Phase I Study of GNKG168 in Acute Lymphoblastic Leukemia and Acute Myelogenous Leukemia

A Phase I Study of GNKG168 in Pediatric Patients With Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia (IND#113600)

This is a phase I trial of an investigational drug called GNKG168 in patients with relapsed and refractory acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) who are in morphologic remission but are positive for Minimum Residual Disease (MRD). GNKG168 is a Toll-like receptor (TLR) agonist. TLR agonists are a novel approach to stimulate an effective anti-tumor immune response as they are able to stimulate both innate and adaptive immune responses. There will be two strata i.e patients who have received hematopoietic stem cell transplant (HSCT) and patients who have never undergone HSCT. GNKG168 will be administered as a 60 min iv infusion. One 14-day cycle consists of 5-day treatment followed by 9 day-rest. Patients will receive 2 cycles before evaluation. The primary objective is to determine the maximum tolerated dose of GNKG168 in relapsed ALL and AML patients.

Study Overview

• Status: Terminated
• Conditions: Relapsed Acute Lymphoblastic Leukemia; Relapsed Acute Myelogenous Leukemia
• Intervention / Treatment: Drug: GNKG168

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States
      • Phoenix Children's Hospital
  • California
    • Long Beach, California, United States
      • Miller Children's Hospital
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
    • Oakland, California, United States
      • Oakland Children's Hospital
    • Palo Alto, California, United States, 94304-1812
      • Stanford University Medical Center
    • San Francisco, California, United States, 94143-0106
      • UCSF School of Medicine
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital, University of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States
      • Children's National Medical Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Cancer Center
  • Georgia
    • Atlanta, Georgia, United States
      • Children's Healthcare of Atlanta, Emory University
  • Illinois
    • Chicago, Illinois, United States
      • Children's Memorial
  • Maryland
    • Baltimore, Maryland, United States
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States
      • Dana Farber
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0914
      • C.S. Mott Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404-4597
      • Childrens Hospital & Clinics of Minnesota
    • Minneapolis, Minnesota, United States
      • University of Minnesota Children's Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
  • New York
    • New York, New York, United States, 10016
      • New York University Medical Center
    • New York, New York, United States
      • Memorial Sloan Kettering
    • New York, New York, United States, 10032
      • Children's Hospital New York-Presbyterian
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Levine Children's Hospital at Carolinas Medical Center
  • Ohio
    • Columbus, Ohio, United States
      • Nationwide Childrens Hospital
  • Oregon
    • Portland, Oregon, United States
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Memphis, Tennessee, United States, 38105-3678
      • St. Jude
    • Nashville, Tennessee, United States
      • Vanderbilt Children's Hospital
  • Texas
    • Dallas, Texas, United States
      • University of Texas at Southwestern
    • Forth Worth, Texas, United States, 76104
      • Cook Children's Medical Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must be ≥1 and ≤ 21 years of age when originally diagnosed with ALL or AML.

• Diagnosis

  1. Patients must have previously histologically confirmed ALL or AML at original diagnosis or previous relapse.
  2. Patients must be in complete remission (CR) with less than 5% blasts in the bone marrow.
• Post-HSCT patients should be in first or greater CR
• Patients who have never received HSCT should be in second or greater CR c. Patient must have detectable MRD (≥0.01%) by flow cytometry as confirmed by Brent Woods' lab. Results must be available at the time of enrollment.
• Karnofsky ≥ 50% for patients >16 years of age and Lansky ≥ 50% for patients ≤16 years of age. (See Appendix I for Performance Scales)
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy.
• At least 14 days must have elapsed since any treatment with systemic chemotherapy including high-dose steroid (prednisone>0.5 mg/kg or equivalent), radiotherapy, biological therapy or any other investigational therapy. (Note: low-dose steroid; prednisone ≤0.5 mg/kg/day or equivalent is allowed.)
• Patients who have never had a Hematopoietic Stem Cell Transplant (HSCT) must not be a suitable candidate for HSCT.

• Previous Hematopoietic Stem Cell Transplant:

  1. Patients having received HSCT are eligible.
  2. Patients having received donor lymphocyte infusions (DLI) are eligible.
  3. At least 60 days must have elapsed from the last DLI.
  4. Must have ≥95% donor T-cell chimerism.
  5. Patients must have been off all immune suppression drugs for 7 days before study entry. (at least 2 weeks for high-dose steroid, i.e. prednisone>0.5 mg/kg or equivalent; see section 3.3.4 b) (Note; low-dose steroid; prednisone ≤0.5 mg/kg/day or equivalent is allowed.)
• Patients must have a serum creatinine that is less than or equal to 1.5 x the institutional upper limit of normal according to age.
• Patient's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be less than or equal to 3 x institutional upper limit of normal.
• Patient's total bilirubin must be less than or equal to 1.5 x institutional upper limit of normal.
• Patient must have a shortening fraction > 27% or an ejection fraction > 45% by echocardiogram (ECHO) or multigated radionuclide angiography (MUGA) .
• Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while on this study.
• Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.
• Patients must have an absolute neutrophil count > 1000/dL, platelets > 100,000/dL AND absolute lymphocyte count > 200 which is not decreasing. Patients with previous HSCT may have a platelet count > 50,000/dL.

Exclusion Criteria:

• Active grade 2 or higher acute GVHD at the time of study entry.
• Active chronic GVHD (moderate or severe). See Appendix 2 for Chronic GVHD Grading.
• Plan for donor lymphocyte infusions during the study period.
• Need for immunosuppressive medications including high-dose corticosteroids (prednisone >0.5 mg/kg or equivalent) (Note: low-dose steroid; prednisone ≤0.5 mg/kg/day or equivalent is allowed.)
• Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• Patient will be excluded if they are currently receiving other investigational drugs.
• Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.
• Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the prescribed protocol therapy, interfere with consent, study participation, follow up, or interpretation of study results.
• Patients with central nervous system 3 disease are excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level 1; GNKG168 0.25 mg/kg/day on days 1 through 5	Drug: GNKG168; GNKG168 will be given intravenously over 1 hour on days 1 through 5 followed by 9 days of rest. Dose will be assigned at study entry.
Experimental: Dose Level 2; GNKG168 0.75 mg/kg/day on days 1 through 5	Drug: GNKG168; GNKG168 will be given intravenously over 1 hour on days 1 through 5 followed by 9 days of rest. Dose will be assigned at study entry.
Experimental: Dose Level 3; GNKG168 1.5 mg/kg/day on days 1 through 5	Drug: GNKG168; GNKG168 will be given intravenously over 1 hour on days 1 through 5 followed by 9 days of rest. Dose will be assigned at study entry.
Experimental: Dose Level 0; If dose level #1 is too toxic the study will back down to dose level 0. GNKG168 0.15 mg/kg/day on days 1 through 5.	Drug: GNKG168; GNKG168 will be given intravenously over 1 hour on days 1 through 5 followed by 9 days of rest. Dose will be assigned at study entry.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of patients with dose limiting toxicity (DLT).	2 months

Secondary Outcome Measures

Outcome Measure	Time Frame
To measure the reduction of MRD in patients treated with GNKG168.	30 days
To measure the length or remission in patients who receive GNKG168.	30 days
To measure the rate of Graft Versus Host Disease (GVHD) in patient with previous HSCT.	30 days
To measure the rate graft failure in patients who previously had a HSCT and who received GNKG168.	30 days

Collaborators and Investigators

• Sponsor: Therapeutic Advances in Childhood Leukemia Consortium
• Investigators: Study Chair: Nobuko Hijiya, MD, Ann and Robert H. Lurie Children's Hospital of Chicago; Study Chair: Kirk Schultz, MD, British Columbia Children's Hospital

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: November 28, 2012
• First Submitted That Met QC Criteria: December 4, 2012
• First Posted (Estimate): December 6, 2012

Study Record Updates

• Last Update Posted (Estimate): November 24, 2015
• Last Update Submitted That Met QC Criteria: November 22, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Pediatric; Relapsed; AML; ALL; Acute Lymphoblastic Leukemia; Childhood; Acute Myelogenous Leukemia; Minimal Residual Disease; MRD; GNKG168
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
• Other Study ID Numbers: T2009-008