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8.3 palliative radiation

Limited data are available with cabozantinb and pembrolizumab and radiotherapy. Thus, palliative radiation should only be undertaken if medically necessary and indicated. If radiation is undertaken, only palliative radiation to symptomatic bone metastases and limited to non‐
target lesions is allowed. Moreover, study treatment with both cabozantinib and pembrolizumab will be held at least 1 week before and resumed at least 1 week after radiation with complete recovery from acute toxicities of radiotherapy. The start and end dates of radiation, as well as the suspension and resumption dates of cabozantinib and pembrolizumab must be recorded in the CRF.
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8.4 prohibited or restricted therapy

The following therapies are prohibited from the time of screening until study treatment has been permanently discontinued:  
- Any investigational agent or investigational medical device. - Oral anticoagulants (e.g. warfarin or other coumarin‐related agents, direct thrombin or direct FXa inhibitors, antiplatelet agents such as clopidogrel, or chronic use of aspirin above low dose levels for cardioprotection per local applicable guidelines).  
- Any non‐protocolsystemic anticancer treatment (e.g. chemotherapy, immunotherapy, radionuclides, drugs or herbal products used specifically for the treatment of the cancer underinvestigation).  
- Local anticancer treatment including palliative radiation, ablation, embolization, or surgery on target lesions used for response monitoring by RECIST v1.1.  
o Note: radiation therapy to a symptomatic solitary lesion or to the brain that is not a target lesion may be allowed at the investigator's discretion.  
- Anti‐HCV therapy. - Live vaccines or live attenuated within 30 days prior to the first dose of study treatment and while participating in the study. Administration of killed vaccines is allowed.  
- Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic etiology. The use of physiologic doses of corticosteroids may be approved after consultation with the PrincipalInvestigator.
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned treatments for clinical management should be removed from the study.  
The following therapies should be avoided until study treatment has been permanently discontinued or until otherwise specified:  
- Erythropoietic stimulating agents (e.g. epoetin alfa and darbepoetin alfa) should not be used based on a report of increased risk of tumor recurrence/progression associated with erythropoietin (Wright et al 2007).  
- Concomitant medications that are known to prolong the QTc interval should be avoided in subjects who receive cabozantinib until they have permanently discontinued cabozantinib treatment (refer to http://www.qtdrugs.org for a list of drugs which have the potential to prolong the QTcinterval).  
- Chronic co‐administration of cabozantinib with strong inducers of the CYP3A4 family (Appendix 4)
may significantly decrease cabozantinib concentrations and should be avoided. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction potential is recommended if possible.  
- Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a subject who has been concurrently receiving a stable dose of cabozantinib, as this could significantly increase the exposure to cabozantinib.  
- Co‐administration of cabozantinib with strong inhibitors of the CYP3A4 family (Appendix 4) may increase cabozantinib concentrations and should be avoided. Grapefruit,starfruit, and Seville oranges may also increase plasma concentrations of cabozantinib and should be avoided. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended if possible.  
Additional information on potential drug interactions with cabozantinib is provided in Section 1.4.3. There are no prohibited therapies during the Post‐Treatment Follow‐up Phase. The risks of solid organ transplantation following treatment with PD‐1 inhibitor therapy have not been extensively studied. The time frame for safe or appropriate liver transplantation after the last dose of pembrolizumab is unknown. Therefore, it is recommended not to perform liver transplantation within at least 120 days (5 half‐lives) of stopping pembrolizumab. The risks and benefits of transplant should be discussed with the participant by the treating investigator.
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9.0 toxicities and dosing modifications

The patient's pre‐existing conditions will be recorded, including signs and symptoms of the disease.  
Subjects will be monitored for AEs from the time of informed consent through their last follow‐up visit (30 days after the date of the last dose of cabozantinib or pembrolizumab treatment, whichever occurs last). Subjects will be instructed to notify the investigator immediately at the onset of any AE experienced.  
Moreover, AEs will be assessed at scheduled study visits or non‐study clinic visits. In addition, any SAE
attributed to treatment occurring after the last follow‐up visit will also berecorded. All AEs and changes in pre‐existing conditions will be documented, whether related or unrelated to study treatment. Seriousness, severity grade, and relationship to study treatment or protocol procedure will be determined by the investigator and reported on the CRF. The NCI CTCAE v5 will be used to grade AEs. For AEs not listed in the CTCAE v5, the investigator will be responsible for selecting the appropriate system organ and severity grade based on their clinical judgement. SAEs that occur aftersigning the consent form but prior to receiving study treatment will not be reported as serious unless the event was caused by a protocol procedure.  
See Section 16.0 for definitions and guidelines on monitoring and reporting of AEs and SAEs.  
9.2 **General guidelines about toxicity assessment and management in combinationtherapy**
Both non‐immune and immune‐related toxicities may occur on study. Any AE that occurs on study will be assessed for grade and attribution to either cabozantinib, pembrolizumab, or bothagents.
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9.0 toxicities and dosing modifications

Cabozantinib and pembrolizumab have class‐specific safety profiles based on their mechanisms of action but may also cause overlapping AEs. Examples of VEGFR TKI‐associated AEs caused by cabozantinib are hypertension and hand‐foot syndrome. Examples of immune‐related AEs caused by pembrolizumab are pneumonitis and endocrinopathies. Examples of overlapping AEs are diarrhea and ALT or AST elevations.  
To distinguish the toxicities of these two agents, the known toxicity profiles and typical timeline of toxicities associated with both study drugs should be taken into account.57 For instance, in the CELESTIAl trial, the median onset of diarrhea among patients who received cabozantinib was 4.1 weeks.21 Immune‐
related AEs may occur shortly after the first dose or several months after the last dose of pembrolizumab treatment, and may affect more than one organ systemsimultaneously.  
Therefore, if an AE is believed to be possibly related to or exacerbated by cabozantinib only, then it must be managed accordingly and cabozantinib may need to be interrupted and/or dose‐adjusted. In this setting, pembrolizumab may be continued if the patient can tolerate it as per discretion of the investigator. However, it is recommended to hold pembrolizumab as well in the setting of severe (grade 3 or higher) AEs related to cabozantinib alone.  
In contrast, if an AE is believed to be possibly related to or exacerbated by pembrolizumab,, then both agents should be interrupted according to the guidelines below, even if the AE is not attributed to cabozantinib.  
For immune‐related AEs (irAEs), early recognition and initiation of treatment is critical to reduce complications. Based on existing clinical study data, most irAEs were reversible and could be managed with interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, pembrolizumab may be held or permanently discontinued and steroids may be administered.  
Guidance on dose modification of cabozantinib and pembrolizumab in the setting of specific AEs is provided in Sections 9.3 and 9.5, but management may differ from this guidance based on the clinical judgement of the investigator.  
If one agent needs to be discontinued indefinitely due to toxicity, the other agent may be continued if the patient can tolerate it as per discretion of the investigator.  
All dose interruptions and adjustments must be recorded clearly and accurately in the CRF, including dates of stopping and resuming drug(s), doses, and reasons for changes. In the event of a treatment pause, subsequent visits/cycles should not be delayed.
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9.3 information on cabozantinib toxicity

AEs may occur within the first few weeks after starting cabozantinib (steady state reached at approximately 2 weeks). Cabozantinib‐related AEs that generally have an early onset include hypocalcemia, hypokalemia, thrombocytopenia, hypertension, PPES, abdominal pain, mucosal inflammation, constipation, diarrhea, and vomiting.  
AEs should be managed with supportive care at the earliest signs of toxicity. In all subjects, dose delays and reductions of cabozantinib to manage toxicity are allowed under the guidelines below. In general, grade 3 cabozantinib‐related AEs require dose interruption until AEs recover to grade 1, at which point treatment may be resumed at the next lower dose. Moreover, dose reductions are recommended for 36 of 107 Protocol V4.0 13Dec2021 grade 2 events that, if persistent, could become serious and/or intolerable. **If cabozantinib is delayed by**
more than 4 weeks, it must be **discontinued**, unless there isreason to believe that the patient will benefit from resuming cabozantinib. In this case, resuming cabozantinib at dose reduction must be discussed with the PI.  
Furthermore, cabozantinib should be discontinued **for the following AEs:** visceral perforation or fistula formation, severe hemorrhage, serious arterial thromboembolic events, nephrotic syndrome, hypertensive emergency, persistent uncontrolled hypertension despite optimal medical management, and RPLS.  
If an AE is believed to be probably/definitely related to cabozantinib, and not related to pembrolizumab, then pembrolizumab may be continued even if cabozantinib needs to be interrupted or discontinued, as long as pembrolizumab is not expected to delay recovery or worsen the AE.
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9.3.1 gastrointestinal disorders

GI perforation, GI fistula, and intra‐abdominal and pelvic abscess: After starting treatment with cabozantinib, subjects should be monitored for early signs of GI perforation such as abdominal pain, nausea, emesis, constipation, and fever especially if known risk factors for developing GI perforation or fistula are present. Discontinue cabozantinib and initiate appropriate management in subjects who have been diagnosed with GI perforation or fistula.  
Diarrhea: Subjects should be instructed to notify their physician immediately at the first signs of poorly formed or loose stool, or an increased frequency of bowel movements. Please see Section 9.5.2 for evaluation and management of diarrhea and specific dosing instructions for both cabozantinib and pembrolizumab. Nausea and vomiting: Antiemetic agents are recommended as clinically appropriate for treatment or prophylaxis of nausea and vomiting, along with supportive care. Patients should be monitored for dehydration and electrolyte abnormalities, and correction of fluid and electrolyte disturbances should be implemented.Antiemeticmedicationsshould be assessed forpotential drug interactions(see Section8.0).
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9.3.2 non-gastrointestinal fistula

Complications from radiation therapy especially of the thoracic cavity including mediastinum have been identified as a possible predisposing risk factor for non‐GI fistula formation in subjects undergoing treatment with VEGF pathway inhibitors. Discontinue cabozantinib and initiate appropriate management in subjects who have been diagnosed with a non‐GIfistula.
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9.3.3 hemorrhage

Hemorrhagic events, including serious and sometimesfatal events, have been reported with cabozantinib. Subjects should be monitored for bleeding with clinical and laboratory assessments while on study. The risk of hemorrhage in cabozantinib‐treated subjects with brain metastases has not been thoroughly analyzed. Subjects enrolled with treated and stable brain metastases should be monitored with a high index of suspicion if symptoms that could be due to a CNS hemorrhageoccur. Cabozantinib should be discontinued in subjects with serious and life‐threatening bleeding events or recent hemoptysis (≥ 2.5 mL of red blood). For other clinically significant bleeding events, cabozantinib may be held and resumed after the bleeding resolves.
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9.3.4 thromboembolic events

Cancer patients are at increased risk of venous thromboembolic events. DVT and pulmonary embolism have been observed in clinical studies with cabozantinib, including fatal events. Subjects who develop a pulmonary embolism and/or DVT should have their study treatment interrupted until therapeutic anticoagulation is established. Treatment with cabozantinib may be resumed in subjects with DVT or pulmonary embolism if it is determined that the event is uncomplicated, the patient is relatively asymptomatic, and anticoagulation does not place them at a significant risk per discretion of the investigator.  
LMWHs are the preferred management for thrombotic events. Oral anticoagulants (e.g. warfarin or other coumarin‐related agents, direct thrombin or direct FXa inhibitors, antiplatelet agents, or chronic use of aspirin above low dose levels for cardioprotection per local applicable guidelines) are notallowed.  
Arterial thrombotic events (e.g. TIA, MI) have been observed in studies with cabozantinib. Further treatment with cabozantinib should be discontinued in subjects who develop an acute MI, cerebral infarction, or any other clinically significant arterial thromboembolic complication.
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9.3.5 hypertension

BP should be monitored in a sitting position in a relaxed setting. Decisions to reduce or interrupt the dose of study treatment must be based on BP readings taken by an experienced health care provider and must be confirmed with a second measurement at least 5 minutes following the firstmeasurement.  
Cabozantinib should be discontinued in subjects with hypertensive emergency.  
The management of hypertension related to cabozantinib is outlined in Table 9.3.5.1.  
| Table 9.3.5.1. Management of hypertension associated with cabozantinib Criteria for dose modification Management and cabozantinib modification Subjects NOT receiving optimized anti‐hypertensive therapy > 150 mm Hg (systolic)a and < 160 mm Hg  OR > 100 mm Hg (diastolic) and<  110 mm Hg - Optimize antihypertensive medications by adding   | new                                                                                                                                                                                                                                                                                               |                                                                                                        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------|
| antihypertensive medications and/or increase the dose of  existing medications.                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                   |                                                                                                        |
| -                                                                                                                                                                                                                                                                                                                                                 | Reduce cabozantinib treatment by one dose level if optimal  antihypertensive therapy (usually to include 3 agents) does not  result in BP <150 mm Hg systolic or <100 mm Hgdiastolic.                                                                                                             |                                                                                                        |
| -                                                                                                                                                                                                                                                                                                                                                 | Ifsubject issymptomatic, interrupt cabozantinib treatment and resume once BP <150 mm Hg systolic or <100 mm Hg diastolic  and symptoms resolve.                                                                                                                                                   |                                                                                                        |
| ≥ 160 mm Hg (systolic)  OR ≥ 110 mm Hg (diastolic)                                                                                                                                                                                                                                                                                                | -                                                                                                                                                                                                                                                                                                 | Reduce cabozantinib by one dose levelb orinterrupt  cabozantinib treatment per investigatordiscretion. |
| -                                                                                                                                                                                                                                                                                                                                                 | Add new anti‐hypertensive medications and/or increasethe  dose of existingmedications.                                                                                                                                                                                                            |                                                                                                        |
| -                                                                                                                                                                                                                                                                                                                                                 | If optimized antihypertensive therapy (usually to include  3 agents) does not result in BP < 150 mm Hg systolic or < 100 mm Hg diastolic, cabozantinib treatment should be  interrupted and resumed at dose reduction (if not already  done) when BP <150 mm Hg systolic or <100 mm Hg diastolic. |                                                                                                        |
| -                                                                                                                                                                                                                                                                                                                                                 | Cabozantinib treatment should be interrupted if upper limits of  systolic BP (≥ 160 mm Hg) are sustained and not adequately  manageable, if systolic BP is > 180 mm Hg or diastolic BP > 110  mm Hg, or if subject issymptomatic.                                                                 |                                                                                                        |
| -                                                                                                                                                                                                                                                                                                                                                 | Re‐start cabozantinib treatment at the most tolerable dose and re‐escalate only if BP falls to and is sustained at < 150 mm Hg  systolic and < 100 mm Hg diastolic.                                                                                                                               |                                                                                                        |
| Hypertensive emergencyc                                                                                                                                                                                                                                                                                                                           | -                                                                                                                                                                                                                                                                                                 | Discontinue cabozantinib treatment.                                                                    |
| BP, blood pressure. a The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                   |                                                                                                        |
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9.3.6 stomatitis and mucositis

Preventive measures before study treatment are recommended, such as modification of ill‐fitting dentures and appropriate care of gingivitis. During treatment with cabozantinib, good oral hygiene and standard local treatments such as gentle cleansing and oral rinses (e.g. with a weak solution of salt and baking soda) should be maintained. Lips should be kept moisturized with lip balm. The use of lipstick, lip‐
gloss, and Vaseline should be avoided.  
Local treatment should be instituted at the earliest onset of symptoms. Obtain bacterial/viral culture if oral infection is suspected and treat infection as clinically indicated.  
Cabozantinib should be interrupted for drug‐related grade 3 stomatitis and mucositis until symptoms improve to grade 1, followed by resumption of drug at the next lower dose.
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9.3.7 skin and subcutaneous tissuedisorders

Wound healing and surgery: Cabozantinib has the potential to cause wound healing complications and wound dehiscence, which may even occur long after a wound has been considered healed. Therefore, surgical and traumatic wounds must not only be completely healed prior to starting cabozantinib treatment, but must also be monitored for wound dehiscence, wound infection, and other signs of impaired wound healing while the subject is being treated with cabozantinib. If dehiscence occurs, cabozantinib treatment should not be restarted until complete healing has taken place.  
Treatment with cabozantinib should be stopped at least 28 days prior to scheduled surgery. The decision to resume treatment with cabozantinib after surgery should be based on clinical judgment of adequate wound healing.  
Palmar‐plantar erythrodysesthesia syndrome (PPES; also known as hand‐foot syndrome): skin rash
(including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been reported with cabozantinib. All subjects on study should be advised on prophylactic measures including the use of emollients, removal of calluses, avoidance of exposure of hands and feet to hot water leading to vasodilatation, protection of pressure‐sensitive areas of hands and feet, and use of cotton gloves and socks to prevent injury and keep the palms and soles dry.  
Early manifestations include tingling, numbness, mild hyperkeratosis, and symmetrical red and swollen areas on the palms and soles. The lateral sides of the fingers or periungual zones may also be affected.  
Adequate interventions are required to prevent worsening of skin symptoms such as blisters, desquamations, ulcerations, or necrosis of affected areas. Analgesics may be required for pain control.  
Aggressive management of symptoms is recommended. Recommendations for treatment of PPES and dose modification of cabozantinib are summarized in Table 9.3.7.1.  
| Table 9.3.7.1. Management of hand‐foot syndrome (PPES) associated with cabozantinib Grade per CTCAE v5 Management and cabozantinib modification Grade 1: Minimal skin  changes or dermatitis  (e.g. erythema,  edema, or hyperkeratosis  without pain) Cabozantinib treatment should be continued at the current dose. Start urea  20% cream twice daily and consider mild‐moderate potency steroid topical..  If PPES worsens at any time or does not improve after 2 weeks, proceed to the  intervention guidelines for Grade 2. Grade 2: Skin changes  (e.g. peeling, blisters,  bleeding, fissures,  edema, or hyperkeratosis) with Cabozantinib treatment may be continued at same dose, dose‐reduced,  and/or interrupted at the discretion of the treating investigator depending on  the degree ofsymptoms. Continue urea 20% cream twice daily AND add a high potency steroid topical, and add analgesics for pain control if needed. If PPES  worsens or affects self‐care, proceed to the intervention guidelines for   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
For other skin toxicities, including possible immune‐mediated skin rash, please see Section 9.5.4.  
| pain; limiting                                                                                                                                              | Grade 3.                                                                                                                                                                                                                                                                                                          |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| instrumental ADL Grade 3: Severe skin  changes (e.g. peeling,  blisters, bleeding,  fissures, edema, or  hyperkeratosis) with pain; limiting self‐care  ADL | Interrupt cabozantinib treatment until severity decreases to Grade 1.  Continue treatment of skin reaction with high potency steroid cream and  analgesics. Resume study drug at a reduced dose if PPES recovers to Grade ≤ 1. Discontinue subject from study treatment if PPES does not improve within  4 weeks. |
| CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non‐steroidal anti‐inflammatory drug; PPES,                                                   |                                                                                                                                                                                                                                                                                                                   |  
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non‐steroidal anti‐inflammatory drug; PPES,  
palmar plantar erythrodysesthesia syndrome.  
1Permitted dose levels are defined in Section 9.4.
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9.3.8 osteonecrosis

Osteonecrosis has been reported in subjects treated with cabozantinib. Additional risk factors include use of bisphosphonates and denosumab, chemotherapy and anti‐angiogenic drugs, use of corticosteroids, local radiotherapy, and dental or orofacial surgery procedures. Osteonecrosis of the jaw (ONJ) can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of osteonecrosis.  
Perform an oral examination prior to initiation of cabozantinib and periodically during cabozantinib treatment. Advise subjectsregarding oral hygiene practice and to quickly reportsymptomsto Investigator. Caution should be used in subjects receiving bisphosphonates. Dental surgery or invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, treatment with cabozantinib should be interrupted for at least 4 weeks prior to the procedure and resumed after complete wound healing has occurred. Bone healing may often require a protracted time. Withhold cabozantinib for development of ONJ until complete resolution.
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9.3.9 proteinuria

Proteinuria has been reported with cabozantinib. Proteinuria should be monitored by measuring UPCR
once every 6 weeks(every 2 cycles) on treatment, and more frequently if abnormal. Table 9.3.9.1 provides treatment guidelinesfor proteinuria related to **cabozantinib.** Cabozantinib should be discontinued in subjects who develop nephrotic syndrome (proteinuria > 3.5 grams per day in combination with low blood protein levels, high cholesterol levels, high triglyceride levels, and edema).  
| RG1007034 Table 9.3.9.1. Management of proteinuria associated with cabozantinib Severity of Management and cabozantinib modification proteinuria (UPCR) ≤ 1 mg/mg (≤ 113.1  - No change in cabozantinib treatment ormonitoring. mg/mmol) - Consider confirming with a 24‐h protein assessment within 7days. - No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or urine  protein ≤ 2 g/24 h on 24‐h urine collection. - Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg on  repeat UPCR testing or urine protein > 2 g/24 h on 24‐h urine collection.  Continue cabozantinib on a reduced dose if UPCR decreases to < 2 mg/mg.  Consider interrupting cabozantinib treatment if UPCR remains > 2 mg/mg  despite a dose reduction until UPCR decreases to < 2 mg/mg. Restart  cabozantinib treatment at a reduced dose after a doseinterruption. - After dose reduction or interruption, repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg on 2 consecutive readings, UPCR monitoring  can revert to once monthly. (Second reading is confirmatory and can be  done within 1 week of first reading.) If UPCR remains > 1 mg/mg and < 2  mg/mg for 1 month or is determined to be stable (< 20% change) for 1  month, check urine protein/creatinine once monthly as clinically indicated. - Interrupt cabozantinib treatment pending repeat UPCR within 7 days and/or  ≥ 3.5 mg/mg (≥ 395.9 mg/mmol) 24‐h urine protein. - If ≥ 3.5 mg/mg on repeat UPCR, continue to interrupt cabozantinib  treatment and check UPCR every 7 days. If UPCR decreases to < 2 mg/mg,  restart cabozantinib treatment at a reduced dose and monitoring of urine  protein/creatinine should continue weekly until the UPCR decreases to < 1  mg/mg. If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or is determined to be stable (< 20% change) for 1 month, check urine  protein/creatinine once monthly or as clinically indicated. Nephrotic syndrome - Discontinue cabozantinib. RCC, renal cell carcinoma; UC, urothelial carcinoma; UPCR, urine protein/creatinine ratio. > 1 and < 3.5mg/mg (> 113.1 and < 395.9 mg/mmol)   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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9.3.10 nervous system disorders

Cabozantinib appears to represent minimal risk of adverse neurological effects based on nonclinical Good Laboratory Practice (GLP)‐compliant toxicology studies. Dysphonia, dysgeusia, headache, dizziness, confusional state, convulsion, depression, memory impairment, hypoesthesia, peripheral neuropathy, insomnia, ataxia, and encephalopathy have been observed in clinical studies with cabozantinib. The development of any new or progressive, unexplained neurological symptoms should be assessed for underlying causes. RPLS has been reported. RPLS should be considered in any subject presenting with seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatmentshould be discontinued in subjects with RPLS.
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9.3.11 hepatocellular toxicity

Elevation of aminotransferases (ALT and AST): Evaluation of subjects with elevated transaminases or bilirubin should be individualized and guided by the presence of specific risk factors such as liver conditions (e.g. liver cirrhosis, liver metastases, thrombosis of portal or hepatic vein), concomitant hepatotoxic medication, alcohol consumption, and cancer‐related causes. Specifically, pembrolizumab is a potential cause of immune‐mediated hepatitis and reactivation or flare of HBV or HCV in affected patients is a possibility. **Please see Section 9.5.3 for evaluation and management of liver toxicity and**
specific dosing instructions for both cabozantinib and pembrolizumab.
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9.3.12 infections and infestations

Infections and abscesses should be treated with appropriate local care and systemic therapy. Cabozantinib should be interrupted if there are open wounds until adequate healing hastaken place. For minor ormildly symptomatic infections (e.g. urinary tract infection, cellulitis), cabozantinib may be continued at the discretion of the investigator if the drug is believed to be unrelated and is not expected to worsen the infection.
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9.3.13 blood and lymphatic system

Hematological toxicities (e.g. neutropenia, thrombocytopenia) have been observed after administration of cabozantinib. Subjects with hematologic toxicities may require additional or more frequent laboratory tests according to institutional guidelines.  
See Section 9.5.1 for guidance on dose modification of cabozantinib for hematologic toxicities. The use of colony‐stimulating growth factors may be considered for significant neutropenia (e.g. grade 3 or higher) believed to be related to cabozantinib. Febrile neutropenia or evidence of infection associated with neutropenia must be assessed immediately and treated appropriately and in a timely manner according to institutional guidelines, with interruption of study treatment untilresolution.  
Supportive care for thrombocytopenia or anemia, such as transfusions, may be considered according to institutional guidelines. However, if there is a recurrent need for transfusions or grade 3 events, dose reduction of cabozantinib to the next lower dose is recommended.
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9.3.14 fatigue

Common causes of fatigue, such as anemia, deconditioning, emotional distress (depression and/or anxiety), poor nutrition, dehydration, sleep disturbance, and hypothyroidism should be ruled out and treated according to standard of care.  
For clinically significant fatigue (e.g. grade 3) related to or exacerbated by cabozantinib, dose interruption and/or dose reduction isrecommended.
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9.3.15 weight loss

Anorexia and weight loss should be managed according to local standard of care including nutritional support. Pharmacologic therapy may be considered for appetite enhancement when not prohibited if there is minimal drug interaction with cabozantinib (see Section 8.4).  
For clinically significant weight loss or anorexia (e.g. grade 3) related to or exacerbated by cabozantinib, dose interruption and/or dose reduction is recommended.
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9.3.16 qtc prolongation

The effect of orally administered cabozantinib 140 mg once daily on QTc interval was evaluated in a placebo‐controlled study in subjects with medullary thyroid cancer. A mean increase in QTcF of 10‐15 ms was observed at 4 weeks after initiating cabozantinib treatment. A concentration‐QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No cabozantinib‐treated subjects in this study had a QTcF > 500 ms. Review of the larger safety database (~5000 subjects exposed to cabozantinib in clinical trials and in post‐
marketing experience) confirmed the absence of safety concerns associated with QT prolongation. There were no events of torsades de pointesreported. Concomitant treatment with strong CYP3A4 inhibitors, which may increase cabozantinib plasma concentrations, should be avoided. An EKG should be obtained every 2 cycles on treatment. At any time on study, if there is an increase in QTcF to an absolute value > 500 ms, two additional EKGs must be performed with intervals not less than 5 min apart within 30 min after the initial EKG.  
If the average QTcF from the three EKGs is > 500 ms, the following actions must be taken:  
- Interrupt cabozantinib treatment.  
- Hospitalize symptomatic subjects(e.g. palpitations, dizziness, syncope, orthostatic hypotension, ventricular arrhythmia on EKG) for a thorough cardiology evaluation andmanagement.  
- Consider cardiology consultation for asymptomatic subjects for evaluation andmanagement.  
- Check electrolytes, especially magnesium, potassium and calcium; correct abnormalities asclinically indicated.  
- Check for concomitant medications that may have contributed to QT prolongation, and if possible, discontinue these medications (http://www.qtdrugs.org).
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc elevation and symptoms have resolved. Cabozantinib treatment may be restarted at a reduced dose level if all of the following conditions are met:  
- Symptoms are determined to be unrelated to the QT intervalprolongation. - The QTcF value > 500 ms is not confirmed.  
- Cabozantinib treatment has been interrupted through a minimum of 1 week following the return of the QTcF to ≤ 500 ms.  
- QT prolongation can be unequivocally associated with an event other thancabozantinib administration and is treatable/has been resolved.
Following reinitiation of study treatment, EKGs must be repeated weekly for 2 weeks, then every 2 weeks for 1 month, then according to the protocol‐defined time points.  
Cabozantinib treatment must be permanently discontinued if either of the following applies:
- Cardiac evaluation confirms that symptoms are the consequence of QT intervalprolongation.  
- Recurrence of QTcF prolongation after reinitiation of study treatment at a reduceddose.
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9.3.17 electrolyte disorders

Serum electrolyte disorders including hyponatremia, hypokalemia, hypomagnesemia, and hypophosphatemia have been reported during treatment with cabozantinib, and serum electrolyte levels should be monitored at least every 3 weeks while receiving cabozantinib. More frequent monitoring may be required. Standard clinical practice guidelines should be used for management of electrolyte disorders and may include oral or intravenousreplacement.
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9.3.18 angioedema

Angioedema should be managed according to standard practice. The subject should be observed until symptoms resolve, with particular attention to effects on airway. If life‐threatening angioedema is probably or definitely related to cabozantinib, the drug must be discontinued.
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9.3.19 endocrine disorders

Treatment‐emergent elevation of thyroid‐stimulating hormone (TSH) has been observed with cabozantinib monotherapy treatment. Currently available data are insufficient to determine the mechanism of thyroid function test alterations and its clinical relevance.  
TSH elevation may also be related to immune‐mediated endocrinopathy caused by pembrolizumab, which occurs in 8% and 5% of patients in the KEYNOTE‐224 and KEYNOTE‐240 trials, respectively (mostly grade 1‐2).35,36 TSH and free T4 and T3 should be checked at least every 6 weeks (every 2 cycles) onstudy.  
Regardless of whether it is related to cabozantinib and/or pembrolizumab, clinically symptomatic hypothyroidism should be treated with thyroxine replacement as per accepted clinical practice guidelines.  
See Section 9.5.5 for treatment guidelines for suspected immune‐mediated endocrineAEs.
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9.4 dose levels of cabozantinib

Cabozantinib must be started at 40 mg orally once daily and reduced to 20 mg orally once daily (minimum dose) for toxicity. Cabozantinib must be discontinued permanently if the minimal dose is not tolerated.  
Re‐escalation to 40 mg once daily is not recommended, but may be allowed if there is a reason to believe that the patient will tolerate this dose after discussion with thePI.  
| Table 9.4.1. Dose levels for cabozantinib Dose Adjustment Level Oral Dose   | Frequency   |            |
|-----------------------------------------------------------------------------|-------------|------------|
| 0 (starting dose)                                                           | 40 mg       | Once daily |
| ‐1                                                                          | 20 mg       | Once daily |
| ‐2                                                                          | Discontinue |            |  
9.5 Guidance on dose modification of cabozantinib and pembrolizumab for non‐immune and immune **toxicities**
Both non‐immune and immune‐mediated toxicities may occur on study.  
The sections below provide guidance on dose modifications for TRAEs, in addition to management recommendations for cabozantinib‐specific toxicities discussed in Section 9.3. However, management may differ from this guidance based on the clinical judgement of the investigator. In all patients, supportive care should be initiated to manage the AEs in addition to dose modification of study drugs.  
For potential irAEs, please refer to the ASCO Clinical Practice Guidelines for Management of Immune‐
Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy.58 If dose is interrupted for TRAEs, cabozantinib must be resumed within 4 weeks of last dose, and pembrolizumab must be resumed within 12 weeks of last dose. Resuming drugs beyond these time points must be discussed with the Study PI.
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9.5.1 non-immune toxicities

Table 9.5.1.1 below provides guidance for dose modification for non‐immune toxicities in general.  
Pembrolizumab should be held if the AE is clinically severe and/or if pembrolizumab might delay recovery or worsen the AE.  
| Table 9.5.1.1. General guidance on dose modification for non‐immune toxicities Grade per CTCAE v5 Cabozantinib modification Pembrolizumab modification  Hematologic TRAEs Grade 1 and 2 - No modification. - No modification. Grade 3 or 4  anemia,  neutropenia,  thrombocytopenia 1  - Hold drug until recovery to  grade 1, then restart at same  dose level OR at reduced dose  level (at the discretion of the  investigator). - 1st and 2nd recurrence: hold  drug until recovery to grade 1,  then restart at reduced dose  level (if not already reduced)  or discontinue drug (if  previously reduced dose). - No modification. Consider  holding drug if no  improvement after holding  cabozantinib. Non‐hematologic TRAEs Grade 1 or 2 - No modification (may be held for  significantly symptomatic  grade 2 toxicity). Supportive  care as indicated. - No modification. Grade 3 - Hold drug untilrecovery to grade 1. If supportive care can be used  and optimized to control  symptoms, then restart at the  same dose level. If grade 3  toxicity occurred on maximal  supportive care then restart at  reduced dose level. - Hold drug until recovery to  grade 1 (or pretreatment  baseline), then restart drug.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| -                                                                                                                                                                               | 1st                              | and 2nd                                                                                                                                                                                          | recurrence despite                                                                  |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------|
| optimal supportive care: hold  drug until recovery to grade 1,  then restart at reduced dose  level (if not already reduced) or discontinue drug (if previously  reduced dose). |                                  |                                                                                                                                                                                                  |                                                                                     |
| Grade 4                                                                                                                                                                         | -                                | Hold drug and provide supportive  care until recovery to grade 1,  then restart at reduced dose level  if the patient is deriving clinical  benefit as determined by the  treating investigator. |                                                                                     |
| -                                                                                                                                                                               | 1st recurrence: discontinuedrug. | -                                                                                                                                                                                                | Hold drug until recovery tograde  1 (or pretreatment baseline),  then restart drug. |
| TRAE, treatment‐related adverse event.                                                                                                                                          |                                  |                                                                                                                                                                                                  |                                                                                     |  
TRAE, treatment‐related adverse event.  
1Supportive transfusions and use of G‐CSF recommended as per institutional guidelines.  
Note:Continuation ofstudy drugsin the setting of asymptomatic grade 3‐4 elevations ofamylase/lipase is permitted after discussion with the study PI.
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9.5.2 diarrhea

Diarrhea is a known toxicity of both cabozantinib and immune checkpoint inhibitors such as pembrolizumab. In the CELESTIAL trial of cabozantinib (starting dose of 60 mg daily) vs. placebo, 54% of patients treated with cabozantinib had diarrhea of any grade, and 10% had grade 3 diarrhea. The median time of onset of diarrhea was 4.1 weeks.21 In the KEYNOTE‐224 trial of pembrolizumab, 11% of patients experienced diarrhea (all grade 1‐2, no grade 3 or 4), while the rate of immune‐mediated colitis was 1%.35 In the randomized KEYNOTE‐240 trial, diarrhea occurred in 16% of patients on the pembrolizumab arm
(1.2% grade 3‐4).36 The combination of multikinase inhibitor and immune checkpoint inhibitor may potentially increase diarrhea. However, the rate of diarrhea was similar with the combination of lenvatinib and pembrolizumab as observed in the early Phase 1b trial (any grade, 43%; grade 3, 3%) compared to lenvatinib alone (any grade, 39%; grade 3, 4%).10,38 Enrolled patients should be closely monitored for diarrhea, and if present, attribution to cabozantinib or pembrolizumab or both must be carefully considered. Timing may guide attribution, as the onset of diarrhea related to cabozantinib tends to occur shortly after starting drug (e.g. within 2 weeks), while the median time to onset of immune‐related colitis related to pembrolizumab was 3.5 months with a median duration of 1.4 months.  
Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions, which increase the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene should be emphasized. Examination of the perianal region should be performed for reported perianal symptoms in patients experiencing diarrhea during treatment with cabozantinib/pembrolizumab. Infections of the perianal region should be treated per local guidelines.
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general management for diarrhea

- Monitor patients for signs and symptoms of colitis (e.g. diarrhea, abdominal pain, bloody stools, fever) and bowel perforation.Administration of antidiarrheal/antimotility agents is recommended at the first sign of diarrhea as initial management (e.g. loperamide 4 mg followed by 2 mg after each episode of diarrhea [maximum: 16 mg loperamide per day]). Some subjects may require treatment with more than one antidiarrheal agent, and the addition of diphenoxylate/atropine and/or tincture of opium can be considered. In addition, general supportive measures should be implemented, such as increasing oral hydration (+/‐ IV isotonic fluids), correcting electrolyte abnormalities, small frequent meals, and stopping lactose‐containing products, high‐fat meals and alcohol. When diarrhea resolves to baseline bowel habits, gradually add solid foods and discontinue or decrease antidiarrheal treatment after 12 h diarrhea‐freeinterval.  
- For grade 1 and 2 diarrhea: supportive measures as above.  
- For intolerable grade 2 diarrhea or grade 2 diarrhea >48 hours despite optimalsupportive measures as above:
o Obtain labs to rule out dehydration and electrolyte abnormalities.  
o Rule out infectious diarrhea (e.g. stool culture, C difficile toxin, entericpanel). o If diarrhea lasts > 7 days, consider imaging (e.g. CT abdomen/pelvis) and GI consultfor colonoscopy for biopsy.  
- If infectious source is ruled out and diarrhea is persistent > 7 days, suspect immune‐mediated colitisForsevere and/or life‐threatening diarrhea:
o Admit to hospital for IV hydration and electrolyte replacements.  
o Rule out infectious diarrhea (e.g. stool culture, C difficile toxin, entericpanel).  
o Obtain imaging (e.g. CT abdomen/pelvis) and GI consult for colonoscopy forbiopsy.  
o
- See Table 9.5.2.1 for dosing of cabozantinib and pembrolizumab in the setting ofnon‐immune diarrhea. For suspected immune‐mediated colitis, also follow guidelines in Table9.5.5.1.  
| Table 9.5.2.1. Guidance for diarrhea due to cabozantinib (non‐immune) Grade per CTCAE v5 Cabozantinib modification Pembrolizumab modification Grade 1 (< 4  stools/day over baseline) - Continue at same dose. - Continue at same dose. Grade 2 (4‐6  stools/day over  baseline) - Continue at same dose, or if  intolerable grade 2 or grade 2 >48  hours despite optimal supportive  measures and anti‐diarrheals,  hold drug until improvement to  grade 1, then restart at samedose  or at reduced dose (at the  discretion of the investigator). - Continue at same dose.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Grade 3 (7 or more  stools/day over  baseline)                                                                               | -                                                                                                                                | Hold drug until recovery to grade  1, then restart at same dose (if  best supportive care was not  previously used) or at reduced  dose (if diarrhea is uncontrolled  despite best supportive care).   |                                                                                      |
|------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|
| -                                                                                                                            | 1st                                                                                                                              | recurrence: hold drug until                                                                                                                                                                            |                                                                                      |
| recovery to grade 1, then restart  at reduced dose (if not already  done) or discontinue drug (if dose  previously reduced). | -                                                                                                                                | Hold drug until recovery to grade 1  (or pretreatment baseline), then  restart drug.                                                                                                                   |                                                                                      |
| Grade 4 (life‐                                                                                                               | -                                                                                                                                | Hold drug until recovery to grade                                                                                                                                                                      |                                                                                      |
| threatening)                                                                                                                 | 1, then restart at reduced dose  level if the patient is deriving  clinical benefit as determined by  the treating investigator. |                                                                                                                                                                                                        |                                                                                      |
| -                                                                                                                            | 1st recurrence: discontinuedrug.                                                                                                 | -                                                                                                                                                                                                      | Hold drug until recovery to grade 1  (or pretreatment baseline), then  restart drug. |
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9.5.3 liver toxicity

HCC patients are at risk for a range of complications that can cause hepatic laboratory abnormalities with or without clinical decompensation. Moreover, temporary hepatic decompensation may occur especially in cirrhotic patients when exposed to a TKI. It may be difficult to distinguish these lab abnormalities related to cabozantinib from immune‐mediated hepatitis of pembrolizumab. Grade 3 immune‐related hepatitis was observed in 3% of patients who received pembrolizumab in the KEYNOTE‐224 trial,35 while 7% of patientstreated with pembrolizumab in the KEYNOTE‐240 trial experienced an immune‐mediated hepatic event, although no HBV/HCV flares occurred.36 Previous studies showed that immune‐mediated hepatitis typically occurs during the first 6‐
12 weeks after initiating an immune checkpoint inhibitor.59 Those with a history of chronic HCV or HBV
infection also have the potential to experience virologic flares.
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hepatic events of clinical interest

- ALT:
a: Among subjects with baseline ALT <2×ULN: ALT ≥5×ULN
b: Among subjects with baseline ALT ≥2×ULN: ALT >3× the baselinelevel c: ALT >500 U/L regardless of baseline level
- Total bilirubin:
a: Total bilirubin >3.0 mg/dL
- Regardless of laboratory values, hepatic decompensation diagnosed clinically,including:
- New onset clinically detectable ascites requiring intervention for >3days
- Hepatic ncephalopathy
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general management for liver toxicity

- In the setting of liver toxicity indicated by abnormal liver function tests (e.g. ALT, AST, ALP, total bilirubin, INR), monitor liver function **at least weekly** until recovery to baseline orstabilization.  
- If there is grade 3 hepatic toxicity, it is recommended that both cabozantinib and pembrolizumab be interrupted and the patient be further evaluated. Consider causes of hepatitis and obtain appropriate workup, including disease progression, viral causes (HBV, HCV, EBV, CMV), drug‐ or alcohol‐induced hepatitis, herbals, infection, biliary obstruction, etc.  
- When an HECI occurs:
- Hold study intervention and notify the Principal Investigator within 24 hours. All cases of retreatment after interruption of study intervention for HECI must be reported to the Principal Investigator and recorded in the database.  
- All participants should be considered for evaluation according to the directions below within 72 hours of onset:
o Consider obtaining a consultation with a hepatologist.  
o Obtain a work‐up for hepatitis if there is no underlying hepatitis, including hepatitis A, B,
C, D, E, Epstein‐Barr virus, andcytomegalovirus.  
o Assess for ingestion of drugs/supplements with hepatotoxicpotential.  
o Assess for alcohol ingestion.  
o Assess for potential bacterial infection, biliary obstruction, oroccultgastrointestinal bleeding.  
o Repeat ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, γ‐glutamyl transpeptidase, INR, and complete blood count withdifferential.  
o Measure HCV RNA viral load (applies only for participants who have current activeHCV
infection or had infection in the past).  
o HBV DNA, HBsAg, HBeAg, HBcAb (total and IgM), HBeAb, and HBsAb regardless of prior HBV status (Note: participants should be questioned about compliance with the use of antiviral agents).  
o Other laboratories or imaging studies as clinically indicated.  
- Consider liver biopsy if indicated.In the setting of HBV flare or change in HBV immunologicstatus:
o Start antiviral therapy if appropriate o Measure HBsAg and HBV DNA on **weekly** basis (if detected at the time of onset ofHECI).  
o Evaluate the following every 2‐3 weeks if not detected at the time of onset ofHECI
- Anti‐HBe, HBe antigen, anti‐HBs, and HBV DNA levels (if not detected at the onset of HECI)
- In the setting of HCV exacerbation in patients with positive HCV RNA, relapse of HCV in patients with previous antiviral treatment, or new HCV infection:
o Recheck HCV genotype at the time of relapse of HCV RNA to rule out newinfection.  
o Measure HCV RNA levels every 2 **weeks**.  
− Please discuss risk benefit with Principal Investigator prior to starting HCV antiviral therapy.‐ If there are other causes of liver dysfunction, treat accordingly (e.g. biliary obstruction).  
- The following table provides guidance on the dosing of cabozantinib and pembrolizumab in the setting of non‐immune liver toxicity.  
- If there issuspicionforpossible pembrolizumab‐mediated hepatitis, alsofollowthemanagementoutlined in Table9.5.5.1:
- Cabozantinib may be held up to 28 days, and pembrolizumab may be held up to 12weeks. - Elevations >3 × ULN of ALT or AST concurrent with >2 × ULN total bilirubin without other explanation can indicate drug‐induced liver injury (DILI) due to cabozantinib. Cabozantinib should be permanently discontinued in cases determined to be DILI according to Hy's Law review.  
- Study treatment should be discontinued indefinitely if grade 3 hepatic dysfunction is not reversed despite dose interruption and treatment of potential causes including immune‐mediatedhepatitis.  
| Table 9.5.3.1. Guidance for liver toxicity due to cabozantinib (non‐immune) Grade per CTCAE v5 Cabozantinib modification1 Pembrolizumab modification1 ALT/AST > 5 x ULN if ALT/AST ≤ 2 x ULN at  baseline OR ALT/AST 3‐  fold increase from D1  level BUT NOT  EXCEEDING 8 X ULN if  ALT/AST > 2 x ULN at baseline - Hold drug until recovery to ≤  grade 2 ALT/AST elevation, then  restart at reduced dose (consider  resume at the same dose if other  cause of liver toxicity found). - 1st recurrence: discontinuedrug. - Hold drug until recovery to  grade 1 (or pretreatment  baseline), then restart drug. ALT or AST > 5 x ULN accompanied by total  bilirubin ≥ 2 x ULN - Hold drug until recovery to ≤  grade 1 ALT/AST and bilirubin  elevation or pre‐treatment  baseline, then restart at reduced  dose (consider resume at the  same dose if other cause of liver  toxicity found). - 1st recurrence: discontinue. - Note: A patient with Gilbert's  syndrome should be managed  according to observed elevation  of ALT and/or AST if the observed  bilirubin increase is below actual increased baseline bilirubin  value. - Hold drug until recovery to  grade 1 (or pretreatment  baseline), then restart drug.   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| RG1007034 Total bilirubin > 3.0  mg/dL irrespective of  ALT/AST values                                                                             | -                                                                                                                                                                                                                                   | Hold drug until recovery to ≤  grade 1 ALT/AST and bilirubin  elevation,then restart at reduced  dose (consider resume at the  same dose if other cause of liver  toxicity found).   |                                                                                      |                                                                                                                                                                                                                                                  |
|----------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| -                                                                                                                                                  | 1st recurrence: discontinue.                                                                                                                                                                                                        | -                                                                                                                                                                                    | Hold drug until recovery to  grade 1 (or pretreatment  baseline), then restart drug. |                                                                                                                                                                                                                                                  |
| -                                                                                                                                                  | Note: For a patient with Gilbert's  syndrome, a continuation of  cabozantinib might be  considered at the discretion of  the investigator if the observed  bilirubin increase is below actual  increased baseline bilirubin  value. |                                                                                                                                                                                      |                                                                                      |                                                                                                                                                                                                                                                  |
| AST and/or ALT > 20 x                                                                                                                              | -                                                                                                                                                                                                                                   | Discontinue drug.                                                                                                                                                                    | -                                                                                    | Hold drug until recovery to                                                                                                                                                                                                                      |
| ULN                                                                                                                                                | grade 1 (or pretreatment baseline), then restart drug.                                                                                                                                                                              |                                                                                                                                                                                      |                                                                                      |                                                                                                                                                                                                                                                  |
| Hepatic  encephalopathy not  reversible and manageable by  therapy2                                                                                | -                                                                                                                                                                                                                                   | Discontinue drug.2                                                                                                                                                                   | -                                                                                    | Discontinue drug.2                                                                                                                                                                                                                               |
| Child‐Pugh score > 8                                                                                                                               | -                                                                                                                                                                                                                                   | Discontinue drug.2                                                                                                                                                                   | -                                                                                    | Hold drug until Child‐Pughscore                                                                                                                                                                                                                  |
| points2                                                                                                                                            | < 8, then resume at drug.2                                                                                                                                                                                                          |                                                                                                                                                                                      |                                                                                      |                                                                                                                                                                                                                                                  |
| GI bleeding suggestive  or portal hypertension  (e.g. esophageal or  gastric varices)                                                              | -                                                                                                                                                                                                                                   | Discontinue drug.                                                                                                                                                                    | -                                                                                    | Hold drug until bleeding has  resolved and intervention  completed if indicated (e.g.  variceal banding) and patient is  stable, then restart at the same  dose as long as Child‐Pugh score < 8 and ALT/AST/bilirubin  elevations are < grade 3. |
| 1 Once dose reduced, cabozantinib dose cannot be increased. Cabozantinib may be held up to 28 days, and  pembrolizumab may be held up to 12 weeks. |                                                                                                                                                                                                                                     |                                                                                                                                                                                      |                                                                                      |                                                                                                                                                                                                                                                  |
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9.5.4 skin toxicity other than

Dose modification of cabozantinib for hand‐foot reaction (or PPES) is covered in Section 9.3.7. Oher skin rashes or abnormalities may occur due to cabozantinib.
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general management of skin toxicities

- Optimize supportivemeasures, including topical emollients, oral antihistamines, and medium‐to high potency topical corticosteroids.  
- For grade 2 and higher skin toxicity, monitor weekly forimprovement.  
- For grade 3 skin toxicity, consider referral toDermatology. - If a grade 3 rash does not improve within 7 days after stopping cabozantinib and pembrolizumab and providing optimal supportive measures, suspect immune‐mediated skintoxicity.  
- See Table 9.5.4.1 for dosing of cabozantinib and pembrolizumab for non‐immune mediated skin toxicity. For immune‐mediated skin toxicity, see Table 9.5.5.1.  
| Table 9.5.4.1. Guidance for non‐immune skin and subcutaneous toxicity other than PPES (e.g. rash,  erthymatous, follicular, macular, dermatitis, pruritis). Grade per  Cabozantinib modification Pembrolizumab modification CTCAE v5 Grade 1 or 2 - Continue at the same doselevel. - Continue at the same doselevel. Grade 3 - Hold drug until recovery to grade 2 or  less, then restart at same dose or at  reduced dose (at the discretion of the  investigator). - 1st and 2nd recurrence: hold until  recovery to grade 2 or less, then  restart at reduced dose level (if not  already reduced) or discontinue drug  (if previously reduced dose). - Hold drug until recovery to grade 1  (or pretreatment baseline), then  restart drug. Grade 4 or  Steven Johnson Syndrome of any  grade - Hold drug untilrecovery to grade 2 or  less, then restart at reduceddose. - 1st recurrence: discontinue drug. - Hold drug until recovery to grade1  (or pretreatment baseline), then  restart drug.   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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9.5.5 immune-related toxicities

Immune‐related AEs (irAEs) may occur after the first dose or several months later. Workup should be performed to rule out other causes. Most irAEs are reversible when the immune checkpoint inhibitor is stopped and steroids and supportive care are initiated. Depending on severity of irAEs, pembrolizumab may be resumed after recovery (after completion of steroid taper) or permanently discontinued.  
The ASCO Clinical Practice Guidelines on the Management of Immune‐Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy58 provides a comprehensive overview of potential irAEs and management. Whenever possible, it is recommended that these guidelines befollowed.
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general management for iraes

- Consider other causes and ensure adequate workup to rule out other etiology if applicable (e.g.  
infectious, drug‐induced).  
- Please see Table 9.5.5.1 for guidance on pembrolizumb dosing for specific irAEs. Whenever pembrolizumab is held for an irAE, cabozantinib should also be held. The latter can resumed when the irAE improves to grade 1
(even if pembrolizumab has not been restarted yet, e.g. during steroidtaper).  
.
Table 9.5.5.1. Dose modification and toxicity management guidelines for other immune‐related AEs..  
| General instructions: 1. Even if the AE is not related to cabozantinib, hold cabozantinib whenever pembrolizumab is held for an  irAE. 2. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at  least 4 weeks. 3. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been  reduced to Grade 1 and corticosteroid has been tapered. Pembrolizumab should be permanently  discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10  mg prednisone or equivalent per day within 12 weeks. 4. For severe and life‐threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other  immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 5. Cabozantinib may be restarted when the irAE improves to grade 1 at the discretion of the treating  investigator. Cabozantinib should be restarted within 4 weeks of drug interruption (this may occur during  steroid taper). If this must be restarted after 4 weeks after interruption for an irAE, please discuss with the  Study PI. Immune‐related  Toxicity grade AEs or conditions  (CTCAEv5.0) Action taken to  irAE management with pembrolizumab corticosteroid and/or  other therapies Monitor and follow‐up Pneumonitis Grade 2 Withhold - Administer  corticosteroids  (initial dose of 1‐2  mg/kg prednisone or  equivalent) followed  by taper - Monitor participants for signs  and symptoms of pneumonitis - Evaluate participants with  suspected pneumonitis with  radiographic imaging and  initiate corticosteroid  treatment - Add prophylactic antibiotics  for opportunisticinfections Grade 3 or 4,  or recurrent  Grade 2 Permanently  discontinue Type 1 diabetes  mellitus (T1DM)  or  Hyperglycemia Newly onset  T1DM or  Grade 3 or 4  hyperglycemia  associated  with evidence of β‐cell  failure Withhold - Initiate insulin  replacement therapy  for participants with  T1DM - Administer anti‐  hyperglycemic in participants with  hyperglycemia - Monitor participants for  hyperglycemia or other signs and symptoms  of diabetes.   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Hypophysitis                      | Grade 2                                                                                                                                                            | Withhold        | -                                                                           | Administer  corticosteroids and  initiate hormonal  replacements as  clinically indicated.        | -   | Monitor for signs and  symptoms of hypophysitis (including   |
|-----------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|-----------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|-----|--------------------------------------------------------------|
| Grade 3 or 4                      | Withhold or                                                                                                                                                        | hypopituitarism |                                                                             |                                                                                                   |     |                                                              |
| permanently                       | and adrenal insufficiency)                                                                                                                                         |                 |                                                                             |                                                                                                   |     |                                                              |
| discontinue1                      |                                                                                                                                                                    |                 |                                                                             |                                                                                                   |     |                                                              |
| Hyperthyroidism                   | Grade 2                                                                                                                                                            | Continue        | -                                                                           | Treat with non‐  selective beta‐  blockers (eg,  propranolol) or thionamides as  appropriate      | -   | Monitor for signs and  symptoms of thyroiddisorders.         |
| Grade 3 or 4                      | Withhold or  permanently  discontinue1                                                                                                                             |                 |                                                                             |                                                                                                   |     |                                                              |
| Hypothyroidism                    | Grade 2‐4                                                                                                                                                          | Continue        | -                                                                           | Initiate thyroid  replacement  hormones (eg,  levothyroxineor liothyroinine)per  standard of care | -   | Monitor for signs and  symptoms of thyroiddisorders.         |
| Nephritis and  Renal  dysfunction | Grade 2                                                                                                                                                            | Withhold        | -                                                                           | Administer  corticosteroids  (prednisone 1‐2 mg/kg or equivalent)  followed by taper.             | -   | Monitor changes of renal  function                           |
| Grade 3 or 4                      | Permanently  discontinue                                                                                                                                           |                 |                                                                             |                                                                                                   |     |                                                              |
| Myocarditis                       | Grade 1 or 2                                                                                                                                                       | Withhold        | -                                                                           | Based on severity of  AE administer  corticosteroids                                              |     |                                                              |
| -                                 | Cabozantinib must  be held until resolved to grade 0.                                                                                                              | -               | Ensure adequate evaluationto  confirm etiology and/or  exclude other causes |                                                                                                   |     |                                                              |
| Grade 3 or 4                      | Permanently  discontinue                                                                                                                                           |                 |                                                                             |                                                                                                   |     |                                                              |
| All other immune‐                 | Intolerable/                                                                                                                                                       |                 |                                                                             |                                                                                                   |     |                                                              |
| related AEs                       | persistent  Grade 2                                                                                                                                                | -               | Ensure adequate evaluationto  confirm etiology and/or  exclude other causes |                                                                                                   |     |                                                              |
| Grade 3                           | Withhold or  discontinue  based on the  type of event.  Events that  require  discontinuation  include and not  limited to:  Gullain‐Barre Syndrome,  encephalitis |                 |                                                                             |                                                                                                   |     |                                                              |
| Grade 4 or recurrent  Grade 3     | Withhold                                                                                                                                                           | -               | Based on type and  severity of AE  administer  corticosteroids              |                                                                                                   |     |                                                              |
| Permanently  discontinue          |                                                                                                                                                                    |                 |                                                                             |                                                                                                   |     |                                                              |  
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE:
For participants with Grade 3 or 4 immune‐related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
9.5.6 Pembrolizumab‐related infusion **reaction** Pembrolizumab may cause severe or life‐threatening infusion‐reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 9.5.6.1. No dose modification is required for cabozantinib.  
| Table 9.5.6.1. Pembrolizumab infusion reaction dose modification and treatment guidelines NCI CTCAE grade Treatment Premedication at  subsequent dosing Grade 1 Mild reaction; infusion  interruption not  indicated;  intervention not indicated Increase monitoring of vital signs as medically  indicated until the participant is deemed  medically stable in the opinion of the  investigator. None Grade 2 Stop Infusion. Participant may be Requires therapy or Additional appropriate medical therapy may premedicated 1.5h (± 30 infusioninterruption but responds  promptly to  symptomatic  treatment (e.g.  antihistamines,  NSAIDs, narcotics, IV minutes) prior to infusion of pembrolizumab with:  Diphenhydramine 50 mg  PO/IV (or equivalent dose of  antihistamine). Acetaminophen 500‐1000  mg PO (or equivalent dose fluids); prophylactic Increase monitoring of vital signs as medically of analgesic). medications indicated indicated until the participant is deemed for ≤24 hrs medically stable in the opinion of the investigator. include but is not limited to: - IV fluids - Antihistamines - NSAIDs - Acetaminophen - Narcotics If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (e.g. from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until symptoms resolve and the participant should be premedicated for the next scheduled dose. Participants who develop grade 2 toxicity despite adequate premedication should be permanently discontinued from further study drug treatment.   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Grades 3 or 4 Grade 3: Prolonged (i.e. not  rapidly responsive to  symptomatic  medication and/or  brief interruption of  infusion); recurrence  of symptoms  following initial  improvement;  hospitalization  indicated for other  clinical sequelae (e.g.  renal impairment,  pulmonary infiltrates)   | Stop Infusion. Additional appropriate medical therapy may  include but is not limited to: - Epinephrine** - IV fluids - Antihistamines - NSAIDs - Acetaminophen - Narcotics - Oxygen - Pressors - Corticosteroids   | No subsequent dosing   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|
| Increase monitoring of vital signs as medically  indicated until the participant is deemed  medically stable in the opinion of the  investigator.                                                                                                                                                         |                                                                                                                                                                                                                     |                        |
| Grade 4: Life‐ threatening; pressor  or ventilatory  support indicated                                                                                                                                                                                                                                    | Hospitalization may be indicated. **In cases of anaphylaxis, epinephrine should  be used immediately. Participant is permanently discontinued  from further study drug treatment.                                   |                        |
| Appropriate resuscitation equipment should be available at the bedside and a physician readily available during  the period of drug administration. For further information, please refer to the CTCAEv5 at http://ctep.cancer.gov.                                                                       |                                                                                                                                                                                                                     |                        |
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9.6 adverse events not related

If an AE is unrelated to either cabozantinib or pembrolizumab (e.g.symptoms due to disease, concomitant medication/procedure, other illness), cabozantinib and pembrolizumab may be continued or held at the discretion of the investigator. In general, treatment may be continued if the AE is not treatment‐related and not clinically significant, the patient is relatively asymptomatic and stable with good performance status, and if treatment will not delay recovery or worsen the AE. **If treatment is held for AEs unrelated**
to treatment, cabozantinib and pembrolizumab should be resumed at the same doses as previously within 4 weeks.
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10.0 study calendar

Table 10.1 summarizes the trial procedures to be conducted at various timepoints. It may be necessary to perform these procedures at unscheduled time points if deemed clinically necessary by the investigator. Furthermore, additional evaluations/testing not outlined in this table may be deemed necessary by the Principal Investigator for reasons related to participantsafety.  
| 1 cycle = 21 days                                                   | Baseline17    | Cycle 1           | Cycle 2+   | Treatment   |      |    |
|---------------------------------------------------------------------|---------------|-------------------|------------|-------------|------|----|
| discontinuation visit19                                             | Follow‐ up20  |                   |            |             |      |    |
| Day                                                                 | Day 8         |                   |            |             |      |    |
| 118                                                                 | (± 2 days)    | Day 15 (± 2 days) | Day 1      | (+ 7 days)  | (± 7 |    |
| (± 2 days)                                                          | days)         |                   |            |             |      |    |
| TREATMENT Cabozantinib1                                             | X             | X                 | X          | X           |      |    |
| Pembrolizumab2                                                      | X             | X                 |            |             |      |    |
| REQUIRED  ASSESSMENTS Informed                                      | X             |                   |            |             |      |    |
| consent/HIPAA Inclusion/exclusion                                   | X             |                   |            |             |      |    |
| criteria3 Medical and smoking                                       | X             |                   |            |             |      |    |
| history Disease                                                     | and           | X                 |            |             |      |    |
| treatment history Vital signs, physical exam, ECOG status,  weight4 | X             | X                 | X          | X           | X    | X  |
| Height5                                                             | X             |                   |            |             |      |    |
| AE and medications                                                  | X             | X                 | X          | X           | X    | X  |
| assessment6 Cabozantinb                                             | Drug          | X                 | X          | X           |      |    |
| Diary Collection7 CBC and differential8                             | X             | X                 | X          | X           | X    |    |
| Serum chemistry8                                                    | X             | X                 | X          | X           | X    |    |
| PT/INR, PTT                                                         | X             | X                 | X          | X           |      |    |
| Lactate                                                             | X             |                   |            |             |      |    |
| dehydrogenase Hepatitis C antibody                                  | X             |                   |            |             |      |    |
| (+/‐ HCV RNA)9 Hepatitis B                                          | core          | X                 |            |             |      |    |
| antibody10 Hepatitis B surface                                      | X             | X                 |            |             |      |    |
| antigen and/or HBV                                                  | (q2C starting |                   |            |             |      |    |  
Table 10.1. Baseline schedule of activities  
| DNA10                                                                                                                    | at C3)                |    |    |
|--------------------------------------------------------------------------------------------------------------------------|-----------------------|----|----|
| TSH with reflex T411                                                                                                     | X                     | X  |    |
| (q2C starting  at C3)                                                                                                    |                       |    |    |
| Cortisol11                                                                                                               | X                     | X  |    |
| (q2C starting  at C3)                                                                                                    |                       |    |    |
| Amylase11                                                                                                                | X                     | X  |    |
| (q2C starting  at C3)                                                                                                    |                       |    |    |
| Lipase11                                                                                                                 | X                     | X  |    |
| (q2C starting at C3)                                                                                                     |                       |    |    |
| Urinary protein to                                                                                                       | X                     | X  |    |
| creatinine ratio11                                                                                                       | (q2C starting at C3)  |    |    |
| EKG11                                                                                                                    | X                     | X  |    |
| (q2C starting  at C3)                                                                                                    |                       |    |    |
| Esophagoduo‐                                                                                                             | X                     |    |    |
| denoscopy (EGD) 12 Pregnancy test                                                                                        | X                     |    |    |
| (WOCP only) Vital status, date of progression if  applicable                                                             | X                     | X  |    |
| DISEASE  ASSESSMENT Alpha fetoprotein13                                                                                  | X                     | X  |    |
| (q3C starting at C4)                                                                                                     | X                     |    |    |
| Radiologic                                                                                                               | imaging               | X  | X  |
| by CT or MRI14                                                                                                           | (q3C starting  at C4) | X  | X  |
| CORRELATIVE  STUDIES Archival tumor tissue  for research  purposes if available. Otherwise, fresh  biopsy is optional.15 | X                     |    |    |
| Blood collection16                                                                                                       | X                     | X  | X  |
| (C2D1 only)                                                                                                              |                       |    |    |
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footnotes

1Daily continuously starting at Cycle 1 Day 1. See Section 9.0 for dose modifications. 2Dosed on Day 1 of each 3‐week cycle. See Section 9.0 for dose modifications. 3See Section 5.0 for inclusion and exclusion criteria.  
4Vital signs include: blood pressure, pulse, respiratory rate, oxygen saturation, temperature. Blood pressure and pulse should be taken at rest while sitting. Physical exam should be performed at baseline, on Day 1 of each cycle, and at the treatment discontinuation visit. A focused physical exam may be 59 of 107 Protocol V4.0 13Dec2021
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footnotes

performed if clinically indicated at Cycle 1 Day 8 and 15.  
5Height only needs to be obtained at baseline.  
6AE assessment using CTCAE v5. All TRAEs will be followed until resolution, return to baseline, or deemed clinically insignificant by the treating investigator, including those that occur during the 30‐day period after treatment discontinuation. In addition, any SAE related to treatment occurring more than 30 days after treatment discontinuation will be followed until either resolution, return to baseline, or determination by the investigator that the event has become stable orirreversible. 7A new diary will be distributed on Day 1 of each cycle and collected on Day 1 of the next cycle. See Appendix 2 for a template of the Cabozantinib Drug Diary.  
8CBC and differential includes: hemoglobin, hematocrit, leukocyte count, neutrophils (segmented and bands), lymphocytes, monocytes, eosinophils, basophils, and platelets. Serum chemistry includes:sodium, bicarbonate, potassium, calcium, magnesium, magnesium, phosphate, glucose, albumin, total protein, blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin. In addition to the scheduled labs asindicated in the table, more frequent lab monitoring may be initiated by the investigator in the event ofAEs.  
9HCV RNA is obtained if hepatitis C virus antibody (HCV Ab) is positive. There is no need to repeatserology or RNA during the study.  
10If hepatitis B virus core antibody (HBcAb) and surface antigen (HBsAg) at baseline are negative, no further testing is needed. If HBcAb+ and/or HBsAg+, HBV DNA should be obtained at baseline. If a patient is HBcAb+ and HBsAg‐ at baseline, HBsAg should be obtained every 2 cycles on study starting at cycle 3 and HBV DNA is obtained if HBsAg becomes positive. If a patient is HBcAb+ and HBsAg+, HBV DNA should be obtained every 2 cycles on study starting at cycle 3. 11These tests should be obtained at baseline (within 14 days prior to registration) and repeated every 2 cycles on study starting at cycle 3.  
12EGD must be done within 6 months prior to study initiation to assess for and treat esophageal and gastric varices.  
13Alpha fetoprotein (AFP) should be measured at baseline (within 14 days prior to registration). If abnormal at baseline, it should be measured on Day 1 of every 3 cycles starting at cycle 4, and at the treatment discontinuation visit.  
14Disease assessment using multiphasic (four‐phase) contrast CT or MRI of abdomen/pelvis, as well as CT
chest with or without contrast should be done at baseline (within 28 days prior to registration), and every 9 weeks on treatment (every 3 cycles). If there is disease progression and the patient continues on treatment beyond progression, repeat imaging must be performed 4 weeks later to confirm progression.  
As clinically indicated, bone scan and contrast imaging of neck may be obtained to monitor disease (see Section 13.3). For the treatment discontinuation visit, the most recent scans are used. For patients who come off study for toxicity, subsequent restaging scans will be requested and assessed at least every 4 months for up to 2 years from study start date to document the date ofprogression. 15Archival tumor tissue is acceptable (paraffin‐embedded tumor core biopsy or surgical specimen). If archival tissue is not available, baseline core needle biopsy may be performed (if safe and feasible).  
16Pre‐treatment Blood will be collected and stored for correlative studies. Research blood will be collected on Cycle 1 Day 1 and Day 8, as well as Cycle 2 Day1. 17Informed consent/HIPAA, medical/smoking history, AE/medication assessment, physical exam/ECOG,
and assessment of inclusion/exclusion criteria are completed within 28 days prior to registration. Baseline lab investigations are completed within 14 days prior to registration, including pregnancy test for women of child‐bearing potential (WOCP) and AFP. Baseline imaging for disease assessment may be obtained within 28 days prior to registration.  
18Cycle 1 day 1 testing need not be repeated if completed within 7 days prior.  
19The treatment discontinuation visit should occur 30 days (+7 days) after the last dose of cabozantinib or pembrolizumab (whichever is latest). Most recent scans are used for the treatment discontinuation visit.  
Note: if a participant initiates a new anti‐cancer therapy within 30 days after the last dose of trial  
treatment, the treatment discontinuation visit must occur before the first dose of the new therapy and AEs occurring until that point will be collected.  
20All patients who were treated will be followed for survival every 4 months with phone calls for up to 3 years from study start date. Patients who came off study for toxicity will be followed for progression with visits or by request of outside medical records every 4 months up to 3 years from study start date, where progression will be assessed by requesting and obtaining subsequent restaging scans. Subsequent anti‐
neoplastic therapy will be collected if available.  
Abbreviations: C, cycle; q2C, every 2 cycles.
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11.0 study assessments 11.1 baseline/screeningevaluations

- Informed consent and HIPAA authorization will be obtained according to ICH/GCPguidelines prior to performing any study‐specific procedures.  
- Medical and smoking history will be recorded.  
o Medical history must include all active conditions and any condition diagnosed within the prior 10 years that are considered to be clinically significant by the investigator.  
Details regarding the disease for which the participant has enrolled in this study will be recorded separately and not listed as medical history.  
- Disease details and treatments will be recorded.  
o This information will include: BCLC stage at diagnosis and current BCLC stage, and all prior cancer treatments (e.g. surgery, ablation, liver‐directedtherapy).  
- Assessment of vital signs, physical examination, assessment of ECOG status, weight, height, baseline AEs and medications.  
o Medication history will include any prior medication use within 28 days before starting on study, including indication and any protocol‐related washout requirement. Treatment for the disease for which the participant has enrolled in this study will be recorded separately and not listed as a priormedication.  
- Assessment of eligibility based on inclusion/exclusion criteria by treatment investigator
(Section 5.0).  
- Multiphasic contrast CT or MRI of abdomen/pelvis and CT chest with or without contrast for baseline disease assessment, as well as confirmation of measurable disease and at least 1 appropriate target lesion per RECIST v1.1. As clinically indicated, bone scan and contrast‐ imaging of neck may be obtained.  
- Archival tissue will be requested if available. If archival tissue is not available, an optional fresh core biopsy may be performed (if safe and feasible).  
o For patients who had prior next‐generation gene sequencing analysis of their tumor, the gene sequencing assay results will be requested.
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within 14 days prior to

- CBC with differential (including hemoglobin, hematocrit, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelets).  
- Serum chemistry (including sodium, bicarbonate, potassium, calcium, magnesium, magnesium, phosphate, glucose, albumin, total protein, blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin).  
- PT/INR and PTT.  
- Lactate dehydrogenase (LDH)
- Pregnancy test by serum HCG (for women of child‐bearing potentialonly). - Alpha fetoprotein.
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11.2 on study evaluations

Patients will be monitored for response to therapy (disease assessment, see Section 13.0) every 9 weeks
(every 3 cycles), and for AEs continuously from the time of consent to 30 days after discontinuation of drug.
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cycles 1 days 1 8

- Assessment of vital signs, physical examination, ECOG status, andweight.  
- Assessment of AEs and medications. Medication start/stop dates and indication for use during the study will be recorded.  
- CBC with differential (Days 1 and 15 only) (including hemoglobin, hematocrit, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, andplatelets).  
- Serum chemistry (Days 1 and 15 only) (including sodium, bicarbonate, potassium, calcium, magnesium, magnesium, phosphate, glucose, albumin, total protein, blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase,and total bilirubin).  
- PT/INR, PTT(Day 1 only).
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cycles 2+ day 1 (+-

- Throughout the trial, patients will complete the Cabozantinib Drug Diary (Appendix 2). This will be collected on Day 1 of eachcycle.  
- Assessment of vital signs, physical examination, ECOG status, andweight.  
- Assessment of AEs and medications. Medication start/stop dates and indication for use during the study will be recorded.  
- CBC with differential (including hemoglobin, hematocrit, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelets).  
- Serum chemistry (including sodium, bicarbonate, potassium, calcium, magnesium, magnesium, phosphate, glucose, albumin, total protein, blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin).  
- PT/INR, PTT.
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every 2 cycles starting at

- HBsAg (for patients who are HBcAb+ and HBsAg‐ at baseline), or HBV DNA (for patients who are HBcAb+ and HBsAg+ at baseline). If HBsAg becomes positive on study, HBV DNA should then be followed.  
- TSH with reflex T4, cortisol, amylase, lipase. - Urinary protein to creatinine ratio. - EKG.
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at the end of every

Multiphasic contrast CT or MRI of abdomen/pelvis, as well as CT chest with or without contrast for disease assessment as per RECIST v1.1. The same imaging technique should be used throughout the study. If there is disease progression and the patient continues treatment beyond progression, repeat imaging must be obtained 4 weeks later to confirm PD. As clinically indicated, bone scan and contrast‐imaging of neck may be obtained.
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11.3 assessment of safety parameters

Blood samples will be collected at the time points specified and analysed in a laboratory facility at the local investigational site. In the event of AEs or lab abnormalities, additional tests and/or more frequent lab monitoring may be obtained at the discretion of the treating investigator.  
Safety laboratory assessment at baseline and on treatment must include at least the following parameters. Also see Appendix 3.  
| At baseline and every cycle Complete blood  Hemoglobin, hematocrit, leukocyte count, neutrophils, lymphocytes,  count monocytes, eosinophils, basophils, platelets Serum chemistry Sodium, bicarbonate, potassium, calcium, magnesium, magnesium,  phosphate, glucose, albumin, total protein, blood urea nitrogen, creatinine,  alanine aminotransferase, aspartate aminotransferase, alkalinephosphatase, total bilirubin. Glomerular Filtration Rate (GFR) will be estimated by the  Cockcroft‐Gault formula using serum creatinine values (see Appendix 7). Coagulation PT/INR, PTT Miscellaneous LDH (baseline only) At baseline and every 2 cycles Hepatitis B virus At baseline: HBcAb and HBsAg.  On study: - HBsAg (for patients who areHBcAb+ and HBsAg‐ at baseline), orHBVDNA  (for patients who are HBcAb+ and HBsAg+ atbaseline). - If HBsAg becomes positive on study, HBV DNA should then befollowed. Monitoring for  TSH with reflex T4, cortisol, amylase, lipase immune toxicity Urine protein Urinary protein to creatinine ratio QTc EKG   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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assessment of other safety parameters

- Physical examination, ECOG performance *score* A physical examination will be performed at screening and at the time points specified in the Study Calendar.  
A full physical exam serves as a clinicaltumor assessment and should include cardiopulmonary and abdominal examinations and an assessment of the mental and neurological status. Wherever possible, the same investigator should perform thisexamination.  
Measurement of height (in cm), body weight (in kg) and body temperature and the evaluation of the ECOG performance score will be performed at the time points specified in the Study Calendars.
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- vital signs

Vital signs include blood pressure and pulse after resting and sitting for at least 5 minutes, respiratory rate, oxygen saturation, and temperature. These will be recorded at the screening visit and at the time points specified in the StudyCalendar.
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- demographics and history

Demographics (sex, birth date), information on smoking history, and pre‐existing medical conditions will be collected during the screening visit.  
Information on the etiology of HCC, including history of HBV, HCV, alcohol abuse, non‐
alcoholic steatohepatitis, or other will be collected at the screening visit. Specifically, for patients known to have HBV or HCV, details on prior anti‐viral therapy, dates of therapy and response will be recorded.  
The date of first diagnosis of HCC (month and year are sufficient) and tumor histology if prior pathology results are available will be reported in the CRF. Moreover, BCLC stage at initial diagnosis and current BCLC stage will be recorded, as well as the current number and locations of metastatic sites (liver, lung, lymph nodes, peritoneum, other), presence of vascular invasion (specify location). Previous treatments including surgery, catheter‐based therapy, and radiotherapy will be documented, including start and end dates (month and year are sufficient) and the best response obtained (complete response, partial response, stable disease, progressive disease, unknown).
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11.4 evaluations at treatment discontinuation

- Collection of the Cabozantinib Drug Diary, if not previously collected. - Assessment of vital signs, physical examination, ECOG status, andweight. - Assessment of AEs andmedications.Medicationstart/stop dates and indication foruse during the study will be recorded.  
- CBC with differential.
- Serum chemistry. - PT/INR and PTT.  
- Alpha fetoprotein. - Most recent imaging will be used for the treatment discontinuation visit: multiphasic contrast CT or MRI of abdomen/pelvis, as well as CT chest with or without contrast. As clinically indicated, bone scan and contrast‐imaging of neck may also beobtained.
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11.5 post-study follow-up

Subjects will return approximately 30 days after their last dose of cabozantinib or pembrolizumab (i.e.  
treatment discontinuation visit) to complete end‐of‐study assessments (see Section 11.4). Unused study drug will be returned by the subject. If a participant initiates a new anti‐cancer therapy within 30 days after the last dose of trial treatment, the treatment discontinuation visit must occur before the first dose of the new therapy.  
All treatment‐related AEs will be followed until resolution, return to baseline, or deemed clinically insignificant by the treating investigator, including those that occur during the 30‐day period after treatment discontinuation. Moreover, any known SAE attributed to study treatment that occurs more than 30 days after treatment discontinuation must be followed until either resolution, return to baseline, or determination by the investigator that the event has become stable or irreversible; all concomitant medications for these SAEs after 30 days from treatment discontinuation must also berecorded. For patients who discontinue study treatment due to toxicities or reasons other than progressive disease, subsequent imaging, if available, will be requested every 4 months up to 2 years from study start date to document time of progression after coming off study. For patients who come offstudy due to progressive disease, patients will be followed forsurvival every 4 months up to 2 years from study start date (no scans will be required). Moreover, subsequent anti‐neoplastic therapy receive after study discontinuation will be collected, if available.
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12.0 criteria for treatment discontinuation

Participants may discontinue study intervention at any time for any reason or be dropped from the study intervention at the discretion of the investigator should any untoward effect occur. In addition, a participant may be discontinued from study intervention by the investigator if study intervention is inappropriate, the study plan is violated, or for administrative and/or othersafety reasons. Specific details regarding procedures to be performed at study intervention discontinuation are provided in Sections 11.4 and 11.5.  
A patient will be discontinued from study treatment under the following circumstances:  
- Progressive disease (PD) as per RECIST v1.1 or the subject no longer experiences clinical benefit as determined by the investigator (see Section 12.1 for criteria for continuing treatment beyond progression).  
- Unacceptable toxicities despite supportive therapy and dosereduction/modification.  
- Discontinuation of pembrolizumab for recurrent grade 2pneumonitis. - An AE or intercurrent illness/condition or personal circumstance which, in the opinion of the investigator, places the participant at unnecessary risk from continued administration of study intervention.  
- Any progression or recurrence of another malignancy, or any occurrence of another malignancy that requires active treatment.  
- Constraints of this protocol are detrimental to the patient's health.  
- Necessity for treatment with other anticancer agents or other treatment prohibited by protocol.  
- TRAE that results in interruption of cabozantinib > 4 weeks and pembrolizumab > 12 weeks, unless there is unequivocal evidence that the subject is benefitting. In this situation, a subject may be able to restarttherapy upon resolution ofthe toxicity and with agreement of the Study PI.  
- Patient requestsdiscontinuation.  
- Sexually active subjects who refuse to use medically accepted barrier methods of contraception (Appendix 8) during the course of the study and for 4 months after discontinuation of study treatment.  
- Women who become pregnant or are breastfeeding.  
- Request by regulatory agencies for termination of treatment of an individual subject or all subjects under the protocol.  
- Significant noncompliance with the protocol schedule in the opinion of theinvestigator.  
- Discontinuation of pembrolizumab may be considered for participants who have attained a confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), receiving at least 2 further cycles of cabozantinib and pembrolizumab beyond the date when the initial CR was declared.  
- Completion of 2 years oftherapy.  
- Participant has any of the following non‐overdose HECIs that are not reversible and manageable by therapy (see below). (Note: Temporary hepatic decompensation may occur in patients with cirrhosis exposed to TKIs.)
o ALT >20 × ULN (confirmed within 1 week)
o Drug‐related total bilirubin >10 x ULN
o CP score of > 8 points o Hepatic encephalopathy o Recurrence of a severe or life‐threatening event, or of any of the laboratory abnormalities listed above, that are presumed to beimmune‐related o Uncontrolled ascites
- Subject is lost to follow‐up.
Patients who come off study should be evaluated at 30 days (+ 7 days) after the last dose of cabozantinib or pembrolizumab (whichever is latest). AE assessment and reporting for patients who discontinue study treatment are described in Section 16.3.2. Furthermore, subjects who come off study for reasons other than PD will be followed for progression, and all patients who come off study will be followed for survival every 4 months for up to 2 years from study start date.  
12.1 Treatment beyond **progression** Cases of pseudo‐progression have been documented in certain tumor types treated with immune‐
oncology agents.60 Patients with initial disease progression on imaging (i.e. PD by RECIST v1.1, iUPD by iRECIST, see Section 13.0) may be allowed to continue on study treatment if they meet all of the criteria below:  
- Patient is tolerating treatment.  
o Note: Patients are allowed to continue beyond progression on monotherapy cabozantinib
(any dose) or pembrolizumab if the other agent was previously discontinued due to toxicity.  
- Patient is deriving clinical benefit from ongoing treatment as assessed by theinvestigator. - Patient continues to meet eligibility criteria. - Disease progression is asymptomatic and does not pose a risk of a serious complication (e.g.  
progression in vertebral metastasis expected to lead to fracture or cord compression with further growth).  
- Patient has stable ECOG performance status and is not expected to decline in the nearfuture. - Treatment beyond progression will not delay an imminent intervention to prevent serious complications of disease progression (e.g. radiation to CNSmetastases).
Patients who meet the above criteria and continue study treatment beyond progression must sign a consent form to do so. If a patient continues treatment beyond progression, repeat imaging will be obtained at 4 weeks to confirm PD (i.e. iCPD by iRECIST). If there is confirmed disease progression, it is generally recommended that the study treatment be discontinued. However, if the patient appears to be deriving clinical benefit fromtreatment and is clinically stable, treatment beyond confirmed PD may be continued with permission obtained from the PI. If disease appears stable and PD cannot be confirmed on subsequent scans (i.e. response remains iUPD), then the patient may continue on study as long as clinically stable. See Section 13.2 for iRECIST criteria. Table 12.1.1 provides guidance on treatment after radiologic evidence of PD.  
| Table 12.1.1. Imaging and treatment after first radiologic evidence of progressive disease. Clinically Stable Clinically Unstable Imaging Treatment Imaging Treatment First radiologic Repeat imaging May continue study Repeat imaging at Discontinue evidence of PD  at 4 to 8 weeks  treatment at the  by RECIST 1.1 to confirm PD. Investigator's  discretion while  awaiting  confirmatory tumor  imaging by site by iRECIST. 4 to 8 weeks to  confirm PD per  Investigator's  discretion only. treatment Repeat tumor No additional Discontinue No additional Not applicable imaging confirms  PD (iCPD) by  iRECIST per Investigator  assessment imaging  treatment  required. (exception is  possible upon  consultation with imaging required.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Principal  Investigator                                                                                                                                                                                                                                                                                           |                                                                                                                                                                 |                                                               |                                                                                      |                        |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|--------------------------------------------------------------------------------------|------------------------|
| Repeat tumor  imaging shows  iUPD by iRECIST  per Investigator  assessment                                                                                                                                                                                                                                        | Repeat imaging  at 4 to 8 weeks  to confirm PD.  May occur at  next regularly scheduled  imaging visit.                                                         | Continue study  treatment at the  Investigator's  discretion. | Repeat imaging at  4 to 8 weeks to  confirm PD per  Investigator's  discretion only. | Discontinue  treatment |
| Repeat tumor                                                                                                                                                                                                                                                                                                      | Continue                                                                                                                                                        | Continue study                                                | Continue regularly                                                                   | May restart study      |
| imaging shows iSD, iPR, or iCR  by iRECIST per  Investigator  assessment.                                                                                                                                                                                                                                         | scheduled imaging                                                                                                                                               | treatment if                                                  |                                                                                      |                        |
| assessments.                                                                                                                                                                                                                                                                                                      | condition has  improved and/or  clinically stable  per Investigator's  discretion. Next  tumor image  should occur  according to the  regular imaging schedule. |                                                               |                                                                                      |                        |
| iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response  Evaluation Criteria in Solid Tumors 1.1 for immune‐based therapeutics; iSD = iRECIST stable disease; iUPD =  regularly scheduled  imaging  assessments.  treatment at the Investigator's  discretion. |                                                                                                                                                                 |                                                               |                                                                                      |                        |
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13.0 guidelines for disease evaluation

The primary endpoint of this study is ORR by RECIST v.1.1. Secondary endpoints include DCR by RECIST
v1.1, as well as ORR and DCR by iRECIST. Response criteria will be assessed by a central radiology team
(OncoRad) at the University of Washington.60,61
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13.1 tumor assessment by recist

- Lesions that are ≥ 10 mm (long axis) on CT (slice thickness 5 mm or less) orMRI
- Lymph nodes must be ≥ 15 mm (short axis) on CT (slice thickness 5 mm or less) orMRI - Up to 5 target lesions in total can be reported, and a maximum of 2 lesions perorgan - Target lesions should be the largest and most reproducible lesions on repeatassessments - Target lesions should be representative of all involvedorgans
Notes:  
− The lymphatic system is considered one organ in RECIST v1.1. Therefore, a maximum of2 lymph nodes that are classified as target lesions should be reported on the RECISTCRF.  
− Lesions that were previously radiated or ablated cannot be target lesions unless therewas subsequent radiographic progression at those sites.
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criteria for non-target lesions

- Any lesions that don't meet the criteria for target lesions or are above the reporting limitfor target lesions
- All other sites of disease that are <10 mm (long axis) on CT orMRI - Lymph nodes that are ≥10 to <15 mm in the short axis on CT orMRI
- Lesionstruly non‐measurable such as ascites, leptomeningeal disease, pleural and pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin orlung
- Lesions that are not suitable for repeat measurement, e.g. abutting other structures or likely to coalesce with other lesions
- Multiple non‐targetlesionsin the same organ should be reportedas a single non‐targetlesion, e.g. multiple liver metastases
Note: The lymphatic system is considered one organ in RECIST v1.1. Therefore, multiple lymph nodes that are classified as non‐target lesions should be reported as a single non‐target lesion on the RECIST CRF.
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measurable disease

- Lesions that can be accurately measured in the longest dimension as ≥10 mm by CT scan, ≥20 mm by chest X Ray, ≥10mm by caliper on clinical exam. Malignant lymph nodes need to be ≥ 15 mm (short axis) on CT.
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non-measurable disease

- All other lesions that do not fit the criteria for measurable disease. All definitions are outlined in RECIST v1.1 reference.61
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13.1.2 definitions of response 12.1.2.1

Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non‐target) must have a reduction in short axis to < 10mm).  
Partial response (PR): At least a 30% decrease in the sum target lesions, taking as reference the baseline sum diameters.  
Progressive disease (PD): Atleast a 20% increase in the sum target lesions, taking asreference the smallest sum on study recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to quality for PD,
taking as reference the smallest sum diameters since the treatment started.  
12.1.2.2 Evaluation of response of non‐target *lesions* Complete response: Disappearance of all non‐target lesions and normalization of tumor marker level. All lymph nodes must be non‐pathological in size (< 10 mm short axis).  
Incomplete response/stable disease: Persistence of one or more non‐target lesion(s) and/or maintenance of tumor marker level above the normal limits.  
Progressive disease: Appearance of 1 or more new lesions and/or unequivocal progression of existing non‐
target lesion(s).
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13.1.3 evaluation of overall response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference the smallest measurements recorded since the treatment started to determine response and progression).  
| Target lesions    | Non‐target lesions          | New lesion   | Overall response   |
|-------------------|-----------------------------|--------------|--------------------|
| CR                | CR                          | No           | CR                 |
| CR                | Non‐CR/Non‐PD               | No           | PR                 |
| CR                | Not evaluated               | No           | PR                 |
| PR                | Non‐PD or not all evaluated | No           | PR                 |
| SD                | Non‐PD or not all evaluated | No           | SD                 |
| Not all evaluated | Non‐PD                      | No           | NE                 |
| PD                | Any                         | Yes or No    | PD                 |
| Any               | PD                          | Yes or No    | PD                 |
| Any               | Any                         | Yes          | PD                 |  
Subjects with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be classified as having "symptomatic deterioration". Every effort should be made to document the objective progression even after discontinuation of treatment.  
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the evaluation of complete response depends on this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status.
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13.1.4 definitions for response evaluations

First documentation of response: The time between initiation of therapy and first documentation of PR
or CR. Duration of response: Duration of overall response ‐ the period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the first date that recurrent or progressive disease is objectively documented, taking as reference the smallest measurements recorded since treatment started. Duration of overall complete response: The period measured from the time that measurement criteria are met for complete response until the first date that recurrent disease is objectively documented.  
Duration of stable disease: The period measured from the time that stable disease is documented until the first date that progressive disease is objectively documented.  
Time to progression: A measurement from the study enrollment until the criteria for disease progression are met (or death occurs), taking as reference the smallest measurements recorded since the therapy started.  
Overall survival: The overall survival time for each subject is the number of days from the day of first treatment to the earlier of (1) death (from any cause) or (2) the last date of subject contact. If the survival time does not correspond to the subject's death, then it is treated ascensored.
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13.2 tumor assessment by irecist

To account for the possible unique pattern of immune‐mediated tumor responses, evaluation by iRECIST
will also be performed as secondary objectives. Below is a general summary of the iRECIST criteria. Please refer to Seymour et al. 2017 for the full iRECIST guidelines.60 Responses assigned under iRECIST are designated with the prefix 'i' (immune).
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13.2.1 similarities and differences between

In iRECIST, the definitions are identical to RECIST v1.1 for the following:  
− Measurable and non‐measurable disease including nodaldisease
− Numbers and sites of targetlesions
− Calculation of sum of diameters(SoD) − CR, PR, SD, duration − Confirmation of CR or PR (for non‐randomizedtrials) − PD for target and non‐targetlesions
However, the management of new lesions and determination of progression differ:  
− For target lesions, the first PD by RECIST v1.1 is iUPD (immune unconfirmedPD). − iUPD must be confirmed 4‐8 weeks later by imaging.  
o iCPD (immune confirmed PD) is established if there is a further increase in SoD of target disease from iUPD of at least 5mm.  
o If there is subsequent iPR, iCR, or iSD (determined by RECIST v1.1 comparedto baseline), then the iUPD date is ignored and the status isreset.  
o If there is no change detected from iUPD, then the timepoint response remainsiUPD
− Treatment past iUPD is considered only if the patient is clinically stable. − iUPD can be assigned multiple times as long as iCPD is not confirmed at the nextassessment.  
− Assignment of non‐target lesions follows similarrules.  
− New targetlesions are recorded separately and notincluded in SoD oftargetlesionsidentified at baseline; the sum of diameters for the new target lesions isdetermined.  
o Appearance of new lesionsresults in iUPD, which requires confirmation at 4‐8 weeks. o iCPD is assigned if, on next imaging, additional new lesions appear, there is an increase in new lesions (at least 5mm), or appearance of new lesions.  
| Target                                              | Non‐target                                                                          | New            | Timepoint                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                      |
|-----------------------------------------------------|-------------------------------------------------------------------------------------|----------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| lesions                                             | lesions                                                                             | lesions        | response with no previous iUPD in  any category1                                                                                                                                                                                                                                                                   | Timepoint response with previous  iUPD in any category                                                                                                               |
| iCR                                                 | iCR                                                                                 | No             | iCR                                                                                                                                                                                                                                                                                                                | iCR                                                                                                                                                                  |
| iCR                                                 | Non‐iCR/                                                                            | No             | iPR                                                                                                                                                                                                                                                                                                                | iPR                                                                                                                                                                  |
| non‐iUPD                                            |                                                                                     |                |                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                      |
| iPR                                                 | Non‐iCR/                                                                            | No             | iPR                                                                                                                                                                                                                                                                                                                | iPR                                                                                                                                                                  |
| non‐iUPD                                            |                                                                                     |                |                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                      |
| iSD                                                 | Non‐iCR/                                                                            | No             | iSD                                                                                                                                                                                                                                                                                                                | iSD                                                                                                                                                                  |
| non‐iUPD                                            |                                                                                     |                |                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                      |
| iUPD                                                | with                                                                                |                |                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                      |
| no change,  or with  decrease  from last  timepoint | Yes                                                                                 | Not applicable | New lesions confirm iCPD if new  lesions were previously identified and  have increased in size (>=5mm in the  sum of diameters for new lesion target  or any increase for new lesion non‐  target) or number; if no change is seen  in new lesions (size or number) from last timepoint, assignment remains  iUPD |                                                                                                                                                                      |
| iSD, iPR, iCR                                       | iUPD                                                                                | No             | iUPD                                                                                                                                                                                                                                                                                                               | RemainsiUPD unlessiCPD is confirmed  by a further increase in size of non‐  target disease (does not need to meet RECIST v1.1 criteria for unequivocal  progression) |
| iUPD                                                | Non‐iCR/ non‐iUPD,  or iCR iUPD with  no change,  or decrease  from last  timepoint | No             | iUPD                                                                                                                                                                                                                                                                                                               | Remains iUPD unless iCPD is confirmed by a further increase in SoD >=5mm;  otherwise, assignment remains iUPD                                                        |
| iUPD                                                | iUPD                                                                                | No             | iUPD                                                                                                                                                                                                                                                                                                               | RemainsiUPD unlessiCPD is confirmed  by a further increase in previously  identified target lesion iUPD in SoD >=5mm or non‐target lesion iUPD                       |
| iUPD                                                | iUPD                                                                                | Yes            | iUPD                                                                                                                                                                                                                                                                                                               | RemainsiUPD unlessiCPD is confirmed  by a further increase in previously  identified target lesion iUPD in SoD >=5mm, previously identified non‐                     |
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13.2.2 timepoint response using irecist

| target iUPD, or increase in size of number of new lesions previously  identified   |     |      |                                                                                                           |
|------------------------------------------------------------------------------------|-----|------|-----------------------------------------------------------------------------------------------------------|
| Non‐iUPD or  progression                                                           | Yes | iUPD | Remains iUPD unless iCPD is confirmed by increase in size or number of new  lesions previously identified |
| Adapted from Seymour et al. 2017.60 Non‐iUPD or  progression                       |     |      |                                                                                                           |  
Yes iUPD Remains iUPD unless iCPD is confirmed by increase in size or number of new lesions previously identified Adapted from Seymour et al. 2017.60 1Preivously identified in assessment immediately before this timepoint.  
Target lesions, non‐target lesions, and new lesions defined according to RECIST v1.1. In the absence of pseudoprogression, RECIST v1.1 and iRECIST categories for CR, PR, SD would be the same.  
Abbreviations: "I" indicates immune responses assigned using iRECIST; iCR, complete response; iPR, partialresponse; iSD, stable disease; iUPD, unconfirmed progressive disease; non‐iCR/non‐iUPD, criteria for neither CR not PD have been met; iCPD, confirmed progressive disease; RECIST, Response Evaluation Criteria in SolidTumors.
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13.3 methods of measurement

Imaging‐based evaluation is required for assessment of response to study treatment. The same imaging modality must be used throughout the study to measure disease.  
Imaging: Only CT or MRI are acceptable forms of imaging for response assessment. Conventional CT and MRI should be performed with cuts of 5 mm or less in slice thickness contiguously. This applies to tumors of the chest, abdomen and pelvis. Head and neck tumors and those of extremities usually require specific protocols. All other forms of assessment, including chest x‐ray, ultrasound, PET without diagnostic CT, and endoscopy, will not be used for diseasemeasurement.  
As per NCCN guidelines for the management of hepatocellular carcinoma, it is recommended that disease assessment be performed using multiphasic contrast CT or MRI of abdomen/pelvis, as well as CT chest with or without contrast. As clinically indicated, bone scan and contrast‐imaging of neck may be obtained to monitor disease.  
(Principles of Imaging, NCCN guidelines version 1.2019, Hepatocellular Carcinoma, https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf)
Alpha fetoprotein (AFP): AFP may be elevated in patients with hepatocellular carcinoma and/orcirrhosis.  
AFP should be obtained at screening for all patients. If abnormal at baseline, it should be obtained on Cycle 1 Day 1, and every 3 cycles afterwards until treatmentdiscontinuation.  
Cytology and histology: Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the measurable tumor has met response or stable disease criteria.  
Clinical examination: Clinically detected lesions will only be considered measurable when they are superficial (e.g. skin nodules, palpable lymph nodes). For skin lesions, documentation by color photography, including a ruler to estimate size of the lesion, is recommended. Photographs should be retained at the institution.
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14.0 drug information

Drug supplies will be labeled in accordance with regulatory requirements. Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. Clinical supplies must be stored in a secure, limited‐access location, and may not be used for any purpose other than that stated in the protocol.
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14.1 cabozantinib 14.1.1 composition and

Cabozantinib tablets are supplied by Exelixis as film‐coated tablets containing cabozantinib malate equivalent to 20 mg of cabozantinib. They also contain microcrystalline cellulose, lactose anhydrous, hydoxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and Opadry® yellow. The 20‐mg tablets are round. Doses of 40 mg will comprise two 20‐mg tablets. The components of the tablets are listed in Table 14.1.1.1.  
| Table 14.1.1.1. Cabozantinib tablet components and composition Ingredient                             | Function          | % w/w1   |
|-------------------------------------------------------------------------------------------------------|-------------------|----------|
| Cabozantinib Drug Substance (25% drug load as free base)                                              | Active Ingredient | 31.68    |
| Microcrystalline Cellulose (Avicel® PH‐102)                                                           | Filler            | 38.85    |
| Lactose Anhydrous (60M)                                                                               | Filler            | 19.42    |
| Hydroxypropyl Cellulose (EXF)                                                                         | Binder            | 3.00     |
| Croscarmellose Sodium (Ac‐Di‐Sol®)                                                                    | Disintegrant      | 6.00     |
| Colloidal Silicon Dioxide                                                                             | Glidant           | 0.30     |
| Magnesium Stearate                                                                                    | Lubricant         | 0.75     |
| Opadry® yellow film coating which includes HPMC 2910/hypromellose 6 cp, titanium dioxide, triacetin,  | Film Coating      | 4.00     |
| and iron oxide yellow 1 weight fraction, expressed in percentage; HPMC, hydroxypropyl methylcellulose |                   |          |
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14.1.2 storage and handling

Refer to the Pharmacy Manual for full details on storage and handling of cabozantinib. Cabozantinib tablets should be stored according to the temperature range listed on the product label and should not be crushed or chewed. Patients should store the cabozantinib capsules in the original package provided and be instructed to keep all medication out of reach of children.
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14.1.3 administration

Subjects will receive cabozantinib 20 mg oral tablets and will start at a dose of 40 mg once daily. Dosage will be adjusted for toxicity (see Section 9.0). Cabozantinib must be taken on an empty stomach. Subjects must be instructed not to eat for at least 2 hours before and at least 1 hour after taking cabozantinib. Subjects should be instructed to take their cabozantinib dose at approximately the same time every day. If a subject misses a dose, the dose may be taken later only if it is within 12 hours of when the missed dose should have been taken. The missed dose should not be made up if it is within 12 hours of the next scheduleddose.  
Cabozantinib tablets should be swallowed whole with at least 8 ounces of water. The tablets should not be crushed.
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14.1.4 treatment accountability

Patients are required to complete the Cabozantinb Drug Diary and return all drug bottles and unused tablets. The number of tablets dispensed and returned will be recorded and reconciled with the diary.  
The investigator or designee will maintain accurate records of receipt of all study treatment including dates of receipt. In addition, accurate records will be kept regarding the date, lot number, and how much study treatment is dispensed and used by each subject in the study. Reasons for deviation from the expected dispensing regimen must also be recorded. At completion of the study, to satisfy regulatory requirements regarding drug accountability, all unused study treatment will be reconciled and destroyed according to applicable state, federal, and local regulations.
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14.2 pembrolizumab 14.2.1 formulation and

Pembrolizumab is supplied by Merck in solution form for injection at a concentration of 100 mg/4 mL. Please refer to the Pharmacy Manual for a comprehensive description of pembrolizumab preparation.
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14.2.2 storage and handling

Pembrolizumab must be stored securely under storage conditions as specified on the drug label and in the Pharmacy Manual.
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14.3.3 treatment accountability

The investigator or designee is responsible for keeping accurate records of the clinical supplies of pembrolizumab received from Merck, the amount dispensed and returned for each subject, and the amount remaining at the conclusion of the trial. Upon completion or termination of the study, all unused and/or partially used investigational product will be destroyed at the site as per institutional policy. It is the responsibility of the investigator or designee to arrange for disposal of all empty containers, following the procedures for proper disposal as per applicable federal, state, local and institutional guidelines. Records of disposed drug must bekept.
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15.0 biological correlative studies 15.1

Archival tumor tissue will be requested, collected, and stored ambiently if available. If archival tissue is not available, an optional fresh tumor biopsy may be performed if safe and feasible. Tissue will be stored for future correlative studies in order to assess correlations of biomarkers with efficacy from cabozantinib and pembrolizumab in HCC patients. If applicable, archival tumor tissue will be obtained from paraffin embedded specimens. Two unstained slides will be required for correlative studies. For patients undergoing fresh tumor biopsy, 3 cores will be obtained to assure at least 50 mm2 of tissue needed for analysis (see below).  
In addition, research blood will be collected on Cycle 1 Day 1and Day 8 and Cycle 2 Day 1.  
All samples will be coded with the patient number. These samples and any data generated can be linked back to the patient only by the study site personnel. Samples will be safely stored at ‐70oC until they are assayed.  
Samples will be retained at the University of Washington for a maximum of 15 years after the last patient visit for the study, or for a shorter period if imposed by the IRB. This retention period enables use of new technologies, response to questions from regulatory agencies, and investigation of variable response that may not be observed until later in the development cabozantinib and pembrolizumab in HCC. Regardless of the technology utilized, data generated will be used only for the specific research scope described in this section. The correlative studies will be planned as detailed in sections15.2‐15.4.
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15.2 immunohistochemistry (ihc)

Archival or fresh tumor tissue will be immunophenotyped by a comprehensive multiplex IHC assay in the Immunopathology Core at FredHutchinson Cancer Centerin orderto detect a range ofimmune cell subsets and their distribution in tumor, including CD8+ and CD4+ effector T cells, regulatory T cells, macrophages, myeloid derived suppressor cells.  
In addition, IHC will also be performed to assess the intratumoral levels of MET and various markers of immune checkpoint pathways (e.g. PD‐1/PD‐L1/PD‐L2, CTLA‐4, LAG3, TIM3). The intratumoral immune profile will be characterized and correlated with response to treatment.
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15.3 rna sequencing

Archival or fresh tumor tissue will be analyzed by RNA sequencing and gene set enrichment assay to explore immune gene expression signatures (e.g. IFN‐g signature, tumor inflammation signature) and activated or suppressed cell pathways that might predict response to cabozantinib and pembrolizumab.  
Moreover, the mutational profile and T cell receptor clonality profile of tumors will be assessed. Signatures associated with tumor response will be explored.
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15.4 flow cytometry and cytokine

Peripheral blood (at baseline, Cycle 1 Day 8, Cycle 2 Day 1) will be analyzed by flow cytometry for immune cell subpopulations (e.g. CD8+/CD4+/regulatory T cells, myeloid derived suppressor cells). Furthermore, serum at the same timepoints will be assayed by the Luminex® cytokine panel. Changes in immune cell subsets and cytokine profiles in response to cabozantinib and pembrolizumab will be assessed and correlated with treatment outcomes.
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16.0 adverse event assessment and

The safety of cabozantinib and pembrolizumab will be evaluated and recorded. Specifically, these are the safety endpoints of interest:  
- Type, incidence, and severity grade (as defined by NCI CTCAE v5) of AEs and SAEs, as well as relatedness of AEs/SAEs to cabozantinib, pembrolizumab or both;
- AEs/SAEs leading to dose reduction; - AEs/SAEs leading to permanent treatment discontinuation;
- Causes of death.
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16.1 definitions

Adverse event (AE): An AE is any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. An adverse event can arise from any use of the drug (e.g. off‐label use, use in combination with another drug) and with any route of administration, formulation, or dose, including an overdose. This definition also includes AEs associated with medication errors and uses of the investigational product outside what is in the protocol, including misuse and abuse.  
Pre‐existing medical conditions that worsen during the study should be recorded as AEs. Abnormal vital signs, ECG, physical examination, and laboratory test results will be recorded as AEs if they are CTCAE v5 grade 3 or above, require clinical intervention, or are otherwise judged clinically relevant by the investigator.  
Worsening of the underlying disease is not considered an AE; however clinical events associated with worsening of disease may be reportable as AEs, including the new onset of or increase in pain.  
Serious adverse event (SAE): The SAE definition and reporting requirements are in accordance with the International Conference of Harmonisation (ICH) Guideline for Clinical Safety Data Management:
Definitions and Standards for Expedited Reporting, Topic E2A.  
An SAE is defined as any untoward medical occurrence that at any dose:
- Results in death;
- Is life‐threatening (i.e. in the opinion of the investigator, the AE places the subject at risk of death; it does notinclude an eventthat, hadit occurred in a more severe form,might have caused death);
- Requires inpatient hospitalization or results in prolongation of an existinghospitalization; o Note: while most hospitalizations necessitate reporting of an SAE, some hospitalizations do not require SAE reporting, asfollows:
Events that occurred during the screening period after the patient signed the consent form but before initiation of study treatment (however, events related to screening procedures should be reported as SAEs);
Elective or previously scheduled surgeries or procedures for pre‐existing conditions that have not worsened after initiation of treatment (however, SAEs must be reported for any surgical complication resulting in unexpected prolongation of the hospital admission);
Events that result in hospital stays of fewer than 24 hours and that do not require admission (e.g. ER visit with diagnosis of urinary tract infection with discharge home on oral antibiotics);
Hospitalizations that are planned for administrative or social reasons during the study (e.g. days on which infusion takes place, long distance from home to site)
will not be recorded as SAEs (however, any event that requires prolongation of a planned hospitalization will be recorded as anSAE).  
- Results in persistent or significant disability orincapacity:
o Note: The term "disability" refers to events that result in a substantial disruption of a subject's ability to conduct normal life function.  
- Is a congenital anomaly or birth defect; - Is an important medical event (IME):
o Note: The term "important medical event" refers to an event that, based upon appropriate medical judgment, may not be immediately life‐threatening or result in death or hospitalization, but may jeopardize the subject or require intervention to prevent one of the other serious outcomeslisted.  
o Examples of IMEs: intensive treatment in the ER or at home for allergic bronchospasm; blood dyscrasias, or convulsions that do not result in hospitalization; or development of product dependency or product abuse.  
- Is a new cancer (other than HCC);
- Is associated with an overdose.  
Unexpected: An AE that is not listed in the investigator's brochure describing the risks of the study drug, or is not listed at the specificity or severity that has been observed.  
Severity of AE: The severity of AEs will be classified according to the NCI CTCAE v5, which describes grades of severity from 1 (mild) through 5 (fatal).
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16.2 attribution to study treatment

Assessment of the relationship or relatedness of an AE to study treatment(cabozantinib, pembrolizumab)
or protocol procedure will be performed by the investigator who is a qualified physician, using the respective Investigator's Brochures as a references. Relevant factors for this determination include exposurehistory,temporalrelationship,reactiontode‐challengeorre‐challenge, andconfoundingfactors such as concomitant medication, concomitant diseases, and relevant history.  
The relationship to study treatment or procedure will be described by the following: *definite, probable*,
possible, *unlikely*, or *unrelated*. For simplification of reporting, AEs may be grouped as:  
- **Not Related (unlikely, unrelated):** an AE that is not associated with the study treatment and is attributable to another cause or there is no evidence to support a causalrelationship;
- Related (definite, probable, **possible):** an AE where a causal relationship between the event and the study treatment is a reasonable possibility. A reasonable causal relationship is meant to convey that there are facts (e.g. evidence such as de‐challenge/re‐challenge) or other clinical arguments to suggest a causal relationship.
Attribution to study drugs for abnormal liver function lab tests should be considered carefully in the context of oncology patients. There should be no evidence of biliary obstruction, such as elevated alkaline phosphatase, progression of malignancy, or other explanation (viral hepatitis, otherhepatotoxicdrugs).
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16.3 parameters of assessment for

AEs and SAEs must be assessed by the treating investigator and recorded based on the following parameters.  
| Parameter                            | Description                                                                                                                                                             |       |              |    |     |           |          |    |            |
|--------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------|--------------|----|-----|-----------|----------|----|------------|
| CTCAE v5                             | Grade 1                                                                                                                                                                 | Mild; | asymptomatic | or | mid | symptoms; | clinical | or | diagnostic |
| grade                                | observations only; intervention not indicated.                                                                                                                          |       |              |    |     |           |          |    |            |
| Grade 2                              | Moderate; minimal, local or non‐invasive intervention indicated;  limiting age‐appropriate instrumental ADL.                                                            |       |              |    |     |           |          |    |            |
| Grade 3                              | Severe or medically significant but not immediately life‐threatening; hospitalization or prolongation or hospitalization indicated; disabling;  limiting self‐care ADL. |       |              |    |     |           |          |    |            |
| Grade 4                              | Life threatening consequences; urgent intervention indicated.                                                                                                           |       |              |    |     |           |          |    |            |
| Grade 5                              | Death related to AE                                                                                                                                                     |       |              |    |     |           |          |    |            |
| Seriousness                          | Does AE meet the definition of an SAE? (see Section 16.1 for definition)                                                                                                |       |              |    |     |           |          |    |            |
| Duration                             | Record the start and stop dates of the adverse event or ongoing. If less than 1 day,  indicate the length of time.                                                      |       |              |    |     |           |          |    |            |
| Action                               | Did the AE cause each of the study drugs to be: held, dose reduced, discontinued, no  action taken?                                                                     |       |              |    |     |           |          |    |            |
| taken Relationship to study  drug(s) | What is the relationship of the AE to each of the study drug: unrelated, unlikely related,  possibly related, probably related, definitely related? (see Section 16.2)  |       |              |    |     |           |          |    |            |
| Treatment                            | Was treatment required for the AE (e.g. antibiotic, supportive medication)?                                                                                             |       |              |    |     |           |          |    |            |
| required Outcome                     | Is AE: ongoing, improved, stable, worsened, resolved?                                                                                                                   |       |              |    |     |           |          |    |            |
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16.4 monitoring and recording aes

Investigators (principal investigator, sub‐investigators) and appropriately qualified clinical research staff willreview participants'treatment activity, clinical status, and safety information/AEs on anongoing basis.
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16.4.2 time frame for aemonitoring

AEs will be monitored from the time of informed consent through 30 days following the final dose of cabozantinib or pembrolizumab (whichever is lates). AEs with an onset date prior to informed consent will be recorded only in the case of worsening of the AE during study participation. All AEs will be followed until resolution, return to baseline, or deemed clinically insignificant by the treating investigator, even if they occur after treatment discontinuation for up to 30 days (or until the patient starts subsequent anticancer therapy, whichever is earliest).  
SAEs of any cause will be monitored from the time of informed consent through 30 days and SAEs attributed to study procedure or treatment occurring more than 30 days after treatment discontinuation must be followed until either resolution, return to baseline, or determination by the investigator that the event has become stable orirreversible. All pregnancies and exposure during breastfeeding will be monitored and reported from the time of treatment initiation through 120 days following cessation of study treatment, or 30 days following cessation of study treatment if the participant initiates new anticancer therapy must be reported by the investigator. If pregnancy or lactation exposure occurs, the site must also contact the subject at least monthly and document the participant's status until the pregnancy has been completed or terminated.  
Additionally, any SAE brought to the attention of an investigator at any time outside of the time period specified above must be reported immediately by the investigator if the event is considered to be drug‐
related.
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16.4.3 laboratory data

All laboratory data required by this protocol and any other clinical investigations should be reviewed. Any abnormal value that leads to a change in subject management (e.g. dose reduction or delay or requirement for additional medication or monitoring) or that is considered to be of clinical significance by the investigator should be reported as an AE or SAE asappropriate.
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16.4.4 recording aes

All AEs, serious and non‐serious, will be recorded in study‐specific CRF forms. AE terms recorded on the CRF will be mapped to preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA). For each AE, the investigator will provide the onset date, end date, severity grade (defined by NCI CTCAE
v5), seriousness, action taken with the study drug(s), treatment required, and outcome (see Section 16.3).  
The list of medications administered for the treatment of the AEs will berecorded. The investigator's signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame.
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16.5 requirements for reporting aes

As soon as an investigator becomes aware of an AE that meets the definition of 'serious,' this must be documented on an SAE Report Form or in an electronic database and include the following: (i) all SAEs that occur from the time of informed consent until 30 days after the treatment discontinuation, and (ii)
all SAEs attributed to study treatment or procedure occurring more than 30 days after treatment discontinuation.  
These SAEs and their follow‐up must be reported within 24 hours to the Exelixis Drug Safety and Merck Global Safety:  
- Any SAE occurring from the time of consent until treatment initiation if it causes the patient to be excluded from the trial, or if is the result of a protocol‐specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure
- Any SAE occurring on study regardless of causality from the time of consent until 30 days after treatment discontinuation
- Any SAE attributed to study treatment or procedure occurring more than 30 days after treatment discontinuation
All reportable SAEs must be sent to the following contacts within 24 hours of the PI's knowledge of the event:  
- Exelixis:reportsmust besentto ExelixisDrug Safety, drugsafety@exelixis.comorfax 650‐837‐
7392
- Merck: reports must be sent to Merck Global Safety, fax215‐661‐6229
The PI will perform adequate due diligence with regardsto obtaining follow‐up information on incomplete reports. All follow‐up information must be sent to Exelixis and Merck within 24 hours of the PI's receipt of the new information. Upon request, queriesmay be issued for follow‐upinformation.
fred hutchinson cancer center university
16.5.2 reporting of pregnancy and

Any pregnancy or lactation exposure that occurs from the time of treatment initiation through 120 days following cessation of treatment, or 30 days following cessation of treatment if the participant initiates new anticancer therapy, whichever is earlier, must be immediately reported by the investigator. All reported pregnancies must be followed to the completion/termination of the pregnancy, which must also be reported when available. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, stillbirth, or other disabling or life‐threatening complication to the mother or newborn must be reported as serious events (Important Medical Events).  
If the pregnancy continues to term, the outcome (health of infant) must also be reported. Such events must be reported within 24 hours to Exelixis Drug Safety and Merck Global Safety (see Section 16.4.1 for contact information). If a male participant impregnates his female partner, the Principal Investigator must be informed immediately and the pregnancy must be reported as well as described above.
fred hutchinson cancer center university
16.5.3 reporting of pembrolizumab overdose

For purposes of this study, an overdose of pembrolizumab is defined as any dose of 1,000 mg or greater
(≥5 times the indicated dose). No specific information is available on the treatment of overdose of pembrolizumab. In the event of overdose, the participant should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinicallyindicated.  
If an AE is attributed to an overdose of pembrolizumab, it must be reported as an SAE, even if no other seriousness criteria are met.  
If an overdose of pembrolizumab is taken without any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non‐serious Event of Clinical Interest (ECI), using the terminology "accidental or intentional overdose without adverse effect."
All reports of overdose with and without an AE must be reported within 24 hours to Exelixis and Merck
(see Section 16.4.1 for contact information).
fred hutchinson cancer center university
16.5.4 events of clinical interest

Selected non‐serious and serious AEs are also known as Events of Clinical Interest (ECI) and must be reported within 2 working days to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215‐661‐ 6229) and Exelixis Drug Safety (drugsafety@exelixis.com or fax 650‐837‐7392).  
Any ECI occurring on study regardless of causality from the time of consent until 30 days after treatment discontinuation must be reported.  
ECIs for this trial include:
1. Overdose of pembrolizumab that is not associated with clinical symptoms or abnormal laboratory results (see Section 16.4.3);
2. Elevated AST or ALT ≥ 3X ULN and elevated total bilirubin ≥ 2X ULN and, at the same time, ALP < 2X ULN.  
- Any ECI occurring from the time of consent until treatment initiation if it causes the patient to be excluded from the trial, or if is the result of a protocol‐specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure
fred hutchinson cancer center university
16.5.5 regulatory reporting

The Investigator will assess the expectedness of each related AE. The current cabozantinib Reference Safety Information (Appendix K of the most recent approved Investigator Brochure) and the pembrolizumab Investigator's Brochure will be used as the reference documents for assessing the expectedness of the event with regards to cabozantinib and pembrolizumab, respectively.  
- Expedited reporting will be conducted in accordance with FHCRC/Cancer Consortium IRB
policies.Specifically, requirements include reporting unanticipated problems involving risks to research participants or others to the FHCRC/Cancer Consortium IRB within 10 calendar days of the investigator's awareness of the problem. AEs that are (1) unexpected, (2) related or possibly related to the research, and (3) suggest that the research presents a greater risk of harm than was previously known or recognized, are among the unanticipated problems subject to these reporting policies. Exelixis and Merck reserve the right to upgrade the Investigator assessment of an SAE.  
- Institutions shall promptly provide all information requested by Exelixis and Merck regarding all adverse events occurring during the conduct of the study.  
- Exelixis and Merck will provide relevant product safety updates and notifications, asnecessary.
Any AE that does not meet expedited reporting criteria may be reported at the time of continuing review.
fred hutchinson cancer center university
17.0 statistical considerations 17.1 sample

The primary objective of this study is to evaluate the ORR in patients with advanced HCC treated with cabozantinib and pembrolizumab. This Phase 2 trial will be based on Simon's optimal two‐stage design.  
The null ORR is assumed to be 20%, which was the ORR (by RECIST v1.1) observed in the sorafenib‐naïve group treated with nivolumab in the CheckMate 040 trial.8 Early phase data with lenvatinib and pembrolizumab as first‐line treatment showed an ORR of 35% in the expansion phase and an ORR of 42%
in the overall patient population (DLT evaluation and expansion phase) using mRECIST criteria.38 Therefore, the null hypothesis that the true ORR is 20% will be tested against a one‐sided alternative that the assumed‐true ORR with the tested combination is 38% by RECIST v1.1. The target assumed‐true ORR
of 38% is believed to adequately represent the potential activity of cabozantinib andpembrolizumab.  
Using Simon's optimal two‐stage design, 13 patients will be accrued in the first stage. If there are 2 or fewer patients with response (CR or PR) (an observed rate of 15% or less), the study will be suspended for lack of sufficient efficacy. Otherwise, 16 additional patients will be accrued for a total of 29 patients. The null hypothesis (of an ORR of 20%) will be rejected if 9 or more patients have a tumor response (CR or PR)
out of 29 patients (an observed ORR of at least 31%). This design yields a type I error rate of 0.10 and power of 80% when the true ORR is 38%. An accrual period of 24 months and follow‐up period of 12 months are anticipated. More than 29 patients may be screened and/or enrolled depending on screen fails or dropouts before startingtreatment.
fred hutchinson cancer center university
17.2 statistical methods

The primary endpoint is ORR per RECIST v1.1, while secondary endpoints include ORR by iRECIST, ORR and DCR by iRECIST, median PFS, and median OS. Only patients who have been on treatment with both cabozantinib and pembrolizumab concurrently for more than 42 days in the first 3 cycles (i.e. received treatment for two‐thirds of the cycle) will be included in the analysis of the primary endpoint. Patients who have received any duration of study treatment will be evaluable for safety. Binary endpoints will be summarized by percentages and associated confidence intervals. ORR will also be represented by a waterfall plot. The distribution for survival times will be estimated using the method of Kaplan‐Meier; associated landmark time percentages and the median value will be based on this. Confidence intervals for median values will use the Brookmeyer‐Crowley method. Any toxicity with at least 5% prevalence has at least an 77% chance of being observed among 29 patients.  
For the exploratory objectives, archival or fresh tumors from all patients will be analyzed by IHC, the presence of specific immune cell subsets and protein marker expression, as well as the staining pattern and location within tumors will be described. The frequencies of immune cell subset will be obtained from flow cytometry at various timepoints, and cell changes from baseline to post‐treatment timepoints will be averaged across patients. The association between immune cell, biomarker expression, gene expression signature, or cytokine level with ORR will be evaluated using Spearman correlation, where p<0.05 is considered significant.