E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic colorectal cancer |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the colon that has spread to another part of the body. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010036 |
E.1.2 | Term | Colorectal carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the IMPALA trial is the evaluation of the efficacy of a novel switch maintenance treatment with lefitolimod (MGN1703) to increase overall survival (OS) in patients with metastatic colorectal cancer with tumor reduction after induction treatment with standard first-line chemotherapy, with or without biological agents. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are efficacy parameters such as progression free survival and survival endpoints, toxicity and safety, tolerability, Quality of Life and patient related outcome (in participating study sites), and translational research. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed written informed consent 2. Male or female patient 18 years or older 3. Histologically confirmed diagnosis of colorectal cancer presenting with unresectable stage IV (UICC) disease (primary tumor may be present) 4. Complete or partial response, as assessed by local investigators according to RECIST 1.1, within 12-30 weeks from start of induction treatment with standard first-line chemotherapy with or without biological agents 5. ECOG PS 0-1 6. Haematology and biochemistry laboratory results within the limits expected for a patient population recovering after receiving induction treatment: - Platelet count ≥ 80x10 9/L - Leukocyte count ≥ 1.50x10 9/L - Lymphocytes ≥ 0.50x10 9/L - Haemoglobin ≥ 9.0 g/dL or 5.59 mmol/L - Total bilirubin ≤ 2.5 times the upper limit of normal (ULN) - AST ≤ 3xULN in absence of liver metastases, or ≤ 5.0xULN in presence of liver metastases - ALT ≤ 3xULN in absence of liver metastases, or ≤ 5.0xULN in presence of liver metastases - Serum creatinine ≤ 2.0xULN 7. Male and female patients of childbearing potential (i.e. not post-menopausal for at least 24 consecutive months and did not undergo surgical sterilization – hysterectomy, bilateral tubal ligation, or bilateral oophorectomy for women, vasectomy for men) using an effective means of contraception with a failure rate of less than 1% per year, e.g. established use of oral, implanted or injected hormonal contraceptives; placement of intra-uterine device (IUD) or intra-uterine system (IUS); use of barrier methods such as condom or diaphragm together with spermicide product; true abstinence (when it is in line with preferred and usual lifestyle of the patient). Contraception will start after screening and continue throughout study until at least one month after the last dose of lefitolimod (MGN1703) or longer if required according to the SmPCs of the used standard therapy medications. Females of child bearing potential must have a negative serum pregnancy test. |
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E.4 | Principal exclusion criteria |
1. History of other malignant tumors within the last 5 years, except basal cell carcinoma or curatively excised cervical carcinoma in situ
2. Known brain metastases (present or treated)
3. Contraindication to receiving lefitolimod (MGN1703) as per current investigator's brochure
4. Known hypersensitivity to any components of the study product
5. Prior allogeneic stem cell transplantation or organ transplantation.
6. Active or uncontrolled infections or undiagnosed febrile condition.
7. Severe anemia requiring repeated blood cell transfusion
8. Pre-existing autoimmune or antibody mediated diseases or immune deficiency
9. Chronic systemic immune therapy or immunosuppressant medication other than steroids within the last 6 weeks; continuous systemic steroid treatment within the last 2 weeks prior to start of study treatment
10. Use of systemic antibiotic therapy within the last 2 weeks prior to start of study treatment
11. Inadequate pulmonary function according to the investigator's judgment, history of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan
12. HIV seropositivity or active HBV/HCV infection
13. Serious concomitant disease or a medical condition that in the judgment of the investigator renders the patient at high risk of treatment complications
14. Female patient who is pregnant or breast feeding
15. Contraindication to receiving the planned standard maintenance treatment according to applicable SmPC
16. Treatment with any anti-cancer investigational drug within 12 months prior to study treatment or participation in another clinical study with other investigational drugs within 28 days prior to study treatment.
17. Vaccination within 1 month prior to start of study treatment
18. Any medical, mental, psychological or psychiatric condition that in the opinion of the investigator would not permit the patient to complete the study or understand the patient information
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary study endpoint is overall survival after randomization (OS), defined as the time between the date of randomization and the date of death from any cause. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary study endpoint is overall survival after randomization (OS), defined as the time between the date of randomization and the date of death from any cause. Measured by imaging (CT/MRI) at screening and throughout study according to local practice. |
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E.5.2 | Secondary end point(s) |
1. Overall survival from start of induction therapy (OSi) 2. Overall survival rates at 3, 4 and 5 years after Randomization 3. Progression free survival on study treatment (PFS on study) after randomization until second disease progression (PD) according to RECIST 1.1 (includes PFS1 and PFS2, see below). 4. Progression free survival after randomization until first PD, necessitating discontinuation of maintenance and re-introduction of all first-line chemotherapy agents (PFS1). 5. PFS after re-introduction of initial induction therapy until PD (usually followed by the start of a second line treatment) (PFS2) 6. Progression free survival after first-line treatment, including induction treatment before randomization, maintenance treatment and re-induction until subsequent PD (usually followed by the start of a second line treatment) (PFS3) 7. PFS rates at 2, 3, 4 and 5 years after randomization 8. Primary and secondary endpoints will also be analyzed by stratification criteria and by maintenance strategy. - Overall response rate (ORR = CR + PR) after randomization according to RECIST v1.1 . PFS will be assessed according to RECIST 1.1. 9. Responses and PD will be confirmed by independent radiological review for exploratory purposes only (the primary assessment will be that of the local investigators) 10. Adverse events (toxicity) according to NCI CTC AE v4.03 11. Quality of Life (QoL) assessment (EORTC QLQ C30 + CR29 and additional tools used locally) in selected study sites 12. Translational research a.) All randomized patients will participate in the immuno-monitoring plan. b.) Histopathological and biological markers information available at the centers will be collected. c.) The Study Steering Committee may also propose additional research projects for the sponsor's approval. Those selected for separate funding will be detailed in annex protocols submitted to local ethics committees for approval at participating institutions and will be conducted in consenting patients only. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. from start of induction;
2. 3, 4 and 5 yrs after random.
3. on treatment after random. to 2nd PD
4. after random. to 1st PD
5. after re-intro of induction therapy until PD
6. after 1st line treat. incl. induction chemo before random, maint treat & reintroduction until PD
7. PFS rates at 2, 3, 4 yrs after random. All PFS by imaging from Scr to EoT according to local practice
8. subgroup analyses: performed at various timepoints
9. imaging from Scr to EoT according to local practice
10. ongoing through study
11. Some sites: Scr, Treat phase/maint; Treat phase/ re-induction at various visits to EOT
12. Bloods: Scr, Treat phase/maintenance;Treat phase/ re-induction at various visits to EOT
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability, Quality of Life and Translational research |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 120 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The primary analysis of the overall survival will be performed after a total of 365 events have been observed in total from both treatment arms. The study will be closed 36 months after the randomization of the last patient. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |