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).

Study Overview

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

Detailed Description

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. The completion of this study and the correlative studies will provide a solid foundation for subsequent phase 2 study and the development of clinical applications of CpG-ODN-based immune therapy as a treatment of childhood leukemia. If safety and efficacy of GNKG168 is proven, it will be intriguing to explore its role to maintain CR in a randomized manner.

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

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

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

2. Diagnosis

   1. Patients must have previously histologically confirmed ALL or AML at original diagnosis or previous relapse. Patients with treatment-related AML are eligible.

   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
   3. Patient must have detectable MRD (≥0.01%) by flow cytometry.
3. Performance Level Karnofsky ≥ 50% for patients >16 years of age and Lansky ≥ 50% for patients ≤16 years of age.

4. Prior Therapy

   1. Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy.
   2. 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.)
   3. At least 28 days must have elapsed since any cellular therapies such as chimeric antigen receptor-modified T cells.
   4. Patients who have never had HSCT must not be a suitable candidate for HSCT. For this protocol, a suitable candidate is defined as one who has an identified donor with plans to undergo transplant within the next 28 days.

   5. Previous HSCT:

      • Patients having received HSCT are eligible and 60 days must have elapsed since stem cell infusion.
      • Patients having received donor lymphocyte infusions (DLI) are eligible.
      • At least 28 days must have elapsed from the last DLI.
      • Must have ≥90% donor chimerism. The test for donor chimerism must have been done within the last 60 days. If patient has subsequently relapsed after HSCT but prior to enrollment on this study, the donor chimerism test is not needed.
      • 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 4b above) (Note; low-dose steroid; prednisone ≤0.5 mg/kg/day or equivalent is allowed.)

5. Renal and Hepatic Function

   1. 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. (Grade 1 per the CTCAE 4.0)
   2. Patient's ALT and AST must be less than or equal to 3 x institutional upper limit of normal. (Grade 1 per the CTCAE 4.0)
   3. Patient's total bilirubin must be less than or equal to 1.5 x institutional upper limit of normal. (Grade 1 per the CTCAE 4.0)
6. Cardiac Function Patient must have a shortening fraction > 27% by ECHO or an ejection fraction > 45% by MUGA.

7. Reproductive Function

   1. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
   2. Female patients with infants must agree not to breastfeed their infants while on this study.
   3. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.
8. Hematological Function Patients must have an absolute neutrophil count > 750/dL, platelets > 75,000/dL AND absolute lymphocyte count > 200/uL which is not decreasing. Patients with previous HSCT may have a platelet count > 50,000/dL.

Exclusion Criteria

Patients will be excluded if they meet any of the following criteria.

1. Graft versus host disease (GVHD) that meets the following criteria:

   1. Active grade 2 or higher acute GVHD at the time of study entry.
   2. Active chronic GVHD (moderate or severe).
2. Plan for donor lymphocyte infusions during the study period.
3. 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.)
4. 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).
5. Patient will be excluded if they are currently receiving other investigational drugs.
6. Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.
7. 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.
8. Patients with CNS 3 disease are excluded. No CNS therapy will be allowed during the first 2 courses of therapy.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Post-HSCT; Patients who have a history of hematopoetic stem cell transplantation (HSCT). GNKG168 will be administered as a 60 minute intravenous infusion daily for 5 consecutive days. It may be repeated every 14 days. Patients should receive minimum 2 courses and up to 6 courses may be administered. Dose will be assigned at study entry.	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. Dose Level 0: 0.15 mg/kg Dose Level 1: 0.25 mg/kg Dose Level 2: 0.75 mg/kg Dose Level 3: 1.5 mg/kg The starting dose level for the trial will be 0.25 mg/kg. If that dose level proves to be intolerable, the dose will be reduced to 0.15 mg/kg (dose level 0). If the 0.15 mg/kg dose level is intolerable due to DLTs, TACL, the Principal Investigator, and Medical Monitor will then decide the best course of action for subsequent administration of GNKG168.; Other Names: CpG685
Experimental: No HSCT; Patients who have never undergone HSCT. GNKG168 will be administered as a 60 minute intravenous infusion daily for 5 consecutive days. It may be repeated every 14 days. Patients should receive minimum 2 courses and up to 6 courses may be administered. Dose will be assigned at study entry.	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. Dose Level 0: 0.15 mg/kg Dose Level 1: 0.25 mg/kg Dose Level 2: 0.75 mg/kg Dose Level 3: 1.5 mg/kg The starting dose level for the trial will be 0.25 mg/kg. If that dose level proves to be intolerable, the dose will be reduced to 0.15 mg/kg (dose level 0). If the 0.15 mg/kg dose level is intolerable due to DLTs, TACL, the Principal Investigator, and Medical Monitor will then decide the best course of action for subsequent administration of GNKG168.; Other Names: CpG685

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Dose Limiting Toxicity (DLT) in the First Two Courses of Therapy	DLT is defined as: A) Any non-hematologic toxicity that is ≥ CTCAE grade 3 and at least possibly related to GNKG168 (the relationship to GNKG168 cannot be ruled out), with the EXCEPTION of the following toxicities when observed at Grade 3: Fatigue; Fever; Anorexia; Rash that turns to grade ≤ 2 within 7 days; Elevation in hepatic transaminases (ALT/SGOT and AST/SGPT), GGT or alkaline phosphatase that returns to ≤ grade 2 within 14 days. It will not be considered a DLT if the patient exits the study and begins alternative therapy before the end of the 14 day evaluation period. B) Grade 3 or 4 hematologic toxicity that is at least possibly related to GNKG168 that does not reverse to baseline within 7 days. C) For patients who have undergone HSCT, DLT will include the onset of Grade 3 or 4 acute GVHD, the onset of moderate to severe chronic GVHD, the onset of bronchiolitis obliterans and graft failure.	Beginning with the first dose of GNKG168 until the end of course 2; courses are 14 days so there will be approximately 28 days of monitoring for DLT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Participants With a Decrease in Minimal Residual Disease (MRD) Present in Patients Treated With GNKG168	Doctors have developed a test to detect very small amounts of leukemia that still exist even though it looks like remission under a microscope. This test is called Minimal Residual Disease (MRD). MRD is very specific and can detect 1 cancer cell out of 10,000 regular cells. The results of the MRD test on bone marrow can show when a patient has a very small amount of cancer cells left in the bone marrow. We will use this test to evaluate the effect of GNKG168 in killing the small amount of cells left in your bone marrow.	Pre-study and End of Course 1 (Day 14)
Occurrence of Graft Versus Host Disease (GVHD) in Patients Who Had Previous HSCT and Received GNKG168	We will evaluate the impact of GNKG168 on induction of clinical GVHD using the consensus scoring system developed by NIH (Filipovich et. al., National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report, Biology of Blood and Marrow Transplantation, Volume 11, Issue 12, Dec. 2005, pp. 945-956)	Weekly during Courses 1 and 2 (i.e, 4 times in 28 days), Day 1 of Courses 3-6 (approximately Days 29, 43 and 57), and when patient is removed from protocol therapy.
Occurrence of Graft Failure in Patients Who Previously Had a HSCT and Received GNKG168	Peripheral blood samples will be evaluated for the presence of cGVHD biomarkers. Change in level of MRD, and MRD response following GNKG168	Day 14
Change in the Percent of ALL or AML Blasts Exhibiting Markers of Immunogenicity and Apoptosis	Change in the percent of ALL or AML blasts exhibiting markers of immunogenicity and apoptosis will be analyzed from bone marrow specimens.	End of Course 1 (Day 14), end of Course 2 (approx. Day 28), end of courses 4 and 6 (approx. Days 56 and 70), and date removed from therapy if previous marrow sample > 2 weeks ago
Duration of of Remission in Patients Who Receive GNKG168	MRD negative Complete Remission : Negative MRD (<0.01%), no evidence of circulating leukemic blasts or extramedullary disease, and recovery of peripheral counts (ANC ≥ 500/µL and PLT count ≥ 50,000 µL).; MRD negative Complete Remission without platelet recovery: Insufficient recovery of platelets (< 50,000/ µL) but otherwise meets the criteria of MRD-CR.; Stable Disease: Patient does not satisfy the criterion for PD, or has recovery of ANC ≥ 500/µL and fails to qualify for MRD-CR or MRD-CRp.; Progressive Disease: At least 5% of circulating leukemic cells or ≥5% in a marrow with count recovery, development of new sites of extramedullary disease, or other laboratory or clinical evidence of PD, with or without recovery of ANC or platelets.; Not evaluable: Patient does not satisfy the criterion for PD, and did not have a marrow evaluation, had inadequate marrow cell count, or had insufficient recovery of ANC for MRD-CR, MRD-CRp or SD classification.	Until patient is no longer being followed (off study)

Collaborators and Investigators

• Sponsor: Therapeutic Advances in Childhood Leukemia Consortium
• Collaborators: SBI Biotech Co., Ltd.
• 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

Publications and helpful links

Helpful Links

• Therapeutic Advances in Childhood Leukemia & Lymphoma Consortium web site

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2014
• Primary Completion (Actual): July 28, 2014
• Study Completion (Actual): July 28, 2014

Study Registration Dates

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

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 18, 2024
• Last Verified: December 1, 2024

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: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Lymphoid; Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Other Study ID Numbers: T2009-008

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No