Clinical trial NCT02838823: Safety and Tolerability of Recombinant Humanized Anti-PD-1 Monoclonal Antibody for Patients With Advanced Breast Cancer
Official title: A Phase I,Open,Mono-center and Dose Escalation Study Investigating Tolerance and Pharmacokinetics of Single and Multiple Doses of Anti-PD-1 Monoclonal Antibody in Patients With Triple-negative Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Breast Cancer
Keywords: anti-PD-1 monoclonal antibody
triple negative breast cancer
safety
Lead sponsor: Shanghai Junshi Bioscience Co., Ltd.
Sponsor class: OTHER
First posted: 2016-07-20
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a mono-center, open-label, phase 1 study evaluating the humanized anti-PD-1 antibody JS001, as a monotherapy in patients with triple negative breast cancer who have failed in routine systemic treatment. The study will be conducted in 2 parts: dose escalation and cohort expansion to investigate tolerability and efficacy.

Detailed description: This is a mono-center, open-label, phase 1 study evaluating the humanized anti-PD-1 antibody JS001, as a monotherapy in patients with triple negative breast cancer who have failed in previous routine systemic treatment. The study will be conducted in 2 parts: dose escalation and cohort expansion. In the first part, nine patients are injected with different dosage of the humanized anti-PD-1 antibody (1mg/kg or 3mg/kg or 10mg/mg, three patients in one group ) once and observed carefully in the following 4 weeks. If no dose-limiting toxicity (DLT) occurs, then they are injected every 2 weeks until disease progresses or unacceptable toxicity occurs. This part is to confirm DLT, maximum tolerated dose (MTD) and recommended dose (RD). In the second part, 6-12 patients are enrolled in each dosage group and injected with the humanized anti-PD-1 antibody every 2 weeks until disease progresses or unacceptable toxicity occurs. This part is to further analyze safety and efficacy of the humanized anti-PD-1 antibody.

Eligibility criteria: Inclusion Criteria:

* Male and Female aged 18 to 70 years are eligible;
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
* Histologic diagnosis of triple negative breast cancer. Have failed at least 1 prior routine regimen for metastatic disease, or failed to tolerate the toxicity, or lack of any routine regimens.
* Histologically confirmed estrogen receptor negative (ER-) and progesterone receptor negative (PR-), human epidermal growth factor receptor 2 negative
* Providing with tumor specimen (for testing the expression of PD -L1 and the infiltrating lymphocytes);
* At least 1 measurable lesion (only 1 measurable lymph node lesion is excluded) (routine CT scan \>=20mm, spiral CT scan \>=10mm, no prior radiation to measurable lesions) Predicted survival \>=6 months;
* Brain or meningeal metastases must be disposed with surgery or radiation, and be stable clinically for at least 8 weeks (prior systemic steroids was allowed, but concurrent administration of systemic steroids with the study drug is excluded).
* Screening laboratory values must meet the following criteria（within past 14 days）:

hemoglobin ≥ 9.0 g/dL neutrophils ≥ 1500 cells/ µL platelets ≥ 100 x 10\^3/ µL total bilirubin ≤ 1.5 x upper limit of normal (ULN) aspartic transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN without, and ≤ 5 x ULN with hepatic metastasis serum creatinine ≤1╳ULN，creatinine clearance \>50ml/min (Cockcroft-Gault equation)

* Without systemic steroids within past 4 weeks
* Males or female of childbearing potential must: agree to use using a reliable form of contraception (eg, oral contraceptives, intrauterine device, control sex desire, double barrier method of condom and spermicidal) during the treatment period and for at least 12 months after the last dose of study drug.
* Must have read, understood, and provided written informed consent voluntarily. Willing to adhere to the study visit schedule and the prohibitions and restrictions specified in this protocol.

Exclusion Criteria:

* Hypersensitivity to recombinant humanized anti-PD-1 monoclonal Ab or its components.
* Prior treatment with mAb within past 3 months (locally administration excluded)
* Prior antitumor therapy (including corticosteroids and immunotherapy) or participation in other clinical trials within past 4 weeks, or have not recovered from toxicities since the last treatment;
* Pregnant or nursing
* Abnormal Blood coagulation
* Positive tests for HIV, HCV, HBsAg or HBcAb with positive test for HBV DNA (\>500IU/ml)
* History with pulmonary tuberculosis;
* Patients with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, such as hypophysitis, pneumonia, colitis, hepatitis, nephritis, hyperthyroidism or hypothyroidism.
* Severe, uncontrolled medical condition that would affect patients' compliance or obscure the interpretation of toxicity determination or adverse events, including active severe infection, uncontrolled diabetes, angiocardiopathy (heart failure \> class II NYHA, heart block \>II grade, myocardial infarction, unstable arrhythmia or unstable angina within past 6 months, cerebral infarction within past 3 months) or pulmonary disease ( interstitial pneumonia, obstructive pulmonary disease or symptomatic bronchospasm).
* Evidence with CNS disease.
* Prior treatment with bone marrow stimulating factors，such as CSF (colony stimulating factor), EPO (erythropoietin), within past 1 weeks
* Prior live vaccine therapy within past 4 weeks.
* Prior major surgery within past 4 weeks (diagnostic surgery excluded).
* Psychiatric medicines abuse without withdrawal, or history of psychiatric illness.
* Prior malignancy active within the previous 5 years except for locally curable cancers that have been apparently cured, such as basal cell skin cancer or carcinoma in situ of the cervix.
* Underlying medical condition that, in the Investigator's opinion, would increase the risks of study drug administration or obscure the interpretation of toxicity determination or adverse events.

Primary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 1.5 years
Secondary outcomes:
measure: PD-1 receptor occupancy of blood
timeFrame: 1.5 years
measure: Objective Response Rate (ORR) by irRC and RECIST 1.1
timeFrame: 3 years
measure: Duration of Response (DOR) by irRC and RECIST 1.1
timeFrame: 3 years
measure: Disease Control Rate (DCR) by irRC and RECIST 1.1
timeFrame: 3 years
measure: Time to response (TTR) by irRC and RECIST 1.1
timeFrame: 3 years
measure: Progression-free survival(PFS) by irRC and RECIST 1.1
timeFrame: 3 years
measure: Overall survival (OS) by irRC and RECIST 1.1
timeFrame: 3 years
measure: Maximum Plasma Concentration (Cmax) after single dose injection of Anti-PD-1 Monoclonal Antibody (mAb)
timeFrame: 1.5 years
measure: Peak Time (Tmax) after single dose injection of Anti-PD-1 mAb
timeFrame: 1.5 years
measure: Area Under the Curve (AUC) after single dose injection of Anti-PD-1 mAb Area Under the Curve [AUC]). Area Under the Curve (AUC) after single dose injection of Recombinant Humanized Anti-PD-1 Monoclonal An
timeFrame: 1.5 years
measure: t1/2 after single dose injection of Recombinant Humanized Anti-PD-1 mAb
timeFrame: 1.5 years
measure: Plasma clearance (CL) after single dose injection of Anti-PD-1 mAb
timeFrame: 1.5 years
measure: Apparent volume of distribution (V) after single dose injection of Anti-PD-1 mAb
timeFrame: 1.5 years
measure: Minimum Plasma Concentration (Cmin) of steady state after multiple dose injection of Anti-PD-1 mAb
timeFrame: 1.5 years
measure: Average Plasma Concentration (Cav) of steady state after multiple dose injection of Anti-PD-1 mAb
timeFrame: 1.5 years
measure: degree of fluctuation (DF) of steady state after multiple dose injection of Anti-PD-1 mAb
timeFrame: 1.5 years
measure: Apparent volume of distribution of steady state (Vss) after multiple dose injection of Anti-PD-1 mAb
timeFrame: 1.5 years
Other outcomes:
measure: correlation analysis of PD-L1 expression of tumor and ORR
timeFrame: 3 years
measure: correlation analysis of PD-L1 expression of tumor and DOR
timeFrame: 3 years
measure: correlation analysis of PD-L1 expression of tumor and DCR
timeFrame: 3 years
measure: correlation analysis of PD-L1 expression of tumor and TTR
timeFrame: 3 years
measure: correlation analysis of PD-L1 expression of tumor and PFS
timeFrame: 3 years
measure: correlation analysis of PD-L1 expression of tumor and OS
timeFrame: 3 years
Locations:
city: Beijing
country: China
facility: Gastrointestinal Oncology Department, Affiliated Cancer Center of Academy of Military Medical Sciences
state: Beijing
Study officials:
affiliation: Gastrointestinal Oncology Department, Affiliated Cancer Center of Academy of Military Medical Sciences
name: Zefei Jiang
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chen R, Peng PC, Wen B, Li FY, Xie S, Chen G, Lu J, Peng Z, Tang SB, Liang YM, Deng X. Anti-Programmed Cell Death (PD)-1 Immunotherapy for Malignant Tumor: A Systematic Review and Meta-Analysis. Transl Oncol. 2016 Feb;9(1):32-40. doi: 10.1016/j.tranon.2015.11.010.
citation: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. doi: 10.1016/S1470-2045(15)00083-2. Epub 2015 Jun 23.
citation: Bian L, Zhang H, Wang T, Zhang S, Song H, Xu M, Yao S, Jiang Z. JS001, an anti-PD-1 mAb for advanced triple negative breast cancer patients after multi-line systemic therapy in a phase I trial. Ann Transl Med. 2019 Sep;7(18):435. doi: 10.21037/atm.2019.09.08.