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1.6.2 mocetinostat non-clinical data

Mocetinostat is a selective, potent, and dose-dependent inhibitor of human Class I
(isoforms 1, 2, and 3) and Class IV (isoform 11) HDACs. There was weak or no activity against Class II HDACs or HDAC 8. Mocetinostat is a potent competitive inhibitor of HDAC 1, with a Ki of 64 nM. Binding was reversible, with high affinity and slow kinetics. Mocetinostat induced acetylation of core histones H4 and H3 in human bladder carcinoma (T24) cells, with an EC50 of 0.4 μM and 0.2 μM, respectively. Acetylation of histones was also observed in A549 human non-small cell lung carcinoma cells and A2780-S human ovarian carcinoma cells. Core histone acetylation was dose-dependent and was correlated with HDAC inhibition. In the in vitro hERG assay, the IC50 for mocetinostat was > 50µM on the potassium current, which far exceeds exposures observed clinically. Results of a cardiovascular safety pharmacology study in Beagle dogs showed no test article-related changes in heart rate, arterial pressure (systolic, mean, or diastolic), or in ECG parameters at dose levels up to 100 mg/m2(5 mg/kg).  
In a bidirectional permeability study with Caco-2 cell lines, mocetinostat is classified as highly permeable; the efflux ratio was < 2, hence it is not a P-gp or BCRP substrate. The fractional binding of mocetinostat to human plasma was measured via equilibrium dialysis. At concentrations of 0.5, 1 and 10 μM, mocetinostat showed binding of 95.1%,
97.5%, and 95.2%, respectively. Mocetinostat is metabolized by cytochrome P-450 enzymes that include CYP 2E1 and 3A, and possibly also CYP 2C8 and 2C19. Caution should be used when mocetinostat is administered with concomitant medications that are inhibitors or inducers of CYP 2E1, or strong inhibitors or inducers of CYP 3A4. Mocetinostat does not appear to be a strong inducer of CYP enzymes but may be an inhibitor of CYP 2C9. Caution should be used when mocetinostat is administered with concomitant medications that are substrates for CYP 2C9. In vitro studies indicate that mocetinostat has a low potential for P-gp inhibition at the levels observed in patients.
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nonclinical studies supporting mocetinostat and

Nonclinical studies evaluated the mechanism of action of mocetinostat, its immune stimulatory properties, and the effect of combination treatment with immune checkpoint inhibitors. Initial studies were performed to assess the effect of mocetinostat on PD-L1, on major histocompatibility complex (MHC) class I and II molecules, and on immune co-stimulatory molecule gene and protein expression, across a panel of NSCLC cell lines in vitro. Mocetinostat demonstrated a concentration-dependent increase in PD-L1 gene expression ranging from 2- to 15-fold in all four NSCLC cell lines evaluated (H23, H1437, H1703, H1792) (Figure 1). In addition, mocetinostat increased PD-L1 cell-surface protein expression in 5 NSCLC cell lines, demonstrated by flow-cytometric analysis utilizing a specific PD-L1 antibody.  The increased expression of PD-L1 on tumor cells by mocetinostat may signal a shift in dependence of tumor cells on evading tumor-immune response via a PD-1-dependent mechanism.  In addition, mocetinostat demonstrated a concentration-dependent increase in gene expression of several members of the human leukocyte antigen (HLA) gene complex, in all four NSCLC lines evaluated (Figure 1).  HLA genes comprise the human MHC Class I and II molecules that regulate the presentation of tumor-associated antigens (TAAs) at the cell surface to enable recognition by cytotoxic T cells (CD8+).  The induction of gene expression of MHC-class-I-related molecules, MIC-A and MIC-B, were also observed in all four NCLC cell lines evaluated.  The effector cytolytic responses of T cells and NK cells against tumor cells are mediated by NKG2D receptor-dependent engagement of MIC-A and MIC-B on target tumor cells, indicating that immune stimulatory properties of mocetinostat involve both innate and adaptive immune responses.  Finally, mocetinostat induced the expression of the immune co-stimulatory molecule CD86, which is required for T-cell activation and antigen-dependent immune response against tumor cells expressing and presenting TAAs. Figure 1:
Mocetinostat Modulates Expression of PD-L1 and Antigen Presentation Regulatory Genes in NCSLC Cell Lines  
  
Gene modulation in NSCLC post mocetinostat treatment. Cells were seeded in 10 cm dishes and incubated with various doses of mocetinostat or DMSO for 48 hours. RNA was extracted with Qiagen RNEasy plus kit. Relative gene expression, by quantitative polymerase chain reaction (PCR), was normalized to DMSO treatment.  
To determine effect on CD4- and CD8-positive effector T cells and immunosuppressive cellular subsets including T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs), mice bearing syngeneic subcutaneous CT26 colon tumors were treated with 100 mg/kg mocetinostat by daily oral gavage. In these studies, mocetinostat demonstrated an increase in splenic CD4-positive T effector cells and mature cytolytic CD8-positive T cells in tumors compared to vehicle controls by day six of administration (Figure 2). In addition, mocetinostat treatment decreased tumor FoxP3-positive immunosuppressive Tregs and CD11b/Gr1-positive MDSCs in tumors compared to vehicle controls by day nine of administration.
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figure 2 mocetinostat modulates key

To determine the effects of mocetinostat and PD-L1 antibody combination therapy on tumor growth, CT26 tumor-bearing mice were treated with either agent alone or in combination over selected administration schedules. On Day 23, a statistically significant decrease in relative tumor volume was observed in the mocetinostat plus PD-L1 antibody combination group with a three day mocetinostat lead-in period compared with either single agent alone.
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1.6.3 mocetinostat clinical data 1.6.3.1

The pharmacokinetics of mocetinostat has been evaluated in clinical trials, after single and repeated dose administration. In general, mocetinostat was rapidly absorbed following administration with 200 mL of a low pH beverage, with maximum concentration (Cmax) occurring 0.5 to 1.5 hours after dosing. The elimination half-life ranged from approximately 7 to 12 hours. As determined from the Cmax and AUC values, exposure to mocetinostat following oral dosing appears to increase with doses up to 110 mg. No significant drug accumulation is expected with administration of mocetinostat three times weekly.
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1.6.3.2 mocetinostat clinical safety

As of November 2016, mocetinostat has been administered orally as a single agent or in combination with chemotherapy to more than 489 clinical trial patients with various forms of hematological or solid tumor diseases. Regimens investigated included daily and three times weekly administration. The recommended Phase 2 treatment regimen for single agent mocetinostat is 90 mg as a fixed dose three times weekly (e.g., Monday, Wednesday and Friday) Among 306 patients participating in clinical trials of mocetinostat single agent, treatment-related AEs were reported in 90.5% of patients. The most frequent AEs considered related to study drug (occurring in ≥5% of patients in a preferred term category) were reported for nausea (61.4%), fatigue (57.5%), diarrhea (46.7%), vomiting (37.3%), anorexia (26.8%), decreased weight (19.3%), anemia (15.4%), thrombocytopenia (13.1%), dyspepsia (11.8%) and abdominal pain (11.4%). The most frequent Grade 3/4 AEs considered related to study drug were the following fatigue (19.0%), thrombocytopenia (8.8%), neutropenia (6.5%), nausea (5.2%), anemia (5.6%),
asthenia (4.6%), and anorexia (4.2%). Events listed in the Investigator's Brochure as mocetinostat ADRs include nausea, vomiting, diarrhea, anorexia, fatigue and asthenia. Bladder toxicity resulting in dysuria and rarely hemorrhagic cystitis has been described in a few patients receiving mocetinostat. Symptoms may include dysuria, pollakiuria, hematuria, urgency, and bladder spasm and have been reported most commonly after multiple cycles of treatment. Pericardial AEs have been reported in clinical trials of mocetinostat. The types of pericardial events included pericarditis, pericardial effusion, and cardiac tamponade. Of the pericardial adverse events, pericardial effusion was the most common. Findings of the analysis include a higher rate of pericardial SAEs among patients with Hodgkin lymphoma (9.5%) as compared to patients with leukemia or NHL (4.5% and 3.8%, respectively). Most of the pericardial AEs occurred during the first cycle of treatment. The majority of pericardial findings, including SAEs, resolved completely without sequelae, and no pericardial event was considered fatal. Screening assessments for pericardial events were not included in the mocetinostat program during most of the prior clinical trial experience. The current study includes screening assessments and exclusion criteria to ensure that baseline status is known. Grade 3 AEs of QTc prolongation (> 500 msec) were reported in 4 of 435 patients in clinical trials with mocetinostat; 3 of those 4 events were also reported as part of SAEs. Three of the 4 patients already had a prolonged QTc at baseline. Three of the events of QTc prolongation occurred in a setting of GI disturbances associated with dehydration and/or hypotension. In 2 cases, there was definite hypokalemia, with concomitant low magnesium in one patient, and in both cases, the QTc values decreased quickly to baseline levels after IV administration of potassium and magnesium. Concomitant treatment with drugs identified as having the potential to cause QTc prolongation may have been a factor in 2 patients.  
Based on reported clinical experience with mocetinostat, guidance to the Investigator is provided for selected adverse events in Section 5.1.3.4.
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1.7 nivolumab

Nivolumab (OPDIVO) is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin. Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. Background information in addition to that presented below is available in the USPI OPDIVO [nivolumab].
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1.7.2 nivolumab non-clinical data

Please refer to the latest US prescribing information USPI OPDIVO [nivolumab].
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1.7.3 nivolumab clinical data

Please refer to the latest US prescribing information USPI OPDIVO [nivolumab].
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1.7.3.1 nivolumab pharmacokinetics

The PK of single-agent nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of OPDIVO every 2 or 3 weeks. The geometric mean (% coefficient of variation [CV%]) clearance (CL) is 8.2 mL/h (53.9%), geometric mean volume of distribution at steady state (Vss) is 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) is 25 days (77.5%). Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was approximately 3.7-fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. Based on a population PK analysis, the clearance of nivolumab increased with increasing body weight supporting a weight-based dose. The population PK analysis suggested that the following factors had no clinically important effect on the clearance of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1 expression, tumor type, tumor size, renal impairment, and mild hepatic impairment. The effect of renal impairment on the clearance of nivolumab was evaluated by a population PK analysis in patients with mild (eGFR 60 to 89 mL/min/1.73 m2; n=313), moderate (eGFR 30 to 59 mL/min/1.73 m2; n=140), or severe (eGFR 15 to 29 mL/min/1.73 m2; n=3) renal impairment. No clinically important differences in the clearance of nivolumab were found between patients with renal impairment and patients with normal renal function. The effect of hepatic impairment on the clearance of nivolumab was evaluated by population PK analyses in patients with mild hepatic impairment (total bilirubin [TB] less than or equal to the upper limit of normal [ULN] and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST; n=92). No clinically important differences in the clearance of nivolumab were found between patients with mild hepatic impairment and patients with normal hepatic function. Nivolumab has not been studied in patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe hepatic impairment (TB greater than 3 times ULN and any AST).
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1.7.3.2 nivolumab anti-drug antibodies

Of 2085 patients who were treated with OPDIVO as a single agent at 3 mg/kg every 2 weeks and evaluable for the presence of anti-nivolumab antibodies, 233 patients (11.2%) tested positive for treatment-emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay and 15 patients (0.7%) had neutralizing antibodies against nivolumab. There was no evidence of altered pharmacokinetic profile or increased incidence of infusion reactions with anti-nivolumab antibody development.
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1.7.3.3 immune-mediated adverse events 1.7.3.3.1

Immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology, including fatal cases, occurred with OPDIVO treatment. In patients receiving OPDIVO as a single agent, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. The median time to onset of immune-mediated pneumonitis was 3.5 months (range: 1 day to 22.3 months). Immune-mediated pneumonitis led to permanent discontinuation of OPDIVO in 1.1%, and withholding of OPDIVO in 1.3% of patients. Approximately 89% of patients with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 26 days (range: 1 day to 6 months). Complete resolution of symptoms following corticosteroid taper occurred in 67% of patients. Approximately 8% of patients had recurrence of pneumonitis after re-initiation of OPDIVO.
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1.7.3.3.2 immune-mediated colitis

Immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology, can occur with OPDIVO treatment. In patients receiving OPDIVO as a single agent, immune-mediated colitis occurred in 2.9% (58/1994) of patients; the median time to onset was 5.3 months (range: 2 days to 20.9 months). Immune-mediated colitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 1% of patients. Approximately 91% of patients with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 23 days (range: 1 day to 9.3 months). Four patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 74% of patients. Approximately 16% of patients had recurrence of colitis after re-initiation of OPDIVO.
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1.7.3.3.3 immune-mediated hepatitis

Immune-mediated hepatitis, defined as requiring use of corticosteroids and no clear alternate etiology, can occur with OPDIVO treatment. In patients receiving OPDIVO as a single agent, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients; the median time to onset was 3.3 months (range: 6 days to 9 months). Immune-mediated hepatitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 1% of patients. All patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 23 days (range: 1 day to 2 months). Two patients required the addition of mycophenolic acid to high-dose corticosteroids. Complete resolution occurred in 74% of patients. Approximately 29% of patients had recurrence of hepatitis after re-initiation of OPDIVO.
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1.7.3.3.4 immune-mediated endocrinopathies hypophysitis

In patients receiving OPDIVO as a single agent, hypophysitis occurred in 0.6% (12/1994) of patients; the median time to onset was 4.9 months (range: 1.4 to 11 months). Hypophysitis led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.2% of patients. Approximately 67% of patients with hypophysitis received hormone replacement therapy and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 14 days (range: 5 to 26 days).
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adrenal insufficiency

In patients receiving OPDIVO as a single agent, adrenal insufficiency occurred in 1% (20/1994) of patients and the median time to onset was 4.3 months (range: 15 days to 21 months). Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.5% of patients. Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy and 25% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 11 days (range: 1 day to 1 month). Hypothyroidism and Hyperthyroidism In patients receiving OPDIVO as a single agent, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients; the median time to onset was 2.9 months (range: 1 day to 16.6 months). Approximately 79% of patients with hypothyroidism received levothyroxine and 4% also required corticosteroids. Resolution occurred in 35% of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO as a single agent; the median time to onset was 1.5 months (range: 1 day to 14.2 months). Approximately 26% of patients with hyperthyroidism received methimazole, 9% received carbimazole, 4% received propylthiouracil, and 9% received corticosteroids. Resolution occurred in 76% of patients.
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type 1 diabetes mellitus

In patients receiving OPDIVO as a single agent, diabetes occurred in 0.9% (17/1994) of patients including two cases of diabetic ketoacidosis. The median time to onset was 4.4 months (range: 15 days to 22 months).
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1.7.3.3.5 immune-mediated nephritis and renal

Immune-mediated nephritis, defined as renal dysfunction or ≥Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate etiology, can occur with OPDIVO treatment. In patients receiving OPDIVO as a single agent, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients; the median time to onset was 4.6 months (range: 23 days to 12.3 months). Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.8% of patients. All patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 21 days (range: 1 day to 15.4 months). Complete resolution occurred in 48% of patients. No patients had recurrence of nephritis or renal dysfunction after reinitiation of OPDIVO.
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1.7.3.3.6 immune-mediated rash

Immune-mediated rash including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can occur with OPDIVO treatment. In patients receiving OPDIVO as a single agent, immune-mediated rash occurred in 9% (171/1994) of patients; the median time to onset was 2.8 months (range: <1 day to 25.8 months). Immune-mediated rash led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.8% of patients. Approximately 16% of patients with rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 12 days (range: 1 days to 8.9 months) and 85% received topical corticosteroids. Complete resolution occurred in 48% of patients. Recurrence of rash occurred in 1.4% of patients who resumed OPDIVO after resolution of rash.
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1.7.3.3.7 immune-mediated encephalitis

OPDIVO can cause immune-mediated encephalitis with no clear alternate etiology. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. In patients receiving OPDIVO as a single agent, encephalitis occurred in 0.2% (3/1994). Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. In the other two patients encephalitis occurred post-allogeneic HSCT.
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1.7.3.3.8 other immune-mediated adverse reactions

Other clinically significant immune-mediated adverse reactions can occur with OPDIVO. Immune-mediated adverse reactions may occur after discontinuation of OPDIVO therapy. Across clinical trials of OPDIVO administered as a single agent or in combination with ipilimumab, the following clinically significant immune-mediated adverse reactions occurred in less than 1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.
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1.7.3.3.9 infusion reactions

Severe infusion reactions have been reported in less than 1.0% of patients in clinical trials of OPDIVO.  
In patients receiving OPDIVO as a single agent, infusion-related reactions occurred in 6.4% (127/1994) of patients.
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1.7.3.4 overall safety reported in

The safety of OPDIVO in metastatic NSCLC was evaluated in a randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen (Trial 2) and a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen (Trial 3). Patients received 3 mg/kg of OPDIVO administered intravenously over 60 minutes every 2 weeks or docetaxel administered intravenously at 75 mg/m2 every 3 weeks. The median duration of therapy in OPDIVO-treated patients in Trial 2 was 3.3 months (range: 1 day to 21.7+ months) and in Trial 3 2.6 months (range: 0 to 24.0+ months). In Trial 2, 36% of patients received OPDIVO for at least 6 months and 18% of patients received OPDIVO for at least 1 year and in Trial 3, 30% of patients received OPDIVO for greater than 6 months and 20% of patients received OPDIVO for greater than 1 year. Trial 2 and Trial 3 excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Across both trials, the median age of OPDIVO-treated patients was 61 years (range: 37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were white. Ten percent of patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%). OPDIVO was discontinued in 11% of patients and was delayed in 28% of patients for an adverse reaction. Serious adverse reactions occurred in 46% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Trial 3, in the OPDIVO arm, seven deaths were due to infection including one case of *Pneumocystis jirovecii* pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. Across both trials, the most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. Other clinically important adverse reactions observed in patients treated with OPDIVO and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (48% Grade 1-4, 5% Grade 3-4), musculoskeletal pain (33%), pleural effusion (4.5%), pulmonary embolism (3.3%).
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1.8 expectations for combination of

The study investigational treatments glesatinib, sitravatinib or mocetinostat administered in combination with nivolumab are unlikely to result in clinically relevant drug-drug interactions (DDI) based on absorption, metabolism, elimination or protein binding. Nivolumab is a mAb and is intravenously administered, whereas the investigational agents are all small molecule therapeutics administered orally; no absorption interactions are expected. No studies on the metabolism of nivolumab have been reported *in vitro* or in humans. Like most therapeutic proteins, nivolumab is not expected to be metabolized by liver cytochrome P-450 (CYP) or other drug metabolizing enzymes and is unlikely to have an effect on CYPs or other metabolizing enzymes in terms of inhibition or induction.
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1.8.2 evaluation of potential for

Frequent adverse events, such as fatigue, musculoskeletal pain, decreased appetite, cough, and constipation, which are non-specific and typical of cancer treatment regimens have been observed with nivolumab, glesatinib, sitravatinib and mocetinostat monotherapy. Potential exists for these AEs to be observed with increased severity or frequency during use of the combined agents. Management of these effects in patients receiving cancer therapy is well precedented. More importantly, immune-related AEs (irAEs) of Special Interest based on observed safety events using nivolumab monotherapy include pneumonitis, colitis, hepatitis, endocrinopathy, nephritis/renal dysfunction, rash, and encephalitis. While glesatinib, sitravatinib and mocetinostat may have immunostimulatory effects, autoimmune adverse effects have not been reported in clinical trials of these investigational study agents nor are they recognized as class effects for these agents. However, the potential for the investigational study treatments to exacerbate or promote these adverse events when administered in combination with nivolumab should be borne in mind. A clinically relevant overlap in toxicity may arise between the immune-related colitis attributed to nivolumab and the non-specific, most often mild to moderate diarrhea observed with the three investigational agents. Immune-related colitis has been reported in 2.9% (58/1994) of patients treated with nivolumab, with a median time to onset of 5.3 months (range: 2 days to 20.9 months). Diarrhea of uncertain etiology has been reported in approximately 55% of patients treated with glesatinib, 48% of patients treated with sitravatinib monotherapy, and 46% of patients treated with mocetinostat, most often beginning within the first month of the start of treatment. Diarrhea (any grade) is less common with nivolumab, occurring in approximately 8% (22/287) of NSCLC patients treated at 3 mg/kg Q2W in the CheckMate 057 clinical trial (USPI OPDIVO [nivolumab]). The time to onset may be helpful in distinguishing diarrhea that may be attributed to autoimmune effects versus non specific toxicity.
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1.8.2.2 glesatinib and nivolumab

A clinically relevant overlap in toxicity may arise between the immune-related hepatitis attributed to nivolumab and the non-specific, most often mild to moderate elevation in liver enzymes observed with glesatinib. Immune-mediated hepatitis was reported in 0.3% (1/287) of NSCLC patients treated with nivolumab, with an onset of approximately 8 months following initiation of therapy. Increases in AST and ALT have been observed in approximately 18% and 12% of patients treated with glesatinib.
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1.8.2.3 sitravatinib and nivolumab

Hypothyroidism, including thyroiditis, was reported in 7% (20/287) of NSCLC patients treated with nivolumab. Hypothyroidism has been reported in approximately 14% (22/153) of patients treated with sitravatinib monotherapy. A clinically relevant overlap in toxicity may arise between the immune-related rash attributed to nivolumab and the non-specific, most often mild (Grade 1) rash observed with sitravatinib. Immune-related rash has been reported in 6% (17/287) of NSCLC patients treated with nivolumab. Rash of uncertain etiology has been reported in 10% (15/153) of patients treated with sitravatinib monotherapy.
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1.8.2.4 mocetinostat and nivolumab

Two AEs observed in previous clinical trials of mocetinostat for which causality and mechanism are unclear are cystitis and pericardial effusion. Although the cause of these AEs is unknown, the potential for an immune-based mechanism exists, therefore increased risk may be associated with the combination of mocetinostat with nivolumab. Robust toxicity management guidelines are in place to address or manage any immune mediated adverse reactions and drug-related toxicities associated with the study treatments.
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1.9 study rationale

Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated clinical activity in non-small cell lung cancer patients (Brahmer-2015, Borghaei-2015, Garon-2015). While this therapy leads to durable clinical responses in a subset of patients, strategies to improve its clinical efficacy and overcome innate or acquired resistance to checkpoint inhibitor monotherapy are needed. Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy is a rational approach to improving outcomes in both CIT-naïve and CIT-experienced patients.  
The use of tyrosine kinase inhibitors (TKIs) to treat cancer is well established based on robust clinical efficacy achieved with well-tolerated inhibitors directed toward oncogenic tyrosine kinases. In addition, selected TKIs have been shown to modulate the immunogenic status of tumors, improve tumor perfusion by reducing intratumoral pressure and modulate subsets of immune cells, increasing the frequency and function of effector immune elements, while decreasing the number and function of immune suppressor cells. Taken together, these effects on the tumor microenvironment (TME) may lead to improved efficacy when TKIs are combined with checkpoint inhibitors. The TAM (Tyro3, Axl and MERTK) receptor tyrosine kinases (RTKs) are expressed by select innate immune cell subpopulations including macrophages and dendritic cells
(Lemke-2008). The TAM receptors cooperate to create and maintain an immunosuppressive TME. MERTK suppresses the M1 macrophage pro-inflammatory cytokine response involving IL‑12, IL‑6 and TNF and enhances M2 macrophage anti-inflammatory cytokine production involving IL‑10, IL-4, TGFβ and HGF
(Camenisch-1999, Tibrewal-2008). Given that anti-tumor host defense is usually mediated by cytotoxic T lymphocytes whose activation and stimulation is supported by Th1 type cytokines, the inhibition of Axl and MERTK are predicted to enhance an anti-tumor immune response. Furthermore, both Axl and MERTK are expressed by natural killer (NK) cells and negatively regulate NK cell activity in the TME as part of a feedback regulatory mechanism resulting in decreased NK cell anti-tumor activity and enhanced tumor progression and metastasis (Paolino-2014). Given the immunosuppressive function of TAM RTKs in the TME, inhibition of Axl and MERTK may complement PD-1/PD-L1 checkpoint inhibition to unleash the host anti-cancer immune response. The MET (Mesenchymal-Epithelial Transition) RTK is implicated in modification of tumor immune responses based on its role in mediating an immunosuppressive TME as well as its role in regulating antigen presenting cell (APC) function. MET is expressed by immature CD14-positive monocytes and can induce an immunosuppressive phenotype when its ligand, hepatocyte growth factor (HGF), is secreted by tumor stroma and mesenchymal stem cells (MSCs) (Chen-2014). Depletion of CD14-positive monocytes or neutralization of HGF secretion by MSCs reverses the suppression of T effector proliferation and triggers a shift back toward a Th1 activated T cell phenotype (Chen-2014). MSCs are also implicated in expansion of immunosuppressive myeloid-derived suppressor cells (MDSCs), which are also dependent on the secretion of HGF (Yen-2013). APCs (i.e., dendritic cells) also express MET and the activation of MET by HGF results in suppression of APC function including both antigen presenting capacity and antigen-dependent T cell responses (Okunishi-2005, Singhal-2011, Benkhoucha-2010). Therefore, inhibition of MET may enhance the antitumor response by restoring APC function and reducing or eliminating MDSCs within the TME. Glesatinib is an orally administered multi-targeted TKI that primarily targets the Axl and MET receptors. Additional RTK targets potentially include the MERTK, DDR2, and PDGFR and  receptors. The TKI profile of glesatinib suggests the potential for synergistic anti-tumor effect when administered in combination with a checkpoint inhibitor. Inhibition of the VEGF receptor family and KIT may further enhance antitumor immunoreactivity by depletion of immunosuppressive cellular subset from the TME including regulatory T cells and (MDSCs). T regulatory cells express VEGFR2 and the inhibition of VEGFR2 utilizing a specific VEGFR2 antibody antagonist or VEGFA neutralizing antibody (but not a VEGFR1 antagonist) inhibited Treg proliferation in vitro and in tumor-bearing mice and patient peripheral blood (Terme-2013). MDSCs notably express both KIT and VEGFR1 and the inhibition of these RTKs using pharmacologic or genetic approaches resulted in the inhibition of MDSC viability in vitro and depletion of this cell population in mouse tumor models (Ko-2009, Ozao-Choy-2009, Farsaci-2012). Sitravatinib is an orally-available, potent small molecule inhibitor of a closely related spectrum of receptor tyrosine kinases (RTKs) including MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2, and selected Eph family members. In addition to the immunostimulatory effects of Axl and MET inhibition, sitravatinib may further condition the TME in favor of antitumor activity by its immunomodulatory effects mediated through VEGFR and KIT inhibition. Taken together, TAM receptors, KIT, VEGFR family and MET activation work together to suppress anti-tumor immunity at several nodes and stages of the cancer-immunity cycle. The activation of TAM receptors functions as an innate immune cell checkpoint and inhibition of these receptors is predicted to complement and augment the activity observed with adaptive checkpoint inhibitor therapy (anti-PD-1) alone. Since activation of the TAM receptors functions as a mechanism to limit inflammation during the natural course of an immune response, it is likely that differing levels of TAM-dependent immunosuppression exists in most tumors, thus providing a rationale for testing inhibitors of these "innate checkpoints" in combination with adaptive checkpoint inhibitor therapy (anti-PD-1) in cancer patients that are immunotherapy naïve. Histone deacetylases (HDACs) have been implicated in the epigenetic regulation of innate and adaptive immunity. Increasing evidence supports the proposal that spectrum-selective inhibitors of class I HDACs can reverse immune evasion and elicit antitumor host response through immunostimulatory mechanisms. The immunomodulatory properties of class I HDAC inhibitors are reported to be mediated through multiple mechanisms including: 1) induction of programmed cell death ligand 1 (PD-L1) expression on the tumor cell surface, 2) induction of tumor associated antigens (TAAs) and MHC Class I and Class II molecules on tumor cells, 3) induction of immunogenic cell death via activation and cross-presentation of tumor antigens by antigen presenting cells (APCs), 4) enhanced function of T effector cells, and 5) decreased function of immunosuppressive cell subsets including Tregs and MDSCs. In addition, HDAC inhibitors are associated with anticancer effects through inhibiting cell cycle progression and inducing apoptosis in tumor cells (Kroesen-2014, Leggatt-2012, West-2012). Mocetinostat is an orally administered spectrum-selective Class I/IV HDAC inhibitor specifically targeting HDACs 1, 2, 3 and 11. Given these pleiotropic immune activating effects of class I HDAC inhibitors, combination therapy of mocetinostat with checkpoint inhibition may result in increased efficacy compared to immunotherapy alone. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. This study will evaluate the clinical activity of nivolumab in combination with 3 separate investigational agents, glesatinib, sitravatinib or mocetinostat. The study will begin with a lead-in dose escalation evaluation in small cohorts of patients administered one of the investigational study treatments in combination with nivolumab. Following identification of the dose level to be used in the Phase 2 evaluation for each investigational study treatment, full enrollment will proceed.
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2 study objectives 2.1 objectives

To evaluate the clinical activity of nivolumab in 3 combination regimens with the investigational agents glesatinib, sitravatinib, and mocetinostat, in patients with non-squamous NSCLC.
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2.1.2 secondary objectives

To evaluate the safety and tolerability of the combination regimens in the selected population.  
To evaluate secondary efficacy endpoints of the combination regimens in the selected population.  
To evaluate the pharmacokinetics (PK) of the investigational agents administered in combination with nivolumab.  
To evaluate the PK of different sitravatinib capsule formulations.
To evaluate the PK of sitravatinib administered with food.
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2.2.2 secondary endpoints

Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities.  
Secondary efficacy endpoints:
o DR; o CBR;
o PFS;
o 1-Year Survival Rate; and o OS.  
Blood plasma concentrations of the investigational agents.
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3 study design

Study MRTX-500 is an open-label, parallel Phase 2 evaluation of nivolumab in combination with 3 investigational agents, glesatinib, sitravatinib or mocetinostat, in patients with locally advanced, unresectable or metastatic non-squamous NSCLC. Patients who have experienced progression of disease on or after treatment with a checkpoint inhibitor (CIT- experienced) as well as those who have experienced disease progression after platinum-based doublet chemotherapy (CIT- naïve) will be enrolled. The primary objective is to evaluate the clinical activity of the combination study treatments using ORR in accordance with RECIST 1.1. Secondary objectives include evaluation of safety, secondary efficacy endpoints, and PK for the investigational agents. The Schedule of Assessments to be performed in the study is presented in Table 1. Pharmacokinetic and blood biomarker sample collection and triplicate ECG assessment time points are presented in Table 2, Table 3, and Table 4. Specifics of two sitravatinib sub-studies are presented in appendices, including the PK evaluation of three sitravatinib capsule formulations (Appendix 5) and, the PK of sitravatinib administered with food (Appendix 6). The treatment arms included in this study are the following: 1. Glesatinib plus nivolumab. 2. Sitravatinib plus nivolumab.  
3. Mocetinostat plus nivolumab.
To control bias in assignment of individual patients to treatment arms and to mitigate the risk of medication errors with the 3 investigational study treatments administered in specific regimens, study sites will be aligned with one specified treatment combination. Site alignment may change as patient cohorts are filled or patient recruitment factors shift at sites.
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3.1 lead-in dose escalation evaluation

The study will begin with a lead-in dose escalation evaluation of two dose levels of each investigational agent in combination with nivolumab, in cohorts of 3 to 8 CITexperienced patients each. The starting dose for each agent (labeled Dose Level 1 in Table 7) represents a full reduction step as typically used in single agent Phase 2 trials. Dose Level 2 in Table 7 is the typical dose used in single agent Phase 2 trials. In addition, a dose de-escalation step may be undertaken as appropriate (labeled Dose Level -1 in Table 7). Table 7 lists the planned dose levels for each agent.
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table 7 investigational study drug

| Dose Level            |                     |        |        |        |
|-----------------------|---------------------|--------|--------|--------|
| Drug                  | Regimen             | 1      | 2      | -1     |
| Glesatinib Tablets    | Twice Daily         | 500 mg | 750 mg | 350 mg |
| Sitravatinib Capsules | Once Daily          | 120 mg | 150 mg | 80 mg  |
| Mocetinostat          | Three Times  Weekly | 70 mg  | 90 mg  | 50 mg  |
| Capsules              |                     |        |        |        |  
Depending on experience in early cohorts of patients in the lead-in dose escalation evaluation, starting doses below those named in Table 7 may be implemented in new cohorts of patients after discussion among Investigators participating in the lead-in evaluation and the Sponsor. Depending on experience with early cohorts of patients, not all dose levels may be explored. Throughout the study, nivolumab will be administered in accordance with approved labeling. Nivolumab is to be administered by intravenous infusion, using either regimen included in the approved label: 240 mg every 2 weeks (Q2W) or 480 every 4 weeks (Q4W). Guidance for adverse event management and associated nivolumab treatment modifications are provided in product labeling and replicated in Section 5.2.
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3.1.1 definition of dose limiting

The National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.03 will be used throughout this study. The definition of DLT for the purpose of dose escalation decisions includes any of the following events considered to be causally related to treatment with an investigational study treatment in combination with nivolumab that occurs during the first 28-day treatment cycle:
Any Grade 4 non-hematological toxicity.  
Any Grade 3 non-hematological toxicity or Grade 3 or 4 hematological toxicity that does not recover to ≤ Grade 2 as indicated by symptoms within 3 days and/or as indicated by laboratory assessment within 8 days after onset of the event despite optimal medical management with or without corticosteroids.  
o A special case is provided for hepatic transaminases - increase over baseline by two-fold or more and meeting Grade 3 or 4 criteria.  
Grade 2 pneumonitis or colitis that does not resolve to ≤ Grade 1 as indicated by symptoms within 3 days after onset of the event despite optimal medical management with or without corticosteroids.  
Febrile neutropenia or neutropenia associated with systemic infection.
Any toxicity that requires suspension of treatment for more than 2 weeks.  
The definition of DLT excludes the following conditions:
Grade 3 fatigue lasting ≤ 7 days. Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that can be effectively managed with hormone replacement therapy.  
Acute infusion-related reaction.
Lymphopenia without infection.  
Thrombocytopenia without clinically significant bleeding.
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3.1.2 enrollment and dose escalation

Patients meeting eligibility criteria as outlined in this protocol may enroll into the lead-in dose escalation evaluation, regardless of whether they did or did not experience clinical benefit during prior treatment with a checkpoint inhibitor. Dose escalation cohorts are expected to include between 3 and 8 patients for each investigational study treatment and dose level evaluated. The first patient to be treated at the starting dose and at each new higher dose of investigational study treatment will be observed for at least one week prior to enrollment of subsequent patients in the cohort. As many as 5 patients may initially be enrolled into each cohort. For a patient within a dose cohort to be considered evaluable for the dose-escalation decision, the patient must have either been on study for one full cycle and have received treatment with nivolumab and at least 75% of scheduled investigational study treatment doses in Cycle 1 or have experienced a DLT in Cycle 1. Decision making for cohort expansion and dose escalation or de-escalation will be in accordance with the mTPI method (Dose-Finding Spreadsheet presented in Appendix 2). To ensure sufficient patient experience at the dose to be used in the Phase 2 study, enrollment at any dose level under consideration may be expanded to include at least 6 patients.
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3.1.3 definition of maximum tolerated

The Maximum Tolerated Dose (MTD) is defined as the highest investigational study treatment dose administered in the combination regimen associated with the decision to
"stay with the current dose" as determined from the Dose-Finding Spreadsheet
(Appendix 2) using the experience of at least 6 patients during the first 28-day treatment cycle.
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3.1.4 selection of phase 2

For each investigational study drug, the dose to be selected for use in the Phase 2 study will be the highest dose evaluated in the lead-in evaluation that is associated with:  
sufficient safety/tolerability to anticipate that patients will typically be able to receive treatment with at least 75% of the intended dose intensity of investigational study treatment and 100% dose intensity of nivolumab; and no observed ≥Grade 3 or serious irAEs causally related to the combination regimen.
A dose level below the MTD may be selected for use in the Phase 2 study.
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3.2 phase 2 study

Following completion of the lead-in dose escalation evaluation, enrollment into the Phase 2 study will proceed. The treatment arms included in this study are the following: 1. Glesatinib plus nivolumab.  
2. Sitravatinib plus nivolumab. 3. Mocetinostat plus nivolumab.
For patients who have experienced progression of disease on or after treatment with a checkpoint inhibitor (CIT-experienced), enrollment into each treatment arm will be stratified by prior outcome of treatment with a checkpoint inhibitor:  
a. Clinical benefit (i.e., RECIST defined partial or complete response or stable disease for at least 12 weeks [-2 week window permitted for radiograph scheduling]) followed by radiographic progression of disease.  
b. No prior clinical benefit (i.e., radiographic progression of disease ≤ 12 weeks after initiation of treatment [+2 week window permitted for radiograph scheduling]).
Thus, the study will include 6 parallel evaluations of clinical activity of nivolumab combination regimens (Figure 3) in patients with prior treatment with a checkpoint inhibitor. Patients enrolled in the lead-in dose escalation evaluation and receiving the dose of investigational study treatment chosen for the Phase 2 study will be included in the analysis of the Phase 2 endpoints. Patients who discontinue the study prior to the first on-study disease assessment for reasons other than disease progression may be replaced. For patients without prior checkpoint inhibitor therapy (CIT-naïve), each investigational study treatment arm (i.e., glesatinib, sitravatinib, and mocetinostat) will be stratified according to PD-L1 status: a. Having tumor with no/low PD-L1 expression. b. Having tumor with high PD-L1 expression. Tumor PD-L1 expression will be determined by the PD-L1 (28-8) companion diagnostics assay completed through the central laboratory. No/low PD-L1 expression is defined as positivity < 5% of tumor cells; high PD-L1 expression is defined as positivity ≥ 5% of tumor cells. Tumor samples used to establish PD-L1 expression for eligibility must have been collected after the most recent systemic therapy. Thus, the study will include 6 parallel evaluations of clinical activity of nivolumab combination regimens (Figure 3) in patients without prior treatment with a checkpoint inhibitor. Disease response and progression as documented by the Investigator in the Case Report Form (CRF) will be the basis for patient management and study expansion decision making. Unconfirmed objective responses recorded in the CRF may be used as the initial basis for expansion of study enrollment; however, follow-up evaluations on patients with unconfirmed responses must continue to support the decision to continue to the full number of patients to be included in the next stage. Disease assessments will be performed until objective disease progression is documented or subsequent anti-cancer therapy is begun. Central radiology review for disease response and progression may be added to the study during Stage 2. If this occurs, central review of all radiologic assessments performed in the study will be expected (including retrospective review of patients enrolled in Stage 1), and central radiology review for disease response will be the basis for the primary statistical analyses to estimate the objective response rate and its confidence interval, as well as the duration of response and PFS.
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statistical design applied to cit-experienced

This Phase 2 study will use a Predictive Probability Design (Lee-2008) in each treatment arm and strata. In creating the statistical designs, the Type 1 error (α) is constrained to <0.05 and Power (1-β) is constrained to ≥0.90.  
The ORR using nivolumab in the population with advanced non-squamous NSCLC having prior disease progression on a checkpoint inhibitor or patients with non-squamous NSCLC without prior checkpoint inhibitor therapy with no/low PD-L1 expression is assumed to be 5% (p0); thus this rate is considered uninteresting. The target ORR using the investigational agents in combination with nivolumab in this study is 30% (p1). Stage 1 of enrollment will include a minimum of 9 evaluable patients in each treatment strata. With exactly 9 evaluable patients at Stage 1, if at least 1 patient has an Objective Response, 8 additional evaluable patients will be enrolled in the treatment stratum, for a total sample size of 17 evaluable patients. If at least 3 Objective Responses are observed in a treatment stratum, further investigation may be warranted. If the true ORR is 5% (null hypothesis), the probability of early termination during the study is 0.63; the Type 1 error is equal to 0.0466 and the power is equal to 0.9045.
clinical research protocol
statistical design applied to cit-naive

The ORR using nivolumab in the population with non-squamous NSCLC having high PD-L1 expression is assumed to be 27% (p0); thus this rate is considered uninteresting. The target ORR using the investigational agents in combination with nivolumab is 50% (p1). Stage 1 of enrollment will include approximately 17 evaluable patients. With exactly 17 evaluable patients at Stage 1, if at least 5 patients have Objective Responses, 27 additional evaluable patients will be enrolled, for a total sample size of 44 evaluable patients. If at least 18 Objective Responses are observed, further investigation may be warranted. If the true ORR is 27% (null hypothesis), the probability of early termination during the study is 0.50; the Type 1 error is equal to 0.0303 and the power is equal to 0.9018. The exact stopping rules for all cohorts will be calculated based on the Predictive Probability Design, once the exact number of patients evaluable at Stage 1 is known. The aim is to get a minimum of 9 evaluable patients at Stage 1 for CIT-experienced and CITnaïve with no/low PD-L1 expression cohorts and a minimum of 17 evaluable patients at Stage 1 for CIT-naïve with high PD-L1 expression cohort. In order to be part of the clinical activity evaluable population, the patient must have at least one on-study disease assessment or discontinue from treatment for progressive disease prior to this assessment. Patients who discontinue treatment prior to the first onstudy disease assessment for an AE, toxicity, or withdraw consent are considered nonevaluable for disease assessment. These patients will not be part of the clinical activity evaluable population.
clinical research protocol
expansion beyond stage 2

The original protocol provided that if results in any strata were of high interest for efficacy, enrollment might be expanded to as many as 100 patients total in each cohort to narrow the 95% Confidence Interval (CI) around the ORR point estimate. Protocol Amendment 3 (Version 4.0) eliminates enrollment expansion beyond Stage 2 except in the sitravatinib segment of the study enrolling patients with CIT-experience. For the sitravatinib segment of the study enrolling patients with CIT-experience, expansion of enrollment beyond Stage 2 will be managed as one cohort that includes all patients, regardless of prior clinical benefit during treatment with CIT. Based on preliminary clinical activity results as of June 2018 (described in Section 1.5.3.2.2), enrollment into the combined cohort will expand to as many as 125 patients total, to further evaluate safety and efficacy in this setting. Expansion of sitravatinib CIT-naïve cohorts beyond Stage 2 of enrollment is not anticipated.
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4 patient selection and enrollment

Patient eligibility must be reviewed and documented by an appropriately qualified member of the Investigator's study team before patients are included in the study. No exceptions to the patient eligibility requirements will be granted by the Sponsor.
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4.1 inclusion criteria

Patients must meet all of the following inclusion criteria as applicable for phase of the study to be eligible for enrollment into the study:  
1. Histologically confirmed non-squamous NSCLC with metastatic or unresectable, locally advanced disease, not amenable to treatment with curative intent.
2. Receipt of at least one prior treatment in the advanced disease setting.  
a) CIT-experienced: Most recent treatment must have included a checkpoint inhibitor (i.e., anti-PD-1 or anti-PD-L1 including nivolumab, pembrolizumab, durvalumab, atezolizumab or avelumab) with the result of progression of disease on or after treatment.
Note: For the PK sub-studies as outlined within Appendix 5 and Appendix 6, treatment with a checkpoint inhibitor (i.e., anti-PD-1 or anti-PD-L1) does not need to be included in the most recent treatment.  
b) CIT-naïve: Receipt of prior platinum-based doublet chemotherapy.  
3. CIT-naïve: Molecular analysis of tumor sample collected following most recent therapy, assessed using the PD-L1 (28-8) CDx assay. Inclusion in the treatment arm will be based on documented no/low PD-L1 expression (positivity < 5% of tumor cells) or high PD-L1 expression (positivity ≥ 5% of tumor cells). Note: This criterion does not apply to the PK sub-studies as outlined within Appendix 5 *and Appendix 6.*
4. Measurable disease as per RECIST version 1.1. 5. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
(Appendix 1).  
6. Adequate bone marrow and organ function demonstrated by:
Absolute neutrophil count  1,000/mm3( 1.0 × 109/L)
Platelet count ≥ 50 × 109/L (> 50,000 per mm3)  
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
≤ 2.5 × Upper Limit of Normal (ULN), or ≤ 5.0 × ULN for patients with documented liver metastases.  
Serum bilirubin ≤ 1.5 × ULN or ≤ 3.0 × ULN for patients with Gilbert Syndrome or documented liver metastases.
Serum creatinine ≤ 1.5 × ULN.  
7. ≥ 18 years of age.  
8. Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP
agrees to use contraception while participating in this study, and for a period of 6 months following termination of study treatment.  
9. Completed informed consent process, including signing IRB/EC-approved informed consent form.
10. Willing to comply with clinical trial instructions and requirements.
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4.2 exclusion criteria

Patients presenting with any of the following will not be included in the study:  
1. Active brain metastases. Patients are eligible if brain metastases are adequately treated and patients are neurologically stable (except for residual signs or symptoms related to the central nervous system (CNS) treatment) for at least 2 weeks prior to enrollment without the use of corticosteroids, or are on a stable or decreasing dose of
≤10 mg daily prednisone (or equivalent).
a. Patients with carcinomatous meningitis  
2. Patients with any history of tumors that test positive for EGFR, *ROS1,* ALK
mutations or ALK fusions or any other well characterized driver mutations (e.g., RET
fusion, TRK alterations, *BRAF* mutations). Note: The following modification to this criterion applies to the PK sub-studies as outlined within Appendix 5 and Appendix 6: Patients with EGFR, ROS1, ALK mutations or ALK fusions are eligible if previously treated with targeted therapy and/or treatment with a targeted therapy is not indicated.  
3. Prior therapies: (Note: This exclusion criterion does *not apply to the PK sub-studies* as outlined within Appendix 5 *and Appendix 6)* a) Immunotherapies not previously specified, including anti-CTLA-4, anti-OX40 and anti–CD137.  
b) Combination therapy with a checkpoint inhibitor and cancer therapy having the same mechanism of action as the investigational agent intended for use in this study (e.g., tyrosine kinase target or HDAC inhibitor, except prior use of valproic acid for seizures).  
4. Unacceptable toxicity on prior checkpoint inhibitor treatment (CIT- experienced patients only):
a. ≥ Grade 3 immune-related AE related to checkpoint inhibitor.  
b. Grade 2 immune-related AE associated with checkpoint inhibitor unless the AE
resolved or was well controlled by withholding the checkpoint inhibitor and/or treatment with steroids, with the exception of prior colitis, myocarditis, and pneumonitis, which are exclusionary.  
c. CNS or ocular AE of any grade related to checkpoint inhibitor.
NOTE: Patients with a prior endocrine AE are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.  
5. Active or prior documented autoimmune disease:
a. Inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).  
b. History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.  
c. Active or prior documented autoimmune disease within the past 2 years.  
NOTE: Patients with Type I diabetes, vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
6. Active or prior immunocompromising conditions:  
a. Current or prior use of immunosuppressive medication within 28 days before the first dose of study treatment, with the exceptions of topical, ocular, intranasal and inhaled corticosteroids (with minimal absorption) or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. A brief course (≤ 3 days) of systemic corticosteroids
>10 mg/day of prednisone (or equivalent corticosteroid) for prophylaxis (e.g.,
contrast dye allergy) or for treatment of non-immune conditions (e.g., delayedtype hypersensitivity reaction caused by a contact allergen) is permitted within the 28 days.  
b. Known acute or chronic human immunodeficiency virus (HIV).
c. History of primary immunodeficiency.  
d. History of allogeneic transplant.  
7. Known acute or chronic hepatitis B or hepatitis C. Patients treated for hepatitis C with no detectable viral load are permitted.  
8. History of hypersensitivity to study treatment excipient. 9. History of stroke or transient ischemic attack within the previous 6 months.
10. Any of the following cardiac abnormalities:  
a. Unstable angina pectoris.  
b. Congestive heart failure ≥ NYHA Class 3.  
c. QTc >480 milliseconds.
d. Sitravatinib and mocetinostat treatment arms:
i. LVEF <40% (sitravatinib and mocetinostat only).  
ii. Current or history of a small, moderate or large pericardial effusion, and/or hemodynamic compromise due to pericardial effusion of any size. Minimal or trivial pericardial effusion is not excluded (mocetinostat only).  
11. Concomitant medication known to cause prolonged QT which cannot be discontinued or changed to a different medication prior to enrollment (Appendix 3).  
12. Known or suspected presence of another malignancy that could be mistaken for the malignancy under study during disease assessments.  
13. Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented within the screening period prior start of study drug.  
14. Breast-feeding or planning to breast feed during the study or within 6 months after study treatment.  
15. Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical history, including laboratory results, which, in the Investigator's opinion, would be likely to interfere with the patient's participation in the study, or with the interpretation of the results.
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4.3 life style guidelines

Patients who are biologically capable of having children and sexually active must agree to use an acceptable method of contraception for the duration of the treatment period and for at least 6 months after the last dose of study treatment. The Investigator will counsel the patient on selection of contraception method and instruct the patient in its consistent and correct use. Examples of acceptable forms of contraception include:  
1. Oral, inserted, injected or implanted hormonal methods of contraception, provided it has been used for an adequate period of time to ensure effectiveness.  
2. Correctly placed copper containing intrauterine device (IUD). 3. Male condom or female condom used WITH a spermicide.
4. Male sterilization with confirmed absence of sperm in the post-vasectomy ejaculate.  
5. Bilateral tubal ligation or bilateral salpingectomy.
The Investigator will instruct the patient to call immediately if the selected birth control method is discontinued or if pregnancy is known or suspected. Note: Women are considered post-menopausal and/or not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 months ago. In case of any ambiguity, the reproductive status of the woman should be confirmed by hormone level assessment.
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4.4 enrollment into study

Following completion of the study-specific informed consent process and review of all screening procedures, patient eligibility will be confirmed by appropriately qualified staff at the investigational site. Patients will be enrolled by entry into a patient registration log provided by the Sponsor and maintained by the study site, and completion of the patient registration procedure detailed in the Study Manual. Each patient will be assigned a sequential number by the study site. The patient number must be used on all documentation and correspondence with the Sponsor, Contract Research Organization (CRO) and laboratory vendors.  
For the evaluation of tumor PD-L1 expression for CIT-naive patients, a 14-day turnaround time should be expected from the time of receipt of adequate samples at the central laboratory to test results returned to the study site.
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5 study treatments 5.1 investigational

Glesatinib will be supplied by the Sponsor as 100 and 250 mg unit dosage strength tablets. The composition of the drug product consists of a blend of MGCD265 free base drug substance, hydroxypropylmethyl cellulose (HPMC), Avicel® (or equivalent), Kollidon® (or equivalent), sodium bicarbonate, sodium chloride, Syloid® (or equivalent),
and magnesium stearate, as necessary.  
Glesatinib tablets will be supplied in high-density polyethylene (HDPE), white opaque bottles. A tamper-proof heat induction seal and a child-resistant closure are used. Tablet bottles will be received by the pharmacy in foil pouches that are to be kept intact until the bottles are dispensed to the patient. The Sponsor provided bottles should be labeled for specific patient use and given to the patient. While stored in the study site pharmacy, glesatinib tablets should be at refrigerated conditions (suggested temperature range 2-8°C, 36-46°F). Once dispensed to patients, tablets bottles should be stored at room temperature (suggested temperature range 15-30°C, 59-86°F). Refer to the Pharmacy Study Manual for details on available unit dose strengths, bottle sizes, and number of units per bottle supplied.
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5.1.1.2 glesatinib administration

Glesatinib tablets will be administered orally, twice daily (BID), in a continuous regimen expressed in 28-day cycles. The starting dose for glesatinib in the lead-in dose escalation evaluation will be 500 mg BID. Depending on safety observations, the glesatinib dose in the subsequent cohort of patients may escalate to 750 mg BID or de-escalate to 350 mg BID. Individual patients should not undergo dose escalation above their starting dose. The following guidelines should be followed for glesatinib administration:  
Doses should be taken approximately every 12 hours at approximately the same times each day.  
At the beginning of the study, tablets should be taken on an empty stomach (at least a 1-hour fast before each dose and no food for a minimum of 1 hour after each dose). If results from an ongoing food-effect study indicate that fasting is unnecessary, an Administrative Letter to Investigators will communicate elimination of this guidance.  
Tablets should be taken with at least 200 mL (1 cup) of water.  
Patients should swallow the tablets whole and not chew them.  
If vomiting occurs after dosing, glesatinib doses should not be replaced.
On days when glesatinib and nivolumab dosing are both scheduled, the first daily dose of glesatinib should precede nivolumab infusion for logistical reasons. This order of dosing is of most interest on days when blood sampling is scheduled for glesatinib PK.
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5.1.1.3 glesatinib dose modification and

In the event of adverse events attributed to glesatinib and deemed intolerable by the Investigator, treatment should be either temporarily or permanently discontinued. For patients who temporarily discontinue treatment, treatment may resume following resolution of treatment-related adverse events to Grade 1 or baseline with the administration of glesatinib at a reduced dose level as outlined in Table 8. Once the dose has been reduced, re-escalation is generally not recommended but may be considered on a case-by-case basis. If the administration of glesatinib is interrupted for reasons other than toxicity, then treatment with the study drug may be resumed at the same dose.
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table 8 glesatinib sequential dose

| 750 mg twice daily 500 mg twice daily 350 mg twice daily 250 mg twice daily   |
|-------------------------------------------------------------------------------|  
Dose reduction below 250 mg BID may be undertaken after discussion with the Sponsor. If treatment with glesatinib is withheld for ≥ 28 consecutive days, then permanent discontinuation from this study drug should be considered.
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5.1.1.4 glesatinib specific adverse event

See Section 5.1.4.2 for management guidelines for non-hematological or hematological toxicities commonly associated with cancer therapies, which will be applied to all three investigational study treatments in this study. The following are guidelines for management of potential adverse events more specific to treatment with glesatinib or agents in the same class of cancer treatment.
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5.1.1.4.1 diarrhea

See Section 5.1.4.2.2 for treatment management guidelines in patients experiencing diarrhea during study treatment. Patients treated with glesatinib should be made aware of the potential of developing diarrhea while taking glesatinib. Prophylactic anti-diarrheal treatment may be implemented at the discretion of the Investigator. A regimen recommended for primary prophylaxis for diarrhea is loperamide 2-4 mg beginning with the first dose of glesatinib, followed by 2 mg every 6–8 hours. Loperamide use may be subsequently titrated as needed. If prophylactic treatment is not used, patients should start treatment with loperamide immediately upon the first sign of diarrhea. If there is no improvement in severity of symptoms within 24 hours, additional anti-diarrheal medication in the form of Lomotil® should be added. If this does not effectively control symptoms, patients should be instructed to contact their physician and their dose held until resolution of symptoms followed by a dose reduction as indicated per protocol. Patients with severe or prolonged diarrhea should be observed and treated for dehydration.
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5.1.2 sitravatinib 5.1.2.1 sitravatinib formulation

Two formulations of sitravatinib capsules are being utilized in this study. The composition of the sitravatinib free base drug product consists of a blend of MGCD516 free base drug substance, microcrystalline cellulose (Avicel® PH302) and polysorbate 80 (Tween® 80) and Aerosil® 200 Pharma.  
Sites that are participating in one or both of the PK Sub-Studies as referenced in Appendix 5 and Appendix 6 of the protocol will also receive Sitravatinib (MGCD516) malate formulation capsules. Two manufacturing methods of the malate formulation were utilized to improve manufacturing process and scalability. The composition of the sitravatinib malate direct blend drug product consists of a blend of MGCD516 malate drug substance, microcrystalline cellulose (Avicel® PH302), colloidal silicon dioxide (Cab-O-Sil),
croscarmellose sodium (Ac-Di-Sol) and magnesium stearate. The composition of the sitravatinib malate roller compaction drug product consists of a blend of MGCD516 malate drug substance, microcrystalline cellulose, mannitol, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate. Sitravatinib drug product in all formulations is packaged in 30-count, high-density polyethylene (HDPE), white opaque, round 60 cc bottles. A tamper-proof heat induction seal and a child-resistant closure are used. The provided bottles may be labeled for specific patient use and given to the patient if the capsule count is the needed number, or the pharmacy may re-dispense the needed number of capsules into Sponsor provided HDPE bottles. Sitravatinib capsule bottles should be stored under refrigerated conditions (2-8°C, 3646°F) at the pharmacy in according to instructions on the label. After dispensing to the patient, bottles of sitravatinib capsules are to be stored at ambient room temperature for the duration of time specified in the Pharmacy Manual. Refer to the Pharmacy Study Manual for details on available unit dose strengths, bottle sizes, and number of units per bottle supplied.
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5.1.2.2 sitravatinib administration

Sitravatinib capsules will be administered orally, once daily (QD), in a continuous regimen expressed in 28-day cycles. In the Phase 1 segment of the study, the starting dose for sitravatinib in the lead-in dose escalation evaluation will be 120 mg QD. Depending on safety observations, the sitravatinib dose in the subsequent cohort of patients may escalate to 150 mg QD or de-escalate to 80 mg QD. Individual patients should not undergo dose escalation above their starting dose. The sitravatinib recommended Phase 2 starting dose is 120 mg QD. The starting dose of sitravatinib for patients enrolled in the PK sub-studies is described in Appendix 5 and Appendix 6. The following guidelines should be followed for sitravatinib administration:
Dosing in the morning is preferred.  
Capsules should be taken on an empty stomach (at least 2-hour fast before each dose and no food for a minimum of 1 hour after each dose). Instructions to be followed for patients enrolled in the sub-study dedicated to evaluating sitravatinib administered with food are provided in Appendix 6.  
Capsules should be taken with ~240 mL (1 cup) of water.  
Patients should swallow the capsules whole and not chew them.  
If vomiting occurs after dosing, sitravatinib doses should not be replaced.
On days when sitravatinib and nivolumab dosing are both scheduled, the daily dose of sitravatinib should precede nivolumab infusion for logistical reasons. This order of dosing is of most interest on days when blood sampling is scheduled for sitravatinib PK.
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5.1.2.3 sitravatinib dose modification and

In the event of adverse events attributed to sitravatinib and deemed intolerable by the Investigator, treatment should be either temporarily or permanently discontinued. For patients who temporarily discontinue treatment, treatment may resume following resolution of treatment-related adverse events to Grade 1 or baseline with the administration of sitravatinib at a reduced dose level as outlined in Table 9. Once the dose has been reduced, re-escalation is generally not recommended but may be considered on a case-by-case basis. If the administration of sitravatinib is interrupted for reasons other than toxicity, then treatment with the study drug may be resumed at the same dose.
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table 9 sitravatinib free base

150 mg once daily (eliminated after lead-in evaluation)  
| 120 mg once daily 80 mg once daily 60 mg once daily*   |
|--------------------------------------------------------|  
* Dose reduction below 60 mg QD may be undertaken after discussion with the Sponsor.  
Sitravatinib Malate Direct Blend Formulation Sequential Dose Reductions for Individual Patients  
| 60 mg once daily 40 mg once daily   |
|-------------------------------------|
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sitravatinib malate roller compaction formulation

| 100 mg once daily 80 mg once daily 60 mg once daily 40 mg once daily   |
|------------------------------------------------------------------------|  
A two-step dose reduction (e.g. 100 mg to 60 mg once daily) is permitted at the discretion of the investigator In the event of sitravatinib-related AE, dose reduction with continuous treatment is preferred over repeated dose interruption. Following sitravatinib dose reduction and control of adverse event, re-challenge at a higher sitravatinib dose is permitted at the discretion of the Investigator. If treatment with sitravatinib is withheld for ≥ 28 consecutive days, then permanent discontinuation from this study drug should be considered. If one study drug is interrupted or discontinued, administration of the other study drug may continue at the discretion of the Investigator.
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5.1.2.4 sitravatinib specific adverse event

See Section 5.1.4.2 for management guidelines for non-hematological or hematological toxicities commonly associated with cancer therapies which will be applied to all three investigational study treatments in this study. The following are guidelines for management of potential adverse events more specific to treatment with sitravatinib or agents in the same class of cancer treatment.
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5.1.2.4.1 hypertension

Hypertension, including Grade 3 events, has been reported with sitravatinib. Dihydropyridine calcium channel blockers such as nifedipine, amlodipine, and nicardipine may be considered if anti-hypertensive therapy is required and should be considered for patients with Grade 3 hypertension without clinically significant increases in blood pressure (BP) (see Table 10). On the other hand, in cases of Grade 3 hypertension with clinically significant increases in blood pressure (see Table 10), temporary suspension of sitravatinib dosing is recommended until blood pressure is controlled. Treatment with sitravatinib may resume at the same or a lower dose at the discretion of the Investigator. If significant hypertension recurs, options include change in medical management of the patient, reduction of sitravatinib dose, or discontinuation of study treatment, at the discretion of the Investigator. In the event of Grade 4 hypertension, sitravatinib should be permanently discontinued (see Table 10).  
| Toxicity                                                                                                                                                                                                                                                                                        | Treatment Delay                             | Reduction               |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------|-------------------------|
| Grade 1 or 2 hypertension                                                                                                                                                                                                                                                                       | Investigator discretion, as per Table 15    |                         |
| Grade 3 hypertension without clinically significant                                                                                                                                                                                                                                             | Investigator discretion. Consider antihypertensives per Section 5.1.2.4.1                                             |                         |
| increases in BP as defined below Grade 3 hypertension with clinically significant  increases in BP defined as either an increase of ≥ 30  mmHg in systolic BP to ≥ 180 mmHg or increase of  ≥ 20 mmHg in diastolic BP to ≥ 110 mmHg,  confirmed with repeated testing after at least 5  minutes | Hold until ≤ Grade 2 or  return to baseline | Investigator discretion |
| Grade 4 hypertension                                                                                                                                                                                                                                                                            | Discontinue                                 | Discontinue             |
| sitravatinib                                                                                                                                                                                                                                                                                    | sitravatinib                                |                         |
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5.1.2.4.2 palmar-plantar erythrodysesthesia

Palmar plantar erythrodysesthesia (PPE) has been reported as a dose-limiting toxicity in the Phase 1 study of sitravatinib. Measures that can be taken to manage PPE include avoidance of exposure of hands and feet to hot water when washing dishes or bathing, or to other sources of heat, avoidance of activities that cause unnecessary force or friction (rubbing) on the hands or feet, avoiding contact with harsh chemicals such as cleaning products, use of tools or household items that result in pressure on the hands, such as garden tools, knives, and screwdrivers, and wearing of loose fitting, well-ventilated shoes and clothes. Treatment may include use of topical moisturizing agents, topical anesthetics, or topical anti-inflammatory medications such as corticosteroid creams. In more severe cases, dose interruption and reduction may be warranted.
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5.1.2.4.3 diarrhea

See Section 5.1.4.2.2 for treatment management guidelines in patients experiencing diarrhea during study treatment. Diarrhea has been reported with sitravatinib treatment, though the mechanism remains unclear, as with other small molecule RTK inhibitors. Patients should be counseled that diarrhea is a possible side effect and advised to take loperamide or a similar medication as needed if diarrhea develops. Any patients developing dehydration or clinically significant electrolyte abnormalities should interrupt treatment, but treatment may be restarted once diarrhea is controlled.
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5.1.2.4.4 hemorrhagic events

The risk of hemorrhagic events with sitravatinib is unknown; however, such events have been reported with inhibitors of VEGFR. Patients with active hemoptysis or gastrointestinal bleeding should not take sitravatinib, and suspension of treatment is recommended for patients developing clinically significant bleeding.
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5.1.2.4.5 thrombotic events

Though thrombotic events (e.g., pulmonary embolism) have been reported with sitravatinib and with inhibitors of VEGFR, the risk of such events with sitravatinib is unknown. Precautions should be taken in patients with recent, clinically significant thrombotic events, and treatment should be discontinued in patients who develop clinically significant thromboembolic complications such as acute myocardial infarction or severe pulmonary embolism.
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5.1.2.4.6 thyroid dysfunction other than

Hypothyroidism and increases in TSH have been reported in patients taking sitravatinib. Patients diagnosed with hypothyroidism should be treated with thyroid replacement and may continue treatment with sitravatinib at the Investigator's discretion.
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5.1.2.4.7 decreased left ventricular ejection

Decreased left ventricular ejection fraction (LVEF) has been reported with sitravatinib. In addition, decreases of LVEF to <50% on-study were observed in patients undergoing scheduled multigated acquisition (MUGA) scans or echocardiograms. The dose of sitravatinib should be interrupted and/or reduced in patients without clinical evidence of congestive heart failure (CHF) but with an ejection fraction <50% and >20% below baseline. Discontinuation should be considered in more severe cases.
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5.1.2.4.8 proteinuria

Although the risk with sitravatinib is unknown, proteinuria has been described with other inhibitors of the VEGFR pathway. Patients who develop ≥2+ proteinuria should undergo 24-hour urine collection for assessment of urine protein; treatment with sitravatinib should be discontinued in the presence of ≥2 grams of proteinuria/24 hours and may restart when protein levels decrease to less than 2 grams/24 hours. Patients who develop nephrotic syndrome should be withdrawn from treatment with sitravatinib.
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5.1.3 mocetinostat 5.1.3.1 mocetinostat formulation

Mocetinostat will be provided by the Sponsor as 10 mg (white opaque), 20 mg (white opaque), 25 mg (Swedish orange), and 50 mg (Swedish orange) unit dose strength capsules. The composition of the drug product consists of the free-base form of MGCD0103 and inert excipients: microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and non-bovine magnesium stearate. Mocetinostat drug product is packaged in high-density polyethylene (HDPE), white opaque, bottles, with a desiccant packet. A tamper-proof heat induction seal and a childresistant closure are used. Refer to the Pharmacy Study Manual for details on available unit dose strengths, bottle sizes, and number of units per bottle supplied. Mocetinostat capsules should be stored protected from light, at room temperature (suggested range is 15-30°C, 59-86°F) according to instructions on the label.
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5.1.3.2 mocetinostat administration

Mocetinostat capsules will be administered orally, three times per week (TIW), in a continuous regimen expressed in 28-day cycles. The starting dose for mocetinostat in the lead-in dose escalation evaluation will be 70 mg TIW. Depending on safety observations, the mocetinostat dose in the subsequent cohort of patients may escalate to 90 mg TIW or de-escalate to 50 mg TIW. Individual patients should not undergo dose escalation above their starting dose. The following guidelines should be followed for mocetinostat administration:  
Patients should be instructed to take the dose of mocetinostat three days per week
(e.g., Monday/Wednesday/Friday), in the morning, at approximately the same time each day.  
Mocetinostat capsules should be taken on an empty stomach (after an overnight fast or at least a 3-hour fast before each dose and no food for a minimum of 2 hours after each dose).  
Capsules should be taken with at least 200 mL (1 cup) of water.  
Patients should swallow the capsules whole and not chew them. If vomiting occurs after dosing, mocetinostat doses should not be replaced.  
Mocetinostat doses should not be taken 2 days in a row and gaps longer than 3 days
(~72 hours) should be avoided when possible.
On days when mocetinostat and nivolumab dosing are both scheduled, the mocetinostat should precede nivolumab infusion for logistical reasons. This order of dosing is of most interest on days when blood sampling is scheduled for mocetinostat PK. Alignment of mocetinostat and nivolumab dosing days is not required. For instance, mocetinostat may be routinely administered on Monday, Wednesday and Friday, and nivolumab administered in the clinic on a Thursday.
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5.1.3.3 mocetinostat dose modification and

In the event of adverse events attributed to mocetinostat and deemed intolerable by the Investigator, treatment should be either temporarily or permanently discontinued. For patients who temporarily discontinue treatment, treatment may resume following resolution of treatment-related adverse events to Grade 1 or baseline with the administration of mocetinostat at a reduced dose level as outlined in Table 11. Once the dose has been reduced, re-escalation is generally not recommended but may be considered on a case-by-case basis. If the administration of mocetinostat is interrupted for reasons other than toxicity, then treatment with the study drug may be resumed at the same dose.
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table 11 mocetinostat sequential dose

| 90 mg three times per week 70 mg three times per week 50 mg three times per week 40 mg three times per week   |
|---------------------------------------------------------------------------------------------------------------|  
Dose reduction below 40 mg TIW may be undertaken after discussion with the Sponsor. If treatment with mocetinostat is withheld for ≥ 28 consecutive days, then permanent discontinuation from this study drug should be considered.
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5.1.3.4 mocetinostat specific adverse event

Pericardial AEs will be defined as outlined in Table 12.  
| Table 12:    | Definitions of Pericardial Events                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                              |
|--------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Event Term   | Definition                                                                                                                                                                                                                                       | Characteristics/Diagnosis                                                                                                                                                                                                                                                                                                                                    |
| Pericarditis | Inflammation of the                                                                                                                                                                                                                              | The major clinical manifestations of acute pericarditis                                                                                                                                                                                                                                                                                                      |
| pericardium  | include: 1) chest pain, 2) pericardial friction rub, 3) ECG  changes (with new, widespread ST elevation or PR  depressions), and 4) pericardial effusion. At least 2 of  these features are usually considered necessary to make the  diagnosis. |                                                                                                                                                                                                                                                                                                                                                              |
| Pericardial  | Excess exudate, or fluid,                                                                                                                                                                                                                        | Once a pericardial effusion is suspected, the diagnostic                                                                                                                                                                                                                                                                                                     |
| effusion     | in the pericardium                                                                                                                                                                                                                               | approach consists of 3 steps: 1) establish the presence of  effusion, 2) assess the hemodynamic impact, and  3) establish the cause. Clinical evaluation and ECG  findings may suggest the presence of a pericardial  effusion, but imaging, usually ECHO, is required to  establish a diagnosis.                                                            |
| Hemodynamic  | Mechanical compression                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                              |
| Compromise   | of the heart by large  amounts of fluid or blood  within the pericardial  space that limits the  normal range of motion  and function of the heart                                                                                               | The diagnosis of hemodynamic compromise is based upon  clinical and imaging evidence. The following physical  findings 1) sinus tachycardia, 2) elevated jugular venous  pressure, and 3) pulsus paradoxus are suggestive of frank  tamponade. Echocardiogram or other imaging of the  pericardium is essential to the diagnosis of hemodynamic  compromise. |  
ECHOs will be used to assess and categorize pericardial fluid as minimal (or trivial), small, moderate or large and will assess for hemodynamic compromise. Pericardial effusions will be assessed and managed as follows (Table 13).  
| Table 13:                                                                                                                                                                                                                                                                                                                                                             | Pericardial Effusion and Patient Management Guidelines                                                                                              |                                                                                                                                 |                                           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------|
| Category                                                                                                                                                                                                                                                                                                                                                              | Definitions                                                                                                                                         | Patient Management De novo (i.e., not present at baseline)  pericardial effusion:                                               |                                           |
| A small echo-free space in the posterior  atrioventricular groove that is visible only  in systole when the heart has pulled away  from the pericardium. Typically  represents a normal amount of pericardial  fluid in a disease-free state.                                                                                                                         |                                                                                                                                                    | Study treatment may be continued at  the discretion of the Investigator.                                                        |                                           |
| Minimal (or trivial)                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                    | Increased ECHO and ECG monitoring  weekly until effusion is no longer  present or has not progressed over a  period of 2 weeks. |                                           |
|                                                                                                                                                                                                                                                                                                                                                                      | Regular assessment schedule  afterwards.                                                                                                            |                                                                                                                                 |                                           |
|                                                                                                                                                                                                                                                                                                                                                                      | Study drug will not be discontinued in  these Patients, at the discretion of the  Investigator, unless the effusion  progresses.                    |                                                                                                                                 |                                           |
|                                                                                                                                                                                                                                                                                                                                                                      | Increased ECHO and ECG monitoring  weekly for the first month after the  new effusion first noted or until the  effusion has regressed (if sooner). |                                                                                                                                 |                                           |
|                                                                                                                                                                                                                                                                                                                                                                      | Treatment for the effusion may be  administered at the discretion of the  Investigator.                                                             |                                                                                                                                 |                                           |
| < 1 cm of posterior echo-free space, with  or without fluid accumulation elsewhere,  present throughout the cardiac cycle,  including diastole (and not only systole).                                                                                                                                                                                                |                                                                                                                                                     |                                                                                                                                 |                                           |
| Small                                                                                                                                                                                                                                                                                                                                                                 | 1 to 2 cm of echo-free space. Moderate                                                                                                              |                                                                                                                                 |                                           |
| Moderate                                                                                                                                                                                                                                                                                                                                                              | effusions tend to be seen along the length  of the posterior wall but not anteriorly.                                                               |                                                                                                                                | Remove immediately from study  treatment. |
|                                                                                                                                                                                                                                                                                                                                                                      | Manage according to the standard of  care at the discretion of the  Investigator.                                                                   |                                                                                                                                 |                                           |
| Large                                                                                                                                                                                                                                                                                                                                                                 | > 2 cm of maximal separation. Large                                                                                                                 |                                                                                                                                | Refer to cardiologist for follow-up as    |
| effusions tend to be seen circumferentially.                                                                                                                                                                                                                                                                                                                          | clinically indicated, until resolution of  stabilization.                                                                                           |                                                                                                                                 |                                           |
| RV compression, IVC dilation without  respiratory variation, abnormal flow  variation across the AV valves without  respiratory variation, enlarged or collapsed  ventricles. RA diastolic collapse in  isolation is too non-specific to signal  hemodynamic compromise, but should be  considered consistent with this diagnosis  when accompanied by other findings |                                                                                                                                                    | Remove immediately from study  treatment.                                                                                       |                                           |
|                                                                                                                                                                                                                                                                                                                                                                      | Refer to cardiologist for follow up as  clinically indicated, until resolution or  stabilization.                                                   |                                                                                                                                 |                                           |
|                                                                                                                                                                                                                                                                                                                                                                      | Collect blood and test for anti-nuclear  antibody (ANA) and anti-histone  antibody.                                                                 |                                                                                                                                 |                                           |
| Hemodynamic  Compromise In exceptional circumstances where ECHO is not considered a technically optimal                                                                                                                                                                                                                                                               |                                                                                                                                                     |                                                                                                                                 |                                           |  
In exceptional circumstances where ECHO is not considered a technically optimal assessment of pericardial space (e.g., overweight patient), other methods (e.g., MRI) should be used for pericardial assessments. In such cases, the guidelines provided in Table 13 would not apply, and the evaluation should be performed in consultation with the Sponsor. In the event that a pericardial effusion is first identified by a method other than ECHO, efforts should be made to obtain an ECHO for assessment of effusion size.
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5.1.4 instructions common to investigational

Investigational study treatment medication labels comply with the legal requirements of the United States and will be printed in the languages required in the countries in which the study is conducted. Only qualified personnel who are familiar with procedures that minimize undue exposure to them and to the environment should undertake the preparation, handling, and safe disposal of chemotherapeutic agents. Investigational study treatment clinical trial material should be stored in an area that is secure, with limited access and monitored for temperature using a calibrated thermostat. Study site personnel will dispense investigational study treatment tablets or capsules on Day 1 of each dose cycle for the first 12 cycles on study, and then may reduce the frequency to every 2 cycles, at the discretion of the Investigator. Sufficient supply will be provided for each cycle and extra tablets/capsules may be provided to cover an additional 2 days in case of delayed clinic visits or lost tablets/capsules. Study tablets/capsules will be dispensed in HDPE bottles provided by the Sponsor. All investigational study treatment supplies will be accounted for in the drug accountability inventory forms supplied by the Sponsor or using locally approved forms that include all required information. The drug accountability inventory forms must identify the study drug, including batch or lot numbers and account for its disposition on a patient-by-patient basis, including specific dates and quantities. The forms must be signed by the individual who dispensed the drug. Patients will be asked to record their daily dosing on Sponsor provided diary cards and report any missed doses or lost doses at the next clinic visit. On the back of each Sponsor provided diary card, written dosing instructions for the specified investigational study treatment tablets or capsules are provided (e.g., fasting instructions, take with water, etc.). Patients should be told to bring study treatment bottle(s) (empty or not) and completed dosing diaries with them to the clinic visit for a compliance check and tablet/capsule count. Study site personnel will retain the bottle(s) until a monitor has completed reconciliation and retain dosing diaries with site study files. At the end of the study, all unused investigational study treatment drug supplies must be destroyed in accordance with local Standard Operating Procedure provided to the Sponsor for the Trial Master File, or returned to the Sponsor or its appointed agent, as directed by the Sponsor.
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5.1.4.2 adverse event management guidelines

Guidance on size of dose reduction steps in response to investigational study treatment toxicity are specified for glesatinib, sitravatinib and mocetinostat in Sections 5.1.1.3, 5.1.2.3 and 5.1.3.3, respectively. Adverse event management guidance specific to investigational study treatments for glesatinib, sitravatinib and mocetinostat in Sections 5.1.1.4, 5.1.2.4 and 5.1.3.4, respectively.
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5.1.4.2.1 investigational study treatment management

None of the three investigational study treatments has been associated with immune-mediated AEs. However, the potential exists for one or more of the treatments to contribute to immune-mediated AEs associated with nivolumab treatment. In the event of an immune-related AE during study treatment, administration of the investigational study treatment and nivolumab should be interrupted until the event stabilizes to Grade ≤1 (consistent with guidance provided in the OPDIVO US Prescribing Information replicated in Section 5.2.5). At the time of resumption of investigational study treatment dosing, a dose reduction may be implemented at the discretion of the Investigator.
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5.1.4.2.2 diarrhea/colitis

The management of diarrhea should be guided by clinical judgment and an assessment of the most likely causative etiology, with special consideration given to the potential for immune-mediated colitis. Non-specific, most often mild to moderate diarrhea has been observed with all three investigational study treatments and nivolumab. Diarrhea has been reported in approximately 55% of patients treated with glesatinib, 23% of patients treated with sitravatinib, and 46% of patients treated with mocetinostat, most often beginning within the first month of treatment. Diarrhea (any grade) is less common with nivolumab, occurring in approximately 8% (22/287) of patients treated for NSCLC with 3 mg/kg Q2W in the CheckMate 057 clinical trial (USPI OPDIVO [nivolumab]). Immune-related colitis has been reported in 2.4% (7/287) of patients treated with nivolumab for NSCLC, with median time to onset of 2.7 months (range: 4 weeks to 19 months). The presence of abdominal pain, mucus or blood in the stool or peritoneal signs should raise the index of suspicion for immune-mediated colitis, as these features are generally not observed with glesatinib, sitravatinib or mocetinostat treatment-associated diarrhea. The diarrhea observed with the investigational study treatments generally improves within several days of interrupting study medication and therefore dechallenge, with close observation may help establish the most likely causality. However, if any features of the clinical presentation, including timing of presentation, failure to improve with dechallenge, laboratory or radiologic tests suggests the presence of immune-mediated colitis, all study medications should be withheld and treatment with immuno-suppressive therapy initiated as detailed in Table 17.
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5.1.4.2.3 increased transaminases

The management of increases in AST and ALT should be guided by the clinical judgment of the Investigator, including an assessment of the most likely causative etiology, with special consideration given to the potential for immune-mediated hepatitis. Increased transaminases should be evaluated to determine whether confounding factors exist, such as viral infection, metastatic lesions or biliary obstruction. Tyrosine kinase inhibitors in general, and MET inhibitors in particular, have been associated with non-specific, most often mild to moderate elevation in AST and ALT. The observed effects of MET inhibitors likely reflect on-target impact on the ligand, hepatocyte growth factor (HGF). Among patients treated with glesatinib, increases in AST and ALT have been observed in approximately 18% and 12%, respectively. Mild to moderate elevations in liver transaminases have also been observed in less than 10% of patient treated with sitravatinib. The elevations observed with both glesatinib and sitravatinib generally occur within the first cycle of treatment and resolve with interruption of treatment. Nivolumab-related immune-mediated hepatitis was reported in 0.3% (1/287) of patients treated for NSCLC, with an onset of approximately 8 months following initiation of therapy. For cases where transaminases increases are not likely to be immune-mediated, treatment management decisions should be made using Investigator discretion in consideration of clinical factors. Recommended treatment modifications are provided in Table 14. However, if any features of the clinical presentation, including timing of presentation, failure to improve with dechallenge, laboratory or radiologic tests suggests the presence of immune-mediated hepatitis, all study medications should be withheld and treatment with immuno-suppressive therapy initiated as detailed in Table 17.
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table 14 investigational study treatment

| Toxicity                    | Treatment Delay                                                                     | Dose Modification                                                                                                                                        |
|-----------------------------|-------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1 (>ULN to 3.0 × ULN) | May be implemented based on Investigator and patient discretion                     |                                                                                                                                                          |
| Grade 2 (>3.0 to 5.0 × ULN) | Not required                                                                        | Decrease by 1 dose level Decrease by at least 2 dose  levels for a first dose reduction;  decrease by at least 1 dose level  if dose is already reduced. |
| 1.                          | See Sections 5.2.4 and 5.2.5 for guidelines on treatment modification for nivolumab |                                                                                                                                                          |
| Grade 3/4 (>5.0 × ULN)      | Hold until ≤ Grade 1 or return to  baseline                                         |                                                                                                                                                          |
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5.1.4.2.4 management of hy's law

In the event a patient develops concurrent increase in AST and/or ALT ≥ 3 × ULN,
bilirubin ≥ 2 × ULN but without concurrent increases in alkaline phosphatase (i.e.,
alkaline phosphatase < 2 × ULN), that is not attributable to liver metastases or biliary obstruction, investigational study treatment should be permanently discontinued.
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5.1.4.2.5 management of investigational study

Per protocol, a complete review of adverse events should be conducted at each clinic visit. Symptomatic Grade 2 sitravatinib-related non-hematological adverse events occurring any time on study, particularly early in treatment (e.g., Cycle 1 Day 15 or Cycle 2 Day 1), are recommended to be managed using dose reduction to the next lower dose level, per the reduction schedule outlined in Table 9, rather than continued dosing until interruption becomes necessary.  
Non-hematological toxicities ≥ Grade 3 and considered to be treatment-related should be managed with investigational study treatment interruption until resolution of toxicity to
≤ Grade 1 or to baseline value. If the toxicity is adequately managed by routine supportive care (such as electrolyte supplementation), treatment may be resumed at the same dose; if not, treatment may be resumed at a reduced dose (Table 15). Treatment with sitravatinib may continue without dose modification (e.g., interruption or reduction) in cases of asymptomatic amylase and/or lipase increases in the absence of other clinical evidence of pancreatitis (e.g., symptoms, electrolyte abnormalities, radiographic changes)
at the investigator's discretion. Recurrence of the toxicity may be managed similarly. If treatment is interrupted for ≥ 28 days, permanent discontinuation from sitravatinib should be considered.  
| Toxicity             | Treatment Delay                                                                                                                                               | Dose Modification                 |
|----------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------|
| Grade 1              | Continue treatment unchanged                                                                                                                                  |                                   |
| Grade 2 Asymptomatic | May be implemented based on Investigator or patient discretion2                                                                                               |                                   |
| Grade 2 Symptomatic  | May be implemented based on Investigator or patient discretion2 Early dose reduction to the next lower dose level is recommended over  treatment interruption |                                   |
| Grade 3 or 4         | Hold until ≤ Grade 1 or return to                                                                                                                             | Resume at dose one or more levels |
| baseline2            | below that inducing the toxicity. Exceptions presented in footnote.2,3                                                                                        |                                   |
| 1                    | Management of selected adverse events for each investigational study treatment are presented in  Sections 5.1.1.4, 5.1.2.4 and 5.1.3.4.                       |                                   |
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table 15 investigational study treatment

a. Grade 3 or 4 electrolyte abnormality that is not clinically complicated and resolves spontaneously or with conventional medical treatment within 72 hours; b. Grade 3 amylase or lipase elevation that is not associated with symptoms or other clinical manifestations (e.g., electrolyte abnormalities, radiographic changes) of pancreatitis.
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5.1.4.2.6 management of investigational study

Hematological toxicities are not a frequent cause of treatment interruption or discontinuation with any of the three investigational study treatments. Observed ≥ Grade 3 hematological events that are considered to be causally related to the administered investigational study treatment should be managed using treatment interruption or dose reduction at the discretion of the Investigator. If treatment is interrupted for ≥ 28 days, permanent discontinuation from study treatment should be considered.
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5.2 nivolumab study drug

Nivolumab will be obtained from commercial sources and managed in accordance with the OPDIVO US Prescribing Information. The following sections provide reprints of information and guidance included in the OPDIVO US Prescribing Information dated April 2018. Refer to the current OPDIVO US Prescribing Information provided by the manufacturer for updates during the conduct of this clinical trial (https://packageinserts.bms.com/pi/pi opdivo.pdf).
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5.2.1 formulation and packaging

OPDIVO is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) particles. OPDIVO injection for intravenous infusion is supplied in single-dose vials. Each mL of OPDIVO solution contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. The formulation may contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6.
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5.2.2 preparation and dispensing

Visually inspect drug product solution for particulate matter and discoloration prior to administration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake the vial.  
Withdraw the required volume of OPDIVO and transfer into an intravenous container.  
Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from
1 mg/mL to 10 mg/mL. For patients with weight less than 40 kg, the total volume of infusion must not exceed 4 mL/kg.  
Mix diluted solution by gentle inversion. Do not shake.  
Discard partially used vials or empty vials of OPDIVO.
The product does not contain a preservative. After preparation, store the OPDIVO infusion either:  
at room temperature for no more than 4 hours from the time of preparation. This includes room temperature storage of the infusion in the IV container and time for administration of the infusion or under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of infusion preparation.
Do not freeze.
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5.2.3 administration

The recommended dose of OPDIVO is 240 mg every 2 weeks (Q2W) or 480 mg every 4 weeks (Q4W) administered as an intravenous infusion over approximately 30 minutes, until disease progression or unacceptable toxicity. Administer the OPDIVO infusion through an intravenous line containing a sterile, non-pyrogenic, low protein binding inline filter (pore size of 0.2 micrometer to 1.2 micrometer). Flush the intravenous line at end of infusion.
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5.2.4 infusion modification and discontinuation

There are no recommended dose modifications for hypothyroidism or hyperthyroidism. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Discontinue OPDIVO in patients with severe or life-threatening infusion reactions. Dose modifications recommended in OPDIVO US Prescribing Information dated April 2018 are reprinted in Table 16. Required dose modifications (i.e., interruption or discontinuation) for nivolumab should be performed per the current OPDIVO US Prescribing Information (USPI OPDIVO [nivolumab]) Section 2.10 and Section 5, in addition to potential dose modifications for sitravatinib in accordance to Section 5.1.2.3.  
| Table 16:                                                                                                                                                                                                  | Recommended Dose Modifications for OPDIVO - Reprinted  from OPDIVO US Prescribing Information    |                         |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|-------------------------|
| Adverse                                                                                                                                                                                                    | Severity *                                                                                       | Dose Modification       |
| Reaction                                                                                                                                                                                                   | Grade 2 diarrhea or colitis                                                                      | Withhold dose a         |
| Colitis                                                                                                                                                                                                    | Grade 3 diarrhea or colitis Grade 4 diarrhea or colitis                                          | Permanently discontinue |
| Grade 2 pneumonitis                                                                                                                                                                                        | Withhold dose a                                                                                  |                         |
| Pneumonitis                                                                                                                                                                                                | Grade 3 or 4 pneumonitis                                                                         | Permanently discontinue |
| Aspartate aminotransferase (AST)/or alanine  aminotransferase (ALT) more than 3 and up to 5 times the upper limit of normal or total bilirubin  more than 1.5 and up to 3 times the upper limit of  normal | Withhold dose b                                                                                  |                         |
| Hepatitis                                                                                                                                                                                                  | AST or ALT more than 5 times the upper limit of  normal or total bilirubin more than 3 times the | Permanently discontinue |
| upper limit of normal Grade 2 or 3 hypophysitis                                                                                                                                                            | Withhold dose a                                                                                  |                         |
| Hypophysitis                                                                                                                                                                                               | Grade 4 hypophysitis                                                                             | Permanently discontinue |
| Grade 2 adrenal insufficiency                                                                                                                                                                              | Withhold dose a                                                                                  |                         |
| Adrenal  Insufficiency                                                                                                                                                                                     | Grade 3 or 4 adrenal insufficiency                                                               | Permanently discontinue |
| Grade 3 hyperglycemia                                                                                                                                                                                      | Withhold dose a                                                                                  |                         |
| Type 1 Diabetes  Mellitus                                                                                                                                                                                  | Grade 4 hyperglycemia                                                                            | Permanently discontinue |
| Serum creatinine more than 1.5 and up to 6 times  the upper limit of normal                                                                                                                                | Withhold dose a                                                                                  |                         |
| Serum creatinine more than 6 times the upper limit  of normal                                                                                                                                              | Permanently discontinue                                                                          |                         |
| Nephritis and  Renal  Dysfunction                                                                                                                                                                          | Grade 3 rash or suspected Stevens-Johnson  syndrome (SJS) or toxic epidermal necrolysis          | Withhold dose a         |
| (TEN)                                                                                                                                                                                                      |                                                                                                  |                         |
| Skin                                                                                                                                                                                                       | Grade 4 rash or confirmed SJS or TEN                                                             | Permanently discontinue |
| New-onset moderate or severe neurologic signs or  symptoms                                                                                                                                                 | Withhold dose a                                                                                  |                         |
| Encephalitis                                                                                                                                                                                               | Immune-mediated encephalitis                                                                     | Permanently discontinue |
| Other Grade 3 adverse reaction  First occurrence                                                                                                                                                           | Withhold dose a                                                                                  |                         |
| Recurrence of same Grade 3 adverse reactions                                                                                                                                                               | Permanently discontinue                                                                          |                         |
| Life-threatening or Grade 4 adverse reaction                                                                                                                                                               | Permanently discontinue                                                                          |                         |
| Grade 3 myocarditis                                                                                                                                                                                        | Permanently discontinue                                                                          |                         |
| Requirement for 10 mg per day or greater  prednisone or equivalent for more than 12 weeks                                                                                                                  | Permanently discontinue                                                                          |                         |
| Persistent Grade 2 or 3 adverse reactions lasting 12  weeks or longer                                                                                                                                      | Permanently discontinue                                                                          |                         |
| Other                                                                                                                                                                                                      | Mirati Therapeutics, Inc.                                                                        |                         |
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5.2.5 nivolumab adverse event management

Table 17 reproduces AE management guidelines provided in OPDIVO US Prescribing Information, Section 5.
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table 17 management of nivolumab

| Immune-mediated AE Defined as Requiring Use of Corticosteroids and no Clear Alternate  Etiology Immune-mediated  Monitor patients for signs with radiographic imaging and symptoms of  pneumonitis pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone  equivalents for moderate (Grade 2) or more severe pneumonitis, followed by  corticosteroid taper.  Permanently discontinue nivolumab for severe (Grade 3) or life-threatening  (Grade 4) pneumonitis and withhold nivolumab until resolution for moderate  (Grade 2) pneumonitis. Immune-mediated  Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents colitis followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4)  colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of  more than 5 days duration; if worsening or no improvement occurs despite  initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone  equivalents. Withhold OPDIVO for moderate or severe (Grade 2 or 3) colitis. Permanently  discontinue OPDIVO for life-threatening (Grade 4) or for recurrent colitis upon  restarting OPDIVO. Immune-mediated  Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents  hepatitis for severe (Grade 3) or life-threatening (Grade 4) transaminase elevations, with or  without concomitant elevation in total bilirubin. Administer corticosteroids at a  dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2)  transaminase elevations. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue  OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated  hepatitis. Immune-mediated endocrinopathies Hypophysitis Administer hormone replacement as clinically indicated and corticosteroids at a  dose of 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for  moderate (Grade 2) or greater hypophysitis. Withhold OPDIVO for moderate  (Grade 2) or severe (Grade 3). Permanently discontinue OPDIVO for lifethreatening (Grade 4) hypophysitis.   |
|---|  
* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4).  
a Resume treatment when adverse reaction returns to Grade 0 or 1. b Resume treatment when AST/ALT returns to baseline.
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table 17 management of nivolumab

| (Continued)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Immune-mediated endocrinopathies (continued) Adrenal  Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents  Insufficiency followed by a corticosteroid taper for severe (Grade 3) or life-threatening (Grade  4) adrenal insufficiency. Withhold OPDIVO for moderate (Grade 2) and  permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade  4) adrenal insufficiency. Hypothyroidism  and  Hyperthyroidism Administer hormone-replacement therapy for hypothyroidism. Initiate medical  management for control of hyperthyroidism. There are no recommended dose  adjustments of OPDIVO for hypothyroidism or hyperthyroidism. Type 1 Diabetes  Withhold OPDIVO in cases of severe (Grade 3) hyperglycemia until metabolic  Mellitus control is achieved. Permanently discontinue OPDIVO for life-threatening  (Grade 4) hyperglycemia. Other Immune-mediated AEs Immune-Mediated  Nephritis and  Renal Dysfunction Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents  followed by corticosteroid taper for life-threatening (Grade 4) increased serum  creatinine. Administer corticosteroids at a dose of 0.5 to 1 mg/lg/day prednisone  equivalents for moderate (Grade 2) or severe (Grade 3) increased serum  creatinine, if worsening or no improvement occurs, increase dose of  corticosteroids to 1 to 2 mg/kg/day prednisone equivalents. Immune-Mediated  Skin Adverse  Reactions For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for  specialized care for assessment and treatment. If SJS or TEN is confirmed,  permanently discontinue OPDIVO. For immune-mediated rash, administer corticosteroids at a dose of 1 to 2  mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe  (Grade 3) or life-threatening (Grade 4) rash. Withhold OPDIVO for severe  (Grade 3) rash and permanently discontinue OPDIVO for life-threatening (Grade  4) rash. Immune-Mediated  Withhold OPDIVO in patients with new-onset moderate to severe neurologic  Encephalitis signs or symptoms and evaluate to rule out infectious or other causes of moderate  to severe neurologic deterioration. If other etiologies are ruled out, administer  corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for patients  with immune-mediated encephalitis, followed by corticosteroid taper.  Permanently discontinue OPDIVO for immune-mediated encephalitis. Other Immune  Mediated Adverse  Reactions For any suspected immune-mediated adverse reactions, exclude other causes.  Based on the severity of the adverse reaction, permanently discontinue or  withhold OPDIVO, administer high-dose corticosteroids, and if appropriate,  initiate hormone-replacement therapy. Upon improvement to Grade 1 or less,  initiate corticosteroid taper and continue to taper over at least 1 month. Consider  restarting OPDIVO after completion of corticosteroid taper based on the severity  of the event. Infusion Reactions Discontinue OPDIVO in patients with severe or life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. |
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5.3 medication error

Medication errors may involve patient exposure to a wrong study drug, at a wrong dosing frequency, or at a wrong dose level (e.g., a dose that is not planned in the study).  
Medication errors occurring during the conduct of this study will be documented as AEs (regardless of whether clinical signs or symptoms are observed) and if serious consequences are observed, will be reported on Serious Adverse Event (SAE) forms. In all cases of medication error, the sponsor should be notified immediately. There is currently no specific treatment in the event of an overdose of glesatinib, sitravatinib, mocetinostat or nivolumab. The Investigator will use clinical judgment to treat any overdose.
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5.4 concomitant therapies 5.4.1 concomitant

Concomitant medications must be locally-approved and used at doses and regimens that are considered standard-of-care for the treated indication. Treatment for co-morbidities, disease signs and symptoms and treatment emergent adverse events should be provided as necessary in the judgment of the Investigator. Patients may continue to use any ongoing medications not prohibited by the inclusion/exclusion criteria or treatment plan.
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anti-diarrheals

In general - Patients should be counseled that diarrhea is a possible side effect of the study treatments and advised to take loperamide or a similar medication as needed if diarrhea develops.  
Glesatinib specific - Patients treated with glesatinib may received prophylactic antidiarrheal treatment at the discretion of the Investigator. A regimen recommended for primary prophylaxis for diarrhea is loperamide 2-4 mg beginning with the first dose of glesatinib, followed by 2 mg every 6–8 hours. Loperamide use may be subsequently titrated as needed.  
Anti-Emetics: Patients may be premedicated for nausea and vomiting. Recommended anti-emetic agents include granisetron 1 mg as premedication, and then granisetron and/or prochlorperazine as needed.  
**Gastric Acid Medications:** Proton pump inhibitors and H2 antagonists should be avoided during treatment on study but are not exclusionary. Switch from use of proton pump inhibitors or H2 antagonists to use of antacids is preferred. Use of antacids should be avoided 4 hours before and 2 hours after administration of investigational study treatment.  
Medications with QTc Prolonging Activity **(Sitravatinib and Mocetinostat only):** The risk of QTc prolongation in patients receiving the investigational study treatments has not been characterized. Use of medications known to prolong QTc and pose risk of Torsades de Pointes (examples listed in Appendix 3) is to be avoided.
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p-450 considerations mocetinostat specific

**Warfarin or Coumarin Derivatives** - Therapeutic doses of warfarin or other coumarin derivative anticoagulants are not permitted in patients treated with mocetinostat. Warfarin has a narrow therapeutic range and mocetinostat can have inhibitory effects on CYP2C9, the main metabolizing enzyme of warfarin. Patients may adopt a different anticoagulant.  
**Contraceptives** - Hormonal contraceptives may be affected by cytochrome P-450 interactions, and are therefore not considered effective for this study, since induction of CYP3A4 may not be excluded in patients receiving mocetinostat.  
**Cautioned Medications** - Caution should be used when mocetinostat is administered to patients taking medications metabolized by CYP2C9, or that inhibit or induce metabolism by CYP2E1 or CYA3A4. See Appendix 3 for examples of medications of interest. If a patient is taking a drug on one these lists, it is encouraged to substitute a different medication if possible.  
Herbal Medications/Preparations: Herbal medications and preparations should be avoided throughout the study. Herbal medications include, but are not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe (yohimbine), saw palmetto, and ginseng.  
Transfusions: Patients may receive transfusions as necessary.  
Antibiotics: Antibiotics should be used as needed. Patients with neutropenic fever or infection should be treated promptly.  
Supportive Care/Palliative Care: Supportive and palliative care for disease related symptoms may be administered at the Investigator's discretion, including the use of analgesics. Growth Factors: Therapeutic colony-stimulating factors should be used in accordance with ASCO guidelines. Immunosuppressive Medications: Use of immunosuppressive mediations should be limited to the extent possible to allow testing of the immune-stimulatory mechanisms proposed in this clinical trial. Immunosuppressive medications should be used as needed to manage immune-mediated AEs and the extent required to manage comorbidities and symptoms of disease.  
Vaccines: Live attenuated vaccines within 100 days of nivolumab dosing are to be avoided. Inactivated vaccines, such as the injectable influenza vaccine, are permitted.
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5.4.2 concomitant surgery or radiation

The use of surgery to manage cancer lesions during study treatment is discouraged. The impact of the investigation study treatments on wound healing has not yet been characterized. For patients with bone involvement, any foreseeable need for palliative radiotherapy should be addressed before study entry, if possible and clinically appropriate (e.g., bone lesions at risk for spontaneous micro-fractures or painful lesions). However, these treatments may be used in cases where it is medically necessary. In the event that major surgery is needed during study treatment, the patient should, if possible, interrupt dosing with the assigned investigational study treatment for the duration specified in Table 18.  
| Drug                  | Discontinue in  Advance   | Resume Following   |
|-----------------------|---------------------------|--------------------|
| Glesatinib Tablets    | 1 week                    | 1 week             |
| Sitravatinib Capsules | 2 weeks                   | 2 weeks            |
| Mocetinostat Capsules | 1 week                    | 1 week             |
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5.4.3 other anticancer or experimental

Use of approved or investigational anticancer treatment will not be permitted during the study treatment period, including chemotherapy, biological response modifiers, hormone therapies* or immunotherapy. No other investigational drug may be used during treatment on this protocol. Concurrent participation in another therapeutic clinical trial is not allowed.  
*Certain ongoing hormonal therapies taken to prevent recurrence of a malignancy not under study (e.g., tamoxifen/aromatase inhibitor for breast cancer) may be permitted after discussion with and agreement of the Sponsor's Medical Monitor.
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6 study assessments 6.1 screening

Voluntary, written, dated, and signed informed consent must be obtained before any study specific procedures are performed. Patients who completed the informed consent process but did not enroll on the study will be considered as screen failures. Limited information will be recorded in the CRF for these patients.
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6.2 study period

For details on procedures during the study period, see Schedule of Assessments as shown in Table 1.
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6.3 end of treatment assessment

All patients will be followed for AEs for at least 28 days after the last dose of Study Treatment. See the Schedule of Assessments (Table 1) for evaluations to be performed at the End of Treatment visit.
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6.4 long-term follow-up and end

Survival status and subsequent therapies will be collected during long term follow-up as outlined in the Schedule of Assessments (Table 1) until death or lost to follow-up. Beyond 28 days after last treatment, follow-up may be performed by telephone contact. Treatments received following participation in the study will be collected in the CRF.
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6.5 patient discontinuation/withdrawal

Patients may discontinue from study treatment or from study follow-up at any time at their own request, or they may be discontinued at any time at the discretion of the Investigator or Sponsor for safety, behavioral reasons, or the inability of the patient to comply with the protocol required schedule of study visits or procedures at a given study site. Criteria that may be used to discontinue patients from receipt of study medication will include, but will not be limited to:  
Objective disease progression according to RECIST 1.1 as determined by the Investigator (patients who may derive clinical benefit may continue on treatment at the discretion of the Investigator);
Global deterioration of health status requiring discontinuation; Adverse event; Significant protocol violation; Lost to follow-up; Refusal for further treatment; Study termination by Sponsor; Death.
Reasons for discontinuation from study follow-up may include:
Study terminated by Sponsor; Lost to follow-up; Refusal for further follow-up for survival;  
Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the patient. At least 2 attempts should be made to contact the patient, and each attempt should be recorded in the source documents. In any circumstance, every effort should be made to document patient outcome, if possible. The Investigator should inquire about the reason for withdrawal, request that the patient returns for a final visit, and if applicable, follow-up with the patient regarding any unresolved adverse events. If the patient withdraws from the study treatment and also withdraws consent for disclosure of future information, no further evaluations should be performed, and no additional data should be collected. The Sponsor may retain and continue to use any data collected before such refusal for further follow-up.
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7 procedures

Every effort should be made to ensure that the protocol required tests and procedures are completed as described. However, it is anticipated that there may be circumstances outside of the control of the Investigator that may make it infeasible to perform a protocol-specified assessment. In these cases, the Investigator will take all steps necessary to ensure the safety and well-being of the patient. When a protocol required test cannot be performed, the Investigator will document in the source document and CRF the reason and any corrective and preventive actions which he/she has taken to ensure that normal processes are adhered to as soon as possible. The study team will be informed of these incidents in a timely fashion.
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7.1 efficacy

All patients enrolled in the study are to be evaluated for disease activity as outlined in the Schedule of Assessments (Table 1). Screening/baseline tumor assessments should include CT or MRI of the chest, abdomen, and pelvis, whole body bone scan, MRI of the brain and evaluation of any superficial lesions. On-study assessments will include all known and suspected sites of disease and will be performed at 8-week intervals until approximately 1-year and then every 16 weeks; bone scans may be performed half as often as other radiology evaluations (i.e., every 16 weeks). The allowable windows for assessments are 4 weeks prior to first study treatment for screening/baseline assessments and 10 days for on-study disease assessments. All known and suspected sites of disease should be evaluated at each assessment. Assessments will be performed until objective disease progression is documented or subsequent anti-cancer therapy is begun.  
CT scans should be performed with contrast agents unless contraindicated for medical reasons. If intravenous contrast is medically contraindicated, the imaging modality to be used (either CT without contrast or MRI) should be the modality which best evaluates the disease, and the choice should be determined by the Investigator in conjunction with the local radiologist. Depending on the adequacy for evaluation of disease, a combination of CT without contrast and MRI should most often be used. CT without contrast is preferred for evaluation of lesions in lung parenchyma. MRI is not adequate for evaluation of lung parenchyma but should also be performed to evaluate all other aspects of the chest. MRI of the abdomen and pelvis should substitute for CT with contrast unless the method does not adequately depict the individual's disease, in which case CT
without contrast is preferred. For patients having effusions or ascites, cytological proof of malignancy should be obtained prior to selection of the effusion as a non-target lesion. Effusions that have not been evaluated using cytology or were found to be non-malignant should not be considered to be cancer lesions. Disease response will be assessed in accordance with RECIST 1.1 (Eisenhauer-2009). Appendix 4 provides guidance in using the response criteria and includes modifications to RECIST 1.1 to address potential temporary treatment effects such as tumor lesion cavitation or flare response. Assessments will be performed until objective disease progression is documented by the Investigator, or subsequent anti-cancer therapy is begun. Patients experiencing tumor response (Partial Response [PR] or Complete Response [CR]) should undergo confirmatory assessment at least 4 weeks after initial documentation of response. It is acceptable to perform confirmatory assessments at the next appointed evaluation per protocol. Bone scan is required as an element of the confirmation of PR or CR if bone lesions were identified at the baseline assessment.  
The Investigator's assessment of disease response and progression will be the basis for patient management and study expansion decision making. Potential exists for individual tumor lesions to cavitate or become otherwise difficult to evaluate for a period of time as the result of beneficial study treatment impact. For example, tumor necrosis and cavitation may result in minor increase in overall individual lesion size or unclear tumor margins prior to recovery to a smaller lesion, development of scar tissue, or complete resolution. For this reason, Investigators may delay reaching the conclusion of disease progression until subsequent on-study disease assessments are performed. Central radiology review to assess RECIST outcome may be undertaken after Stage 1 of the study. Materials to be forwarded for independent review will be all imaging studies performed at screening and on study, preferably in digital format, using an electronic transfer through a portal to the review vendor or transfer on compact disc or optical disc. All digital media must be in DICOM format. Films may be forwarded for review if necessary; all films should be originals (second original films acceptable) rather than copies of films.
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7.2 safety assessments 7.2.1 adverse

Assessment of adverse events will include type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE, Version 4.03]), timing, seriousness, and relatedness to study treatment.  
Signs and symptoms of the patient's cancer diagnosis and/or comorbidities present at baseline will be recorded in the CRF as AEs beginning on Day 1 of study treatment and onward throughout the study. The actual date of onset should be recorded in all cases. Ongoing AEs that change in attribution or severity should have the date of change entered as the "end date" and a new AE record should be opened with the changed details.
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7.2.2 physical examination and vital

A physical examination including all major body systems is mandated at Screening and End of Treatment Visits only. During study treatment, symptom directed physical examinations will be performed. Vital signs to be assessed include weight, body temperature, blood pressure, and pulse rate. Height will be recorded at screening only. On days were both vital signs and PK sampling are scheduled, the vital signs should be assessed prior to blood sampling. Clinically significant findings noted during screening will be reflected on the medical history CRF, while those noted during study treatment will be collected on the AE CRFs.
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7.2.3 laboratory safety assessments

Laboratory safety assessments for which data will be collected in this study will include hematology, coagulation, thyroid tests, urinalysis and chemistry parameters presented in Table 19. Laboratory tests will be drawn at the time points described in the Schedule of Assessments (Table 1) and analyzed at local laboratories. Additional laboratory tests may be performed per standard of care, at the Investigator's discretion for the purpose of planning treatment administration, dose modification, following adverse events, or as clinically indicated.  
| Table 19:                            | Laboratory Safety Parameters                                                                                                                |
|--------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------|
| Hematology Panel                     | Blood Chemistry Panel                                                                                                                       |
| Hemoglobin                           | Aspartate aminotransferase (AST)                                                                                                            |
| Platelet count                       | Alanine aminotransferase (ALT)                                                                                                              |
| White blood cell count (WBC)         | Alkaline phosphatase                                                                                                                        |
| Neutrophil count                     | Total bilirubin (if Total bilirubin is ≥2×ULN and  no evidence of Gilbert's syndrome, then  fractionate into direct and indirect bilirubin) |
| Lymphocyte count                     | Lipase Amylase                                                                                                                              |
| Coagulation                          | Sodium                                                                                                                                      |
| International normalized ratio (INR) | Potassium                                                                                                                                   |
| Partial thromboplastin time (PTT)    | Chloride Bicarbonate [CO2 ]                                                                                                                 |
| Urinalysis (dip stick)               | Blood urea nitrogen (BUN)                                                                                                                   |
| Blood                                | Creatinine                                                                                                                                  |
| Protein                              | Glucose (non-fasted) Albumin                                                                                                                |
| Thyroid Function Test                | Total Calcium                                                                                                                               |
| Thyroid-stimulating hormone (TSH)    | Magnesium                                                                                                                                   |
| Free-T4                              | Uric acid                                                                                                                                   |  
Pregnancy Testing: For patients of childbearing potential, a serum or urine pregnancy test will be performed by the local laboratory at screening. Pregnancy tests will also be done whenever pregnancy is suspected during the study. Additional pregnancy testing may be necessary if required by local practices or regulations.
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7.2.4 electrocardiogram (ecg)

Single and triplicate ECGs are to be performed as outlined in the Schedule of Assessments (Table 1). It is preferable that the machine used has a capacity to calculate the standard intervals automatically. Assessments reported by automated read as prolongation of QTc should be over-read by a cardiologist to ensure accuracy of interpretation.
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7.2.5 echocardiogram (echo)

Echocardiograms will be performed in the sitravatinib and mocetinostat treatment arms at screening, and thereafter as in the Schedule of Assessments (Table 1). Additional assessments of LVEF and evaluation of pericardial effusions may be performed as clinically indicated at the Investigator's discretion if there are signs or symptoms of cardiotoxicity. Where abnormalities indicating pericardial effusion exist, weekly assessments should be performed until normalization as described in Section 5.1.3.4.1. In exceptional circumstances where ECHO is not considered a technically optimal assessment of pericardial space (e.g., overweight patient), other methods (e.g., MRI) should be used for pericardial assessments.
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7.3 laboratory studies

Full details on sample collection, processing, storage and shipment are presented in the Study Laboratory Manual.
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7.3.1 pharmacokinetic evaluation

The PK of the investigational study treatments will be determined using blood samples collected at specified time points prior to and following study treatment dosing. Every effort will be made to collect these PK samples at the exact nominal times relative to dosing. A variation window is allowed for each time point as outlined in Table 2, Table 3, and Table 4. The actual time of each sample collection will be recorded on the source document and CRF. All plasma or serum samples will be stored frozen and shipped on dry ice according to instructions provided. Analysis of samples will be performed using specific validated bioanalytical methods. Full details on sample collection, processing, storage and shipment will be provided in the Study Laboratory Manual.
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7.3.5 sample collection for pd-l1

Tumor tissue testing for PD-L1 expression is required for patients enrolling in the CITnaïve patient cohort through the central laboratory. The sample tested must have been collected following completion of the most recent systemic treatment regimen. For CIT-experienced patients, tumor tissue collection for testing for PD-L1 expression and/or evaluation of tumor gene alterations is an optional but highly desirable assessment. Archival samples are acceptable if more recent tumor specimens are not available. Samples should be collected via a core needle of 18 gauge or larger or be collected by an incisional or excisional tumor biopsy. Where institutional practice uses a smaller gauge needle, samples should be evaluated for tumor cell quantity (i.e., > 100 tumor cells) to allow for adequate PD-L1 immunohistochemistry analyses. Samples should be formalin fixed and embedded in paraffin. Samples from fine needle aspirates (FNA) or decalcified bone are not appropriate for these evaluations. Further guidance on sample preparation and submission can be found in the Study Laboratory Manual.
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7.4 post-treatment follow-up

Survival status and subsequent therapies will be collected during long term follow-up as outlined in the Schedule of Assessments (Table 1) until death or lost to follow-up. Beyond 28 days after last treatment, follow-up may be performed by telephone contact. Treatments received following participation in the study will be collected in the CRF.
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8 adverse event reporting 8.1

The contact information for the sponsor's Medical Monitor personnel for this trial is available in the study contact list located in the Study Manual.
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8.2 adverse events

An adverse event (AE) is any reaction, side effect or other undesirable medical event that occurs during participation in a clinical trial, regardless of treatment group or suspected causal relationship to study treatment. A treatment emergent AE (TEAE) is an AE that occurs after the first dose of any study treatment or any preexisting condition that increases in severity after the first dose of study treatment. All observed or volunteered AEs will be recorded in source documents and reported in the CRF. The best available medical terminology should be used to describe AEs in source documents and CRFs. Terms describing the diagnosis are preferred over individual signs and symptoms of the diagnosis. If determination of the diagnosis is delayed, record signs and symptoms and add the diagnosis as an AE when available; follow all recorded AEs to resolution. Examples of AEs include but are not limited to:
Signs or symptoms of co-morbidity, illness, or toxicity of study treatment;  
Signs or symptoms of worsening malignancy under study (disease progression assessed by measurement of malignant lesions should not be reported as an AE).  
Laboratory abnormalities (see Section 8.2.1 for guidance for reporting in CRF); Hypersensitivity;
Drug abuse, dependency, overdose, withdrawal or misuse;  
Signs or symptoms of drug interactions; Extravasation; Exposure during pregnancy or via breastfeeding; Medication error; or Occupational exposure.
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8.2.1 laboratory abnormalities

An abnormal laboratory test result should be reported as an AE in the CRF only if it is associated with one or more of the following:  
Clinical symptoms;
Requires additional tests (beyond repeats), treatment or intervention; Results in change in study treatment dosing;  
Requires discontinuation from study treatment; and/or Considered by the Investigator or Sponsor to be an AE.
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hy's law

Hepatic function abnormality defined by an increase in AST and/or ALT to ≥ 3 × ULN concurrent with an increase in total bilirubin to ≥ 2 × ULN but without increase in alkaline phosphatase (i.e., alkaline phosphatase < 2 × ULN) meets the criteria for Hy's Law and raises the concern for drug-induced liver injury when no other cause of the abnormal laboratory results are identified. Follow-up investigations and inquiries will be initiated promptly by the investigational site to determine whether the findings are reproducible and/or whether there is objective evidence that clearly supports causation by a disease (e.g., cholelithiasis and bile duct obstruction with distended gallbladder) or an agent other than the investigational product.  
Cases meeting Hy's Law should be reported as SAEs. Study drug should be permanently discontinued for a Hy's Law case.
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8.2.2 severity assessment

AEs occurring during this study will be graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03). Documentation of AE grading in the source documents and CRF should be consistent with provided definitions.
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8.2.3 causality

For each AE, the Investigator should determine and document whether there exists a reasonable possibility that the study treatment caused or contributed to the AE. The Investigator's assessment should be recorded in the source document. The CRF will provide the options for attribution to study treatment as "related" and "not related." If the Investigator's causality assessment is "unknown but not related to investigational product," this should be recorded in the CRF as "not related." If the Investigator does not know whether or not the study treatment is causally-related to the event, reporting for study purposes will be as "related" to study treatment.  
Collection of causal relationship for AEs associated with study procedures (e.g., tumor biopsy) is provided for separately in the CRF.
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8.3 serious adverse events 8.3.1

An SAE is any event that meets any of the following criteria:
Results in death; Is life-threatening (immediate risk of death);
Requires inpatient hospitalization or prolongation of existing hospitalization;  
Results in persistent or significant disability/permanent damage (substantial disruption of the ability to conduct normal life functions);
Results in congenital anomaly/birth defect. Other: Important medical events that may not result in death, be life-threatening, or require hospitalization, may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such events are:
o Intensive treatment in an emergency room or at home for allergic bronchospasm o Blood dyscrasias or convulsions that do not result in inpatient hospitalization o Development of drug dependency or drug abuse
Progression of the malignancy under study, including any signs or symptoms of progression that may require hospitalization, should not be reported as an SAE unless the outcome is fatal within the safety reporting period.
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definition of terms

Life threatening: An AE is life threatening if the patient was at immediate risk of death from the event as it occurred; i.e., it does not include a reaction that if it had occurred in a more serious form might have caused death. For example, drug-induced hepatitis that resolved without evidence of hepatic failure would not be considered life-threatening even though drug-induced hepatitis can be fatal. Hospitalization: In general, hospitalization signifies that the patient has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician's office or outpatient setting. When in doubt as to whether 'hospitalization' occurred or was necessary, the AE should be considered serious. Hospitalization for elective surgery or routine clinical procedures that are not the result of AE (e.g., elective surgery for a preexisting condition that has not worsened) need not be considered AEs or SAEs. If anything untoward is reported during the procedure, that occurrence must be reported as an AE, either 'serious' or 'non-serious' according to the usual criteria. Disability/permanent damage: An AE is disabling or caused permanent damage if it resulted in a substantial disruption of a person's ability to conduct normal life functions, e.g., a significant, persistent or permanent change, impairment, damage or disruption in body function/structure, physical activities and/or quality of life. Adverse Event of Special Interest (AESI): AESIs are of scientific and medical interest specific to understanding of the Investigational Product and may require close monitoring and rapid communication by the Investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and understand them in association with the use of this investigational product. Immune-related Adverse Events (irAE): An irAE is defined as an adverse event that is associated with drug exposure and is consistent with an immune-mediated mechanism of action and where there is no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE.
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8.3.2 exposure during pregnancy

Exposure during pregnancy (i.e., exposure in-utero [EIU]) may occur in a female study participant, the female partner of a male study participant or study site personnel working with the investigational product (e.g., occupational exposure) if:  
A female becomes or is found to be pregnant during treatment or within 6 months after discontinuing treatment or having been directly exposed to the investigational product; A male is exposed to the investigational product prior to or around the time of conception or during the pregnancy of his partner.
If exposure in-utero occurs, the Investigator must submit an SAE form and an EIU Supplemental Form within 24 hours of awareness of the exposure, regardless of whether an AE or SAE has occurred. In the event of pregnancy in a female study participant, if the pregnancy is continued, study treatment will be immediately discontinued.  
In the event of exposure of the pregnant partner of a male study participant, the study participant should be asked to deliver an EIU Pregnant Partner Release of Information Form to his partner. The Investigator must document on the EIU Form that the patient was given this letter to provide to his partner. Follow-up to obtain pregnancy outcome information is to be conducted for all EIU reports. In the case of a live birth, the health of the neonate should be assessed at the time of birth and for up to 3 months after birth. Further follow-up of birth outcomes will be handled on a case-by-case basis (e.g., follow-up on preterm infants to identify developmental delays). In the event the pregnancy is terminated, the reason(s) for termination should be reported and, if clinically possible, the structural integrity of the terminated fetus should be assessed by gross visual inspection. If the outcome of the pregnancy meets the criteria for an SAE (i.e., ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly), an SAE report should be submitted to the Sponsor.
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8.4 reporting of saes and

The active reporting period for SAEs begins from the time that the patient provides informed consent (i.e., prior to undergoing any study-specific procedure or assessment) and continues until 28 days post last administration of either therapy. All SAEs will be followed until the event has resolved or stabilized to a chronic condition, whichever is later. Death must be reported if it occurs during the active reporting period for SAEs regardless of whether a subsequent anticancer therapy is administered. Serious adverse events occurring to a patient after the active reporting period has ended should be reported to the Sponsor if the Investigator becomes aware of them and if the Investigator assesses at least a reasonable possibility of being related to study drug. The reporting period for non-serious AEs begins from the day of first dose of study treatment and continues until at least 28 days after last administration of study treatment and/or until recovery from all acute toxicities associated with the drug administration to a chronic condition, whichever is later. If a patient begins a subsequent anticancer therapy, the AE reporting period ends at the time the new treatment is started.
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8.4.2 reporting requirements

All SAEs must be reported within 24 hours of Investigator/site knowledge of the event, irrespective of the extent of available AE information, by faxing the SAE report to the Sponsor's pharmacovigilance representative designated in the Study Manual. The 24-hour timeframe also applies to additional new information (follow-up) on previously forwarded SAE reports and to the initial and follow-up reporting of exposure during pregnancy and exposure via breastfeeding. The need for an expedited report to regulatory authorities will be determined by the Sponsor and necessary reporting will be performed by the Sponsor. The Sponsor will notify study Investigators of all Suspected, Unexpected (as judged against the Investigator Brochure) Serious Adverse Reaction (SUSAR) reports. The Investigator is responsible for reporting all SUSARs to the IRB/EC. All AEs (including SAEs) must be documented in source documents and reported in the CRF. Please note that the CRF and SAE report forms may collect information in somewhat different formats. Where the requested data overlap in different formats, the information should be consistent between the two forms.
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9 statistics

Detailed methodology for summary and statistical analyses of the data collected in this study will be documented in a Statistical Analysis Plan (SAP), which will be maintained by the Sponsor. The SAP may modify the plans outlined in the protocol; however, any major modifications of the primary endpoint definition and/or its analysis will also be reflected in a protocol amendment.
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9.1 hypothesis and sample size

Approximately 24 patients may be enrolled into the lead-in dose escalation portion of the study. A precise sample size cannot be defined, as it is dependent on the number of dose escalations based on the mTPI method, and the number of patients enrolled in the expansion cohorts. The mTPI method (Ji-2013) will be employed in decision making concerning dose escalation within each regimen investigated. The assumptions to be applied in establishing the mTPI methodology are:
each specific regimen exploration will include up to 30 patients;  
the MTD is defined to have 0.25 probability of toxicity; and the acceptable variance around the MTD is ± 0.05 (i.e., the region of the MTD is 20% to 30% incidence of dose limiting toxicity).
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9.1.2 phase 2

This Phase 2 study will use a Predictive Probability Design (Lee-2008) in each treatment arm and strata. In creating the statistical designs, the Type 1 error (α) is constrained to
<0.05 and Power (1-β) is constrained to ≥0.90.
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statistical design applied to cit-experienced

The ORR using nivolumab in the population with advanced non-squamous NSCLC having prior disease progression on a checkpoint inhibitor or patients with non-squamous NSCLC without prior checkpoint inhibitor therapy with no/low PD-L1 expression is assumed to be 5% (p0); thus this rate is considered uninteresting. The target ORR using the investigational agents in combination with nivolumab in this study is 30% (p1). Stage 1 of enrollment will include a minimum of 9 evaluable patients in each treatment strata. With exactly 9 evaluable patients at Stage 1, if at least 1 patient has an Objective Response, 8 additional evaluable patients will be enrolled in the treatment stratum, for a total sample size of 17 evaluable patients. If at least 3 Objective Responses are observed in a treatment stratum, further investigation may be warranted. If the true ORR is 5% (null hypothesis), the probability of early termination during the study is 0.63; the Type 1 error is equal to 0.0466 and the power is equal to 0.9045.
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statistical design applied to cit-naive

The ORR using nivolumab in the population with non-squamous NSCLC having high PD-L1 expression is assumed to be 27% (p0); thus this rate is considered uninteresting. The target ORR using the investigational agents in combination with nivolumab is 50% (p1). Stage 1 of enrollment will include approximately 17 evaluable patients. With exactly 17 evaluable patients at Stage 1, if at least 5 patients have Objective Responses, 27 additional evaluable patients will be enrolled, for a total sample size of 44 evaluable patients. If at least 18 Objective Responses are observed, further investigation may be warranted. If the true ORR is 27% (null hypothesis), the probability of early termination during the study is 0.50; the Type 1 error is equal to 0.0303 and the power is equal to 0.9018. The exact stopping rules for all cohorts will be calculated based on the Predictive Probability Design, once the exact number of patients evaluable at Stage 1 is known. The aim is to get a minimum of 9 evaluable patients at Stage 1 for CITexperienced and CIT-naïve with lo/no PD-L1 expression cohorts and a minimum of 17 evaluable patients at Stage 1 for CIT-naïve with high PD-L1 expression cohort.
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expansion beyond stage 2

For the sitravatinib segment of the study enrolling patients with CIT-experience, expansion of enrollment beyond Stage 2 will be managed as one cohort that includes all patients, regardless of prior clinical benefit during treatment with CIT. Based on preliminary clinical activity results as of June 2018 (described in Section 1.5.3.2.2), enrollment into the combined cohort will expand to approximately 125 patients total. The purpose for enrollment expansion is to further evaluate safety and efficacy in this setting. Expansion of sitravatinib CIT-naïve cohorts beyond Stage 2 of enrollment is not anticipated. Table 20 presents estimates of the 95% CI around the observed ORR for several potential outcomes using the sample size of 125 patients, and the Clopper-Pearson method.  
| Number of             |     |           |
|-----------------------|-----|-----------|
| Observed Responses    | ORR | 95% CI    |
| Among 125 Patients 19 | 15% | 9.4-22.7  |
| 25                    | 20% | 13.4-28.1 |
| 31                    | 25% | 17.5-33.3 |
| 38                    | 30% | 22.5-39.3 |
| 44                    | 35% | 26.9-44.3 |
| 50                    | 40% | 31.3-49.1 |
| 63                    | 50% | 41.3-59.5 |
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9.2 data handling

Listings of all patient data will be prepared. Data summaries will be presented in tabular and/or graphical format and summarized descriptively, where appropriate. Further details of planned analyses will be described in the SAP. For all variables, only the observed data from patients will be used in the statistical analyses; there is no plan to estimate missing data. Patients without a valid clinical response assessment will be assigned a best overall response of not evaluable (NE). Data from patients who are lost to follow-up or have missing observations before reaching an endpoint in any of the time-to-event analyses will be treated as censored with specific rules defined in the SAP.
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9.3 analysis populations 9.3.1 modified

The Modified Intent-to-Treat (mITT) population is defined as all patients who receive treatment with both an investigational study treatment and nivolumab on this study. The primary efficacy analyses of the primary and secondary efficacy endpoints will be performed in the mITT population. In addition, the mITT population will be used in making decisions to expand the study to the next stage of enrollment.
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9.3.2 clinical activity evaluable population

In order to be considered eligible for the clinical activity evaluable population, the patient must have at least one on-study disease assessment or discontinue from treatment for progressive disease. Patients who discontinue treatment prior to the first on-study disease assessment for an AE, toxicity, or withdraw consent are considered non-evaluable for disease assessment and will not be part of the clinical activity evaluable population. This population will be used to present tumor responses as well as to make decision on the Predictive Probability design.
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9.3.3 safety population

The Safety population is defined as all patients who received at least 1 dose of either investigational study treatment or nivolumab. The Safety population will be used for all safety analyses.
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9.3.4 molecular marker evaluable population

The molecular marker evaluable population will consist of all patients who receive at least one dose of either investigational study treatment or nivolumab for whom PD-L1 expression or circulating PD-L1 results are available.
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9.3.5 pharmacokinetic evaluable population

The Pharmacokinetic evaluable population will consist of all patients who received treatment with an investigational study drug and had sufficient concentration-time data to permit calculation of PK parameters for the investigational agent. For patients who were noncompliant with respect to administration of investigational agent, or for patients with incomplete data, a decision as to their inclusion in the analysis will be made on a case-by-case basis.
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9.3.6 pharmacodynamic evaluable population

The Pharmacodynamic evaluable population will consist of all patients who receive at least one dose of investigational agent or nivolumab for whom PD results are available.
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9.4 efficacy endpoint definitions and

Objective disease response will be categorized in accordance with RECIST v1.1 (Appendix 4). Objective Response Rate (ORR) is defined as the percent of patients documented to have a confirmed Complete Response (CR) or Partial Response (PR). If central review of disease response is undertaken, ORR as reported by the central radiology review laboratory will be used to calculate ORR and the exact 95% confidence intervals (CI). ORR as reported by the Investigator will be used in study expansion decision making (PPD design) and supportive analyses. Descriptive statistics (frequency and percentage) for ORR, CR, and PR will be presented. The exact 95% CI of these response rates will be calculated. An exact test for single proportion (two-sided α=5%) will be performed to test H0: ORR ≤ 5% against H1: ORR
> 5%. Other details will be described in the SAP.
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9.4.2 clinical benefit rate

Clinical Benefit Rate (CBR) is defined as the percent of patients documented to have a confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD) documented during at least 2 on-study assessments and including at least 14 weeks on study (e.g., allowance for 2-week window around Week 17 assessment).
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9.4.3 duration of response

Duration of Response (DR) is defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of Objective Progression of Disease (PD) or to death due to any cause in the absence of documented PD. Censoring for the DR endpoint will be assigned on the date of the last tumor assessment if no assessment of tumor progression is identified and the patient does not die while on study. DR will only be calculated for the subgroup of patients with an objective response. The Kaplan-Meier method will be used to obtain the estimate of median DR.
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9.4.4 progression free survival

Progression-free survival (PFS) is defined as the time from date of first study treatment to first PD or death due to any cause in the absence of documented PD. Censoring for the PFS endpoint will be assigned on the date of the last tumor assessment if no assessment of tumor progression is identified and the patient does not die while on study. For patients in whom two or more sequential assessments are missed, followed by the finding of tumor progression, the PFS endpoint will be censored on the date of the last tumor assessment before the gap. Patients lacking an evaluation of disease after first study treatment will have their PFS time censored on the date of first dose with duration of 1 day. Patients who start a new anti-cancer therapy prior to documented PD will have the endpoint censored at the date of the last tumor assessment prior to the start of the new therapy. The Kaplan-Meier method will be used to obtain the estimate of median progression-free survival time.
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9.4.5 overall survival

Time to death is defined as the time from date of first study treatment to death due to any cause. Censoring for the survival endpoint will be assigned on the date of the last on-study follow-up that the patient is reported to be alive. The Kaplan-Meier method will be used to estimate the median OS and 1-year Survival Rate; the 95% confidence interval of the 1-year survival rate will also be reported.
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9.5 safety data presentations and

Adverse events will be classified using the medical dictionary for regulatory activities (MedDRA) classification system. Listings will include the verbatim term, preferred term, and system organ class (SOC). The number of patients with treatment emergent AEs and the incidence of TEAEs by SOC and preferred term will be summarized. TEAEs will be summarized by maximum intensity and relationship to study therapy. Separate summaries will be provided for TEAEs, TESAEs, treatment-related AEs, treatment-related SAEs, and other significant AEs (e.g., AEs leading to study discontinuation).
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9.5.2 prior and concomitant medications

Collected prior and concomitant medications will be coded using the WHO medical dictionary; patients who received these medications will be listed and summarized.
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9.5.3 clinical and laboratory assessments

Clinical and laboratory assessments include clinical laboratory tests (hematology, coagulation, urinalysis, thyroid function tests and chemistry), vital signs, ECHO and 12-lead ECGs. Clinical laboratory results will be listed by patient and, as appropriate, summarized descriptively, which will include a display of change from baseline. Selected parameters will be presented in shift tables of baseline against worst grade test result. Laboratory values outside of the normal ranges will be identified. Laboratory values that meet Grade 3 or 4 criteria according to NCI CTCAE v.4.03 will be listed and summarized. ECG assessments will be evaluated for change of QTc from baseline as an exposure:
response analysis. The Investigator's interpretation of QTc will be used in the clinical management of patients. The study analysis will use Fridericia's formula applied programmatically to the ECG data collected in CRFs. Vital signs, ECHO and ECG measurements will be listed for each patient at each visit. Descriptive statistics of observed values and changes from baseline will be summarized by treatment group.
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9.5.4 patient demographics baseline characteristics

Presentations of patient characteristics will include a summary of the following for all patients enrolling in the study:
Demographics Baseline disease characteristics Pre-existing conditions/concurrent illness Prior therapies/surgeries A summary of patient enrollment and disposition will include reasons for study discontinuation.
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9.5.5 analysis of study treatment

Study treatment administration will be described in terms of the total number of cycles administered, the median (range) of cycles administered for each agent separately and for the combination, dose intensity, and reasons for the deviations from planned therapy.
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9.6 other study endpoints 9.6.1

The PK sparse exposure data from this study may be used in the development of population PK and PK/PD models for each investigational agent. Pharmacokinetic parameters will be determined, listed, and summarized for the PK evaluable population in the Pharmacokinetic Analysis Plan (PKAP). Only samples with acceptable PK (as defined in the PKAP) will be included in the summary statistics and a listing of individual data points or patients excluded from the analysis will be presented. Plasma concentrations will be listed by patient for the PK Population. Summary statistics of investigational agent concentrations will be reported by dose level, Day and Cycle. The exposure levels as well as the PK parameters of the investigational drugs reported in earlier studies will be compared to the current study PK exposure and parameters to evaluate the potential effect of nivolumab on investigation drugs' PK. Details of this analysis will be provided in the PKAP. Possible relationships between PK parameters, PD variables, safety, and clinical activity may be examined.
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9.6.2 pharmacodynamic and exploratory analyses

9.7 **Interim Analysis**  
  
No interim statistical analysis is planned during this study.