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This is a single arm study. Patients with high risk neuroblastoma who have residual measurable disease will receive a combination of 5 days of anti-GD2 with expanded activated NK cells.

Haploidentical donor NK cells will be expanded over 10 days and infused in combination with anti-GD2. Anti-GD2 will be given as daily infusion for 5 days ; D-1, 0,+1, +2 and +3. NK cells will be infused at single dose on day 0. The patient will receive cyclophosphamide 60mg/kg on day -3 and day -2 prior to the NK cell infusion. IL- 2 will be given subcutaneously for 6 doses every alternate day starting on day -1, for NK cell survival.

Anti-GD2 in combination with NK cells

Miriam Kimpo, MD

Chetan Dhamne, MBBS, MS, MD

Dr. Miriam Kimpo, MD

Dr.Chetan Dhamne, MBBS, MS. MD

Dario Campana, MD, PhD

Neuroblastoma is a neoplasm of the sympathetic nervous system which affects mostly children younger than 5 years of age. It is a heterogeneous disease, with nearly 50% of patients presenting with a high-risk phenotype. After standard treatment, the 2-year event-free survival (EFS) for high risk neuroblastoma (EFS) is only about 50%. Immunotherapy with anti-GD2 antibodies has been shown to improve EFS in Children's Oncology Group and SIOPEN trials.

The anti-GD2 antibody mediates neuroblastoma cell killing primarily through antibody-dependent cell-mediated cytotoxicity (ADCC). Natural killer (NK) cells are the main effectors of ADCC. We postulate that infusion of expanded activated NK cells from healthy haploidentical donors along with anti-GD2 antibody will enhance neuroblastoma killing.

Adoptive transfer of haploidentical NK cells has been shown to be safe in clinical trials at NUH. There is experience combining antibody infusion with autologous NK cells in the clinical trial with good safety data.

The proposed trial is a phase I/II study to determine the safety and efficacy of expanded activated haploidentical NK cells in combination with anti-GD2 (ch14.18/CHO). We plan to enrol patients with high risk or relapsed neuroblastoma with evidence of residual disease who are at high risk of recurrence or progression on current treatment.

In the proposed protocol , we plan to infuse NK cells at escalating dose levels to find the optimum dose tolerated by the patients in combination with anti-GD2 (ch14.18/CHO) . There are 3 NK cell dose levels :

Dose level 1 (1 x 10\^6/kg) , Dose level 2 (1 x 10\^7/kg) , Dose level 3 (1 x 10\^8/kg)

If a partial response or stable disease is observed, further infusions of NK cells can be administered. There will be intra- and inter - patient dose escalation.

The donor will be either parent, based on the best NK cell donor as determined by the study team. The donor will be harvested and NK cells expanded prior to infusion into the patient along with anti-GD2 (ch14.18/CHO).

The study aims to study safety and efficacy of a combination of NK cells and anti-GD2 (ch14.18/CHO).

To determine the feasibility, safety and effectiveness of anti-GD2 in combination with expanded, activated NK cells in research participants with Neuroblastoma

Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK Cells

Pilot Study of Anti-GD2 and Expanded, Activated Natural Killer Cell Infusion for Neuroblastoma

Disease status at primary and metastatic soft tissue sites will be assessed using MIBG scans or PET scan as applicable. RECIST and Curie scoring systems will be used to assess response. Metastatic bone disease will be assessed using MIBG or PET scan. Bone marrow will be assessed by histology or flow cytometry. Disease response will be defined as Complete response/remission (CR), Partial response (PR), Minor response, Stable disease (SD), or Progressive disease(PD).

NK cells will be identified by flow cytometry in peripheral blood and their percentages and absolute numbers will be calculated.

Cytokine panel to assess levels of IL15 serially post lymphodepletion regimen

National University Hospital, Singapore

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Two infusions of Natural Killer (NK) cells and ALT803

Two infusions of Natural Killer (NK) Cells

Dose escalation of Natural Killer (NK) Cells from two infusion of starting at Dose Level 1 (1x10\^7 cells/kg), dose Level-1 (1x10\^6 cells/kg) if 2 of 6 patients at Level 1 develop DLTs. Escalation to dose level 2 (2.5X10\^7) and Dose level 3 (5X10\^7) is dependent on DLT

Natural Killer (NK) Cells

ALT803

David Wald, MD, PhD

The purpose of this study is to find the number of natural killer (NK) cells from non-HLA matched donors that can be safely infused into patients with cancer. NK cells are a form of lymphocytes that defend against cancer cells. NK cells in cancer patients do not work well to fight cancer. In this study, the NK cells are being donated by healthy individuals without cancer who are not "matched" by human leukocyte antigen (HLA) genes to patients. After receiving these NK cells, patients may also be given a drug called ALT803. ALT803 is a protein that keeps NK cells alive, helps them grow in number and supports their cancer-fighting characteristics. HLA-unmatched NK cell infusion is investigational (experimental) because the process has not approved by the Food and Drug Administration (FDA).

Primary Objective:

To determine the maximum tolerated dose (MTD) of ex vivo expanded non-HLA matched donor NK cells in combination with ALT-803

Secondary Objectives:

* Describe safety profile / toxicity of combining ALT-803 with NK cell adoptive therapy.
* Determine antitumor activity of allogeneic NK cells with ALT-803 support.
* Determine if a lymphocyte depleting regimen is adequate for preventing early elimination of HLA-mismatched donor NK cells by host T-cells.

Study Design:

This is a phase I study with "3+3" design with three planned dose levels of NK cells and a fixed dose of ALT-803. Three patients will be enrolled sequentially to each dose level, starting with dose level 1. Patients will be segregated to either receive ALT803 as cytokine support after NK cell infusion (starting with same dose level as Level 1) or no cytokine administration. Patients in the arm receiving ALT803 will be either hematologic malignancy patients (Cohort A) or Colon/Soft tissue sarcoma patients (Cohort B). Absence of dose limiting toxicity (DLT) in the DLT assessment period of 28 days must be documented for all patients enrolled a cell dose without ALT803 before the next cohort of patients to receive cytokines at that dose level can be enrolled. Patients can also be enrolled in parallel to the next cell dose level without cytokines.

Phase I Trial of Universal Donor NK Cell Therapy in Combination With ALT803

Phase I Trial of Universal Donor NK Cell Therapy in Combination With ALT-803

MTD Will be determined by dose limiting toxicity (DLT). The MTD will be defined as the dose level immediately below that at which 2 of 6 subjects experience a dose limiting toxicity.

Measure of safety of natural killer (NK) cells in the absence of HLA matching

Complete Remission (CR): Bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count \>1.0x10\^9/L; platelet count \>100x10\^9/L.

CR with incomplete recovery (CRi): All CR criteria except residual neutropenia or thrombocytopenia.

Partial Remission (PR):Hematologic criteria of CR; decrease of bone marrow blast percentage to 5-25%; and decrease of pretreatment bone marrow blast percentage by ≥50%.

Cytogenetic CR (CRc): Reversion to normal karyotype at the time of morphologic CR.

Resistant disease (RD): Failure to achieve CR, CRi, or PR. Death in aplasia: Deaths occurring ≥7 days after initial treatment. Death from indeterminate cause: Deaths before completing therapy, or \<7 days following completion; or deaths occurring ≥7 days after therapy with no blasts in the blood Relapse: Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood; or development of extramedullary disease

* Measurable disease: at least one measurable lesion.
* Measurable lesions: those that can be measured in at least one dimension as \>20 mm with conventional techniques or as \>10 mm with spiral CT scan.
* Non-measurable lesions: all other lesions, including small lesions that are not confirmed and followed by imaging techniques.
* Baseline documentation of "Target" lesions: all measurable lesions up to a maximum of five lesions per organ and 10 lesions in total. Target lesions should be selected on the basis of their size and their suitability for accurate repeated measurements.
* Non-target lesions: all other lesions should be identified as non-target lesions. Non-target lesions include measurable lesions that exceed the maximum numbers per organ or total of all involved organs as well as non-measurable lesions.

Lymphoma response of Complete remission, partial remission, relapsed disease, stable disease, progressive disease and best response based on the Journal of Clinical Oncology criteria defined by Cheson in 2014

* Complete response (CR): complete disappearance of disease at and negative serum immunofixation.
* Partial response (PR): \>50% reduction of serum monoclonal protein concentration with \>50% reduction of tumor infiltrate and resolution of symptoms attributable to WM.
* Minor response (MR): \> 25% but l\<50% reduction of serum monoclonal immunoglobulin M (IgM) determined by protein electrophoresis and no new symptoms or signs of active disease.
* Stable disease: \< 25% reduction and \<25% increase of serum monoclonal IgM without progression of adenopathy, organomegaly, cytopenias, or clinically significant symptoms caused by disease and/or signs of WM.
* Progressive disease: fails to meet criteria for response or stable disease. Progression also requires at least a 25% increase of serum monoclonal protein from the lowest value or worsening of cytopenias, lymphadenopathy, or organomegaly, or appearance of disease-related complications.

CR/CCR

* Complete resolution of skin patches, plaques and tumors (or erythroderma)
* No evidence of abnormal lymph nodes
* Absence of circulating Sézary cells
* No evidence of new tumor (CCR) plus confirmation by skin biopsy (CR) PR
* ≥50% improvement in the summation of (∆ Skin + ∆ Lymph Node + ∆ Peripheral Blood) with at least ≥30% improvement in ∆ Skin
* No worsening in Lymph Node or Sézary cells
* No evidence of new tumors (cutaneous or non-cutaneous)

Stable Disease at 90 Days (SD90)

• Fails to meet criteria for PR or CR but absence of new cutaneous or non-cutaneous disease over 90 days

Progressive Disease (PD)

* ≥ 50% increase from nadir or baseline in styrylpyridine derivative (SPD) or any node or lesion
* ≥ 50% increase from nadir in gestational trophoblastic disease (GTD) of any node previously \>1cm in shortest diameter
* Appearance of any new cutaneous or non-cutaneous lesion during or at the end of therapy.

Stringent Complete Response (sCR)

* CR as defined below plus:

  • Normal FLC ratio and Absence of clonal cells in bone marrow CR
* Negative immunofixation on the serum and urine and:

  * Disappearance of any soft tissue plasmacytomas
  * ≤5% plasma cells in bone marrow Very good partial response (VGPR)
* Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100mg per 24h PR
* ≥ 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥ 90% or to \<200 mg per 24h
* If the serum and urine protein are unmeasurable, ≥ 50% decrease in the difference between involved and uninvolved FLC levels is required
* If the serum and urine protein are unmeasurable, and serum free light assay is also unmeasurable, ≥ 50% decrease in plasmacells is required SD
* Not meeting criteria for CR, VGPR, PR, or progressive disease

Complete hematologic response

• White blood cell count \<10,000/microL with no immature granulocytes and \<5 percent basophils on differential, platelet count \<450,000/microL, and spleen not palpable.

Cytogenetic responses

* Complete cytogenetic response: No Philadelphia chromosome positive cells present.
* Partial cytogenetic response: 1 to 35 percent Philadelphia chromosome positive cells present.
* Major cytogenetic response includes patients with complete and partial cytogenetic response (ie, 0 to 35 percent Philadelphia chromosome positive cells present).
* Minor-minimal cytogenetic response: 36 to 95 percent Philadelphia chromosome positive cells present.

Molecular response:

* Complete molecular response: break cluster region - Abelson family kinases (BCR-ABL) transcript nondetectable and nonquantifiable in an assay that has at least 4 to 5 log range.
* Major molecular response: An at least three log reduction in BCR-ABL transcript levels from baseline.

Complete Response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm (the sum may not be "0" if there are target nodes). Partial Response: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Progressive Disease: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions may be considered progression).

Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.

The duration of overall response is measured from the time of NK Cell infusion until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

Overall survival is measured from the date of first infusion of NK cells to the date of death from any cause; patients not known to have died at last follow up are censored on the date they were last known to be alive.

Only those patients achieving complete response (CR) or complete response with incomplete recovery (CRI). It is measured from the date of infusion of NK cells until the date of relapse or death from any cause; patients not known to have relapsed or died at last follow up are censored on the date they were last examined.

Measurement of in vivo NK cell levels following cell product infusion will be done on peripheral blood by flow cytometry (CD3- CD56+ positive cells). This will be done on peripheral blood samples of patients. Measurement of successful donor NK cell persistence (absence of cell product rejection) will be defined as measurement of \>100 NK cell/µL

Brenda Cooper, MD

Medical Oncology Specialist

Precancerous Conditions

Analgesics

Decitabine

Interleukin-2

Vorinostat

Antimetabolites

Enzyme Inhibitors

Analgesics, Non-Narcotic

Histone Deacetylase Inhibitors

Patients who received treatment for high risk myelodysplastic syndromes (MDS). Treatment Received: Decitabine 10 mg/m\^2/day intravenous (IV) over 1 hour days 1-5; Vorinostat 200 mg by mouth (PO) twice a day days 6-15; Il-2 activated donor natural killer cells (NK) infusion IV over 15 to 60 minutes day 17; Interleukin-2 6 million units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17. Repeat treatment course 6 to 8 weeks after cycle 1 start date.

administered intravenous (IV), 10 mg/m\^2/day over 1 hour on days 1-5.

200 mg by mouth (PO) twice a day on days 6-15

6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17

infusion intravenously (IV) over 15 to 60 minutes day 17

Natural killer (NK) cells

Erica Warlick, M.D.

This is a Phase II therapeutic trial combining Decitabine days 1-5 with oral Vorinostat twice daily days 6-15 followed by a single infusion of CD3-/CD19- enriched donor natural killer (NK) cells on day 17 and a short course of Interleukin-2 (IL-2) to facilitate NK cell survival and expansion. Two courses of treatment will be given separated by 6-8 weeks. The intent is to administer all treatment in the outpatient setting.

A single donor apheresis will be collected on day 15 of cycle 1, enriched for NK cells with the large scale CliniMacs device (Miltenyi) and activated by overnight incubation with IL-2. After washing, the final NK cell product will be divided in two, with half given fresh on day 17 of course #1 and half stored frozen until day 17 of course #2.

Clinical response will be formally assessed 4-6 weeks after the start of 2nd course based on International Working Group (IWG) criteria; however, bone marrow evaluations will be completed to assess for any sign of significant disease progression between cycle 1 and 2.

Decitabine and Vorinostat Conditioning Followed by CD3-/CD19- NK Cells Infusion for High Risk Myelodysplastic Syndromes

Decitabine and Vorinostat With CD3/CD19 Depleted Haploidentical Donor Natural Killer (NK) Cells for the Treatment of High Risk Myelodysplastic Syndromes (MDS)

Clinical response includes: Complete Response (less than 5% myeloblasts present in the bone marrow and in the peripheral blood a hemoglobin of at least 11g/dl, platelets of at least 100 X 10E9/L, neutrophils of at least 1.0 X 10E9/L, and blasts 0%); Partial Response (all Complete Response criteria if previously abnormal except bone marrow myeloblasts are decreased by more than 50% over pre-treatment, but still greater than 5%); and hematologic improvement (a hemoglobin increase of greater than 1.5g/dl or decreased red blood cell transfusions by at least 4 per 8 week period, a platelet increase of more than 30 X 10E9/L for patients with a baseline of more than 20 X 10E9/L or an increase by 100% for those with a baseline of less than 20 X 10E9/L, and a neutrophil increase of at least 100% and an absolute increase of greater than 0.5 X 10E9/L.

Adverse events (AEs) will be graded using Common Terminology Criteria for Adverse Events v4.0 (CTCAE). Non-hematologic adverse events are defined as untoward medical occurrences associated with the use of a study drug whether or not considered study drug related, excluding those events involving white blood cells, neutrophils, red blood cells or platelets. In general, grade 3 AEs are defined as 1) being severe or medically significant but,not immediately life-threatening; 2) requiring hospitalization or prolongation of hospitalization; 3) disabling; or 4) limiting self care activities. Grade 4 AEs are defined as 1) having life-threatening consequences; or 2) requiring urgent intervention. Grade 5 AEs are defined as causing death related to an adverse event.

NK cell expansion is defined as the presence of donor NK cells in the recipient at Day 8 post NK cell infusion.

Mayo Clinic

Masonic Cancer Center, University of Minnesota

Patients who received treatment for high risk myelodysplastic syndromes (MDS). Treatment Received: Decitabine 10 mg/m\^2/day intravenous (IV) over 1 hour days 1-5; Vorinostat 200 mg by mouth (PO) twice a day days 6-15; Il-2 activated donor natural killer cells (NK) infusion IV over 15 to 60 minutes day 17; Interleukin-2 6 million units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17. Repeat treatment course 6 to 8 weeks after cycle 1 start date.

Decitabine: administered intravenous (IV), 10 mg/m\^2/day over 1 hour on days 1-5.

Vorinostat: 200 mg by mouth (PO) twice a day on days 6-15

Interleukin-2: 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17

Natural killer (NK) cells: infusion intravenously (IV) over 15 to 60 minutes day 17

Patients With High Risk MDS

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

Dr. Erica Warlick

The Number of Patients Who Achieved a Clinical Response

Number of Patients Who Experienced Grade 3 or Higher Non-hematologic Adverse Events

7 of the 9 patients were not evaluable for this outcome measure - 5 went on to stem cell transplant and 2 died before reaching the 4-6 month post start of cycle 1 milestone.This left 2 evaluable patients for the outcome measure, and thus this endpoint is not informative due to lack of evaluable patients.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK Cells	NCT03242603	Neuroblastoma R...	Anti-GD2 in com...	6 Months - 25 Years	National University Hospital, Singapore
Phase I Trial of Universal Donor NK Cell Therapy in Combination With ALT803	NCT02890758	Acute Myeloid L... Myelodysplastic... Acute Lymphobla... Chronic Myeloid... Chronic Lymphoc... Non Hodgkin Lym... Hodgkin Lymphom... Myeloproliferat... Plasma Cell Mye... Colon Carcinoma Adenocarcinoma ... Soft Tissue Sar... Ewing's Sarcoma Rhabdomyosarcom...	Natural Killer ... ALT803	18 Years -	Case Comprehensive Cancer Center
Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK Cells	NCT03242603	Neuroblastoma R...	Anti-GD2 in com...	6 Months - 25 Years	National University Hospital, Singapore
Decitabine and Vorinostat Conditioning Followed by CD3-/CD19- NK Cells Infusion for High Risk Myelodysplastic Syndromes	NCT01593670	Myelodysplastic...	Decitabine Vorinostat Interleukin-2 Natural killer ...	18 Years - 75 Years	Masonic Cancer Center, University of Minnesota
Decitabine and Vorinostat Conditioning Followed by CD3-/CD19- NK Cells Infusion for High Risk Myelodysplastic Syndromes	NCT01593670	Myelodysplastic...	Decitabine Vorinostat Interleukin-2 Natural killer ...	18 Years - 75 Years	Masonic Cancer Center, University of Minnesota

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