Rare Tumor
Conditions
Keywords
Rare tumor, NGS, actionable alterations, precision medicine, immunotherapy
Brief summary
A Phase II, open label, non-randomized, multiple-arm, single-center clinical trial in patients with advanced rare solid tumors who failed to standard treatment.
Detailed description
Based on the fact that a high incidence rate (14.2%) of rare tumor (incidence rate \<2.5/100,000) as defined in this study according to the National Cancer Registry data from National Cancer Center of China, as well as the current status of lacking guidelines and consensus of rare tumor treatment. We proposed this study A Phase II, open label, non-randomized, multiple-arm, single-center clinical trial in patients with advanced rare solid tumors who failed to standard treatment, aims to evaluate the safety and efficacy of targeted drugs of specific tumor-driven genes in patients with advanced rare solid tumors with corresponding actionable alterations, as well as the safety and efficacy of immune checkpoint (PD-1) inhibitors in patients with advanced rare solid tumors without actionable alterations. Patients with advanced rare tumors who failed to standardized treatment carrying actionable alterations as EGFR mutation (exon 19 deletion mutation, L858R replacement mutation), ALK gene fusion, ROS-1 gene fusion, C-MET gene amplification or mutation (D1010 mutation, 14 exon mutation, y1003 mutation), BRAF mutation, CDKN2A mutation, BRCA1/2 mutation, HER-2 mutation, HER-2 over expression/amplification, C-KIT mutation, will enroll targeted therapy arms and be given corresponding targeted drugs (Dacomitinib, Crizotinib). And patients without targeted alterations mentioned above will enroll PD-1 inhibitor arm and to be treated with Sintilimab. After acquired resistance patients treated with olaparib and palbociclib will receive combination treatment with durvalumab. After acquired resistance patients treated with vemurafenib will receive combination treatment with atezolizumab. The statistics of current study adopts Simon's two-stage Minimax design: In the first stage of clinical research, 12 subjects will be observed. If the number of CR + PR is less than 1, the trial will be terminated, otherwise, the group will continue to expand to 16 subjects. Therefore, in the first stage, there are 12\*5/(1-10%)=54 patients of targeted treatment group and 126 patients in the immunotherapy group, 180 patients totally in the first stage. If they all enter the second stage, the final target treatment group is 16\*5/(1-10%) = 72 patients and the immunotherapy group which has 168 patients which brings to a total of 240 patients. The sample size of the study shall be adjusted according to the interim analysis. Primary Endpoint of this study is objective response rate (ORR) in immunotherapy group and targeted therapy group assessed by Blinded Independent Central Review (BICR) and investigator. Secondary Endpoints are Progression-Free Survival (PFS) in the targeted treatment group assessed by Blinded Independent Central Review and investigator; PFS (RECIST 1.1) and iPFS (iRECIST) in the single drug immunotherapy group assessed by Blinded Independent Central Review and investigator; Duration of Response (DoR) in the targeted therapy and single immunotherapy groups assessed by the investigator; Durable Clinical Benefit (DCB) in the single drug immunotherapy group; Incidence of Adverse Events (AE) in subjects ect.
Interventions
DRUGAlmonertinib 110 MG
Patients with advanced rare tumors who failed to standardized treatment carrying EGFR mutations will be administrated with Almonertinib.
DRUGDacomitinib 45 MG
Patients with advanced rare tumors who failed to standardized treatment carrying EGFR mutations will be administrated with Dacomitinib.
DRUGAlectinib 150 MG
Patients with advanced rare tumors who failed to standardized treatment carrying ALK fusion will be administrated with Alectinib.
Patients with advanced rare tumors who failed to standardized treatment carrying ALK fusion, ROS-1 fusion, C-MET amplification, C-MET mutation will be administrated with Crizotinib.
DRUGPyrotinib 160/80 MG
Patients with advanced rare tumors who failed to standardized treatment carrying HER-2 mutation or HER-2 over expression/amplification will be administrated with Pyrotinib.
DRUGImatinib 400 MG
Patients with advanced rare tumors who failed to standardized treatment carrying CKIT mutation will be administrated with Imatinib.
Patients with advanced rare tumors who failed to standardized treatment carrying BRCA1/2 mutation will be administrated with Olaparib.
Patients with advanced rare tumors who failed to standardized treatment carrying CDKN2A mutation will be administrated with palbociclib.
DRUGVemurafenib 240 MG
Patients with advanced rare tumors who failed to standardized treatment carrying BRAF mutation will be administrated with Vemurafenib.
DRUGSintilimab 100MG
Patients with advanced rare tumors who failed to standardized treatment carrying no targeted alterations will be administrated with Sintilimab.
DRUGAtezolizumab 1680 MG
Patients with BRAF mutation treated with vemurafenib, after acquired resistance, will combine vemurafenib with atezolizumab.
Sponsors
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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; ECOG score needs to be evaluated 7 days before the first treatment; 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 obvious disease progress before radiotherapy or after radiotherapy; 6. Within the scope of CMPA approved drug indications, the disease has progressed after the standard treatment recommended by NCCN or CSCO guidelines (if there is standard treatment, the recommended level is IA-IIA), or there is no standard effective treatment plan, or it is no longer suitable for standard anti-tumor treatment, or the patients refuse the standard treatment plan; 7. Fresh biopsy tissue samples (obtained within 12 weeks before the first use of the drug, 4 pieces of coarse needle biopsy must be provided, and no other anti-tumor treatment, systemic anti infection treatment, vaccination, et al.) and peripheral blood samples must be provided for molecular typing; 8. Must have a primary or metastatic paraffin specimen (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 ). If requirements are not met, investigator are allowed the decision to enroll subjects according to the specific situation. 9. If there is pleural or peritoneal effusion, the specimens must be taken for pathological cytological examination of which 300 ml samples must be provided; 10. In the condition that the primary lesions biopsy specimen has been provided, if the metastatic lesion is able to be biopsied, it is suggested to keep the specimen for pathological testing and provide fresh tissue specimen (optional); when obtaining EGFR mutation, ALK fusion, ROS-1 fusion, C-MET amplification, C-MET mutation, BRAF mutation, BRCA1/2 mutation, C-KIT mutation, HER-2 mutation HER-2 over expression/amplification, CDKN2A mutation patients will enroll in corresponding sub-study of targeted therapy; if no above mentioned actionable mutation is identified, patients will enroll immunotherapy sub-study. (Each sub-study has separate inclusion and
Exclusion criteria
besides general ones) 11. After the progression of the subject's disease, if conditions permit, fresh tissue samples shall be obtained from the same biopsy lesions and the metastasis lesions of the previously obtained samples; 12. 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); 13. 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. All patients (male and female) agree to use an effective form of contraceptive measures and continue its use for the duration of treatment and within 8 weeks after the end of treatment; 14. Signed, written informed consent of volunteers that join the group shall follow the study treatment plan, follow-up plan and cooperate to observe the adverse events and efficacy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Measured from first dose until confirmed response or progression, assessed up to 2 years. | The percentage of patients with a confirmed Blinded Independent Central Review (BICR) and investigator-assessed complete or partial response according to Response Evaluation Criteria In Solid Tumours (RECIST) 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| iRECIST Evaluated Progression Free Survival (iPFS) | Measured from response until progression, assessed up to 2 years. | The interval between the initiation of study treatment and the first documentation of CUPD (second confirmation of Disease Progression) or death due to any cause as defined by the iRECIST standard in the single drug immunotherapy group |
| Duration of Response (DoR) | Measured from response until progression, assessed up to 2 years. | The time from the date of first response until date of disease progression or death in the absence of disease progression. |
| Disease Control Rate (DCR) | Measured from first dose until confirmed response or progression, whichever came first, assessed up to 2 years. | The percentage of patients treated with targeted and single immunotherapy assessed by the investigator, |
| Durable Clinical Benefit (DCB) | Measured from first dose until confirmed response or progression, whichever came first, assessed up to 2 years. | Partial Response (PR) or Complete Response (CR) or Stable Disease (SD) in the single drug immunotherapy group and without Disease Progression at more than six months. |
| Progression-Free Survival (PFS) | Measured from first dose until progression, assessed up to 2 years. | The time from first dose until the date of objective disease progression or death (by any cause in the absence of progression). |
| One year of Overall Survival rate (1-year OS rate) | Measured from first dose until death, assessed up to 2 years. | Percentage of patients who is alive at 1-year from first dose of treatment. |
| Incidence of Adverse Events (AE) in subjects | Continuously from first dose to end of safety follow up after study treatment discontinuation, assessed up to 2 years. | To evaluate safety and tolerability of each study treatment. |
| The 6-month PFS rate | Measured from response until progression, assessed up to 2 years. | The proportion of patients who are alive and progression-free more than 6 months after the first dose of study therapy Progression-free Survival (PFS) the proportion of patients with PFS ≥ 6 months in the total enrollment since the start of the study. |
| Overall survival (OS) | Measured from first dose until death or final cohort data cut-off, whichever came first, assessed up to 2 years. | The median survival time of patients |
Countries
China
Contacts
Primary ContactNing Li, Doctor
Backup ContactShuhang Wang, Doctor
Outcome results
None listed