A Trial Exploring the Efficacy of EMD 1201081 in Combination With Cetuximab in Second-Line Cetuximab-Naïve Subjects With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (R/M SCCHN)

• To evaluate the overall response (by RECIST 1.0) or disease control status (CR + PR + SD) of subjects treated with EMD 1201081 + cetuximab compared to cetuximab alone in subjects with R/M SCCHN. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To evaluate the duration of response of subjects treated with EMD 1201081 + cetuximab compared to cetuximab alone in subjects with R/M SCCHN. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To evaluate overall survival time in subjects treated with EMD 1201081 + cetuximab as second-line treatment. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To study the safety and tolerability of the combination EMD 1201081 + cetuximab in the overall trial population. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To assess the response rate of subjects treated with EMD 1201081 + cetuximab after they have progressed on cetuximab alone. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To evaluate the time to tumor progression in subjects treated with EMD 1201081 + cetuximab. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To characterize selected biomarkers in consenting subjects. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To evaluate the effects of EMD 1201081 on the development of anti-cetuximab antibodies and cetuximab pharmacokinetics (immunogenicity). [ Time Frame: During 6 month of treatment and at end of treatment visit ] [ Designated as safety issue: Yes ]

• To evaluate the overall response (by RECIST 1.0) or disease control status (CR + PR + SD) of subjects treated with EMD 1201081 + cetuximab compared to cetuximab alone in subjects with R/M SCCHN. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To evaluate the duration of response of subjects treated with EMD 1201081 + cetuximab compared to cetuximab alone in subjects with R/M SCCHN. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To evaluate overall survival time in subjects treated with EMD 1201081 + cetuximab as second-line treatment. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To study the safety and tolerability of the combination EMD 1201081 + cetuximab in the overall trial population. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To assess the response rate of subjects treated with EMD 1201081 + cetuximab after they have progressed on cetuximab alone. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To evaluate the time to tumor progression in subjects treated with EMD 1201081 + cetuximab. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]
• To characterize selected biomarkers in consenting subjects. [ Time Frame: During 6 months of treatment and 1 year follow-up period. Subjects will be requested to visit the hospital every 3 months during the follow-up period. ] [ Designated as safety issue: Yes ]

The purpose of this research is to determine if EMD 1201081 in combination with cetuximab is more efficient than cetuximab alone to control the cancer.

EMD 1201081 is an immune modulatory oligonucleotide (IMO) containing phosphorothioate oligodeoxynucleotide and acts as an agonist of Toll-like receptor 9 (TLR9).

EMD 1201081 has been studied in six clinical trials in over 170 subjects either as a monotherapy or in combination with chemotherapeutic agents or targeted therapies. Two studies have been conducted in healthy volunteers. In the other five studies, patients with advanced solid tumors, renal cell carcinoma, non-small cell lung cancer and colorectal cancer have been treated with EMD 1201081. Two studies are still ongoing. Future clinical development of EMD 1201081 will focus on colorectal cancer (CRC) and squamous cell cancer of the head and neck (SCCHN).

Subject of this application is the phase II study EMR 200068-006 in recurrent or metastatic squamous cell cancer of the head and neck (R/M SCCHN) in which patients with recurrent or metastatic squamous cell cancer of the head and neck will be treated with cetuximab plus EMD 1201081 or cetuximab alone. The study will be conducted as a multicenter study in several EU Member States and the USA.

EMD 1201081 in combination with cetuximab will be evaluated for antitumor activity in subjects by examining its effects on accepted clinical endpoints. Progression-free survival will be evaluated in subjects treated with EMD 1201081 plus cetuximab compared to cetuximab alone in cetuximab-naïve subjects with recurrent and/or metastatic SCCHN who have progressed on a cytotoxic therapy.

Cetuximab, approved in colorectal cancer and SCCHN in combination with platinum-based chemotherapy and SCCHN in combination with radiotherapy in the EU, will be provided as Investigational Medicinal Product (IMP) in this study. Commercially available Cetuximab will be provided in the US.

• Drug: Cetuximab in combination with EMD 1201081
  The EMD 1201081 dose investigated in this trial will be 0.32 mg/kg given once weekly subcutaneously. Dose increases beyond 0.32 mg/kg are not allowed. Because of site injection reactions or other EMD 1201081 related side effects, it may be necessary to reduce or skip a dose of EMD 1201081. Investigators should make every effort to ensure that subjects receive all EMD 1201081 doses. The cetuximab dose will be based on the BSA. Cetuximab will be given as an initial infusion of 400 mg/ m2 followed by a weekly cetuximab infusions of 250 mg/m2 until the subject withdraws from the trial.
• Drug: Cetuximab alone
  Cetuximab will be given as an initial infusion of 400 mg/ m2 followed by a weekly cetuximab infusions of 250 mg/m2 until the subject withdraws from the trial.

• Active Comparator: A
  Intervention: Drug: Cetuximab in combination with EMD 1201081
• Active Comparator: B
  Intervention: Drug: Cetuximab alone

Inclusion Criteria:

1. Signed and dated written informed consent prior to any trial-specific procedure.
2. Male or female, age ≥ 18 years.
3. Histologically confirmed squamous cell carcinoma of the head and neck that is recurrent and/or metastatic; documented in the medical record.
4. History of progressing disease on a first-line cytotoxic chemotherapy regimen such as 5-FU + cisplatin, taxanes, etc. for their R/M SCCHN. (A history of chemotherapy/ radiation therapy for localized disease does not count as a first-line regimen.)
5. The subject is suited for systemic therapy in the opinion of the Investigator.
6. At least one radiographically documented lesion assessable according to RECIST 1.0. Lesions in previously irradiated areas should be measurable (i.e. the lesion must be adequately measurable in at least one dimension; longest diameter to be recorded as ≥ 2 cm by conventional techniques or ≥ 1 cm by spiral CT scan). If the sole site of measurable disease is in a prior radiation field, there must be unequivocal evidence of progression at ≥ 8 weeks since the completion of radiation or a positive biopsy.
7. ECOG performance status of 0 or 1.
8. If female, either post-menopausal, surgically sterile, or having a negative urine or serum pregnancy test (β-HCG) at screening and practicing medically accepted contraception. If male, practicing contraception if risk of conception exists. For relevant subjects, the duration of contraception should be 1 week prior to the start of therapy through 4 weeks after receipt of trial therapy.
9. Recovered from previous toxicities of prior cytotoxic regimen to CTCAE Grade 1 (with the exception of alopecia).
10. Hemoglobin ≥ 9 g/dL (without transfusion support, no transfusion within 7 days of screening).
11. Neutrophils ≥ 1.5 x 10(9)/L.
12. Platelets ≥ 100 x 10(9)/L.
13. PT/PTT ≤ 1.5 times the upper limit of normal for the site, unless there is therapeutic anti-coagulation (see below; INR values should be converted to PT for screening).
14. Serum creatinine ≤ 1.5 times the upper limit of normal for the site.
15. ALT and AST ≤ 3 times the upper limit of normal for the site.
16. Be willing and able to comply with the protocol procedures for the duration of the trial.

Exclusion Criteria:

1. History of prior exposure to cetuximab or panitumumab or any other approved or investigational anti-EGFR agents.
2. Undifferentiated nasopharyngeal carcinoma.
3. Chemotherapy, radiotherapy or any investigational agents within 4 weeks of first dose of trial medication.
4. Major surgical or planned procedure within 30 days prior to first dose of trial medication (isolated biopsies are not counted as major surgical procedures).
5. Other active malignancy besides non-metastatic basal cell or squamous cell carcinoma of the skin or second primary squamous cell carcinoma of the head and neck.
6. Impaired cardiac function (e.g. left ventricular ejection fraction < 45% defined by echocardiograph or other study), history of uncontrolled serious arrhythmia, unstable angina pectoris, congestive heart failure (NYHA III and IV), myocardial infarction within the last 12 months prior to trial entry, signs of pericardial effusion.
7. Hypertension uncontrolled by standard pharmacologic therapies.
8. History of diagnosed interstitial lung disease.
9. Patient requires systemic anti-coagulation (e.g. warfarin > 10 mg/day).
10. Pregnancy or breast feeding.
11. Legal incapacity or limited legal capacity.
12. Significant medical or psychiatric disease which makes the trial inappropriate for the subject in the Investigator's opinion.
13. Any brain metastasis and/or leptomeningeal disease (known or suspected).
14. Significant pre-existing immune deficiency such as infection by HIV (documented or known).
15. Clinically significant ongoing infection.
16. Known hypersensitivity to the trial treatments.
17. Participation in another clinical trial within the past 30 days.
18. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such.
19. Other significant disease that in the Investigator's opinion would exclude the subject from the trial.