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Study of Fully Human B7H3 CAR-T in Treating Recurrent Malignant Ovarian Cancer

Primary Purpose

Ovarian Cancer

Status

Recruiting

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

fhB7H3.CAR-Ts

About this trial

This is an interventional treatment trial for Ovarian Cancer focused on measuring Fully Human B7H3 CAR-T, Recurrent Ovarian Cancer

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

Procurement and T-cell production eligibility: a previously evaluation confirmed autologous peripheral blood mononuclear cells can be used for T-cell production
Written informed consent and authorization for release of personal health information
Subject has adequate performance status as defined by ECOG score of ≤ 2.
Expected life expectancy is no less than 12 weeks.
Subjects must have histologically or cytologically confirmed ovarian cancer. And cancer tissue or ascitic cancer cells are measured positive for B7H3 expression.
Subjects must have recurrent or refractory disease after or during first-line treatment.
Defined as:
Radiographic progression or Continuous Elevation of CA125.
Subjects must have evaluable disease - defined as:
Measurable disease with tumor length ≥ 10mm or enlarged lymph nodes ≥ 15mm according to RECIST v1.1 criteria.
Adequate organ function - defined as:
1. Blood routine:
  white blood cell count ≥ 3 × 10^9 / L; neutrophil count ≥ 1.5 × 10^9 / L; hemoglobin ≥ 9g/dL; platelet count ≥ 80 × 10^9 / L; INR< 1.5 × ULN; PT, APTT< 1.5 × ULN
2. The liver, kidney, lung and cardiopulmonary function:
Urea and serum creatinine ≤ 1.5 × ULN; Left ventricular ejection fraction ≥ 40%; Baseline oxygen saturation ≥ 95%; Total bilirubin ≤ 1.5 × ULN; ALT and AST ≤ 3 × ULN.
Not pregnant with negative serum pregnancy test within 3 days prior to enrollment.
Female subjects of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of highly effective methods of contraception from the time of informed consent until 8 weeks after study treatment discontinuation.
-

Exclusion Criteria:

Subject has primary immunodeficiency syndrome or history of severe allergic reaction.
Subject has active infection with HIV, HTLV, HBV, HCV.
Subject has severe, uncontrolled intercurrent bacterial, viral or fungal infection.
Subject has a history of gastrointestinal perforation, clinical and/or radiographic evidence of bowel obstruction, or intra-abdominal abscess within 3 months prior to starting treatment.
Subject has active malignancy under treatment other than ovarian cancer.
Subject has Grade ≥ 3 cardiac dysfunction or symptomatic arrhythmia requiring intervention.
Subject is current using of systemic corticosteroids at doses ≥10 mg prednisone daily or its equivalent.
Subject has not recovered from toxicity of previous anti-tumor treatment (CTCAE 5.0).
Subject is pregnant or breastfeeding.
Unwilling or unable to provide consent/assent for participation in the study. -

Sites / Locations

The Affiliated Hospital of Xuzhou Medical UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

fhB7H3.CAR-T cells

Arm Description

In phase I study, 9 enrolled patients diagnosed with advanced ovarian cancer will receive one-time infusion of fhB7H3.CAR-Ts at the doses of 1×10^6/kg, 3×10^6/kg and 5×10^6/kg, 3 patients for each dose. To further confirm the therapeutic efficacy, in phase II study, 6 enrolled patients will receive an optimal dose (balancing effectiveness and toxicity) of fhB7H3.CAR-Ts. Prior to receiving the infusions, patients will undergo lymphodepletion with fludarabine and cyclophosphamide.

Outcomes

Primary Outcome Measures

Dose limiting toxicity of fully human B7H3 CAR-T cells

Dose limiting toxicity (DLT), including the type, frequency, severity and duration of adverse events, such as cytokine release syndrome (CRS), on-target off-tumor, immune effector cell-associated neurotoxicity syndrome, will be monitored and assessed.

Objective response of fully human B7H3 CAR-T cells

Objective response rate (ORR) including complete response (CR), partial response (PR), and/or stable disease, will be determined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Complete Response (CR): disappearance of all target lesions. Partial Response (PR): >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease (SD): no response or less response than Partial or Progressive. Progressive Disease (PD): 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

In vivo persistence of fully human B7H3 CAR-T cells

Presence and number of CAR T cells in the peripheral blood and ascites will be assessed.

Full Information

NCT ID

NCT05211557

First Posted

January 13, 2022

Last Updated

January 25, 2022

Sponsor

The Affiliated Hospital of Xuzhou Medical University

Collaborators

Xuzhou Medical University, IIT MediTech (Jiangsu) Co. Ltd

1. Study Identification

Unique Protocol Identification Number

NCT05211557

Brief Title

Study of Fully Human B7H3 CAR-T in Treating Recurrent Malignant Ovarian Cancer

Official Title

A Single-Arm, Open-Label Study to Evaluate Safety and Efficacy of Fully Human B7H3 CAR-T in Treating Patients With Recurrent Malignant Ovarian Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

January 2022

Overall Recruitment Status

Recruiting

Study Start Date

November 16, 2021 (Actual)

Primary Completion Date

August 31, 2023 (Anticipated)

Study Completion Date

August 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

The Affiliated Hospital of Xuzhou Medical University

Collaborators

Xuzhou Medical University, IIT MediTech (Jiangsu) Co. Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

This is single center, open-label phase I, non-randomized study which will enroll patients with recurrent advanced ovarian cancer to evaluate the safety, feasibility, and efficacy of fully human B7H3 CAR-T cells (fhB7H3.CAR-Ts) via using a '3+3+3' dose escalation design. In the dose expansion cohort, six patients will be enrolled to further assess their efficacy with the optimal dosage.

Detailed Description

The purpose of this study is to test the safety and efficacy of a newly developed fully human scFv-armed B7H3 targeting chimeric antigen receptor T cells (fhB7H3.CAR-Ts), which are supposed to attack and eliminate B7H3-positive cancer cells. The patients who have been diagnosed as recurrent or relapsed malignant ovarian cancer, especially ovarian cancer patients with refractory ascites, will be potentially enrolled after assessing the expression of B7H3 antigen in tumor tissue by immunohistochemistry staining or ascitic tumor cells by flow cytometry. After enrollment, participants' peripheral blood mononuclear cells will be collected and used to manufacture fhB7H3.CAR-Ts. Before infusion, the patients will receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine for three consecutive days. Two days later after lymphodepletion, the fhB7H3.CAR-Ts would be given through an abdominal catheter for intraperitoneal infusion. From the day of infusion, participants' peripheral blood and ascites will be collected twice a week in the first month for monitoring the survival of fhB7H3.CAR-Ts and evaluating the therapeutic efficacy. Additional follow-up and examination will be performed monthly for the first three month and then trimonthly until one year. Thereafter, annual follow-up will be completed for 5 years. In addition, since the fhB7H3.CAR-Ts containing a RQR8 safety-switch which could be targeted and removed by Rituximab. Participants who experience life-threatening toxicities caused by uncontrollable proliferation of fhB7H3.CAR-Ts will receive infusion of Rituximab (Rituxan or Ruxience or Halpryza) to assess the ability of RQR8 safety-switch to eliminate infused fhB7H3.CAR-Ts. This is an investigator-initiated clinical study to assess first-line clinical performance of novel fhB7H3.CAR-Ts which may help other advanced and recurrent ovarian cancer patients in the future.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ovarian Cancer

Keywords

Fully Human B7H3 CAR-T, Recurrent Ovarian Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

fhB7H3.CAR-T cells

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

fhB7H3.CAR-Ts

Intervention Description

Three dose levels will be evaluated: Dose Level 1 (1×10^6/kg), dose Level 2 (3×10^6/kg) and dose Level 3 (5×10^6/kg). If dose limiting toxicities (DLTs) are observed in each doses, Dose Level -1 (0.5×10^6/kg /infusion) will be evaluated. Other Name: B7H3 targeting chimeric antigen receptor T cells Drug: Fludarabine 30 mg/m2 i.v. for 3 consecutive days (Day -5~Day -3) Other Name: FLUDARA Drug: Cyclophosphamide 750 mg/m2 i.v. for once (Day -5) Other Name: Cytoxan

Primary Outcome Measure Information:

Title

Dose limiting toxicity of fully human B7H3 CAR-T cells

Description

Time Frame

1 month

Title

Objective response of fully human B7H3 CAR-T cells

Description

Time Frame

1 month

Secondary Outcome Measure Information:

Title

In vivo persistence of fully human B7H3 CAR-T cells

Description

Presence and number of CAR T cells in the peripheral blood and ascites will be assessed.

Time Frame

1 month

Other Pre-specified Outcome Measures:

Title

Progress free survival (PFS)

Description

PFS will be assessed from the time of lymphodepletion prior to infusion of fhB7H3.CAR-Ts to

Time Frame

up to 5 years

Title

Overall survival (OS)

Description

OS will be assessed from the date of lymphodepletion prior to infusion of fhB7H3.CAR-Ts to the date of death.

Time Frame

up to 5 years

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Procurement and T-cell production eligibility: a previously evaluation confirmed autologous peripheral blood mononuclear cells can be used for T-cell production Written informed consent and authorization for release of personal health information Subject has adequate performance status as defined by ECOG score of ≤ 2. Expected life expectancy is no less than 12 weeks. Subjects must have histologically or cytologically confirmed ovarian cancer. And cancer tissue or ascitic cancer cells are measured positive for B7H3 expression. Subjects must have recurrent or refractory disease after or during first-line treatment. Defined as: Radiographic progression or Continuous Elevation of CA125. Subjects must have evaluable disease - defined as: Measurable disease with tumor length ≥ 10mm or enlarged lymph nodes ≥ 15mm according to RECIST v1.1 criteria. Adequate organ function - defined as: Blood routine: white blood cell count ≥ 3 × 10^9 / L; neutrophil count ≥ 1.5 × 10^9 / L; hemoglobin ≥ 9g/dL; platelet count ≥ 80 × 10^9 / L; INR< 1.5 × ULN; PT, APTT< 1.5 × ULN The liver, kidney, lung and cardiopulmonary function: Urea and serum creatinine ≤ 1.5 × ULN; Left ventricular ejection fraction ≥ 40%; Baseline oxygen saturation ≥ 95%; Total bilirubin ≤ 1.5 × ULN; ALT and AST ≤ 3 × ULN. Not pregnant with negative serum pregnancy test within 3 days prior to enrollment. Female subjects of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of highly effective methods of contraception from the time of informed consent until 8 weeks after study treatment discontinuation. - Exclusion Criteria: Subject has primary immunodeficiency syndrome or history of severe allergic reaction. Subject has active infection with HIV, HTLV, HBV, HCV. Subject has severe, uncontrolled intercurrent bacterial, viral or fungal infection. Subject has a history of gastrointestinal perforation, clinical and/or radiographic evidence of bowel obstruction, or intra-abdominal abscess within 3 months prior to starting treatment. Subject has active malignancy under treatment other than ovarian cancer. Subject has Grade ≥ 3 cardiac dysfunction or symptomatic arrhythmia requiring intervention. Subject is current using of systemic corticosteroids at doses ≥10 mg prednisone daily or its equivalent. Subject has not recovered from toxicity of previous anti-tumor treatment (CTCAE 5.0). Subject is pregnant or breastfeeding. Unwilling or unable to provide consent/assent for participation in the study. -

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Liantao Li, M.D., Ph.D.

Phone

+86-516-85582530

liliantao@xzhmu.edu.cn

First Name & Middle Initial & Last Name or Official Title & Degree

Xin Ding, M.D., Ph.D.

Phone

+86-516-83355832

dingxin81@163.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Junnian Zheng, M.D., Ph.D.

Organizational Affiliation

The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Longzhen Zhang, M.D., Ph.D.

Organizational Affiliation

The Affiliated Hospital of Xuzhou Medical University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Gang Wang, Ph.D.

Organizational Affiliation

Xuzhou Medical University

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Affiliated Hospital of Xuzhou Medical University

City

Xuzhou

State/Province

Jiangsu

ZIP/Postal Code

221002

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Liantao Li, M.D., Ph.D.

Phone

+86-516-85582530

liliantao@xzhmu.edu.cn

First Name & Middle Initial & Last Name & Degree

Xin Ding, M.D., Ph.D.

Phone

+86-516-83355832

dingxin81@163.com

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Study of Fully Human B7H3 CAR-T in Treating Recurrent Malignant Ovarian Cancer

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