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

Sponsor

Therapeutic Advances in Childhood Leukemia Consortium (Other)

Overall Status

Terminated

CT.gov ID

NCT01743807

Collaborator

(none)

Enrollment

Locations

Arms

19.9

Duration (Months)

0.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Relapsed Acute Lymphoblastic Leukemia Relapsed Acute Myelogenous Leukemia	Drug: GNKG168	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

4 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Nov 1, 2012

Actual Primary Completion Date :

Jul 1, 2014

Actual Study Completion Date :

Jul 1, 2014

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

Number of patients with dose limiting toxicity (DLT). [2 months]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Patients must have previously histologically confirmed ALL or AML at original diagnosis or previous relapse.
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:

Patients having received HSCT are eligible.
Patients having received donor lymphocyte infusions (DLI) are eligible.
At least 60 days must have elapsed from the last DLI.
Must have ≥95% donor T-cell chimerism.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital	Phoenix	Arizona	United States
2	Miller Children's Hospital	Long Beach	California	United States
3	Childrens Hospital Los Angeles	Los Angeles	California	United States	90027
4	Oakland Children's Hospital	Oakland	California	United States
5	Stanford University Medical Center	Palo Alto	California	United States	94304-1812
6	UCSF School of Medicine	San Francisco	California	United States	94143-0106
7	The Children's Hospital, University of Colorado	Aurora	Colorado	United States	80045
8	Children's National Medical Center	Washington	District of Columbia	United States
9	University of Miami Cancer Center	Miami	Florida	United States	33136
10	Children's Healthcare of Atlanta, Emory University	Atlanta	Georgia	United States
11	Children's Memorial	Chicago	Illinois	United States
12	Johns Hopkins University	Baltimore	Maryland	United States
13	Dana Farber	Boston	Massachusetts	United States
14	C.S. Mott Children's Hospital	Ann Arbor	Michigan	United States	48109-0914
15	Childrens Hospital & Clinics of Minnesota	Minneapolis	Minnesota	United States	55404-4597
16	University of Minnesota Children's Hospital	Minneapolis	Minnesota	United States
17	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
18	New York University Medical Center	New York	New York	United States	10016
19	Children's Hospital New York-Presbyterian	New York	New York	United States	10032
20	Memorial Sloan Kettering	New York	New York	United States
21	Levine Children's Hospital at Carolinas Medical Center	Charlotte	North Carolina	United States	28203
22	Nationwide Childrens Hospital	Columbus	Ohio	United States
23	Oregon Health and Science University	Portland	Oregon	United States
24	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
25	St. Jude	Memphis	Tennessee	United States	38105-3678
26	Vanderbilt Children's Hospital	Nashville	Tennessee	United States
27	University of Texas at Southwestern	Dallas	Texas	United States
28	Cook Children's Medical Center	Forth Worth	Texas	United States	76104
29	Seattle Children's Hospital	Seattle	Washington	United States	98105

Sponsors and Collaborators

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