ImmPACT Expanded Multiple Antigen Specific Endogenously Derived T Cells (MASE-T) to Patients With Metastatic Melanoma

Adoptive Transfer of ImmPACT Expanded Multiple Antigen Specific Endogenously Derived T Cells (MASE-T) in Combination With Lymphodepletion and Anti-PD-1 to Patients With Metastatic Melanoma

With the introduction of checkpoint inhibitors substantial improvements have been made in the treatment of malignant melanoma (MM). Despite this still a a subset of patients, approximately 50 %, experience no response to therapy.

One of the strategies to overcome these obstacles have been ACT with tumour infiltrating lymphocytes (TILs). Most TIL based ACT products are non-specifically expanded providing growth preference to co-infiltrated virus specific T cells, and it is currently challenging to expand T cells in an antigen-specific manner, while at the same time obtaining the ideal functional characteristics for specific and strong tumour-killing capacity with sufficient persistence.

In this phase I trial artificial antigen-presenting scaffolds for antigen-driven T cell expansion are used. These scaffolds will generate a MASE-T cell product enriched for selected specificities towards antigens known to be expressed by melanoma cells The aim of the study is to demonstrate that treatment with af MASE-T cell product i safe and feasible. Further the study will elucidate whether treament with the MASE-T cell product leads to objective responses and improves progression free survival (PFS).

Study Overview

• Status: Recruiting
• Conditions: Malignant Melanoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Biological: Multiple Antigen Specific Endogenously derived T cells; Drug: Pembrolizumab

Detailed Description

There are around 350-400 new cases of patients with metastatic melanoma (MM) per year in Denmark. MM is a very aggressive cancer with a poor prognosis. Traditional oncological treatments such as surgery, chemotherapy and radiation therapy have a poor effect, and the 5-year overall survival has hitherto been less than 10 %.Substantial improvements have been made in the treatment of MM; especially immunotherapy is showing promising results with checkpoint inhibitors (CPI) such as programmed cell death protein 1 (PD-1) and Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA-4) blocking antibodies administered as standard treatment in the frontline. The 5-year overall survival has now reached 52 %, 44 % and 26 % in nivolumab/ipilimumab, nivolumab, and ipilimumab respectively. However, a subset of patients - approximately 50 % experience no response to therapy, with clear primary resistance. One of the strategies to overcome these obstacles have been ACT with tumour infiltrating lymphocytes (TILs). A crucial condition for optimal ACT based on TILs is the generation of sufficient numbers of tumourreactive T cells. However, the expansion of TILs requires extensive ex vivo culturing often at the cost of T cell differentiation and functional activity. Most TIL based ACT products are non-specifically expanded providing growth preference to co-infiltrated virus specific T cells, and it is currently challenging to expand T cells in an antigen-specific manner, while at the same time obtaining the ideal functional characteristics for specific and strong tumour-killing capacity with sufficient persistence. Recent data suggest that the majority of tumour specific T cells responsible for tumour rejection under CPI are recruited from peripheral blood and lymph system, while not present in the tumour prior to treatment. This is supported by the finding that most tumour resident T cells are dysfunctional.

To overcome the current limitations in the treatment of malignant melanoma artificial antigen-presenting scaffolds for antigen-driven T cell expansion, generating a MASE-T cell product enriched for selected specificities towards antigens known to be expressed by melanoma cells has been designed. The antigen-scaffolds will ensuring optimal T cell stimulation by mimicking the in vivo stimulation of T cells by dendritic cells in the lymph nodes. The scaffolds contain both the antigen specific element - in the form of a peptide-MHC molecule and cytokine (IL2 and IL21), to provide growth and functional signals to the antigen specific T cell. As a result of this T cell expansion strategy, we can obtain a T cell product enriched for tumourantigen specific T cells. Superior functional activity towards tumor cells and antigen recognition compared to conventional T cell expansion strategies has been demonstrated in-vitro. Importantly, antigen-specific T cells in the MASE-T cell product possess a 'younger' phenotype, which has previously been described to correlate with improved in vivo persistence.

The study is a phase 1, non-randomized study. The trial will be conducted in two parts (A and B). Patients will be treated as followed:

• Part A (6 patients): Lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2/day i.v. on day -4, -3, -2 and fludarabine 30 mg/m2/day i.v. on day -4, -3) followed by i.v. infusion of the MASE-T product on day 0. If the production of the MASE-T cell product was feasible for the majority (≥50%) of patients intended to treat in Arm A and the toxicity was acceptable, six patients will further be included in part B.
• Part B (6 patients): Lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2/day i.v. on day -4, -3, -2 and fludarabine 30 mg/m2/day i.v on day -4, -3) followed by i.v infusion of the MASE-T product on day 0. Pembrolizumab 2 mg/kg will be administered on day -1 and day +21.

The primary objective is to evaluate the safety and feasibility of the MASE-T treatment alone or in combination with Pembrolizumab in patients with stage IV metastatic melanoma according to Common Terminology Criteria for Adverse Events (CTCAE version 5.0).

The secondary objectives are to evaluate T cell profile and persistence in vivo from tumor biopsies and blood samples as well as evaluation of the clinical efficacy of the treatment according to RECIST 1.1 and iRECIST. In addition, best overall response (BOR), duration of response (DOR), overall survival (OS), progression-free survival (PFS) will be monitored.

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Tine J Monberg, M.D.; Phone Number: +4538682983; Email: tine.monberg@regionh.dk
• Study Contact Backup: Name: Inge M Svane, Prof, M.D.; Phone Number: +4538683868; Email: inge.marie.svane@regionh.dk

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Recruiting
    • National Center for Cancer Immune Therapy (CCIT-DK)
    • Contact: Tine J Monberg, MD; Phone Number: +4538682983; Email: tine.monberg@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 ≤ 75
2. Progressive disease on or after anti-PD-1/anti-PD-L1 monotherapy or progressive disease on or after anti PD-1 plus anti-CTLA-4 therapy
3. The patient has histologically confirmed metastatic melanoma
4. HLA-A2 positive
5. At least one measurable parameter according to RECIST version 1.1 guidelines
6. ECOG performance status of 0 or 1
7. No significant toxicity from previous cancer treatments (CTC ≤ 1)
8. Women of childbearing potential: Negative serum pregnancy test and must use effective contraception. This applies from screening 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 effective contraceptives
9. Men with female partner of childbearing potential must use effective contraception from screening and until 6 months after treatment. Effective contraceptives are as described above for the female partner. In addition, documented vasectomy and sterility or double barrier contraception are considered effective contraceptives
10. Signed statement of consent after receiving oral and written study information
11. Willingness to participate in the planned treatment and follow-up and capable of handling

12. The patient has met the following haematological and biochemical criteria:

    1. AST and ALT ≤2,5 X ULN or ≤5 X ULN with liver metastases
    2. Serum total bilirubin ≤1,5 X ULN or direct bilirubin ≤ ULN for patient with total bilirubin level > 1,5 ULN
    3. Serum creatinine ≤1,5 X ULN
    4. ANC (Absolute Neutrophil Count) ≥1,000/mcL
    5. Platelets ≥ 75,000 /mcL
    6. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L

Exclusion Criteria:

1. Another malignancy or concurrent malignancy unless disease-free for 3 years
2. Requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive drugs within the last 3 weeks prior to screening
3. Prior treatment with adoptive transfer of Tumor Infiltrating T cells (TIL)
4. Grade 3-4 adverse events upon treatment with PD-1 checkpoint inhibitors (only phase B)
5. The patient has CNS metastases and/or carcinomatous meningitis
6. The patient has any condition that will interfere with patient compliance or safety (including but not limited to psychiatric or substance abuse disorders)
7. The patient is pregnant or breastfeeding
8. The patient has an active infection requiring systemic therapy
9. The patient has received a live virus vaccine within 30 days of planned start of therapy
10. Significant medical disorder according to investigator; e.g severe asthma or chronic obstructive lung disease, dysregulated heart disease or dysregulated diabetes mellitus.
11. Concurrent treatment with other experimental drugs
12. Any significant active autoimmune disease
13. Severe allergy or anaphylactic reactions earlier in life
14. Known hypersensitivity to one of the active drugs or one or more of the excipients.
15. Unrelieved lower urinary tract obstruction

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Part A; Six patients will be included in Part A. After inclusion 300 mL blood will be drawn from the patients for the production of the MASE-T cell product. Four days prior to MASE-T infusion the patient will receive lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2/day i.v. on day -4, -3, -2 and fludarabine 30 mg/m2/day i.v. on day -4, -3) followed by i.v. infusion of the MASE-T product on day 0.	Drug: Cyclophosphamide; Cyclophosphamide 500 mg/m2 is administered i.v. on day -4, -3 and -2; Drug: Fludarabine Phosphate; Fludarabine Phosphate 30 mg/m2 is administered on day -4 and -3; Biological: Multiple Antigen Specific Endogenously derived T cells; Antigen specific, ex vivo expanded T cells derived from peripheral blood T cells; Other Names: MASE-T
Other: Part B; Six patients will be includede in Part B. After inclusion 300 mL blood will be drawn from the patients for the production of the MASE-T cell product. Four days prior to MASE-T infusion the patient will receive lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2/day i.v. on day -4, -3, -2 and fludarabine 30 mg/m2/day i.v on day -4, -3) followed by i.v infusion of the MASE-T product on day 0. Pembrolizumab 2 mg/kg will be administered on day -1 and day +21.	Drug: Cyclophosphamide; Cyclophosphamide 500 mg/m2 is administered i.v. on day -4, -3 and -2; Drug: Fludarabine Phosphate; Fludarabine Phosphate 30 mg/m2 is administered on day -4 and -3; Biological: Multiple Antigen Specific Endogenously derived T cells; Antigen specific, ex vivo expanded T cells derived from peripheral blood T cells; Other Names: MASE-T; Drug: Pembrolizumab; Pembrolizumab 2 mg/kg is administered on day -1 and on day 21. The medicine is administered over 30 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability of the treatment	Fraction of patients experiencing grade III or worse adverse events	Through study completion. An average of 3 years
Number of patients excluded due to feasibility issues	Number of patients excluded due to treatment related feasibility issues compared to the number of patients enrolled in the study.	Through study completion. An average of 3 years
Number of patients excluded due to safety issues	Number of patients excluded due to treatment related safety issues compared to the number of patients enrolled in the study.	Through study completion. An average of 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best overall response (BOR)	Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) assessed by CT scan.	Until progression, assessed up to 6 months after last treatment.

Collaborators and Investigators

• Sponsor: Inge Marie Svane
• Collaborators: Technical University of Denmark
• Investigators: Study Director: Inge M Svane, Prof., M.D., Study Director, National Center for Cancer Immune Therapy, Depth of Oncology, Herlev Hospital; Principal Investigator: Tine J Monberg, M.D., Ph.d. student, National Center for Cancer Immune Therapy, Depth of Oncology, Herlev Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2021
• Primary Completion (Anticipated): August 1, 2023
• Study Completion (Anticipated): August 1, 2024

Study Registration Dates

• First Submitted: May 22, 2021
• First Submitted That Met QC Criteria: May 22, 2021
• First Posted (Actual): May 27, 2021

Study Record Updates

• Last Update Posted (Actual): September 16, 2021
• Last Update Submitted That Met QC Criteria: September 14, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Adoptive Cell Therapy; Immune Therapy; Multiple Antigen Specific Endogenously derived T cells
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Pembrolizumab; Fludarabine; Fludarabine phosphate
• Other Study ID Numbers: MM2011

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No