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

Study Overview
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Brief Summary
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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.

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

Conditions
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Relapsed Acute Lymphoblastic Leukemia, Relapsed Acute Myelogenous Leukemia

Intervention / Treatment
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* Drug: GNKG168


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1<br>GNKG168 0.25 mg/kg/day on days 1 through 5 | Drug: GNKG168<br>* 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.<br>|
| Experimental: Dose Level 2<br>GNKG168 0.75 mg/kg/day on days 1 through 5 | Drug: GNKG168<br>* 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.<br>|
| Experimental: Dose Level 3<br>GNKG168 1.5 mg/kg/day on days 1 through 5 | Drug: GNKG168<br>* 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.<br>|
| Experimental: Dose Level 0<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed, Minimal Residual Disease, MRD, Acute Lymphoblastic Leukemia, Acute Myelogenous Leukemia, ALL, AML, GNKG168, Pediatric, Childhood