Safety Study of Chimeric Antigen Receptor Modified T-cells Targeting NKG2D-Ligands

• ClinicalTrials.gov Identifier: NCT02203825
• Recruitment Status: Completed
• First Posted: July 30, 2014
• Last Update Posted: June 1, 2018
• Sponsor: Celyad Oncology SA
• Collaborators: Dana-Farber Cancer Institute; National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Celyad Oncology SA

Tracking Information

• First Submitted Date: July 25, 2014
• First Posted Date: July 30, 2014
• Last Update Posted Date: June 1, 2018
• Study Start Date: March 2015
• Actual Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 12, 2015)

Safety and feasibility of intravenous administration of CM-CS1 T-cells. [ Time Frame: 24 months ]

Safety will be defined by the occurence of study-related serious and non-serious adverse events. Feasibility will be defined by the frequency of subjects enrolled who do not receive CM-CS1 T-cells.

• Original Primary Outcome Measures (submitted: July 29, 2014): Number of participants with serious and non-serious adverse events related to CM-CS1 T cell infusion. [ Time Frame: 30 days ]

Current Secondary Outcome Measures (submitted: March 12, 2015)

Clinical and biologic responses [ Time Frame: 24 months ]

Clinical anti-tumor effect by standard criteria Progression-Free survival Persistence and function of CM-CS1 T-cells

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety Study of Chimeric Antigen Receptor Modified T-cells Targeting NKG2D-Ligands
• Official Title: A Phase 1 Study of Chimeric Antigen Receptor Modified T-cells Targeting NKG2D-Ligands in Patients With Acute Myeloid Leukemia (AML)/Advanced Myelodysplastic Syndrome (MDS-RAEB) and Multiple Myeloma.
• Brief Summary: This Phase I clinical trial is evaluating chimeric-antigen receptor (CAR) T-cells (CM-CS1 T cells) which recognize NKG2D-ligands on the surface of cancer cells. This study evaluates the safety and feasibility of administering a single intravenous dose of CM-CS1 CAR T-cells to patients with AML, MDS-RAEB and Multiple Myeloma.

Detailed Description

This is a study for patients with AML or MDS-RAEB that is not in remission and for which there are no reasonable standard treatment options and for patients with relapsed/refractory multiple myeloma with progressive disease.

In this study, the participant's white blood cells (T-cells) will be collected and modified such that the T-cells are able to recognize specific molecules (called NKG2D-ligands), that are expressed on the surface of cancer cells in these diseases. This modification is a genetic change to the T-cells. The modified T cells, called CM-CS1 T-cells, are then given back to the participant by a single intravenous infusion. In this study, participants will not receive any chemotherapy prior to infusion of the CM-CS1 T-cells.

The study will evaluate whether it is safe and feasible to administer CM-CS1 T-cells to participants with AML/MDS-RAEB and multiple myeloma. It will also evaluate whether the CM-CS1 T-cells have a beneficial effect against the cancer cells. Another goal of the study is to learn more about the persistence and function of the CM-CS1 T-cells in the body.

Participants will be followed very closely during the first month after infusion. They are required to remain within 50 miles of Brigham and Women's Hospital (Boston, MA) for 10 days after the infusion and will be followed three times per week for the first 21 days and at day 28. Subsequently, participants will be followed monthly until 6 months after infusion, every 3 months until 15 months after infusion and at 24 months after infusion. Because this study involves gene transfer, participants will be followed yearly for up to 15 years.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acute Myeloid Leukemia
• Myelodysplastic Syndrome
• Multiple Myeloma

Intervention

Biological: CM-CS1 T-cell infusion

Each patient will receive a single dose of CM-CS1 T-cells by intravenous infusion.

Study Arms

Experimental: CM-CS1 T-cell infusion

The treatment will consist of a single infusion of CM-CS1 cells.

The following dose levels will be evaluated:

Cohort 1: 1x 10^6 CM-CS1 T-cells Cohort 2: 3x 10^6 CM-CS1 T-cells Cohort 3: 1x 10^7 CM-CS1 T-cells Cohort 4: 3x 10^7 CM-CS1 T-cells

Intervention: Biological: CM-CS1 T-cell infusion

• Publications *: Murad JM, Baumeister SH, Werner L, Daley H, Trebeden-Negre H, Reder J, Sentman CL, Gilham D, Lehmann F, Snykers S, Sentman ML, Wade T, Schmucker A, Fanger MW, Dranoff G, Ritz J, Nikiforow S. Manufacturing development and clinical production of NKG2D chimeric antigen receptor-expressing T cells for autologous adoptive cell therapy. Cytotherapy. 2018 Jul;20(7):952-963. doi: 10.1016/j.jcyt.2018.05.001. Epub 2018 Jun 29.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 9, 2016): 12
• Original Estimated Enrollment (submitted: July 29, 2014): 21
• Actual Study Completion Date: March 2018
• Actual Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

General eligibility criteria:

• ECOG performance status 0 or 1.Patients with multiple myeloma who have an ECOG performance status of 2 based on peripheral neuropathy from prior therapies are eligible.
• Ability to understand and the willingness to sign a written informed consent document.
• Pathological confirmation of AML, MDS-RAEB or Multiple myeloma.
• Agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of CM-CS1 CART-cell administration.
• Ability to adhere with the study visit schedule and other protocol procedures.
• Willingness to remain within a 50 mile radius of Brigham Women's Hospital during the initial 10 days following CM-CS1 infusion

Disease specific eligibility criteria for patients with AML, MDS-RAEB:

• Pathological confirmation of AML, MDS-RAEB according to WHO classification (CMML is excluded) that is not in remission (defined as >5% blasts in bone marrow or peripheral blood) and for which there are no reasonable standard treatment options.
• No known or suspected CNS disease. A neurologic exam is required and signs or symptoms suggestive of potential CNS disease require CNS imaging.
• Disease status deemed not to require additional therapy for at least 4 weeks from enrollment.
• Life expectancy of greater than 4 weeks.

• Participants must have satisfactory organ function as defined below:

  1. Total bilirubin ≤2.0 × institutional upper limit of normal (Except for subjects with known Gilbert's syndrome)
  2. AST(SGOT)/ALT(SGPT) ≤3 × institutional upper limit of normal
  3. Creatinine ≤ 2.0 mg/dL

Disease specific eligibility criteria for patients with multiple myeloma:

• Diagnosis of active multiple myeloma according to the International Myeloma Working Group diagnostic criteria.
• Relapsed or relapsed/refractory multiple myeloma with progressive disease

• Presence of measurable disease as defined as one or more of the following:

  1. Serum M-protein >0.5g/dl
  2. Urine M-protein > 200mg/24hr
  3. Serum FLC assay: involved FLC level > 10mg/dl with abnormal serum FLC ratio
  4. Measurable plasmocytoma in non-secretory patients.
• Previous treatment with both an immunomodulator and a proteosome inhibitor therapy
• Life expectancy of greater than 12 weeks
• No known or suspected CNS involvement. A neurologic exam is required and signs or symptoms of potential CNS involvement require CNS imaging. Peripheral neuropathy is acceptable.

• Participants must have satisfactory organ and marrow function as defined below:

  1. Absolute neutrophil count > 500/mcL. Screening ANC should be independent of G-CSF and GM-CSF support for at least 1 week and of pegylated G-CSF for at least 2 weeks
  2. Platelets >20,000/mcL. Subjects may receive platelet transfusions, if clinically indicated, in accordance with institutional guidelines.
  3. Total bilirubin ≤2.0 × institutional upper limit of normal. (Except patients with known Gilbert's syndrome)
  4. AST(SGOT)/ALT(SGPT) ≤3 × institutional upper limit of normal
  5. Creatinine ≤ 2.0 mg/dL

Exclusion Criteria:

• Participants who have received chemotherapy or radiotherapy within 3 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier.
• Concurrent systemic steroid or other immunosuppressive therapy.
• Participants who are concurrently receiving any other investigational agents, or have received another investigational agent within 3 weeks before enrollment.
• Participants who have received prior allogeneic stem cell transplantation, gene therapy, or adoptive T-cell therapy.
• Active infections necessitating use of treatment antibiotics/antivirals during the screening period (prophylaxis is acceptable) or evidence of an active communicable infectious disease.
• Participants who underwent major surgery within 4 weeks before day 0 of planned CM-CS1 T-cell infusion (this does not include placement of vascular access device or tumor biopsies).
• Participants with any known history of primary immunodeficiency.
• History of allergic reactions or hypersensitivity attributed to Human serum albumin or Plasma-lyte A.
• Uncontrolled intercurrent illness or serious uncontrolled medical disorder
• Pregnancy or breastfeeding
• Known HIV-positive participants are ineligible because the effect of transducing HIV-infected lymphocytes with the chimeric NKG2D- transgene on the disease course is unknown.
• Clinically relevant active infection including active hepatitis B or C or any other concurrent disease which in the judgment of the Investigator would make the subject inappropriate for enrollment on this study.
• Active autoimmune disease

• History of a malignancy other than one of the malignancies in this study with exception of the following circumstances:

  1. Patients with a history of malignancy who have been adequately treated and have been disease-free for at least 2 years are not excluded.
  2. Patients with adequately treated active non-invasive cancers (such as non-melanomatous skin cancer or in-situ bladder, cervical and breast cancers) are not excluded.
• Unwillingness to use an effective contraceptive method during the study and at least 4 months after administration of CM-CS1 T-cells unless subject is naturally infertile.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02203825
• Other Study ID Numbers: CM-14-001; 5R44HL099217-03 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Celyad Oncology SA
• Original Responsible Party: Celdara Medical, LLC
• Current Study Sponsor: Celyad Oncology SA
• Original Study Sponsor: Celdara Medical, LLC

Collaborators

• Dana-Farber Cancer Institute
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Sarah Nikiforow, MD; PhD; Dana-Farber Cancer Institute

• PRS Account: Celyad Oncology SA
• Verification Date: May 2018