3.1.6.7 of protocol document. For all patients, receipt of systemicphysiologic replacement steroids, topical and/or inhaled corticosteroids isacceptable.

• Patients receiving medications that are strong inhibitors or inducers of CYP3A4within 7 days of enrollment (refer to Appendix B, Table 10 for prohibitedmedications)

• Patients receiving medications that cause significant QTc prolongation as outlinedin Table 12 of Appendix B.

• Patients who have had tumor molecular testing with sequencing of the RB1 gene andwere 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 ofpalbociclib and ganitumab on the developing human fetus are unknown.

• Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with palbociclib and ganitumab, breastfeedingmothers are not eligible.

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

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to palbociclib or ganitumab.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements.

• Participants with a personal history of any of the following: syncope due to anintrinsic cardiac etiology (note that syncope due to vasovagal episodes ordehydration/orthostasis would NOT exclude a participant), pathologic ventriculararrhythmias (including, but not limited to, ventricular tachycardia and ventricularfibrillation), or sudden cardiac arrest.

• Patients with known HIV, hepatitis B, and/or hepatitis C (testing not required aspart of screening).

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

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

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