Phase 1 Study Of Intrathecal Cellular Adoptive Immunotherapy Using Autologous CD8+ Antigen-Specific T Cells For Patients With Leptomeningeal Melanoma

Phase 1 Study Of Intrathecal Cellular Adoptive Immunotherapy Using Autologous CD8+ Antigen-Specific T Cells For Patients With Leptomeningeal Melanoma

The proposed study is a single arm Phase I trial aimed at treating up to 6 HLA-A*0201+ and HLA-A*24 02+ individuals with leptomeningeal disease from metastatic melanoma.

Primary Objective:

Evaluate the safety of adoptively transferred intrathecal ETC targeting melanoma tumors in patients with leptomeningeal disease.

Secondary Objectives:

1. Evaluate the duration of in vivo persistence (peripheral blood and CSF) and anti-tumor efficacy achieved following adoptive transfer of antigen specific ETC.
2. Overall survival for up to one year after end of patient monitoring.

Primary Endpoint:

Safety and Toxicity Evaluation

Secondary Endpoint:

1. Persistence of transferred T cells.

   1. The numeric and functional persistence of transferred CTL will be performed on CSF samples (where available) and peripheral blood obtained from patients prior to T cell infusion (baseline sample), and as scheduled above. The numeric frequency of transferred T cells will be determined using peptide MHC-tetramer analysis or specific CDR3 TCR quantitative PCR of transferred CTL if necessary. The function of transferred CTL will be determined by intracellular cytokine staining of tetramer+ CD8+ cells following in vitro stimulation.
   2. Tetramer analysis. Since all patients on study will be HLA-A2+ and HLA-A24+, the use of tetramers to track several well-characterized tumor-associated HLA-A2 and HLA-A24-restricted responses will be feasible. These include responses to several melanosomal antigens: (tyrosinase, MART1/MelanA, gp100, SLC45A2) and CT antigens: (PRAME, MAGE-A1, MAGE-A10). Flow-based tetramer staining permits multiparametric analysis such that surface markers of differentiation (CD62L, CCR7, CD27, CD28) can be used to further characterize the effector, effector memory or central memory phenotype of the induced population of antigen-specific T cells.

2. Overall survival

Inclusion Criteria:

1. Patients must have radiographic and/or CSF cytological evidence of LMD.

2. Must have a confirmed diagnosis of primary CNS melanoma, melanocytomas or metastatic melanoma (cutaneous, acral-lentiginous, uveal, or mucosal in origin), based on histological analysis of metastatic tissue and/or cancer cells, archival tissue permitted.

3. Male or female subjects ≥18 years of age.

4. Expression of HLA-A2 or HLA-A24.

5. ECOG/ Zubrod performance status ≤1 at screening visit for this treatment

6. Ability to understand and the willingness to sign a written informed consent document.

7. The effects of Endogenous T Cell (ETC) Therapy on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:

   • Postmenopausal (no menses in greater than or equal to 12 consecutive months).
   • History of hysterectomy or bilateral salpingo-oophorectomy.
   • Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
   • History of bilateral tubal ligation or another surgical sterilization procedure.
   • Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

8. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of Endogenous T Cell (ETC) Therapy administration.

9. Reproductive Status

   • Investigators shall counsel women of childbearing potential participants, on the importance of pregnancy prevention and the implications of an unexpected pregnancy. The investigator shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
   • Local laws and regulations may require the use of alternative and/or additional contraception methods.

   Female Participants:

   • Female participants must have documented proof that they are not of childbearing potential.
   • Note: Women who are not of childbearing potential are exempt from contraceptive requirements.
   • WOCBP must have a negative highly sensitive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study intervention. An extension up to 72 hours prior to start of study treatment is permissible in situations where results cannot be obtained within the standard 24-hour window.
   • If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
   • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to potentially decrease the risk for inclusion of a woman with an undetected pregnancy.
   • WOCBP must agree to follow instructions for method(s) of contraception as described and included in the ICF.
   • WOCBP are permitted to use hormonal contraception methods. A female participant is eligible to participate if she is not pregnant or breastfeeding.

   participant is eligible to participate if she is not pregnant or breastfeeding.

10. Concurrent Therapy

    • Patients may receive steroids to control symptoms related to CNS involvement, but the dose must be ≤ 4 mg per 24 hours of dexamethasone (or the equivalent). Patient's symptoms should experience stability of neurological symptoms for at least 7 days and without increasing needs for steroids. Physiologic replacement doses for adrenal insufficiency are allowed on this protocol but should not exceed 40 mg of hydrocortisone daily (or its equivalent).
    • Patients who have been treated with an approved targeted therapy (BRAF inhibitor and/or MEK inhibitor) will be allowed to remain on concurrent approved targeted therapy.
    • Patients who have received an approved systemic biologic therapy (e.g., antiPD-1, anti-CTLA4, IL-2, interferon) must have received their last treatment ≥ 2 weeks prior to the start of treatment with IT ECT, but can continue with treatment of anti-PD1 and/or CTLA-4
    • Treatment with anti-epileptics is allowed while on protocol.
    • No other concomitant intrathecal therapy with another agent will be allowed.

11. Washout periods from other therapies Patients who have received radiation to brain and/or spine, including whole brain radiation, stereotactic radiosurgery (SBRT), are eligible, but must have completed radiation treatment at least 7 days prior to the start of treatment with IT ECT.

    • Patients that received previous IT therapy must have received their last treatment ≥ 7 days prior to the start of treatment with IT ECT.
    • Patients who have received systemic chemotherapy must have received their last treatment ≥ 14 days prior to the start of treatment with IT ECT.
    • Patients who have received an approved systemic biologic therapy (e.g., antiPD-1, anti-CTLA4, IL-2, interferon) must have received their last treatment ≥ 2 weeks prior to the start of treatment with IT ECT, but can continue with treatment of anti-PD1 and/or CTLA-4 (see exclusion paragraph)
    • Patients who have received any other investigational agents must have received their last treatment ≥ 14 days prior to the start of treatment with IT ECT.

Exclusion Criteria:

1. Any underlying medical or psychiatric condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.
2. All associated toxicity from previous or concurrent cancer therapy must be resolved (to ≤ grade 1 or baseline) prior to study treatment administration. This excludes non-serious toxicities. However, stable endocrinopathies requiring replacement therapy will be allowed.