Clinical Trials /

Study of Adoptively Transferred, Gene-engineered T Cells With CD40 Activation and PD-1 Blockade in Incurable Cancers

NCT04520711

Description:

This is a phase I/Ib study of adoptively transferred T-cell receptor gene-engineered T cells (TCR-T) targeting tumor-specific antigens, with in vivo CD40 activation and PD-1 blockade, for patients with incurable cancers. The study design is a safety lead-in TCR-T with CD40/PD-1 (3+3), followed by Simon's Two-Stage expansion design, 80% power and 5% one-sided alpha: stage-one futility assessment at n = 10; stage-two assessment at n = 22, (accrual up to 24 to allow for potential study drop-out).

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Adoptively Transferred, Gene-engineered T Cells With CD40 Activation and PD-1 Blockade in Incurable Cancers
  • Official Title: A Phase I/Ib Study of Adoptively Transferred T-cell Receptor Gene-engineered T Cells (TCR-T) Targeting Tumor-specific Antigens, With in Vivo CD40 Activation and PD-1 Blockade, for Patients With Incurable Cancers

Clinical Trial IDs

  • ORG STUDY ID: 2020000584
  • NCT ID: NCT04520711

Conditions

  • Malignant Epithelial Neoplasms

Interventions

DrugSynonymsArms
TCR-transduced T cells
CDX-1140
Pembrolizumab

Purpose

This is a phase I/Ib study of adoptively transferred T-cell receptor gene-engineered T cells (TCR-T) targeting tumor-specific antigens, with in vivo CD40 activation and PD-1 blockade, for patients with incurable cancers. The study design is a safety lead-in TCR-T with CD40/PD-1 (3+3), followed by Simon's Two-Stage expansion design, 80% power and 5% one-sided alpha: stage-one futility assessment at n = 10; stage-two assessment at n = 22, (accrual up to 24 to allow for potential study drop-out).

Detailed Description

      Patients will be infused with T cells engineered to express TCRs targeting one to five
      tumor-specific antigens expressed by their autologous tumor. The number of T cells infused
      will range from 1e9 to 1e11. Monoclonal antibodies targeting PD-1 (pembrolizumab) and CD40
      (CDX-1140, Celldex Therapeutics)43 will be administered, in that order, starting within 24
      hours of cell infusion and re-administered at approximately 3 week intervals. Clinic visits
      will include longitudinal evaluation of toxicities and monitoring of immunological
      parameters. The presence or absence of replication competent retrovirus (RCR) will be
      evaluated for the first year following adoptive cell transfer, or longer, if there is
      evidence of RCR.

      Tumor Response assessment by RECIST 1.1 is performed every 9-12 weeks. Study treatment
      continues until progression. Option repeat TCR-T infusion is allowed and in addition may
      incorporate preconditioning chemotherapy using a de-intensified non-myeloablative (NMA)
      regimen consisting of a single dose of gemcitabine and a single dose of either
      cyclophosphamide or epirubicin, designed to elicit immunogenic cell death and transient
      lymphopenia.

      The primary objective of this study is to determine the safety of the adoptive transfer of
      TCR-gene engineered T cells targeting TSA in combination with CD40 and PD-1 immunotherapy.
      The secondary objective is to determine whether this therapy can mediate objective clinical
      responses as determined by objective criteria (e.g. RECIST 1.1). The study will also
      characterize the differentiation and functional state of the TCR-gene modified T cells before
      and after cell therapy and monitor their persistence in the patient after treatment. Up to 24
      patients will be enrolled in this study. Based on published trials treating patients with
      TCR-transduced T cells, adverse events such as fever, chills, dyspnea, hypotension, fatigue,
      edema, rash, and rarely acute cytokine release syndrome, may occur.

      Clinical and immunological data will be analyzed which will determine whether this therapy is
      safe and effective, and whether there are biomarkers or immunological signatures that
      correlate to efficacy and/or lack of efficacy. This data will determine whether additional
      studies are warranted.
    

Trial Arms

NameTypeDescriptionInterventions

Eligibility Criteria

        Inclusion Criteria:

        Patients with evaluable and pathologically confirmed advanced malignancy who have exhausted
        curative-intent treatment options. Enrollment is intended for epithelial cancers, though
        exceptions may be considered on a case-by-case basis, per discretion of study PI.

        Suitable TSA for TCR-gene therapy identified in patient's cancer as confirmed by Dr. Eric
        Tran.

        Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.

        Laboratory values:

          -  WBC ≥ 2000/uL

          -  Neutrophils ≥ 1000/uL

          -  Hgb > 8.0 g/dl (patients may be transfused to reach this level)

          -  Platelets > 100,000 cells/mm3

          -  Creatinine ≤ 2.0 mg/dL

          -  AST & ALT ≤ 2.5 × ULN, or ≤ 5 × ULN for participants with liver metastases

          -  Alkaline phosphatase ≤ 2.5 × ULN, or ≤ 5 × ULN for participants with liver metastases

          -  Total bilirubin ≤ 2 × ULN (except patients with Gilbert's syndrome, who must have a
             total bilirubin ≤ 3.0 mg/dL). If total bilirubin is >1.5, conjugated bilirubin must be
             ≤ ULN (conjugated bilirubin only needs to be tested if total bilirubin exceeds ULN).
             If there is no institutional ULN, then conjugated bilirubin must be < 40% of total
             bilirubin.

        Patients positive for hepatitis B core antibody (anti-HBc, total), are eligible only if HBV
        DNA is non-detectable by qPCR.

        Patients positive for hepatitis C virus (HCV) antibody are eligible only if HCV RNA is
        non-detectable by qPCR.

        Patients positive for HIV 1/2 antibodies, are eligible if ARV treatment compliant with
        documented stable CD4 > 300 for at least 6 months and undetectable viral load.

        Women of childbearing potential must have negative serum/urine bHCG pregnancy test ≤ 24
        hours prior to start of study and with each subsequent dose of study treatment.

        Ability to give informed consent and comply with the protocol.

        Anticipated lifespan greater than 12 weeks.

        Men and women of childbearing potential, must agree to take appropriate pregnancy
        precautions during treatment and through 180 days after last dose of study treatment, see
        Appendix {A}. Patients and/or partners who are surgically sterile or postmenopausal are
        exempt from this requirement. Males must agree not to donate sperm for at least 90 days
        after discontinuing study treatment.

        Exclusion Criteria:

        Concurrent enrollment in another clinical study, unless it is an observational
        (non-interventional) clinical study or during the follow-up period of an interventional
        study.

        Receipt of any investigational anticancer therapy during the last 28 days or 5 half-lives,
        whichever is shorter, prior to the first dose of study treatment.

        Any concurrent chemotherapy, investigational agent, biologic, or hormonal therapy for
        cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions
        (e.g., hormone replacement therapy) is acceptable.

        Local treatment of isolated lesions for palliative intent is acceptable (e.g., local
        surgery or radiotherapy), excluding target lesions, Palliative radiation therapy cannot be
        administered less than 1 week prior to the first dose of study treatment.

        Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
        radiation within 4 weeks of the first dose of study drug. Participants must have recovered
        from all radiation-related toxicities, not require corticosteroids for this purpose and not
        have had radiation pneumonitis.

        Major surgical procedure (as defined by the Investigator) within 28 days prior to the first
        dose of study treatment. Note: Local surgery of isolated lesions for palliative intent is
        acceptable.

        History of organ transplant, including allogeneic stem cell transplantation.

        Uncontrolled intercurrent illness as deemed by the investigator, including but not limited
        to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled
        hypertension, unstable angina pectoris, unstable cardiac arrhythmia, interstitial lung
        disease or history of, serious chronic gastrointestinal conditions associated with
        diarrhea, active noninfectious pneumonitis, or psychiatric illness/social situations that
        would limit compliance with study requirement, substantially increase risk of incurring AEs
        or compromise the ability of the patient to give written informed consent.

        History of another primary malignancy except for:

          -  Malignancy treated with curative intent and with no known active disease ≥1 year
             before the first dose of investigational product and of low potential risk for
             recurrence.

          -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
             disease.

          -  Adequately treated carcinoma in situ without evidence of disease.

        History of leptomeningeal carcinomatosis

        Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis.
        Patients whose brain metastases have been treated may participate provided they show
        radiographic stability (imaging at least four weeks apart showing no evidence of
        intracranial progression). In addition, any neurologic symptoms that developed either as a
        result of the brain metastases or their treatment must have resolved or be stable either,
        without the use of steroids, or are stable on a steroid dose of ≤10mg/day of prednisone or
        its equivalent and anti-seizure medications for at least 14 days prior to the start of
        treatment. Patients on a stable dose of seizure medicines for epilepsy unrelated to cancer
        are eligible for the trial.

        History of active primary immunodeficiency.

        Active tuberculosis infection (clinical evaluation that includes clinical history, physical
        examination and radiographic findings, and TB testing in line with local practice).

        Active autoimmune disease requiring systemic immunosuppression in excess of physiologic
        maintenance doses of corticosteroids (> 10 mg/day of prednisone or equivalent).:

          -  Autoimmune disease that is not active (in remission), but in the judgment of the
             investigator could risk substantial morbidity in the event of relapse, may be grounds
             for exclusion. This can include a prior history of pneumonitis or other autoimmune
             sequelae of prior immunotherapy.

          -  Physiologic corticosteroid replacement therapy at doses > 10 mg/day of prednisone or
             equivalent for adrenal or pituitary insufficiency and in the absence of active
             autoimmune disease is permitted.

          -  Participants with asthma that requires intermittent use of bronchodilators, inhaled
             steroids, or local steroid injections may participate.

          -  Participants using topical, ocular, intra-articular, or intranasal steroids (with
             minimal systemic absorption) may participate.

        Brief courses of corticosteroids for prophylaxis (e.g., contrast dye allergy) or study
        treatment-related standard premedication are permitted.

        Receipt of live attenuated vaccine within 28 days prior to the first dose of study
        treatment. Note: patients should not receive live vaccine during study treatment and up to
        30 days after the last dose of study treatment.

        Known allergy or hypersensitivity to study drug(s) or compounds of similar biologic
        composition to the study drug(s), or any of the study drug excipients.

        Any unresolved NCI CTCAE Grade ≥2 toxicities from prior anti-cancer therapy with the
        exception of vitiligo, alopecia, and the laboratory values defined in the inclusion
        criteria.

        Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
        consultation with the Principal Investigator or one of the Co-Principal Investigators.

        Patients with irreversible toxicity not reasonably expected to be exacerbated by study
        treatment may be included only after consultation with the Principal Investigator or one of
        the Co-Principal Investigators.

        Immune-related toxicity during prior checkpoint inhibitor therapy for which permanent
        discontinuation of therapy is recommended (per product label or consensus guidelines) OR
        any immune-related toxicity requiring intensive or prolonged immunosuppression to manage
        (with the exception of endocrinopathy that is well controlled on replacement hormones).

        Significant cardiovascular disease including unstable angina pectoris, uncontrolled
        hypertension or arrhythmia, congestive heart failure (NYHA Class III or IV) related to
        primary cardiac disease, uncontrolled ischemic or severe valvular heart disease. Patients
        with a history of myocardial infarction, cerebral vascular accident, thrombosis or
        pulmonary embolus within 12 months prior to the first dose of study treatment are excluded
        from this study.

        Any other acute or chronic medical or psychiatric condition or laboratory abnormality that
        could increase the risk associated with trial participation or trial drug administration or
        could interfere with the interpretation of trial results and, in the judgment of the
        investigator, would make the patient inappropriate for entry into the trial.

        Women who are pregnant, lactating or expecting to conceive, or men who father children
        within the projected duration of the study.

        Unable or unwilling to comply with study requirements, including returning for follow-up
        visits.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety
Time Frame:2 years
Safety Issue:
Description:analysis of adverse events

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:2 years
Safety Issue:
Description:percentage of subjects having CR or PR
Measure:Duration of response
Time Frame:2 years
Safety Issue:
Description:the time from the earliest date of disease response (CR or PR) until earliest date of disease progression or death due to any cause
Measure:Clinical benefit rate
Time Frame:2 years
Safety Issue:
Description:percentage of subjects having CR, PR, or SD (with minimum duration > 4 months)
Measure:Overall survival
Time Frame:2 years
Safety Issue:
Description:determined by survival follow-up

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Providence Health & Services

Last Updated

August 18, 2020