Patient case: 64-year-old male with cholangiocarcinoma; genetic feature: BRAF (V600E)

Clinical trial: A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes

Summary: To determine the feasibility and safety of administering a regimen of TIL/IL-2, using a cell product manufactured in the Yale Advanced Cell Therapy Laboratories, in subjects with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist used alone or in combination with anti-CTLA-4.

Detailed description: This trial is a pilot study of re-infusion of tumor infiltrating lymphocytes (TIL) from a patient's own tumor to treat metastatic melanoma. In brief, subjects with metastatic melanoma that has progressed on anti-PD1, anti-PDL1 and/or anti-CTLA-4 therapies will have a metastatic melanoma tumor resected. TIL will be isolated from that tumor and expanded in vitro in the presence of interleukin-2 (IL-2) on site at the Yale Advanced Cell Therapy Laboratories. Subjects will then undergo myelosuppressive chemotherapy and then unselected TIL will be re-infused into the subject. Following re-infusion, subjects will be treated with up to 10 doses of intermediate dose IL-2. Subjects will be hospitalized for parts of the chemotherapy regimen and then for cell infusion and IL-2 treatment. Subjects will then be followed for safety and tumor response.

Eligibility: Inclusion Criteria:
  -  1. Histologically or cytologically confirmed metastatic melanoma with at least one lesion that is resectable for TIL generation (at least 1.5 cm in diameter). Subjects must have measurable or evaluable disease.
  2. Clinical performance status of ECOG 0 or 1 at the time of surgical harvest. Assessment by the treating physician that ECOG performance status of no higher than 2 can be maintained at least for the period of cell generation, lymphoablation, cell infusion and IL-2 administration (for at least 6 weeks following cell harvest)
  3. Tumor that is not responsive to prior therapy with a PD-1/PD-L1 antagonist alone or in combination with anti-CTLA-4
  4. BRAF mutation status must be known prior to cell harvest; for subjects with BRAF V600E or V600K mutations, there must have been at least one site of disease progression during treatment with an approved BRAF inhibitor (dabrafenib or vemurafenib), and in the opinion of the investigator must be able to tolerate withholding of BRAF inhibitor treatment for the period between initiation of lymphoablation and recovery of cell counts following TIL infusion.
  5. ≥ 18 years of age.
  6. If indicated, willing to practice birth control during treatment and for 4 months after receiving the preparative regimen.
  7. Able to understand and sign the Informed Consent Document
  8. Hematology: Absolute neutrophil count ≥ 1000/mm3 without support of filgrastim Normal WBC (> 3000/mm3). Hemoglobin ≥ 8.0 g/dl (can be transfused to this level) Platelet count greater than 75,000/mm3
  9. Serology: Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Subjects who are HIV seropositive can have decreased immune competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.) Seronegative for HTLV-1 and HTLV-2 antibodies Seronegative for hepatitis B or hepatitis C. Seronegative for syphilis Seropositive for EBV (the risk for post-transplant lymphoproliferative disorder is significantly higher for EBV- subjects who receive EBV+ blood products after myelosuppressive therapy).
  10.Chemistry: Serum ALT/AST < five times the upper limit of normal. Serum creatinine ≤ 2.0 mg/dl. Total bilirubin ≤ 2 mg/dl, except in subjects with Gilbert's Syndrome, who must have a total bilirubin ≤ 3 mg/dl.
  11. At least 7 days must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and toxicities must have recovered to ≤ grade
  1 (except for toxicities such as alopecia or vitiligo and certain immune checkpoint inhibitor toxicities as noted in #12). Subjects may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to ≤ grade
  1 or as specified in the eligibility criteria in Section 3.1.
  12. Subjects who have received any anti-CTLA-4, anti-PD-1 or anti-PD-L1 antibody and experienced treatment- related colitis must have complete resolution of diarrhea/colitis as assessed by clinical history. For adrenal insufficiency and hypothyroidism, subjects must be on stable doses of prednisone (≤10 mg daily) and/or levothyroxine, respectively. All other immune checkpoint toxicity must have resolved to ≤ grade 1 as assessed by history or exam with the exception of vitiligo, or cardiac, neurologic or pulmonary toxicity, which must have resolved to grade 0.
  Exclusion Criteria:
  1. Prior cell transfer therapy that included non-myeloablative or ablative chemotherapy.
  2. Women of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
  3. Systemic steroid therapy required prednisone > 10 mg daily or its equivalent.
  4. Any contraindication to neutropenia or thrombocytopenia for up to 2 weeks (no active major infection, no site of active, clinically significant bleeding)
  5. Active coagulation disorders
  6. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
  7. Opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Subjects who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
  8. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  9. Any patient known to have an LVEF ≤ 45%. Also:
  Clinically significant atrial and/or ventricular arrhythmias including but not limited to:
  atrial fibrillation, ventricular tachycardia, second or third degree heart block.
  Ischemia found on a cardiac stress echocardiogram or a stress-MUGA
  10. Documented FEV1 less than or equal to 60% predicted tested in subjects with:
  A prolonged history of cigarette smoking Symptoms of respiratory dysfunction
  11. Active second malignancy

Relevance to patient case: not relevant