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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

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ClinicalTrials.gov Identifier: NCT03041701
Recruitment Status : Active, not recruiting
First Posted : February 3, 2017
Last Update Posted : September 16, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE February 2, 2017
First Posted Date  ICMJE February 3, 2017
Last Update Posted Date September 16, 2021
Actual Study Start Date  ICMJE July 7, 2017
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 20, 2021)
  • Phase II: Number of patients who experience an objective clinical response (CR or PR) when treated with ganitumab plus dasatinib [ Time Frame: Prior to cycle 2,3,5,7 etc. ]
    Efficacy
  • Phase I: Determination of 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
Original Primary Outcome Measures  ICMJE
 (submitted: February 2, 2017)
  • 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. ]
  • 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. [ Time Frame: Prior to cycle 2, 3, 5, 7 etc. ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2017)
  • To assess the PFS in patients receiving this combination. [ Time Frame: Prior to cycle 2,3,5,7 etc. ]
    Efficacy
  • 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. ]
    Efficacy
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2017)
  • To assess the PFS in patients receiving this combination. [ Time Frame: Prior to cycle 2,3,5,7 etc. ]
  • 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. ]
  • 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. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
Brief 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 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:

  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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Rhabdomyosarcoma
  • Rhabdomyosarcoma, Alveolar
  • Rhabdomyosarcoma, Embryonal
Intervention  ICMJE
  • Drug: Dasatinib
    Once daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles.
  • Drug: Ganitumab
    Once every 2 weeks beginning on day 0.
Study Arms  ICMJE
  • Experimental: 1
    Phase I: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib
    Interventions:
    • Drug: Dasatinib
    • Drug: Ganitumab
  • Experimental: 2
    Phase II: Combination of ganitumab and dasatinib at the MTD (or highest safe dose)
    Interventions:
    • Drug: Dasatinib
    • Drug: Ganitumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 15, 2021)
13
Original Estimated Enrollment  ICMJE
 (submitted: February 2, 2017)
24
Estimated Study Completion Date  ICMJE October 31, 2022
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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(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 (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 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 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03041701
Other Study ID Numbers  ICMJE 170049
17-C-0049
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Christine M Heske, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 14, 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP