A Randomized Phase II Study on the Optimization of Immunotherapy in Squamous Carcinoma of the Head and Neck
A Randomized Phase II Study on the Optimization of Immunotherapy in Squamous Carcinoma of the Head and Neck
AIO-KHT-0117 (OPTIM) is a phase II, open-label randomized, multicenter study of nivolumab and
 ipilimumab on the optimization of immunotherapy in squamous carcinoma of the head and neck
 after prior platinum-based therapy.
This is a randomized, open-label, multicenter, phase II trial. Patients with recurrent or
 metastatic squamous cell carcinoma of the head and neck will be enrolled in this trial will
 initiate palliative systemic treatment with nivolumab monotherapy (240 mg fixed dose Q2W).
 Tumor response will be assessed after 4, 8, 12, 18 and 24 weeks to capture early progressors.
 Patients with (radiologic) tumor progression during the first 6 months of NIVO mono will be
 randomized (1:1) to receive either docetaxel (75 mg/m2 Q3W) or nivolumab+ipilimumab
 combination (Nivolumab 3mg/kg Q2W + Ipilimumab 1mg/kg Q6W) until progressive disease [PD] or
 death. Patients without PD within 6 months NIVO monotherapy continue treatment under study
 surveillance for a maximum of 12 months measured from first dose of NIVO or until documented
 disease progression.
Inclusion Criteria:

 1. Written informed consent including participation in translational research and any
 locally required authorization (EU Data Privacy Directive in the EU) obtained from the
 subject prior to performing any protocol-related procedures, including screening
 evaluations

 2. Age ≥ 18 years at time of study entry

 3. Histological or cytological confirmed recurrent or metastatic squamous cell carcinoma
 of the head and neck (HNSCC) or nasal sinus not amenable to local therapies

 4. Availability of tumor tissue from biopsy for determination of PD-L1 and HPV status
 according to the following priority ranking: i) recent biopsy (≤3 months old) without
 intervening therapy; ii) any recent biopsy (≤3 months old); iii) any archival tumor
 tissue (> 3 months old) [Biopsy should be excisional, incisional or core biopsy. Fine
 needle aspiration is not allowed.]

 5. Progression or recurrence during or after platinum-based palliative chemotherapy for
 relapsed or metastatic disease OR Progression within 6 months after completion of
 definitive platinum-containing radiochemotherapy for locally advanced disease

 6. At least 1 measurable lesion according to RECIST 1.1

 7. ECOG performance status 0-1

 8. Completion of local therapy for brain metastases with discontinuation of steroids
 prior to start of study treatment

 9. Adequate blood count, liver enzymes, and renal function

 -  neutrophil count > 1.5 x 10^6/mL

 -  platelet count ≥ 100 x 10^9/L (>100,000 per mm³)

 -  hemoglobin ≥ 9 g/dL

 -  INR ≤ 1.5 and PTT ≤ 1.5 x lower limit during the last 7 days before therapy

 -  AST (SGOT)/ALT (SGPT) < 3 x institutional upper limit of normal (5 x lower limit
 in case of liver metastases)

 -  bilirubin < 1.5 x ULN

 -  serum creatinine ≤ 1.5 x institutional ULN or creatinine clearance (CrCl) ≥ 40
 mL/min

 10. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
 test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to
 the start of study drug.

 11. Women of childbearing potential (WOCBP) must use appropriate method(s) of
 contraception. [WOCBP should use an adequate method to avoid pregnancy for 5 months
 (30 days plus the time required for nivolumab to undergo five half-lives) after the
 last dose of nivolumab.] Women who are not of childbearing potential (ie, who are
 postmenopausal or surgically sterile) do not require contraception.

 12. Men who are sexually active with WOCBP must use any contraceptive method with a
 failure rate of less than 1% per year. [Men receiving nivolumab and who are sexually
 active with WOCBP will be instructed to adhere to contraception for a period of up to
 7 months after the last dose of IMP.] Men who are not of childbearing potential (ie,
 surgically sterile or azoospermic ) do not require contraception

 13. Subject is willing and able to comply with the protocol for the duration of the study
 including undergoing treatment and scheduled visits and examinations including follow
 up.

 Exclusion Criteria:

 1. Nasopharynx carcinoma or carcinoma of salivary glands

 2. Life expectancy less than 3 months

 3. Any condition or comorbidity that, in the opinion of the investigator, would interfere
 with evaluation of study treatment or interpretation of patient safety or study
 results, including but not limited to:

 1. Minor surgery ≤ 24 hours prior first dose of nivolumab monotherapy

 2. Anticancer treatment during the last 30 days prior to start of nivolumab
 monotherapy, including systemic therapy, or major surgery [palliative
 radiotherapy has to be completed at least 2 weeks prior to start of nivolumab
 monotherapy]

 3. Known active HBV, HCV or HIV infection

 4. Active tuberculosis

 5. Any other active infection requiring systemic therapy

 6. History of allogeneic tissue/solid organ transplant (including hematopoietic stem
 cell transplantation)

 7. Diagnosis of immunodeficiency or patient is receiving chronic systemic steroid
 therapy or any other form of immunosuppressive therapy within 7 days prior to the
 first dose of nivolumab-monotherapy or randomization.

 8. Has an active autoimmune disease requiring systemic treatment within the past 3
 months before enrolment or a documented history of clinically severe autoimmune
 disease, or a syndrome that requires systemic steroids or immunosuppressive
 agents. Subjects with vitiligo, hypothyroidism, diabetes mellitus type I or
 resolved childhood asthma/atopy are an exception to this rule. Subjects that
 require intermittent use of bronchodilators or local steroid injections would not
 be excluded from the study. Subjects with hypothyroidism stable on hormone
 replacement or Sjorgen's syndrome will not be excluded from the study. Psoriasis
 not requiring treatment is not excluded from the study.

 9. Live vaccine within 30 days prior to the first dose of nivolumab-monotherapy or
 during study treatment.

 10. Other active malignancy requiring treatment

 11. Clinically significant or symptomatic cardiovascular/cerebrovascular disease in
 (incl. myocardial infarction, unstable angina, symptomatic congestive heart
 failure, serious uncontrolled cardiac arrhythmia) within 6 months before
 enrollment

 12. History or clinical evidence of CNS metastases

 Exceptions are: Subjects who have completed local therapy and who meet both of the
 following criteria:

 -  are asymptomatic and

 -  have no requirement for steroids 6 weeks prior to start of nivolumab-monotherapy.
 Screening with CNS imaging (CT or MRI) is required only if clinically indicated
 or if the subject has a history of CNS metastases

 4. Medication that is known to interfere with any of the agents applied in the trial.

 5. Has known hypersensitivity to nivolumab or ipilimumab or docetaxel or any of the
 constituents of the products.

 6. Any other efficacious cancer treatment except protocol specified treatment at study
 start.

 7. Patient has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or has
 not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
 administered more than 4 weeks earlier. [Subjects with ≤ Grade 2 alopecia are an
 exception to this criterion and may qualify for the study.]

 8. Female subjects who are pregnant, breast-feeding or male/female patients of
 reproductive potential who are not employing an effective method of birth control
 (failure rate of less than 1% per year). [Acceptable methods of contraception are:
 implants, injectable contraceptives, combined oral contraceptives, intrauterine
 pessars (only hormonal devices), sexual abstinence or vasectomy of the partner].

 9. Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1), anti-PD-L1,
 anti-Programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand,a member of
 the Tumor Necrosis Factor Receptor [TNFR] family), or anti-Cytotoxic
 T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any
 other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
 pathways)

 10. Participation in another clinical study with an investigational product during the
 last 30 days before inclusion or 7 half-lifes of previously used trial medication,
 whichever is longer

 11. Previous treatment in the present study (does not include screening failure)
 [Criterion is not applicable during re-assessment of eligibility for randomization].

 12. Patient who has been incarcerated or involuntarily institutionalized by court order or
 by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.

 13. Patients who are unable to consent because they do not understand the nature,
 significance and implications of the clinical trial and therefore cannot form a
 rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].