An Open Label, Multicenter Phase 1-2 Study to Investigate the Effectiveness, Safety and Immunogenicity of a Monotherapy With Intradermal IMA910 Plus GM-CSF Following Pre-treatment With Low-dose Cyclophosphamide in Advanced Colorectal Carcinoma Patients Who Have Successfully Completed a 12 Week First-line Treatment With Oxaliplatin-based Chemotherapy.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 92
- 试验地点
- 41
- 主要终点
- Disease control rate
研究概览
简要总结
This study is being conducted in order determine whether IMA910 as single agent with GM-CSF as adjuvant following pre-treatment with low-dose cyclophosphamide is safe and shows sufficient anti-tumour effectiveness in patients with advanced CRC to warrant further development. Secondary objectives of this study are investigation of immunological parameters and additional effectiveness endpoints. Furthermore, safety, immunological parameters and effectiveness of IMA910 as single agent with GM-CSF in combination with imiquimod following pre-treatment with low-dose cyclophosphamide will be investigated in a 2nd cohort of patients.
The regular study duration for individual patients in the 1st and 2nd cohort comprises regularly 18-42 days of screening (excluding HLA-typing), 33 weeks of treatment (16 vaccinations) and 4 weeks follow-up. Thus, the period between start of screening and end of trial is about 10 months per patient. Patients will be followed for response to subsequent treatments (chemotherapies with or without targeted agents) and survival every 2 months after EOS visit until death.
Patients in the 1st and 2nd cohort will be withdrawn from study treatment once a progress according to RECIST is noted. An enrolment plan for the first 6 patients included into the 1st cohort will be part of this study to ensure maximum safety of the study participants. The enrollment of the first 6 patients into the 2nd cohort will also follow an enrolment plan to ensure maximum safety.
详细描述
This is a multicentre, open-label, Phase 1-2 study in patients with locally advanced and/or metastatic colorectal cancer (CRC) to investigate the effectiveness, safety and immunogenicity of the tumour multi-peptide vaccine IMA910 plus GM-CSF (1st cohort) given as monotherapy after successful (CR, PR or SD) completion of a 12 week first-line oxaliplatin-based standard chemotherapy (e.g. FOLFOX, XELOX). Safety, immunogenicity and effectiveness of IMA910 plus GM-CSF in combination with imiquimod will be investigated in a 2nd cohort of patients with locally advanced and/or metastatic colorectal cancer (CRC) after successful (CR, PR or SD) completion of a 12 week first-line oxaliplatin-based standard chemotherapy (e.g. FOLFOX, XELOX).
The aim of this study is to investigate whether IMA910 plus GM-CSF (1st cohort) is an effective maintenance therapy with a favorable toxicity profile. A single dose of low-dose cyclophosphamide is applied as an immune modulator 3 days before the start of vaccination. Effectiveness is measured in terms of the disease control rate (DCR) at Visit 14 (= 27 weeks of vaccination) according to RECIST. The baseline tumour response assessment is performed after a first-line oxaliplatin-based standard chemotherapy for 12 weeks. The DCR is compared to a no effect level of 21% derived from the PFS curve of the chemotherapy-free interval cohort (arm B) of the OPTIMOX 2 study. Tumour response assessments will be performed every 9 weeks according to RECIST. Further a 2nd cohort of patients will be treated with IMA910 plus GM-CSF in combination with imiquimod and a single dose of lowdose cyclophosphamide. The aim of the 2nd cohort is to investigate whether the addition of imiquimod is safe, enhances the immune response to IMA910 and shows effectiveness.
Patients in the 1st and 2nd cohort will be withdrawn from study treatment once a progress according to RECIST is noted. An enrolment plan for the first 6 patients included into the 1st cohort will be part of this study to ensure maximum safety of the study participants. The enrollment of the first 6 patients into the 2nd cohort will also follow an enrolment plan to ensure maximum safety.
Patients must be HLA-A*02-positive. Patients must have been diagnosed with unresectable, locally advanced and/or metastatic colorectal cancer before first-line chemotherapy. Patients must have completed a 12 week first-line oxaliplatin-based standard chemotherapy (e.g. FOLFOX or XELOX) with either complete or partial response or stable disease as the outcome. In case the 12 week first-line oxaliplatin-based standard chemotherapy results in resectable disease the patient may not be enrolled and routinely undergoes surgical resection of residual tumour. Patients must be aged 18 years or older and must have histological confirmed colorectal adenocarcinoma (CRC) and radiological evidence (CT/MRI) of unresectable locally advanced and/or metastatic CRC prior to 12 week first-line oxaliplatin-based standard chemotherapy.
This study will employ low-dose Cyclophosphamide (administered as a single i.v. infusion at a dose of 300 mg/m2 3 days prior to the vaccination) in order to increase the immune response to IMA910 (5.78 mg i.d.). Patients will receive 7 vaccinations of IMA910 plus GM-CSF (75 μg i.d.) in the first 6 weeks of treatment (induction period) followed by 9 vaccinations at 3-week intervals for a further 27 weeks (maintenance period). The patients will receive a total of 16 vaccinations over a period of 33 weeks. An end of study visit (EOS, Visit 17) will be performed 4 weeks after the last treatment. Patients enrolled into the 2nd cohort of the study will receive the same treatment as described above and will additionally receive a topical application of 250 mg imiquimod cream (12.5 mg imiquimod) 10 minutes (up to 20 minutes) after each application of IMA910 (Visit 1-16) and from day 3 onwards 250 mg imiquimod cream (12.5 mg imiquimod) 24 hours (but up to 48 hours at the latest) after each application of IMA910 (Visit 3-16). The topical application of imiquimod additionally 24 hours (but up to 48 hours at the latest) after IMA910 application will be done by the patient at home. Imiquimod cream will be applied to a marked 5x5 cm area around the injection site of GM-CSF and IMA910.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged at least 18 years
- •HLA type: HLA-A*02-positive
- •Histologically confirmed colorectal adenocarcinoma (CRC)
- •Radiological evidence (CT/MRI) of unresectable locally advanced and/or metastatic CRC prior to 12 week first-line oxaliplatin-based standard chemotherapy
- •12 week first-line chemotherapy with an oxaliplatin-based regimen according to an established standard protocol (e.g. FOLFOX or XELOX) administered at the following minimum dosages over this 12 week period: Oxaliplatin 400 mg/m2, Fluorouracil (5FU) 10.000 mg/m2 or Capecitabine 84.000 mg/m2 (a time window for application of first-line chemotherapy of +4 weeks is allowed)
- •Response (CR, PR) or stabilization (SD) following a 12 week first-line oxaliplatin-based standard chemotherapy shown by radiological evidence (CT/MRI after last cycle of firstline oxaliplatin-based standard chemotherapy compared to CT/MRI taken before start of first-line oxaliplatin-based standard chemotherapy)
- •Patients accept a chemotherapy-free interval under close observation (CT or MRI scans performed every 9 weeks)
- •Maximum period between start of study treatment (Cyclophosphamide) and start of the last cycle of standard chemotherapy (= first day of last cycle of standard chemotherapy) is 42 days; minimum period is 18 days
- •Karnofsky Performance Status ≥80%
- •Able to understand the nature of the study and give written informed consent
- •Willing and ability to comply with the study protocol for the duration of the study
排除标准
- •Any adjuvant systemic or local chemotherapy if ended ≤6 months before start of systemic first-line oxaliplatin-based standard chemotherapy
- •Progressive disease during or at the end of 12 week systemic first-line oxaliplatin-based standard chemotherapy
- •CT/MRI scans taken more than 9 weeks before start of first-line oxaliplatin-based standard chemotherapy
- •Response to 12 week first-line oxaliplatin-based standard chemotherapy resulting in resectable disease; curative treatment intended
- •Immunosuppressive therapy within 10 days before first vaccination e.g. corticosteroid treatment (inhalative corticosteroids for e.g. asthma are allowed)
- •Radiotherapy during and/or following the 12 week first-line oxaliplatin-based standard chemotherapy (palliative radiotherapy for bone metastasis is allowed)
- •Concurrent or prior participation in a clinical trial applying interventional procedures (e.g. application of investigational drugs, surgical interventions) within the last 30 days before Screening 2 = Visit B
- •History of other malignant tumours within the last 5 years, except basal cell carcinoma or curatively excised cervical carcinoma in situ
- •Presence of known brain metastasis on MRI or CT scans
- •Current partial or complete bowel obstruction
- •Patients with a history or evidence of systemic autoimmune disease
- •Any vaccination within 2 weeks before first vaccination
- •Any planned prophylactic vaccination from study entry until the end of the induction period (Week 6 after first vaccination, exception: if medically indicated)
- •Major surgery ≤4 weeks before first vaccination
- •Any of the following abnormal laboratory values:
- •Haematology:
- •Hb <9 g/dL
- •WBC <2.5 x 109/L
- •Neutrophils <1.5 x 109/L
- •Lymphocytes <1.0 x 109/L
- •Platelets <75 x 109/L
- •Liver function:
- •Serum bilirubin >1.5 x upper normal limit (unless a history of Gilbert's disease)
- •ALAT or ASAT >3 x upper normal limit (>5 x ULN if liver metastases are present)
- •Alkaline Phosphatase >3 x upper normal limit (>5 x ULN if liver metastases are present)
- •Renal function: serum creatinine >200 μmol/L (2.3 mg/dL)
- •Known active hepatitis B or C infection
- •Known HIV infection
- •Active infections requiring oral or intravenous antibiotics
- •Any other infection with a biological agent that can cause a severe disease and poses a severe danger to lab personnel working on patient tissues. Examples are: rabies, Mycobacterium tuberculosis, Coccidioides immitis
- •Patients with other significant diseases currently uncontrolled by treatment which might interfere with study completion, including gastrointestinal, hepatic, renal, respiratory, cardiovascular, haematological, coagulation, metabolic or hormonal diseases with clinically relevant abnormal organ function for example:
- •Heart failure or non-compensated active heart disease (=NYHA Class III and IV)
- •Severe coronary heart disease, cardiac arrhythmia requiring medication, or uncontrolled hypertension
- •Symptomatic neurotoxicity (motor or sensory) = Grade 3 according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE)
- •Severe pulmonary dysfunction
- •Psychiatric disabilities, seizures or central nervous system disorders that may interfere with the ability to give informed consent or perform adequate follow-up in the investigator's opinion
- •Pregnancy or breast-feeding
- •Hypersensitivity to the study drugs (cyclophosphamide, GM-CSF, IMA910) including excipients
结局指标
主要结局
Disease control rate
时间窗: after 27 weeks of vaccination
Safety assessment
时间窗: continuously
Safety assessment with special emphasis on the inclusion of the first 6 patients enrolled according to a pre-specified enrolment plan
次要结局
- Progression free survival(until tumor progression or death)
- Biomarkers(Pre-Vaccination and End of Study)
- Effect of imiquimod (2nd Cohort) on immune response(till End of Study)
- Tumour response rates and SD rate(after 27 and 37 weeks)
- Duration of response(till End of Study)
- Analysis of tumor tissue(optional if available)
- Overall Safety(continuously till End of Study)
- Cellular immunomonitoring(till 27 weeks of vaccination or End Of Study)
- Non-Cellular immunomonitoring(till 27 weeks of vaccination)
- DCR(after 37 weeks on study)
- Overall survival(unitl death)