- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02890758
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
Study Overview
Status
Conditions
- Soft Tissue Sarcoma
- Acute Myeloid Leukemia
- Hodgkin Lymphoma
- Acute Lymphoblastic Leukemia
- Chronic Lymphocytic Leukemia
- Non Hodgkin Lymphoma
- Chronic Myeloid Leukemia
- Myelodysplastic Syndrome
- Plasma Cell Myeloma
- Rhabdomyosarcoma
- Colon Carcinoma
- Adenocarcinoma of Rectum
- Myeloproliferative Syndromes
- Ewing's Sarcoma
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Ohio
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Cleveland, Ohio, United States, 44106
- University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients must have histologic confirmation of relapsed and or refractory hematologic malignancy, locally advanced or metastatic colon/rectal carcinoma, or refractory and/or relapsed soft tissue sarcomas and have failed at least one standard line of therapy.
- Patients will be eligible if they have either declined standard treatment regimens or if there is no standard approach to curative salvage therapy per National Comprehensive Cancer Network (NCCN) guidelines in the setting of relapsed/refractory disease.
- In addition, patients for whom a potential 29-day delay in treatment will not interfere with the subject's potential therapeutic options can be eligible per the treating physician's discretion.
Malignancies can include:
- Acute myeloid leukemia
- Myelodysplastic syndrome
- Acute lymphoblastic leukemia
- Chronic myeloid leukemia
- Chronic lymphocytic leukemia
- Non Hodgkin Lymphoma
- Hodgkin Lymphoma
- Myeloproliferative syndromes
- Plasma cell myeloma
- Colon/rectal carcinoma
Soft tissue sarcomas including but not limited to Ewing's sarcoma and Rhabdomyosarcoma
- Patients must have recovered from acute toxicities of prior chemotherapy or stem cell transplant. Any prior non-hematologic vital organ toxicity (cardiac, pulmonary, hepatic, renal) of previous therapy must have resolved to grade 1 or less.
- All previous chemotherapy or radiation must be completed at least 3 weeks prior to study entry. Immunologic therapy must be completed at least 3 weeks prior to study entry. Patients with prior stem cell transplant must be greater than 365 days post-transplant.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤2
Organ function criteria (There is no exclusion for the presence of cytopenias),
- Serum total bilirubin <2 mg/dl (except if known Gilbert syndrome and normal transaminases)
- Aspartate aminotransferase (AST) (SGOT) < 2.5 X institutional upper limit of normal
- Alanine aminotransferase (ALT) (SGPT) < 2.5 X institutional upper limit of normal
- Pulmonary function (DLCO) >40% of the expected value corrected for alveolar volume and hemoglobin
- Serum Creatinine ≤ 1.5 X institutional upper limit of normal
- Subjects must have the ability to understand and the willingness to sign a written informed consent document.
- Women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) 4 weeks prior to study entry and for the duration of study participation. Women of child-bearing age must have documented negative pregnancy test prior to start of lympho-depleting regimen.
Exclusion Criteria:
- Subjects receiving any other investigational agents.
- Subjects for whom a potential 29-day delay in treatment will interfere with the subject's potential therapeutic options.
- Patients with untreated malignant involvement of the central nervous system (CNS) should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Head imaging will be necessary to document absence of CNS involvement in patients with colon/rectal cancer and soft tissue sarcomas. Patients with hematologic malignancies who have undergone treatment for malignant involvement of the CNS must have no evidence of residual disease by imaging or CSF sampling prior to study enrollment.
- History of allergic reactions to chemotherapy agents used in this protocol as part of lymphodepletion regimen (Fludarabine and Cyclophosphamide)
- Patients with uncontrolled intercurrent illness including, but not limited to ongoing active uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- Pregnant or breastfeeding women are excluded from this study.
- HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with chemotherapeutic agents. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
- Chronic active untreated hepatitis B or C infection.
- Recipients of previous allogeneic transplants who have rash involving more than 10% body surface area attributed to graft versus host disease (GVHD) (> Grade 1 GVHD of skin). Stem cell transplant recipients will be excluded if they are still receiving immunosuppression including steroids for GVHD or have active GVHD in any organ (except for Grade 1 only of skin, not requiring treatment).
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Cytokine Arm
Two infusions of Natural Killer (NK) cells and ALT803
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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
given at 6mcg/kg weekly for four weeks
Other Names:
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Active Comparator: No Cytokine Arm
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
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
MTD of ex vivo expanded non-HLA matched donor NK cells in combination with ALT-803
Time Frame: Up to 28 days
|
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.
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Up to 28 days
|
Number of participants without Graft Versus Host Disease (GVHD)
Time Frame: up to 28 days after beginning treatment
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Measure of safety of natural killer (NK) cells in the absence of HLA matching
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up to 28 days after beginning treatment
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of patients with hematological response
Time Frame: Up to 12 months after beginning treatment
|
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 |
Up to 12 months after beginning treatment
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Patients response for radiographically measurable lesions
Time Frame: Up to 12 months after beginning treatment
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Up to 12 months after beginning treatment
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Patients with malignant lymphoma response
Time Frame: Up to 12 months after beginning treatment
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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
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Up to 12 months after beginning treatment
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Patients response for Waldenstrom's macroglobulinemia (WM)
Time Frame: Up to 12 months after beginning treatment
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|
Up to 12 months after beginning treatment
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Patients response for cutaneous lymphomas
Time Frame: Up to 12 months after beginning treatment
|
CR/CCR
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)
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Up to 12 months after beginning treatment
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Patients response for multiple myeloma
Time Frame: Up to 12 months after beginning treatment
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Stringent Complete Response (sCR)
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Up to 12 months after beginning treatment
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Patients response for chronic myeloid leukemia (CML)
Time Frame: Up to 12 months after beginning treatment
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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
Molecular response:
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Up to 12 months after beginning treatment
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Patients response for metastatic colon/rectal carcinoma and soft tissue sarcomas
Time Frame: Up to 12 months after beginning treatment
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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. |
Up to 12 months after beginning treatment
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Average duration of response
Time Frame: Up to 12 months after beginning treatment
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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).
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Up to 12 months after beginning treatment
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Average duration of Overall Survival
Time Frame: Up to 12 months after beginning treatment
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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.
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Up to 12 months after beginning treatment
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Average duration of relapse free survival
Time Frame: Up to 12 months after beginning treatment
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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.
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Up to 12 months after beginning treatment
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in vivo Natural Killer (NK) levels
Time Frame: up to 28 days after beginning treatment
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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
|
up to 28 days after beginning treatment
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Collaborators and Investigators
Sponsor
Investigators
- Study Director: David Wald, MD, PhD, University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Immune System Diseases
- Neoplasms, Connective and Soft Tissue
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Disease
- Bone Marrow Diseases
- Hematologic Diseases
- Hemorrhagic Disorders
- Myeloproliferative Disorders
- Hemostatic Disorders
- Paraproteinemias
- Blood Protein Disorders
- Neoplasms, Plasma Cell
- Leukemia, Lymphoid
- Leukemia, B-Cell
- Osteosarcoma
- Neoplasms, Bone Tissue
- Neoplasms, Connective Tissue
- Neoplasms, Muscle Tissue
- Myosarcoma
- Sarcoma
- Lymphoma
- Syndrome
- Myelodysplastic Syndromes
- Multiple Myeloma
- Leukemia
- Leukemia, Myeloid
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Leukemia, Lymphocytic, Chronic, B-Cell
- Sarcoma, Ewing
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Rhabdomyosarcoma
Other Study ID Numbers
- CASE2Z16
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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