A Multi-Cancer, Multi-State, Platform Study of Durvalumab (MEDI4736) and Oleclumab (MEDI9447) in Pancreatic Adenocarcinoma, Non-Small Cell Lung Cancer and Squamous Cell Carcinoma of the Head and Neck to Correlate Clinical, Molecular and Immunologic Parameters With DNA Methylation
A Multi-Cancer, Multi-State, Platform Study of Durvalumab (MEDI4736) and Oleclumab (MEDI9447) in Pancreatic Adenocarcinoma, Non-Small Cell Lung Cancer and Squamous Cell Carcinoma of the Head and Neck to Correlate Clinical, Molecular and Immunologic Parameters With DNA Methylation
This is a phase II, single center, open label, multi-cohort platform study to identify a
 signature in tumor tissues, blood or stool that might help identify participants who are more
 likely to experience tumor shrinkage or side effects from the combination of the study drugs
 durvalumab and oleclumab. In addition, this study will see if participants with certain types
 of advanced cancer benefit from the experimental drug combination of durvalumab and
 oleclumab, will evaluate the safety and tolerability of durvalumab and oleclumab, and to
 understand the effects that durvalumab and oleclumab have at a molecular level in tumor cells
 and their effects on the immune system. This study will look at subjects with locally
 advanced or recurrent/metastatic pancreatic ductal adenocarcinoma (PDAC), non-small-cell
 carcinoma (NSCLC) and squamous cell carcinoma of head and neck (SCCHN).

 Within each cancer type, 40 patients will be enrolled (for a total of 120 patients on study):
 20 patients will be enrolled with locally advanced disease ("window") and treated with
 durvalumab 1500 mg given by IV x 1 dose and oleclumab 3000 mg x 2 doses every 2 weeks prior
 to definitive therapy (e.g. surgery), and 20 patients will be enrolled with
 recurrent/metastatic ("metastatic") disease and treated with durvalumab 1500 mg given by IV
 every 4 weeks and oleclumab 3000 mg given by IV every 2 weeks x 4 doses then IV every 4 weeks
 till disease progression, toxicity, withdrawal of subject consent, or another discontinuation
 reason. For locally advanced PDAC patients, approximately 10 of the 20 subjects may receive
 6-8 cycles of modified FOLFIRINOX (mFFX) prior to the administration of durvalumab and
 oleclumab.
The study hypothesis is that the combination of oleclumab (anti-cluster of differentiation
 [CD]73) with durvalumab (anti programmed cell death ligand 1 [PD-L1]) will demonstrate
 adequate safety, tolerability, and antitumor activity in subjects with locally advanced or
 recurrent/metastatic: pancreatic ductal adenocarcinoma (PDAC), non-small-cell lung cancer
 (NSCLC) and squamous cell carcinoma of head and neck (SCCHN), and that circulating free
 methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) can yield
 cancer type-agnostic predictive biomarker(s) of response and/or toxicity in subjects
 receiving this combination.
Inclusion Criteria:

 1. Age ≥ 18 years at the time of screening or age of consent

 2. Written informed consent and any locally required authorization (eg, data privacy)
 obtained from the subject prior to performing any protocol-related procedures,
 including screening evaluations

 3. ECOG of 0 or 1

 4. Weight ≥ 35 kg

 5. Must have a life expectancy of at least 12 weeeks

 6. Histological or cytological confirmation

 7. At least 1 measurable lesion according to RECIST version 1.1

 8. Archival tumor formalin-fixed, paraffin-embedded (FFPE) specimens for correlative
 biomarker studies are required (1 H&E and 15 unstained slides) unless no such sample
 is available or insufficient sample exists. Subjects with insufficient archived tumor
 samples are still eligible

 9. Adequate organ and marrow function

 10. Females of childbearing potential who are sexually active with a nonsterilized male
 partner must use at least one highly effective method of contraception from screening
 to 180 days after the final dose of study treatment

 11. Nonsterilized male subjects who are sexually active with a female partner of
 childbearing potential must use a male condom with spermicide from screening to 180
 days after receipt of the final dose of study treatment

 Exclusion Criteria:

 1. Receipt of any conventional or investigational anticancer therapy within 21 days or
 palliative radiotherapy within 14 days prior to the scheduled first dose of study
 treatment.

 2. Prior receipt of any immune-mediated therapy

 3. Concurrent enrollment in another therapeutic clinical study. Enrollment in
 observational studies will be allowed

 4. Any toxicity (excluding alopecia) from prior standard therapy that has not been
 completely resolved to baseline at the time of consent

 5. Subjects with a history of Grade 3 or greater thromboembolic events in the prior 12
 months or thromboembolic event of any grade with ongoing symptoms

 6. Subjects with prior history of myocardial infarction, transient ischemic attack,
 congestive heart failure ≥ Class 3 based on New York Heart Association Functional
 Classification or stroke within the past 3 months prior to the scheduled first dose of
 study treatment

 7. Active or prior documented autoimmune disorders within the past 3 years prior to the
 scheduled first dose of study treatment

 8. HIV, Hep A, B, or C

 9. History of primary immunodeficiency, solid organ transplantation, or active
 tuberculosis

 10. Other invasive malignancy within 2 years

 11. Known allergy or hypersensitivity to investigational product formulations

 12. History of more than one event of infusion related reactions (IRR) requiring permanent
 discontinuation of IV drug treatment

 13. Active grade 3 or greater edema

 14. Uncontrolled intercurrent illness

 15. Any history of leptomeningeal disease or cord compression

 16. Untreated CNS metastatic disease.

 17. Current or prior use of immunosuppressive medication within 14 days prior to the
 scheduled first dose of study treatment.

 18. Receipt of live, attenuated vaccine within 30 days prior to the scheduled first dose
 of study treatment

 19. Major surgery within 28 days prior to scheduled first dose of study treatment or still
 recovering from prior surgery

 20. Females who are pregnant, lactating, or intend to become pregnant during their
 participation in the study

 21. Subjects who are involuntarily incarcerated or are unable to willingly provide consent
 or are unable to comply with the protocol procedures

 22. Any condition that, in the opinion of the investigator, would interfere with safe
 administration or evaluation of the investigational products or interpretation of
 subject safety or study results