Treatment of Advanced or Metastatic Triple-negative Breast Cancer With Adoptive Therapy of PD1+ TILS (TILS001)

Treatment of Advanced or Metastatic Triple-negative Breast Cancer With Adoptive Therapy of PD1+ Tumor-infiltrating Lymphocytes (TILS001 Trial)

This is a prospective, multicenter, phase I/II, open-label, two-stage design of PD1+ TILs infusion in metastatic or advanced TNBC. TILS001 includes 3 parts. Previous to each phase inclusion, a specific ICF must be signed by the patient. Participants potentially eligible to participate in the clinical trial will be offered to sign a ICF three times prior to TILs treatment: 1) prior to or during induction therapy to allow for collection of archival FFPE tissue samples for determination PD1 by mRNA (Part #1), 2) prior to a fresh metastatic biopsy for selection, isolation and partial expansion of PD1+ TILs (Part #2) and 3) prior to allow for remaining study procedures and TILs therapy (Part #3, Main Consent).

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Triple-Negative Breast Carcinoma
• Intervention / Treatment: Drug: PD1+ TILs (NUMARZU-001) product infusion

Detailed Description

This trial has been developed in TNBC, a breast cancer subtype with a particularly poor prognosis. The product used for treating participating patients will be selected PD1-positive TILs. Such TILs will be manufactured in Hospital Clinic under the name of NUMARZU-001. The procotol has been designed in three parts to better select participating patients. Molecular pre-screening has been established to select tumors with a higher probability of enrichment by PD1-positive TILs. The pre- screening consists of performing a tumor biopsy and selecting isolation and expansion of PD1- postive TILs to manufacture the final product NUMARZU-001. This part could last almost four weeks, as such patients will continue with the established treatment in the meanwhile. Finally, NUMARZU-001 will be administered if the patient is eligible for part three of the protocol.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Tomás Pascual; Phone Number: + 34 933 436 302; Email: tomas.pascual@gruposolti.org
• Study Contact Backup: Name: Laura Angelats; Email: LANGELATS@clinic.cat

Study Locations

• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
    • Contact: Cristina Saura
  • Madrid, Spain, 28041
    • Hospital 12 de Octubre
    • Contact: Eva Ciruelos
  • Pamplona, Spain, 31008
    • Clinica Universidad de Navarra
    • Contact: Marta Santisteban

Participation Criteria

Eligibility Criteria

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

Description

Eligibility criteria for Part #1 (Molecular pre-screening: Determination of PD1 by mRNA analysis from an archival FFPE tumor sample):

Participants are eligible to be included in the study only if all of the following criteria apply:

1. Age ≥ 18 years. Enrollment of patients > 70 years of age is allowed after consultation and approval of the study medical monitor.
2. Estimated life expectancy of ≥6 months.
3. Histologically confirmed diagnosis of unresectable or metastatic breast cancer.
4. Histologically confirmed diagnosis of advanced triple-negative breast cancer (based on the most recently analyzed biopsy from locally recurrent or metastatic site, local laboratory) meeting the following criteria: HER2-negative in situ hibridation test or an immunohistochemistry (IHC) status of 0 or 1+, and ER and PgR expressions <10% as determined locally by IHC assay as per most recent ASCO/CAP guidelines.
5. Metastatic triple-negative breast cancer, being candidate to first-line taxane-based containg regimen. Biologic treatments (such as: atezolizumab and bevazicumab) are permitted as per standard criteria. Previous (neo)adjuvant taxanes are permitted (if completed ≥12 months before recurrence).
6. For patients included in the run-in safety phase, multiple lines of chemotherapy are permitted.

7. Patients must not have history of other malignancy within the past 3 years with the following exceptions:

   a. adequately treated non-melanoma skin cancer without evidence of disease at the time of enrollment b. adequately treated cervical carcinoma in situ without evidence of disease at the time of enrollment c. adequately treated breast d. prostatic intraepithelial neoplasia without evidence of prostate cancer at the time of enrollment e. adequately treated superficial or in-situ carcinoma of the bladder without evidence of disease at the time of enrollment.

8. Subject likely to be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge.
9. Absence of psychiatric or physiologic history, substance abuse, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
10. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
11. Pregnant or breast-feeding women will NOT be elegible.
12. Subject has known sensitivity to any of the products or components to be administered during dosing will NOT be eligible.
13. NOT having an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or sponsor staff directly involved in this trial, unless prospective institutional review board (IRB)/independent ethics committee (IEC) approval (by chair or designee) is given allowing exception to this criterion for a specific subject
14. Patients must NOT had undergone prior allogeneic hematopoietic stem cell transplantation
15. Patients with a history or evidence of symptomatic autoimmune will NOT be eligible: glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
16. Absence of active bacillus tuberculosis history.
17. Absence of a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required.
18. Absence of a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required.

19. To be able to provide either a newly obtained tumor biopsy (preferred) or archival tumor tissue of a FFPE tumor block. The tumor tissue should be of good quality based on total and viable tumor content and must be evaluated centrally for gene expression analysis prior to enrollment in Part #2. Patients whose tumor tissue is NOT evaluable for PD1 expression central testing are not eligible.

    • Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions or biopsies from bone metastases.
    • Fine needle aspiration, brushing, cell pellet from pleural effusion or lavage samples are not acceptable.

Eligibility criteria for Part #2 (Pre-Screening Phase: Selection, isolation and partial expansion of PD1+ TILs from a fresh tumor sample):

Participants are eligible to be included in the study only if all of the previous and the following criteria apply:

1. Patients will be elegible for Part #2 if they have a PD-1 mRNA expression above the 50th percentile (as described in L Paré et al; Annals of Oncol, 2018 Oct 1;29(10):2121-2128) in the FFPE tumor sample analysed in Part 1.
2. At least 1 resectable target lesion to generate TIL of a minimum 1.0 cm in diameter post- resection; surgical removal with minimal morbidity (defined as any procedure for which expected hospitalization is ≤3 days). Fine needle aspiration, brushing, cell pellet from pleural effusion, biopsies from lymph node are not acceptable, biopsies from bone metastases and lavage samples are not acceptable.
3. Patients should be candidate OR receiving a first line of treatment
4. Patients must NOT have clinically active cerebral metastases. Carcinomatous meningitis is no allowed regardless of clinical stability.

Eligibility criteria for Part #3 (Screening and treatment Phase: Complete expansion of PD1+TILs. Treatment of patients with PD1+ TILs infusion):

Participants are eligible to be included in the study only if all of the previous and the following criteria apply. For being included in this section, the following criteria must apply:

1. PD1+ TILs selection in Part #1 and successful partial expansion of tumor sample in Part #2
2. Resolution of all acute toxic effects of prior induction chemotherapy regimen to NCI CTCAE version 5.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
3. Patients must have received an acceptable, standard, chemotherapy containing taxane for the treatment of metastatic breast cancer prior to study enrollment. Eligible patients are expected to have completed 6 cycles of taxane chemotherapy. Patients are eligible if no evidence of disease progression by local assessment (i.e. CR, PR or SD) is observed. A minimum of 4 cycles of treatment are acceptable for patients experiencing significant toxicity associated with treatment as long as they are without evidence of disease progression (i.e. CR, PR or SD). The maximum number of cycles is 12. Patients can be included in Part#3 either immediately following completion of their induction therapy or after a gap of ≤12 weeks between their last infusion/dose of chemotherapy and the initiation of NMA-LD.

4. Adequate organ function determined within 28 days prior to enrollment, defined as follows:

   • Hematological
   • ANC ≥ 1.5 x 109/L
   • Platelet count ≥ 100 x 109/L
   • Hemoglobin ≥ 9 g/dL (without need for hematopoietic growth factor or transfusion support)
   • Renal
   • Serum creatinine ≤ 1.5 x upper limit of normal (ULN), OR 24-hour creatinine clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 x ULN. (Note: Creatinine clearance need not be determined if the baseline serum creatinine is within normal limits. Creatinine clearance should be calculated per institutional standard).
   • Hepatic
   • Serum bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with total bilirubin level > 1.5 x ULN
   • Aspartate aminotransferase (AST) ≤ 2.5 x ULN OR ≤ 5 x ULN for subject with liver metastases.
   • Alanine aminotransferase (ALT) ≤ 2.5 x ULN OR ≤ 5 x ULN for subject with liver metastases.
   • Coagulation
   • International normalization ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless the subject is receiving anticoagulant therapy as long as PT and partial thromboplastin time (PTT)/activated PTT (aPTT) is within therapeutic range of intended use of anticoagulants

20. Female subject of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to enrollment. If the urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

21. For patients ≥ 60 years or patients who have a history of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias, a cardiac stress tests must be performed showing normal LVEF, NYHA functional classification < class 1 and if any wall movement abnormalities, they must be reversible 22. Left ventricular ejection fraction (LVEF) ≥ 50% at baseline as determined by either ECHO or MUGA 23. Patients must have recovered from prior toxicities (i.e. ≥ grade 1) from prior therapies. Grade 2 for neuropathy is allowed.

24. Patients must not be currently receiving treatment with another investigational device or drug study. No other investigational procedures (of any kind) are permitted while participating in this study. Maintentance therapy with atezolizumab or bevacizumab is allowed.

25. Systemic steroid therapy is not permitted (patients who require replacement therapy for adrenal insufficiency may be enrolled if steroid treatment dose do not exceed 10 mg of prednisone or equivalent).

26. Patients with evidence of clinically significant immunosuppression will NOT be eligible such as the following:

1. diagnosis of immunodeficiency
2. concurrent opportunistic infection

27. Patients with evidence of (non-infectious) pneumonitis that required steroids or current pneumonitis will NOT be elegible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: PD1+ TILs (NUMARZU-001) product infusion; The treatment administration is divided in NMA-LD chemotherapy(auxiliary medication)T ILs product (IMP) and IL-2 (auxiliary medication).

Drug: PD1+ TILs (NUMARZU-001) product infusion; The cryopreserved NUMARZU-001 product will be thawed in 37ºC water bath and will be infused by gravity, a 5 mL to 10 mL/ minute. Concomitant medications will be given to the patient starting within 24 hours prior to NUMARZU-001 product infusion*. This therapy will include the following: Hydration as per institutional standards (Saline solution 0,9% NaCl 500ml every 8 hours) 24 hours prior the NUMARZU-001 product infusion.; Within 30 to 60 minutes prior to infusion of NUMARZU-001, premedicate the patient with acetaminophen (650 mg) and diphenhydramine (25 to 50 mg IV), or another H1- histamine antagonist. Continuous supervision of the patient by site medical staff is required until completion of infusion of the NUMARZU-001 product, to monitor for potential signs and symptoms (e.g. hypersensitivity reaction).; Other Names: TILs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of grade 3-5 adverse event (AE)	Incidence of grade 3-5 adverse event (AE) assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 5.0, and any grade AE assessed by CTCAE that leads to treatment discontinuation and possibly related to treatment, that occur in the first 24h following PD1+ TILs infusion (prior to IL-2 treatment).; Incidence of grade 3-5 AEs assessed by the NCI CTCAE version 5.0 taking into account the whole process, which includes NMA-LD chemotherapy followed by TILs infusion and at least one dose of IL-2 treatment.	24 weeks from the administration of PD1+ TILS (NUMARZU-001 product)
Progression-Free Survival	Progression-Free Survival at 6 months (PFS6) defined as the proportion of patients alive and without progression (as determined locally by the investigator according with Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 version) 24 weeks from the administration of PD1+ TILS (NUMARZU-001 product);	24 weeks from the administration of PD1+ TILS (NUMARZU-001 product)

Collaborators and Investigators

• Sponsor: Fundacio Clinic Barcelona
• Collaborators: SOLTI Breast Cancer Research Group
• Investigators: Study Chair: Aleix Prat, SOLTI Breast Cancer Research Group

Study record dates

Study Major Dates

• Study Start (Anticipated): July 25, 2022
• Primary Completion (Anticipated): September 30, 2024
• Study Completion (Anticipated): September 30, 2027

Study Registration Dates

• First Submitted: July 4, 2022
• First Submitted That Met QC Criteria: July 8, 2022
• First Posted (Actual): July 11, 2022

Study Record Updates

• Last Update Posted (Actual): July 11, 2022
• Last Update Submitted That Met QC Criteria: July 8, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Breast Cancer; TNBC; metastatic; triple negative
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms
• Other Study ID Numbers: TILS001 trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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