Melanoma MetastaticPhase 1CRISPR-TILNCT06783270
T-cell Therapy with CRISPR PD1-edited Tumor Infiltrating Lymphocytes for Patients with Metastatic Melanoma
A Phase 1 study testing TIL therapy in people with Melanoma Metastatic, run by Inge Marie Svane at 1 site in Denmark.
Trial summary
The purpose of this study is to assess wether it is safe and feasible to treat patients with tumor infiltrating lymphocytes that have been silenced for PD-1, using CRISPR-Cas9. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Melanoma Metastatic
- What is being tested?
- TIL therapy
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteDenmark
- Study dates
- 16 Dec 2024to 1 Jan 2028
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
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 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed inoperable or metastatic melanoma (stage IIIc or IV).
- Progressive disease after standard treatment with anti-PD-1 check-point inhibition or combination of aforementioned with anti-CTLA-4 check-point inhibition.
- Age: 18 - 75 years at the time of signed Informed consent.
- ECOG performance status of ≤1 (Appendix 2).
- Is fit for tumor resection and has at least one lesion (> 1 cm3) available for surgical resection for manufacture of TIL. (Unless TILs are already available through metastasectomy prior to enrollment in this study, as described in step one under study design)
- At least one measurable parameter in accordance with RECIST 1.1 -criteria (excluding the lesion to be resected).
Show all 31Show fewer
- LVEF assessment with documented LVEF ≥50% by either TTE or MUGA.
- Sufficient organ function, including:
- Absolute neutrophil count (ANC) ≥ 1.500 /μl
- Leucocyte count ≥ lower normal limit
- Platelets ≥ 100.000 /μl and <700.000 /μl
- Hemoglobin ≥ 6.0 mmol/l
- eGFR > 70
- S-bilirubin ≤ 1.5 times upper normal limit (Exception: Subjects with liver metastasis ≤ 2.5 × ULN)
- ASAT/ALAT ≤ 2.5 times upper normal limit (Exception: Subjects with liver metastasis ≤ 5.0 × ULN)
- Alkaline phosphatase ≤ 5 times upper normal limit
- Lactate dehydrogenase ≤ 5 times the upper normal limit
- Sufficient coagulation: APPT<40 and INR<1.5
- Signed statement of consent after receiving oral and written study information
- Willingness to participate in the planned controls and capable of handling toxicities.
- Subject must receive CRISPR-TIL as the next therapy following tumor resection unless bridging therapy is administered:
- Bridging therapy is discouraged. However, if in the opinion of the Investigator, the subject requires immediate therapy after tumor resection, the subject may receive bridging therapy for the period during which the subject is awaiting the manufacture of TIL-infusion product. Bridging therapy may be a continuation of the therapy the subject was receiving prior to tumor resection or may be a new therapy.
- Following this bridging therapy, the subject must adhere to the mandatory washout periods (described in exclusion criterion 1) and must continue to have measurable disease prior to receiving CRISPR-TIL.
- Age and Reproductive Status:
- Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test AND must agree to use an effective method of contraception starting at the first dose of chemotherapy for at least 12. WOCB must also agree to refrain from egg donation, storage, or banking during these same time periods. The following are considered safe methods of contraception:
- Hormonal anticonception (birth control pills, spiral, depot injection with gestagen, subdermal implantation, hormonal vaginal ring, and transdermal depot patch)
- Intrauterine device
- Surgical sterilization
- Surgical sterilization of male partner with verification of no sperm after the procedure
- Menopause (for more than 12 months)
- Male subjects must be surgically sterile or agree to use a double-barrier contraception method or abstain from sexual activity with an WOCBP starting at the first dose of chemotherapy and for 6 months thereafter. Male subjects must also agree to refrain from sperm donation, storage, or banking.
Who cannot join
- Subject has received or plans to receive the following therapy/treatment prior to tumor resection (TR) or lymphodepleting chemotherapy (LDC):
- Cytotoxic chemotherapy: Washout period 3 weeks before TR and LDC.
- Small molecules/TKI: Washout period 1 week before TR and LDC.
- Immune therapy (monoclonal AB therapy, CPI, and biologics): 2 weeks before TR and LDC
- Prior T-cell therapy, including gene therapy using an integrating vector.
- Corticosteroids at dose equivalent > 10 mg prednisone or any other immunosuppressive therapy. 2 weeks before TR and LDC. Note: Use of topical steroids is not an exclusion.
Show all 31Show fewer
- Investigational treatment: 4 weeks or 5 half-lives, whichever is shorter before TR and LDC.
- Radiation to the pelvis and/or multiple bones containing ≥ 25% of bone marrow: 4 weeks before TR and LDC.
- Whole brain radiotherapy or brain stereotactic radiosurgery: 4 weeks before TR and LDC.
- Radiotherapy to the target lesions: 3 months prior to TIL infusion. A lesion with unequivocal progression post-radiotherapy may be considered a target lesion.
- A history of prior malignancies. Patients treated for another malignancy can participate if they are without signs of disease for a minimum of 2 years after treatment. Subjects with curatively treated ductal carcinoma in situ (DCIS or LCIS) breast cancer for which they are taking hormonal therapy is acceptable. Resectable squamous or basal cell carcinoma of the skin is acceptable.
- Patients with metastatic ocular/mucosal or other non-cutaneous melanoma. Unknown primary melanoma is eligible.
- Toxicity from previous anti-cancer therapy must have resolved to ≤ Grade 1 or baseline prior to enrollment (except for non-clinically significant toxicities e.g., alopecia, vitiligo). Subjects with Grade 2 toxicities who are deemed stable or irreversible (e.g., peripheral neuropathy) can be enrolled.
- Patients who have more than 2 CNS metastases or who have any CNS lesion that is symptomatic, greater than 1 cm in diameter, or show significant surrounding edema on MRI scan will not be eligible until they have been treated and demonstrated no clinical or radiologic CNS progression for at least 2 months.
- The following patients will be excluded because of their inability to receive high-dose interleukin-2 (See appendix 5):
- History of coronary revascularization
- Documented LVEF of less than 45% in patients with clinically significant atrial and/or ventricular arrhythmias including but not limited to atrial fibrillation, ventricular tachycardia, 2o or 3o heart block
- Documented FEV-1 less than or equal to 60% predicted value for patients with: A prolonged history of cigarette smoking (greater than 20 pack years), large tumor burden in the lungs, or Symptoms of respiratory distress.
- Known hypersensitivity to one of the active drugs or one or more of the excipients.
- Severe medical conditions, such as severe asthma/COLD, significant cardiac disease, and poorly regulated insulin-dependent diabetes mellitus among others.
- Creatinine clearance (eGFR) < 70 ml/min*.
- Acute/chronic infection with HIV, hepatitis, and syphilis among others.
- Severe allergies or previous anaphylactic reactions.
- Active autoimmune or immune-mediated disease that has not yet resolved. Subjects with the following will be eligible:
- Immune-mediated AEs secondary to immunotherapy which have resolved to ≤ Grade 1 without steroids;
- Hypothyroidism, Type I diabetes, adrenal insufficiency, or pituitary insufficiency that are stable on replacement therapy;
- Disorders such as asthma, vitiligo, psoriasis, or atopic dermatitis that are well-controlled without requiring systemic immunosuppression;
- Other stable immune conditions that do not require prednisone higher than 10 mg/day or their equivalent dose for other corticosteroid agents may be acceptable with the agreement of the Sponsor.
- Pregnant women and women breastfeeding.
- Subjects deemed unlikely to fully comply with protocol requirements by the study investigator.
- In selected cases it can be decided to include a patient with a eGFR < 70 ml/min with the use of a reduced dose of chemotherapy.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Denmark1 site, 1 recruiting
- Recruiting
CCIT-DK
Herlev, Capital Region, 2730
Joel E Sohlin, MD, +4538689198, joel.emanuel.sohlin@regionh.dk
Inge Marie Svane, MD, phd, prof., +4538682131, inge.marie.svane@regionh.dk
About this study
The purpose of this study is to assess wether it is safe and feasible to treat patients with tumor infiltrating lymphocytes that have been silenced for PD-1, using CRISPR-Cas9.
Read the detailed description
In this study the investigators will treat patients with advanced (inoperable) or metastatic melanoma with tumor infiltrating lymphocytes (TILs) in combination with lymphodepleting chemotherapy and high-dose interleukin-2. The TILs are harvested from a patient tumor and expanded a thousand-fold in a laboratory over approximately 6 weeks before being infused back into the patient. This is a well known and tried treatment regimen, often called TIL-therapy or TIL-ACT. In this study the investigators will add CRISPR-Cas9 modification to the production process of the TILs to silence the expression of PD-1 on the surface of the infused cells. The aim of this study is to demonstrate wether treatment with these PD1-deficient TILs (CRISPR-TILs) is safe and feasible.
- Conditions
- Melanoma Metastatic
- Being tested
- TIL therapy
- Keywords
- TIL-therapy, TIL-ACT
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TIL therapyBiological
Compared to traditional TIL-therapy, this study will include silencing of the PD-1 coding gene in the TILs using non-viral CRISPR-Cas9 prior to the rapid expansion protocol.
| Study group | Role | What they receive |
|---|---|---|
| Autologous CRISPR-PD1 modified tumor infiltrating lymphocytes | Experimental | Tumor infiltrating lymphocytes expanded ex vivo from an excised tumor and treated with CRISPR-Cas9 to effectively silence the PD-1 coding gene in the T-cells. This is given as an intravenous infusion after lymphodepleting chemotherapy using cyclophosphamide and fludarabine-phosphate and followed by up to 6 doses of high-dose interleukin-2 infusions. Receives: Biological: TIL therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Feasibility
Assess feasibility measured by the number of subjects who undergo surgery and successfully undergo CRISPR-TIL infusion
Measured: From surgery to CRISPR-TIL infusion (5-10 weeks)
Incidence rate of treatment-emergent adverse events
Determine the safety and tolerability measured by the incidence rate of grade 3 treatment-emergent adverse events and serious adverse events by severity and their relationship to the CRISPR-TIL infusion.
Measured: From admission to 2nd evaluation (3 months after CRISPR-TIL infusion)
Secondary outcomes (1)
Objective response rate
Assess the clinical effect of the treatment by use of the objective response rate (using RECIST 1.1).
Measured: From treatment until the 12 months evaluation scan.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jan 2025
- Study start16 Dec 2024
- Primary completion1 Jan 2027 (estimated)
- Study completion1 Jan 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Melanoma MetastaticStudies of the same condition, open and under way.
- 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
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Inge Marie Svane
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Inge Marie Svane, Herlev Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06783270
- Sponsor's protocol ID
- MM2318
- Other IDs
- 2023-510417-25-01, 2023
- Acronym
- CRISPR-TIL
- Status last verified
- Jan 2025
- First submitted
- 13 Dec 2024
- Last updated
- 20 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Due to a small patient cohort, all individual patient data will be recognizable and assignable to the persons themselves
Publications
Chamberlain CA, Bennett EP, Kverneland AH, Svane IM, Donia M, Met O. Highly efficient PD-1-targeted CRISPR-Cas9 for tumor-infiltrating lymphocyte-based adoptive T cell therapy. Mol Ther Oncolytics. 2022 Jan 10;24:417-428. doi: 10.1016/j.omto.2022.01.004. eCollection 2022 Mar 17.
PubMed 35141398
Study at a glance
From the registry record, last updated by the sponsor on 20 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- T-cell Therapy with CRISPR PD1-edited Tumor Infiltrating Lymphocytes for Patients with Metastatic Melanoma
- ClinicalTrials.gov ID
- NCT06783270
- Acronym / sponsor ID
- CRISPR-TIL / MM2318
- Conditions
- Melanoma Metastatic
- Keywords
- TIL-therapy, TIL-ACT
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 10 participants (estimated)
- Lead sponsor
- Inge Marie SvaneUniversity, hospital or other
- Study start
- 16 Dec 2024 (actual)
- Primary completion
- 1 Jan 2027 (estimated)
- Study completion
- 1 Jan 2028 (estimated)
- First posted
- 20 Jan 2025 (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.
The purpose of this study is to assess wether it is safe and feasible to treat patients with tumor infiltrating lymphocytes that have been silenced for PD-1, using CRISPR-Cas9.
Detailed description
In this study the investigators will treat patients with advanced (inoperable) or metastatic melanoma with tumor infiltrating lymphocytes (TILs) in combination with lymphodepleting chemotherapy and high-dose interleukin-2. The TILs are harvested from a patient tumor and expanded a thousand-fold in a laboratory over approximately 6 weeks before being infused back into the patient. This is a well known and tried treatment regimen, often called TIL-therapy or TIL-ACT. In this study the investigators will add CRISPR-Cas9 modification to the production process of the TILs to silence the expression of PD-1 on the surface of the infused cells. The aim of this study is to demonstrate wether treatment with these PD1-deficient TILs (CRISPR-TILs) is safe and feasible.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Autologous CRISPR-PD1 modified tumor infiltrating lymphocytes | Experimental | Biological: TIL therapyTumor infiltrating lymphocytes expanded ex vivo from an excised tumor and treated with CRISPR-Cas9 to effectively silence the PD-1 coding gene in the T-cells. This is given as an intravenous infusion after lymphodepleting chemotherapy using cyclophosphamide and fludarabine-phosphate and followed by up to 6 doses of high-dose interleukin-2 infusions. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (31 listed)
- Histologically confirmed inoperable or metastatic melanoma (stage IIIc or IV).
- Progressive disease after standard treatment with anti-PD-1 check-point inhibition or combination of aforementioned with anti-CTLA-4 check-point inhibition.
- Age: 18 - 75 years at the time of signed Informed consent.
- ECOG performance status of ≤1 (Appendix 2).
- Is fit for tumor resection and has at least one lesion (> 1 cm3) available for surgical resection for manufacture of TIL. (Unless TILs are already available through metastasectomy prior to enrollment in this study, as described in step one under study design)
Key exclusion criteria (31 listed)
- Subject has received or plans to receive the following therapy/treatment prior to tumor resection (TR) or lymphodepleting chemotherapy (LDC):
- A history of prior malignancies. Patients treated for another malignancy can participate if they are without signs of disease for a minimum of 2 years after treatment. Subjects with curatively treated ductal carcinoma in situ (DCIS or LCIS) breast cancer for which they are taking hormonal therapy is acceptable. Resectable squamous or basal cell carcinoma of the skin is acceptable.
- Patients with metastatic ocular/mucosal or other non-cutaneous melanoma. Unknown primary melanoma is eligible.
- Toxicity from previous anti-cancer therapy must have resolved to ≤ Grade 1 or baseline prior to enrollment (except for non-clinically significant toxicities e.g., alopecia, vitiligo). Subjects with Grade 2 toxicities who are deemed stable or irreversible (e.g., peripheral neuropathy) can be enrolled.
- Patients who have more than 2 CNS metastases or who have any CNS lesion that is symptomatic, greater than 1 cm in diameter, or show significant surrounding edema on MRI scan will not be eligible until they have been treated and demonstrated no clinical or radiologic CNS progression for at least 2 months.
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 |
|---|---|---|
| TIL therapyCompared to traditional TIL-therapy, this study will include silencing of the PD-1 coding gene in the TILs using non-viral CRISPR-Cas9 prior to the rapid expansion protocol. | Biological | Autologous CRISPR-PD1 modified tumor infiltrating lymphocytes |
Primary outcome
Feasibility
Time frame: From surgery to CRISPR-TIL infusion (5-10 weeks)
Assess feasibility measured by the number of subjects who undergo surgery and successfully undergo CRISPR-TIL infusion
Incidence rate of treatment-emergent adverse events
Time frame: From admission to 2nd evaluation (3 months after CRISPR-TIL infusion)
Determine the safety and tolerability measured by the incidence rate of grade 3 treatment-emergent adverse events and serious adverse events by severity and their relationship to the CRISPR-TIL infusion.
1 secondary outcome
Objective response rate
Time frame: From treatment until the 12 months evaluation scan.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Jan 2025.
- Background: PubMed 35141398Chamberlain CA, Bennett EP, Kverneland AH, Svane IM, Donia M, Met O. Highly efficient PD-1-targeted CRISPR-Cas9 for tumor-infiltrating lymphocyte-based adoptive T cell therapy. Mol Ther Oncolytics. 2022 Jan 10;24:417-428. doi: 10.1016/j.omto.2022.01.004. eCollection 2022 Mar 17.
- CTIS registrationLink provided by the sponsor.
- Individual participant dataSharing planned: No. Due to a small patient cohort, all individual patient data will be recognizable and assignable to the persons themselves
Related trials for Melanoma Metastatic
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
RecruitingPhase 1
IL-17 Blockade to Decrease irAEs (REPLAY)
Metastatic Melanoma
RecruitingPhase 3
A Study With Combinations of Anti-LAG-3 and Anti-PD-1 Antibodies in Adult Participants With Advanced or Metastatic Melanoma (Harmony Head-to-Head)
Melanoma
RecruitingPhase 1
Pharmacokinetics, Safety, and Immunogenicity Comparison of Bmab1700 and Opdivo® as Adjuvant Monotherapy in Participants With Melanoma
Melanoma
Active, not recruitingPhase 1/2
A Study of ST-1898 for Unresectable or Metastatic Melanoma
Unresectable or Metastatic Melanoma
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.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing TIL therapy in people with Melanoma Metastatic, run by Inge Marie Svane at 1 site in Denmark.
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 31 inclusion and 31 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: looking for participants now, as of the sponsor's last update on 20 Jan 2025. 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 Denmark. 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?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Joel E Sohlin, MD (+4538689198, joel.emanuel.sohlin@regionh.dk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Feasibility (time frame: From surgery to CRISPR-TIL infusion (5-10 weeks)). 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?
On the ClinicalTrials.gov record for NCT06783270, which also lists 1 linked publication.
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 20 Jan 2025.