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Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Hematologic Malignancies

ConditionsMalignancy, HematologicNeoplasms, HematologicNeoplasms, HematopoieticBlood CancerHematological NeoplasmsHematopoietic MalignanciesDysmyelopoietic SyndromesHematopoetic MyelodysplasiaMyeloid Leukemia, AcuteNonlymphoblastic Leukemia, AcuteLeukemia, Lymphocytic, Acute
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18-120
SponsorNational Cancer Institute (NCI)

About this trial

Background:

Blood cancers (such as leukemias) can be hard to treat, especially if they have mutations in the TP53 or RAS genes. These mutations can cause the cancer cells to create substances called neoepitopes. Researchers want to test a method of treating blood cancers by altering a person s T cells (a type of immune cell) to target neoepitopes.

Objective:

To test the use of neoepitope-specific T cells in people with blood cancers

Eligibility:

People aged 18 with any of 9 blood cancers.

Design:

Participants will have a bone marrow biopsy: A sample of soft tissue will be removed from inside a pelvic bone. This is needed to confirm their diagnosis and the TP53 and RAS mutations in their cancer cells. They will also have a skin biopsy to look for these mutations in other tissue.

Participants will undergo apheresis: Blood will be taken from their body through a vein. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different vein.

The T cells will be grown to become neoepitope-specific T cells.

Participants receive drugs for 3 days to prepare their body for the treatment. The modified T cells will be given through a tube inserted into a vein. Participants will need to remain in the clinic at least 7 days after treatment.

Participants will have 8 follow-up visits in the first year after treatment. They will have 6 more visits over the next 4 years. Long-term follow-up will go on for 10 more years.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Detection of at least one of the neoepitope-forming TP53 or RAS mutations that are listed in Table 3 in on the TruSight Oncology (TSO) 500 sequencing panel (NSR device) performed in the NCI Laboratory of Pathology is required. RAS mutations can be in NRAS, KRAS or HRAS as these oncogenes have the same amino acid sequence at the location of the targeted neoepitopes. A variant allele frequency (VAF) of at least 5% is required for a mutation to be eligible. This criterion can be met at any time within 60 days prior to apheresis regardless of treatment history during this 60-day period. DNA for sequencing comes from bone marrow.

Presence of the correct HLA type needed to present one of the targeted neoepitopes as shown in Table 3. HLA typing data from any time-point prior to apheresis can be used to meet this requirement.

For AML and MDS, bone marrow myeloblast percentage must be >=5% of nucleated cells in either bone marrow aspirate or biopsy. Myeloblasts can be defined by immunohistochemistry or by cytochemistry stains including but not limited to myeloperoxidase.

For T-ALL, bone marrow T-cell blast percentage must be >=5% of nucleated cells in either bone marrow aspirate or biopsy. T cells can be defined by cytochemistry or immunohistochemistry or flow cytometry.

Disqualifiers

Corticosteroids given for any indication at doses greater than 5 mg/day of prednisone or equivalent within 14 days before either apheresis or start of protocol chemotherapy.

Participants with MDS/Myeloproliferative neoplasia overlap syndromes are not eligible.

Participants with acute promyelocytic leukemia are not eligible.

Participants who received a mis-matched sibling or haploidentical transplant are not eligible.

Trial design

Design model

Sequential

Treatments tested in this trial

  • aldesleukin

    Drug

    Aldesleukin 600,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 10 doses).

  • cyclophosphamide

    Drug

    300 mg/m\^2 IV infusion over 30 minutes. Daily x 3 doses on days -5, -4, -3.

  • fludarabine phosphate

    Drug

    30 mg/m\^2 IV infusion over 30 minutes administered immediately following cyclophosphamide on day -5, -4, -3. Participants with renal dysfunction receive a lower dose of fludarabine.

  • Individual Patient TCR-Transduced PBL

    Biological/Vaccine

    Up to 1.5x10\^11 total cells for non-transplant subjects. 1x10\^10 total cells for post-alloHSCT subjects.

  • TruSight Oncology (TSO) 500

    Device

    TSO500 sequencing panel performed in the NCI Laboratory of Pathology to detect TP53 or RAS mutations

Treatment groups

86 Participants
are divided into 2 treatment groups
Group A: 1/Experimental: No allo-HSCTExperimental treatment 5 interventions
Group B: 2/Experimental: prior allo-HSCTExperimental treatment 5 interventions

Trial outcomes

Primary outcomes

1

Safety

Adverse Events (AE) per CTCAE v5.0, by type, grade, and frequency

Time frame
From time of the lymphodepleting chemotherapy through 5 years after neoepitope-specific T cell infusion or until off study.

Secondary outcomes

1

Overall response rate

Defined by the Overall Response Rate (CR+PR) and the CR rate, duration of response. Duration of response will be calculated from the first date of a response until relapse, progression, or initiation of a new anti-malignancy therapy

Time frame
up to 5 years
2

Feasibility of manufacturing and administering neoepitope-specific T cells

Feasibility will be measured as the fraction of participants with successful infusion of neoepitope-specific T-cell. Successful neoepitope-specific T-cell infusion will be achieved when at least 1x10\^10 total cells are infused

Time frame
30 days post treatment completion

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

National Cancer Institute (NCI)

Lead sponsor

Source ClinicalTrials.gov
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