Clinical Trial 23082

• Overview

  Study Title:

  Phase I/II Clinical Trial of CD40L-augmented Tumor Infiltrating Lymphocytes (TIL) for Patients with Advanced Melanoma

  Objective:

  Primary: To evaluate the safety and toxicity of CD40L-augmented TIL administered in patients with advanced melanoma. To evaluate the efficacy of CD40L-augmented TIL administered in patients with advanced melanoma, by assessing the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Immune-related Response Evaluation Criteria in Solid Tumors (iRECIST). To evaluate the feasibility and toxicity of CD40L-augmented TIL administered in patients with rare histological subtypes of advanced melanoma. Secondary: To evaluate the efficacy of CD40L-augmented TIL administered in patients advanced melanoma by assessing duration of response (DOR). To evaluate the progression-free survival (PFS) and overall survival (OS) of CD40L-augmented TIL administered in patients with advanced melanoma. To evaluate the preliminary efficacy of CD40L-augmented TIL administered in patients with rare histological subtypes of advanced melanoma by assessing DOR and ORR in Cohort 2. Objective response rate (ORR) by RECIST and iRECIST as a percentage of the total response-evaluable patients. Duration of response (DOR) in months, of the total response-evaluable patients. PFS and Overall Survival (OS) in months of the total safety-evaluable patients, and the total treated patients. Duration of response (DOR) in months, of Cohort 2 patients. ORR via RECIST 1.1 and iRECIST in Cohort 2. Time-to-event distributions for OS and PFS will be estimated in responders (CR or PR) versus non-responders (stable disease [SD] or progressive disease [PD]) at both 6 months and 12 months using the Landmark Method.

• Treatments

  Therapies:

  Cell Therapy; Chemotherapy (NOS)

  Medications:

  Aldesleukin (Interleukin-2); IL-2 (Interleukin-2); Interleukin-2 (); Proleukin (Interleukin-2); TIL (); cyclophosphamide (); cytoxan (cyclophosphamide); fludarabine (Fludarabine phosphate)

• Inclusion Criteria

  Key Inclusion Criteria:
  • Participants must have histologically confirmed, unresectable (Stage III/IV) or metastatic melanoma as follows: Cutaneous, non-acral, melanoma (including melanoma of unknown primary) or Cutaneous acral melanoma or Mucosal melanoma or Ocular melanoma (including uveal, iris, conjunctival melanoma).
  • Participants must have failed, be refractory to, or unable to tolerate at least one line of standard of care in the opinion of the Investigator. For participants with cutaneous nonacral melanoma, standard of care therapy includes a PD-1/L1 or combination therapy with anti-PD1 and anti-CTLA4 or combination therapy of anti-PD1 and anti-LAG3 or if BRAF V600 activating mutation positive, a BRAF ± MEK inhibitor. Participants are allowed to be enrolled in this trial if they failed one line of any of those standards of care therapy regimens.
  • Any systemic therapy, including anti-cancer monoclonal antibodies, must have been completed at least 4 weeks from the start of lymphodepleting therapy, and any prior therapy-related AEs must have resolved to Grade ≤ 1 except for alopecia and vitiligo. Neuropathy must have resolved to Grade ≤ 2. BRAF/MEK targeted therapy as a bridging therapy will be allowed for patients who already received BRAF/MEK targeted therapy for melanoma management and demonstrated disease progression on those agents before enrollment to this study. If the patient was not previously intolerant – in order to prevent potential disease hyper-progression due to abrupt stoppage of targeted therapy during manufacturing period, bridging therapy will be allowed with continuation of BRAF/MEK targeted therapies and should be stopped at least 2 weeks (+/-10 days) from the start of lymphodepleting therapy. Other bridging therapy options will include but not be limited to chemotherapy (preferably 1 cycle, more than 1 is allowed), and/or radiation therapy and should be completed at least 2 weeks from the start of lymphodepleting therapy.
  • Participants must be between the ages of 18 and 75 years old. Additionally, participants who are ≥ 50 years of age must undergo a cardiology evaluation including a cardiac stress test or coronary computed tomography after which they must be deemed to be low/acceptable risk. This cardiac evaluation may be omitted for patients who underwent testing within 6 months and have no interval change in cardiopulmonary clinical status. Additionally, participants between the ages of 71-75 must meet all other inclusion criteria and have express written permission provided by the clinical PI.
  • ECOG performance status of 0 or 1.
  • Participants must have adequate organ and marrow function as defined in the protocol.
  • Seronegative for Human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen, and hepatitis C (HCV) antibody (if HCV antibody positive, must be tested for HCV RNA, which must be negative to be eligible).
  • Participants with brain metastases are eligible provided that the brain metastases have been successfully treated with stereotactic radiosurgery or resection and clinically stable for at least 4 weeks.
  • Participants must be willing and able to undergo an apheresis procedure.
  • Women of child-bearing potential must have a negative pregnancy test.
  • The effects of CD40L-augmented TIL on the developing human fetus are unknown. For this reason and because TIL agents, as well as other therapeutic agents used in this trial including IL-2 are known to be teratogenic, both males and females of childbearing potential must be willing to practice birth control starting with screening through 1 year after the last study drug is administered for females or 6 months for males.
  • Should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study, she should inform her treating physician immediately.
  • Other criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Participants, regardless of age, who have a current or past medical history of ischemic heart disease, or clinically significant atrial or ventricular rhythm abnormality are excluded unless they undergo a cardiac stress test and cardiology clearance examination and are determined to be low or acceptable risk. Note: Participants with any clinically significant cardiac wall movement abnormality are excluded.
  • Participants with either a primary immunodeficiency disorder (i.e., severe combined immunodeficiency syndrome) or acquired immunodeficiency disorders (such as HIV/AIDS).
  • Pregnant women are excluded from this study because the agents used in this study have teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CD40L-augmented TIL or the other agents in the study, breastfeeding should be discontinued if the mother is enrolled in the study.
  • Participants taking systemic steroid therapy (other than replacement therapy or prednisone equivalent of ≤10mg daily) or therapy with any immunosuppressive medications such as mycophenolate mofetil (MMF). Participants who require more than 10mg of prednisone or equivalent other steroid therapy should taper their steroid therapy to 10 mg prednisone 1 week prior to planned first interventional drug therapy (lymphodepleting therapy). Participants who are on baseline replacement therapy or prednisone equivalent of ≤10mg daily and require stress doses of steroid therapy will be allowed to receive stress dose steroids during the trial interventions. Participants who require dapsone for pneumocystis pneumonia (PCP) prophylaxis during TIL therapy are eligible.
  • Participants who have a history of severe immediate hypersensitivity reaction to the study agents including cyclophosphamide, fludarabine, or IL-2 or any of their constituents.
  • Participants with a left ventricular ejection fraction (LVEF) ≤ 45% or New York Heart Association (NYHA) functional classification > 1.
  • Forced expiratory volume (FEV1) ≤ 60% of predicted value and DLCO (corrected) > Participants who, in the opinion of the Investigator, have a medical condition that would subject the patient to prohibitive risk by participation in this study, or who may be unable to safely complete the apheresis, tumor harvest, lymphodepletion regimen, TIL infusion, or aldesleukin administration.
  • Participants with active infections requiring antibiotics.
  • Participants with autoimmune disease currently requiring systemic treatment with immunosuppressive doses of corticosteroids (>10 mg of prednisone-equivalent daily dosing), immunosuppressive biologic agents, or disease modifying antirheumatic drug agents (DMARDs).
  • Participants requiring chronic anti-coagulant therapy that cannot either be discontinued or changed to an anti-coagulant such as a low molecular weight heparin, which has a relatively short half-life, if clinically indicated during the period of thrombocytopenia resulting from the lymphodepletion regimen.
  • Has evidence of impeding perforation, obstruction or bleeding (requiring transfusion) due to the tumor.
  • Patients who received prior live cell therapy are excluded, unless express written permission is provided by the clinical PI.
  • Patients between the ages 71-75 are excluded, unless they meet all other inclusion criteria and express written permission is provided by the clinical PI.
  • Other criteria may apply.

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