Ganitumab and Dasatinib in Treating Patients with Relapsed or Refractory Embryonal or Alveolar Rhabdomyosarcoma

Status: Active

Description

This phase I / II trial studies the side effects and best dose of dasatinib when given together with ganitumab and to see how well they work in treating patients with embryonal and alveolar rhabdomyosarcoma that has come back or does not respond to treatment. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with ganitumab, may induce changes in body’s immune system and may interfere with the ability of tumor cells to grow and spread. Giving dasatinib and ganitumab may work better in treating patients with embryonal and alveolar rhabdomyosarcoma.

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, National Cancer Institute (NCI) or by the Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles (CHLA)
  • Patients must have measurable disease as per RECIST (version 1.1)
  • 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 * 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), 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 one month 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] version [v.]5.0) level prior to enrollment (does not apply to alopecia)
  • Patients must have the ability to swallow tablets
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky > 50% (if >= 16 years of age); or children < 16 years old must have a Lansky performance of >= 50%
  • Absolute neutrophil count >= 1,000/mcL
  • Platelets >= 75,000/mcL
  • Total bilirubin =< 1.5 X upper limit of normal (ULN), with exception of patients with Gilbert syndrome
  • Alanine aminotransferase (ALT) =< 3.0 X ULN
  • Creatinine within normal institutional limits OR
  • Creatinine clearance >= 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 international normalized ratio (INR) =< 1.4 and partial thromboplastin time (PTT) =< 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: Fridericia's correction formula (QTcF) < 480 milliseconds (Fridericia correction), and ejection fraction (EF) >= 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 IV alimentation, prior 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 corrected QT (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

Locations & Contacts

Maryland

Bethesda
National Institutes of Health Clinical Center
Status: Active
Contact: Site Public Contact
Phone: 800-411-1222

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the safe dose of dasatinib when given with ganitumab in patients with relapsed or refractory embryonal or alveolar rhabdomyosarcoma (RMS). (Phase I)

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 (complete response [CR] and partial response [PR]) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. In addition, a second primary objective will estimate the fraction that is without progression at 4 months. (Phase II)

SECONDARY OBJECTIVES:

I. To assess the progression free survival (PFS) in patients receiving this combination.

II. To determine the fraction of patients with stable disease >= 6 months as defined by RECIST criteria in patients receiving this combination.

III. To describe the toxicity and confirm the tolerability of the combination of ganitumab and dasatinib in patients with relapsed or refractory RMS.

EXPLORATORY OBJECTIVES:

I. To determine the genomic and proteomic profile of subjects’ tumors to identify gene mutations, gene amplifications, ribonucleic acid (RNA)-expression levels, and protein-expression levels. Correlations between genomic/proteomic profiles and efficacy outcomes will be assessed.

II. To retrospectively analyze archival tissue for quantitation of insulin-like growth factor 1 receptor (IGF-1R) and to correlate tumor responses with the presence of target.

III. To examine IGF-1R expression, phospho-YES, insulin receptor expression and IGF-2 expression in tumor tissue obtained from biopsy samples.

IV. To conduct genomic analysis of archival and relapse biopsy samples and compare them to germline samples. For these studies, patients will be co-enrolled on the pediatric omics study (10-C-0086).

OUTLINE: This is a phase I, dose-escalation study of dasatinib followed by a phase II study.

Patients receive dasatinib orally (PO) once daily (QD) or twice daily (BID) on days -7 to 27 of cycle 1 and days 0-27 of cycle 2 and all subsequent cycles. Patients also receive ganitumab intravenously (IV) over 60-120 minutes once every 2 weeks. Cycles repeat every 35 days for cycle 1 and every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days or until disease progression.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
NCI - Center for Cancer Research

Principal Investigator
Christine M. Heske

Trial IDs

Primary ID 10003
Secondary IDs 17-C-0049, NCI-2016-00927, 17-C-0049 A, 17-C-0049 D
Clinicaltrials.gov ID NCT03041701