ClinicalTrials.gov

History of Changes for Study: NCT03412877
Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Mutated Neoantigens in People With Metastatic Cancer
Latest version (submitted April 17, 2020) on ClinicalTrials.gov
  • A study version is represented by a row in the table.
  • Select two study versions to compare. One each from columns A and B.
  • Choose either the "Merged" or "Side-by-Side" comparison format to specify how the two study versions are to be displayed. The Side-by-Side format only applies to the Protocol section of the study.
  • Click "Compare" to do the comparison and show the differences.
  • Select a version's Submitted Date link to see a rendering of the study for that version.
  • The yellow A/B choices in the table indicate the study versions currently compared below. A yellow table row indicates the study version currently being viewed.
  • Hover over the "Recruitment Status" to see how the study's recruitment status changed.
  • Study edits or deletions are displayed in red.
  • Study additions are displayed in green.
Study Record Versions
Version A B Submitted Date Changes
1 January 26, 2018 None (earliest Version on record)
2 January 27, 2018 Study Status
3 January 30, 2018 Study Status
4 January 31, 2018 Study Status
5 February 1, 2018 Study Status
6 February 2, 2018 Study Status
7 February 3, 2018 Study Status
8 February 6, 2018 Study Status
9 February 7, 2018 Study Status
10 February 8, 2018 Study Description, Study Status and Contacts/Locations
11 February 9, 2018 Study Status
12 February 10, 2018 Study Status
13 February 13, 2018 Study Status
14 February 14, 2018 Study Status
15 February 15, 2018 Study Status
16 February 16, 2018 Study Status
17 February 17, 2018 Study Status
18 February 20, 2018 Study Status
19 February 22, 2018 Study Status
20 February 23, 2018 Study Status
21 February 24, 2018 Study Status
22 February 27, 2018 Study Status
23 February 28, 2018 Study Status
24 March 1, 2018 Study Status
25 March 2, 2018 Study Status
26 March 3, 2018 Study Status
27 March 6, 2018 Study Status
28 March 7, 2018 Study Status
29 March 8, 2018 Study Status
30 March 9, 2018 Study Status
31 March 10, 2018 Study Status
32 March 13, 2018 Study Status
33 March 14, 2018 Study Status
34 March 15, 2018 Study Status
35 March 16, 2018 Study Status
36 March 17, 2018 Study Status
37 March 20, 2018 Study Status
38 March 21, 2018 Study Status
39 March 22, 2018 Study Status
40 March 23, 2018 Study Status
41 March 24, 2018 Study Status
42 March 28, 2018 Recruitment Status, Study Status, References and Contacts/Locations
43 March 29, 2018 Study Status
44 March 30, 2018 Study Status
45 March 31, 2018 Study Status
46 April 3, 2018 Study Status
47 April 4, 2018 Study Status
48 April 5, 2018 Study Status and Study Description
49 April 6, 2018 Study Status
50 April 7, 2018 Study Status
51 April 10, 2018 Study Status
52 April 11, 2018 Study Status
53 April 12, 2018 Study Status
54 April 14, 2018 Study Status
55 April 17, 2018 Study Status
56 April 18, 2018 Study Status
57 April 19, 2018 Study Status
58 April 20, 2018 Study Status
59 April 21, 2018 Study Status
60 April 24, 2018 Study Status
61 April 25, 2018 Study Status
62 April 26, 2018 Study Status
63 April 27, 2018 Study Status
64 April 28, 2018 Study Status
65 May 1, 2018 Study Status
66 May 2, 2018 Study Status
67 May 3, 2018 Study Status
68 May 4, 2018 Study Status
69 May 5, 2018 Study Status
70 May 8, 2018 Study Status
71 May 9, 2018 Study Status and Contacts/Locations
72 May 10, 2018 Study Status
73 May 11, 2018 Study Status
74 May 12, 2018 Study Status
75 May 15, 2018 Study Status
76 May 16, 2018 Study Status
77 May 17, 2018 Study Status
78 May 18, 2018 Study Status
79 May 19, 2018 Study Status
80 May 22, 2018 Study Status
81 May 23, 2018 Study Status and Contacts/Locations
82 May 24, 2018 Study Status
83 May 25, 2018 Study Status
84 May 29, 2018 Study Status
85 May 30, 2018 Study Status
86 May 31, 2018 Study Status
87 June 1, 2018 Study Status
88 June 2, 2018 Study Status
89 June 5, 2018 Study Status
90 June 6, 2018 Study Status
91 June 7, 2018 Study Status
92 June 8, 2018 Study Status
93 June 9, 2018 Study Status
94 June 12, 2018 Study Status
95 June 13, 2018 Study Status
96 June 14, 2018 Study Status
97 June 15, 2018 Study Status
98 June 16, 2018 Study Status
99 June 19, 2018 Study Status
100 June 20, 2018 Study Status
101 June 21, 2018 Study Status
102 June 22, 2018 Study Status, References and Outcome Measures
103 June 23, 2018 Study Status
104 June 26, 2018 Study Status
105 June 27, 2018 Study Status
106 June 28, 2018 Study Status
107 June 29, 2018 Study Status
108 June 30, 2018 Study Status
109 July 3, 2018 Study Status
110 July 5, 2018 Study Status
111 July 6, 2018 Study Status
112 July 7, 2018 Study Status
113 July 10, 2018 Study Status
114 July 11, 2018 Study Status
115 July 12, 2018 Study Status
116 July 13, 2018 Study Status
117 July 14, 2018 Study Status
118 July 17, 2018 Study Status
119 July 18, 2018 Study Status
120 July 19, 2018 Study Status
121 July 20, 2018 Study Status
122 July 21, 2018 Study Status
123 July 24, 2018 Study Status
124 July 25, 2018 Study Status
125 July 26, 2018 Study Status
126 July 27, 2018 Study Status
127 July 28, 2018 Study Status
128 July 31, 2018 Study Status
129 August 1, 2018 Study Status
130 August 2, 2018 Study Status
131 August 3, 2018 Study Status
132 August 4, 2018 Study Status
133 August 7, 2018 Study Status
134 August 8, 2018 Study Status
135 August 9, 2018 Study Status
136 August 10, 2018 Study Status
137 August 11, 2018 Study Status
138 August 14, 2018 Study Status
139 August 15, 2018 Study Status
140 August 16, 2018 Study Status
141 August 17, 2018 Study Status
142 August 18, 2018 Study Status
143 August 21, 2018 Study Status
144 August 22, 2018 Study Status
145 August 23, 2018 Study Status
146 August 24, 2018 Study Status
147 August 25, 2018 Study Status
148 August 28, 2018 Study Status
149 August 30, 2018 Study Status
150 August 31, 2018 Study Status
151 September 4, 2018 Study Status
152 September 5, 2018 Study Status
153 September 6, 2018 Study Status
154 September 7, 2018 Study Status
155 September 8, 2018 Study Status
156 September 11, 2018 Study Status
157 November 24, 2018 Study Status
158 December 1, 2018 Eligibility, Study Description and Study Status
159 December 4, 2018 Study Status and Study Description
160 January 8, 2019 Study Status, Eligibility and Outcome Measures
161 January 26, 2019 Study Status
162 April 5, 2019 Arms and Interventions and Study Status
163 April 13, 2019 Study Status
164 June 7, 2019 Study Status
165 June 19, 2019 Study Design, Eligibility, Outcome Measures, Study Description and Study Status
166 June 26, 2019 Outcome Measures and Study Status
167 June 29, 2019 Study Status and Eligibility
168 July 24, 2019 Study Status
169 November 30, 2019 Study Status and Contacts/Locations
170 December 13, 2019 Study Status
171 December 28, 2019 Outcome Measures, Arms and Interventions, Study Design, Eligibility, Study Description and Study Status
172 December 31, 2019 Arms and Interventions, Outcome Measures and Study Status
173 January 9, 2020 Study Status
174 April 17, 2020 Study Status
Comparison Format:

Scroll up to access the controls

Changes (Merged) for Study: NCT03412877
January 26, 2018 (v1) -- July 24, 2019 (v168)

Changes in: Study Status, References, Contacts/Locations, Outcome Measures, Study Design, Study Description, Eligibility and Arms and Interventions

Study Identification
Unique Protocol ID: 180049
Brief Title: Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Mutated Neoantigens in People With Metastatic Cancer
Official Title: Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Mutated Neoantigens in People With Metastatic Cancer
Secondary IDs: 18-C-0049
Study Status
Record Verification: January 23, 2018 July 23, 2019
Overall Status: Not yet Recruiting
Study Start: February 1, 2018 September 6, 2018
Primary Completion: December 31 March 23, 2021 2027 [Anticipated]
Study Completion: December 29 March 23, 2023 2028 [Anticipated]
First Submitted: January 26, 2018
First Submitted that
Met QC Criteria:
January 26, 2018
First Posted: January 29, 2018 [Actual]
Last Update Submitted that
Met QC Criteria:
January 26, 2018 July 24, 2019
Last Update Posted: January 29 July 25, 2018 2019 [Actual]
Sponsor/Collaborators
Sponsor: National Cancer Institute (NCI)
Responsible Party: Sponsor
Collaborators:
Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring:
Study Description
Brief Summary:

Background:

In gene transfer therapy, cells are taken from a person s tumor to isolate mutations. White blood cells are then taken from the person's body, changed with a type of virus to attack the tumor cells, and returned to the person.

Objective:

To see if gene transfer therapy shrinks tumors.

Eligibility:

People with certain metastatic cancer for which standard treatments have not worked

Design:

Participants will complete screening and stages 1-3 under another protocol. Screening includes:

Getting tumor cells from a previous procedure Undergoing a biopsy or surgery at the NIH to obtain pieces of tumor in order to grow tumor cells

Medical history

Physical exam

Scans

Blood, urine, heart, and lung tests

The study has 7 stages:

  1. Screening tests repeated over 1-2 weeks. Participants will have leukapheresis: Blood is removed by a needle in one arm. A machine removes white blood cells. The rest of the blood is returned by a needle in the other arm. An IV catheter will be placed in the chest.
  2. Care at home over 6-12 weeks.
  3. Stopping therapy for 4-6 weeks while their cells are changed in a lab.
  4. Hospital stay for 1 week to get chemotherapy by IV.
  5. Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells live longer.
  6. Recover in the hospital for 1 2 weeks. Participants will get drugs and have blood and urine tests.
  7. Participants will take an antibiotic and maybe an antiviral for at least 6 months after treatment. They will have repeat screening tests at visits every few months for the first year, every 6 months for the second year, then as determined.

    ...

Detailed Description:

Background:

  • The administration of autologous tumor-infiltrating lymphocytes (TIL) can mediate complete, durable regressions in 20- to 25% of patients with metastatic melanoma. Recent studies have shown that these TIL predominantly recognize unique mutated neoantigens expressed by the cancer not shared by other melanomas.
  • Administration of bulk autologous TIL to patients with a variety of other solid cancers, including cancers of the gastrointestinal tract and genitourinary tract, have little if any therapeutic impact.
  • Recent studies in the National Cancer Institute Surgery Branch, (NCI-SB), have shown that TIL from non-melanoma solid cancers can also contain T-cells reactive against non-shared unique mutated neoantigens expressed in the cancer. The frequency of these T-cells is very low (often < 0.1%) and it is thus difficult to isolate and grow mutation reactive T-cells to levels required for effective therapy.
  • In a single patient with chemo-refractory metastatic cholangiocarcinoma we were able to grow a relatively pure population of neoantigen reactive TIL and administration of these cells mediated a near-complete regression of all metastatic disease now lasting 2 (Omega) 2.5 years.
  • We have now developed approaches to identify these rare neoantigen reactive T-cells from common non-melanoma cancers, to isolate their T-cell receptors (TCR), and to genetically engineer autologous peripheral blood lymphocytes (PBL) to express these TCRs with high efficiency. The neoantigen TCR gene-modified cells can recognize and destroy the autologous cancer in vitro.
  • With these techniques, we have isolated a number of TCRs selectively recognizing shared mutated oncogenes (e.g., KRAS, TP53) in the context of several major histocompatibility complexes (MHC-I and MHC-II). For patients with the appropriate MHC restriction, whose tumors express these shared mutated oncogenes, these TCRs represent an additional option for broadening the patient s anti-tumor repertoire with autologous gene-modified cells.
  • We are now proposing a This clinical protocol to will treat patients with refractory solid cancers using the adoptive transfer of autologous PBL transduced with genes encoding TCRs that recognize unique mutated neoantigens expressed by the cancer.

Objectives:

-Primary objective:

--To --Determine the rate of objective response (using RECIST v1.1 criteria) of patients with solid cancers who receive autologous PBL that have been transduced with genes encoding T-cell receptors that recognize mutated neoantigens in the autologous cancer.

Eligibility:

-Patients who are 18 years of age or older must be/have:

  • Age greater than or equal to 18 years and less than or equal to 70 years
  • Measurable Solid cancer with at least one lesion that is resectable for TIL generation with minimal morbidity plus at least one other lesion that can be measured, that falls into one of four cohorts: (1) gastrointestinal and genitourinary cancers , ; (2) breast and , ovarian, and other solid cancers , ; (3) non-small cell lung cancer (NSCLC) , ; and, (4) glioblastoma. Metastatic disease is required for cohorts 1-3, but not for cohort 4.
  • Evaluable solid cancer that has recurred following standard chemotherapy or standard systemic therapy
  • Normal basic laboratory values.
  • At least one lesion suitable for surgical resection for the preparation of the cell product
  • No allergies or hypersensitivity to high-dose aldesleukin administration
  • No concurrent major medical illnesses or any form of immunodeficiency.

Design:

  • Patients will have already undergone resection or biopsy to obtain tumor for generation of autologous TIL cultures. This will have been conducted under the NCI-SB cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols).
  • Patients will undergo resection or biopsy to obtain tumor for generation of autologous TIL cultures. Patients will be entered into four cohorts that include (1) gastrointestinal and genitourinary cancers, (2) breast and ovarian, and other solid cancers, (3) non-small cell lung cancer (NSCLC), and (4) glioblastomas. Exomic sequencing, and often RNA-Seq will be performed to identify the mutations expressed in the patient s cancer. Multiple autologous TIL cultures will be grown and tested for reactivity against mutations from the autologous tumor using assays we have developed that involve the exposure of autologous antigen-presenting cells to long peptides containing the mutation or tandem mini-genes encoding the mutation.
  • T-cell cultures with reactivity against mutations will be identified and the individual T-cell receptors that recognize the mutation will be synthesized and used to create a retrovirus for transduction of the TCR into the patient s autologous PBL.
  • Patients that present with tumors expressing mutated shared oncogenes (KRAS or TP53) that also express the appropriate restriction element may be treated with autologous PBLs retrovirally -transduced with TCR(s) previously isolated in the Surgery Branch targeting the shared mutated antigen. These patients will be administered a cell infusion product of TCRs targeting mutated shared oncogenes (KRAS or TP53). Their cell infusion product will not include PBL transduced with unique (i.e., non-shared) TCR(s).
  • Patients will be entered into four cohorts: (1) gastrointestinal and genitourinary cancers; (2) breast, ovarian, and other solid cancers; (3) non-small cell lung cancer (NSCLC); and, (4) glioblastoma. Autologous PBL (transduced with either TCR(s) targeting mutated shared oncogenes TP53 or KRAS, or, TCR(s) targeting individual neoantigens) will then be expanded to large numbers using our standard rapid expansion protocol and administered to the patient following a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine. Patients will then begin high-dose aldesleukin after the infusion of autologous transduced PBL. At the discretion of the Principal Investigator (PI), patients enrolled in Cohort 3 may receive low-dose aldesleukin.
  • Clinical and immunologic response will be evaluated about 4-6 weeks after cell infusion and periodically thereafter.
  • It is anticipated that approximately one patient per month may enroll on the trial for each of the four histologic groups. Thus, accrual of up to 4 x 50=200 total evaluable patients may be completed in approximately 2-4 years. In order to allow for a small number of inevaluable patients, the accrual ceiling will be set to 210.
  • Transduced autologous PBL will then be expanded to large numbers using our standard

rapid expansion protocol and administered to the patient following a non-myeloablative

lymphodepleting regimen.

  • All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine. Patients will then receive the infusion of autologous transduced PBL and begin high-dose aldesleukin (720,000 IU/kg IV every 8 hours for up to 10 doses). At the discretion of the PI, patients enrolled in cohort 3 may receive low-dose aldesleukin (72,000 IU/kg IV every 8 hours for up to 10 doses).
  • Clinical and immunologic response will be evaluated about 4-6 weeks after cell infusion and periodically thereafter.
  • It is anticipated that approximately one patient per month may enroll into the trial for each of the 4 histologic groups. Thus, accrual of up to 4 x 50=200 total evaluable patients may be completed in approximately 2 to 4 years. In order to allow for a small number of inevaluable patients, the accrual ceiling will be set to 210.
Conditions
Conditions: Glioblastoma
Non-Small Cell Lung Cancer
Ovarian Cancer
Breast Cancer
Gastrointestinal/Genitourinary Cancer
Keywords: Gene Therapy
Immunotherapy
Cell Therapy
Adoptive Cell Therapy
Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2
Interventional Study Model: Parallel Assignment Single Group Assignment
Number of Arms: 1
Masking: None (Open Label)
Allocation: N/A
Enrollment: 210 [Anticipated]
Arms and Interventions
Arms Assigned Interventions
Experimental: 1-Experimental Therapy
Non-myeloablative lymphocyte depleting chemotherapy regimen of cyclophosphamide and fludarabine + Individual Patient TCR-Transduced PBL + high or low-dose aldesleukin
Drug: Cyclophosphamide
Days -7 and -6: Cyclophosphamide 60 mg/kg/day x 2 days IV in 250 mL D5W infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days.
Drug: Fludarabine
Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Aldesleukin
Aldesleukin 720,000 IU/kg IV over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 10 doses). Patients in cohort 3 may receive 72,000 IU/kg IV.
Biological: Individual Patient TCR-Transduced PBL
Day 0: Cells will be infused at a dose not to exceed 1.5E11 in 400 mL intravenously over 20-30 minutes or as clinically determined by an investigator for patient safety via non-filtered tubing, gently agitating the bag during infusion to prevent cell clumping. Day 0: Cells will be infused intravenously on the Patient Care Unit over 20-30 minutes.
Outcome Measures
Primary Outcome Measures:
1. Response rate
Percentage of patients who have a clinical response to treatment (objective tumor regression)

[Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2 years, then per PI discretion]
Secondary Outcome Measures:
2. Phenotypic and functional characteristics of PBL
Phenotypic and functional characteristics of PBL

[Time Frame: 2-4 years post cell infusion]
3. In vivo survival of TCR gene-engineered cells
TCR and vector presence will be quantitated in PBMC samples using established PCR techniques

[Time Frame: 6 weeks post-treatment and then as indicated]
Eligibility
Minimum Age: 18 Years
Maximum Age: 70 Years
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:
  • INCLUSION CRITERIA:
  • Solid cancer that can be measured, that falls into one of four cohorts: (1) gastrointestinal and genitourinary cancers; (2) breast, ovarian, and other solid cancers; (3) non-small cell lung cancer (NSCLC); and, (4) glioblastoma.

    --Note: Metastatic disease is required for Cohorts 1-3, but not required for cohort 4. NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous carcinoma or adenocarcinomas. Neuroendocrine tumors are not eligible.

  • Confirmation of diagnosis of cancer by the NCI Laboratory of Pathology.
  • Measurable solid cancer with at least one lesion that is resectable for TIL generation with minimal morbidity plus at least one other lesion that can be measured that falls into one of four cohorts:
    1. gastrointestinal and genitourinary cancers
    2. breast and ovarian, and other solid cancers
    3. non-small cell lung cancer (NSCLC)
    4. glioblastoma
      • Note: Metastatic disease is required for cohorts 1-3, but not required for cohort 4.
      • Note: NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous carcinoma or adenocarcinomas. Neuroendocrine tumors are not eligible.
  • Refractory to approved standard systemic therapy. Specifically:
    • Patients with metastatic colorectal cancer must have received oxaliplatin or irinotecan.
    • Patients with breast and ovarian cancer must be refractory to both 1st line first and 2nd second line treatments.
    • Patients with NSCLC must have received at least one platinum-based chemotherapy regimen and at least one FDA approved targeted treatment (when appropriate).
    • Patients with glioblastoma must have progression of disease after radiotherapy (including patients that undergo surgery for recurrent disease and are rendered NED). This includes recurrent GBM glioblastoma after receiving all standard first-line treatment, including surgery (if feasible due to neurosurgical and neuro-anatomical considerations) and adjuvant radiotherapy +/- chemotherapy.
  • For Cohorts 1-3 , : patients with 3 or fewer brain metastases that are less than or equal to 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 one month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
  • For cohort 4 only (glioblastoma), patients must either not be receiving steroids, or be on a stable dose of steroids for at least five days prior to registration.
  • Age greater than or equal to 18 years and less than or equal to 70 years.
  • For Cohorts 1-3 , : clinical performance status of ECOG 0 or 1.
  • For cohort 4 , (glioblastoma), : Patients must have Karnofsky performance status of greater than or equal to 60.
  • Willing to sign a durable power of attorney.
  • Patients of both genders must be willing to practice birth control during treatment and from the time of enrollment on this studyand for four months after treatment.
  • Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  • Able to understand and sign a written informed consent document.
  • Serology:
    • Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can may have decreased immune-competence and thus may be less responsive to the experimental treatment and more susceptible to its toxicities.)
    • Seronegative for active hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
  • Hematology:
    • Absolute neutrophil count ANC > 1000/mm^3 without the support of filgrastim
    • Normal WBC (> 3000/mm^3). WBC greater than or equal to 3000/mm^3
    • Platelet count > greater than or equal to 100,000/mm^3
    • Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cut-off.
  • Chemistry:
    • Serum ALT/AST < less than or equal to 5.0 x ULN
    • Serum creatinine less than or equal to 1.6 mg/dl.
    • 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 or equal to 3.0 mg/dl.
  • More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients' toxicities must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures within the past three weeks, as long as all toxicities have recovered to grade 1 or less.
  • For cohort 3, More than two four weeks must have elapsed since any prior palliation for major bronchial occlusion or bleeding systemic therapy at the time the patient receives the preparative regimen, and patients s ' toxicities must have recovered to a grade 1 or less.
  • For cohort 4, patients must be at least four weeks from radiation therapy. Additionally, patients must be at least six weeks from nitrosoureas, four weeks from temozolomide, three weeks from procarbazine, two weeks from vincristine and four weeks from last bevacizumab administration. Patients must be at least four weeks from other cytotoxic therapies not listed above and two weeks for non-cytotoxic agents (e.g., interferon) including investigative agents.
  • Subjects must be co-enrolled in protocol 03-C-0277.

Note: Patients may have undergone minor surgical procedures within the past three weeks, as long as all toxicities have recovered to grade 1 or less.

  • For cohort 3: more than two weeks must have elapsed since any prior palliation for major bronchial occlusion or bleeding at the time the patient receives the preparative regimen, and patient s toxicities must have recovered to a grade 1 or less.
  • For cohort 4: patients must be at least four weeks from radiation therapy. Additionally, patients must be at least six weeks from nitrosoureas, four weeks from temozolomide, three weeks from procarbazine, two weeks from vincristine and four weeks from last bevacizumab administration. Patients must be at least four weeks from other cytotoxic therapies not listed above and two weeks for non-cytotoxic agents (e.g., interferon) including investigative agents.
  • For Cohort 4: Patients must either not be receiving steroids, or be on a stable dose of steroids, for at least five days prior to registration.
  • Ability of subject to understand and the willingness to sign a written informed consent document.
  • Willing to sign a durable power of attorney.
  • Subjects must be co-enrolled on protocol 03-C-0277.

EXCLUSION CRITERIA:

  • Women of child-bearing potential who are pregnant or breastfeeding because of the potential potentially dangerous effects of the treatment on the fetus or infant.
  • Concurrent systemic steroid therapy required , except for patients with glioblastoma (cohort 4).
  • Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
  • For cohort 3 , : Any major bronchial occlusion or bleeding not amenable to palliation.
  • For cohort 4 , : Clinically significant hemorrhagic or ischemic stroke, including transient ischemic attacks and other central nervous system bleeding in the preceding 6 six months that were not related to glioma surgery. History of prior intratumoral bleeding is not an exclusion criterion; however, patients with a history of prior intratumoral bleeding, will need to undergo a non-contrast head CT to exclude acute bleeding.
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
  • Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its

Note: History of prior intratumoral bleeding is not an exclusion criterion; however, patients with a history of prior intratumoral bleeding, will need to undergo a non-contrast head CT to exclude acute bleeding.

  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
  • Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its

toxicities.)

  • History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
  • For Cohorts 1, 2, or 4: Clinically significant patient history which in the judgment of the Principal Investigator (PI) would compromise the patients' ability to tolerate high-dose aldesleukin.

Note: At the discretion of the PI, patients enrolled in cohort 3 may receive low-dose aldesleukin.

  • History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
  • History of coronary revascularization or ischemic symptoms.
  • Any patient known to have an LVEF less than or equal to 45%.
  • Documented LVEF less than or equal to 45% tested in patients:
    • Age greater than or equal to 65 years
    • With clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second- or third-degree heart block or have a history of ischemic heart disease and/or chest pain
  • Clinically significant patient history which in the judgment of the PI would compromise the patients' ability to tolerate high-dose aldesleukin. (Note: At the discretion of the PI, patients enrolled in cohort 3 may receive low-dose aldesleukin.)
  • Documented FEV1 less than or equal to 50% predicted tested in patients with:
    • A prolonged history of cigarette smoking ( approximately greater than or equal to 20 pack- / year smoking history, within the past two years).
    • Symptoms of respiratory dysfunction
  • Patients who are receiving any other investigational agents.
Contacts/Locations
Central Contact: Ellen Bodurian
Telephone: (866) 820-4505
Email: ellen.bodurian IRC@nih.gov
Study Officials: Steven A Rosenberg, M.D.
Principal Investigator
National Cancer Institute (NCI)
Locations: United States, Maryland
National Institutes of Health Clinical Center
[Recruiting]
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center 866-820-4505 ncisbirc irc@ mail. nih.gov
IPDSharing
Plan to Share IPD:
References
Citations: Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015 Apr 3;348(6230):62-8. doi: 10.1126/science.aaa4967. Review. PubMed 25838374 Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, Wunderlich JR, Somerville RP, Hogan K, Hinrichs CS, Parkhurst MR, Yang JC, Rosenberg SA. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014 May 9;344(6184):641-5. doi: 10.1126/science.1251102. PubMed 24812403
Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE, Dudley ME. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011 Jul 1;17(13):4550-7. doi: 10.1158/1078-0432.CCR-11-0116. Epub 2011 Apr 15. PubMed 21498393 Lu YC, Yao X, Crystal JS, Li YF, El-Gamil M, Gross C, Davis L, Dudley ME, Yang JC, Samuels Y, Rosenberg SA, Robbins PF. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin Cancer Res. 2014 Jul 1;20(13):3401-10. doi: 10.1158/1078-0432.CCR-14-0433. PubMed 24987109
Robbins PF, Lu YC, El-Gamil M, Li YF, Gross C, Gartner J, Lin JC, Teer JK, Cliften P, Tycksen E, Samuels Y, Rosenberg SA. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med. 2013 Jun;19(6):747-52. doi: 10.1038/nm.3161. Epub 2013 May 5. PubMed 23644516
Links: Description: NIH Clinical Center Detailed Web Page
Available IPD/Information:

Scroll up to access the controls Scroll to the Study top

U.S. National Library of Medicine | U.S. National Institutes of Health | U.S. Department of Health & Human Services