Neoplasms

All Conditions

Rare Diseases

Rhabdomyosarcoma

Rhabdomyosarcoma, Embryonal

Rhabdomyosarcoma, Alveolar

Myosarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Sarcoma

Rhabdomyosarcoma Alveolar

Soft Tissue Sarcoma

All Drugs and Chemicals

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Antibodies, Monoclonal

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Insulin, Globin Zinc

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Mitogens

Dasatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Phase I Dose Level 1: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib

Phase I Dose Level 2: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib

Phase 2 Dose Level 1: Combination of ganitumab and dasatinib at the maximum tolerated dose (MTD) (or highest safe dose)

Once daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles.

Twice daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles.

Ganitumab

Christine M Heske, M.D.

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.

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:

1. Phase I: To determine the safe dose of dasatinib when given with ganitumab in patients with relapsed or refractory embryonal or alveolar RMS.
2. 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.

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

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

Clinical data available during the study and indefinitely.

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.

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

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.

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.

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.

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.

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.

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.

National Cancer Institute (NCI)

Principal Investigator

Phase 1 Dose Level 1 Dose Escalation: Dasatinib 60mg/m\^2 by mouth (PO) every day (QD) at Day-7. Ganitumab 18mg/kg intravenous (IV) every two weeks starting at Day 0.

Cycle 1 is Day -7 to 27; all other cycles are Day 0 to 27

Phase 1 Dose Level 1 Dose Escalation Dasatinib 60 mg/m^2 Every Day (QD)/Ganitumab 18 mg/kg

Phase 1 Dose Level 2 Dose Escalation: Dasatinib 60mg/m\^2 by mouth (PO) twice a day (BID) at Day-7. Ganitumab 18mg/kg intravenous (IV) every two weeks starting at Day 0.

Cycle 1 is Day -7 to 27; all other cycles are Day 0 to 27

Phase 1 Dose Level 2 Dose Escalation Dasatinib 60 mg/m^2 Twice Daily (BID)/Ganitumab 18 mg/kg

Phase 2 Dose Level 1 Maximum Tolerated Dose: Dasatinib 60mg/m\^2 by mouth (PO) every day (QD) at Day-7. Ganitumab 18mg/kg intravenous (IV) every two weeks starting at Day 0.

Cycle 1 is Day -7 to 27; all other cycles are Day 0 to 27

Phase 2 Dose Level 1 Maximum Tolerated Dose Dasatinib 60 mg/m^2 Every Day (QD)/ Ganitumab 18 mg/kg

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Hispanic

Not Hispanic

Ethnicity unknown

Black

White

Asian

Race unknown

White + Unknown

Race/Ethnicity, Customized

United States

Region of Enrollment

Dr. Christine Heske

All participants on: Phase 1 Dose Level 1 and Phase 1 Dose Level 2.

All Participants

Phase I: Safe Dose of Dasatinib When Given With Ganitumab in Participants With Relapsed or Refractory Embryonal or Alveolar Rhabdomyosarcoma (RMS)

Complete Response

Partial Response

Per protocol, participants (pts) who receive dasatinib at the maximum tolerated (MTD) dose+ganitumab during phase(ph) I will be included in the evaluation of ph II objectives, if evaluable. 5/7 pts on the Ph 1 at the MTD are evaluable and were analyzed with RECIST (versus 0/7 analyzed) since all evaluable pts underwent disease response analysis. Same applies to ph 2 (1/1 evaluable/analyzed). Pts treated at dose level 2 were not analyzed for this objective because dose level 2 was not the MTD.

Phase II: Number of Participants Who Experience an Objective Clinical Response (CR or PR) When Treated With Ganitumab Plus Dasatinib

Phase II: Number of Participants That is Without Progression at 4 Months

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

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	NCT03041701	Rhabdomyosarcom... Rhabdomyosarcom... Rhabdomyosarcom...	Dasatinib Dasatinib Ganitumab	2 Years -	National Institutes of Health Clinical Center (CC)
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	NCT03041701	Rhabdomyosarcom... Rhabdomyosarcom... Rhabdomyosarcom...	Dasatinib Dasatinib Ganitumab	2 Years -	National Institutes of Health Clinical Center (CC)
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	NCT03041701	Rhabdomyosarcom... Rhabdomyosarcom... Rhabdomyosarcom...	Dasatinib Dasatinib Ganitumab	2 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for rhabdomyosarcoma, alveolar