A Phase I Clinical Study for Evaluating the Safety and Efficacy of MASCT-I in Patients With Advanced Solid Tumors

Multi-center, Phase I Clinical Study to Evaluate the Safety and Tolerability of Multiple Antigen Stimulating Cellular Therapy-I (MASCT-I) in Patients With Advanced Solid Tumor, and to Preliminarily Evaluate the Anti-tumor Efficacy of MASCT-I Alone, in Combination With Chemical Drugs, and in Combination With PD1 Antibody

The purpose of this study is to evaluate Safety and tolerability of MASCT-I in patients with advanced solid tumors, either alone or in combination with chemical drugs or in combination with PD1 antibody.

The multiple-antigen specific cell therapy which was developed by Hengrui Yuanzheng is optimized continuously and has been upgraded from the first-generation MASCT technology to MASCT-I. MASCT-I is a technology which add PD1 antibody in vitro cell culture process of MASCT cell culture to block PD1 receptor on immunocytes, release the brake on immunocytes' reinfusion and interaction with tumor cells for enhancing the efficacy of immunocytes' killing tumor cells. At present, the development and validation of manufacturing process has been completed, and it is urgently needed to conduct the validation of clinical effect.

This is a Multi-center, phase I clinical study to evaluate the safety and tolerability of multiple antigen stimulating cellular therapy-I (MASCT-I) in patients with advanced solid tumor, and to preliminarily evaluate the anti-tumor efficacy of MASCT-I alone, in combination with chemical drugs, and in combination with PD1 antibody. About 193 cases of adult patients with advanced solid tumors will be recruited.

Major Inclusion Criteria:

1. Age 18-70 at screening;
2. Obtain written informed consent of the subject/legal representative prior to conducting any program related procedures, including evaluation during the screening period;
3. Scored 0 -1 on ECOG;
4. Life expectancy ≥6 months;
5. Cardiopulmonary function is basically normal;
6. Results of blood test and biochemistry at baseline meeting the following criteria:Hemoglobin≥85g/L,Leucocyte≥3.0×109/L,Absolute neutrophil count(ANC)≥1.5×109/L,Trombocyte≥70×109/L,ALT/AST ≤ 2.5×ULN or ≤ 5×ULN for patients with hepatic metastases, ALP≤2.5 times of upper limit of normal, Serum total bilirubin < 1.5×ULN,Serum urea nitrogen and creatinine ≤ 1.5×ULN,patients with urothelial carcinoma,Serum urea nitrogen and creatinine ≤ 2.5×ULN, Serum albumin ≥30g/L

For the first group of subjects, the following criteria should be met:

1. Patients who suffer from advanced (unresectable) or recurrent solid tumors (only limited to bladder cancer and soft tissue sarcoma) confirmed by histology and cytology and are treated unsuccessfully with various standard therapies;
2. According to RECIST1.1 criteria, there must be one measurable focus;
3. Time interval between end of other anti-tumor measures and this study treatment is at least 1 month;

For the second group of subjects, the following criteria should be met:

1. Urothelial carcinoma: histologically or cytologically confirmed that gemcitabine + platinum-based first-line chemotherapy achieved clinical benefit after 4-6 cycles of advanced recurrence or metastasis;
2. Soft tissue sarcoma or osteosarcoma: Subjects who histologically or cytologically demonstrated clinical benefit after at least 4 cycles of doxorubicin-based first-line chemotherapy following advanced recurrence or metastasis. For some subjects who are intolerant or insensitive to chemotherapy, screening can also be conducted after other first-line treatment regiments achieve clinical benefit.
3. Cholangiocarcinoma: Histologically or cytologically confirmed, first-line treatment after advanced recurrence or metastasis is beneficial.

Note: Clinical benefit is defined as complete response (CR), partial response (PR), or disease stabilization (SD). The disease stabilizes for more than 2 months.

For subjects in the third group, the following criteria should be met:

1. Urothelial carcinoma: histologically or cytologically confirmed disease progression after advanced recurrence or metastasis following gemcitabine + platinum regimen first-line chemotherapy;
2. Soft tissue sarcoma or osteosarcoma: histologically or cytologically confirmed disease progression after advanced recurrence or metastasis followed by first-line chemotherapy dominated by adriamycin; For some subjects who are intolerant or insensitive to chemotherapy, they can also be screened after other first-line treatment regiments fail.
3. Cholangiocarcinoma: histologically or cytologically confirmed, progression after first-line treatment after advanced recurrence or metastasis;
4. According to RECIST1.1, at least one measurable lesion must be present;
5. An interval of at least 4 weeks between the end of other anticancer treatments and the treatment in this study;

For the fourth group of subjects, the following criteria should be met:

1. Solid tumor with advanced recurrence or metastasis;
2. PD1 antibody therapy has been used before, and the disease is progressing. The interval between the end of PD1 antibody therapy and this study is at least 4 weeks;
3. According to RECIST1.1, at least one measurable lesion must be present;
4. The interval between the end of other anticancer treatments and the treatment in this study should be at least 4 weeks;

For the fifth group of subjects, the following criteria should be met:

1. Subjects with pathologically confirmed soft tissue sarcoma, locally advanced or metastatic, and inoperable, have not undergone systemic treatment;
2. According to RECIST1.1, at least one measurable lesion must be present

For the sixth group of subjects, the following criteria should be met:

1. Histologically or cytologically confirmed inoperable locally advanced or metastatic urothelial carcinoma (T4b, any N; Or any T, N 2-3) or metastatic urothelial carcinoma (M1, stage IV) including renal pelvis, ureter, bladder, and urethra);
2. Had not previously received systemic chemotherapy for locally advanced or metastatic urothelial carcinoma (UC);
3. At least one measurable lesion was evaluated (based on RECIST1.1 criteria); If the measurable lesion has previously undergone radiotherapy, it needs to be clearly documented that it is now a lesion after disease progression.
4. For subjects who had previously received local intravesical infusion chemotherapy or immunotherapy, this local therapy needed to be completed at least 4 weeks prior to the initiation of the first chemotherapy in this trial
5. Glomerular filtration rate ≥30ml/ min (creatinine clearance was calculated using the standard Cockcroft-Gault formula);

Major Exclusion Criteria:

1. Subjects have clinically manifested central nervous system metastases (such as brain edema, need for hormonal intervention, or progression of brain metastases). Subjects who have received previous treatment for brain or meningeal metastasis, such as clinical stability (MRI) for at least 2 months, and have ceased systemic sex hormone therapy (>10mg/ day prednisone or other therapeutic hormones) for more than 2 weeks may be included;
2. Subjects are receiving immunosuppressive, or systemic, or absorbable local hormone therapy for immunosuppression purposes (>10mg/ day prednisone or other therapeutic hormones) and continue to receive such therapy within 2 weeks prior to enrollment;
3. Subjects are taking immunomodulator drugs and continue to use them within 2 weeks prior to enrollment;
4. Subjects have received MASCT or other cellular immunotherapy or PD1 antibody therapy in the previous year (subjects in the fourth group are not limited to PD1 antibody therapy);
5. Subject has any active autoimmune disease or a history of autoimmune disease;
6. The subject has active tuberculosis;
7. Subject has hepatitis C or HIV infection, or syphilis infection;
8. Patients with gastrointestinal stromal tumor, Ewing sarcoma and rhabdomyosarcoma
9. Patients with recurrence or metastasis during the adjuvant treatment after radical surgery or within 6 months after the end of the treatment (only for patients in Group 5 and Group 6):
10. Those who have used targeted therapy, radiotherapy, immunotherapy or other treatment schemes with clear anti-tumor effect within 4 weeks before enrollment, such as arrotinib, gemcitabine and traditional Chinese medicine; However, if the focus of radiotherapy is not a target focus or there is clear progress after radiotherapy, it can be considered to be included in the group (only for the fifth and sixth groups of subjects);
11. Those who are not suitable for treatment with A1 scheme (only for the fifth group of subjects)
12. Hearing impairment with CTCAE grade>2 (for the sixth group)
13. Peripheral neuropathy with CTCAE grade >2 (such as sensory degeneration, sensory abnormality, including tingling sensation) (for the sixth group);
14. The investigators believed that the subjects were not suitable for chemotherapy containing platinum or gemcitabine (for the sixth group);