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 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 pelvis; * 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 chair. * Monoclonal antibody: At least 21 days must have elapsed after the last dose of antibody. * 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 3.1.5.4. * 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 Disease: * 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 enrollment. * 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 3.1.6.7 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.