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

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. 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.

Eligibility Criteria:
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.