Axitinib and Pembrolizumab in Subjects With Advanced Alveolar Soft Part Sarcoma and Other Soft Tissue Sarcomas

• Sponsor: Jonathan Trent, MD, PhD (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02636725
• Collaborator: Merck Sharp & Dohme LLC (Industry), Pfizer (Industry)
• Enrollment: 33
• Location: 1
• Arms: 2
• Anticipated Duration (Months): 79.4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this research study is to test if Axitinib together with Pembrolizumab can slow tumor growth and know the side effects of the combination treatment.

Condition or Disease	Intervention/Treatment	Phase
Alveolar Soft Part Sarcoma; Soft Tissue Sarcomas	Drug: Axitinib; Drug: Pembrolizumab	Phase 2

Detailed Description

Arm 2, the Axitinib Plus Pembrolizumab Expansion Cohort, did not open.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Concurrent Axitinib and Pembrolizumab in Subjects With Advanced Alveolar Soft Part Sarcoma (ASPS) and Other Soft Tissue Sarcomas (STS)
• Actual Study Start Date: Apr 19, 2016
• Actual Primary Completion Date: May 8, 2018
• Anticipated Study Completion Date: Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Axitinib Plus Pembrolizumab Group Participants in this group will receive combination treatment of Axitinib plus Pembrolizumab for up to 2 years followed by monotherapy of Axitinib until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.	Drug: Axitinib; 5 mg tablets twice daily oral dose administered for 7 consecutive weeks on Cycle 1. A safety lead-in consisting of the initial five patients, intrapatient dose escalation of Axitinib will be permitted based on the absence of predefined toxicities. Twice daily oral dose between 2 mg to 10 mg Axitinib tablets will be administered on subsequent 6 week cycles until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.; Other Names: Inlyta ; Drug: Pembrolizumab; 200 mg intravenous infusion administered every 21 weeks beginning week 2 of Cycle 1 for a maximum of up to 2 years or until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.; Other Names: MK-3475 Keytruda
Experimental: Axitinib Plus Pembrolizumab Expansion Cohort Expansion cohort for up to 10 additional patients with alveolar soft part sarcoma. Participants in this group will receive combination treatment of Axitinib plus Pembrolizumab for up to 2 years followed by monotherapy of Axitinib until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.	Drug: Axitinib; 5 mg tablets twice daily oral dose administered for 7 consecutive weeks on Cycle 1. A safety lead-in consisting of the initial five patients, intrapatient dose escalation of Axitinib will be permitted based on the absence of predefined toxicities. Twice daily oral dose between 2 mg to 10 mg Axitinib tablets will be administered on subsequent 6 week cycles until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.; Other Names: Inlyta ; Drug: Pembrolizumab; 200 mg intravenous infusion administered every 21 weeks beginning week 2 of Cycle 1 for a maximum of up to 2 years or until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.; Other Names: MK-3475 Keytruda

Outcome Measures

Primary Outcome Measures

1. Percentage of Evaluable Participants Achieving Progression-Free Survival (PFS) at 3 Months [3 Months]

   Percentage of participants who are disease progression free 3 months after initiation of therapy. Disease progression will be evaluated from imaging measures using the Response Evaluation Criteria for Solid Tumors (RECIST) 1.1.

Secondary Outcome Measures

1. Percentage of Evaluable Participants Achieving Objective Response Rate (ORR) [Up to 2 Years]

   Objective Response Rate (ORR) is defined as achieving complete response (CR) or partial response (PR) from imaging measures using (RECIST) 1.1.

2. Percentage of Evaluable Participants Achieving Clinical Benefit Response (CBR) [Up to 2 Years]

   CBR is defined as achieving complete response (CR), partial response (PR) or stable disease (SD) from imaging measures using (RECIST) 1.1.

3. Time to Progression (TTP) [Up to 2 years]

   Time to progression (TTP) is defined as time from treatment initiation to first occurrence of progression by Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 or death.

4. Overall Survival (OS) [Up to 5 years]

   OS is (OS) is defined as the elapsed time from treatment initiation to death from any cause, whichever is earlier. Patients alive or those lost to follow-up will be censored at the last date of contact (or last date known to be alive).

5. Number of Participants Experiencing Serious Adverse Events (SAEs), Dose-Limiting Toxicities, and Grade 3 or Higher Treatment-Emergent Adverse Events [Up to 25 months]

   The number of participants experiencing serious adverse events (SAEs), dose-limiting toxicities (DLTs), and grade 3 or higher treatment-emergent adverse events (AEs). AEs, SAEs and DLTs will be evaluated by treating physician using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. Treatment-emergent adverse events are those found to be definitely, probably and possibly related to study therapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients must have histologically confirmed sarcoma with pathology review required for any outside samples.

2. The following histologies may be enrolled without prior treatment:

• alveolar soft part sarcoma,

• clear cell sarcoma,

• epithelioid hemangioendothelioma, and

• chordoma.

1. The following histologies may be enrolled ONLY if refractory to anthracycline-based chemotherapy or if the patient refuses to undergo standard of care treatment:

• synovial sarcoma,

• rhabdomyosarcoma,

• malignant peripheral nerve sheath tumors,

• dedifferentiated, pleomorphic or myxoid/round cell liposarcoma,

• leiomyosarcoma,

• malignant phylloides tumor,

• high grade undifferentiated pleomorphic sarcomas (HGUPS/MFH),

• angiosarcoma,

• spindle cell sarcoma, not otherwise specified (NOS)

• malignant myoepithelioma.

1. The following histologies may be enrolled ONLY if refractory to at least one line of chemotherapy or if the patient refuses to undergo standard of care treatment:

• solitary fibrous tumor/hemangiopericytoma.

1. The following histologies may be enrolled ONLY if refractory to at least first-line targeted therapy or if the patient refuses to undergo standard of care treatment:

• gastrointestinal stromal tumors,

• extraskeletal myxoid chondrosarcoma,

• PEComa.

1. Primary tumors of bone including Ewing's sarcoma, osteosarcoma, and dedifferentiated chondrosarcoma may only be enrolled if there are measurable target lesions occurring in soft tissue and they are refractory to standard of care anthracycline-based chemotherapy.

2. Any other histology or standard of care therapy not specifically addressed will be reviewed by the principal investigator and pathologist for final determination of eligibility.

3. Measurable disease as defined by RECIST v1.1 (provided in Section 14.0).

4. Radiographic progression as defined by RECIST v1.1, based on comparison between two radiographic studies no greater than 6 months apart.

5. Inability to undergo complete resection of the disease by surgery.

6. Adequate organ function as defined:

• Hematological

• Absolute neutrophil count (ANC) ≥1,000 / microliter (mcL)

• Platelets ≥75,000 / mcL

• Hemoglobin ≥8 g/dL without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)

• Renal

• Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or calculated creatinine clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN. (GFR can also be used in place of creatinine or CrCl). Creatinine clearance should be calculated per institutional standard.

• Hepatic

• Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN.

• Aspartate Aminotransferase (AST/SGOT) and Alanine Transaminase (ALT/SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases.

• Albumin >2.5 mg/dL

• Coagulation

• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.

• Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.

1. Age ≥ 16 years.

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

3. Patients must consent and be willing to undergo three core needle biopsies at baseline, prior to starting Cycle 3, and at off-study. At least one tumor site must be amenable to biopsy in the judgment of the interventional radiologist.

4. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

5. Females of child bearing potential that are sexually active must agree to either practice 2 medically accepted highly effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 120 days after the last dose of study drug. See Appendix G for protocol-approved highly effective methods of contraceptive combinations. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.

• Negative test for pregnancy is required of females of child-bearing potential; A female of child bearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:

1. has not undergone a hysterectomy or bilateral oophorectomy; or 2. has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months or 730 days).

• Conception while on treatment must be avoided

1. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Prior history of vasectomy does NOT replace requirement for contraceptive use.

2. Suitable venous access to allow for all study related blood sampling

3. Ability to understand and willingness to sign a written informed consent document.

4. For minors that are 16 to 18 years of age, assent and parental (or legally acceptable representative) written informed consent must be obtained.

Exclusion Criteria:

1. Prior therapy with axitinib. Patients are permitted to have received prior tyrosine kinase inhibitor (TKI) therapy including imatinib, sunitinib, pazopanib, or similar. Patients may have received prior Programmed death 1 (PD-1)/Programmed death-ligand 1 (PD-L1) directed therapy.

2. Hypersensitivity to axitinib, pembrolizumab or any of its excipients.

3. Patients may not be receiving any other investigational agents (within 4 weeks prior to Cycle 1, day 1).

4. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Cycle 1, day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

5. Patient has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1, Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

6. Additional known malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.

7. Patients with end-organ dysfunction as defined in inclusion criterion (i.e. #11 above).

8. Patients with bone-only lesions.

9. Patients with underlying immune deficiency, chronic infections including HIV, hepatitis, or tuberculosis (TB) or autoimmune disease.

10. Patients with underlying hematologic issues including bleeding diathesis, known previous GI bleeding requiring intervention within the past 6 months, active pulmonary emboli or deep vein thromboses (DVT) that are not stable on anticoagulation regimen.

11. Has known history of, or any evidence of active, non-infectious pneumonitis.

12. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

13. Concomitant (or receipt of) treatment with medications that may affect the metabolism of pembrolizumab and/or axitinib within 7 days prior to Cycle 1, day 1 of axitinib.

14. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

15. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

16. Any uncontrolled, intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia

17. Prolonged corrected QT (QTc) interval on Screening EKG >475 ms.

18. Ejection Fraction <40% by 2D echocardiogram (ECHO) at Screening.

19. Any serious medical or psychiatric illness/condition including substance use disorders likely in the judgment of the Investigator(s) to interfere or limit compliance with study requirements/treatment.

20. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Miami	Miami	Florida	United States	33136

Sponsors and Collaborators

• Jonathan Trent, MD, PhD
• Merck Sharp & Dohme LLC
• Pfizer

Investigators

• Principal Investigator: Jonathan C Trent, MD, University of Miami

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 15, 2020

More Information

Publications

None provided.

• Responsible Party: Jonathan Trent, MD, PhD, Professor of Medicine, University of Miami
• ClinicalTrials.gov Identifier: NCT02636725
• Other Study ID Numbers: 20150932
• First Posted: Dec 22, 2015
• Last Update Posted: Nov 26, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Jonathan Trent, MD, PhD, Professor of Medicine, University of Miami: Advanced Alveolar Soft Part Sarcoma; ASPS; STS
• Additional relevant MeSH terms: Sarcoma; Sarcoma, Alveolar Soft Part; Pembrolizumab; Axitinib

Study Results

Participant Flow

Arm/Group Title	Axitinib Plus Pembrolizumab Group
Arm/Group Description	Participants in this group will receive combination treatment of Axitinib plus Pembrolizumab for up to 2 years followed by monotherapy of Axitinib until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first. Axitinib: 5 mg tablets twice daily oral dose administered for 7 consecutive weeks on Cycle 1. A safety lead-in consisting of the initial five patients, intrapatient dose escalation of Axitinib will be permitted based on the absence of predefined toxicities. Twice daily oral dose between 2 mg to 10 mg Axitinib tablets will be administered on subsequent 6 week cycles until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first. Pembrolizumab: 200 mg intravenous infusion administered every 21 weeks beginning week 2 of Cycle 1 for a maximum of up to 2 years or until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.
Period Title: Baseline
STARTED	33
COMPLETED	30
NOT COMPLETED	3
Period Title: Baseline
STARTED	30
COMPLETED	30
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Axitinib Plus Pembrolizumab Group
Arm/Group Description	Participants in this group will receive combination treatment of Axitinib plus Pembrolizumab for up to 2 years followed by monotherapy of Axitinib until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first. Axitinib: 5 mg tablets twice daily oral dose administered for 7 consecutive weeks on Cycle 1. A safety lead-in consisting of the initial five patients, intrapatient dose escalation of Axitinib will be permitted based on the absence of predefined toxicities. Twice daily oral dose between 2 mg to 10 mg Axitinib tablets will be administered on subsequent 6 week cycles until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first. Pembrolizumab: 200 mg intravenous infusion administered every 21 weeks beginning week 2 of Cycle 1 for a maximum of up to 2 years or until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.
Overall Participants	33
Age (Count of Participants)
<=18 years	1 3%
Between 18 and 65 years	24 72.7%
>=65 years	8 24.2%
Sex: Female, Male (Count of Participants)
Female	15 45.5%
Male	18 54.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 24.2%
Not Hispanic or Latino	25 75.8%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 6.1%
Native Hawaiian or Other Pacific Islander	1 3%
Black or African American	0 0%
White	29 87.9%
More than one race	1 3%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Evaluable Participants Achieving Progression-Free Survival (PFS) at 3 Months
Description	Percentage of participants who are disease progression free 3 months after initiation of therapy. Disease progression will be evaluated from imaging measures using the Response Evaluation Criteria for Solid Tumors (RECIST) 1.1.
Time Frame	3 Months

Outcome Measure Data

Analysis Population Description

Evaluable participants received 80% of scheduled axitinib doses and two infusions of pembrolizumab, have measurable disease at baseline and at least one post-baseline disease assessment.

Arm/Group Title	Axitinib Plus Pembrolizumab Group
Arm/Group Description	Participants in this group will receive combination treatment of Axitinib plus Pembrolizumab for up to 2 years followed by monotherapy of Axitinib until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first. Axitinib: 5 mg tablets twice daily oral dose administered for 7 consecutive weeks on Cycle 1. A safety lead-in consisting of the initial five patients, intrapatient dose escalation of Axitinib will be permitted based on the absence of predefined toxicities. Twice daily oral dose between 2 mg to 10 mg Axitinib tablets will be administered on subsequent 6 week cycles until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first. Pembrolizumab: 200 mg intravenous infusion administered every 21 weeks beginning week 2 of Cycle 1 for a maximum of up to 2 years or until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.
Measure Participants	30
Number (95% Confidence Interval) [percentage of participants]	70 212.1%

2. Secondary Outcome

Title	Percentage of Evaluable Participants Achieving Objective Response Rate (ORR)
Description	Objective Response Rate (ORR) is defined as achieving complete response (CR) or partial response (PR) from imaging measures using (RECIST) 1.1.
Time Frame	Up to 2 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Percentage of Evaluable Participants Achieving Clinical Benefit Response (CBR)
Description	CBR is defined as achieving complete response (CR), partial response (PR) or stable disease (SD) from imaging measures using (RECIST) 1.1.
Time Frame	Up to 2 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time to progression (TTP) is defined as time from treatment initiation to first occurrence of progression by Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 or death.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is (OS) is defined as the elapsed time from treatment initiation to death from any cause, whichever is earlier. Patients alive or those lost to follow-up will be censored at the last date of contact (or last date known to be alive).
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Number of Participants Experiencing Serious Adverse Events (SAEs), Dose-Limiting Toxicities, and Grade 3 or Higher Treatment-Emergent Adverse Events
Description	The number of participants experiencing serious adverse events (SAEs), dose-limiting toxicities (DLTs), and grade 3 or higher treatment-emergent adverse events (AEs). AEs, SAEs and DLTs will be evaluated by treating physician using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. Treatment-emergent adverse events are those found to be definitely, probably and possibly related to study therapy.
Time Frame	Up to 25 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 3 years
Adverse Event Reporting Description	In this protocol, adverse events include only treatment-emergent adverse events. Adverse events that are definitely, probably or possible related to study therapy are reported.
Arm/Group Title	Axitinib Plus Pembrolizumab Group
Arm/Group Description	Participants in this group will receive combination treatment of Axitinib plus Pembrolizumab for up to 2 years followed by monotherapy of Axitinib until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first. Axitinib: 5 mg tablets twice daily oral dose administered for 7 consecutive weeks on Cycle 1. A safety lead-in consisting of the initial five patients, intrapatient dose escalation of Axitinib will be permitted based on the absence of predefined toxicities. Twice daily oral dose between 2 mg to 10 mg Axitinib tablets will be administered on subsequent 6 week cycles until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first. Pembrolizumab: 200 mg intravenous infusion administered every 21 weeks beginning week 2 of Cycle 1 for a maximum of up to 2 years or until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.
All Cause Mortality
	Axitinib Plus Pembrolizumab Group
	Affected / at Risk (%)	# Events
Total	17/33 (51.5%)
Serious Adverse Events
	Axitinib Plus Pembrolizumab Group
	Affected / at Risk (%)	# Events
Total	9/33 (27.3%)
Cardiac disorders
Pericardial effusion	1/33 (3%)	1
Gastrointestinal disorders
Abdominal Pain	1/33 (3%)	1
Diarrhea	1/33 (3%)	2
Nausea and Vomiting	1/33 (3%)	1
Vomiting	1/33 (3%)	1
Infections and infestations
Papulopustular rash	1/33 (3%)	1
Investigations
Alanine aminotransferase increased	1/33 (3%)	1
Aspartate aminotransferase increased	1/33 (3%)	1
Transaminitis	1/33 (3%)	1
Metabolism and nutrition disorders
Anorexia	1/33 (3%)	1
Dehydration	1/33 (3%)	1
Hypertriglyceridemia	1/33 (3%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/33 (3%)	1
Nervous system disorders
Radiculitis	1/33 (3%)	1
Seizure	2/33 (6.1%)	2
Syncope	1/33 (3%)	1
Renal and urinary disorders
Acute renal failure	1/33 (3%)	1
Uremia	1/33 (3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/33 (6.1%)	2
Pneumothorax	1/33 (3%)	2
Other (Not Including Serious) Adverse Events
	Axitinib Plus Pembrolizumab Group
	Affected / at Risk (%)	# Events
Total	33/33 (100%)
Blood and lymphatic system disorders
Anemia	3/33 (9.1%)	4
Cardiac disorders
Chest Pain - Cardiac	1/33 (3%)	1
Ear and labyrinth disorders
Ear congestion	4/33 (12.1%)	4
Ear Pain	1/33 (3%)	1
Vertigo	1/33 (3%)	1
Endocrine disorders
Hyperthyroidism	2/33 (6.1%)	4
Hypothyroidism	18/33 (54.5%)	18
Gastrointestinal disorders
Abdominal Pain	10/33 (30.3%)	15
Bloating	2/33 (6.1%)	5
Constipation	8/33 (24.2%)	8
Diarrhea	18/33 (54.5%)	39
Dry Mouth	3/33 (9.1%)	3
Dyspepsia	1/33 (3%)	1
Gastroesophageal reflux disease	5/33 (15.2%)	5
Acid reflux	1/33 (3%)	1
Mouth sensitivity	3/33 (9.1%)	3
Mouth soreness	1/33 (3%)	1
Rectal irritation	1/33 (3%)	1
Stomatitis	1/33 (3%)	1
Hemorrhoids	3/33 (9.1%)	4
Mucositis Oral	13/33 (39.4%)	25
Nausea	17/33 (51.5%)	27
Oral dysesthesia	2/33 (6.1%)	2
Oral hemorrhage	2/33 (6.1%)	2
Oral Pain	2/33 (6.1%)	2
Stomach pain	1/33 (3%)	1
Toothache	1/33 (3%)	1
Vomiting	11/33 (33.3%)	14
General disorders
Chills	1/33 (3%)	1
Edema face	1/33 (3%)	1
Edema limbs	1/33 (3%)	1
Fatigue	26/33 (78.8%)	53
Decreased appetite	1/33 (3%)	1
Headaches (morning)	1/33 (3%)	1
Itching skin	1/33 (3%)	2
Weakness	1/33 (3%)	1
Non-cardiac chest pain	4/33 (12.1%)	5
Pain	9/33 (27.3%)	12
Immune system disorders
Disseminated Herpes Zoster	1/33 (3%)	1
Infections and infestations
Herpes simplex - Eye lesion	1/33 (3%)	1
Papulopustular rash	4/33 (12.1%)	5
Rash pustular	1/33 (3%)	1
Injury, poisoning and procedural complications
Bruising	1/33 (3%)	1
Investigations
Alanine aminotransferase increased	11/33 (33.3%)	23
Alkaline phosphatase increased	7/33 (21.2%)	12
Aspartate aminotransferase increased	11/33 (33.3%)	18
Blood bilirubin increased	1/33 (3%)	1
Creatinine increased	5/33 (15.2%)	7
Ejection fraction decreased	1/33 (3%)	1
Hemoglobin increased	5/33 (15.2%)	7
Elevated triglycerides	1/33 (3%)	1
Elevated thyroid stimulating hormone (TSH)	3/33 (9.1%)	3
Eosinophilia	1/33 (3%)	1
Hand sensitivity	2/33 (6.1%)	2
Hyperlipidemia	1/33 (3%)	1
Increased blood urea nitrogen (BUN)	1/33 (3%)	2
Lung discomfort	1/33 (3%)	1
Mouth sensitivity	1/33 (3%)	1
Mouth sensitivity - spicy foods	1/33 (3%)	1
Mouth sores	1/33 (3%)	2
Muscle aches	1/33 (3%)	1
Sputum production	1/33 (3%)	1
Platelet count decreased	3/33 (9.1%)	3
Weight loss	4/33 (12.1%)	4
White blood cell decreased	2/33 (6.1%)	2
Metabolism and nutrition disorders
Acidosis	1/33 (3%)	1
Anorexia	10/33 (30.3%)	24
Hyperglycemia	3/33 (9.1%)	3
Hypertriglyceridemia	1/33 (3%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	1/33 (3%)	1
Back Pain	3/33 (9.1%)	3
Chest wall pain	2/33 (6.1%)	2
Joint effusion	2/33 (6.1%)	3
Foot sensitivity	1/33 (3%)	1
Hand sensitivity	2/33 (6.1%)	2
Intermittent hand sensitivity	1/33 (3%)	1
Oligoarthritis	1/33 (3%)	1
Pain in extremity	5/33 (15.2%)	5
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	7/33 (21.2%)	7
Nervous system disorders
Headache	4/33 (12.1%)	8
Hand sensitivity	1/33 (3%)	1
Right-sided sciatica	1/33 (3%)	1
Paresthesia	1/33 (3%)	1
Syncope	1/33 (3%)	1
Psychiatric disorders
Insomnia	5/33 (15.2%)	5
Renal and urinary disorders
Hematuria	1/33 (3%)	1
Proteinuria	2/33 (6.1%)	2
Urinary urgency	1/33 (3%)	1
Glycosuria	1/33 (3%)	1
Reproductive system and breast disorders
Breast Pain	1/33 (3%)	1
Vaginal irritation	2/33 (6.1%)	3
Respiratory, thoracic and mediastinal disorders
Allergic Rhinitis	2/33 (6.1%)	2
Cough	11/33 (33.3%)	14
Dyspnea	2/33 (6.1%)	3
Epistaxis	1/33 (3%)	1
Hoarseness	6/33 (18.2%)	7
Nasal congestion	6/33 (18.2%)	6
Postnasal drip	2/33 (6.1%)	2
Hemoptysis	1/33 (3%)	1
Rhinorrhea	1/33 (3%)	1
Shortness of breath with exertion	1/33 (3%)	1
Wheezing	2/33 (6.1%)	2
Skin and subcutaneous tissue disorders
Alopecia	1/33 (3%)	1
Dry skin	1/33 (3%)	1
Erythema multiforme	1/33 (3%)	1
Palmar-plantar erythrodysesthesia syndrome	8/33 (24.2%)	10
Rash acneiform	1/33 (3%)	1
Rash maculo-papular	1/33 (3%)	1
Acne	1/33 (3%)	1
Eczema exacerbation	1/33 (3%)	1
Fingertip sensitivity	1/33 (3%)	1
Foot rash	1/33 (3%)	1
Foot sensitivity	2/33 (6.1%)	2
Hand and foot sensitivity	1/33 (3%)	1
Lip skin thickening	1/33 (3%)	1
Skin irritation	1/33 (3%)	1
Telangiectasia	1/33 (3%)	1
Vascular disorders
Hypertension	13/33 (39.4%)	20
Hypotension	1/33 (3%)	1
Thromboembolic event	1/33 (3%)	1

Limitations/Caveats

Arm 2, the Axitinib Plus Pembrolizumab Expansion Cohort, did not open.

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.