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

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 1 IGF 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 MAPK/ERK and PI3K/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:

Primary Objective:

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 (CR and
PR) as defined by 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 8-10 patients per year may be accrued onto this
trial. Thus, 2 to 3 years is expected to completed accrual. In order to allow for a very
small number of inevaluable patients, the accrual ceiling for the phase II component
will be set at 18 patients.

- 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. RNA sequencing will
be conducted to provide expression data and give relevance to 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.

- INCLUSION CRITERIA:

- Patients of any age must have histologically or cytologically confirmed embryonal or
alveolar rhabdomyosarcoma (RMS) confirmed by the Laboratory of Pathology, NCI or by
the Department of Pathology and Laboratory Medicine, 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 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, and had their
last substantial bone marrow radiation at least 6 weeks prior to enrollment.

- Participants must have had their last dose of alkylating agents 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 (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.

- 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

- ALT less than or equal to 3.0X 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 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: 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 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 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 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 Willebrand s 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.