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Palbociclib and Ganitumab for the Treatment of Relapsed or Refractory Ewing Sarcoma

Trial Status: Active

This phase II trial studies how well palbociclib and ganitumab work in patients with Ewing sarcoma that has come back (relapsed) or does not respond to treatment (refractory). Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as ganitumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving palbociclib and ganitumab may work better in treating patients with Ewing sarcoma compared to either palbociclib or ganitumab alone.

Inclusion Criteria

  • Karnofsky performance status >= 50% for patients >= 16 years of age and Lansky >= 50% for patients < 16 years of age
  • Participants must have relapsed or refractory Ewing sarcoma with: * Response Evaluation Criteria in Solid Tumors (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 primitive neuroectodermal tumor (PNET); and * Molecular evidence of translocation involving EWSR1 or FUS (also known as TLS), such as fluorescent in situ hybridization (FISH), real time polymerase chain reaction (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. 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 radiotherapy (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 total body irradiation (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. * 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.
  • SUBJECTS WITHOUT KNOWN BONE MARROW INVOLVEMENT BY DISEASE: Absolute neutrophil count > 1000 /uL
  • SUBJECTS WITHOUT KNOWN BONE MARROW INVOLVEMENT BY DISEASE: Hemoglobin >= 8 g/dL (transfusion allowed)
  • SUBJECTS WITHOUT KNOWN BONE MARROW INVOLVEMENT BY DISEASE: Platelets >= 100,000 /uL and transfusion independent, defined as not receiving a platelet transfusion for at least 7 days prior to complete blood count (CBC) documenting eligibility
  • SUBJECTS WITH BONE MARROW INVOLVEMENT BY DISEASE AS DEMONSTRATED ON CLINICALLY-INDICATED BONE MARROW BIOPSY: Absolute neutrophil count > 750 /uL
  • SUBJECTS WITH BONE MARROW INVOLVEMENT BY DISEASE AS DEMONSTRATED ON CLINICALLY-INDICATED BONE MARROW BIOPSY: Hemoglobin >= 8 g/dL (transfusion allowed)
  • SUBJECTS WITH BONE MARROW INVOLVEMENT BY DISEASE AS DEMONSTRATED ON CLINICALLY-INDICATED BONE MARROW BIOPSY: Platelets >= 50,000 /uL and transfusion independent, defined as not receiving a platelet transfusion for at least 7 days prior to CBC documenting eligibility
  • SUBJECTS WITH BONE MARROW INVOLVEMENT BY DISEASE AS DEMONSTRATED ON CLINICALLY-INDICATED BONE MARROW BIOPSY: Not known to be refractory to platelet or red cell transfusions
  • 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
  • Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 135 U/L * For the purpose of this study, the upper limit of normal (ULN) for ALT is 45 U/L
  • Aspartate aminotransferase (AST) =< 90 U/L * For the purpose of this study, the ULN for AST is 30 U/L
  • Serum albumin >= 2 g/dL
  • A serum creatinine based on age/gender as follows: * Age: Maximum Serum Creatinine (mg/dL) * 12 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female) * 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female) * >= 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female) OR * Creatinine clearance >= 70 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
  • Corrected QT (QTc) =< 480 msec on electrocardiogram (ECG)
  • Diarrhea < grade 2 by CTCAE version 5
  • 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
  • Patients must be able to swallow pills
  • For patients with central nervous system (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 ** 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 * Patients receiving medications that cause significant QTc prolongation
  • 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 human immunodeficiency virus (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-body surface area (BSA) based flat dosing

Massachusetts

Boston
Boston Children's Hospital
Status: ACTIVE
Contact: David Stephen Shulman
Phone: 617-632-6670
Brigham and Women's Hospital
Status: ACTIVE
Contact: David Stephen Shulman
Phone: 617-632-6670
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: David Stephen Shulman
Phone: 617-632-6670
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Edwin Choy

PRIMARY OBJECTIVES:

I. To estimate the objective radiographic response rate to the combination of palbociclib and ganitumab in patients with relapsed or refractory Ewing sarcoma.

II. To describe the toxicity of the combination of palbociclib and ganitumab in patients with relapsed or refractory Ewing sarcoma.

SECONDARY OBJECTIVE:

I. To estimate progression-free survival and overall survival in patients with relapsed or refractory Ewing sarcoma treated with the combination of palbociclib and ganitumab.

CORRELATIVE BIOLOGY OBJECTIVES:

I. To evaluate serial measurements of circulating tumor deoxyribonucleic acid (DNA) burden as a surrogate marker of response to protocol therapy.

II. To evaluate serial measurements of insulin-like growth factor (IGF)-1 related serum proteins as potential pharmacodynamic markers of IGF pathway inhibition.

III. To explore secondary somatic mutations and tumor protein and ribonucleic acid (RNA) markers as potential predictive markers of clinical benefit from the combination of palbociclib and ganitumab.

IV. To bank tumor material, germline DNA, and peripheral blood for potential future research for participating subjects who provide additional consent.

OUTLINE:

Patients receive palbociclib orally (PO) once daily (QD) on days 1-21, and ganitumab intravenously (IV) over 30-120 minutes on days 1 and 15. Treatments repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then periodically up to 1 year.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
David Stephen Shulman

  • Primary ID 19-373
  • Secondary IDs NCI-2019-08651
  • Clinicaltrials.gov ID NCT04129151