Study of ARRY-614 Plus Either Nivolumab or Nivolumab+Ipilimumab

Inclusion Criteria:

• Age ≥18 years.

• For Phase Ib: Trial participants must have a histologically confirmed malignancythat is metastatic or unresectable for which curative measures do not exist or areno longer effective. a.Trial participants must have nivolumab or ipilimumab therapy available and must beappropriate for this therapy.

• For Phase II:

1. Participants with melanoma who previously experienced disease progression onanti-PD1 (with or without ipilimumab).

2. Participants with RCC who previously experienced disease progression onanti-PD1 (with or without ipilimumab).

3. Participants with NSCLC or HNSCC who previously experienced disease progressionon anti-PD1 (with or without ipilimumab).

4. Progression on prior anti-PD1/L1 or anti-PD1/anti-CTLA4 antibodies must meetdefinitions for primary or secondary resistance and regrowth after stoppingtherapy as below or there must be documentation by the treating investigator ofrapid disease progression such that these criteria cannot be assessed (suggestions from the Society for ImmunoTherapy of Cancer PD1 ResistanceWorking Group).

• Have an ECOG PS score of 0 or 1 (Appendix 13.A).

• Have an expected survival of ≥3 months.

• Have at least one evaluable and measurable lesion as defined by RECIST v1.1.

• The first five patients in each Phase II cohort must have tumors determined to beeasily accessible for biopsy and must be willing to have two biopsies

• Have recovered from toxicities associated with prior anticancer therapy to baselineor Grade 1 unless stabilized under medical management per investigator.

• Have adequate bone marrow function as evidenced by:

1. Absolute neutrophil count ≥1,500/mm3 or 1.5 ×109/L

2. Hemoglobin ≥8 g/dL

3. Platelets ≥100,000/mm3 or 100 × 109/L

• Have adequate hepatic function as evidenced by:

1. Serum total bilirubin ≤2 × upper limit of normal (ULN), unless considered dueto Gilbert's disease

2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x theinstitutional ULN or ≤ 5.0x institutional ULN in the presence of known livermetastases.

• Patients with creatinine clearance > 30 mL/min, (measured using Cockcroft-Gaultequation or the estimated glomerular filtration rate from the Modification of Dietin Renal Disease Study) are included in the study.

• Be able to understand and willing to sign the informed consent form (or have legalrepresentation) and to comply with scheduled visits, treatment plans, procedures,and laboratory tests, including serial peripheral blood sampling, biopsies, andurine sampling, during the study. A legally authorized representative may consent onbehalf of a subject who is otherwise unable to provide informed consent ifacceptable to and approved by the site's IRB/Independent Ethics Committee (IEC).

• Female patients with reproductive potential must have a negative serum pregnancytest prior to the start of therapy, or a confirmation from an obstetrician in caseof equivocal serum pregnancy results. Females of reproductive potential are definedas sexually mature women who have not undergone a hysterectomy, bilateraloophorectomy, or tubal occlusion or who have not been naturally postmenopausal (ie,who have not menstruated) for at least 24 consecutive months (ie, have not hadmenses at any time in the preceding 24 consecutive months). Women with reproductivepotential, as well as fertile men and their partners who are female withreproductive potential, must agree to use two effective forms of contraception (including at least one barrier form) from the time of giving informed consentthroughout the study and for 5 months after the last dose of therapy for women, and 7 months after last dose for men. Effective forms of contraception are defined ashormonal PO contraceptives, injectables, patches, intrauterine devices, intrauterinehormone-releasing systems, bilateral tubal ligation, condoms with spermicide, ormale partner sterilization.

• Patients positive for human immunodeficiency virus (HIV) are NOT excluded from thisstudy, but HIV-positive patients must have:

1. A stable regimen of highly active anti-retroviral therapy (HAART)

2. No requirement for concurrent antibiotics or antifungal agents for theprevention of opportunistic infections

3. A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standardPCR-based test

Exclusion Criteria:

• Received systemic anticancer therapy or an investigational agent <2 weeks prior toDay 1 (washout from prior immune based anticancer therapy is 4 weeks). In addition,the first dose of study treatment should not occur before a period ≥5 half-lives ofthe investigational agent has elapsed (excluding nivolumab therapy or combinationanti-PD1/ipilimumab combination therapy in RCC - prior ipilimumab not permitted inmelanoma cohort).

• For ST, have underwent hepatic radiation, chemoembolization, and radiofrequencyablation <4 weeks prior to Day 1.

• Participants must not have had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 (with exception of anti-PD1/ipilimumab combinationtherapy) or have not recovered (i.e. < Grade 1 at baseline) from adverse events dueto agents administered more than 4 weeks earlier.

• Participants must not have a diagnosis of immunodeficiency or be receiving systemicsteroid therapy at a dose of >10 mg prednisone daily or equivalent at time of firstdose of trial treatment (this criterion does not apply to HIV-positive patients asdetailed in the inclusion criteria).

• Participants must not have active autoimmune disease that has required systemictreatment in the past 2 years (i.e. with use of disease modifying agents,corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine,insulin, or physiologic corticosteroids replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

• Participants must not have a known history of non-infectious pneumonitis thatrequired steroids for treatment.

• Participants must not have evidence of active interstitial lung disease.

• Have known symptomatic brain metastases requiring steroids. Patients with previouslydiagnosed brain metastases are eligible if they have completed their treatment andhave recovered from the acute effects of radiation therapy or surgery prior to studyentry, have discontinued corticosteroid treatment for these metastases for at least 1 week and have radiographically stable disease for at least 1 month prior to studyentry. Note: up to 10 mg per day of prednisone equivalent will be allowed.

• Have a history of another primary cancer that is active requiring treatment,progressing or for which the investigator believes will make disease assessmentunreliable.

• Underwent major surgery within 4 weeks of Day 1 or have not recovered frompost-surgery toxicities.

• Are pregnant or breastfeeding.

• Have an active infection requiring systemic anti-infective therapy or with anunexplained fever >38.5°C within 7 days of Day 1 (at the discretion of theInvestigator, patients with tumor fever may be enrolled).

• Have any known hypersensitivity to any of the components of ARRY-614 oranti-PD1/ipilimumab combination therapies.

• Have significant active cardiac disease within 6 months prior to the start of studytreatment, including New York Heart Association (NYHA) Class III or IV congestiveheart failure); myocardial infarction; unstable angina; and/or stroke.

• Have known LVEF <40% by ECHO scan (or by other methods according to institutionalpractice) obtained within 28 days prior to the start of study treatment (testing isnot otherwise mandatory).

• Have known active hepatitis B (HBV) or hepatitis C (HCV) infections. Patients with asustained viral response to HCV treatment or immunity to prior HBV infection will bepermitted. Patients with chronic HBV that is adequately suppressed per institutionalpractice will be permitted.

• Have any other acute or chronic medical or psychiatric condition, including recent (within 12 months of Day 1) or active suicidal ideation or behavior, or a laboratoryabnormality that may increase the risk associated with study participation orinvestigational product administration or may interfere with the interpretation ofstudy results and, in the judgment of the Investigator, would make the subjectinappropriate for entry into this study.

• Have known active inflammatory gastrointestinal disease, chronic diarrhea, previousgastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or otherconditions that limit the ingestion or gastrointestinal absorption of drugsadministered PO. Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential).

• Have been committed to an institution by an order issued either by the judicial oradministrative authorities.