IMA910 Plus GM-CSF With Low-Dose Cyclophosphamide Pre-Treatment in Advanced Colorectal Carcinoma Patients Following a Successful 12 Week First-Line Treatment With Oxaliplatin-Based Chemotherapy (IMA910-101)

Condition(s) targeted: Colorectal Carcinoma

Intervention: Endoxana, IMA910, Leukine (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: immatics Biotechnologies GmbH

Official(s) and/or principal investigator(s):
Jürgen Frisch, MD, Study Director, Affiliation: immatics biotechnolgies GmbH

Overall contact:
Andrea Mayer-Mokler, Phone: +49 7071 565 125, Ext: 18, Email: mayer@immatics.com

This study is being conducted in order to 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. The regular study duration for individual patients comprises regularly 3-6 weeks of screening, 33 weeks of treatment (16 vaccinations) and 4 weeks follow-up. Thus, the period between start of screening and end of study is about 10 months per patient. Patients will be withdrawn from study treatment once a progress according to RECIST is noted. An enrolment plan for the first 6 patients included in this study will be used to ensure maximum safety of the study participants.

Official title: 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.

Study design: Treatment, Open Label, Active Control, Single Group Assignment, Safety/Efficacy Study

Primary outcome:

Disease control rate

Safety assessment of the first six enrolled patients

Secondary outcome:

Tumour response rates and SD rate

DCR

Duration of response

and OS

Cellular and non-cellular immunomonitoring

Biomarkers

Analysis of tumour tissue

Overall Safety

Detailed description: This is a multicenter, 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 IMA910 plus GM-CSF given as single-therapy 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 is an effective maintenance therapy with a favourable toxicity profile. A single dose of low-dose Cyclophosphamide is applied as an immune modulator 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 (combination of bevacizumab to the first-line treatment is not allowed). Tumour response assessments will be performed every 9 weeks according to RECIST. The patient will be taken off study if a progress according to RECIST is noted.

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 first vaccination) in order to increase the immune response to IMA910 (5. 8 mg i. d.). Patients will receive 7 intradermal injections of IMA910 plus GM-CSF (75 microgram i. d.) in the first 6 weeks of treatment (induction period) followed by 9 vaccinations at 3-weekly intervals for further 27 weeks (maintenance period). In total the patients will receive 16 vaccinations over a period of 33 weeks.

At screening a CT or MRI of the chest, abdomen/pelvis will be performed to assess baseline tumour status. Brain scans have to be performed if clinically indicated to detect suspected brain metastasis. Bone scans of the extremities have to be performed in case of known metastasis of the extremities or suspected metastasis. During the study tumour assessments will be performed every 9 weeks by either CT or MRI of the chest, abdomen and pelvis. In patients with bone metastases of the extremities detected at baseline or during the study, repeat assessments of the sites of bone metastases will be performed after 14 and 37 weeks.

Cellular immunomonitoring (T-cell responses to peptides contained in IMA910 and analysis of other immune cell populations that may influence T-cell responses such as Tregs), serum levels of antibodies and molecules with suspected influence on immune response will be assessed on several occasions during the study. In a subgroup of patients the following parameters may be assessed in tumour tissue (depending on the amount and quality of tissue): expression of target genes encoding the TUMAPs contained in IMA910 and of genes which might be influenced by IMA910, presentation of TUMAPs contained in IMA910, presence of tumour infiltrating lymphocytes and presence of molecules with suspected influence on immune response.

Safety assessment will comprise continuous adverse event reporting, regular physical examinations and regular assessments of vital signs, haematology, blood chemistry and urine. A 12-lead ECG will be performed at screening and at the end of the study. Pregnancy testing will be performed according to applicable legislation in the country where the trial is being performed. At the very least, women of childbearing potential must undergo a pregnancy test during screening for the study, before the first dose and at the end of the study.

In the initial phase of the study 6 patients will be treated step-wise and observed for 21 days according to a pre-specified enrolment plan. The first step is the enrolment of 1 patient followed by an observation period of 21 days, thereafter enrolment of 2 patients followed by an observation period of 21 days thereafter 3 patients followed by an observation period of 21 days. The sponsor will evaluate the adverse events and laboratory data following every enrolment step and initiate the enrolment of the next enrolment step. After 6 patients enrolled in that way the subsequent enrolment can be performed without further restrictions.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- 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 first-line 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 and start of the last cycle of

standard chemotherapy (= first day of last cycle of standard chemotherapy) is 6 weeks; minimum period is 3 weeks

- 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

Exclusion Criteria:

- 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 6 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 within the last 60 days

- 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:

1. 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

2. 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)

3. 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:

1. Heart failure or non-compensated active heart disease (=NYHA Class III and IV)

2. Severe coronary heart disease, cardiac arrhythmia requiring medication, or uncontrolled hypertension

3. Symptomatic neurotoxicity (motor or sensory) = Grade 3 according to Common Terminology Criteria for Adverse Events v3. 0 (CTCAE)

4. 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

Andrea Mayer-Mokler, Phone: +49 7071 565 125, Ext: 18, Email: mayer@immatics.com

Oncologisch Centrum, UZ Gent, Gent 9000, Belgium; Active, not recruiting

Medische Oncologie, Imeldaziekenhuis, Bonheiden 2820, Belgium; Not yet recruiting
Doreen Iwens, Phone: +32/15504712, Email: Doreen.Iwens@imelda.be
Veerle Moons, MD, Principal Investigator

AZ Klina, Brasschaat 2930, Belgium; Not yet recruiting
Gwen Colfs, Phone: +32/3-650-52-73, Email: gwen.colfs@klina.be
Didier Verhoeven, MD, Principal Investigator

Oncologie-Hematologie, Centre Hospitalier Notre Dame-Reine Fabiola, Charleroi 6000, Belgium; Not yet recruiting
Gabrielle Betrame, Phone: +32/71-93-47-06, Email: gabrielle.beltrame@chndrf.be
Jean-Luc Cancon, MD, Principal Investigator

Internistische onkologische Studienzentrale, Dresden 01307, Germany; Active, not recruiting

Krankenhaus Nordwest der Stiftung Hospital zum heiligen Geist, II. med. Klinik, Frankfurt a.M. 60488, Germany; Active, not recruiting

University of Tübingen, Department of med. Oncology, Hematology, Immunology, Rhematology and Pulmology, Tübingen 72076, Germany; Recruiting
Corinna Jäth, Phone: +49/7071-29-80611, Email: corinna.jaeth@med.uni-tuebingen.de
Frank Mayer, PD Dr. Dr., Principal Investigator

Universitätsklinikum Ulm, Dep. Of Internal Medicine I, Studiensekretariat, CCCU, CTOA, Ulm 89081, Germany; Recruiting
Yvonne Kriebisch, Phone: +49/731-500-44764, Email: ivonne.kriebisch@uniklinik-ulm.de
Götz von Wichert, PD Dr., Principal Investigator

Kliniken Villingen, Schwarzwald-Baar-Klinik, Dept. Of Hematology & Oncology, Villingen-Schwenningen 78050, Germany; Recruiting
Yasmin Hoffmann, Phone: +49/7721-93-4022, Email: yasmin.hoffmann@sbk.vs.de
Wolfram Brugger, Prof. Dr., Principal Investigator

Prosper-Hospital, Med. Klinik I, Recklinghausen 45659, Germany; Recruiting
Annette Schröder, Phone: +49/23-61-54-15029, Email: annette.schroeder@prosper-hospital.de
Thomas Höhler, Prof. Dr., Principal Investigator

Medical School Hannover, MHH, Gastroenterologie, Hannover 30625, Germany; Recruiting
Monique Hörning, Phone: +49/511-532-6779, Email: hoerning.monique@mh-hannover.de
Stefan Kubicka, Prof. Dr., Principal Investigator

National Institute of Oncology, Department of Internal Medicine, Department of Chemotherapy "B", Budapest 1122, Hungary; Recruiting
Erika Hitre, MD, Phone: +36/30-430-15-13, Email: hitre@oncol.hu
Atila Kiss
Istvan Lang, MD, Principal Investigator

Állami Egészségügyi Központ (volt MÀV Kórház), Dept. of Oncology, Budapest 1062, Hungary; Not yet recruiting
Geza Lakner, MD
Geza Lakner, MD, Principal Investigator

Uszoki Hospital, Budapest 1145, Hungary; Not yet recruiting
Màrta Baki, MD
Màrta Baki, MD, Principal Investigator

Semmelweis University, Oncoradiology, Budapest 1085, Hungary; Recruiting
Edit Pthö, Phone: +36/208-258-824, Email: dank@radi.sote.hu
Magdolna Dank, Principal Investigator

Péterfy Hospital, Budapest 1076, Hungary; Not yet recruiting
Tamas Magyar, MD
Tamas Magyar, MD, Principal Investigator

University of Szeged, Department of Oncotherapy, Szeged 6720, Hungary; Recruiting
Zita Ferenczi, Phone: +36/62-544-984, Email: ferenczi@onko.szote.u-szeged.hu
László Thurzo, MD, Principal Investigator

Pauls Stradins University Hospital, Riga 1002, Latvia; Active, not recruiting

Latvia oncological Center, Riga 1079, Latvia; Active, not recruiting

SPZOZ Szpital Uniwersytecki w Krakowie, Oddzial Kliniczny Kliniki Onkologii, Krakow 31-501, Poland; Not yet recruiting
Joanna Huszno
Janusz Pawlega, Prof. Dr., Principal Investigator

Klinika Chemioterapii Nowotworów, Regionalny Ośrodek Onkologiczny, Wojewódzki Szpital Specjalistyczny im. M.Kopernika Uniwersytetu Medycznego Łódz, Lodz 93-509, Poland; Not yet recruiting
Anna Pluszanska, Prof. Dr.
Anna Pluszanska, Prof. Dr., Principal Investigator

Katedra i Klinika Hematologii, Onkologii i Cherob Wewnetrznych AM SP Centralny Szpital Kliniczny w Warszawie, Warszawa 02-097, Poland; Not yet recruiting
Anna Swieboda, MD
Wieslaw Wiktor Jedrzejzczak, Prof. Dr., Principal Investigator

Institute for Oncology and Radiology of Serbia, National Cancer Research Center, Clinical Research and Exp. Pharmacology, Belgrade 11000, Serbia; Active, not recruiting

Oncology Institute of Vojvodina, Sremska 21204, Serbia; Recruiting
Ivan Nikolic, MD, Phone: +381/214-805-569, Email: nikolic.ivan@onko.onk.ns.ac.yu
Dusan Jovanovic, Prof. Dr., Principal Investigator

Starting date: June 2008
Ending date: April 2010
Last updated: November 4, 2008