A Safety Study of the Pan-immunotherapy in Patients With Unresectable/Metastatic Solid Tumors or Lymphomas

A Phase I, Two-arm, Open-label, Single-center, Dose-escalation Study to Evaluate the Safety, Tolerability and Recommended Dose and Delivery Mode of the Pan-immunotherapy in Subjects With Unresectable/ Metastatic Solid Tumors or Lymphomas

Identification of T cell inhibitory signals, including PD-1/PD-L1, has prompted the development of a new class of cancer immunotherapy that could restore an adequate immunosurveillance against the neoplasm and enhance T-cell-mediated anticancer immune responses. However, elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which enable providing several therapeutic targets and tailoring of combinations of immune therapies. Manganese has been confirmed to activate antigen-presenting cells and function as mucosal immunoadjuvants in pre-clinical studies. This study is a first-in-man, Phase I, 3 + 3 dose escalation study of a combined regimen of Manganese and anti-PD-1 antibody with or without chemotherapies in subjects with unresectable/ metastatic solid tumors or lymphomas. This study is designed to assess the safety, tolerability, pharmacokinetic profile (PK profile), mode of delivery and Recommended Phase 2 Dose (RP2D) of this regimen.

Study Overview

• Status: Unknown
• Conditions: Lymphoma; Solid Tumor
• Intervention / Treatment: Drug: Manganese Chloride; Drug: Anti-PD-1 antibody; Combination product: Systemic therapy

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

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100853
      • Recruiting
      • Biotherapeutic Department of Chinese PLA General Hospital
      • Principal Investigator: Kaichao Feng, M.S
      • Principal Investigator: Yan Zhang, M.S
      • Principal Investigator: Meixia Chen, M.S
      • Sub-Investigator: Jiejie Liu, B.S
      • Sub-Investigator: Xiang Li, B.S
      • Sub-Investigator: Liang Dong, B.S

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects must have histologically proven unresectable/ metastatic solid tumors or lymphomas.
2. ≥ 18 years old.
3. Life expectancy of at least 6 months.
4. Eastern Cooperative Oncology Group performance status 0-2.
5. Subjects must have at least one measurable lesion ≥ 1 cm as defined by response criteria.
6. Subjects must have received at least two frontline therapies, except for patients initially diagnosed with local advanced or metastatic pancreatic cancer or cholangiocarcinoma.
7. Subjects must be off prior therapy for at least 4 weeks prior to Day 1. Subjects with autologous hematopoietic stem-cell transplantation are eligible which must be more than 3 months. Subjects with Anti-PD-1 antibody are eligible which must be resistance.
8. Adequate organ function.
9. Participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug.

Exclusion Criteria:

1. Subjects with any autoimmune disease or history of syndrome that requires corticosteroids or immunosuppressive medications.
2. Serious uncontrolled medical disorders or active infections, pulmonary infection especially.
3. T cell lymphomas or leukemia.
4. Prior organ allograft.
5. Women who are pregnant or breastfeeding.
6. Women with a positive pregnancy test on enrollment or prior to investigational product administration.
7. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dose-Escalation, intranasally; With a standard 3+3 dose escalation design, the enrollment will proceed until the maximum tolerated dose (MTD) has been defined or the highest dose level has been reached.	Drug: Manganese Chloride; Administered intranasally in Arm 1 (0.05, 0.1 or 0.2 mg/kg/d) and by inhalation in Arm 2 (0.1, 0.2 or 0.4mg/kg/d) once daily in a 3-week cycle; Drug: Anti-PD-1 antibody; Administered intravenously, at 2-4mg/kg on day 3 in a 3-week cycle; Other Names: PD-1 inhibitor; Anti-PD-1 monoclonal antibody; Combination product: Systemic therapy; Whether and which should be given depends on the treatment regimen before enrollment.
Active Comparator: Dose-Escalation, inhalation; With a standard 3+3 dose escalation design, the enrollment will proceed until the MTD has been defined or the highest dose level has been reached.	Drug: Manganese Chloride; Administered intranasally in Arm 1 (0.05, 0.1 or 0.2 mg/kg/d) and by inhalation in Arm 2 (0.1, 0.2 or 0.4mg/kg/d) once daily in a 3-week cycle; Drug: Anti-PD-1 antibody; Administered intravenously, at 2-4mg/kg on day 3 in a 3-week cycle; Other Names: PD-1 inhibitor; Anti-PD-1 monoclonal antibody; Combination product: Systemic therapy; Whether and which should be given depends on the treatment regimen before enrollment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects with treatment-related adverse events (AEs)	Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v5.0. AEs were considered to be treatment-related if they had started or worsened within the interval from first study drug administration until the follow-up visit.	Approximately 6 months
Number of subjects with specific Manganese-related adverse events	Manganese-related AEs were considered to be that start or worsen after administration Manganese administration，improve after withdrawal, and even occur again after re-administration.	Approximately 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preliminary efficacy evaluation	Objective response rate (ORR) and disease control rate (DCR) will be evaluated by investigators per the RECIST V1.1.	Approximately 6 months
The q3w pharmacokinetic profile of Manganese	PK parameters such as Maximum concentration (Cmax) are assessed.	Approximately 3 months
Number of participants with laboratory test abnormalities	The laboratory tests of serum cytokines and chemokines will be performed on day 1 and 3 of each cycle, and the abnormality will be determined by the investigator.	Approximately 3 months

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2018
• Primary Completion (Anticipated): December 31, 2019
• Study Completion (Anticipated): May 31, 2020

Study Registration Dates

• First Submitted: June 14, 2019
• First Submitted That Met QC Criteria: June 18, 2019
• First Posted (Actual): June 19, 2019

Study Record Updates

• Last Update Posted (Actual): August 28, 2019
• Last Update Submitted That Met QC Criteria: August 27, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: metastatic; unresectable; anti-PD-1 antibody; Manganese
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Trace Elements; Micronutrients; Antibodies; Immunoglobulins; Immune Checkpoint Inhibitors; Manganese
• Other Study ID Numbers: CHN-PLAGH-BT-039

Drug and device information, study documents

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