Metastatic MelanomaEarly Phase 1NCT03526185
A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes
A Early Phase 1 study testing Tumor Infiltrating Lymphocytes and Nivolumab and Ipilimumab in people with Metastatic Melanoma, run by Yale University at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Melanoma
- What is being tested?
- Tumor Infiltrating Lymphocytes and Nivolumab and Ipilimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- 6 Feb 2018to 1 Dec 2020
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- For Cohorts 1 and 2:
- Metastatic melanoma;
- A metastatic lesion at least 1.5 cm in diameter that can be removed surgically
- Measurable or evaluable disease not including the resected lesion
- ECOG PS of 0 or 1 prior to cell 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)
- Tumor refractory to or progressing following prior PD-1/PD-L1 therapy alone or in combination with an anti-CTLA-4 agent
- Ability to understand risks and benefits of the treatment and to give informed consent
Who cannot join
- For Cohorts 1 and 2:
- Received prior cell transfer therapy that included non-myeloablative or ablative chemotherapy
- Any significant major organ dysfunction (see protocol)
- Residual toxicity > gr1 from immune checkpoint inhibitor other than persistent endocrinopathy on hormone replacement; all symptoms of prior colitis and enteritis must have resolved completely as assessed by history
- Any contraindication to neutropenia or thrombocytopenia for up to 2 weeks (no active major infection, no site of active, clinically significant bleeding)
- Concurrent major medical illnesses
Show all 23Show fewer
- Any form of immunodeficiency
- Requirement for steroids > 10 mg prednisone daily or equivalent
- Severe hypersensitivity to any of the agents used in this study
- Contraindications for IL-2 administration
- At the time of lymphoablation subjects must meet baseline eligibility criteria with the following additions and exceptions:
- Confirmation by lab that cell product can be ready for harvest and infusion within 7 days
- For Cohort 2 only:
- At the time of the start of anti-PD-1/anti-CTLA-4 therapy, subjects must meet baseline eligibility criteria with the following additions and exceptions:
- Patient cannot have a steroid requirement > 10 mg prednisone daily or equivalent
- Patients who have received prior PD-1/PD-L1 antagonist therapy and developed severe autoimmune disease precluding further immune checkpoint therapy
- Any organ dysfunction that makes the subject ineligible for anti-PD1 and anti-CTLA-4 treatment as deemed by the treating investigator
- ECOG PS of 0-2
- Hgb of at least 8.0 gm/dl (may be transfused to this level)
- Creatinine not greater than 2.5 mg/dl
- AST or ALT not > 5x ULN and total bilirubin not > 2.5 mg/dl
- No clinically significant change in major organ function compared to initial eligibility evaluation
- Prior to initiating the lymphoablation regimen, there can be no untreated brain lesion > 1.0 cm, and/or with significant evidence of hemorrhage. Subjects may begin lymphoablation no less than 1 full day after completing WBRT or stereotactic radiotherapy for brain lesions.
Trial locations and contacts
1 site in 1 country.
United States1 site
Yale New Haven Hospital
New Haven, Connecticut, 06510
About this study
Official title: A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Melanoma
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. Additionally, a second cohort of patients with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist alone or in combination with anti-CTLA-4 will receive anti-PD-1 and anti-CTLA-4 therapy with Nivolumab and Ipilimumab.
Read the detailed description
The objectives of this study have been expanded since its original registration to inlcude an additional cohort of patients (now designated Cohort 1 and Cohort 2). Cohort 1 is the original group of patients described in the initial registration of the study.
Cohort 1 Objectives:
- 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.
- To assess for evidence of clinical activity.
- To conduct a preliminary assessment of the TCR clonotypes present in marker positive CD8+ cells (4-1BB, LAG-3, TIM-3, PD-1) versus marker-negative CD8+ T-cells early in the expansion cultures and compare to clonotypes late in the final product and in peripheral blood lymphocytes (PBL) 1 and 2 months post infusion.
Cohort 2 Objectives:
- 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, followed by anti-PD-1 and anti-CTLA-4 therapy with Nivolumab and Ipilimumab in subjects with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist alone or in combination with anti-CTLA-4.
- To evaluate the efficacy of TIL/IL-2 therapy in combination with subsequent anti-PD-1 Nivolumab and anti-CTLA-4 Ipilimumab by assessing the objective response rate by immune-related RECIST (irRECIST).
- To conduct a preliminary assessment of the TCR clonotypes present in marker positive CD8+ cells (e.g. 4-1BB, LAG-3, TIM-3, PD-1) versus marker-negative CD8+ T-cells early in the expansion cultures and compare to clonotypes late in the final product and in peripheral blood lymphocytes (PBL) 1 and 2 months post infusion.
- Conditions
- Metastatic Melanoma
- Being tested
- Tumor Infiltrating Lymphocytes, Nivolumab and Ipilimumab
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tumor Infiltrating LymphocytesDrug
Also called Autologous TIL, Unselected TIL, Young TIL
The regimen consists of treatment with cyclophosphamide and fludarabine,followed by infusion of up to 3x1011 lymphocytes (minimum of 1x109) expanded in vitro from subjects own resected tumor followed by the administration of aldesleukin (IL-2).
Nivolumab and IpilimumabDrug
- Within 1 week post discharge subjects will be treated with Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg every 3 weeks for 4 doses. Following this, patients will receive Nivolumab 480 mg every 4 weeks. Adjuvant Nivolumab will continue until evidence of disease progression or inability to tolerate treatment.
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 | Experimental | * Subjects will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m2/day) on days -5 through -1.
* Prophylactic antibiotics will be administered as medically indicated until recovery of ANC to > 500 and recovery of ALC to > 400
* On day 0 subjects will receive the infusion of autologous TIL and one hour later (but can be delayed up to 24 hours) will begin low-dose aldesleukin (IL-2) (72,000 IU/kg IV every 12 hours for up to 10 doses). Receives: Drug: Tumor Infiltrating Lymphocytes |
| Cohort 2 | Experimental | * Subjects will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m2/day) on days -5 through -1.
* Prophylactic antibiotics will be administered as medically indicated until recovery of ANC to > 500 and recovery of ALC to > 400
* On day 0 subjects will receive the infusion of autologous TIL and one hour later (but can be delayed up to 24 hours) will begin low-dose aldesleukin (IL-2) (72,000 IU/kg IV every 12 hours for up to 10 doses).
* Within 1 week post discharge subjects will be treated with Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg every 3 weeks for 4 doses. Following this, patients will receive Nivolumab 480 mg every 4 weeks. Adjuvant Nivolumab will continue until evidence of disease progression or inability to tolerate treatment. Receives: Drug: Tumor Infiltrating Lymphocytes; Drug: Nivolumab and Ipilimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Adverse Events
To determine the safety of administering a regimen of TIL/IL-2, incidence of drug-related adverse events (AEs) will be summarized across adverse event type in terms of frequency by event type.
Measured: up to 12 months
Serious Adverse Events
To determine the safety of administering a regimen of TIL/IL-2, serious adverse events (SAEs) will be summarized across event type in terms of frequency by event type. SAE's will include events leading to discontinuation, deaths and clinical laboratory test abnormalities
Measured: up to 12 months
Secondary outcomes (1)
Objective response rate to TIL
Objective response rate (ORR) of the TIL/IL-2 regimen based on investigator review of radiographic images using RECIST 1.1 criteria
Measured: up to 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 May 2018
- Study start6 Feb 2018
- Primary completion1 Dec 2020
- Study completion1 Dec 2020
Why it stopped: lack of funds
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic MelanomaStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- 2 separate cohorts are included in the study design. These groups will not be directly compared.
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Michael Hurwitz, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03526185
- Sponsor's protocol ID
- 2000020477
- Status last verified
- Jul 2022
- First submitted
- 22 Jan 2018
- Last updated
- 25 Jul 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Melanoma
- ClinicalTrials.gov ID
- NCT03526185
- Acronym / sponsor ID
- 2000020477
- Conditions
- Metastatic Melanoma
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: lack of funds
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Study start
- 6 Feb 2018 (actual)
- Primary completion
- 1 Dec 2020 (actual)
- Study completion
- 1 Dec 2020 (actual)
- First posted
- 16 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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. Additionally, a second cohort of patients with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist alone or in combination with anti-CTLA-4 will receive anti-PD-1 and anti-CTLA-4 therapy with Nivolumab and Ipilimumab.
Detailed description
The objectives of this study have been expanded since its original registration to inlcude an additional cohort of patients (now designated Cohort 1 and Cohort 2). Cohort 1 is the original group of patients described in the initial registration of the study.
Cohort 1 Objectives:
- 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.
- To assess for evidence of clinical activity.
- To conduct a preliminary assessment of the TCR clonotypes present in marker positive CD8+ cells (4-1BB, LAG-3, TIM-3, PD-1) versus marker-negative CD8+ T-cells early in the expansion cultures and compare to clonotypes late in the final product and in peripheral blood lymphocytes (PBL) 1 and 2 months post infusion.
Cohort 2 Objectives:
- 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, followed by anti-PD-1 and anti-CTLA-4 therapy with Nivolumab and Ipilimumab in subjects with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist alone or in combination with anti-CTLA-4.
- To evaluate the efficacy of TIL/IL-2 therapy in combination with subsequent anti-PD-1 Nivolumab and anti-CTLA-4 Ipilimumab by assessing the objective response rate by immune-related RECIST (irRECIST).
- To conduct a preliminary assessment of the TCR clonotypes present in marker positive CD8+ cells (e.g. 4-1BB, LAG-3, TIM-3, PD-1) versus marker-negative CD8+ T-cells early in the expansion cultures and compare to clonotypes late in the final product and in peripheral blood lymphocytes (PBL) 1 and 2 months post infusion.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 2 separate cohorts are included in the study design. These groups will not be directly compared.
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Experimental | Drug: Tumor Infiltrating Lymphocytes* Subjects will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m2/day) on days -5 through -1. * Prophylactic antibiotics will be administered as medically indicated until recovery of ANC to > 500 and recovery of ALC to > 400 * On day 0 subjects will receive the infusion of autologous TIL and one hour later (but can be delayed up to 24 hours) will begin low-dose aldesleukin (IL-2) (72,000 IU/kg IV every 12 hours for up to 10 doses). |
| Cohort 2 | Experimental | Drug: Tumor Infiltrating Lymphocytes, Drug: Nivolumab and Ipilimumab* Subjects will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m2/day) on days -5 through -1. * Prophylactic antibiotics will be administered as medically indicated until recovery of ANC to > 500 and recovery of ALC to > 400 * On day 0 subjects will receive the infusion of autologous TIL and one hour later (but can be delayed up to 24 hours) will begin low-dose aldesleukin (IL-2) (72,000 IU/kg IV every 12 hours for up to 10 doses). * Within 1 week post discharge subjects will be treated with Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg every 3 weeks for 4 doses. Following this, patients will receive Nivolumab 480 mg every 4 weeks. Adjuvant Nivolumab will continue until evidence of disease progression or inability to tolerate treatment. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Metastatic melanoma;
- A metastatic lesion at least 1.5 cm in diameter that can be removed surgically
- Measurable or evaluable disease not including the resected lesion
- ECOG PS of 0 or 1 prior to cell 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)
Key exclusion criteria (23 listed)
- Received prior cell transfer therapy that included non-myeloablative or ablative chemotherapy
- Any significant major organ dysfunction (see protocol)
- Residual toxicity > gr1 from immune checkpoint inhibitor other than persistent endocrinopathy on hormone replacement; all symptoms of prior colitis and enteritis must have resolved completely as assessed by history
- Any contraindication to neutropenia or thrombocytopenia for up to 2 weeks (no active major infection, no site of active, clinically significant bleeding)
- Concurrent major medical illnesses
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tumor Infiltrating LymphocytesAlso: Autologous TIL, Unselected TIL, Young TILThe regimen consists of treatment with cyclophosphamide and fludarabine,followed by infusion of up to 3x1011 lymphocytes (minimum of 1x109) expanded in vitro from subjects own resected tumor followed by the administration of aldesleukin (IL-2). | Drug | Cohort 1, Cohort 2 |
| Nivolumab and Ipilimumab• Within 1 week post discharge subjects will be treated with Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg every 3 weeks for 4 doses. Following this, patients will receive Nivolumab 480 mg every 4 weeks. Adjuvant Nivolumab will continue until evidence of disease progression or inability to tolerate treatment. | Drug | Cohort 2 |
Primary outcome
Adverse Events
Time frame: up to 12 months
To determine the safety of administering a regimen of TIL/IL-2, incidence of drug-related adverse events (AEs) will be summarized across adverse event type in terms of frequency by event type.
Serious Adverse Events
Time frame: up to 12 months
To determine the safety of administering a regimen of TIL/IL-2, serious adverse events (SAEs) will be summarized across event type in terms of frequency by event type. SAE's will include events leading to discontinuation, deaths and clinical laboratory test abnormalities
1 secondary outcome
Objective response rate to TIL
Time frame: up to 12 months
Results and safety
The study was stopped early (reason given: lack of funds). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jul 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Tumor Infiltrating Lymphocytes and Nivolumab and Ipilimumab in people with Metastatic Melanoma, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 25 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: lack of funds). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Adverse Events (time frame: up to 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jul 2022.