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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03041701
Recruitment Status : Terminated (The pharmaceutical company discontinued availability of the drug and we were forced to close the study before phase II was completed. Only one participant was enrolled on phase II.)
First Posted : February 3, 2017
Results First Posted : April 14, 2022
Last Update Posted : April 14, 2022
Sponsor:
Information provided by (Responsible Party):
Christine Heske, M.D., National Cancer Institute (NCI)

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 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.


Condition or disease Intervention/treatment Phase
Rhabdomyosarcoma Rhabdomyosarcoma, Alveolar Rhabdomyosarcoma, Embryonal Drug: Dasatinib Drug: Ganitumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 7, 2017
Actual Primary Completion Date : September 15, 2021
Actual Study Completion Date : October 16, 2021


Arm Intervention/treatment
Experimental: Phase 1 Dose Level 1: Ganitumab and Dasatinib
Phase I Dose Level 1: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib
Drug: Dasatinib
Once daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles.
Other Name: Sprycel

Drug: Ganitumab
Once every 2 weeks beginning on day 0.
Other Name: Insulin-like Growth Factor 1 Receptor (IGF-1R) Antibody AMG479

Experimental: Phase 1 Dose Level 2: Ganitumab and Dasatinib
Phase I Dose Level 2: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib
Drug: Dasatinib
Twice daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles.
Other Name: Sprycel

Drug: Ganitumab
Once every 2 weeks beginning on day 0.
Other Name: Insulin-like Growth Factor 1 Receptor (IGF-1R) Antibody AMG479

Experimental: Phase 2 Dose Level 1: Ganitumab and Dasatinib
Phase 2 Dose Level 1: Combination of ganitumab and dasatinib at the maximum tolerated dose (MTD) (or highest safe dose)
Drug: Dasatinib
Once daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles.
Other Name: Sprycel

Drug: Ganitumab
Once every 2 weeks beginning on day 0.
Other Name: Insulin-like Growth Factor 1 Receptor (IGF-1R) Antibody AMG479




Primary Outcome Measures :
  1. Phase I: Safe Dose of Dasatinib When Given With Ganitumab in Participants With Relapsed or Refractory Embryonal or Alveolar Rhabdomyosarcoma (RMS) [ Time Frame: First 35 days of treatment ]
    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.

  2. Phase II: Number of Participants Who Experience an Objective Clinical Response (CR or PR) When Treated With Ganitumab Plus Dasatinib [ Time Frame: Participants were followed for the duration of their treatment which ranged from 0-6 cycles (each cycle is 28 days) and averaged approximately 2 months. ]
    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.

  3. Phase II: Number of Participants That is Without Progression at 4 Months [ Time Frame: At 4 months ]
    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.


Secondary Outcome Measures :
  1. 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 [ Time Frame: Participants were followed for the duration of their treatment which ranged from 0-6 cycles (each cycle is 28 days) and averaged approximately 2 months. ]
    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.

  2. 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 [ Time Frame: 6 months ]
    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.

  3. Phase I: Number of Participants With Grade ≥3 Adverse Events Related to Treatment With Ganitumab and Dasatinib [ Time Frame: Date treatment consent signed to date off study, approximately 14 months and 18 days for phase 1 dose level 1, 27 months and 2 days for phase 1 dose level 2, and 1 month and 24 days for phase 2 dose level 1. ]
    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.

  4. Phase II: Number of Participants With Grade ≥3 Adverse Events Related to Treatment With Ganitumab and Dasatinib [ Time Frame: Date treatment consent signed to date off study, approximately 14 months and 18 days for phase 1 dose level 1, 27 months and 2 days for phase 1 dose level 2, and 1 month and 24 days for phase 2 dose level 1. ]
    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.


Other Outcome Measures:
  1. Phase I: Number of Participants With a Dose-Limiting Toxicity (DLT) [ Time Frame: First 35 days of treatment ]
    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.

  2. Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) [ Time Frame: Date treatment consent signed to date off study, approximately 14 months and 18 days for phase 1 dose level 1, 27 months and 2 days for phase 1 dose level 2, and 1 month and 24 days for phase 2 dose level 1. ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   2 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients of any age must have histologically or cytologically confirmed embryonal or alveolar rhabdomyosarcoma (RMS) confirmed by the Laboratory of Pathology, National Cancer Institute (NCI) or by the Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles (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 insulin-like growth factor 1 receptor (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 (Common Terminology Criteria for Adverse Events (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.
  • Eastern Cooperative Oncology Group (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
    • Alanine aminotransferase (ALT) less than or equal to 3.0X upper limit of normal (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 prothrombin time (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: corrected Q-T interval (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 cytochrome P450 3A4 (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 intravenous (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 Willebrands 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03041701


Locations
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United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90054-0700
United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Christine M Heske, M.D. National Cancer Institute (NCI)
  Study Documents (Full-Text)

Documents provided by Christine Heske, M.D., National Cancer Institute (NCI):
Informed Consent Form  [PDF] April 13, 2020

Additional Information:
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Responsible Party: Christine Heske, M.D., Principal Investigator, National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03041701    
Other Study ID Numbers: 170049
17-C-0049
First Posted: February 3, 2017    Key Record Dates
Results First Posted: April 14, 2022
Last Update Posted: April 14, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Clinical data available during the study and indefinitely.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Clinical data will be made available via subscription to the Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).
Access Criteria: Clinical data will be made available via subscription to the Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Requests for all collected individual participant data (IPD) data from clinical trials, conducted under a binding collaborative agreement between National Cancer Institute (NCI)/Division of Cancer Treatment and Diagnosis (DCTD) and a pharmaceutical/biotechnology company, that are not under data safety monitoring board (DSMB) monitoring must be in compliance with the terms of the binding collaborative agreement and must be approved by NCI/DCTD and the Pharmaceutical Collaborator (i.e., the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) Director in conjunction with the NCI/DCTD Regulatory Affairs Branch).

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Christine Heske, M.D., National Cancer Institute (NCI):
ERMS
ARMS
Monoclonal Antibody
YES
RMS
Additional relevant MeSH terms:
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Rhabdomyosarcoma
Rhabdomyosarcoma, Alveolar
Rhabdomyosarcoma, Embryonal
Myosarcoma
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sarcoma
Dasatinib
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors