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

Rhabdomyosarcoma Clinical Trial

Official title: 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

Status Terminated

Clinical Trial Summary

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.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Rhabdomyosarcoma

• NCT number: NCT03041701
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: July 7, 2017
• Completion date: October 16, 2021