Imetelstat Sodium in Treating Young Patients With Refractory or Recurrent Solid Tumors or Lymphoma

A Phase 1 Study of Imetelstat, a Telomerase Inhibitor, in Children With Refractory or Recurrent Solid Tumors and Lymphomas

RATIONALE: Imetelstat sodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I clinical trial is studying the side effects and best dose of imetelstat sodium in treating young patients with refractory or recurrent solid tumors or lymphoma.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific; Small Intestine Cancer; Brain and Central Nervous System Tumors; Lymphoproliferative Disorder
• Intervention / Treatment: Other: pharmacological study; Other: laboratory biomarker analysis; Drug: imetelstat sodium

Detailed Description

OBJECTIVES:

Primary

• To estimate the maximum-tolerated dose (MTD) and/or recommended phase II dose of imetelstat sodium in children with refractory or recurrent solid tumors or lymphoma.
• To define and describe the toxicities of imetelstat sodium.
• To characterize the pharmacokinetics of imetelstat sodium in children with refractory or recurrent solid tumors or lymphoma.

Secondary

• To determine, in a preliminary manner, the antitumor effects of imetelstat sodium in children with refractory or recurrent solid tumors or lymphoma. (exploratory)
• To provide preliminary assessment of the biological activity of imetelstat sodium in children with recurrent or refractory malignancies by assessing telomerase activity, telomere length, hTERT protein, hTERT mRNA, and hTR levels in patient peripheral blood mononuclear cells (PBMNC) samples pretreatment and on treatment. (Exploratory)
• To assess telomerase activity, hTERT expression, telomere length, hTERT protein, hTERT mRNA, and hTR levels in patients' pretreatment tumor samples. (Exploratory)

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive imetelstat sodium IV over 2 hours on days 1 and 8. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection at baseline and periodically during study for pharmacokinetic and correlative studies. Tumor tissue samples from diagnosis and/or subsequent tumor resections or biopsies may also be collected for correlative studies.

After completion of study therapy, patients are followed up for 30 days.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital For Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Sainte Justine
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Uab Comprehensive Cancer Center
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Children's Memorial Hospital - Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley's Children Cancer Center at Riley Hospital for Children
  • Maryland
    • Bethesda, Maryland, United States, 20892-1182
      • Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
  • Massachusetts
    • Boston, Massachusetts, United States, 2115
      • Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0286
      • C.S. Mott Children's Hospital at University of Michigan Medical Center
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Knight Cancer Institute At Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
    • Houston, Texas, United States, 77030-2399
      • Baylor University Medical Center - Houston
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center at Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 19 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of refractory or recurrent solid tumors, including lymphoma

  • No CNS tumors or known CNS metastases (Part A, dose escalation)

  • CNS tumors or known CNS metastases allowed (Part B, maximum-tolerated dose or recommended phase II dose)

    • No prior or concurrent CNS hemorrhage on a baseline MRI within the past 14 days

  • All patients must have histologic verification of malignancy at original diagnosis or relapse except for:

    • Intrinsic brain stem tumors
    • Optic pathway gliomas
    • Pineal tumors and elevations of CSF or serum tumor markers including alpha-fetoprotein or beta-HCG
• Measurable or evaluable disease
• Disease for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood count criteria and they are not known to be refractory to red cell or platelet transfusions

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 50-100% (patients > 16 years of age) OR Lansky PS 50-100% (patients ≤ 16 years of age)
• ANC ≥ 1,000/mm³
• Platelet count ≥ 100,000/mm³ (transfusion-independent, defined as not receiving platelet transfusion within the past 7 days prior to enrollment)

• Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR a serum creatinine based on age and/or gender as follows:

  • 0.6 mg/dL (1 to < 2 years of age)
  • 0.8 mg/dL (2 to < 6 years of age)
  • 1.0 mg/dL (6 to < 10 years of age)
  • 1.2 mg/dL (10 to < 13 years of age)
  • 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
  • 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)
• Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 times upper limit of normal (ULN)
• ALT ≤ 110 U/L (ULN for ALT is 45 U/L)
• Serum albumin ≥ 2 g/dL
• aPTT < 1.2 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use an effective contraception method
• No uncontrolled infection
• No patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

PRIOR CONCURRENT THERAPY:

• Recovered from acute toxic effects of all prior anti-cancer chemotherapy, immunotherapy, or radiotherapy
• At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea)
• At least 14 days since prior long-acting growth factor (e.g., Neulasta) or ≥ 7 days since prior short-acting growth factor
• At least 7 days since prior biologic or anti-neoplastic agent
• At least 6 weeks since any type of prior immunotherapy (e.g., tumor vaccines)
• At least 3 half-lives since last dose of a monoclonal antibody

• At least 2 weeks since prior local palliative radiotherapy (small port)

  • At least 24 weeks since prior total-body irradiation, craniospinal radiotherapy, or radiation to ≥ 50% of the pelvis
  • At least 6 weeks since prior substantial bone marrow radiation
• At least 12 weeks since prior transplantation or stem cell infusion with no evidence of active graft vs host disease
• Prior and concurrent stable or decreasing dose of corticosteroids within the past 7 days allowed
• No prior allogeneic transplant
• No other concurrent investigational drug
• No other concurrent anticancer agents including chemotherapy, radiotherapy, immunotherapy, or biologic therapy
• No concurrent cyclosporine, tacrolimus, or other agents to prevent either graft-versus-host disease post-bone marrow transplant or organ rejection post-transplant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment	Other: pharmacological study; Other: laboratory biomarker analysis; Drug: imetelstat sodium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum-tolerated dose and/or recommended phase II dose of imetelstat sodium in children with refractory or recurrent solid tumors or lymphoma	21 Days
Toxicities of imetelstat sodium	Up to 30 days post-treatment

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Patrick A. Thompson, MD, Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: January 7, 2011
• First Submitted That Met QC Criteria: January 7, 2011
• First Posted (Estimate): January 10, 2011

Study Record Updates

• Last Update Posted (Estimate): January 30, 2014
• Last Update Submitted That Met QC Criteria: January 29, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: unspecified childhood solid tumor, protocol specific; childhood Burkitt lymphoma; recurrent childhood small noncleaved cell lymphoma; recurrent childhood large cell lymphoma; childhood immunoblastic large cell lymphoma; recurrent/refractory childhood Hodgkin lymphoma; recurrent cutaneous T-cell non-Hodgkin lymphoma; small intestine lymphoma; intraocular lymphoma; angioimmunoblastic T-cell lymphoma; recurrent mycosis fungoides/Sezary syndrome; post-transplant lymphoproliferative disorder; cutaneous B-cell non-Hodgkin lymphoma; recurrent childhood lymphoblastic lymphoma; childhood diffuse large cell lymphoma; childhood grade III lymphomatoid granulomatosis; recurrent childhood grade III lymphomatoid granulomatosis; noncutaneous extranodal lymphoma; recurrent childhood anaplastic large cell lymphoma; recurrent childhood cerebellar astrocytoma; recurrent childhood cerebral astrocytoma; recurrent childhood brain stem glioma; recurrent childhood visual pathway and hypothalamic glioma; childhood central nervous system germ cell tumor; peripheral T-cell lymphoma; childhood nasal type extranodal NK/T-cell lymphoma; recurrent childhood visual pathway glioma; childhood central nervous system choriocarcinoma; childhood central nervous system germinoma; childhood central nervous system mixed germ cell tumor; childhood central nervous system teratoma; childhood central nervous system yolk sac tumor; recurrent childhood central nervous system embryonal tumor; recurrent childhood pineoblastoma; childhood pineal parenchymal tumor; recurrent childhood subependymal giant cell astrocytoma; hepatosplenic T-cell lymphoma; recurrent childhood anaplastic astrocytoma; recurrent childhood anaplastic oligoastrocytoma; recurrent childhood anaplastic oligodendroglioma; recurrent childhood diffuse astrocytoma; recurrent childhood fibrillary astrocytoma; recurrent childhood gemistocytic astrocytoma; recurrent childhood giant cell glioblastoma; recurrent childhood glioblastoma; recurrent childhood gliomatosis cerebri; recurrent childhood gliosarcoma; recurrent childhood oligoastrocytoma; recurrent childhood oligodendroglioma; recurrent childhood pilocytic astrocytoma; recurrent childhood pilomyxoid astrocytoma; recurrent childhood pleomorphic xanthoastrocytoma; recurrent childhood protoplasmic astrocytoma; childhood nodular lymphocyte predominant Hodgkin lymphoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Nervous System Diseases; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Neoplasms; Lymphoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Lymphoproliferative Disorders; Intestinal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Imetelstat; Motesanib diphosphate
• Other Study ID Numbers: ADVL1112; COG-ADVL1112