Tumor Infiltrating Lymphocytes and High-Dose Aldesleukin with or without Autologous Dendritic Cells in Treating Patients with Metastatic Melanoma

Status: Active

Description

This randomized phase II trial studies how well therapeutic tumor infiltrating lymphocytes and high-dose aldesleukin with or without autologous dendritic cells work in treating patients with melanoma that has spread to other areas of the body. Vaccines made from a person's tumor cells and special blood cells (dendritic cells) may help the body build an effective immune response to kill tumor cells. Aldesleukin may stimulate the white blood cells to kill tumor cells. It is not yet known whether therapeutic tumor infiltrating lymphocytes and high-dose aldesleukin are more effective when given together with or without dendritic cells in shrinking or slowing the growth of melanoma. The clinical benefits of receiving tumor infiltrating lymphocytes (TIL) in combination with the B-Raf proto-oncogene, serine / threonine kinase (BRAF) inhibitor will be studied, in patients who have progressive disease (PD) with using the BRAF inhibitor prior to TIL treatment. Leptomeningeal disease (LMD) is unfortunately a common development in patients with melanoma, with an extremely poor prognosis, translating into an overall survival of only weeks. With the novel approach of combining intrathecal TILs and intrathecal interleukin (IL)-2, researchers hope to induce long term disease stabilization or remission of LMD.

Eligibility Criteria

Inclusion Criteria

  • Patients must have metastatic melanoma, uveal melanoma or stage III in-transit or regional nodal disease (Turnstile I)
  • Patients must receive an magnetic resonance imaging (MRI)/computed tomography (CT) of the brain or positron emission tomography (PET)/CT within 6 months of consenting; if new lesions are present, principal investigator (PI) or his designee should make final determination regarding enrollment (Turnstile I)
  • Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0-2 (Turnstile I)
  • Patients previously treated with immunotherapy, targeted therapy, or no therapy will be eligible; patients receiving cytotoxic agents will be evaluated by the PI or his designee as to suitable eligibility (Turnstile I)
  • Patients must be HLA-A2 for cohort A (Turnstile II-Chemotherapy/Cell Infusion-Inclusion Criteria)
  • Patients must have adequate TIL available (Turnstile II)
  • Patients must have measurable metastatic melanoma (Turnstile II - Chemotherapy/Cell Infusion -Inclusion Criteria)
  • Patients may have brain lesions which measure =< 1cm each; lesions that are > 1 cm that have been treated with stereotactic radiosurgery (SRS) and in the opinion of the PI or his designee no longer represents active disease will also be allowed (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria)
  • Patients of both genders must practice birth control for four months after receiving the preparative regimen (Turnstile II - Chemotherapy/Cell Infusion - Inclusion Criteria)
  • Patients must have a documented negative pregnancy test (urine or serum) for women who have menstruation in the past 12 months and without sterilization surgery
  • Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), the patient agrees to continue to use a barrier method of contraception throughout the study such as: condom, diaphragm, hormonal, intrauterine device (IUD), or sponge plus spermicide; abstinence is an acceptable form of birth control (Turnstile II)
  • Pregnancy testing will be performed within 7 days prior to treatment (Turnstile II)
  • Clinical performance status of ECOG 0 - 2 at the time of chemotherapy infusion (Turnstile II - Chemotherapy/Cell Infusion - Inclusion Criteria)
  • Absolute neutrophil count greater than or equal to 750/mm^3 (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria)
  • Platelet count greater than or equal to 75,000/mm^3 (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria)
  • Hemoglobin greater than or equal to 8.0 g/dl (Turnstile II - Chemotherapy/Cell Infusion)
  • Serum alanine aminotransferase (ALT) less than three times the upper limit of normal (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria)
  • Serum creatinine less than or equal to 1.6 mg/dl (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria)
  • Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's syndrome who must have a total bilirubin less than 3.0 mg/dl (Turnstile II - Chemotherapy/Cell Infusion - Inclusion Criteria)
  • Patients in Cohort A will be randomized to receive either TIL alone or TIL plus dendritic cells
  • A stress cardiac test (stress thallium, stress multi gated acquisition scan [MUGA], dobutamine echocardiogram or other stress test that will rule out cardiac ischemia) within 6 months of lymphodepletion (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria)
  • Pulmonary function tests (forced expiratory volume in one second [FEV1] > 65% or forced vital capacity [FVC] > 65% of predicted) within 6 months of lymphodepletion (Turnstile II - Chemotherapy/Cell Infusion - Inclusion Criteria)
  • MRI/CT of brain within 42 days of lymphodepletion; CT scan of chest/abdomen/pelvis or PET/CT within 30 days of lymphodepletion; Exception: patients randomized to receive dendritic cells may have an MRI of the brain within 30 days of lymphodepletion (Turnstile II-Chemotherapy/Cell Infusion-Inclusion Criteria)
  • Patients must be receiving a v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) inhibitor and failed to achieve PR or CR or have progressive disease in response to B-RAF treatment (Cohort C)
  • Patients with MRI evidence of LMD, with or without evidence of malignant cells in CSF (“positive cytology”), or; patients with evidence of malignant cells in the CSF (positive cytology), with or without MRI evidence of LMD, or; patients with surgically-proven LMD (leptomeningeal involvement on pathology review) +/- MRI or CSF evidence by MRI or CSF cytology (Cohort D)
  • Many patients present with concomitant systemic disease outside of the central nervous system; extra-central nervous system (CNS) disease status should meet the following criteria: * Patients with concomitant systemic disease under control with current or prior systemic treatment, as per primary treating physician * Patients without any evidence of systemic disease, either receiving systemic treatment or on active observation (Cohort D)
  • Previous Therapies * Patients who are currently being treated with intrathecal (IT) IL-2 for LMD are eligible; no wash out period is required * Patients who have been previously treated with other IT therapies are eligible, as long as there is at least a 2 week wash out period * Patients who have previously received therapy with systemic TIL therapy are eligible * Patients with ventriculo-peritoneal (VP) shunts must have VP shunts with on/off valves and must be expected to tolerate VP shunt valve off for more than 6 hours; patients who have received CNS irradiation, including whole brain radiation or stereotactic radiosurgery, are eligible, if they are at least 1 weeks post CNS-irradiation (Cohort D); patients who are currently being treated with IT IL-2 for LMD are eligible; no wash out period is required. (Cohort D)
  • Other Requirements * Patients must be able to give informed consent * Patients must have ECOG performance status 0, 1 or 2 and/or Karnofsky performance status (KPS) > 50 * Patients must be able to swallow * Patients must be able to sit up with or without assistance * Patients must be able to undergo contrast-enhanced MRI (Cohort D)

Exclusion Criteria

  • Has had prior systemic cancer cytotoxic chemotherapy within the past four weeks at the time of the start of the lymphodepletion regimen
  • Has had prior B-RAF or mitogen-activated protein kinase kinase (MEK) targeted therapy within 7 days prior to the start of lymphodepletion regimen (Cohort A and Cohort B)
  • Is not receiving B-RAF treatment (Cohort C) (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  • Achieves PR or CR in response to B-RAF treatment (Cohort C)
  • Women who are pregnant or nursing will be excluded (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  • Any active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, such as abnormal stress test and/or abnormal PFT; PI or designee shall make the final determination regarding appropriateness of enrollment (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  • Any form of primary or secondary immunodeficiency; must have recovered immune competence after chemotherapy or radiation therapy as evidenced by lymphocyte counts (> 500/mm^3), white blood cell (WBC) (> 3,000/mm^3) or absence of opportunistic infections (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  • Require steroid therapy or steroid-containing compounds, or have used systemic steroids in the past 30 days, or have used topical or inhalational steroids in the past 2 weeks prior to lymphodepletion; Exception: patients on physiologic dose of steroid (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  • Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent or render immunotherapy unsafe or contraindicated (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
  • Patients with rapidly advancing systemic disease, especially those without good options of systemic treatment for their disease outside the CNS (Cohort D)
  • Patients with rapidly advancing parenchymal brain metastases (Cohort D)
  • Pregnant patients (Cohort D)
  • Patients with rapid decline in neurological function as documented on exam and/or as per clinical judgment of treating physician (Cohort D)

Locations & Contacts

Texas

Houston
M D Anderson Cancer Center
Status: Active
Contact: Patrick Hwu
Phone: 713-792-2921
Email: phwu@mdanderson.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Cohort A and Cohort B: To determine whether patients receiving the combination of dendritic cells and high dose IL-2 have sustained persistence of infused T cells compared to patients treated with T cells and high dose IL-2 alone.

II. Cohort C: Overall response rate of TIL treatment for patients who have not achieved partial response (PR) or complete response (CR) or have progressive disease from treatment of the BRAF inhibitor alone.

III. Cohort D: Confirm the safety of adoptively transferred, TIL into the cerebrospinal fluid (CSF).

SECONDARY OBJECTIVES:

I. Evaluations for tumor response and studies to determine whether dendritic cells enhance the infused T cells in anti-tumor activity and their ability to migrate to the tumor site.

II. Evaluate the characteristics of the infused T cells that correspond with effectiveness in vivo.

III. Correlation of clinical parameters with survival (overall survival and progression-free survival).

IV. Evaluations of clinical imaging and CSF response.

TERTIARY OBJECTIVES:

I. Assess if the intrathecally-infused T cells persist in the CSF.

II. Assess circulating tumor cells in the CSF.

III. Assess various cytokine and other analyses, as feasible.

OUTLINE: Patients are assigned to 1 of 4 cohorts.

COHORT A (closed to new patient entry as of 01/14/2016): Human leukocyte antigen (HLA)-A2 positive patients with TIL cultures containing > 0.1% melanoma-associated antigen recognized by T cells (MART)-specific T cells will be randomized to Arm I or Arm II.

ARM I: Patients receive cyclophosphamide intravenously (IV) over 2 hours on days -7 to -6 and fludarabine phosphate IV over 30 minutes on days -5 to -1. Patients also receive therapeutic tumor infiltrating lymphocytes IV over 15-60 minutes on day 0 and high-dose aldesleukin IV over 15 minutes every 8-16 hours for up to 15 doses on days 1-5 and 22-26.

ARM II: Patients receive cyclophosphamide, fludarabine phosphate, therapeutic tumor infiltrating lymphocytes, and aldesleukin as in Arm I. Patients also receive therapeutic autologous dendritic cells pulsed with MART-1:26-35(27L) peptide IV over 15-30 minutes approximately 4 hours after tumor infiltrating lymphocytes on day 0.

COHORT B: HLA-A2 non-selected patients with adequate growth of TIL, will receive cyclophosphamide, fludarabine, therapeutic tumor infiltrating lymphocytes, and high-dose aldesleukin as in Cohort A Arm I.

COHORT C: Patients of any HLA type who have not achieved partial response (PR) or complete response (CR) or have progressive disease from treatment of a BRAF inhibitor alone receive cyclophosphamide, fludarabine phosphate, tumor infiltrating lymphocytes, and high-dose aldesleukin IV as in Cohort A Arm I. In addition, patients in this cohort, will continue to receive BRAF-inhibitor which can be taken prior to, during and after the lymphodepletion and TIL treatment.

COHORT D: Patients receive tumor infiltrating lymphocytes IV on days 1 and 15, and aldesleukin intrathecally on days 2, 4, 9, 11, 16, and 18. After this period, patients will receive aldesleukin twice weekly that will be gradually changed to weekly. After 4-6 weeks the patients will be switched to aldesleukin maintenance, normally every 4-6 weeks a single aldesleukin infusion.

After completion of study treatment, patients are followed up every 3-4 weeks for 2 months and then every 1-3 months for 10 months.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
M D Anderson Cancer Center

Principal Investigator
Patrick Hwu

Trial IDs

Primary ID 2004-0069
Secondary IDs NCI-2012-01368
Clinicaltrials.gov ID NCT00338377