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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

Description:

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 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.

Related Conditions:
  • Alveolar Rhabdomyosarcoma
  • Embryonal Rhabdomyosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 170049
  • SECONDARY ID: 17-C-0049
  • NCT ID: NCT03041701

Conditions

  • Rhabdomyosarcoma
  • Rhabdomyosarcoma- Alveolar
  • Rhabdomyosarcoma-Embryonal

Interventions

DrugSynonymsArms
Dasatinib1
Ganitumab1

Purpose

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 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

      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 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. 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.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalPhase I: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib
  • Dasatinib
  • Ganitumab
2ExperimentalPhase II: Combination of ganitumab and dasatinib at the MTD (or highest safe dose)
  • Dasatinib
  • Ganitumab

Eligibility Criteria

        -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: To determine the safe dose of dasatinib when given with ganitumab in patients with relapsed or refractory embryonal or alveolar RMS.
Time Frame:Prior to cycle 2, 3, 5, 7 etc.
Safety Issue:
Description:Safety

Secondary Outcome Measures

Measure:To assess the PFS in patients receiving this combination.
Time Frame:Prior to cycle 2,3,5,7 etc.
Safety Issue:
Description:Efficacy
Measure:To determine the fraction of patients with stable disease >= 6 months as defined by RECIST criteria in patients receiving this combination.
Time Frame:Prior to cycle 2,3,5,7 etc.
Safety Issue:
Description:Efficacy
Measure:To describe the toxicity and confirm the tolerability of the combination of ganitumab and dasatinib in patients with relapsed or refractory RMS.
Time Frame:Prior to cycle 2,3,5,7 etc.
Safety Issue:
Description:Safety

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • ERMS
  • ARMS
  • Monoclonal Antibody
  • YES
  • RMS

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