Study of Precision Treatment for Rare Tumours in China Guided by PDO and NGS

A Phase II Clinical Study on Precision Treatment of Rare Tumours in China Guided by Patient-Derived Tumor Organoids (PDO) and Next-Generation Sequencing (NGS)

The objective of this Phase II, open-label, multicenter, non-randomised controlled clinical trial is to guide precision treatment for patients with rare tumours based on Patient-Derived Organoids/Next-Generation Sequencing drug screening.

Rare tumours, defined as those with an annual incidence rate of less than 2.5/100,000 according to the data from the National Cancer Registry of the National Cancer Center of China, represent a significant unmet medical need due to the lack of high-level evidence-based clinical practice guidelines and standard regimens. Patient-Derived Organoids(PDOs), which preserves the histologic and genetic characteristics of patients; tumours, have demonstrated predictive value of clinical outcomes. Prior studies have shown that PDOs-based drug screens can predict treatment response with high sensitivity and specificity.The investigators thus propose the study: A Phase II Clinical Study on Precision Treatment of Rare Tumours in China Guided by Patient-Derived Organoids and Next-Generation Sequencing. Investigators aim to determine clinical efficacy of PDOs/NGS-guided precision treatment in patients with rare tumours. After tumour samples were collected, drug screening using PDOs and NGS will be conducted. Molecular Tumor board(MTB) will review the results and develop an individualised treatment regimens. Primary endpoint of this study is objective response rate (ORR). Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and duration of response (DoR).

Inclusion Criteria:

1. Male or female, the age at the time of signing the informed consent is no less than 18 years old;
2. Patients with advanced or metastatic rare solid tumor confirmed by histological confirmed;
3. ECOG score is 0 or 1;
4. Expected survival ≥12 weeks;
5. According to Response Evaluation Criteria in Solid Tumor (RECIST 1.1), there is at least one imaging measurable lesions, which has not previously undergone radiotherapy or with obvious disease progress after radiotherapy;
6. Surgical specimens of paired tumor tissue and adjacent normal tissue, or fresh biopsy tissue samples or ≥500ml serous cavity effusion with positive pathological cytological examination must be provided. These specimens must be obtained without prior exposure to any other anti-tumor treatment, systemic anti-infection treatment, vaccination, et al. and are intended for organoid culture;
7. Must have a primary or metastatic paraffin-embedded tissue (without radiotherapy) other than bone metastatic lesions before enrollment (within 2 years, 15-20 sheets, 4-6μm thick white slices, of which 5 need to be glued and baked ) and peripheral blood samples for NGS gene testing. If NGS results are already available but sufficient paraffin-embedded tissue cannot be provided, investigator are allowed the decision to enroll subjects according to the specific situation;
8. In the condition that the primary lesions biopsy specimen has been provided, if the metastatic lesion is able to be biopsied(determined by investigator), it is suggested to keep the specimen for pathological testing and provide fresh tissue specimen;
9. After the progression of the subject's disease, if conditions permit(determined by investigator), fresh tissue samples shall be obtained from the same biopsy lesions and the metastasis lesions of the previously obtained samples;
10. Toxic and side effects caused by previous treatment need to be restored to ≤ Grade 1 or returned to the baseline value (NCI-CTCAE version 5.0, except for hair loss);
11. Negative pregnancy test (only applicable for women with childbearing potential). No childbearing potential is defined as being postmenopausal for longer than one year or having undergone surgical sterilization or hysterectomy;
12. All patients (male and female) agree to use an effective form of contraceptive measures during the treatment and within 8 weeks after the end of treatment;
13. Signed, written informed consent of volunteers that join the group shall follow the trial treatment plan, follow-up plan and cooperate to observe the adverse events and efficacy.

Exclusion Criteria:

1. No patient lesions available for organoid model construction;

2. History of interstitial lung disease or radiation pneumonitis of any type;

3. Central Nervous System (CNS) metastases with brain metastases-related symptoms, which is not stable in neurology, or need to increase steroid dosage to control CNS disease. (Note: Patients with controlled CNS metastasis are eligible to participate in this study);

4. Current uncontrollable third cavity effusion, such as a large amount of pleural effusion，ascites , or pericardial effusion;

5. Major surgical operations or incomplete healing of injury within 4 weeks prior to study treatment's first administration and chest radiotherapy of > 30 Gy within 6 months;

6. History of receiving other investigational drugs within 14 days or 5 half-lives (whichever is longer) prior to the first administration;

7. History of receiving live vaccine within 30 days prior to the first administration. Seasonal influenza vaccines that do not contain live viruses are allowed;

8. Current active infection requiring systemic treatment (antibiotics); or any of the following:

   1. HIV positive or known history of acquired immunodeficiency syndrome;
   2. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is defined as HBsAg positive and the number of HBV DNA copies exceeds the upper limit of normal value, or HCV AB positive;
   3. Active tuberculosis (with exposure history or positive tuberculosis test; with clinical and / or imaging manifestations);
   4. Positive antibody of Treponema Pallidum

9. Current evidenced uncontrollable systemic diseases (such as severe mental, neurological, epilepsy or dementia, unstable or uncompensated respiratory, cardiovascular, liver or kidney diseases, uncontrolled hypertension [still greater than or equal to CTCAE Grade 3 hypertension after drug treatment]);

10. History of myocardial infarction, coronary artery / peripheral artery bypass or cerebrovascular accident within 3 months;

11. Diagnosed with a second type of malignant tumor within 5 years before the first diagnosis of a rare solid tumor (excluding completely resected basal cell carcinoma, bladder carcinoma in situ, cervical carcinoma in situ);

12. History of receiving of any organ transplantation, including allogeneic stem cell transplantation. Transplantation without immunosuppression (corneal transplantation, hair transplantation) is excluded;

13. Cardiovascular disease or symptom includes any of the following:

    1. History of Congestive Heart Failure requiring treatment and of New York Heart Association class III / IV CHF (see Appendix 3) ;
    2. Current ventricular arrhythmia requiring antiarrhythmic drugs treatment, or uncontrollable or unstable arrhythmia;
    3. Severe conduction disorder (such as grade II or III AV block);
    4. Angina requiring treatment;
    5. QT interval (QTC) of 12 lead ECG is ≥ 450 ms in male and ≥ 470 MS in female;
    6. History of congenital long QT syndrome, congenital short QT syndrome, torsade de pointe or pre-excitation syndrome;
    7. History of LVEF decline to below 50% determined by echocardiography or MUGA scan;
    8. History of myocardial infarction in the past 6 months.

14. Inadequate bone marrow reserve or organ function;

15. Pregnant or lactating women;

16. History of swallowing dysfunction, active gastrointestinal disease or other diseases that significantly affect the absorption, distribution, metabolism and excretion of oral drugs. The patients with history of subtotal gastrectomy. (Note: this standard is not applicable to the sub schemes with the investigational drug as injection).