Insulin-like Growth Factor 1 Receptor (IGF-1R) Antibody AMG479 (Ganitumab) in Combination With the Src Family Kinase (SFK) Inhibitor Dasatinib in People With Embryonal and Alveolar Rhabdomyosarcoma

Study Overview
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Brief Summary
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Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Two types are embryonal RMS (ERMS) and alveolar RMS (ARMS). Dasatinib may block over-expression of a certain enzyme. Ganitumab may block a certain growth factor, which might suppress tumor growth. This drug combination may help slow tumor growth in people with ERMS and ARMS. Objective: To see if dasatinib combined with ganitumab is safe and shrinks or slows the growth of tumors in people with ERMS and ARMS. Eligibility: People any age who have ERMS or ARMS that did not respond to previous treatment and who can swallow tablets Design: Participants will be screened with: Medical history Physical exam Blood, urine, and heart tests Scans/x-rays Tissue sample: This can be from previous surgery or biopsy. Optional biopsy: A small piece of the tumor is removed with a needle. Participants will be asked to co-enroll in another protocol. Participants will get a drug interaction handout and wallet card that show what foods and medications to avoid. Participants will be treated in cycles. The first cycle is 35 days, and the rest are 28 days. Participants will take dasatinib by mouth daily. They will get ganitumab through an intravenous (IV) every 2 weeks. They will have a physical exam every 1-2 weeks, and urine and heart tests before most cycles. Participants will continue treatment as long as they do not have severe side effects, or their tumors do not get worse. After ending treatment, participants will have a visit. This includes repeats of the screening tests.

Detailed Description
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Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. The annual incidence in the United States is 4-7 cases per million children under 15 years, which represents 250 new cases per year. Two major histologic subtypes exist: embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS), the latter of which carries a particularly poor prognosis. Over-expression of both the type like growth factor 1 (1 IGF) receptor insulin-like growth factor type 1 receptor (IGF-1R) and its ligands has been observed in multiple malignancies, including pediatric sarcomas, and abnormal activation of this pathway contributes to sarcoma development and progression. Downstream signaling cascades of IGF-1R further regulate tumor cell proliferation, survival, and metastasis through the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK) and phosphatidylinositol 3-kinases (PI3Ks)/mammalian target of rapamycin (mTOR) pathways. In the majority of RMS, IGF-1R is highly expressed. Monoclonal antibodies targeting IGF-1R interfere with ligand binding and decrease the expression of the receptor on cell surfaces by internalization and degradation of the receptor. A number of these have been tested in the clinical setting. Results from a phase II trial using monotherapy with monoclonal antibodies against IGF-1R resulted in clinically meaningful responses in about 10-15% of patients with RMS. However, the vast majority of these responses were short-lived with a rapid onset of resistance. YES is a member of the SRC family tyrosine kinases (SFKs), non-receptor tyrosine kinases that function in a number of signaling pathways necessary for cell growth, differentiation and survival. Preclinical work suggests involvement of YES in a number of solid tumor types, including colon carcinoma, oral squamous cell carcinoma, glioma, pancreatic cancer, mesothelioma, and RMS. Recently, the Helman lab published preclinical work showing that in both embryonal and alveolar RMS models, blockade of IGF-1R results in YES activation and that YES activation is associated with resistance to IGF-1R blockade. In addition, combination blockade of IGF-1R and YES in vitro results in downregulation of phospho-AKT in some cell lines. Treatment blocking both IGF-1R and YES results in enhanced growth inhibition of multiple cell lines of both embryonal and alveolar RMS in vitro and in vivo. Objectives: Phase I: To determine the safe dose of dasatinib when given with ganitumab in patients with relapsed or refractory embryonal or alveolar RMS. Phase II: To determine if the use of ganitumab plus dasatinib is able to be associated with a modest fraction of patients who experience an objective clinical response (complete response (CR) and partial response (PR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. In addition, a second primary objective will estimate the fraction that is without progression at 4 months. Eligibility: Patients must have a diagnosis of relapsed or refractory embryonal or alveolar RMS, be able to swallow tablets, have archival tissue available. Patients must have adequate performance status and adequate major organ function and have recovered from acute toxicity of all prior therapies. Design: This is an open label, multi-site, phase I/II study designed to determine if ganitumab given in combination with dasatinib in children and adults with relapsed or refractory embryonal or alveolar RMS for whom no curative options exist. In the phase I portion, using a standard 3 + 3 design, limited dose escalations will be performed to define the maximum tolerated dose (MTD) or the highest safe dose tested of dasatinib when given in combination with ganitumab in this patient population. In the phase II component, sixteen (16) evaluable patients, including up to 6 patients from the phase I portion treated at the selected phase II dose, will be enrolled to rule out a 5% fraction with a clinical response in favor of a 30% fraction with a clinical response, using a one sided 0.10 significance level exact test for a binomial proportion. In practice, the fraction of the 16 patients that have objective responses will be determined and reported along with 80% and 95% confidence intervals. If there are 3 objective responses in 16 evaluable patients, the lower one-sided exact 90% confidence interval is 7.1%, thus ruling out 5%. It is anticipated that approximately 10-15 patients per year may be accrued onto this trial. Thus, 2 to 3 years is expected to completed accrual. In all patients, mechanisms of response and resistance will be assessed by analyzing archival tissue for expression of IGF-1R, insulin receptor, IGF-2 expression and phospho-YES expression, and through genomic sequencing (on protocol 10-C-0086). Genomic sequencing of tumor cells from tissue relative to non-tumor cells from whole blood will be profiled to identify the genomic variances that may contribute to response or disease progression and provide an understanding of molecular abnormalities. Ribonucleic acid (RNA) sequencing will be conducted to provide expression data and give relevance to deoxyribonucleic acid (DNA) mutations; Quantitative proteomics analysis will be conducted on all patients to determine the exact amounts of specific proteins and/or to confirm expression of genes that are correlative of response and disease progression. Genomic and transcriptomic analysis will be conducted on patients who consent to protocol 10-C-0086, Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of a Repository for Related Biological Studies. All genomic, transcriptomic, and proteomic molecular analyses will be retrospective and exploratory. In patients who agree to undergo biopsy of their tumor, provided the tissue is easily accessible and can be biopsied safely with minimal morbidity, mechanisms of response and resistance will be assessed by analyzing biopsy tissue expression of IGF- 1R, insulin receptor, IGF-2 expression and phospho-YES expression, and through genomic sequencing.

Official Title
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A Phase I/II Trial of the Insulin-Like Growth Factor 1 Receptor (IGF-1R) Antibody AMG479 (Ganitumab) in Combination With the Src Family Kinase (SFK) Inhibitor Dasatinib in Patients With Embryonal and Alveolar Rhabdomyosarcoma

Conditions
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Rhabdomyosarcoma, Rhabdomyosarcoma, Alveolar, Rhabdomyosarcoma, Embryonal

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Dasatinib
* Drug: Ganitumab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients of any age must have histologically or cytologically confirmed embryonal or alveolar rhabdomyosarcoma (RMS) confirmed by the Laboratory of Pathology, National Cancer Institute (NCI) or by the Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles (CHLA). Patients must have measurable disease. Patients must be able to undergo appropriate imaging studies to monitor tumor response. Archival tissue of tumors (slides or blocks (blocks preferred)) must be available for analysis. If tissue is not available, patients willing to undergo a pre-treatment biopsy may enroll. Prior Therapies: There is no maximum number of prior medical therapies. There must be no curative or life prolonging treatments available. Patients who have received other insulin-like growth factor 1 receptor (IGF-1R) antibodies or inhibitors are eligible, as long as an appropriate washout period has elapsed (see below). Participants must have had their last fraction of external beam radiation therapy that is local and palliative at least 2 weeks prior to enrollment (except for radiation therapy to the lungs as noted below) and had their last substantial bone marrow radiation at least 6 weeks prior to enrollment. Participants must have had their last radiation therapy of the lungs at least 8 weeks prior to enrollment. Participants must have had their last dose of temozolomide at least 4 weeks prior to enrollment; their last dose of other cytotoxic chemotherapy at least 3 weeks prior to enrollment; their last dose of biological therapy, such as biological response modifiers (e.g., cytokines), immunomodulatory agents, vaccines, differentiating agents, used to treat their cancer at least 7 days prior to enrollment, their last dose of a monoclonal antibody the shorter of 3 half- lives or 28 days prior to enrollment, and their last dose of any investigational agent at least 4 weeks prior to enrollment. Participants must have recovered from the acute toxic effects of prior therapy to a grade 1 (Common Terminology Criteria for Adverse Events (CTCAE) v.5.0) level prior to enrollment (does not apply to alopecia). Age. There are no age limits for this study, but patients must have the ability to swallow tablets. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 or Karnofsky >50% (if greater than or equal to 16 years of age); or children < 16 years old must have a Lansky performance of greater than or equal to 50%. Patients must have normal organ and marrow function as defined below: absolute neutrophil count greater than or equal to 1,000/mcL platelets greater than or equal to 75,000/mcL total bilirubin less than or equal to 1.5X upper limit of normal (ULN), with exception of patients with Gilbert syndrome Alanine aminotransferase (ALT) less than or equal to 3.0X upper limit of normal (ULN) creatinine within normal institutional limits OR creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal. Normal blood glucose for age Hematologic parameters for patients undergoing biopsy only: Patients should have INR less than or equal to 1.4 and prothrombin time (PT) less than or equal to 40 seconds (unless due to lupus anticoagulant). In patients not meeting these parameters, clearance by hematology will be required prior to undergoing a biopsy. Cardiac Function: corrected Q-T interval (QTc) < 480 msec, and ejection fraction greater than or equal to 50% Contraception. The effects of these agents on the developing human fetus are unknown. For this reason, men and women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after completion of administration of either agent. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Negative pregnancy test is required for women of childbearing potential. Ability of subject or Legally Authorized Representative (LAR)) to understand and the willingness to sign a written informed consent document. Patients will be strongly encouraged to participate in 10-C-0086. If a patient does not agree to enroll on 10-C-0086, germline genetic analysis will not be performed. EXCLUSION CRITERIA: Patients who are receiving any other investigational agents. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. History of allergic reactions attributed to compounds of similar chemical or biologic composition to dasatinib or ganitumab or other agents used in study. Patients who require concurrent treatment with any medications or substances that are potent inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated list, or medical reference text such as the Physician's Desk Reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. Patients who require concurrent treatment with antithrombotic and/or anti-platelet agents (e.g., warfarin, heparin, low molecular weight heparin, aspirin, and/or ibuprofen). Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation r surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain dasatinib tablets are excluded. Patients with a history of radiation pneumonitis. Patients may not have any clinically significant cardiovascular disease including the following: myocardial infarction or ventricular tachyarrhythmia within 6 months major conduction abnormality (unless a cardiac pacemaker is present). Patients with any cardiopulmonary symptoms of unknown cause (e.g., shortness of breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with or without stress test as needed in addition to electrocardiogram (EKG) to rule out QTc prolongation. The patient may be referred to a cardiologist at the discretion of the principal investigator. Patients with underlying cardiopulmonary dysfunction should be excluded from the study. Uncontrolled intercurrent illness including, but not limited to, the following: ongoing or active infection; history of significant bleeding disorder, including congenital (von Willebrands disease) or acquired (anti-factor VIII antibodies) disorders; large pleural effusions; or psychiatric illness/social situations that would limit compliance with study requirements. Patients with known pre-existing diabetes mellitus will be excluded because of the risk of hyperglycemia with ganitumab. Pregnant women are excluded from this study because animal studies with dasatinib have shown embryolethality and fetal skeletal alterations at non-toxic maternal doses. Because there is an unknown but potential risk for adverse events in nursing human infants secondary to treatment of the mother with dasatinib, breastfeeding should be discontinued if the mother is treated with dasatinib.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Level 1: Ganitumab and Dasatinib<br>Phase I Dose Level 1: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib | Drug: Dasatinib<br>* Once daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles.<br>* Other names: Sprycel;Drug: Ganitumab<br>* Once every 2 weeks beginning on day 0.<br>* Other names: Insulin-like Growth Factor 1 Receptor (IGF-1R) Antibody AMG479;|
| Experimental: Phase 1 Dose Level 2: Ganitumab and Dasatinib<br>Phase I Dose Level 2: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib | Drug: Dasatinib<br>* Twice daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles.<br>* Other names: Sprycel;Drug: Ganitumab<br>* Once every 2 weeks beginning on day 0.<br>* Other names: Insulin-like Growth Factor 1 Receptor (IGF-1R) Antibody AMG479;|
| Experimental: Phase 2 Dose Level 1: Ganitumab and Dasatinib<br>Phase 2 Dose Level 1: Combination of ganitumab and dasatinib at the maximum tolerated dose (MTD) (or highest safe dose) | Drug: Dasatinib<br>* Once daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles.<br>* Other names: Sprycel;Drug: Ganitumab<br>* Once every 2 weeks beginning on day 0.<br>* Other names: Insulin-like Growth Factor 1 Receptor (IGF-1R) Antibody AMG479;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Safe Dose of Dasatinib When Given With Ganitumab in Participants With Relapsed or Refractory Embryonal or Alveolar Rhabdomyosarcoma (RMS) | The safe dose or maximum tolerated dose (MTD) is defined as the dose level at which no more than 1 of up to 3-6 participants experience a dose-limiting toxicity (DLT) during the first cycle of treatment, and the dose below that at which at least 2 (of ≤6) participants have DLT as a result of the drug. A DLT is any toxicity of grade 3 or higher, with the specific exception of grade 3 nausea and vomiting of < 5 days duration, grade 3 fever or infection < 5 days duration, and grade 3 neutropenia or thrombocytopenia, for example. | First 35 days of treatment | 
| Phase II: Number of Participants Who Experience an Objective Clinical Response (CR or PR) When Treated With Ganitumab Plus Dasatinib | Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. | Participants were followed for the duration of their treatment which ranged from 0-6 cycles (each cycle is 28 days) and averaged approximately 2 months. | 
| Phase II: Number of Participants That is Without Progression at 4 Months | Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Progressive disease is least a 20% increase in the sum of the diameters of target lesions) taking as reference the smallest sum of diameters while on study. | At 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Progression Free Survival (PFS) in Participants Receiving Insulin-like Growth Factor 1 Receptor (IGF-1R) Antibody AMG479 (Ganitumab) in Combination With the Src Family Kinase (SFK) Inhibitor Dasatinib | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Progressive disease is at least a 20% increase in the sum of the diameters of target lesions) taking as reference the smallest sum of diameters while on study. | Participants were followed for the duration of their treatment which ranged from 0-6 cycles (each cycle is 28 days) and averaged approximately 2 months. | 
| Phase II: Number of Participants With Stable Disease >= 6 Months as Defined by the Response Evaluation Criteria in Solid Tumors (RECIST) in Participants Receiving Ganitumab With Dasatinib | Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Stable disease is neither sufficient shrinkage to qualify for partial response (i.e., at least a 30% decrease in the sum of the diameters of target lesions) nor sufficient increase to qualify for progressive disease (i.e., at least a 20% increase in the sum of the diameters of target lesions) taking as reference the smallest sum of diameters while on study. | 6 months | 
| Phase I: Number of Participants With Grade ≥3 Adverse Events Related to Treatment With Ganitumab and Dasatinib | Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event. | Date treatment consent signed to date off study, approximately 14 months and 18 days for phase 1 dose level 1, 27 months and 2 days for phase 1 dose level 2, and 1 month and 24 days for phase 2 dose level 1. | 
| Phase II: Number of Participants With Grade ≥3 Adverse Events Related to Treatment With Ganitumab and Dasatinib | Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event. | Date treatment consent signed to date off study, approximately 14 months and 18 days for phase 1 dose level 1, 27 months and 2 days for phase 1 dose level 2, and 1 month and 24 days for phase 2 dose level 1. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ERMS, ARMS, Monoclonal Antibody, YES, RMS