Trial Title:
IFNα Expressing Mesenchymal Stromal Cells for Locally Advanced/Metastatic Solid Tumors
NCT ID:
NCT05699811
Condition:
Locally Advanced or Metastatic Solid Tumors
Conditions: Official terms:
Neoplasms
Paclitaxel
Cyclophosphamide
Tislelizumab
Antibodies
Antibodies, Monoclonal
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
MSC-IFNα
Description:
MSC-IFNα form a dose of 2×10^6 cells/kg, intravenous infusion every 4-6 weeks
Arm group label:
MSC-IFNα combined with immunochemotherapy
Arm group label:
MSC-IFNα monotherapy
Intervention type:
Drug
Intervention name:
Nab paclitaxel
Description:
125mg/m2, intravenous infusion every 4-6 weeks
Arm group label:
MSC-IFNα combined with immunochemotherapy
Other name:
Abraxane
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
200mg/m2, intravenous infusion every 4-6 weeks
Arm group label:
MSC-IFNα combined with immunochemotherapy
Intervention type:
Drug
Intervention name:
Anti-PD-1 monoclonal antibody
Description:
200mg, intravenous infusion every 4-6 weeks
Arm group label:
MSC-IFNα combined with immunochemotherapy
Other name:
Toripalimab Injection
Other name:
Sintilimab Injection
Other name:
Camrelizumab Injection
Other name:
Tislelizumab Injection
Summary:
The goal of this first-in-human, single-center, prospective, open-label, phase 1/2 trial
is to evaluate the safety and efficacy of the interferon alpha expressing mesenchymal
stromal cells (MSC-IFNα) combined with or without immunochemotherapy in patients with
locally advanced/metastatic solid tumors. The main questions aimed to answer are 1) to
evaluate the safety and feasibility of MSC-IFNα in the treatment of locally
advanced/metastatic solid tumors;2) to evaluate the anti-tumor effects of the MSC-IFNα
combined with or without immunochemotherapy in the treatment of locally
advanced/metastatic solid tumors; 3) to evaluate the pharmacokinetics/pharmacodynamics of
MSC-IFNα and related immune effector cells.
Detailed description:
[Introduction] Mesenchymal Stromal Cells (MSCs) have been shown to home to the sites of
injury or damage and secrete immunomodulatory factors. This feature makes MSCs an ideal
carrier to deliver drugs or cytokines to the tumor microenvironment (TME) and therefore
have a potential therapeutic role in cancer treatment.
Interferon(IFN) has been widely used for cancer treatment for its pleiotropic antitumor
effects. IFN receptor signals mediate intrinsic and extrinsic effects on tumor cells and
the TME, including tumor-infiltrating lymphocytes as well as tumor-associated stroma.
Additionally, IFNs also exert direct intrinsic antitumor effects including inhibition of
cell proliferation by inducing cell cycle arrest, cell death via apoptosis and
ferroptosis, cell differentiation, and senescence, thus acting as a tumor suppressor.
Accumulating evidence suggests that IFNs play critical roles in cancer immunotherapy,
however, the variations in responses and the adverse effects have reduced their
popularity in clinical applications. New IFN-based strategies should be considered as a
high priority.
Our team has developed a protocol to genetically express IFNα in bone marrow-derived
MSCs. In vitro and in vivo experiments have shown that the MSC-IFNα cells possess a
potent ability to home to TME and to secret IFNα. By changing TME, MSC-IFNα induces
strong anti-tumor effects in several cancer types in animal models. In addition,
preliminary data also indicated that the combination of IFNα-MSCs with chemotherapy
and/or programmed death-1(PD-1)/programmed death-ligand 1(PD-L1)blockade may bring an
even stronger anti-tumor immunity.
In this study, by producing MSC-IFNα cells with human umbilical-cord-derived mesenchymal
stromal cells (hUC-MSCs, passage 5 to passage 7), the investigators plan to conduct a
first-in-human, prospective, open-label, phase 1/2 trial to evaluate the safety and
efficacy of MSC-IFNα combined with or without immunochemotherapy in patients with locally
advanced/metastatic solid tumors.
[Study design] Phase 1 Arm 1. Safety evaluation of MSC-IFNα monotherapy A total of 3-9
subjects will be enrolled for the safety evaluation of MSC-IFNα monotherapy. All
treatment-related adverse events (TRAE) will be recorded for at least 28 days after cell
infusion. Subjects with any grade 3-4 TRAE that lasts for 7 days or more within the 28
days after infusion will be determined as treatment intolerance (TI).
The first 3 subjects will receive MSC-IFNα infusion 1-4 times every 4-6 weeks at a dose
of 2×10^6 cells/kg. If TI occurred in any of the 3 subjects, another 3 subjects will be
enrolled and received a 70% reduced MSC-IFNα dose (i.e. 6×10^5 cells/kg, 2x10^5/kg, and
so on) until tolerable dose (no TI in all 3 subjects) was reached.
Arm 2. Safety and efficacy evaluation of MSC-IFNα combined with immunochemotherapy.
A total of 3-9 subjects will be enrolled and receive MSC-IFNα infusion (tolerable dose
determined in Arm 1) every 4-6 weeks for 4 cycles. Immunochemotherapy, namely
nab-paclitaxel (125 mg/m2, 5 days before cell infusions), cyclophosphamide (200 mg/m2,4
days before cell infusions) and anti-PD-1 antibody (200mg, 7 days after infusion) will be
given. From the 5th cycle, subjects will receive MSC-IFNα combined with anti-PD-1
antibody (200mg, 7 days after infusion) every 4-6 weeks for another 4 cycles for efficacy
consolation. From the 9th cycle, subjects will receive anti-PD-1 antibody (200mg) alone
every 3 weeks for another 4 cycles for efficacy maintenance. The safety, efficacy, and
other required data will be collected and the optimized combined regimen (OCR) of
MSC-IFNα and immunochemotherapy will be determined. MSC-IFNα related AE will be
continuously monitored in this arm, and reduced MSC-IFNα dose will be considered if
necessary.
Phase 2 A total of 10-30 subjects will be enrolled and received the OCR determined in the
phase 1 of the trial. The safety, efficacy, and other required data will be collected.
During the treatment, efficacy in all subjects will be assessed at baseline and every 8
weeks thereafter until confirmed progressive disease, death, intolerable toxicity,
withdrawal of consent, or end of the study, whichever occurs first.
During post-treatment follow-up, efficacy and TRAEs in all subjects will be assessed
every 12 weeks until death, withdrawal of consent, loss to follow-up, or end of the
study, whichever occurs first.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Age from 18 to 75 years with estimated life expectancy >3 months.
2. Histopathological confirmed locally advanced or metastatic solid tumors including,
but not limited to, lung cancer, breast cancer, colorectal cancer, hepatocellular
carcinoma, and sarcomas.
3. Failed to at least first-line and second-line treatments or initially diagnosed
locally advanced/metastatic solid tumors that have no National Comprehensive Cancer
Network(NCCN) guideline-recommended therapy.
4. Have at least one measurable target lesion.
5. Previous treatment must be completed for more than 4 weeks prior to the enrollment
of this study.
6. Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 to 2 at
the time of enrollment.
7. Have adequate organ function, which should be confirmed within 2 weeks prior to the
first dose of study drugs.
8. Previous treatment with anti-PD-1/PD-L1 antibodies is allowed.
9. Ability to understand and sign a written informed consent document.
10. Women of child-bearing potential must agree to use adequate contraception (hormonal
or barrier method of birth control; abstinence) prior to study entry and up to 90
days after the last dose of the drug.
Exclusion Criteria:
1. Active, known, or suspected autoimmune diseases.
2. Known brain metastases or active central nervous system (CNS). Subjects with CNS
metastases who were treated with radiotherapy for at least 3 months prior to
enrollment, have no central nervous symptoms, and are off corticosteroids, are
eligible for enrollment, but require a brain MRI screening.
3. Subjects are being treated with either corticosteroid (>10 mg daily prednisone
equivalent) or other immunosuppressive medications within 14 days of enrollment.
4. History of psychiatric disorders including depression, suicidality, and mania.
5. History of allergy or intolerance to study drug components.
6. Substance abuse, medical, psychological, or social conditions that may interfere
with the patient's participation in the study or evaluation of the study results.
7. Uncontrolled concurrent illness, including ongoing or active systemic infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
(excluding insignificant sinus bradycardia and sinus tachycardia), or psychiatric
illness/social situations and any other illness that would limit compliance with
study requirements and jeopardize the safety of the patient.
8. History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency
syndrome (AIDS).
9. Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy
test performed within 7 days before enrollment, and a negative result must be
documented.
10. Previous or concurrent cancer within 3 years prior to treatment start.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Department of Biotherapeutic, Chinese PLA General Hospital
Address:
City:
Beijing
Country:
China
Status:
Recruiting
Contact:
Last name:
WeiDong Han, Ph.D
Phone:
+86-10-66937463
Email:
hanwdrsw@163.com
Contact backup:
Last name:
GuangHua Rong, Ph.D
Phone:
+86-10-66947473
Email:
guanghua.rong@gmail.com
Start date:
February 23, 2023
Completion date:
December 31, 2026
Lead sponsor:
Agency:
Chinese PLA General Hospital
Agency class:
Other
Collaborator:
Agency:
Wuxi Sinotide New Drug Discovery Institutes
Agency class:
Other
Source:
Chinese PLA General Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05699811
https://www.nature.com/articles/s41388-022-02201-4
