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.

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Patients in the 1st and 2nd cohort will be withdrawn from study treatment once a progress according to RECIST is noted.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.