A PHASE 1B/2 OPEN-LABEL STUDY TO EVALUATE SAFETY, CLINICAL ACTIVITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AVELUMAB* (MSB0010718C) IN COMBINATION WITH OTHER CANCER IMMUNOTHERAPIES IN PATIENTS WITH ADVANCED MALIGNANCIES

1. Histological or cytological diagnosis of advanced/metastatic solid tumor with the following tumor types. Combinatie A: For Phase 1b,
patients with NSCLC that have progressed on standard therapy or for which no standard
therapy is available, and for Phase 2, patients with NSCLC, melanoma, SCCHN, and TNBC in any line of therapy.
NSCLC patients in Phase 2 with tumor anaplastic lymphoma kinase (ALK)
translocations or epidermal growth factor receptor (EGFR) mutations
must have received or been refractory/intolerant to standard therapy.
Patients with a history of PD-1 or PD-L1 refractory disease (best
response of PD) will not be eligible.
Combination B:
For phase 1b, patients with advanced solid tumors that have progressed
on standard therapy or for which no standard therapy is available. For
Phase 2, patients with NSCLC, melanoma, or SCCHN in any line of
therapy, or locally advanced/metastatic CRC that has progressed after at
least 1 line of standard therapy. NSCLC patients in Phase 2 with tumor
ALK translocations or EGFR mutations must have received or been
refractory / intolerant to standard therapy. Measurable disease by
RECIST v1.1 with at least 1 measureable lesion that has not
previously been irradiated.Availability of tumor specimens: For Phase 1b: Archival formalin-fixed
paraffin-embedded (FFPE) tissue is required if available. For Phase 2:
FFPE tissue must be available from the most recent primary or
metastatic tumor biopsy or resection prior to start of study therapy,
taken within 1 year prior to study entry, with no intervening systemic
anti-cancer therapy. This tissue may be prepared from a de novo biopsy
obtained prior to study entry. Core needle or excision biopsies are
preferred.
Human papilloma virus (HPV) status based on locally approved testing
for patients with SCCHN, and microsatellite instability (MSI) status
based on locally approved testing for patients with CRC.
2. Age >=18 years.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
4. Estimated life expectancy of at least 3 months.
5. Adequate Bone Marrow Function, defined as:
a. Absolute Neutrophil Count (ANC) >=1.5 x 109/L ( >=1,500/µl);
b. Platelets >=100 x 109/L (>=100,000/ µl);
c. Hemoglobin >=9 g/dL (>5.6 mmol/L).
Patients must be transfusion independent (ie, no blood product transfusions for a period
of at least 14 days prior to study entry).
6. Adequate Renal Function, including estimated creatinine clearance >=50 mL/min as
calculated using the Cockcroft-Gault (CG) equation.
7. Adequate Liver Function, including:
a. Total serum bilirubin <=1.5 x upper limit of normal (ULN);
b. Aspartate and Alanine aminotransferase (AST & ALT) <=2.5 x ULN.
6. Resolved acute effects of any prior therapy to baseline severity or NCI
CTCAE v4.03 Grade <=1 (except alopecia and Grade <=2 sensory
neuropathy are acceptable).
9. Negative serum pregnancy test (for females of childbearing potential) at screening.
10. Male patients able to father children and female patients of childbearing potential and at
risk for pregnancy must agree to use two highly effective methods of contraception
throughout the study and for at least 60 days after the last dose of assigned treatment, as required by local regulations.
Female patients who are not of childbearing potential (ie, meet at least one of the
following criteria):
Have undergone a documented hysterectomy and/or bilateral oophorectomy;
Have medically confirmed ovarian failure; or
Achieved postmenopausal status, defined as follows: cessation of regular menses for
at least 12 consecutive months with no alternative pathological or physiological
cause; a serum follicle-stimulating
hormone (FSH) level within the laboratory*s reference range for postmenopausal
women.
11. Evidence of a personally signed and dated informed consent document indicating that the
patient has been informed of all pertinent aspects of the study.
12. Patients who are willing and able to comply with scheduled visits, treatment plans,
laboratory tests, and other procedures.

1. Monoclonal antibody based anti-cancer therapy within 28 days prior to
study entry or small-molecule based anti-cancer therapy (targeted
therapy or chemotherapy) within 14 days prior to study entry.
2. Current or prior use of immunosuppressive medication within 7 days
prior to study entry The following are exceptions to this exclusion criterion: Intranasal,
inhaled, topical steroids, or local steroid injections (eg, intra-articular injection); Systemic
corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent;
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
3. Active autoimmune disease that requires systemic steroids (equivalent of >10 mg
prednisone) or immunosuppressive agents within 7 days prior to study entry. Exceptions
include: patients with controlled diabetes type 1, controlled hypo- or hyperthyroidism,
resolved childhood asthma/atopy, vitiligo, or psoriasis not requiring immunosuppressive
treatment.
4. Known prior or suspected hypersensitivity to investigational products or any component
in their formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v4.03 Grade >=3), and any history of anaphylaxis, or
uncontrolled asthma (ie, 3 or more features of partly controlled asthma).33
5. Major surgery within 4 weeks or radiation therapy within 14 days prior to study entry.
Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been
completed 48 hours prior to study entry and there is at least one measurable lesion that
has not been irradiated.
6. Patients with known symptomatic brain metastases requiring steroids. Patients with
previously diagnosed brain metastases are eligible if they have completed their treatment
and have recovered from the acute effects of radiation therapy or surgery prior to study
entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks
prior to study entry, and are neurologically stable.
7. Previous high-dose chemotherapy requiring stem cell rescue.
8. Prior allogeneic stem cell transplant or organ graft.
9. Any of the following within the 6 months prior to study entry: myocardial infarction,
uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive
heart failure, cerebrovascular accident or transient ischemic attack.
10. Symptomatic pulmonary embolism within 6 months prior to study
entry
11. Known HIV or AIDS-related illness
12. Active infection requiring systemic therapy
13. Positive HBV or HCV test indicating acute or chronic infection
14. Administration of a live vaccine within 4 weeks prior to study entry
15. Diagnosis of other malignancy within 5 years, except for adequately
treated basal cell or squamous cell skin cancer, or carcinoma in situ of
the breast or cervix, or low-grade (Gleason <=6) prostate cancer
16. Patients who are site staff members directly involved in the conduct
of the study and their family members, site staff members otherwise
supervised by the investigator, or patients who are Pfizer employees
directly involved in the conduct of the study
17. Participation in other studies involving investigational drug(s) within
4 weeks prior to study entry and/or during study participation
18. Persisting toxicity related to prior therapy NCI CTCAE v4.03 Grade
>1 (alopecia and Grade <=2 sensory neuropathy is acceptable).
19. Other severe acute or chronic medical condition, including colitis,
inflammatory bowel disease, and pneumonitis or psychiatric condition,
recent or active suicidal ideation or behavior, or end stage renal disease
on hemodialysis, or laboratory abnormality that may increase the risk
associated with study participation or investigational products
administration or may interfere with the interpretation of results and, in
the judgment of the Investigator, would make the patient inappropriate
study entry
20. Male and female patients able to have children who are unwilling or
unable to use 2 highly effective method(s) of contraception for the
duration of the study and for at least 60 days after the last dose of
investigational product or longer as required by local regulations.