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 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 17004917-C-0049
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 2

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.

Conditions

Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal

Keywords

ERMS; ARMS; Monoclonal Antibody; YES; RMS

Outcome Measures

Primary Outcomes (3)

• Phase I: Safe Dose of Dasatinib When Given With Ganitumab in Participants With Relapsed or Refractory Embryonal or Alveolar Rhabdomyosarcoma (RMS)

  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.

  First 35 days of treatment

• Phase II: Number of Participants Who Experience an Objective Clinical Response (CR or PR) When Treated With Ganitumab Plus Dasatinib

  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.

  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.

• Phase II: Number of Participants That is Without Progression 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.

  At 4 months

Secondary Outcomes (4)

• 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

  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.

• 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

  6 months

• Phase I: Number of Participants With Grade ≥3 Adverse Events Related to Treatment With Ganitumab and Dasatinib

  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.

• Phase II: Number of Participants With Grade ≥3 Adverse Events Related to Treatment With Ganitumab and Dasatinib

  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.

Other Outcomes (2)

• Phase I: Number of Participants With a Dose-Limiting Toxicity (DLT)

  First 35 days of treatment

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  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.

Study Arms (3)

Phase 1 Dose Level 1: Ganitumab and Dasatinib

EXPERIMENTAL

Phase I Dose Level 1: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib

Drug: Dasatinib; Drug: Ganitumab

Phase 1 Dose Level 2: Ganitumab and Dasatinib

EXPERIMENTAL

Phase I Dose Level 2: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib

Drug: Dasatinib; Drug: Ganitumab

Phase 2 Dose Level 1: Ganitumab and Dasatinib

EXPERIMENTAL

Phase 2 Dose Level 1: Combination of ganitumab and dasatinib at the maximum tolerated dose (MTD) (or highest safe dose)

Drug: Dasatinib; Drug: Ganitumab

Interventions

Dasatinib DRUG

Once daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles.

Also known as: Sprycel

Phase 1 Dose Level 1: Ganitumab and Dasatinib; Phase 2 Dose Level 1: Ganitumab and Dasatinib

Ganitumab DRUG

Once every 2 weeks beginning on day 0.

Also known as: Insulin-like Growth Factor 1 Receptor (IGF-1R) Antibody AMG479

Phase 1 Dose Level 1: Ganitumab and Dasatinib; Phase 1 Dose Level 2: Ganitumab and Dasatinib; Phase 2 Dose Level 1: Ganitumab and Dasatinib

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

Children's Hospital Los Angeles

Los Angeles, California, 90054-0700, United States

Location

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Akshintala S, Sundby RT, Bernstein D, Glod JW, Kaplan RN, Yohe ME, Gross AM, Derdak J, Lei H, Pan A, Dombi E, Palacio-Yance I, Herrera KR, Miettinen MM, Chen HX, Steinberg SM, Helman LJ, Mascarenhas L, Widemann BC, Navid F, Shern JF, Heske CM. Phase I trial of Ganitumab plus Dasatinib to Cotarget the Insulin-Like Growth Factor 1 Receptor and Src Family Kinase YES in Rhabdomyosarcoma. Clin Cancer Res. 2023 Sep 1;29(17):3329-3339. doi: 10.1158/1078-0432.CCR-23-0709.

  PMID: 37398992 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal

Interventions

Dasatinib; ganitumab; Receptor Protein-Tyrosine Kinases

Condition Hierarchy (Ancestors)

Myosarcoma; Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Protein-Tyrosine Kinases; Protein Kinases; Phosphotransferases (Alcohol Group Acceptor); Phosphotransferases; Transferases; Enzymes; Enzymes and Coenzymes; Intracellular Signaling Peptides and Proteins; Proteins; Amino Acids, Peptides, and Proteins; Receptors, Cell Surface; Membrane Proteins

Results Point of Contact

• Title: Dr. Christine Heske
• Organization: National Cancer Institute

christine.heske@nih.gov

240-760-6197

Study Officials

• Christine M Heske, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 2, 2017
• First Posted: February 3, 2017
• Study Start: July 7, 2017
• Primary Completion: September 15, 2021
• Study Completion: October 16, 2021
• Last Updated: April 14, 2022
• Results First Posted: April 14, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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).

Locations

US (2)