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4.8 management of adverse events

Immuno-oncology agents are associated with AEs that can differ in severity and duration compared to AEs caused by other therapeutic classes. APX005M, cabiralizumab and nivolumab are considered immuno-oncology agents in this protocol. Early recognition and management of AEs associated with immuno-oncology agents may mitigate severe toxicity. Subjects should receive appropriate supportive care measures as deemed necessary by the treating Investigator.  
Suggested supportive care measures for the management of AEs with potential immunologic etiology are outlined below. These treatment guidelines are intended to be applied when the Investigator determines the events to be related to the APX005M + cabiralizumab ± nivolumab combination and should not substitute for investigational product dose delays and/or modifications. Additional guidance for management of AEs with potential immunologic etiology is provided in the APX005M, cabiralizumab and nivolumab Investigator's Brochures. If after evaluation the event is determined by the Investigator not to be related to investigational products, the Investigator does not need to follow the treatment guidance outlined in this section. For each disorder, attempts should be made to rule out other causes such as metastatic disease, or bacterial/viral infection, which might require additional supportive care. Steroid tapering may be necessary for prolonged exposures to corticosteroids, or if symptoms worsen when the corticosteroid dose is decreased.
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diarrhea/colitis

Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis.  
- **Grade 1-2:** for subjects developing Grade 1–2 diarrhea loperamide (2 mg every 2 hours)
is strongly recommended at the first onset of symptoms. For subjects with persistent diarrhea despite the use of loperamide (>7 days or recurrent) or Grade 2 colitis, the use of oral corticosteroids (0.5–1 mg/kg/day methylprednisolone or oral equivalent) is recommended. Other antidiarrheal agents (e.g. octreotide) may be used if necessary. When symptoms improve to Grade 1, steroids may be tapered as deemed appropriate by the investigator. If steroids are administered for over weeks, consider prophylactic antibiotics for opportunistic infections. If symptoms worsen or persist >5 days despite steroids treatment, treat as grade 3-4.  
- **Grade 3-4:** treat with corticosteroids (1–2 mg/kg/day methylprednisolone or IV
equivalent) followed by oral corticosteroids until symptoms improve to Grade 1 or less. Add prophylactic antibiotics for opportunistic infections and consider lower endoscopy. If persist or recurs continuously after improvement, consider infliximab 5mg/kg (unless sepsis or perforation is detected).
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creatinine elevation

- **Grade 2-3:** treat with corticosteroids (0.5–1 mg/kg/day methylprednisolone or oral equivalent) until symptoms improve to Grade 1 or less. Consider renal biopsy with nephrology consult. If persist > 14 days treat as grade 4.  
- **Grade 4:** treat with corticosteroids (1–2 mg/kg/day methylprednisolone or IV equivalent)
followed by oral corticosteroids until symptoms improve to Grade 1 or less. Consider renal biopsy and consult nephrologist. Add prophylactic antibiotics for opportunistic infections. If worsen consider clinical referrals as needed.
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pneumonitis

- **Grade 2:** Treat with IV or oral corticosteroids until symptoms improve to Grade 1 or less. Consider prophylactic antibiotics for opportunistic infection. Consider bronchoscopy, lung biopsy and hospitalization. If does not improve after 2 weeks treat as grade 3-4.  
- **Grade 3-4:** Consider pulmonary or infectious disease consults. Hospitalize and treat immediately with IV corticosteroids (2–4 mg/kg/day methylprednisolone or IV equivalent). Add prophylactic antibiotics for opportunistic infections. Consider bronchoscopy and lung biopsy. If does not improve after 48h or worsens, add additional anti-inflammatory measures (e.g. cyclosporine, IVIG, mycophenolate mofetil)
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liver function tests

- **Grade 3 transaminitis:** Monitor liver function tests more frequently until returned to Grade 2 or less. Start oral or IV corticosteroids if transaminitis > 5 to ≤ 12x ULN persists for > 7 days. Continue steroids until returns to Grade 1 or less. If the first transaminase value is 12X ULN or greater, start steroids immediately.
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- grade 4 alt and/or

corticosteroids for 24-48 hours followed by oral corticosteroids until improvement to Grade 1 or less. If worsening in 3-5 days, administer additional immunosuppressive measures (e.g. mycophenolate mofetil), as needed. Consider adding prophylactic antibiotics for opportunistic infections. Consult gastroenterologist.
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- grade >=2 transaminitis (>3x

corticosteroids (1–2 mg/kg/day methylprednisolone or IV equivalent) followed by oral corticosteroids. Consider adding prophylactic antibiotics for opportunistic infections. Consult gastroenterologist. Continue steroids until symptoms improve to Grade 1 or less. If worsening in 3-5 days, add mycophenolate mofetil 1g BID. If no improvement consider additional immunosuppressive measures per local guidelines.
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endocrinopathy

- **Asymptomatic TSH elevation:** monitor fT4 if TSH is <0.5 x LLN, > 2 x ULN or consistently out of range in two subsequent measurements.  
Symptomatic endocrinopathy: evaluate endocrine function. For abnormal laboratory results initiate hormone repletion.  
- Suspicion of adrenal **crisis:** rule out sepsis, administer IV fluids, treat as for symptomatic endocrinopathy. Otherwise, administer stress dose of IV steroids with mineralocorticoid activity.
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skin adverse events.

- **Grade 1-2:** symptomatic treatment (e.g. antihistamines, topical steroids). If unresponsive, consider steroid burst. If worsens treat as grade 3-4.  
- **Grade 3-4:** Consider skin biopsy. Treat with steroids as deemed appropriate by the treating physician (1–2 mg/kg/day methylprednisolone or IV equivalent).
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infusion reaction/cytokine release syndrome

Precautions should be observed during the administration of APX005M, nivolumab and cabiralizumab. Emergency agents including oxygen, oral and endotracheal airways, intubation equipment epinephrine, antihistamines, and corticosteroids should be available and used if required at the Investigator's discretion.  
Subjects should be instructed that symptoms associated with cytokine release syndrome/infusion reaction can occur within 48 hours following the administration of the investigational products, and if such symptoms develop while they are at home, they should contact the Investigator and/or seek emergency medical care if appropriate.  
- **Grade 1:** decrease infusion rate as per protocol
- **Grade 2:** Stop infusion and treat symptoms following guidelines in Table 4. If symptoms resolve within two hours, the infusion may be restarted at 50% of the original infusion rate (e.g., from 100 mL/hr to 50 mL/hr).  
- **Grade 3-4:** stop infusion and treat symptoms following guidance in Table 4. If subjects resume study treatment after previously having a grade 3 infusion-related reaction and/or cytokine release syndrome, a 48-hour inpatient observation period is mandatory after the infusion to perform frequent vital sign checks. If grade > 3 infusion-related reaction/cytokine release syndrome does not recur upon rechallenge, further cycles may be administered in the outpatient setting.  
| Suspected Cytokine Release/Infusion-related                                                                              | Recommended Treatment                                                                       |                          |
|--------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|--------------------------|
| Toxicity - Mild toxicity requiring symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgia, malaise) | -                                                                                           | Vigilant supportive care |
| -                                                                                                                        | Maintain adequate hydration                                                                 |                          |
| -                                                                                                                        | Antipyretics, non-steroidal antiinflammatory drugs,  antihistamines, anti-emetics, analgesics as needed                                                                                             |                          |
| -                                                                                                                        | In case of mild symptoms persisting for > 24 hours assess for infections; empiric treatment |                          |
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table 4 guidelines for management

| of concurrent bacterial infections   |                                                                                                                                                                                                                                                           |    |                  |
|--------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|------------------|
| -                                    | Symptoms or clinical findings requiring and responding to moderate intervention, such as: o O2 requirement < 40% o Hypotension responsive to fluids ± low dose of  one vasopressor (e.g., < 50 mg/min phenylephrine)  o CTCAE v5.0 Grade 2 organ toxicity | -  | All of the above |
| -                                    | Monitor cardiac and other organ  functions closely                                                                                                                                                                                                        |    |                  |
| -                                    | Corticosteroids if not resolving  with measures above                                                                                                                                                                                                     |    |                  |
| -                                    | All of the above                                                                                                                                                                                                                                          |    |                  |
| -                                    | Monitor cardiac and other organ  functions closely                                                                                                                                                                                                        |    |                  |
| -                                    | Corticosteroids if not resolving  with measures above                                                                                                                                                                                                     |    |                  |
| -                                    | Tocilizumab if not responsive to steroids and other measures                                                                                                                                                                                              |    |                  |
| -                                    | Symptoms or clinical findings requiring aggressive intervention, such as: o O2 requirement ≥ 40% o Hypotension requiring high dose or multiple vasopressors  o Ventilator support required                                                                |    |                  |
| -                                    | CTCAE v5.0 Grade ≥3 organ toxicity                                                                                                                                                                                                                        |    |                  |
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neurological toxicity

- **Grade 2:** symptomatic treatment per local guidelines. Consider steroids (0.5–1 mg/kg/day methylprednisolone or PO equivalent). If worsen treat as grade 3-4.  
- **Grade 3-4 or grade 2 for >28 days:** obtain neurological consult and treat symptoms per local guidelines. Administer corticosteroids (1–2 mg/kg/day methylprednisolone or IV equivalent). Add prophylactic antibiotics for opportunistic infections. Continue steroids until symptoms improve to Grade 2 or less. If symptoms worsen or for atypical presentation consider IVIG, high doses steroids (e.g. 1g methylprednisolone) or other immunosuppressive measures per local guidelines.
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periorbital edema - grade 1

- **Grade 2-4:** Consider IV or oral corticosteroids until symptoms improve to Grade 1 or less. Consider adding eye drops, or analgesics as needed. Seek ophthalmologic consult if needed.
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uveitis

- **Grade 1:** Watch for worsening of symptoms including visual disturbances, light sensitivity, decrease vision, monitor weekly.  
- **Grade 2-4:** Treat with IV or oral corticosteroids until symptoms improve to Grade 1 or less. Consider additional immunosuppressive agents if not responsive (such as infliximab). Consider adding prophylactic antibiotics for opportunistic infections and seek ophthalmologic consult.
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ck increase

- **CK > 10x ULN:** Consider measuring CK isoenzymes as clinically indicated. If CK
isoenzymes are abnormal consider measuring troponin levels and other assessments (including uromyoglobin) as clinically indicated. If CK isoenzymes are normal monitor CK level as clinically indicated.  
- **CK > 15x ULN:** If clinically indicated, measure CK isoenzymes and test more frequently until returned to Grade 2. If CK isoenzyme panel is normal continue monitoring the subject. If CK isoenzyme panel is abnormal then consider measuring troponins.
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4.9 criteria for holding discontinuing

Management of suspected adverse drug reactions may require temporary treatment hold (until retreatment criteria are met), reducing the dose of APX005M, or discontinuation of some or all investigational products as per Table 5. If a subject experiences several toxicities, the recommended dose modification should be based on the highest grade toxicity. Up to two dose reductions are permitted for APX005M. There are no dose reductions for cabiralizumab or nivolumab.  
| Toxicity             | Grade                                                        | APX005M                                                      | Cabiralizumab                    | Nivolumab                        |              |
|----------------------|--------------------------------------------------------------|--------------------------------------------------------------|----------------------------------|----------------------------------|--------------|
| Hold                 | Hold                                                         |                                                              |                                  |                                  |              |
| 1st occurrence: Hold |                                                              |                                                              |                                  |                                  |              |
| Gastrointestinal AEs | If not improving  in 28 days with oral steroids: Discontinue | If not improving  in 28 days with oral steroids: Discontinue |                                  |                                  |              |
| 2-3                  |                                                              |                                                              |                                  |                                  |              |
| Diarrhea/colitis     | 2n d occurrence: dose reduction¥                             |                                                              |                                  |                                  |              |
| 4                    | Discontinue                                                  | Discontinue                                                  | Discontinue                      |                                  |              |
| Vomiting             | 2-4                                                          | Hold                                                         | Hold                             | Hold                             |              |
| Endocrine AEs        | Hypophysitis/  Endocrinopathies                              | 2-4                                                          | Hold only if clinically unstable | Hold only if clinically unstable | Hold only if |
| clinically unstable  |                                                              |                                                              |                                  |                                  |              |
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table 5 criteria for holding

| Toxicity                                                                       | Grade                                                                                                                                   | APX005M             | Cabiralizumab                    | Nivolumab                        |
|--------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|---------------------|----------------------------------|----------------------------------|
| Hold only if                                                                   |                                                                                                                                         |                     |                                  |                                  |
| Hyperthyroidism                                                                | 2-4                                                                                                                                     | clinically unstable | Hold only if clinically unstable | Hold only if clinically unstable |
| 3                                                                              |                                                                                                                                         |                     |                                  |                                  |
| (> 5 to ≤ 12x ULN)  and bilirubin <2x ULN                                      | Continue                                                                                                                                | Continue            | Continue                         |                                  |
| 3 (> 12x  ULN) for                                                             |                                                                                                                                         |                     |                                  |                                  |
| >14 days and  not  decreasing on  steroids and bilirubin <2x ULN               | Hold                                                                                                                                    | Hold                | Hold                             |                                  |
| Increased AST/ALT                                                              | 2-3 and total bilirubin >2x ULN or  3x baseline  for patients with Gilbert's syndrome and no  cholestasis or INR >1.5  not on  warfarin |                     |                                  |                                  |
| Hepatic AEs                                                                    | Discontinue                                                                                                                             | Discontinue         | Discontinue                      |                                  |
| 4                                                                              | Discontinue                                                                                                                             | Discontinue         | Discontinue                      |                                  |
| 2                                                                              | Hold                                                                                                                                    | Hold                | Hold                             |                                  |
| Hold                                                                           | Hold                                                                                                                                    | Hold                |                                  |                                  |
| If >48 hours  with no  cholestasis or  > 5 days with cholestasis:  Discontinue | If >48 hours  with no                                                                                                                   |                     |                                  |                                  |
| cholestasis or >  5 days with cholestasis: Discontinue                         | If >48 hours  with no                                                                                                                   |                     |                                  |                                  |
| cholestasis or >  5 days with cholestasis: Discontinue                         |                                                                                                                                         |                     |                                  |                                  |
| Increased bilirubin                                                            | 3  4                                                                                                                                    | Discontinue         | Discontinue                      | Discontinue                      |
| Page 76 of 135                                                                 | Confidential                                                                                                                            |                     |                                  |                                  |  
| CA025-007 Clinical Protocol                              | Version 10                                | 21-Mar-2022                               |                                           |               |
|----------------------------------------------------------|-------------------------------------------|-------------------------------------------|-------------------------------------------|---------------|
| Toxicity                                                 | Grade                                     | APX005M                                   | Cabiralizumab                             | Nivolumab     |
| Hold                                                     | Hold                                      | Hold                                      |                                           |               |
| 3                                                        | If not improving in 28 days:  Discontinue | If not improving  in 28 days: Discontinue | If not improving  in 28 days: Discontinue |               |
| Skin AEs                                                 | Rash or other skin  toxicity              | Hold                                      | Hold                                      |               |
| 4                                                        | If not improving in 28 days:  Discontinue | If not improving in 28 days:  Discontinue | Discontinue                               |               |
| 2                                                        | Continue                                  | Continue                                  | Hold                                      |               |
| Neurological AEs                                         | Neurological Toxicity                     | 1st occurrence: Hold                      |                                           |               |
| 3                                                        | Hold                                      | Hold                                      | 2nd occurrence: Discontinue               |               |
| 4                                                        | Hold                                      | Hold                                      | Discontinue  Administer additional        |               |
| premedication  and increase the  infusion time to 60 min |                                           |                                           |                                           |               |
| Administer additional                                    |                                           |                                           |                                           |               |
| premedication.  Increase infusion  time to 90 min        | Administer additional                     |                                           |                                           |               |
| premedication.  Increase infusion time to 60 min         |                                           |                                           |                                           |               |
| 1-2                                                      |                                           |                                           |                                           |               |
| Infusion Reaction/ Cytokine Release Syndrome             | Nivolumab                                 |                                           |                                           |               |
| infusion reaction                                        | Hold. Re                                           |                                           |                                           |               |
| challenge with                                           |                                           |                                           |                                           |               |
| nivolumab must be  discussed with  study PI              |                                           |                                           |                                           |               |
| 3                                                        | Hold                                      | Hold                                      |                                           |               |
| 4                                                        | Discontinue                               | Discontinue                               | Discontinue                               |               |
| Administer additional                                    |                                           |                                           |                                           |               |
| premedication.  Increase infusion  time to 90 min        | Administer additional                     |                                           |                                           |               |
| premedication.  Increase infusion time to 60 min         |                                           |                                           |                                           |               |
| 1-2                                                      | Already given                             |                                           |                                           |               |
| Cabiralizumab infusion reaction                          | 3                                         | Hold                                      | Discontinue                               | Already given |
| 4                                                        | Discontinue                               | Discontinue                               | Discontinue                               |               |  
| CA025-007 Clinical Protocol                         | Version 10                | 21-Mar-2022           |                                                                                                                                                                                             |                                                                                        |
|-----------------------------------------------------|---------------------------|-----------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|
| Administer  additional                              |                           |                       |                                                                                                                                                                                             |                                                                                        |
| premedication.  Increase  infusion time to  90 min* | Already given             | Already given         |                                                                                                                                                                                             |                                                                                        |
| 1-2                                                 |                           |                       |                                                                                                                                                                                             |                                                                                        |
| APX005M infusion reaction/                          | Hold and dose reduce¥ for | Already given         | Already given                                                                                                                                                                               |                                                                                        |
| next cycle                                          |                           |                       |                                                                                                                                                                                             |                                                                                        |
| 3                                                   |                           |                       |                                                                                                                                                                                             |                                                                                        |
| cytokine release syndrome                           | 4                         | Discontinue           | Discontinue                                                                                                                                                                                 | Discontinue                                                                            |
| 1st occurrence: Hold                                | 1st occurrence: Hold      | 1st occurrence:  Hold |                                                                                                                                                                                             |                                                                                        |
| Pulmonary AEs                                       | Pneumonitis               | 2-3                   | 2nd occurrence or  if not improving  in 14 days:  Discontinue  2nd occurrence or  if not improving  in 14 days:  Discontinue  2nd occurrence or if  not improving in  14 days:  Discontinue |                                                                                        |
| 4                                                   | Discontinue               | Discontinue           | Discontinue                                                                                                                                                                                 |                                                                                        |
| Hold                                                | Hold                      | Hold                  |                                                                                                                                                                                             |                                                                                        |
| Renal AEs                                           | Creatinine Elevation      | 2-3                   | If not improving in 21 days: Discontinue                                                                                                                                                    | If not improving  in 21 days:  Discontinue  If not improving in  21 days:  Discontinue |
| 4                                                   | Discontinue               | Discontinue           | Discontinue                                                                                                                                                                                 |                                                                                        |
| Systemic AEs                                        | Fatigue                   | 3                     | Hold.                                                                                                                                                                                       |                                                                                        |
| Consider dose                                       |                           |                       |                                                                                                                                                                                             |                                                                                        |
| reduction for next  cycle                           | Hold                      | Hold                  |                                                                                                                                                                                             |                                                                                        |  
| CA025-007 Clinical Protocol                                                                                              | Version 10                                 | 21-Mar-2022                                                                            |                        |             |
|--------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|----------------------------------------------------------------------------------------|------------------------|-------------|
| Toxicity                                                                                                                 | Grade                                      | APX005M                                                                                | Cabiralizumab          | Nivolumab   |
| Neutropenia                                                                                                              | 4                                          | Hold                                                                                   | Hold                   | Hold        |
| Hematologic AEs                                                                                                          | Febrile                                    |                                                                                        |                        |             |
| Neutropenia                                                                                                              | 3-4                                        | Hold                                                                                   | Hold                   | Hold        |
| 2-3                                                                                                                      | Hold                                       | Continue                                                                               | Continue               |             |
| 3 with                                                                                                                   |                                            |                                                                                        |                        |             |
| significant  bleeding or  transfusion or  4                                                                              |                                            |                                                                                        |                        |             |
| Thrombocytopenia                                                                                                         | Hold.                                      |                                                                                        |                        |             |
| Dose reduction¥                                                                                                          | Hold                                       | Hold                                                                                   |                        |             |
| Hold at                                                                                                                  |                                            |                                                                                        |                        |             |
| discretion of  treating  investigator                                                                                    |                                            |                                                                                        |                        |             |
| 2-3                                                                                                                      | Continue                                   |                                                                                        |                        |             |
| Periorbital edema                                                                                                        | Continue                                   |                                                                                        |                        |             |
| Ocular AEs                                                                                                               | 4                                          | Continue                                                                               | Discontinue            | Continue    |
| Hold                                                                                                                     | Hold                                       | Hold                                                                                   |                        |             |
| 2                                                                                                                        |                                            |                                                                                        |                        |             |
| Uveitis                                                                                                                  | If not improving  in 28 days:  Discontinue | If not improving  in 28 days:  Discontinue  If not improving in  28 days:  Discontinue |                        |             |
| 3-4                                                                                                                      | Discontinue                                | Discontinue                                                                            | Discontinue            |             |
| Laboratory AEs CK increase without  clinical or  laboratory evidence  of myocarditis or  myositis 4 (> 15 to <  20x ULN) | Continue                                   | Hold until returns  to < 15x ULN                                                       | Continue               |             |
| 4 (>20x ULN)                                                                                                             | Resume once <  10x ULN                     | Discontinue                                                                            | Resume once <  10x ULN |             |
| 3 or Severe                                                                                                              | Hold                                       | Hold                                                                                   | Hold                   |             |
| Toxicity All Other DrugRelated                                                                                                                          | 4                                          | Discontinue                                                                            | Discontinue            | Discontinue |
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4.10 dose reduction

Dose reduction for nivolumab and cabiralizumab are not permitted. Dose reduction for APX005M is permitted as below and as per Section 4.8 and Section 4.9.
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y=apx005m dose reductions

10 21-Mar-2022  
| Dose Level            | DL1            | DL2   | DL3   |
|-----------------------|----------------|-------|-------|
| (mg/kg)               | (0.03)         | (0.1) | (0.3) |
| First Dose Reduction  | 0.01           | 0.06  | 0.2   |
| Second Dose Reduction | Not applicable | 0.03  | 0.1   |
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4.11 treatment discontinuation criteria

Subjects *must* discontinue receiving investigational products for any of the following reasons:
- Withdrawal of informed consent (patient's decision to withdraw for any reason)  
- Toxicity requiring discontinuation of all investigational products as outlined in the dose modification guidelines
- Any clinically significant AE, abnormal laboratory test results, or intercurrent illness which, in the opinion of the Investigator, indicates that continued participation in the study is not in the best interest of the patient
- Failure to recover from a disease or treatment-related AE to baseline or ≤ Grade 1 within 12 weeks of last dose of investigational product (except Grade 2 alopecia and Grade 2 fatigue), unless the subject is benefiting from therapy and after discussion with and approval by the PI
- Failure to recover within 4 weeks of last dose of investigational product if AE is related to infusion reaction/cytokine release
- Inability to reduce corticosteroid to 10 mg or less of prednisone or equivalent per day within 12 weeks of last dose of investigational product
- Patients who are required to have prohibited concomitant medications - Pregnancy - Termination of the study by the Sponsor - Loss of ability to freely provide consent through imprisonment or involuntary incarceration for treatment of a psychiatric or physical (e.g., infectious disease) illness
- Documented disease progression or clinical deterioration while receiving active study therapy
- Requirement for alternative therapy - Non-compliance with study procedures, including use of prohibited medications - Subject is lost to follow-up
- Death For comprehensive discontinuation rules, refer to the Table 5 in Section 4.4. The PI can be contacted at any time if further clarification is needed. Other treatment discontinuation not specifically listed in Table 5 (Section 4.4) may include:  
- Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires discontinuation, with the following exceptions: - Dosing delays to manage drug-related adverse events are allowed for up to 12 weeks between doses. Prior to re-initiating treatment in a patient with a dosing delay lasting
> 6 weeks from the previous dose, the PI must be consulted. Tumor assessments should continue as per-protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory studies should also continue per protocol, or more frequently if clinically indicated during such dosing delays or per the Investigator's discretion.  
- Dosing delays lasting > 6 weeks from the previous dose that occur for non-drugrelated reasons may be allowed if approved by the PI. Prior to re-initiating treatment in a patient with a dosing delay lasting > 6 weeks, the PI must be consulted. Tumor assessments should continue per protocol every 8 weeks for the first 4 months and every 12 weeks (±7 days) thereafter, even if dosing is delayed. Periodic study visits to assess safety and laboratory studies should also continue per-protocol or more frequently if clinically indicated during such dosing delays or per the Investigator's discretion.  
- Any AE, laboratory abnormality, or intercurrent illness which, in the opinion of the Investigator, presents a substantial clinical risk to the patient with continued APX005M, cabiralizumab and/or nivolumab dosing.
All patients who discontinue study treatment should comply with protocol specified followup procedures as outlined in Section 5. The only exception to this requirement is when a patient withdraws consent for all study procedures or loses the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of a psychiatric or physical illness).  
If a patient was discontinued, the reason for discontinuation must be entered on the appropriate CRF. The date and reason for cessation of nivolumab, cabiralizumab, and APX005M will be documented, and the Investigator must make every effort to perform the End-of-Treatment Visits. Adverse event reporting will continue until 100 (±7) days after the last dose of study drug or until initiation of subsequent anti-cancer therapy. Patients with ongoing SAEs will be followed until resolution or stabilization.
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4.12 infusion delays and missed

In case an infusion cannot be administered at a scheduled visit, it must be administered as soon as possible. If the delay is more than two days, the infusion at the originally scheduled visit will be considered a missed dose and the procedures at the next visit should be performed. There must be at least 12 days between study drug administration.
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4.13 treatment beyond progression

Accumulating evidence indicates a minority of patients treated with immunotherapy may derive clinical benefit despite initial evidence of progressive disease [60]. Patients treated with nivolumab, cabiralizumab and APX005M combination therapy will be permitted to continue treatment beyond initial RECIST v1.1 defined progressive disease, assessed by the Investigator, as long as the following criteria are met:  
- Patients who will be treated beyond disease progression must review and sign an ICF
before continuing on study drug
- The patient demonstrates investigator-assessed clinical benefit, and do not have rapid disease progression
- Tolerance of study drugs - No decline in current ECOG performance status - Treatment beyond progression will not delay an imminent intervention to prevent serious complications of disease progression (e.g., CNS metastases)
- Absence of signs, symptoms, and worsening laboratory values that would indicate rapid disease progression
A radiographic assessment/scan should be performed approximately 8 weeks (±7 days) after initial Investigator-assessed progression to determine whether there has been a decrease in the tumor size or continued progressive disease. The assessment of clinical benefit should be balanced by clinical judgment as to whether the patient is clinically deteriorating and unlikely to receive any benefit from continued treatment with investigational products.  
If the Investigator feels that any patient receiving nivolumab, cabiralizumab and APX005M will obtain clinical benefit by continuing treatment, the patient may remain on the trial and continue to receive monitoring according to the time and event schedules per protocol. For the patients who continue nivolumab, cabiralizumab and APX005M study therapy beyond progression, further progression is defined as an additional 10% increase in tumor burden from time of initial progression. This includes an increase in the sum of diameters of all target lesions and/or the diameters of new measurable lesions compared to the time of initial progression. APX005M, cabiralizumab and nivolumab treatment should be discontinued permanently upon documentation of further progression.
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4.14 treatment compliance

Study drug will be administered by qualified trained site personnel in the clinical facility. The Investigator or their designated study personnel will maintain a log (Drug Accountability Log) of all study drugs received dispensed and destroyed. The Investigator and the study personnel will ensure that each patient receives the calculated dose of the study drug based on body weight.  
Drug supplies will be inventoried and accounted for throughout the study. The Drug Accountability Log will be reviewed by the PI during site visits and at the completion of the study. Any discrepancy should be brought to the attention of the Sponsor. Records of study medication administration (date, start and stop time, and dose administered relative to time of preparation) will be recorded on the patient's CRF.
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4.15 destruction of study drug

Any unused study drugs can only be destroyed on site after being inspected and reconciled by the responsible site monitor unless study drug vials must be immediately destroyed as required for safety, or to meet local regulations (e.g., cytotoxics or biologics).  
- On-site destruction is allowed provided the following minimal standards are met:  
- On-site disposal practices must not expose humans to risks from the drug. - On-site disposal practices and procedures are in agreement with applicable laws and regulations, including any special requirements for controlled or hazardous substances.  
- Written procedures for on-site disposal are available and followed. The procedures must be filed with the site's Standard Operating Procedures (SOPs) and a copy provided to the Sponsor upon request.  
- Records are maintained that allow for traceability of each vial, including the date disposed of, quantity disposed, and identification of the person disposing of the containers. The method of disposal (i.e., incinerator, licensed sanitary landfill, or licensed waste disposal vendor) must also be documented.  
- Accountability and disposal records are complete, up-to-date, and available for the PI to review throughout the clinical trial period.
If conditions for destruction cannot be met, the responsible PI will make arrangements for return of study drug (Section 4.16). It is the Investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local, and institutional guidelines and procedures and provided that appropriate records of disposal are kept.
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4.16 return of study drug

If study drug will not be destroyed on site upon completion or termination of the study, all unused and/or partially used study drug that was supplied must be returned. The return of study drug will be arranged by the responsible PI.
list of key study personnel
5. study assessments and procedures

The schedule of assessment tables are attached to the protocol as Appendix A, Appendix B, and Appendix C.
list of key study personnel
5.2 study procedures by visit

Patients who have fully consented to participation in the study will undergo screening assessments within 28 days (4 weeks) prior to administration of the first infusion of APX005M, cabiralizumab, and/or nivolumab (unless otherwise stated). To determine if the patient meets all inclusion criteria and does not violate any exclusion criteria, the following procedures will be performed (Appendix A).  
- Written, signed informed consent must be collected prior to any study-specific procedures  
- Collection of a formalin fixed, paraffin-embedded (FFPE) tissue block and/or a fresh tumor biopsy from an accessible site will be mandatory, unless the Investigator deems that the subject does not have tumor in a site amenable to biopsy. Tumor biopsy collection will be performed at least 24 hours prior to dosing (as in Appendix D).  
- Complete medical and disease history
- Demographic and baseline characteristics
- Complete physical examination including height and weight
- Vital signs (blood pressure, pulse, respiratory rate, and temperature in resting position after 5 minutes rest)
- Photo of periorbital region - ECOG performance status evaluation
- Screening labs (as described in Appendix A)
- Clinical safety labs (as described in Appendix A) - 12-lead ECG (required at screening, and if clinically indicated during the study)  
- Radiological imaging: After determining progression on an anti-PD-1/PD-L1 agent, body imaging of disease sites with PET CT, CT scans, and/or MRI is to be performed within 28 days prior to Cycle 1 Day 1. MRI brain is also to be performed within 28 days prior to C1D1. If the Investigator deems that MRI of the brain cannot be performed, CT Head with and without intravenous contrast is acceptable. If the imaging is performed as part of the patient's standard of care is within 28 days of Cycle 1 Day 1, it does not need to be
repeated if the documentation of results is provided and is adequate for RECIST v1.1.  
- Serum pregnancy test (β-hCG) for women of childbearing potential within 7 days of Cycle 1 Day 1
- SAE reporting, if applicable
- Document prior and concomitant medications
list of key study personnel
5.2.1.2 cycle 1 day 1

The following procedures will be performed:
- Prior to study drug infusion infusion (within ≤72 hours unless otherwise stated):  
- Verification of eligibility - Update medical and disease history to capture any changes from screening - Physical examination including weight - Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- ECOG performance status evaluation - Clinical safety labs (as described in Appendix A; results must be reviewed before dosing)
- Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of dosing
- Blood collection for:
Biomarker blood sample collection (analyses described in Appendix D) Serum PK (for APX005M only)
- pre-infusion (APX005M)  
- end of infusion (APX005M)
- if possible, 4 hours (±30 minutes) from start of infusion (APX005M)
Pre-treatment serum anti-drug antibody (ADA) levels (for APX005M only),
Cycle 1 Day 1 and Day 1 of every 3rd cycle (Cycles 3, 6, 9, 12, etc.)  
- AE reporting, if applicable
- Review of concomitant medications
- Study drug administration  
- Pre- and post-study each drug administration:
Vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting position after 5 minutes rest)
Additional post-dose vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting position after 5 minutes rest) at 4 hours (+ 30 minutes)
list of key study personnel
post-apx005m infusion

- 4 hour post-dose vital sign criteria for discharge include:
Systolic BP no more than 30 mmHg below baseline Oxygen saturation > 90%
Heart rate no more than 30 beats per minute above baseline, unless febrile If febrile, subjects can be discharged home as long as their temperature is less than 101 degrees Fahrenheit Patients must remain near the vicinity of a hospital with rapid access to an intensive care unit setting during the initial 48 hour period after treatment.
list of key study personnel
5.2.1.3 cycle 1 day 2

Patients will return to the study center on Day 2 for 24-hour (± 6 hours) post-dose assessments. No treatment will be administered during this visit, but the following assessments will be completed:
- Physical examination (focused, symptom-based exam)  
- Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- Clinical safety labs (as described in Appendix A) - Blood collection for:
- Biomarker blood sample collection (analyses described in Appendix D)  
- Serum PK at 24 hours (+ 6 hours) from the start of infusion (APX005M)
- AE reporting, if applicable - Review of concomitant medications
list of key study personnel
5.2.1.4 cycle 1 day 3

Patients will return to the study center on Day 3 for 48-hour (± 6 hours) post-dose assessments. No treatment will be administered during this visit, but the following assessments will be completed:
- Physical examination (focused, symptom-based exam)  
- Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- Blood collection for:
- Biomarker blood sample collection (analyses described in Appendix D) - Serum PK at 48 hours (+ 6 hours) from the start of infusion (APX005M)
- AE reporting, if applicable  
- Review of concomitant medications
list of key study personnel
5.2.1.5 cycle 1 day 8

Patients will return to the study center on Day 8 for post-dose assessments. No treatment will be administered during this visit, but the following assessments will be completed:  
- Physical Exam (focused, symptom-based exam) - Vital Signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- Clinical Safety Labs (as described in Appendix A)
- Blood collection for:
- Biomarker blood sample collection (as described in Appendix D) - Serum PK at 168 hours (+ 6 hours) from the start of infusion (APX005M)
- AE reporting, if applicable - Review of concomitant medications
list of key study personnel
5.2.1.6 cycle 2 day 1

The following procedures will be performed:
- Prior to study drug infusion infusion (within ≤72 hours unless otherwise stated):  
- Physical examination including weight - Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- ECOG performance status evaluation - Clinical safety labs (as described in Appendix A; results must be reviewed before dosing)
- Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of dosing
- Blood collection for:
Biomarker blood sample collection (analyses described in Appendix D)
Serum PK (for APX005M only)
- pre-infusion (APX005M) - end of infusion (APX005M) - if possible, 4 hours (±30 minutes) from the start of infusion (APX005M)
- AE reporting, if applicable
- Review of concomitant medications  
- Study drug administration
- Pre- and post-study each drug administration:
Vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting position after 5 minutes rest)
Additional post-dose vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting position after 5 minutes rest) at 4 hours (+ 30 minutes) post-APX005M infusion
- 4 hour post-dose vital sign criteria for discharge include:
Systolic BP no more than 30 mmHg below baseline Oxygen saturation > 90%
Heart rate no more than 30 beats per minute above baseline, unless febrile If febrile, subjects can be discharged home as long as their temperature is less than 101 degrees Fahrenheit Patients must remain near the vicinity of a hospital with rapid access to an intensive care unit setting during the initial 48 hour period after treatment.
list of key study personnel
5.2.1.7 cycle 2 day 2

Patients will return to the study center on Day 2 for 24-hour (± 6 hours) post-dose assessments. No treatment will be administered during this visit, but the following assessments will be completed:
- Physical examination (focused, symptom-based exam)  
- Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- Clinical safety labs (as described in Appendix A) - Blood collection for:
- Biomarker blood sample collection (analyses described in Appendix D) - Serum PK at 24 hours (+ 6 hours) from start of infusion (APX005M)
- AE reporting, if applicable - Review of concomitant medications
list of key study personnel
5.2.1.8 cycle 2 day 3

Patients will return to the study center on Day 3 for 48-hour (± 6 hours) post-dose assessments. No treatment will be administered during this visit, but the following assessments will be completed:
- Physical examination (focused, symptom-based exam)  
- Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- Blood collection for:
- Biomarker blood sample collection (analyses described in Appendix D) - Serum PK at 48 hours (+ 6 hours) from the start of infusion (APX005M)
- AE reporting, if applicable - Review of concomitant medications
list of key study personnel
5.2.1.9 cycle 2 day 8

Patients will return to the study center on Day 8 for post-dose assessments. No treatment will be administered during this visit, but the following assessments will be completed:
- Physical Exam (focused, symptom-based exam)  
- Vital Signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- Clinical Safety Labs (as described in Appendix A) - Blood collection for:
- Biomarker blood sample collection (as described in Appendix D) - Serum PK at 168 hours (+ 6 hours) from start of infusion (APX005M)
- AE reporting, if applicable - Review of concomitant medications
list of key study personnel
5.2.1.10 subsequent cycles day 1

A ± 2 day window is allowed for Day 1 in subsequent cycles post Cycle 2, Day 1. Dosing will be discontinued if the patient experiences either disease progression or unacceptable toxicity. At each infusion visit, patients are to remain at the study site after each administration of APX005M until completion of all post-dose assessments for safety monitoring. The following assessments will be performed at each visit unless otherwise noted (Appendix A).  
Prior to study drug infusion (within ≤72 hours unless otherwise stated):
- Physical examination including weight  
- Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- ECOG performance status evaluation - Clinical safety labs (as described in Appendix A; results must be reviewed before dosing)
- Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of dosing
- Blood collection for:
Biomarker blood sample collection (analyses described in Appendix D)
Serum PK (for APX005M only) on Day 1 of every 3rd cycle (Cycles 3, 6, 9, 12, etc.) during dose escalation
- pre-infusion (APX005M)
- end of infusion (APX005M)
Pre-treatment serum anti-drug antibody (ADA) levels (for APX005M only) on Day 1 of every 3rd cycle (Cycles 3, 6, 9, 12, etc.) during dose escalation  
- Body and brain imaging will be performed every 8 weeks (±7 days) from the first dose for the first 4 months for patients who remain on treatment and every 12 weeks (±7 days) thereafter and 28 days (± 7 days) after the last dose of study treatment. See Appendix A for further details.  
- Biopsy at primary tumor or metastatic site will be collected within 7 days prior to Cycle 5 Day 1 and at least 24 hours prior to dosing
- AE reporting, if applicable - Review of concomitant medications
- Study drug administration Pre- and post-study each drug administration: Vital signs: Patients can be discharged from clinic if: oxygen saturation > 90%, SBP no more than 30 mmHg below baseline, heart rate no more than 30 beats per minute above baseline, unless febrile. If febrile, subjects can be discharged home as long as their temperature is less than 101 degrees Fahrenheit.
list of key study personnel
5.2.1.11 end-of-treatment follow-up period

Patients will return to the study center twice, approximately 28 (± 7) days, followed by a subsequent visit 100 (±7) days after their last infusion of study drug, to complete the End-ofTreatment Follow-up Period.  
The following assessments will be performed:
- Physical examination including weight  
- Vital signs (blood pressure, pulse, respiratory rate, and temperature in resting position after 5 minutes rest)
- ECOG performance status evaluation
- Clinical safety labs (as described in Appendix A) - 12-lead ECG (28 [±7] days, post last infusion of study drug visit only).  
- Radiological imaging: CT or MRI scan does not need to be repeated if performed within 8 weeks prior to the End-of-Treatment Visits or if tumor progression was previously determined.  
- Urine pregnancy test (β-hCG) for women of childbearing potential
- Tumor biopsy when feasible for patients who progressed, (28 [±7] days, post last infusion of study drug visit only) (for analyses described in Appendix D)
- Biomarker blood sample collection
- Serum anti-drug antibody (ADA) levels (for APX005M only)  
- AE reporting, if applicable, until 100 (±7) days after the last dose of study drug or until initiation of subsequent anti-cancer therapy. Patients with ongoing SAEs will be followed until resolution or stabilization.  
- Review of concomitant medications
list of key study personnel
.2.2 phase 1b .2.2.1 screening

Patients who have fully consented to participation in the study will undergo screening assessments within 28 days (4 weeks) prior to administration of the first infusion of nivolumab, cabiralizumab, and APX005M (unless otherwise stated). To determine if the patient meets all inclusion criteria and does not violate any exclusion criteria, the following procedures will be performed (Appendix B).  
- Written, signed informed consent must be collected prior to any study-specific procedures  
- Collection of a formalin fixed, paraffin-embedded (FFPE) tissue block and/or a fresh tumor biopsy from an accessible site will be mandatory, unless the Investigator deems that the subject does not have tumor in a site amenable to biopsy. Tumor biopsy collection will be performed at least 24 hours prior to dosing (as in Appendix D).  
- Complete medical and disease history
- Demographic and baseline characteristics - Complete physical examination including height and weight
- Vital signs (blood pressure, pulse, respiratory rate, and temperature in resting position after 5 minutes rest)
- Photo of periorbital region - ECOG performance status evaluation
- Screening labs (as described in Appendix B)
- Clinical safety labs (as described in Appendix B)  
- 12-lead ECG (required at screening, and if clinically indicated during the study) - Radiological imaging: After determining progression on an anti-PD-1/PD-L1 agent, body imaging of disease sites with PET CT, CT scans, or MRI is to be performed within 28 days prior to Cycle 1 Day 1. MRI brain is also to be performed within 28 days prior to C1D1. If MRI brain cannot be performed for reasons deemed by the Investigator, CT
Head with and without contrast should be performed. If the imaging is performed as part of the patient's standard of care within 28 days of Cycle 1 Day 1, it does not need to be repeated if the documentation of results is provided and is adequate for RECIST v1.1.  
- Serum pregnancy test (β-hCG) for women of childbearing potential within 7 days of Cycle 1 Day 1
- SAE reporting, if applicable
- Document prior and concomitant medications
list of key study personnel
.2.2.2 cycle 1 day 1

The following procedures will be performed:
- Prior to study drug infusion (within ≤72 hours unless otherwise stated):
- Verification of eligibility  
- Update medical and disease history to capture any changes from screening
- Physical examination including weight  
- Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- ECOG performance status evaluation - Clinical safety labs (as described in Appendix B); results must be reviewed before dosing)
- Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of dosing
- Blood collection for:
Biomarker blood sample collection (analyses described in Appendix D)
Pre-treatment serum anti-drug antibody (ADA) levels (for APX005M only) pretreatment and post-infusion and on Day 1 of every 3rd cycle thereafter (Cycles 3,
6, 9, 12, etc.)
Serum PK (for APX005M only) and on Day 1 of every 3rd cycle thereafter
(Cycles 3, 6, 9, 12, etc.)
- pre-infusion (APX005M) - end of infusion (APX005M)
- AE reporting, if applicable - Review of concomitant medications
- Study drug administration  
- Pre- and post-study each drug administration:
Vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting position after 5 minutes rest)
Additional post-dose vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting position after 5 minutes rest) at 4 hours (+ 30 minutes) after the start of the APX005M infusion
- 4 hour post-dose vital sign criteria for discharge include:
Systolic BP no more than 30 mmHg below baseline Oxygen saturation > 90%
Heart rate no more than 30 beats per minute above baseline, unless febrile If febrile, subjects can be discharged home as long as their temperature is less than 101 degrees Fahrenheit Patients must remain near the vicinity of a hospital with rapid access to an intensive care unit setting during the initial 48 hour period after treatment.
list of key study personnel
.2.2.3 cycle 1 day 2

Patients will return to the study center on Day 2 for 24-hour (± 6 hours) post-dose assessments. No treatment will be administered during this visit, but the following assessments will be completed:
- Physical examination  
- Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- Clinical Safety Labs
- AE reporting, if applicable
- Review of concomitant medications
- Blood collection for:
Biomarker blood sample collection (analyses described in Appendix D)
list of key study personnel
.2.2.4 cycle 2 day 1

The following procedures will be performed (a ± 2 day window is allowed for Day 1 in subsequent cycles post Cycle 1, Day 1):
- Prior to study drug infusion infusion (within ≤72 hours unless otherwise stated):  
- Physical examination including weight - Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- ECOG performance status evaluation - Clinical safety labs (as described in Appendix B; results must be reviewed before dosing)
- Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of dosing
- Blood collection for:
Biomarker blood sample collection (analyses described in Appendix D)  
- AE reporting, if applicable
- Review of concomitant medications
- Study drug administration  
- Pre- and post-study each drug administration:
Vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting position after 5 minutes rest)
Additional post-dose vital signs (heart rate, blood pressure, respiratory rate, and temperature in resting position after 5 minutes rest) at 4 hours (+ 30 minutes) after the start of the APX005M infusion
- 4 hour post-dose vital sign criteria for discharge include:
Systolic BP no more than 30 mmHg below baseline Oxygen saturation > 90%
Heart rate no more than 30 beats per minute above baseline, unless febrile If febrile, subjects can be discharged home as long as their temperature is less than 101 degrees Fahrenheit Patients must remain near the vicinity of a hospital with rapid access to an intensive care unit setting during the initial 48 hour period after treatment.
list of key study personnel
.2.2.5 cycle 2 day 2

Patients will return to the study center on Day 2 for 24-hour (± 6 hours) post-dose assessments. No treatment will be administered during this visit, but the following assessments will be completed:
- Physical examination  
- Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- Clinical safety labs (as described in Appendix B) - AE reporting, if applicable - Review of concomitant medications
- Blood collection for:
Biomarker blood sample collection (analyses described in Appendix D)
•
list of key study personnel
.2.2.6 phase 1b subsequent cycles

At each infusion visit, patients are to remain at the study site after each administration of APX005M until completion of all post-dose assessments for safety monitoring. The following assessments will be performed at each visit unless otherwise noted (Appendix B) (a ± 2 day window is allowed for Day 1 in subsequent cycles post Cycle 1, Day 1):
- Prior to study drug infusion infusion (within ≤72 hours unless otherwise stated):  
- Physical examination including weight - Vital signs (blood pressure, pulse, respiratory rate and temperature in resting position after 5 minutes rest)
- ECOG performance status evaluation - Clinical safety labs (as described in Appendix A; results must be reviewed before dosing)
- Urine pregnancy test (β-hCG) for women of childbearing potential within 24 hours of dosing
- Blood collection for:
Biomarker blood sample collection (analyses described in Appendix D)
Pre-treatment serum anti-drug antibody (ADA) levels (for APX005M only) on Day 1 of every 3rd cycle (Cycles 3, 6, 9, 12, etc.)
Serum PK (for APX005M only) on Day 1 of every 3rd cycle (Cycles 1, 3, 6, 9, 12, etc.)
- 15 (±5) minutes pre-infusion (APX005M) - 15 (±5) minutes post-infusion (APX005M)
- Body and brain imaging will be performed every 8 weeks (±7 days) from the first dose for the first 4 months for patients who remain on treatment and every 12 weeks (±7 days) thereafter and 28 days (± 7 days) after the last dose of study treatment. See Appendix B for further details.  
- Biopsy at primary tumor or metastatic site will be collected within 7 days prior to Cycle 5 Day 1 and at least 24 hours prior to dosing
- AE reporting, if applicable - Review of concomitant medications
- Study drug administration
Pre- and post-study each drug administration: Vital signs: Patients can be discharged from clinic if: oxygen saturation > 90%, SBP no more than 30 mmHg below baseline, heart rate no more than 30 beats per minute above baseline, unless febrile. If febrile, subjects can be discharged home as long as their temperature is less than 101 degrees Fahrenheit.
list of key study personnel
5.2.3 long-term follow-up for all

Patients should continue onto Long-Term Follow-up after completing the End-of-Treatment Follow-up Period. Patients will be followed every 12 (±2) weeks for survival. Patients who discontinue treatment while showing clinical benefit (complete response [CR], partial response [PR], or stable disease [SD]) should have tumor assessments during these visits for duration of response. Long-Term Follow-up for survival may be conducted by telephone, rather than by an in-person visit, once tumor progression is determined or use of subsequent anti-cancer therapy has been initiated. During the Long-Term Follow-up Period, if the patient undergoes local therapy (e.g., resection, radiation) or new systemic therapy is initiated, this should be documented. Patients should be followed until death, loss to follow-up, withdrawal of consent, or study termination by the Sponsor.
list of key study personnel
5.3 study assessments 5.3.1 safety

At baseline, a medical history will be obtained to capture relevant underlying conditions. The baseline examinations should include weight, height, ECOG Performance Status (Appendix ), ECG, blood pressure, heart rate, temperature, and oxygen saturation by pulse oximetry at rest (also monitor amount of supplemental oxygen, if applicable) within 28 days prior to first dose.  
Safety assessments including serum hematology, chemistry, ECOG, weight and other assessments including ECG (if clinically indicated) will be done as part of standard care during each visit prior to dosing as noted in Appendix A, Appendix B, and Appendix C. Serum chemistry labs will be checked at screening and any abnormalities outside of the normal range will be followed closely with evaluation of symptoms and follow-up laboratory data. Patients will also be monitored for any infusion-related AEs during dosing and followed up accordingly based on protocol guidelines. Pre-medications including steroids, antihistamines or other treatments will be given prior to future dosing if a patient develops infusion reactions per protocol guidelines. Any patient who has received study drug will be evaluated for safety. Toxicity assessments will be continuous during the treatment phase and End-of-Treatment Follow-up Period clinic visits. Once patients reach the Long-Term Follow-up Period (and tumor progression has been determined or use of subsequent anti-cancer therapy has been initiated), documented telephone calls or email correspondence to assess the patient's status are acceptable.  
AEs and laboratory values will be graded according to the NCI CTCAE v5.0.  
Oxygen saturation by pulse oximetry at rest (also the amount of supplemental oxygen, if applicable) should be assessed at each on-study visit prior to dosing. If a patient shows changes on pulse oximetry or other pulmonary-related signs (hypoxia, fever) or symptoms (e.g. dyspnea, cough, fever) consistent with possible pulmonary AEs, the patient should be immediately evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity management guidelines in Section 4.8 and Section 4.9. Physical examinations are to be performed as clinically indicated. If there are any new or worsening clinically significant changes since the last exam, report changes on the appropriate non-serious AE or SAE page. Additional measures, including non-study required laboratory tests, should be performed as clinically indicated or to comply with local regulations. Laboratory toxicities (e.g., suspected drug-induced liver enzyme evaluations) will be monitored during the follow-up phase via on-site/local labs until all study drug-related toxicities resolve, return to baseline, or are deemed stable. Additional testing or assessments may be performed as clinically necessary or as required by institutional or local regulations.
list of key study personnel
5.3.2 efficacy assessments 5.3.2.1 primary

The primary efficacy parameter is the objective response rate (ORR; number of patients with confirmed response of CR or PR, divided by the total number of treated patients who are evaluable for a response). Tumor response status will be assessed using RECIST v1.1 by investigator review. Board-certified radiologists will determine radiographic response and/or progression following enrollment in according to RECIST v1.1.
list of key study personnel
5.3.2.1.1 tumor assessment

Tumor assessments will be performed at Screening (within 28 days prior to first dose), then every 8 weeks (± 7 days) for a total of 2 sets of imaging studies, followed by every 12 weeks (+ 7 days) thereafter. Imaging will include an initial MRI of the brain with and without contrast as well as body imaging with either PET CT, CT scans, or MRI. If an MRI of the brain is contraindicated, a head CT with and without contrast should be performed. Brain imaging can be performed every 6 months unless clinically indicated in shorter intervals, such as in patients with metastatic melanoma. All patients should have tumor response parameters assessed at the End-of-Treatment visit unless a tumor assessment has been performed within 8 weeks prior to an End-of-Treatment Visit or if tumor progression was previously determined. Patients who enter Long-Term Follow-up while showing clinical benefit should have tumor assessments every 12 weeks (±7 days) for duration of response. The same measuring modality should be preferably used by the site to maintain consistency across the study.  
Response will be evaluated using RECIST v1.1.
list of key study personnel
5.3.2.2 additional efficacy parameters

Additional efficacy parameters may include the following: Overall Survival (OS, 1-year OS, and median OS), progression-free survival (PFS), and duration of response (DOR) for those patients with confirmed responses, based on RECIST v 1.1. CT or MRI will be performed at screening, during treatment, and at the End-of-Treatment Visit per protocol. Measurements of change in tumor burden must be reviewed and documented after each measurement.
list of key study personnel
5.3.2.3 tumor biopsy for fresh

Biopsy at the primary tumor site or metastatic site will be collected prior to Cycle 1 Day 1 and on-treatment (within 7 days prior to Cycle 5, Day 1, and at least 24 hours prior to dosing) for all patients. Patients may also have on-treatment biopsy upon documented tumor response and posttreatment biopsy upon documented tumor progression, as deemed safe and accessible by the Investigator (Appendix E). If available, tumor tissue obtained from post-treatment procedures such as surgery may also be collected. Biopsied lesions may become inflamed, bleed, or change dimensions, which could result in inaccurate tumor measurements. Therefore, it is recommended not to use the biopsied lesion as a target lesion when assessing the response by RECIST v 1.1 criteria when possible.
list of key study personnel
5.3.3 pharmacokinetic assessments

Blood samples for the PK evaluation of APX005M will be collected from all patients in the Phase 1 dose escalation component, as described in Section 5 and in Appendix A and Appendix D. Blood samples will be collected and processed for serum according to the instructions provided in the Laboratory Manual.
list of key study personnel
5.3.4 biomarker assessments

A variety of factors that could potentially predict clinical response to the combination of APX005M, cabiralizumab and nivolumab will be investigated in peripheral blood and in tumor specimens collected from patients prior to and during treatment. Data from these investigations will be evaluated for associations with response and/or safety (AE) data. In addition, analyses of markers between the treatment arms will provide the necessary data to identify and validate biomarkers with predictive vs prognostic value. Complete instructions on the collection, processing, handling and shipment of all samples described herein will be provided in a Laboratory Manual.
list of key study personnel
5.3.4.1 tumor tissue specimens

Mandatory tumor tissue specimens in the form of a paraffin embedded block, and/or fresh frozen tissue, will be submitted. These biopsy samples should be excisional, incisional or core needle as fine needle aspirates or other cytology specimens are insufficient for downstream biomarker analyses. Patients undergoing core needle biopsy will be required to provide a minimum of two cores. Tissue samples are being collected to evaluate the PD effect of study drugs on the tumor microenvironment. These samples may also undergo RNA sequencing to determine the effect of study drugs on gene expression, single cell RNA-seq, CyTOF and quantitative immunofluorescence. These analyses may help predict future response to treatment. A summary of analyses to be performed are described in Appendix D.  
Tumor biopsy specimens will be obtained before treatment and on-treatment to examine immune infiltrates and expression of selected tumor markers. Tumor biopsies may be obtained upon documentation of tumors that have responded and/or progressed on or after treatment to understand mechanisms of resistance. Samples may be assessed for the expression of immune or disease related genes and/or proteins, as well as for the presence of immune cell populations using a variety of methodologies including but not limited to immunofluorescence, CyTOF, bulk RNA-seq, and single cell RNA Seq. Blood samples for exploratory serum biomarker analyses will be drawn at the time points indicated in the Schedule of Assessments (Appendix A, Appendix B, and Appendix C). Blood samples will be processed to collect serum and PBMCs. and stored frozen prior to analysis. In addition to the PK analyses mentioned above, serum samples will be analyzed to determine the PD effect of study drugs on cytokines, CSF1R ligand, and CD40 ligand concentrations. Whole blood will be collected, spun and stored to profile PBMCs by methods such as CyTOF or single cell RNA-seq. Samples may be also assessed by multiplex ELISA, seromics, and/or other relevant multiplex-based protein assay methods. Serum marker analyses may also help establish a biomarker signature that may predict benefit or correlate with efficacy that can be used to inform this and future studies. Timings of sample collection are listed in Appendix C and analyses to be performed are described in Appendix D.
list of key study personnel
5.3.4.2 flow cytometry

Pre-treatment and on-treatment whole blood and PBMC samples will be analyzed by flow cytometry to study the effects of APX005M, cabiralizumab and nivolumab on various peripheral blood immune cell subsets. Timing of sample collection is listed in Appendix C and analyses to be performed are described in Appendix D.
list of key study personnel
6. adverse events

An Adverse Event *(AE)* is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation, patient-administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. The causal relationship to study drug is determined by an investigator and should be used to assess all AEs. The causal relationship can be one of the following:
- Definitely related  
- Possibly related - Unlikely related - Not related: There is not a reasonable causal relationship between study drug administration and the AE.
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a patient. (In order to prevent reporting bias, patients should not be questioned regarding the specific occurrence of one or more AEs.)
list of key study personnel
6.1 collection of adverse events

Any new symptoms, injury or worsening of symptoms that occur following signing of the informed consent form (ICF) but prior to first infusion (Cycle 1 Day 1) will be considered pretreatment events and reported on the Medical History page of the electronic case report form (eCRF), unless they directly correlate to a study-related procedure. Adverse event reporting will continue until 100 (±7) days after the last dose of study drug or until initiation of subsequent anti-cancer therapy.
list of key study personnel
6.2 serious adverse events

A Serious Adverse Event *(SAE)* is any untoward medical occurrence that at any dose:
- Results in death. Death may occur as a result of the underlying disease process. All events other than progression of underlying disease that result in death during the reporting period up to 100 (±7) days after the last dose of study drugs or until initiation of subsequent anti-cancer therapy, whichever comes first, must be treated as an SAE and reported as such.  
- Is life-threatening (defined as an event in which the patient was at risk of death at the time of the event)
- Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE below)
- Results in persistent or significant disability/incapacity  
- Is a congenital anomaly/birth defect
- Is an important medical event (defined as a medical event that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the patient or may require intervention [e.g., medical, surgical] to prevent one of the other serious outcomes listed in the definition above.]). Potential DILI is also considered an important medical event. (See Section 6.7 for the definition of potential DILIs.)
- Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study drug is an SAE.
Although pregnancy and potential drug-induced liver injury (DILI), are not always serious by regulatory definition, these events must be handled as SAEs and reported within the SAEs timeline (See Section 6.2.1 for reporting pregnancies). Any component of a study endpoint that is considered related to study therapy should be reported as an SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported).  
Note: The following hospitalizations are not considered SAEs in this clinical study:  
- Visit to the emergency room or other hospital department <24 hours, that does not result in admission (unless considered an important medical or life-threatening event)
- Elective surgery, planned prior to signing consent - Admissions as per protocol for a planned medical/surgical procedure - Routine health assessment requiring admission for baseline/trending of health status
(e.g., routine colonoscopy)
- Medical/surgical admission other than to remedy ill health and planned prior to entry into the study. Appropriate documentation is required in these cases.  
- Admission encountered for another life circumstance that carries no bearing on health status and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver respite, family circumstances, administrative reason).  
- Admission for administration of anti-cancer therapy in the absence of any other SAEs - Hospitalization for an event solely related to disease progression or for an elective or planned procedure to treat a pre-existing condition
- Admission to hospice or care facility to support activities of daily living
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6.2.1 serious adverse event reporting

The Investigator should report any SAE that occurs after the first study drug dose and until 100 (±7) days after the last dose of study drug or until initiation of subsequent anti-cancer therapy, whichever comes first. Protocol-specified procedure related SAE will be collected following signing of ICF.  
An SAE report should be completed for any event where doubt exists regarding its seriousness.  
If the Investigator believes that an SAE is not related to study drug, but is potentially related to the conditions of the study (such as withdrawal of previous therapy or a complication of a study procedure), the relationship should be specified in the narrative section of the SAE Report Form.  
- SAEs, related or unrelated to study drug, and pregnancies must be reported to the PI
within 24 hours of becoming aware of the event. SAEs must be recorded on the SAE Report Form, and pregnancies must be recorded on a Pregnancy Surveillance Form (paper forms). SAE and pregnancy data reporting must be done on the paper SAE/Pregnancy Surveillance Forms provided by the Industry Collaborators. They are to be transmitted via email or fax to the Yale DSMC. If related to study drugs, SAEs will be reported to the HIC within 48 hours.
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yale safety reporting

The PIs and IND holders will monitor the clinical trial for safety. The PI will assess all expedited adverse events and will periodically review all adverse events observed on the trial. Yale Cancer Center standard operating procedures (SOPs) for assessment and reporting of adverse events are followed which are in compliance with 21 CFR 312.32 and 312.22. The clinical trial data consisting of all required observations, AEs, and laboratory data are entered into a computerized database in a timely manner. The accuracy and completeness of the database, timely submission of SAEs and compliance with the protocol, is assured by periodic auditing conducted by the Yale Cancer Center Office of Protocol Review and Monitoring, which reports to the Yale Data Safety & Monitoring Committee (DSMC). Safety data will be submitted to the DSMC at least once yearly or more often as required by the DSMP. The DSMC will conduct an internal audit of the study every 6-12 months, per institutional requirements. On a regular interval basis, status reports of all laboratory parameters, AEs and SAEs are reviewed by the PI to view composite data across subjects. Regular meetings are held to discuss ongoing patient treatment and adverse events. Expedited SAE reports submitted by the Investigator to FDA are also copied to the HIC and other relevant institutional safety committees within the timeframes required by Yale. These will also be copied to BMS and Apexigen. The Principal Investigator will distribute manufacturerprovided safety reports and updated Toxicity Lists to the institution's HIC and all relevant personnel involved in the conduct of the study. The Toxicity List, in addition to the Investigator's Brochure, will be used as a reference for reporting any new SAE. Possible actions taken by the PI or the Yale DSMC if a new unexpected toxicity is identified from the above safety review, or if the periodic review of all adverse events and laboratory data indicates a pattern of incidence or severity of toxicity that raises a safety concern, can be to:
1. Revise consent form 2. Amend the protocol 3. Suspend the protocol All AEs found to be expected or non-serious, will be included in the Annual Report.
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sae reporting to bms and

- All Serious Adverse Events (SAEs) that occur following the subject's written consent to participate in the study through 100 (+7) days of discontinuation of dosing or until initiation of subsequent anti-cancer therapy, whichever comes first, must be reported to BMS Worldwide Safety and to Apexigen Safety, whether related or not related to study drug. If applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a follow-up skin biopsy).  
- Following the subject's written consent to participate in the study, all SAEs, whether related or not related to study drug, are collected, including those thought to be associated with protocol-specified procedures. The investigator should report any SAE occurring after these aforementioned time periods, which is believed to be related to study drug or protocol-specified procedure.  
- An SAE report should be completed for any event where doubt exists regarding its seriousness;
- If the investigator believes that an SAE is not related to study drug, but is potentially related to the conditions of the study (such as withdrawal of previous therapy or a complication of a study procedure), the relationship should be specified in the narrative section of the SAE Report Form.  
A Medwatch SAE form will be used to report SAEs to BMS and Apexigen.
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- worldwide.safety@bms.com

- drugsafety@apexigen.com
- For studies with long-term follow-up periods in which safety data are being reported, include the timing of SAE collection
- The Sponsor will reconcile the clinical database AE cases (case level only) transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms.com) and to Apexigen Safety (drugsafety@apexigen.com)
o The Investigator will request from BMS GPV&E, aepbusinessprocess@bms.com the SAE reconciliation report and include the BMS protocol number every 3 months and prior to data base lock or final data summary.  
o The Investigator will request from Apexigen Safety, drugsafety@apexigen.com a CA025-007 specific listing of SAEs and include the Apexigen protocol number on an ever 3-month basis and prior to data base lock or final data summary o GPV&E and Apexigen Safety will send the investigator the report to verify and confirm all SAEs have been transmitted to BMS GPV&E and Apexigen Safety.  
o The data elements listed on the GPV&E reconciliation report will be used for case identification purposes. If the Investigator determines a case was not transmitted to BMS GPV&E and Apexigen Safety, the case should be sent immediately to BMS (Worldwide.Safety@bms.com) and Apexigen (drugsafety@apexigen.com).  
- In addition to the Sponsor Investigator's responsibility to report events to their local health authority (HA), suspected serious adverse reactions (whether expected or unexpected) shall be reported by BMS and by Apexigen to the relevant competent health authorities in all concerned countries according to local regulations (either as expedited and/or in aggregate reports).  
- In accordance with local regulations, BMS and Apexigen will notify sponsor investigators of  
all reported SAEs that are suspected (related to the investigational product) and unexpected (i.e., not previously described in the IB). An event meeting these criteria is termed a Suspected Unexpected Serious Adverse Reaction (SUSAR). Sponsor investigator notification of these events will be in the form of either a SUSAR Report or a Semi-Annual SUSAR Report.  
o Other important findings which may be reported by BMS or by Apexigen as an Expedited Safety Report (ESR) include: increased frequency of a clinically significant expected SAE, an SAE considered associated with study procedures that could modify the conduct of the study, lack of efficacy that poses significant hazard to study subjects, clinically significant safety finding from a nonclinical (eg, animal) study, important safety recommendations from a study data monitoring committee, or sponsor decision to end or temporarily halt a clinical study for safety reasons.  
o Upon receiving an ESR from BMS or Apexigen, the investigator must review and retain the ESR with the IB. Where required by local regulations or when there is a central IRB/IEC for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will determine if the informed consent requires revision. The investigator should also comply with the IRB/IEC procedures for reporting any other safety information.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS and Apexigen within 24 hours \ 1 Business Day of becoming aware of the event. SAEs must be recorded on either CIOMS, MedWatch, or approved site SAE form. Pregnancies must be reported and submitted to BMS and to Apexigen. Investigator will perform due diligence follow-up using the BMS Pregnancy Form which the investigator must complete.  
BMS SAE Email **Address:** Worldwide.Safety@BMS.com Apexigen SAE Email Address: drugsafety@apexigen.com BMS SAE **Facsimile Number:** +1 609-818-3804 Apexigen SAE Facsimilie Number **(required for SAE and pregnancy reporting):**
+1 510-295- 6449
- If only limited information is initially available, follow-up reports are required If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE reports should include the same investigator term(s) initially reported.) If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day to BMS and Apexigen using the same procedure used for transmitting the initial SAE report. All SAEs should be followed to resolution or stabilization. The causal relationship to study drug is determined by a physician and should be used to assess all adverse events (AE). The causal relationship can be one of the following: Related: There is a reasonable causal relationship between study drug administration and the AE. Not related: There is not a reasonable causal relationship between study drug administration and Page 106 of 135 The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned regarding the specific occurrence of one or more AEs.)
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non-serious adverse event

- Non-serious Adverse Events (AE) are to be provided to BMS and to Apexigen in aggregate via interim or final study reports as specified in the agreement or, if a regulatory requirement [e.g., IND US trial] as part of an annual reporting requirement.  
- Non-serious AE information should also be collected from the start of a placebo lead-in period or other observational period intended to establish a baseline status for the subjects.
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non-serious adverse event collection and

The collection of non-serious AE information should begin at initiation of study drug. All nonserious adverse events (not only those deemed to be treatment-related) should be collected continuously during the treatment period and for a minimum of 100 (+7) days following the last dose of study treatment or until initiation of subsequent anti-cancer therapy, whichever comes first. Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become serious. Follow-up is also required for non-serious AEs that cause interruption or discontinuation of study drug and for those present at the end of study treatment as appropriate.
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laboratory test abnormalities

All laboratory test results captured as part of the study should be recorded following institutional procedures. Test results that constitute SAEs should be documented and reported to BMS as such. The following laboratory abnormalities should be documented and reported appropriately:
- any laboratory test result that is clinically significant or meets the definition of an SAE - any laboratory abnormality that required the participant to have study drug discontinued or interrupted any laboratory abnormality that required the subject to receive specific corrective therapy.  
It is expected that wherever possible, the clinical rather than laboratory term would be used by the reporting investigator (eg, anemia versus low hemoglobin value).
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pregnancy

If, following initiation of the investigational product, it is subsequently discovered that a study participant is pregnant or may have been pregnant at the time of investigational product exposure, including during at least 5 half-lives after product administration, the investigational product will be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for participant). The investigator must immediately notify Worldwide.Safety@bms.com of this event via either the CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE reporting procedures.  
Protocol-required procedures for study discontinuation and follow-up must be performed on the participant.  
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, where applicable, offspring information must be reported on the CIOMS,
MedWatch, BMS Pregnancy Surveillance Form, or approved site SAE form. A BMS Pregnancy Surveillance Form may be provided upon request. Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In order for Sponsor or designee to collect any pregnancy surveillance information from the female partner, the female partner must sign an informed consent form for disclosure of this information.
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overdose

An overdose is defined as the accidental or intentional administration of any dose of a product that is considered both excessive and medically important. All occurrences of overdose must be reported as an SAE.
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other safety considerations

Any significant worsening noted during interim or final physical examinations, electrocardiograms, X-rays, and any other potential safety assessments, whether or not these procedures are required by the protocol, should also be recorded as a non-serious or serious AE, as appropriate, and reported accordingly. Adverse Events that are routinely collected according to GCP shall be submitted to BMS every three (3) months by the last working day of the third month. The Adverse Event information required to be sent to BMS is noted in the 'Bristol-Myers Squibb Early Asset Investigator Sponsored Research (ISR) Import Plan' which describes the method of collection and submission to BMS via the mailbox: MG-RD-GPVEPHARMACOVIGILANCE@bms.com When the file is submitted to BMS, it must be noted whether the file contains:
All Non Serious Adverse Events (only adverse events not previously submitted to BMS within the 3 months)
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6.3 non-serious adverse events a

Non-serious AEs should also be followed to resolution or stabilization, or reported as SAEs if they become serious (see Section 6.2.1). Follow-up is also required for non-serious AEs that cause interruption or discontinuation of study drug and for those present at the end-of-study treatment, as appropriate. All identified non-serious AEs must be recorded and described on the appropriate AE page of the CRF. Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that are reported during the course of the study.
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6.4 laboratory test result abnormalities

The following laboratory test result abnormalities should be captured on the appropriate CRF page or SAE Report Form as appropriate:
- Any laboratory test result that is clinically significant or meets the definition of an SAE  
- Any laboratory test result abnormality that required the patient to have study drug discontinued or interrupted
- Any laboratory test result abnormality that required the patient to receive specific corrective therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the reporting Investigator (e.g., anemia versus low hemoglobin value).
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6.5 pregnancy

If, following initiation of the investigational product, it is discovered that a study patient is pregnant or may have been pregnant at the time of investigational product exposure, including during at least 5 half-lives after product administration, the investigational product will be permanently discontinued in an appropriate manner. The Investigator must immediately notify the Industry Collaborators of this event and complete and forward a Pregnancy Form to the Sponsor (or designee) within 24 hours and in accordance with SAE reporting procedures described in Section 6.2.1. Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, where applicable, offspring information, must be reported on the Pregnancy Surveillance Form. Any pregnancy that occurs in a female partner of a male study participant should be reported to the Sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
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6.6 overdose

Any dose of study drug in excess of 50% of the dose level specified in the protocol is considered to be an overdose. Signs and symptoms of an overdose that meet any SAE criterion must be reported as an SAE in the appropriate time frame and documented as clinical sequelae to an overdose. There is no known antidote for a drug overdose to either cabiralizumab or nivolumab. In the event of an overdose, patients should be closely monitored and given appropriate supportive treatment.
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6.7 potential drug induced liver

Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs. Potential drug induced liver injury is defined as: 1. ALT or AST elevation >3x ULN
and 2. Total bilirubin >2x ULN (> 2x baseline in patients with Gilbert's syndrome) without initial findings of cholestasis (elevated serum alkaline phosphatase) or INR > 1.5 xULN (in the absence of anticoagulation) and  
3. No other immediately apparent possible causes of aminotransferase elevation and
Page 110 of 135
10 21-Mar-2022 hyperbilirubinemia including, but not limited to viral hepatitis, pre-existing chronic or acute liver disease, or the administration of other drugs known to be hepatotoxic.
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7. statistical considerations 7.1 sample

The primary endpoint of safety and MTD of APX005M in combination with cabiralizumab and nivolumab will be determined by a 3+3 dose escalation design as described above. In this first phase, patients will be enrolled regardless of disease (melanoma, NSCLC, and RCC). The maximum tolerated dose (MTD) will be estimated independently of cohort. Upon completion of this determination, we will proceed to three parallel two-stage designs, separately for each of the three disease cohorts using the MTD. Patients exposed to the MTD in the dose escalation phase will be carried over to the appropriate two-stage design. Simon's two-stage design will be used in the phase 1b portion of the trial which will include 3 separate and parallel disease-specific cohorts (melanoma, NSCLC, and RCC). For each of the three tumor types, an immune therapy regimen which is modestly active in patients whose disease had progressed on PD-1/PD-L1 inhibitors would have a response rate (RR) of 10%. The null hypothesis that the true response rate is 10% will be tested against a one-sided alternative. A regimen worthy of further investigation in any of the three tumor types will have a RR of 25%. In the first stage, 13 patients of each cancer will be accrued. If there are 1 or fewer responses in these 13 patients, that cohort will be stopped. Otherwise, 21 additional patients of the same disease cohort will be accrued for a maximum total of 34 patients per disease cohort. Each of the three null hypotheses will be rejected if 6 or more responses are observed in 34 patients for each cohort. This design yields a type I error rate of 0.1 and a power of 80% when the true response rate is 25% in each of the three cohorts. There will not be a correction for multiplicity across the three separate cohorts.
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7.2 demographics and baseline characteristics

Demographic data, medical history, other baseline characteristics, concomitant disease, and concomitant medication will be summarized by cohort and overall. To determine whether the criteria for study conduct are met, corresponding tables and listings will be provided. These will include an assessment of protocol deviations, study drug accountability, and other data that may impact the general conduct of the study.
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7.3 efficacy analyses

For each disease type, response to treatment will be summarized for all treated patients for ORR, defined as the ratio of the number of patients that achieve an objective response (a BOR of CR or PR) to total number of patients who are evaluable for a response, which may include patients who die or for which clinical progression has occurred even if a post-treatment scan has not been performed. Exact confidence interval will be constructed for the response rate. Overall Survival, survival at 1 year, and median survival will be estimated by the Kaplan-Meier method. The corresponding confidence interval will also be presented.
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7.4 safety analyses

Safety analyses will be performed for all treated patients. Incidence of AEs, clinical laboratory information, vital signs, ECOG performance status, weight, and ECGs will be tabulated and summarized. Incidence of AEs will be summarized overall and with separate summaries for SAEs, AEs leading to discontinuation, AEs leading to death, and NCI-CTCAE v5.0 Grade 3 or higher AEs. Weight and vital signs will be summarized descriptively (n, mean, standard deviation, median, minimum, and maximum). ECOG performance status will be summarized categorically and descriptively. Shift tables displaying patient counts and percentages classified by baseline grade and maximum grade on treatment will be provided for laboratory data by cohort and overall. A marked laboratory change is defined as a shift from a baseline Grade 0 to Grade 3 (non-hematologic) or Grade 4 (hematologic) on treatment, or a shift from a baseline Grade 1 to Grade 4 on treatment. The number and percentage of patients with marked laboratory changes will be tabulated by cohort and overall.
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7.5 pharmacokinetic analyses

Individual and mean serum concentration of APX005M versus time data will be plotted by dose level. Summary statistics will be tabulated for the serum concentration-time data and estimated PK parameters of APX005M, as appropriate. For APX005M, PK parameters including Cmax, AUC, Cmin, CL, and Vss will be estimated.
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7.6 biomarker analyses

To assess the PD effects of APX005M, cabiralizumab and nivolumab on various exploratory biomarkers (such as soluble factors, peripheral blood immune cell subsets, and other markers as assessed) summary statistics for these markers and their changes (or percent changes) from baseline will be tabulated by visit and dose. In addition, the time course of exploratory biomarker outcomes will be investigated graphically by summary plots or individual patient plots over time. Patterns of change in these biomarker values over time and how the patterns differed among dose levels may be additionally investigated using appropriate modeling, for example, by linear mixed effects models. Possible associations of biomarker measures with clinical efficacy measures including OS will be investigated based on data availability. Methods such as, but not limited to, logistic regression may be used to further investigate such associations. If at the time of database lock for the primary and secondary endpoints, biomarker data related to the exploratory objectives are not available, these biomarker results may not be included in the clinical study report (CSR) but reported separately.  
Selected serum **markers:** Analyses are descriptive in nature and intended to examine the distribution of expression and assess potential associations between expression and efficacy measures. If there is an indication of a meaningful association, future work will evaluate expression as a predictive biomarker, including selection of an optimal expression cut-off to classify patients as positive or negative. See Appendix D.
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8. ethical considerations 8.1 good

The procedures set out in this study protocol are designed to ensure that the Sponsor and Investigator abide by GCP guidelines of the ICH and the Declaration of Helsinki [81]. The study also will be carried out in compliance with local legal requirements. The study will be conducted in compliance with the protocol. The protocol and any amendments and the Informed Consent Form (ICF) will receive Institutional Review Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study. All potential serious breaches must be reported to the Sponsor immediately. A serious breach is a breach of the conditions and principles of GCP in connection with the study or the protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity of the patients of the study or the scientific value of the study. Personnel involved in conducting this study will be qualified by education, training, and experience to perform their respective tasks. This study will not use the services of study personnel where sanctions have been invoked or where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment).
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8.2 institutional review board/independent ethics

Before study initiation, the Investigator must have written and dated approval/favorable opinion from the IRB/IEC for the protocol, ICF, patient recruitment materials (e.g., advertisements), and any other written information to be provided to patients. The Investigator or Sponsor should also provide the IRB/IEC with a copy of the IB or product labeling information to be provided to patients and any updates.  
The Investigator should provide the IRB/IEC with reports, updates and other information (e.g.,
expedited safety reports, amendments, and administrative letters) according to regulatory requirements or institution procedures.
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8.3 informed consent

All information about the clinical study, including patient information and the ICF, is prepared and used for the protection of the human rights of the patient according to ICH GCP guidelines and the Declaration of Helsinki [81].  
The ICF, prepared by the Investigator with the assistance of the Sponsor, must be approved along with the study protocol by the IEC/IRB and be acceptable to the Sponsor. Before each patient is enrolled on the study, written informed consent will be obtained according to the regulatory and legal requirements. A copy of the signed ICF will be retained by the patient and the original will be filed in the Investigator's site file, unless otherwise agreed. The Investigator will not undertake any investigation specifically required only for the clinical study until valid consent has been obtained. The terms of the consent and when it was obtained must be documented in the source documents and in the CRF. If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IRB/IEC, and signed by all patients subsequently enrolled in the study as well as those currently enrolled in the study. All signed and dated ICFs must remain in each patient's study file and must be available for verification by PIs at any time.  
The rights, safety, and well-being of the patients are the most important considerations and should prevail over interests of science and society.
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9. study management 9.1 compliance

The study shall be conducted as described in this approved protocol. All revisions will be approved by the sponsor. Investigators should not implement any deviation or change to the protocol without prior review and documented approval of the HIC of an amendment, except where necessary to eliminate an immediate hazard(s) to Patients.  
If a deviation or change to a protocol is implemented to eliminate an immediate hazard prior to obtaining HIC approval, as soon as possible the deviation or change will be submitted to:
- HIC for review and approval
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- bms and apexigen

If an amendment substantially alters the study design or increases the potential risk to the patient: (1) the consent form must be revised and submitted to the HIC for review and approval; (2) the revised form must be used to obtain consent from patients currently enrolled in the study if they are affected by the amendment; and (3) the new form must be used to obtain consent from new patients prior to enrollment.
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9.1.2 yale safety reporting and

The PI and IND holders will monitor the clinical trial for safety. The PI will assess all expedited adverse events and will periodically review all adverse events observed on the trial. Yale Cancer Center standard operating procedures (SOPs) for assessment and reporting of adverse events are followed which are in compliance with 21 CFR 312.32 and 312.22. The clinical trial data consisting of all required observations, AEs, and laboratory data are entered into a computerized database in a timely manner. The accuracy and completeness of the database, timely submission of SAEs and compliance with the protocol, is assured by periodic auditing conducted by the Yale Cancer Center Office of Protocol Review and Monitoring, which reports to the Yale Data Safety & Monitoring Committee (DSMC). Safety data will be submitted to the DSMC at least once yearly or more often as required by the DSMP. The DSMC will conduct an internal audit of the study every 6-12 months, per institutional requirements. On a regular interval basis, status reports of all laboratory parameters, AEs and SAEs are reviewed by the PI to view composite data across subjects. Regular meetings are held to discuss ongoing patient treatment and adverse events. Expedited SAE reports submitted by the Investigator to FDA are also copied to the HIC and other relevant institutional safety committees within the timeframes required by Yale. These will also be copied to BMS and Apexigen. The Principal Investigator will distribute manufacturerprovided safety reports and updated Toxicity Lists to the institution's HIC and all relevant personnel involved in the conduct of the study. The Toxicity List, in addition to the Investigator's Brochure, will be used as a reference for reporting any new SAE. Possible actions taken by the PI or the Yale DSMC if a new unexpected toxicity is identified from the above safety review, or if the periodic review of all adverse events and laboratory data indicates a pattern of incidence or severity of toxicity that raises a safety concern, can be to: 1. Revise consent form 2. Amend the protocol 3. Suspend the protocol All AEs found to be expected or non-serious, will be included in the Annual Report. AEs considered to be serious will be communicated to the industry collaborators Bristol-Myers Squibb and Apexigen within 24 hours.  
During the study, the DSMC will perform routine monitoring visits to review protocol compliance, compare CRFs and individual patients' medical records, assess drug accountability, and ensure that the study is being conducted according to pertinent regulatory requirements. CRF entries will be verified with source documentation. The review of medical records will be performed in a manner to ensure that patient confidentiality is maintained. Yale University will take particular care in ensuring that original imaging source data (images, echo images, etc.) are maintained and accessible for monitoring, and that these original source data are then archived on a long-term basis in compliance with ICH GCP (Section 9.1). These images must be stored in a secure location until the Sponsor (or designee) authorizes their destruction, and must be retrievable by study patient number in the event of an audit.
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9.1.2.1 source documentation

All data obtained during this study should be entered into the CRFs promptly. All source documents from which CRF entries are derived should be placed in the patient's medical records. CRF fields for which source documents will typically be needed include laboratory assessments, physical exam reports, nursing notes, ECG recordings, hospital records, and CT or MRI reports. The CRFs for each patient will be checked against source documents at the study site by the Site Monitor. Instances of missing or uninterpretable data will be discussed with the Investigator for resolution.
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9.1.3 investigational site training

The Sponsor or designee will provide quality investigational staff training prior to study initiation. Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, CRFs, study documentation, informed consent, and enrollment of WOCBP.
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9.2 records 9.2.1 records retention

The study site will maintain a study file, which should contain, at minimum, the Investigator's Brochures, the protocol and any amendments, the protocol for tissue sampling, drug accountability records, correspondence with the IEC/IRB and the Sponsor (or designee), and other study-related documents.  
The Sponsor agrees to keep records and those documents that include but are not limited to the identification of all participating patients, medical records, study-specific source documents, source worksheets, all original signed and dated ICFs, copies of all eCRFs, query responses, and detailed records of drug disposition to enable evaluations or audits from regulatory authorities and FivePrime or its designees. The Sponsor shall retain records required to be maintained for a period of 5 years following the date a marketing application in an ICH region is approved for the drug for the indication for which it is being investigated or, if no application is to be filed or if the application is not approved for such indication, until at least 5 years after the investigation is discontinued. However, these documents should be retained for a longer period if required by the applicable regulations or if needed by the Sponsor. In addition, the Investigator must make provision for the patients' medical records to be kept for the same period of time. No data should be destroyed without the agreement of the Sponsor. Should the Investigator wish to assign the study records to another party or move them to another location, the Sponsor must be notified in writing of the new responsible person and/or the new location. Patients' medical records and other original data will be archived in accordance with the archiving regulations or facilities of the investigational site.
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9.2.2 study drug records

It is the responsibility of the Investigator to ensure that a current disposition record of each study drug is maintained at each study site where study drugs are inventoried and dispensed. Records or logs must comply with applicable regulations and guidelines and should include:
- Amount received and placed in storage area  
- Amount currently in storage area - Label identification number or batch number - Amount dispensed to and returned by each patient, including unique patient identifiers - Non-study disposition (e.g., lost, wasted) - Amount destroyed at study site, if applicable - Amount returned to designated parties
- Dates and initials of person responsible for Investigational Product dispensing/accountability as per the Delegation of Authority Form.
list of key study personnel
9.2.2.1 case report forms

An Investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the investigation on each individual treated or entered as a control in the investigation. Data that are derived from source documents and reported on the electronic CRF (eCRF) must be consistent with the source documents or the discrepancies must be explained. eCRFs will be prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will be reported on the paper SAE form and Pregnancy Surveillance form, respectively. Spaces may be left blank only in those circumstances permitted by study-specific CRF completion guidelines. The confidentiality of records that could identify patients must be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). The Investigator will maintain a signature sheet to document signatures and initials of all persons authorized to make entries and/or corrections on CRFs. The completed CRF, including any paper SAE/pregnancy report forms, must be promptly reviewed, signed, and dated by the Investigator or qualified physician who is a subinvestigator and who is delegated this task on the Delegation of Authority Form. For eCRFs, review and approval/signature is completed electronically using the Yale electronic data capture tool. The PI must retain a copy of the CRFs including records of the changes and corrections. Each individual electronically signing eCRFs must meet the PI's training requirements and must only access the PI's electronic data capture tool using the unique user account provided by the PI. User accounts are not to be shared or reassigned to other individuals.
list of key study personnel
10. references

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[23] Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, et al. TissueResident Macrophage Enhancer Landscapes are Shaped by the Local Microenvironment. Cell 2014;159:1312-26. [24] Noy R, Pollard JW. Tumor-Associated Macrophages: from Mechanisms to Therapy. Immunity 2014. [25] Komohara Y, Jinushi M, Takeya M. Clinical Significance of Macrophage Heterogeneity in Human Malignant Tumors. Cancer Sci 2014;105:1-8. [26] Hamilton JA, Achuthan A. Colony Stimulating Factors and Myeloid Cell Biology in Health and Disease. Trends in Immunology 2013;34:81-9. [27] Masteller EL, Wong BR. Targeting IL-34 in Chronic Inflammation. Drug Discov Today 2014;19:1212-6. [28] Dai X-M, Ryan GR, Hapel AJ, Dominguez MG, Russell RG, Kapp S, et al. Targeted Disruption of the Mouse Colony-Stimulating Factor 1 Receptor Gene Results in Osteopetrosis, Mononuclear Phagocyte Deficiency, Increased Primitive Progenitor Cell Frequencies, and Reproductive Defects. Blood 2002;99:111-20. [29] Ruffell B, Coussens LM. Macrophages and Therapeutic Resistance in Cancer. Cancer Cell 2015;27:462-72.  
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[33] Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation. J Exp Med 2000;192:1027-34.  
[34] Nishimura H, Honjo T. PD-1: An Inhibitory Immunoreceptor Involved in Peripheral Tolerance. Trends in Immunology 2001;22:265-8. [35] Carter LL, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, et al. PD-1:PD-L inhibitory pathway affects both CD4+and CD8+ T cells and is overcome by IL-2. Eur J Immunol 2002;32:634-43.  
[36] Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a Second Ligand for PD-1 and Inhibits T cell Activation. Nat Immunol 2001;2:261-8. [37] Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation. J Immunol 2004;173:945-54.  
[38] Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 inhibits Tcell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh0. FEBS Letters 2004;574:37-41. [39] Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of Lupus-like Autoimmune Diseases by Disruption of the PD-1 Gene Encoding an ITIM Motif-Carrying Immunoreceptor. Immunity 1999;11:141-51. [40] Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune Dilated Cardiomyopathy in PD-1 ReceptorÐDeÞcient Mice. Science 2001;291:319-22. [41] Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, et al. Autoantibodies Against Cardiac Troponin I are Responsible for Dilated Cardiomyopathy in PD-1-deficient Mice. Nat Med 2003;9:1477-83. [42] Ansari MJI, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, et al. The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice. J Exp Med 2003;198:63-9. [43] Blazar BR, Carreno BM, Panoskaltsis-Mortari A, Carter L, Iwa Y, Yagita H, et al. Blockade of Programmed Death-1 Engagement Accelerates Graft-Versus-Host Disease Lethality by an IFN-y-Dependent Mechanism. J Immunol 2003;171:1272-7. [44] Salama AD, Chitnis T, Imitola J, Akiba H, Tushima F, Azuma M, et al. Critical Role of the Programmed Death-1 (PD-1) Pathway in Regulation of Experimental Autoimmune Encephalomyelitis. J Exp Med 2003;198:71-8. [45] Bristol-Myers Squibb. Highlights of Prescribing Information. 2017:1-23. [46] Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nature reviews Immunology 2003;3:745-56. [47] Banchereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, van Kooten C, et al. The CD40 antigen and its ligand. Annu Rev Immunol 1994;12:881-922. [48] Clark EA, Ledbetter JA. How B and T cells talk to each other. Nature 1994;367:425-8. [49] Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 1998;16:111-35. [50] Khong A, Nelson DJ, Nowak AK, Lake RA, Robinson BW. The use of agonistic anti-CD40 therapy in treatments for cancer. Int Rev Immunol 2012;31:246-66. [51] Law CL, Grewal IS. Therapeutic interventions targeting CD40L (CD154) and CD40: the opportunities and challenges. Advances in experimental medicine and biology 2009;647:8-36. [52] Rakhmilevich AL, Alderson KL, Sondel PM. T-cell-independent antitumor effects of CD40 ligation. Int Rev Immunol 2012;31:267-78. [53] Tong AW, Stone MJ. Prospects for CD40-directed experimental therapy of human cancer. Cancer Gene Ther 2003;10:1-13. [54] Dunn G, Bruce A, Ikeda H, Old L, RD. S. Cancer Immunoediting from Immunosurveillance to Tumor Escape. Nat Immunol 2002;3:991-8. [55] Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D. Global Cancer Statistics CA Cancer J Clin 2011;61:69-90. [56] Pardoll D. Does the Immune System See Tumors as Foreign or Self? Annu Rev Immunol 2003;21:807-39. [57] Zitvogel L, Tesniere A, Kroemer G. Cancer Despite Immunosurveillance: Immunoselection and Immunosubversion Nat Rev Immunol 2006;6:715-27. [58] Greenwald R, Freeman G, Sharpe A. The B7 Family Revisited. Ann Rev Immunol 2004;23:515-48. [59] Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The Function of Programmed Cell Death 1 and Its Ligands in Regulating Autoimmunity and Infection. Nat Immunol 2007;8:239-45. [60] Wolchok J, Hoos A, O'Day S, Weber J, Hamid O, Lebbe C, et al. Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria Clin Cancer Res 2009;15:7412-20. [61] Zippelius A, Schreiner J, Herzig P, Muller P. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer immunology research 2015;3:236-44. [62] Winograd R, Byrne KT, Evans RA, Odorizzi PM, Meyer AR, Bajor DL, et al. Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma. Cancer immunology research 2015;3:399-411.  
[63] Ngiow SF, Young A, Blake SJ, Hill GR, Yagita H, Teng MW, et al. Agonistic CD40 mAbDriven IL12 Reverses Resistance to Anti-PD1 in a T-cell-Rich Tumor. Cancer research 2016;76:6266-77. [64] Apexigen. APX005M Investigator's Brochure. [65] Cassier PA, Gomez-Roca CA, Italiano A, Cannarile M, Ries C, Brillouet A, et al. Phase 1 Study of RG7155, a Novel Anti-CSF1R Antibody, in Patients with Locally Advanced Pigmented Villonodular Synovitis (PVNS). J Clin Oncol 2014;32. [66] Radi ZA, Koza-Taylor PH, Bell RR, Obert LA, Runnels HA, Beebe JS, et al. Increased Serum Enzyme Levels Associated with Kupffer Cell Reduction with No Signs of Hepatic or Skeletal Muscle Injury. Am J Pathol 2011;179:240-7. [67] Radi Z, Guzman R, Bell R. Increased Connective Tissue Extracellular Matrix in the OP/OP Model of Osteopetrosis. Pathobiology 2009;76:199-203. [68] Velu V, Titanji K, ZHu B, Husain S, Pladevega A, Lai L. Enhancing SIV-Specific Immunity in *vivo* by PD-1 Blockade. Nature 2009;458:206-10. [69] Kaufmann D, Walker B. Programmed Death-1 as a Factor in Immune Exhaustion and Activation in HIV Infection. Curr Opin HIV Aids 2008;3:362. [70] Rutebemberwa A, Ray S, Astemborksi J, Levine J, Liu L, Dowd K. High Programmed Death-1 Levels on Hepatitis C Virus-Specific T Cells During Acute Infection are Associated with Viral Persistance and Require Preservation of Cognate Antigen During Chronic Infection. J Immunol 2008;181:8215-25. [71] Wang C, Thudium KB, Han M, Wang X-T, Huang H, Feingersh D, et al. In Vitro Characterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, and In Vivo Toxicology in Non-Human Primates. Cancer Immunol Res 2014;2:846-56.  
[72] Habicht A, Dada S, Jurewicz M, Fife B, Yagita H, Azuma M. A Link Between PDL1 and T Regulatory Cells in Fetomaternal Tolerance. J Immunol 2007;179:5211-9. [73] Barr TA, Heath AW. Functional activity of CD40 antibodies correlates to the position of binding relative to CD154. Immunology 2001;102:39-43. [74] Butowski N, Colman H, De Groot JF, Omuro AM, Nayak L, Wen PY, et al. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro-oncology 2016;18:557-64. [75] Cassier PA, Italiano A, Gomez-Roca CA, Le Tourneau C, Toulmonde M, Cannarile MA, et al. CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study. The Lancet Oncology 2015;16:949-56. [76] Genovese MC, Hsia E, Belkowski SM, Chien C, Masterson T, Thurmond RL, et al. Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis Despite Disease-Modifying Antirheumatic Drug Therapy. The Journal of Rheumatology 2015;42:1752-60. [77] Sadis S, Mukherjee A, Olson S, Dokmanovich M, Maher R, Cai CH, et al. Safety, Pharmacokinetics, and Pharmacodynamics of PP-0360324, a Human Monoclonal Antibody to Monocyte/Macrophage Colony Stimulating Factor, in Healthy Volunteers. ACR/ARHP Scientific Meeting 2009. New London, CT Pfizer Global Research and Development; 2009.  
[78] Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, et al. StructureGuided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. New England Journal of Medicine 2015;373:428-37. [79] Gabbay M, Thomas J, Gibbs A, Hold P. A Randomized Crossover Trial of the Impact of Additional Spermicide on Condom Failure Rates. Sexually Transmitted Diseases 2008;35:862-8. [80] Kestelman P, Trussell J. Efficacy of the Simultaneous Use of Condoms and Spermicides. Family Planning Perspectives 1991;23:226-32. [81] Declaration of Helsinki. Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. In: 64th WMA General Assembly, editor.: World Medical Associan, Inc.; 2013. p. 8.
list of key study personnel
11. appendices

| Appendix A:   | Schedule of Assessments - Phase 1 Dose Escalation: Cabiralizumab and APX005M (Cohorts 1, 3, and 5) and Nivolumab, Cabiralizumab, and APX005M (Cohorts 2, 4, and 6) 122   |
|---------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Appendix B:   | Schedule of Assessments - Phase 1b: Nivolumab + Cabiralizumab + APX005M 126                                                                                              |
| Appendix C:   | Schedule of PK and PD Blood Sample Collection 130                                                                                                                        |
| Appendix D:   | PD Analyses 132                                                                                                                                                          |
| Appendix E:   | Biopsy Requirements 134                                                                                                                                                  |
| Appendix F:   | ECOG Performance Status 135                                                                                                                                              |  
Appendix A: Schedule of Assessments - Phase 1 Dose Escalation: Cabiralizumab and APX005M (Cohorts 1, 3, and 5) and Nivolumab,  
Cabiralizumab, **and APX005M (Cohorts 2, 4, and 6)**  
| Cabiralizumab, and APX005M (Cohorts 2, 4, and 6)   | End-of-Treatment                                                                                                                                         |         |          |                  |                   |       |       |       |        |                                               |    |
|----------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|---------|----------|------------------|-------------------|-------|-------|-------|--------|-----------------------------------------------|----|
| Screening                                          | Cycle 1                                                                                                                                                  | Cycle 2 | Cycle xs | Follow-up Period | Long-Term Periodu |       |       |       |        |                                               |    |
| Day –28 to                                         | Follow-up                                                                                                                                                |         |          |                  |                   |       |       |       |        |                                               |    |
| Day 0                                              | Day 1b                                                                                                                                                   | Day 2   | Day 3    | Day 8            | Day 1b            | Day 2 | Day 3 | Day 8 | Day 1b | 28 (±7) days and 100 (±7) days post-last dose |    |
| Procedurea                                         |                                                                                                                                                          |         |          |                  |                   |       |       |       |        |                                               |    |
| Informed Consent                                   | x                                                                                                                                                        |         |          |                  |                   |       |       |       |        |                                               |    |
| Review/Confirm                                     | x                                                                                                                                                        | x       |          |                  |                   |       |       |       |        |                                               |    |
| Eligibility Criteria  Medical History /            | x                                                                                                                                                        | x       |          |                  |                   |       |       |       |        |                                               |    |
| Demographics Physical Examinationc                 | x                                                                                                                                                        | x       | x        | x                | x                 | x     | X     | x     | x      | x                                             |    |
| Height and Weightd                                 | x                                                                                                                                                        | x       | x        | x                | x                 |       |       |       |        |                                               |    |
| Vital Signse                                       | x                                                                                                                                                        | x       | x        | x                | x                 | x     | x     | X     | x      | x                                             | x  |
| Photo of Periorbital                               | x                                                                                                                                                        |         |          |                  |                   |       |       |       |        |                                               |    |
| Region ECOG Performance                            | x                                                                                                                                                        | x       | x        | x                | x                 |       |       |       |        |                                               |    |
| Statusf Screening Labsg                            | x                                                                                                                                                        |         |          |                  |                   |       |       |       |        |                                               |    |
| Clinical Safety Labsh                              | x                                                                                                                                                        | x       | x        | x                | x                 | x     | x     | x     | x      |                                               |    |
| 12-Lead ECGi                                       | x                                                                                                                                                        | x       |          |                  |                   |       |       |       |        |                                               |    |
| CT or MRI Tumor                                    | x                                                                                                                                                        | x       | x        | x                |                   |       |       |       |        |                                               |    |
| Assessmentj,k Serum Pregnancy Testl                | x                                                                                                                                                        | x       | x        | x                |                   |       |       |       |        |                                               |    |
| Tumor Biopsym                                      | x                                                                                                                                                        | x       | x        |                  |                   |       |       |       |        |                                               |    |
| PK Samplingn                                       | x                                                                                                                                                        | x       | x        | x                | x                 | X     | x     |       |        |                                               |    |
| PD/Biomarker blood                                 | x                                                                                                                                                        | x       | x        | x                | x                 | x     | X     | x     | x      | x                                             |    |
| Samplingo, p Anti-drug Antibodiesn                 | x                                                                                                                                                        | x       | x        |                  |                   |       |       |       |        |                                               |    |
| Study Drug(s)q,r                                   | x                                                                                                                                                        | x       | x        |                  |                   |       |       |       |        |                                               |    |
| Adverse Eventss                                    | x ---------------------------------------------------------------------------------------------------------------------------------------------------- x |         |          |                  |                   |       |       |       |        |                                               |    |
| Prior/Concomitant                                  | x ---------------------------------------------------------------------------------------------------------------------------------------------------- x |         |          |                  |                   |       |       |       |        |                                               |    |
| Medications                                        |                                                                                                                                                          |         |          |                  |                   |       |       |       |        |                                               |    |  
| End-of-Treatment    |         |         |          |                  |                             |       |       |       |        |                                               |
|---------------------|---------|---------|----------|------------------|-----------------------------|-------|-------|-------|--------|-----------------------------------------------|
| Screening           | Cycle 1 | Cycle 2 | Cycle xs | Follow-up Period | Long-Term Follow-up Periodu |       |       |       |        |                                               |
| Day –28 to Day 0    | Day 1b  | Day 2   | Day 3    | Day 8            | Day 1b                      | Day 2 | Day 3 | Day 8 | Day 1b | 28 (±7) days and 100 (±7) days post-last dose |
| Procedurea          |         |         |          |                  |                             |       |       |       |        |                                               |
| Long-Term Follow-up | x       |         |          |                  |                             |       |       |       |        |                                               |
| Contactt            |         |         |          |                  |                             |       |       |       |        |                                               |
list of key study personnel
notes for phase 1 dose

a. Unless specified, prior to infusion procedures are to be completed within 24 hours of scheduled time point and to be synchronized with administration of assigned study drug. Any clinical assessment, laboratory study, or additional non-specified tests may be obtained at any time, if clinically indicated.  
b. Each cycle will be 14 days long, with administration of cabiralizumab, APX005M, + nivolumab on Day 1; a ± 2 day window is allowed for Day 1starting with Cycle 3. c. Standard physical examination will be performed as determined by the Investigator, particularly to follow physical findings to resolution. Targeted physical exams should be conducted at any time to follow up on AE reports. A symptom-directed physical exam can be performed for days 2, 3, and 8 of Cycles 1 and 2.  
d. Height is only required to be recorded at screening. Weight is required to be recorded at Day 1 of each cycle. Dose will be adjusted only if weight change is >10% from first dose on Cycle 1 Day 1.  
e. Vital signs include pulse, respiratory rate, blood pressure, and temperature in the resting position (sitting or supine). Measure prior to dose and after completion of each IV infusion for all cycles.  
For Day 1 of Cycles 1 and 2 only, additionally measure vital signs 4 hours (+ 30 min) post-APX005M infusion. Pulse oximetry is performed at rest prior to dosing for day 1 of each cycle and otherwise as clinically indicated. At the Investigator's discretion, vital sign monitoring may be extended beyond the time points specified. Additional measures should be performed as clinically indicated.  
f. Patient ECOG Status assessments are to be performed within 72 hours prior to dosing (Day 1 of each cycle).  
g. Screening labs include serology for Hepatitis B (HBsAg) and Hepatitis C (HCV antibody). h. Clinical Safety Labs:
Hematology including CBC with differential, platelets, hemoglobin, hematocrit, RBC, and RBC indices Chemistry includes CK (creatine kinase), AST (aspartate transaminase), ALT (alanine transaminase), alkaline phosphatase, bicarbonate, bilirubin, (direct and total), BUN (blood urea nitrogen),
calcium, chloride, creatinine, glucose, LDH (lactate dehydrogenase), phosphorus, potassium, sodium, and, if applicable, serum pregnancy. Albumin, amylase, lipase, thyroid panel includes TSH, Free T4, PT/INR, and PTT (aPTT) perform at Screening and as indicated. If CK elevation is clinically significant, obtain troponins (cardiac and skeletal), CK isoenzymes, aldolase, and ECG; repeat CK and these additional tests within 48 hours or other interval as clinically indicated, until resolved or stable. If either AST or ALT is elevated, obtain total serum bilirubin, alkaline phosphatase; repeat within 48 hours or other interval, as clinically indicated, until resolved or stable. Additional tests may be obtained at any time, if clinically indicated.  
Urinalysis: Urine dipstick will only be done at screening, and when clinically indicated.  
i. Obtain ECG records at Screening and the Day 28 post last infusion End-of-Treatment Visit. Additional ECGs should be obtained at any time, if serum CK or cardiac troponin is elevated; if abnormal (excluding sinus tachycardia), ECGs should be obtained (if clinically indicated), until the abnormality is resolved or clinically stable. Additional ECGs may be obtained at any time, if clinically indicated. ECGs for each patient should be obtained from the same machine whenever possible. To minimize variability, it is important that patients be in a resting position for at least 5 minutes prior to each ECG evaluation. Body position should be consistently maintained for each ECG evaluation to prevent changes in heart rate. Environmental distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG resting period and during ECG recording.  
j. PET CT, CT scans or MRI of the Tumor sites and MRI brain measured as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). If patient terminates prior to scheduled CT or MRI
scans, patient should have scans done at End-of-Treatment Visits (does not need to be repeated if performed within 8 weeks prior to End-of-Treatment Visits or if tumor progression was previously determined). Patients who enter Long-Term Follow-up while showing clinical benefit should have tumor assessments q12w for duration of response. The same measuring modality should be used by the site to maintain consistency across the various time points. (Documentation of skin lesions by color photography, including a ruler to measure the size of the lesion, is suggested and should follow the CT or MRI schedule.) If there is a contraindication to brain MRI, CT head with and without contrast can be performed.  
k. Performed every 8 weeks (±7 days) from the first dose for the first 4 months for patients who remain on treatment and every 12 weeks (±7 days) thereafter and 28 days (± 7 days) after the last dose of study treatment. The exception is MRI of the brain, which can be performed every 6 months in patients with NSCLC and RCC, unless clinically indicated to be done in shorter intervals. CT or MRI scans do not need to be repeated if performed within 8 weeks prior to the End-of-Treatment Visits or if tumor progression was previously determined.  
l. All women of childbearing potential will have a serum pregnancy test at screening, and urine pregnancy test on Day 1 of each cycle and at the End-of-Treatment Visits. m. Biopsy at primary tumor or metastatic tumor site will be collected at screening [at least 24 hours prior to dosing] and prior to Cycle 5 Day 1 [within 7 days prior to Cycle 5 Day 1 and at least 24 hours prior to dosing]. It is recommended that patients who have documented response receive another biopsy within 28 (±14) days post tumor assessment and/or patient who have progression receive another biopsy at the final End-of–Treatment visit. The post-response and post-progression biopsies are optional. Collect an FFPE tissue block or 10 slides of archival tumor sample at Screening.  
n. Serum PK for APX005M and ADA samples will be collected as indicated in Appendix C. o. Samples will be collected for PD and biomarker analyses for correlative studies. p. Biomarker blood sample collection will be collected on Day 1, 2, 3, and 8 of Cycles 1 and 2, and on Day 1 of every cycle thereafter. See Appendix C and D for further information.  
q.Nivolumab and cabiralizumab will both be administered by IV infusion over 30 minutes (± 5 minutes). APX005M will be administered by IV infusion over 60 minutes. Nivolumab will be given first (in Cohorts 2, 4, and 6), with a 30- to 60-minute rest, followed by cabiralizumab as a 30-minute infusion. APX005M will be administered 30 minutes after cabiralizumab and will be given for a 60 minute infusion period. For Cohorts 1, 3, and 5, cabiralizumab will be given first, followed by APX005M with the same parameters as above.  
r. Cabiralizumab and APX005M will be administered every 2 weeks in 14-day cycles for cohorts 1, 3, and 5. Nivolumab, cabiralizumab, and APX005M will be administered every 2 weeks in 14-day cycles for cohorts 2, 4, and 6. The dosing may continue until PD or unacceptable toxicity.  
s. These assessments are to be performed prior to each dose (with the exceptions noted in Appendix C) for those patients who continue treatment without signs of progressive disease or toxicity. t. Patients should be contacted every 12 (±2) weeks for survival status. Patients should have tumor scans every 8 weeks for the first 4 months on study drugs, followed by every12 (±2) weeks thereafter, if tumor progression was not previously determined and/or use of subsequent anti-cancer therapy has not been initiated. Any new anti-cancer therapy should be documented.  
| Long-Term Follow-up Periodt         |                                                                                               |         |          |                                                                |        |    |    |
|-------------------------------------|-----------------------------------------------------------------------------------------------|---------|----------|----------------------------------------------------------------|--------|----|----|
| End-of-Treatment                    |                                                                                               |         |          |                                                                |        |    |    |
| Screening                           | Cycle 1                                                                                       | Cycle 2 | Cycle xs | Follow-up Period 28 (±7) days and 100 (±7) days post-last dose |        |    |    |
| Day –28 to Day 0                    | Day 1b                                                                                        | Day 2   | Day 1b   | Day 2                                                          | Day 1b |    |    |
| Procedurea                          | Week 0                                                                                        | Week 1  | Week 3   | Week > 5                                                       |        |    |    |
| Informed Consent                    | x                                                                                             |         |          |                                                                |        |    |    |
| Review/ConfirmEligibility           | x                                                                                             | x       |          |                                                                |        |    |    |
| Criteria Medical History /          | x                                                                                             | x       |          |                                                                |        |    |    |
| Demographics Physical Examinationc  | x                                                                                             | x       | x        | x                                                              | X      | x  | x  |
| Height and Weightd                  | x                                                                                             | x       | x        | x                                                              | x      |    |    |
| Vital Signse                        | x                                                                                             | x       | x        | x                                                              | X      | x  | x  |
| Photo of Periorbital Region         | x                                                                                             |         |          |                                                                |        |    |    |
| ECOG Performance Statusf            | x                                                                                             | x       | x        | x                                                              | x      |    |    |
| Screening Labsg                     | x                                                                                             |         |          |                                                                |        |    |    |
| Clinical Safety Labsh               | x                                                                                             | x       | x        | x                                                              | X      | x  | x  |
| 12-Lead ECGi                        | x                                                                                             | x       |          |                                                                |        |    |    |
| CT or MRI Tumor                     | x                                                                                             | x       | x        | x                                                              |        |    |    |
| Assessmentj,k Serum Pregnancy Testl | x                                                                                             | x       | x        | x                                                              | x      |    |    |
| Tumor Biopsym                       | x                                                                                             | x       | x        |                                                                |        |    |    |
| PK Samplingn                        | x                                                                                             | x       | x        |                                                                |        |    |    |
| Anti-drug Antibodiesn               | x                                                                                             | x       | x        |                                                                |        |    |    |
| PD/Biomarker blood sample           | x                                                                                             | x       | x        | x                                                              | x      | x  |    |
| collectiono Study Drugsp,q          | x                                                                                             | x       | x        |                                                                |        |    |    |
| Adverse Eventsr                     | x ----------------------------------------------------------------------------------------- x |         |          |                                                                |        |    |    |
| Page 127 of 135                     | Confidential                                                                                  |         |          |                                                                |        |    |    |  
| Long-Term Follow-up Periodt   |                                                                                               |         |          |                                                                |        |
|-------------------------------|-----------------------------------------------------------------------------------------------|---------|----------|----------------------------------------------------------------|--------|
| End-of-Treatment              |                                                                                               |         |          |                                                                |        |
| Screening                     | Cycle 1                                                                                       | Cycle 2 | Cycle xs | Follow-up Period 28 (±7) days and 100 (±7) days post-last dose |        |
| Day –28 to Day 0              | Day 1b                                                                                        | Day 2   | Day 1b   | Day 2                                                          | Day 1b |
| Procedurea                    | Week 0                                                                                        | Week 1  | Week 3   | Week > 5                                                       |        |
| Prior/ConcomitantMedications  | x ----------------------------------------------------------------------------------------- x |         |          |                                                                |        |
| Long-TermFollow-up            | x                                                                                             |         |          |                                                                |        |
| Contactss                     |                                                                                               |         |          |                                                                |        |
list of key study personnel
notes for phase 1b schedule

a. Unless specified, prior to infusion procedure are to be completed within 72 hours of scheduled time point and to be synchronized with study drug administration day. Any clinical assessment, laboratory study, or additional non-specified tests may be obtained at any time, if clinically indicated.  
b. Each cycle will be 14 days long, with administration of nivolumab + cabiralizumab + APX005M on Day 1. The first day of treatment in Cycle 1 is defined as Day 1; a ± 2 day window is allowed for Day 1 in subsequent cycles.  
c. Standard physical examination will be performed, particularly to follow physical findings to resolution. Targeted physical exams should be conducted at any time to follow up on AE reports. d. Height is only required to be recorded at screening. Weight is required to be recorded at Day 1 of each cycle. Dose will be adjusted only if weight change is >10% from first dose. e. Vital signs include pulse, respiratory rate, blood pressure, and temperature in the resting position (sitting or supine). Measure prior to dose and after completion of each IV infusion. Pulse oximetry is performed at rest prior to dosing for day 1 of each cycle and otherwise as clinically indicated. At the Investigator's discretion, vital sign monitoring may be extended beyond the time points specified. Additional measures should be performed as clinically indicated.  
f. Patient ECOG Status assessments are to be performed within 96 hours prior to dosing (Day 1 of each cycle). g. Screening labs include serology for Hepatitis B (HBsAg), Hepatitis C (HCV antibody) h. Clinical Safety Labs:
Hematology including CBC with differential, platelets, hemoglobin, hematocrit, RBC, and RBC indices.  
Chemistry includes CK (creatine kinase), AST (aspartate transaminase), ALT (alanine transaminase), alkaline phosphatase bicarbonate, bilirubin, (direct and total), BUN (blood urea nitrogen),
calcium, chloride, creatinine, glucose, LDH (lactate dehydrogenase), phosphorus, potassium, sodium, and, if applicable, serum pregnancy. Albumin, amylase, lipase, thyroid panel includes TSH, Free T4, PT/INR, and PTT (aPTT) perform at Screening and as indicated, If CK elevation is clinically significant, obtain troponins (cardiac and skeletal), CK isoenzymes, aldolase, and ECG; repeat CK and these additional tests within 48 hours or other interval as clinically indicated, until resolved or stable. If either AST or ALT is elevated, obtain total serum bilirubin, alkaline phosphatase; repeat within 48 hours or other interval, as clinically indicated, until resolved or stable. Additional tests may be obtained at any time, if clinically indicated.  
Urinalysis: Urine dipstick will only be done at screening, and when clinically indicated.  
i. Obtain ECG records at screening and the Day 28 post last infusion End-of-Treatment Visit. Additional ECGs should be obtained at any time, if serum CK or cardiac troponin is elevated; if abnormal (excluding sinus tachycardia), ECGs should be obtained (if clinically indicated), until the abnormality is resolved or clinically stable. ECGs for each patient should be obtained from the same machine whenever possible. To minimize variability, it is important that patients be in a resting position for at least 5 minutes prior to each ECG evaluation. Body position should be consistently maintained for each ECG evaluation to prevent changes in heart rate. Environmental distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG resting period and during ECG recording. Additional tests may be obtained at any time, if clinically indicated.  
j. PET CT, CT scans or MRI of the Tumor sites and MRI brain measured as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). If patient terminates prior to scheduled CT or MRI
scans, patient should have scans done at End-of-Treatment Visits (does not need to be repeated if performed within 8 weeks prior to End-of-Treatment Visits or if tumor progression was previously determined). Patients who enter Long-Term Follow-up while showing clinical benefit should have tumor assessments q12w for duration of response. The same measuring modality should be used by the site to maintain consistency across the various time points. (Documentation of skin lesions by color photography, including a ruler to measure the size of the lesion, is suggested and should Page 128 of 135  
follow the CT or MRI schedule.) If there is a contraindication to brain MRI, CT head with and without contrast can be performed.  
k. Performed every 8 weeks (±7 days) from the first dose for the first 4 months for patients who remain on treatment and every 12 weeks (±7 days) thereafter and 28 days (± 7 days) after the last dose of study treatment. The exception is MRI of the brain, which can be performed every 6 months in patients with NSCLC and RCC, unless clinically indicated to be done in shorter intervals. CT or MRI scans do not need to be repeated if performed within 8 weeks prior to an End-of-Treatment Visit or if tumor progression was previously determined.  
l. All women of childbearing potential will have a serum pregnancy test at screening, and urine pregnancy tests will be done on Day 1 of every Cycle and at End-of-Treatment Visits.  
m. Biopsy at primary tumor or metastatic tumor site will be collected at screening [at least 24 hours prior to dosing] and prior to Cycle 5, Day 1 [within 7 days prior to Cycle 5 Day 1 and at least 24 hours prior to dosing]. It is recommended that patients who have documented response receive another biopsy within 28 (±14) days post tumor assessment and/or patient who have progression receive another biopsy at the 28-days End-of–Treatment visit. The post-response and post-progression biopsies are optional. If available, collect an FFPE tissue block or 10 slides of archival tumor sample at Screening.  
n. Samples will be collected for PK analysis and anti-drug antibodies (ADA) as in Appendix C. o. Biomarker blood sample collection will be collected on Day 1 of each cycle and on C1D2 and C2D2. See Appendix C and D for further information. p. Nivolumab and cabiralizumab will both be administered by IV infusion over 30 minutes (± 5 minutes. Nivolumab will be given first, with a 30-to 60-minute rest, followed by cabiralizumab as a 30-minute infusion. A 30-minute rest period will then occur, followed by APX005M as a 60-minute infusion.  
q. Nivolumab + cabiralizumab + APX005M study drug will be administered every 2 weeks in 14-day cycles and will continue until PD or unacceptable toxicity. r. These assessments are to be performed prior to each subsequent dose (with exceptions noted in Appendix C) for patients who continue treatment without signs of progressive disease or toxicity. s. Patients should be contacted every 12 (±2) weeks for survival status. Patients should have tumor scans 12 (±2) weeks, if tumor progression was not previously determined and/or use of subsequent anti-cancer therapy has not been initiated. Any new anti-cancer therapy should be documented.  
| Appendix C: Schedule of PK and tumor and Blood Biomarker Sample Collection Study Cycle Study Day Time Point Type of Sample Screening Screening (Day –28) At least 24 hours prior Tumor Biopsy (or archival FFPE tumor block to dosing available) Cycles 1 and 2 only Day 1 Prior to infusion PK for APX005M (serum) Biomarker blood sample collection Anti-drug antibody blood sample (Cycle 1 only) End of infusion PK for APX005M (serum) If possible, 4 (±30 min) PK for APX005M (serum) hours from start of infusion   |                                                                   |                                   |                                                        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|-----------------------------------|--------------------------------------------------------|
| Phase 1 dose escalation                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Day 2                                                             | 24 (±6) hours from                | PK for APX005M (serum)                                 |
| start of infusion                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Biomarker blood sample collection                                 |                                   |                                                        |
| Day 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 48 (±6) hours from                                                | PK for APX005M (serum)            |                                                        |
| start of infusion                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Biomarker blood sample collection                                 |                                   |                                                        |
| Day 8                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 168 (±6) hours from start of infusion                             | Biomarker blood sample collection |                                                        |
| Prior to Cycle 5 only                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Within 7 days prior to C5D1 and at least 24 hours prior to dosing | Prior to infusion                 | Tumor Biopsy                                           |
| Subsequent Cycles on every cycle (Cycles 3, 4, 5, etc.                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Day 1                                                             | Prior to infusion                 | Biomarker blood sample collection                      |
| Subsequent Cycles on every 3rd cycle (Cycles 3, 6, 9, 12, etc.)                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Day 1                                                             | Prior to infusion                 | PK for APX005M (serum) Anti-drug antibody blood sample |
| End of infusion                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | PK for APX005M (serum)                                            |                                   |                                                        |
| Screening                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Screening (Day –28)                                               | At least 24 hours prior           | Tumor Biopsy (or archival FFPE tumor block             |
| to dosing                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | available)                                                        |                                   |                                                        |
| Cycles 1, 2, and each cycle therafter                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Day 1                                                             | Prior to infusion                 | Biomarker blood sample collection                      |
| Phase 1b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | PK for APX005M (serum)*                                           |                                   |                                                        |
| *Every 3rd cycle (Cycles 1, 3, 6, 9 , 12, etc.)                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Anti-drug antibody blood sample*                                  |                                   |                                                        |
| End of infusion                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | PK for APX005M (serum)*                                           |                                   |                                                        |  
| CA025-007 Clinical Protocol Day 2 of C1 and C2                    | Prior to Infusion   | Biomarker blood sample collection     |
|-------------------------------------------------------------------|---------------------|---------------------------------------|
| Within 7 days prior to C5D1 and at least 24 hours prior to dosing | Prior to infusion   | Biopsy Tissue (prior to Cycle 5 only) |  
| End-of-Treatment Followup Period (28 [±7] days and 100 [±7] days post-last dose)                    | Treatment        | Post completion of                                                                                                    | Optional biopsy for patients who have documented   |
|--------------------|------------------|-----------------------------------------------------------------------------------------------------------------------|----------------------------------------------------|
| discontinuation/PD | treatment course | response within 28 (+14) days post-tumor assessment Anti-drug antibody blood sample Biomarker blood sample collection |                                                    |
list of key study personnel
appendix d pd analyses

Exploratory endpoints will include description of antitumor activity of APX005M administered in combination with nivolumab and cabiralizumab as measured in mandatory serial tumor biopsy and blood collection specimens. Biopsies will be taken pre-treatment (at least 24 hours prior to dosing), before Cycle 5 Day 1 (within 7 days and at least 24 hours prior to dosing), and at time of disease progression, if this occurs. PBMCs (for CyTOF and single cell RNA Seq) and plasma (for ELISA cytokine panel) samples will also be collected at the same time points. These samples will be used to study biomarkers to assess for prediction of response or resistance to therapy and to search for pharmacodynamic indicators of anti-tumor activity. Tumor assessment will include the following:
- Routine histologic examination - Quantitative immunofluorescence (QIF)
- Flow cytometry by CyTOF
- Single cell RNA-seq studies QIF utilizing formalin-fixed paraffin embedded (FFPE) tumors will be profiled for: Marker expression will be analyzed in responders versus non-responders. Assays for the biomarkers listed in the table above have already been developed. Flow cytometry by CyTOF will be performed on tumor infiltrating immune cells and PBMCs to explore and potentially validate the markers outlined for QIF. We will profile shifts in TAM
types from pre-treatment to post-treatment initiation and will also measure production of TNF-α, IFN-γ, IL-6, IL-12, p40, CCL3, CCL4, and CCL5. Cell sorting by FACS will be performed for CD3, CD4, and CD68. We aim to determine the functional properties of the immune infiltrates in promoting or inhibiting tumor growth. Biomarkers of effect for cabiralizumab include:
- Peripheral blood changes in CD14+/CD16hi non-classical monocytes Biomarkers of effect for APX005M include:
- Peripheral blood analysis for antigen presenting cell activation using flow cytometry: Cell surface immune markers that will be examined include but are not limited to: CD19,
list of key study personnel
cd123 cd11c cd86 mhc class

Please note that patients undergoing core biopsy will be required to provide two cores for these analysis - one snap frozen and one paraffin embedded. All samples will be banked at Yale in the Kluger laboratory.
list of key study personnel
appendix e biopsy requirements

Biopsy at primary tumor or metastatic tumor site are mandatory and will be collected at:
.  
At time of screening At least 24 hours prior to dosing o Prior to Cycle 5 Day 1
.  
Within 7 days prior to Cycle 5 Day 1 and at least 24 hours prior to dosing o It is recommended that patients who have documented response receive another biopsy within 28 (±14) dys post tumor assessment and/or patients who have progression receive another biopsy at the final End-of–Treatment visit. The post-response and post-progression biopsies are optional.  
If available, patients will be required to provide an archival FFPE tissue block as well at screening.  
Patients undergoing core biopsy for the study will be required to provide two cores for these analysis –
one snap frozen and one paraffin embedded.
list of key study personnel
appendix f ecog performance status

0 Fully active, able to carry on all pre-disease activities without restriction. 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light sedentary nature (light housework, office work).  
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.  
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.  
4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.