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Adoptive Cell Therapy Across Cancer Diagnoses

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ClinicalTrials.gov Identifier: NCT03296137
Recruitment Status : Recruiting
First Posted : September 28, 2017
Last Update Posted : August 1, 2018
Sponsor:
Information provided by (Responsible Party):
Inge Marie Svane, Herlev Hospital

Brief Summary:
This study will perform tumor-infiltrating lymphocyte (TIL)-based adoptive T-cell therapy in combination with checkpoint inhibition on cancer patients across all cancer diagnoses.

Condition or disease Intervention/treatment Phase
Cancer Biological: Autologous tumor-infiltrating lymphocytes Drug: Ipilimumab Drug: Nivolumab Drug: proleukin Drug: Cyclophosphamide Drug: Fludara Phase 1 Phase 2

Detailed Description:

Adoptive cell therapy (ACT) is a personalized form of immunotherapy, where lymphocytes isolated from the patient's own tumor tissue are expanded 1000-fold ex-vivo and then infused back into the patient. The lymphocytes are then able to recognize and attack remaining cancer cells. This approach has shown remarkable clinical results in several trials conducted worldwide for patients with advanced melanoma - some with durable remissions. Promising clinical results were obtained in smaller trials where patients with disparate solid tumors were treated with tumor-infiltrating lymphocytes (TILs). At Center for Cancer Immune Therapy (CCIT) at Herlev Hospital, there are currently clinical trials undergoing in ovarian and renal cancer, and internationally ACT is being tested in an increasing number of cancer diagnoses, some trials are even recruiting patients across cancer types. Studies have shown that a high intratumoral infiltration with TILs in is correlated to the general clinical outcome of the disease in virtually all solid tumors, and thus clinical trials with TIL-based ACT to different cancer diagnoses have been undertaken.

To support the TIL-mediated tumor elimination, in classical ACT protocols patients go through a highly specialized treatment regime before and after TIL infusion. This regime includes lymphodepletion with 7 days non-myeloablative chemotherapy, to provide an immunological window of opportunity for the infused TILs, and concomitant immune stimulation with interleukin-2 (IL-2). Checkpoint inhibition to support the anti-tumor activity of TILs is currently under extensive investigation in several other trials worldwide. Thus, lymphodepletion and IL-2 stimulation are well-established as supportive therapy and already an integrated part of current ACT protocols and while checkpoint inhibition is a new addition at CCIT; internationally other centers have ongoing comparable trials.

Drug-based immunotherapy in the form of checkpoint inhibitors (anti-PD-1 and anti-CTLA-4) has yielded impressive clinical results across tumor histologies. Recent results indicate that the effect of immunotherapy relies not so much on the cancer diagnoses but rather on the genomic and immunologic features of the individual patient's cancer disease. Both ACT and checkpoint inhibition work by tipping the immunological balance in favor of activation and away from suppression or avoidance by the cancer cells. Scientific evidence now show that administering anti-CTLA-4 and PD-1 could provide a benefit in the ACT setting, and several ongoing clinical trials are testing combinations of ACT and checkpoint inhibition. To synergistically maximize the immunological potential, we wish to combine ACT with an anti-CTLA-4 antibody (Ipilimumab) prior to tumor resection and an anti-PD-1 antibody (Nivolumab) in combination with TIL infusion.

Patients will be treated with one dose of Ipilimumab 14 days before undergoing surgery to harvest tumor material for TIL production. Patients is admitted on day -8 in order to undergo lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7. On day -2 patients will start treatment with Nivolumab every 2 weeks for a total of 4 doses to increase the activity of the infused TIL product.

Available evidence indicates that ACT is a safe and feasible treatment option in an increasing number of solid tumors, and that it should be tested in all cancer patients regardless of their cancer diagnosis.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Adoptive Cell Therapy Across Cancer Diagnoses
Actual Study Start Date : October 13, 2017
Estimated Primary Completion Date : October 13, 2019
Estimated Study Completion Date : March 13, 2020

Arm Intervention/treatment
Experimental: All participants Biological: Autologous tumor-infiltrating lymphocytes
Tumor-infiltrating lymphocytes grown ex-vivo from resected from cancer tissue and reapplied to the patient via an intravenous infusion.

Drug: Ipilimumab
One treatment with ipilimumab (3 mg/kg) prior to tumor resection.

Drug: Nivolumab
4 doses of nivolumab. Starting 2 days prior to TIL infusion and every 2 weeks hereafter.

Drug: proleukin
2 MIE s.c. injection, after TIL infusion and continuing for 2 weeks

Drug: Cyclophosphamide
2 doses (60 mg/kg) prior to TIL infusion

Drug: Fludara
5 doses (25 mg/m2) prior to TIL infusion




Primary Outcome Measures :
  1. Number and type of reported adverse events [ Time Frame: Up to 2,5 years from begin of study ]
    Determine the safety of the administration of TIL therapy including checkpoint inhibitors, lymphodepleting chemotherapy and Interleukin-2 for patients with cancer by reporting adverse events according to CTCAE v. 4.0.


Secondary Outcome Measures :
  1. Treatment response, progressive disease [ Time Frame: Up to 7 years from begin of study ]
    Clinical response in progression-free survival to treatment according to RECIST 1.1

  2. Treatment response, surival [ Time Frame: Up to 7 years from begin of study ]
    Clinical response in terms of overall survival.

  3. Treatment related immune response [ Time Frame: 3 years from begin of study ]
    Flow cytometry-based immunological evaluation of peripheral blood



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Only patients within the Danish Healthcare system are eligible for enrollment.

Inclusion Criteria:

  • Histologically verified metastatic or locally advanced cancer diagnosis
  • At least one lesion (>1 cm3) available for surgical resection
  • Not candidate for standard treatment options
  • Age of 18-70 years
  • Performance status of 1 or 0.
  • Life expectancy > 6 months
  • One or more measurable parameter according to RECIST 1.1.
  • No significant toxicity from previous cancer treatments (CTC≤1). Except aloplecia (CTC≤2) or neuropathy (CTC≤2)
  • Sufficient organ function, including:
  • Absolute neutrophil count (ANC) ≥ 1.500 /µl
  • Leucocyte count ≥ normal limit
  • Platelets ≥ 100.000 /µl and <700.000 /µl
  • Hemoglobin ≥ 6,0 mmol/l (regardless of prior transfusion)
  • S-creatinine < 140
  • S-bilirubin ≤ 1,5 times upper normal limit
  • ASAT/ALAT ≤ 2,5 times upper normal limit
  • Alkaline phosphatase ≤ 5 times upper normal limit
  • Lactate dehydrogenase (LDH) ≤ 5 times upper normal limit
  • Sufficient coagulation: PP-time>40 and INR<1,5
  • Women in the fertile age must use effective contraception. This applies from inclusion and until 6 months after treatment. Birth control pills, spiral, depot injection with gestagen, subdermal implantation, hormonal vaginal ring and transdermal depot patch are all considered safe contraceptives.
  • Signed statement of consent after receiving oral and written study information
  • Willingness to participate in the planned treatment and follow-up and capable of handling toxicities.

Exclusion Criteria:

  • A history of prior malignancies. Patients treated for another malignancy can only participate if they are without signs of disease for a minimum of 3 years after last treatment.
  • Primary brain tumor or verified brain metastases
  • Known hypersensitivity to one of the active drugs or excipients.
  • Significant medical conditions, including but not limited to severe asthma/COLD, significant cardiac disease, poorly regulated insulin dependent diabetes mellitus.
  • Creatinine clearance below 70 ml/min .
  • Acute or chronic infections with HIV, hepatitis, syphilis etc.
  • Severe allergies or previous anaphylactic reactions.
  • Active autoimmune disease, such as autoimmune neutropenia/thrombocytopenia or hemolytic anemia, systemic lupus erythematosus, Sjögren's syndrome, sclerodermia, myasthenia gravis, goodpastures disease, addison's disease, hashimoto's thyroiditis, graves' disease etc.
  • Pregnant women and women who are breastfeeding.
  • Simultaneous treatment with systemic immunosuppressive drugs (including prednisolone methotrexate etc.)
  • Simultaneous treatment with other experimental drugs.
  • Simultaneous treatment with other systemic anti-cancer treatments.
  • Patients with active or uncontrollable hypercalcemia.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03296137


Contacts
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Contact: Inge Marie Svane, MD, Prof 38683868 inge.marie.svane@regionh.dk
Contact: Anders H Kverneland, MD 38683868 anders.kverneland@regionh.dk

Locations
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Denmark
Center for Cancer immune Therapy (CCIT), Dept. of Hematology and dept. of Oncology Recruiting
Copenhagen, Denmark, 2730
Contact: Anders H Kverneland, MD       anders.kverneland@regionh.dk   
Sponsors and Collaborators
Inge Marie Svane
Investigators
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Principal Investigator: Anders H Kverneland, MD Center for Cancer Immune Therapy, Herlev Hospital
Study Director: Inge Marie Svane, MD, Prof. Center for Cancer Immune Therapy, Herlev Hospital

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Responsible Party: Inge Marie Svane, M.D. Professor, Herlev Hospital
ClinicalTrials.gov Identifier: NCT03296137     History of Changes
Other Study ID Numbers: AA1720
First Posted: September 28, 2017    Key Record Dates
Last Update Posted: August 1, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Inge Marie Svane, Herlev Hospital:
immune therapy
TILs
Adoptive cell therapy
Additional relevant MeSH terms:
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Aldesleukin
Cyclophosphamide
Nivolumab
Ipilimumab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents