Phase Ib and Phase II Studies of MK-3475 in Combination + for Renal Cell Carcinoma:

• Sponsor: Arkadiusz Z. Dudek, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT02348008
• Collaborator: Merck Sharp & Dohme LLC (Industry), Big Ten Cancer Research Consortium (Other)
• Enrollment: 61
• Locations: 9
• Arms: 2
• Actual Duration (Months): 57.2
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is an open label, multi-institutional, single arm study of dose escalation phase Ib cohort, followed by a phase II cohort of anti-PD-1 antibody MK-3475 in combination with bevacizumab. No randomization or blinding is involved.

Condition or Disease	Intervention/Treatment	Phase
Clear Cell Renal Carcinoma	Drug: MK-3475; Drug: Bevacizumab; Drug: MK-3475; Drug: Bevacizumab	Phase 1/Phase 2

Detailed Description

OUTLINE: This is a multi-center study.

The phase Ib dose escalation study will evaluate MK-3475 in combination with bevacizumab in subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease. The phase II trial will determine the activity of the combination of MK-3475 and bevacizumab in first line therapy for subjects with metastatic clear cell renal carcinoma.

PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:

Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 5mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.

PHASE II INVESTIGATIONAL TREATMENT:

The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. Treatment will continue until disease progression, unacceptable toxicity, subject refusal, or subject death either from progression of disease, the therapy itself, or from other causes. Subjects who voluntarily stop the study, have progressive disease, or unacceptable toxicities will be followed for a total of 24 months.

Karnofsky Performance Status (KPS) ≥ 70% within 28 days prior to registration for protocol therapy.

Life Expectancy: 6 months or greater

The following baseline labs must be completed within 28 days prior to registration for protocol therapy:

Hematopoietic:

• Absolute neutrophil count (ANC) ≥ 1.5 × 10 9/L

• Platelets ≥ 100 × 10 9/L

• Hemoglobin (Hgb) ≥ 9.0 g/dL

Renal:

• Serum creatinine ≤ 1.5 × upper limit of normal (ULN)

• OR, if serum creatinine > 1.5 × ULN, estimated glomerular filtration rate (eGFR) ≥ 40 mL/min

Hepatic:

• Total serum bilirubin ≤ 1.5 × ULN

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN

• OR, AST and ALT ≤ 5 × ULN if liver function abnormalities are due to underlying malignancy

Coagulation:

• INR < 1.5 × ULN

• OR for subjects receiving warfarin or LMWH, the subjects must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase Ib and Phase II Studies of Anti-PD-1 Antibody MK-3475 in Combination With Bevacizumab for the Treatment of Metastatic Renal Cell Carcinoma: Big Ten Cancer Research Consortium GU14-003
• Actual Study Start Date: Mar 1, 2015
• Actual Primary Completion Date: Dec 5, 2019
• Actual Study Completion Date: Dec 5, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A - Phase 1b Dose Escalation Cohort Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.	Drug: MK-3475; Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV; Other Names: Pembrolizumab ; Drug: Bevacizumab; Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV; Other Names: Avastin
Other: Arm B - Phase II Investigational Treatment The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle.	Drug: MK-3475; Arm B: Phase II Treatment: 200mg IV; Other Names: Pembrolizumab ; Drug: Bevacizumab; Arm B: Phase II Treatment: administered at the maximum safe dose of 5mg or 10mg as established in the Phase 1b dose escalation cohort study.; Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. Phase 1b: Maximum Safe Dose of Treatment Regimen [Every 21 days while on treatment (estimated 4 months)]

   To establish the maximum tested safe dose of bevacizumab in combination with 200mg of MK-3475(pembrolizumab) for subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease.

2. Overall Response Rate [Every 6 weeks while on treatment (estimated 10 months)]

   To determine the activity of combination of MK-3475 and bevacizumab in first line therapy for subjects with treatment naïve metastatic clear cell RCC as assessed by response rates (complete or partial response) By calculating the proportion of subjects with a response (CR, PR) based on RECIST 1.1 where: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started

Secondary Outcome Measures

1. Progression-Free Survival [Up to two years from enrollment]

   To determine median progression-free survival (PFS) for this patient population, per RECIST 1.1 where: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started

2. Overall Survival [Up to 2 years from registration]

   To determine if treatment regimen improves overall survival for this patient population. Median overall survival will be calculated up to 2 years from registration.

3. Clinical Benefit Rate [Every 6 months while on treatment (estimated 4-10 months)]

   To determine the proportion of subjects with clinical benefit (complete response, partial response, or stable disease) based on RECIST 1.1, where: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started

4. Characterize Adverse Events [Every week while on treatment (estimated 4-10 months)]

   Characterize adverse effects (AE) of pembrolizumab in combination with bevacizumab in subjects with metastatic RCC after failure of at least one systemic therapy. Toxicity will be assessed using CTCAE version 4. All grade 3 and 4 treatment-related adverse events will be reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female ≥ 18 years of age at time of consent.

• Phase Ib dose escalation cohort study: subjects with histologically assessed metastatic clear cell RCC (defined as more than 50% clear cell component) after failure of at least one systemic therapy for metastatic disease (including, but not limited to prior therapy with interleukin 2, interferon, bevacizumab, VEGF TKI, and mTOR) for metastatic disease. NOTE: A biopsy to prove metastatic disease is not required.

• Phase II study: subjects with treatment-naïve histologically assessed metastatic clear cell RCC (defined as more than 50% clear cell component) and who are candidates for standard first-line therapy. NOTE: A biopsy to prove metastatic disease is not required.

• Measurable disease, defined as at least 1 tumor that fulfills the criteria for a target lesion according to RECIST 1.1, and obtained by imaging within 28 days prior to registration for protocol therapy.

• Karnofsky Performance Status ≥ 70% within 28 days prior to registration for protocol therapy.

• Life expectancy of 6 months or greater as determined by the treating physician.

• Adequate hepatic function within 28 days prior to registration for protocol therapy defined as meeting all of the following criteria:

• total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 x ULN

• and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases

• and alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases

• Adequate renal function within 28 days prior to registration for protocol therapy defined by either of the following criteria:

• serum creatinine ≤ 3 mg/dL

• OR if serum creatinine > 3 mg/dL, estimated glomerular filtration rate (GFR) ≥ 20 mL/min

• Adequate hematologic function within 28 days prior to registration for protocol therapy defined as meeting all of the following criteria:

• hemoglobin ≥ 9 g/dL

• and absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L

• and platelet count ≥ 100 × 10^9/L

• Adequate coagulation functioning within 28 days prior to registration for protocol therapy defined by either of the following criteria:

• INR < 1.5 × ULN

• OR for subjects receiving warfarin or LMWH, the subjects must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy.

• Provided written informed consent and HIPAA authorization for release of personal health information, approved by an Institutional Review Board/Independent Ethics Committee (IRB/IEC).

• Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A negative serum or urine pregnancy test is required within 72 hours of study registration. If the urine test cannot be confirmed as negative, a serum pregnancy test will be required.

• Women of childbearing potential (WOCP) must be willing to use two effective methods of birth control such as an oral, implantable, injectable, or transdermal hormonal contraceptive, an intrauterine device (IUD), use of a double barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total abstinence for the course of the study until 120 days after the last dose of study drug.

• Men who are not surgically sterile (vasectomy) must agree to use an acceptable method of contraception. Male subjects with female sexual partners who are pregnant, possibly pregnant, or who could become pregnant during the study must agree to use condoms from the first dose of study drug through at least 120 days after the last dose of study drug. Total abstinence for the same study period is an acceptable alternative.

• Availability of tissue if applicable (from the primary tumor or metastases) for correlative studies.

• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

• Phase Ib: Received prior monoclonal antibody therapy other than bevacizumab within 4 weeks of study registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events of such agents administered more than 4 weeks earlier.

• Phase II: has had prior therapy for metastatic renal cell carcinoma.

• Surgery within 4 weeks prior to study treatment except for minor procedures: NOTES: Hepatic biliary stent placement is allowed. Subject must have adequately recovered from the toxicity and/or complications of major surgery prior to study registration, as determined by the treating physician.

• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. 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 study registration. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.

• Previously received an organ or allogeneic progenitor/stem cell transplant.

• Received a live vaccine within 30 days prior to the first dose of trial treatment: Examples of live vaccines include, but are not limited to: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed.

• History of blood clots, pulmonary embolism, or deep vein thrombosis unless controlled by anticoagulant treatment.

• Known history of human immunodeficiency virus [(HIV) HIV 1/2 antibodies].

• Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration.

• 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).

NOTE: Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

• Received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events from previously administered agents. NOTE: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and can still be considered for the study.

• Any clinically significant infection defined as any acute viral, bacterial, or fungal infection that requires specific treatment. NOTE: Anti-infective treatment must be completed ≥ 7 days prior to study registration.

• Evidence of interstitial lung disease, history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.

• Known history of active tuberculosis.

• Any other severe, uncontrolled medical condition, including uncontrolled diabetes mellitus or unstable congestive heart failure.

• Known allergy to pembrolizumab or any of its excipients.

• Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies.

• Any condition that, in the opinion of the treating physician, would exclude the subject from receiving bevacizumab. Examples may include but are not limited to:

• Hemoptysis (defined as > ½ teaspoon of blood)

• Pre-existing bleeding diathesis, coagulopathy or hemorrhage

• Myocardial infarction or cerebrovascular accident within 6 months prior to study registration

• Any drugs or supplements that interfere with blood clotting can raise the risk of bleeding during treatment with bevacizumab. These drugs include vitamin E, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen (Advil, Motrin), and naproxen (Aleve, Naprosyn), warfarin (Coumadin), ticlopidine (Ticlid), and clopidogrel (Plavix).These agents should be used with caution.

• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for enrollment in this study.

• Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study registration.

• Any condition that, in the opinion of the investigator, might jeopardize the safety of the subject or interfere with protocol compliance.

• Any mental or medical condition that prevents the subject from giving informed consent or participating in the trial.

• No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, Gleason ≤ grade 7 prostate cancers, or other cancer for which the subject has been disease-free for at least 5 years.

• Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).

• Treatment with any investigational agent within 28 days prior to registration for protocol therapy and the subject must have recovered from the acute toxic effects of the regimen.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University, Robert H. Lurie Cancer Center	Chicago	Illinois	United States	60611
2	University of Illinois Cancer Center	Chicago	Illinois	United States	60612
3	University of Iowa, Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
4	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
5	Michigan State University, Breslin Cancer Center	Lansing	Michigan	United States	48910
6	University of Minnesota: Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
7	University of Nebraska, Fred and Pamela Buffet Cancer Center	Omaha	Nebraska	United States	68198
8	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
9	Penn State Hershey Cancer Institute	Hershey	Pennsylvania	United States	17033

Sponsors and Collaborators

• Arkadiusz Z. Dudek, MD
• Merck Sharp & Dohme LLC
• Big Ten Cancer Research Consortium

Investigators

• Study Chair: Arkadiusz Z Dudek, M.D., Ph.D., Big Ten Cancer Research Consortium

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 11, 2018

More Information

Additional Information:

• Big Ten Cancer Research Consortium Website

Publications

None provided.

• Responsible Party: Arkadiusz Z. Dudek, MD, Sponsor-Investigator, Big Ten Cancer Research Consortium
• ClinicalTrials.gov Identifier: NCT02348008
• Other Study ID Numbers: BTCRC GU14-003
• First Posted: Jan 28, 2015
• Last Update Posted: Jul 31, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Arkadiusz Z. Dudek, MD, Sponsor-Investigator, Big Ten Cancer Research Consortium: MK-3475; Pembrolizumab; Bevacizumab
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Kidney Neoplasms; Bevacizumab; Pembrolizumab

Study Results

Participant Flow

Arm/Group Title	Arm A - Phase 1b Dose Escalation Cohort	Arm A - Phase Ib Dose Ecalation Cohort 2	Arm B - Phase II Investigational Treatment
Arm/Group Description	Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. MK-3475: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV Bevacizumab: Arm A: Phase 1b Cohort 1: 10mg IV;	Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. MK-3475: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV Bevacizumab: Arm A: Phase 1b Cohort 2: 15mg IV	The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. MK-3475: Arm B: Phase II Treatment: 200mg IV Bevacizumab: Arm B: Phase II Treatment: administered at the maximum safe dose of 5mg or 10mg as established in the Phase 1b dose escalation cohort study.
Period Title: Overall Study
STARTED	3	10	48
COMPLETED	0	0	29
NOT COMPLETED	3	10	19

Baseline Characteristics

Arm/Group Title	Arm A - Phase 1b Dose Escalation Cohort	Arm B - Phase II Investigational Treatment	Total
Arm/Group Description	Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. MK-3475: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV Bevacizumab: Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV	The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. MK-3475: Arm B: Phase II Treatment: 200mg IV Bevacizumab: Arm B: Phase II Treatment: administered at the maximum safe dose of 5mg or 10mg as established in the Phase 1b dose escalation cohort study.	Total of all reporting groups
Overall Participants	13	48	61
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55	61	60
Sex: Female, Male (Count of Participants)
Female	2 15.4%	15 31.3%	17 27.9%
Male	11 84.6%	33 68.8%	44 72.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	5 10.4%	5 8.2%
Not Hispanic or Latino	10 76.9%	38 79.2%	48 78.7%
Unknown or Not Reported	3 23.1%	5 10.4%	8 13.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	10 76.9%	45 93.8%	55 90.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 23.1%	3 6.3%	6 9.8%
Region of Enrollment (participants) [Number]
United States	13 100%	48 100%	61 100%
Karnofsky Performance Status (KPS) (Count of Participants)
KPS 70	2 15.4%	3 6.3%	5 8.2%
KPS 80	3 23.1%	10 20.8%	13 21.3%
KPS 90	1 7.7%	20 41.7%	21 34.4%
KPS 100	7 53.8%	15 31.3%	22 36.1%
Prior Nephrectomy (Count of Participants)
Yes	11 84.6%	43 89.6%	54 88.5%
No	2 15.4%	5 10.4%	7 11.5%
Bone Metastases (Count of Participants)
Yes	6 46.2%	10 20.8%	16 26.2%
No	7 53.8%	38 79.2%	45 73.8%
Metastatic RCC Prognosis (by IMDC/Heng Score) (Count of Participants)
Favorable	5 38.5%	10 20.8%	15 24.6%
Intermediate	3 23.1%	31 64.6%	34 55.7%
Poor	5 38.5%	7 14.6%	12 19.7%

Outcome Measures

1. Primary Outcome

Title	Phase 1b: Maximum Safe Dose of Treatment Regimen
Description	To establish the maximum tested safe dose of bevacizumab in combination with 200mg of MK-3475(pembrolizumab) for subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease.
Time Frame	Every 21 days while on treatment (estimated 4 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A - Phase 1b Dose Escalation Cohort
Arm/Group Description	Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. MK-3475: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV Bevacizumab: Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV
Measure Participants	13
Number [mg/kg]	15

2. Primary Outcome

Title	Overall Response Rate
Description	To determine the activity of combination of MK-3475 and bevacizumab in first line therapy for subjects with treatment naïve metastatic clear cell RCC as assessed by response rates (complete or partial response) By calculating the proportion of subjects with a response (CR, PR) based on RECIST 1.1 where: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
Time Frame	Every 6 weeks while on treatment (estimated 10 months)

Outcome Measure Data

Analysis Population Description

Results for Arm A - Phase Ib are reported as a single group, no per-group analyses were planned or performed.

Arm/Group Title	Arm A - Phase 1b Dose Escalation Cohort	Arm B - Phase II Investigational Treatment
Arm/Group Description	Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. MK-3475: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV Bevacizumab: Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV	The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. MK-3475: Arm B: Phase II Treatment: 200mg IV Bevacizumab: Arm B: Phase II Treatment: administered at the maximum safe dose of 5mg or 10mg as established in the Phase 1b dose escalation cohort study.
Measure Participants	13	48
Number (95% Confidence Interval) [percentage of participants]	41.7 320.8%	60.9 126.9%

3. Secondary Outcome

Title	Progression-Free Survival
Description	To determine median progression-free survival (PFS) for this patient population, per RECIST 1.1 where: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
Time Frame	Up to two years from enrollment

Outcome Measure Data

Analysis Population Description

Results for Arm A - Phase Ib are reported as a single group, no per-group analyses were planned or performed.

Arm/Group Title	Arm A - Phase 1b Dose Escalation Cohort	Arm B - Phase II Investigational Treatment
Arm/Group Description	Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. MK-3475: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV Bevacizumab: Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV	The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. MK-3475: Arm B: Phase II Treatment: 200mg IV Bevacizumab: Arm B: Phase II Treatment: administered at the maximum safe dose of 5mg or 10mg as established in the Phase 1b dose escalation cohort study.
Measure Participants	13	47
Median (95% Confidence Interval) [months]	9.9	20.7

4. Secondary Outcome

Title	Overall Survival
Description	To determine if treatment regimen improves overall survival for this patient population. Median overall survival will be calculated up to 2 years from registration.
Time Frame	Up to 2 years from registration

Outcome Measure Data

Analysis Population Description

Results for Arm A - Phase Ib are reported as a single group, no per-group analyses were planned or performed.

Arm/Group Title	Arm A - Phase 1b Dose Escalation Cohort	Arm B - Phase II Investigational Treatment
Arm/Group Description	Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. MK-3475: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV Bevacizumab: Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV	The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. MK-3475: Arm B: Phase II Treatment: 200mg IV Bevacizumab: Arm B: Phase II Treatment: administered at the maximum safe dose of 5mg or 10mg as established in the Phase 1b dose escalation cohort study.
Measure Participants	13	47
Median (95% Confidence Interval) [Months]	17.9	NA

5. Secondary Outcome

Title	Clinical Benefit Rate
Description	To determine the proportion of subjects with clinical benefit (complete response, partial response, or stable disease) based on RECIST 1.1, where: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
Time Frame	Every 6 months while on treatment (estimated 4-10 months)

Outcome Measure Data

Analysis Population Description

Results for Arm A - Phase Ib are reported as a single group, no per-group analyses were planned or performed.

Arm/Group Title	Arm A - Phase 1b Dose Escalation Cohort	Arm B - Phase II Investigational Treatment
Arm/Group Description	Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. MK-3475: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV Bevacizumab: Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV	The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. MK-3475: Arm B: Phase II Treatment: 200mg IV Bevacizumab: Arm B: Phase II Treatment: administered at the maximum safe dose of 5mg or 10mg as established in the Phase 1b dose escalation cohort study.
Measure Participants	13	46
Number [percentage of subjects]	91.67	100

6. Secondary Outcome

Title	Characterize Adverse Events
Description	Characterize adverse effects (AE) of pembrolizumab in combination with bevacizumab in subjects with metastatic RCC after failure of at least one systemic therapy. Toxicity will be assessed using CTCAE version 4. All grade 3 and 4 treatment-related adverse events will be reported.
Time Frame	Every week while on treatment (estimated 4-10 months)

Outcome Measure Data

Analysis Population Description

The analysis population for this objective was defined in the protocol as "all subjects who received at least one dose of study drug". No per-arm or per-cohort analyses were planned or performed.

Arm/Group Title	All Subjects
Arm/Group Description	Adverse events are summarized for all study participants who received at least one dose of study drug.
Measure Participants	60
Duodenal ulcer: Grade 4	1
Hyponatremia: Grade 4	1
Hypertension: Grade 3	15
Proteinuria: Grade 3	6
Adrenal insufficiency: Grade 3	4
Pain/Headaches: Grade 3	3
Pneumonitis: Grade 3	2
Hyponatremia: Grade 3	2
Generalized muscle weakness: Grade 3	2
Dehydration: Grade 3	2
Skin Rashes: Grade 3	2
Anemia: Grade 3	2
Nausea: Grade 3	1
Vomiting: Grade 3	1
Thromboembolic event: Grade 3	1
Seizure: Grade 3	1
Myocardial infarction: Grade 3	1
Mucositis oral: Grade 3	1
Immune mediated hepatitis: Grade 3	1
Immune mediated gastritis: Grade 3	1
Hypothyroidism	1
Hematuria	1
Flu like symptoms: Grade 3	1
Diarrhea: Grade 3	1
Arthralgia: Grade 3	1
Alkaline phosphatase increased: Grade 3	1

Adverse Events

Time Frame	Every week while on treatment (estimated 4-10 months)
Arm/Group Title	All Subjects
Arm/Group Description	Adverse events are summarized for all study participants who received at least one dose of study drug. Per the protocol, the safety analysis population "will comprise all subjects who received at least one dose of study drug". Consequently, no per-group analyses were planned or performed.
All Cause Mortality
	All Subjects
	Affected / at Risk (%)	# Events
Total	28/61 (45.9%)
Serious Adverse Events
	All Subjects
	Affected / at Risk (%)	# Events
Total	32/61 (52.5%)
Blood and lymphatic system disorders
ANEMIA	1/61 (1.6%)	1
Cardiac disorders
ACUTE CORONARY SYNDROME	1/61 (1.6%)	1
CARDIAC DISORDERS	1/61 (1.6%)	1
HEART FAILURE	1/61 (1.6%)	1
MYOCARDIAL INFARCTION	1/61 (1.6%)	1
Endocrine disorders
ADRENAL INSUFFICIENCY	5/61 (8.2%)	5
HYPOTHYROIDISM	1/61 (1.6%)	1
Gastrointestinal disorders
COLITIS	1/61 (1.6%)	1
DUODENAL ULCER	1/61 (1.6%)	1
GASTROINTESTINAL DISORDERS	2/61 (3.3%)	2
PANCREATITIS	1/61 (1.6%)	1
General disorders
NON-CARDIAC CHEST PAIN	1/61 (1.6%)	1
PAIN	2/61 (3.3%)	2
Infections and infestations
ABDOMINAL INFECTION	1/61 (1.6%)	1
INFECTIONS AND INFESTATIONS	1/61 (1.6%)	1
SMALL INTESTINE INFECTION	1/61 (1.6%)	1
SOFT TISSUE INFECTION	1/61 (1.6%)	1
UPPER RESPIRATORY INFECTION	1/61 (1.6%)	1
URINARY TRACT INFECTION	1/61 (1.6%)	1
Metabolism and nutrition disorders
ANOREXIA	1/61 (1.6%)	1
HYPERCALCEMIA	2/61 (3.3%)	2
HYPERGLYCEMIA	1/61 (1.6%)	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA	1/61 (1.6%)	1
BACK PAIN	1/61 (1.6%)	1
BUTTOCK PAIN	1/61 (1.6%)	1
CHEST WALL PAIN	1/61 (1.6%)	1
GENERALIZED MUSCLE WEAKNESS	1/61 (1.6%)	1
MUSCLE WEAKNESS LOWER LIMB	1/61 (1.6%)	1
Nervous system disorders
HEADACHE	1/61 (1.6%)	1
SEIZURE	1/61 (1.6%)	2
STROKE	1/61 (1.6%)	1
SYNCOPE	1/61 (1.6%)	1
TRANSIENT ISCHEMIC ATTACKS	1/61 (1.6%)	1
Renal and urinary disorders
ACUTE KIDNEY INJURY	2/61 (3.3%)	2
HEMATURIA	1/61 (1.6%)	2
PROTEINURIA	1/61 (1.6%)	1
Reproductive system and breast disorders
PELVIC PAIN	1/61 (1.6%)	1
Respiratory, thoracic and mediastinal disorders
DYSPNEA	2/61 (3.3%)	2
PLEURAL EFFUSION	1/61 (1.6%)	1
PNEUMONITIS	3/61 (4.9%)	3
Vascular disorders
HYPOTENSION	1/61 (1.6%)	1
THROMBOEMBOLIC EVENT	1/61 (1.6%)	1
VASCULAR DISORDERS	1/61 (1.6%)	1
Other (Not Including Serious) Adverse Events
	All Subjects
	Affected / at Risk (%)	# Events
Total	60/61 (98.4%)
Blood and lymphatic system disorders
ANEMIA	12/61 (19.7%)	18
BLOOD AND LYMPHATIC SYSTEM DISORDERS	2/61 (3.3%)	3
LEUKOCYTOSIS	3/61 (4.9%)	4
Cardiac disorders
ATRIAL FIBRILLATION	2/61 (3.3%)	2
CARDIAC DISORDERS	4/61 (6.6%)	4
CHEST PAIN - CARDIAC	1/61 (1.6%)	1
LEFT VENTRICULAR SYSTOLIC DYSFUNCTION	1/61 (1.6%)	1
PALPITATIONS	1/61 (1.6%)	1
SINUS BRADYCARDIA	4/61 (6.6%)	4
SINUS TACHYCARDIA	2/61 (3.3%)	2
SUPRAVENTRICULAR TACHYCARDIA	1/61 (1.6%)	1
Ear and labyrinth disorders
EAR AND LABYRINTH DISORDERS	1/61 (1.6%)	1
EAR PAIN	1/61 (1.6%)	1
VERTIGO	1/61 (1.6%)	1
Endocrine disorders
ADRENAL INSUFFICIENCY	3/61 (4.9%)	5
ENDOCRINE DISORDERS	1/61 (1.6%)	1
HYPERPARATHYROIDISM	1/61 (1.6%)	1
HYPERTHYROIDISM	3/61 (4.9%)	3
HYPOTHYROIDISM	14/61 (23%)	16
Eye disorders
BLURRED VISION	3/61 (4.9%)	3
DRY EYE	2/61 (3.3%)	3
EYE DISORDERS	4/61 (6.6%)	6
EYE PAIN	2/61 (3.3%)	2
WATERING EYES	3/61 (4.9%)	3
Gastrointestinal disorders
ABDOMINAL DISTENSION	1/61 (1.6%)	1
ABDOMINAL PAIN	10/61 (16.4%)	15
ANAL HEMORRHAGE	1/61 (1.6%)	1
BLOATING	2/61 (3.3%)	2
COLITIS	2/61 (3.3%)	4
CONSTIPATION	25/61 (41%)	34
DENTAL CARIES	2/61 (3.3%)	2
DIARRHEA	25/61 (41%)	40
DRY MOUTH	4/61 (6.6%)	4
DYSPEPSIA	5/61 (8.2%)	5
DYSPHAGIA	4/61 (6.6%)	4
FLATULENCE	3/61 (4.9%)	3
GASTRIC ULCER	3/61 (4.9%)	3
GASTRITIS	4/61 (6.6%)	5
GASTROESOPHAGEAL REFLUX DISEASE	8/61 (13.1%)	9
GASTROINTESTINAL DISORDERS	13/61 (21.3%)	18
HEMORRHOIDAL HEMORRHAGE	2/61 (3.3%)	2
HEMORRHOIDS	3/61 (4.9%)	3
LOWER GASTROINTESTINAL HEMORRHAGE	1/61 (1.6%)	1
MUCOSITIS ORAL	9/61 (14.8%)	14
NAUSEA	27/61 (44.3%)	38
ORAL DYSESTHESIA	4/61 (6.6%)	4
ORAL PAIN	2/61 (3.3%)	2
PANCREATITIS	2/61 (3.3%)	2
RECTAL HEMORRHAGE	1/61 (1.6%)	1
STOMACH PAIN	3/61 (4.9%)	3
TOOTHACHE	2/61 (3.3%)	2
VOMITING	15/61 (24.6%)	27
General disorders
CHILLS	5/61 (8.2%)	5
EDEMA FACE	1/61 (1.6%)	1
EDEMA LIMBS	19/61 (31.1%)	24
FATIGUE	44/61 (72.1%)	66
FEVER	3/61 (4.9%)	3
FLU LIKE SYMPTOMS	3/61 (4.9%)	4
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS	8/61 (13.1%)	15
IRRITABILITY	1/61 (1.6%)	1
LOCALIZED EDEMA	3/61 (4.9%)	3
NECK EDEMA	1/61 (1.6%)	1
NON-CARDIAC CHEST PAIN	2/61 (3.3%)	2
PAIN	12/61 (19.7%)	14
Hepatobiliary disorders
CHOLECYSTITIS	1/61 (1.6%)	1
HEPATOBILIARY DISORDERS	2/61 (3.3%)	2
Immune system disorders
ALLERGIC REACTION	2/61 (3.3%)	2
Infections and infestations
BRONCHIAL INFECTION	1/61 (1.6%)	1
INFECTIONS AND INFESTATIONS	4/61 (6.6%)	4
LIP INFECTION	1/61 (1.6%)	1
LUNG INFECTION	1/61 (1.6%)	1
NAIL INFECTION	1/61 (1.6%)	1
PAPULOPUSTULAR RASH	1/61 (1.6%)	1
RHINITIS INFECTIVE	1/61 (1.6%)	2
SINUSITIS	7/61 (11.5%)	12
SKIN INFECTION	3/61 (4.9%)	3
SOFT TISSUE INFECTION	1/61 (1.6%)	2
TOOTH INFECTION	3/61 (4.9%)	5
UPPER RESPIRATORY INFECTION	15/61 (24.6%)	22
URINARY TRACT INFECTION	8/61 (13.1%)	9
Injury, poisoning and procedural complications
BRUISING	4/61 (6.6%)	4
BURN	2/61 (3.3%)	2
FALL	5/61 (8.2%)	5
FRACTURE	1/61 (1.6%)	1
INJURY, POISONING AND PROCEDURAL COMPLICATIONS	3/61 (4.9%)	3
Investigations
ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED	5/61 (8.2%)	6
ALANINE AMINOTRANSFERASE INCREASED	9/61 (14.8%)	15
ALKALINE PHOSPHATASE INCREASED	11/61 (18%)	16
ASPARTATE AMINOTRANSFERASE INCREASED	12/61 (19.7%)	17
BLOOD BILIRUBIN INCREASED	5/61 (8.2%)	8
CHOLESTEROL HIGH	5/61 (8.2%)	5
CREATININE INCREASED	21/61 (34.4%)	38
HEMOGLOBIN INCREASED	2/61 (3.3%)	5
INR INCREASED	2/61 (3.3%)	2
INVESTIGATIONS	10/61 (16.4%)	20
LIPASE INCREASED	1/61 (1.6%)	1
LYMPHOCYTE COUNT DECREASED	2/61 (3.3%)	2
NEUTROPHIL COUNT DECREASED	1/61 (1.6%)	1
PLATELET COUNT DECREASED	6/61 (9.8%)	9
SERUM AMYLASE INCREASED	1/61 (1.6%)	1
WEIGHT GAIN	8/61 (13.1%)	9
WEIGHT LOSS	18/61 (29.5%)	19
Metabolism and nutrition disorders
ANOREXIA	25/61 (41%)	35
DEHYDRATION	6/61 (9.8%)	9
HYPERCALCEMIA	10/61 (16.4%)	13
HYPERGLYCEMIA	11/61 (18%)	22
HYPERKALEMIA	15/61 (24.6%)	19
HYPERNATREMIA	3/61 (4.9%)	3
HYPOALBUMINEMIA	8/61 (13.1%)	10
HYPOCALCEMIA	4/61 (6.6%)	4
HYPOGLYCEMIA	4/61 (6.6%)	4
HYPOKALEMIA	1/61 (1.6%)	1
HYPOMAGNESEMIA	2/61 (3.3%)	2
HYPONATREMIA	11/61 (18%)	27
METABOLISM AND NUTRITION DISORDERS	2/61 (3.3%)	2
Musculoskeletal and connective tissue disorders
ARTHRALGIA	7/61 (11.5%)	10
ARTHRITIS	10/61 (16.4%)	10
BACK PAIN	16/61 (26.2%)	21
BONE PAIN	5/61 (8.2%)	5
BUTTOCK PAIN	2/61 (3.3%)	2
FLANK PAIN	3/61 (4.9%)	4
GENERALIZED MUSCLE WEAKNESS	5/61 (8.2%)	5
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER	22/61 (36.1%)	29
MYALGIA	7/61 (11.5%)	8
NECK PAIN	2/61 (3.3%)	2
OSTEONECROSIS OF JAW	1/61 (1.6%)	2
PAIN IN EXTREMITY	16/61 (26.2%)	28
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)	2/61 (3.3%)	2
Nervous system disorders
ATAXIA	1/61 (1.6%)	1
COGNITIVE DISTURBANCE	1/61 (1.6%)	1
DIZZINESS	12/61 (19.7%)	15
DYSGEUSIA	7/61 (11.5%)	7
HEADACHE	25/61 (41%)	34
MEMORY IMPAIRMENT	1/61 (1.6%)	1
NERVOUS SYSTEM DISORDERS	5/61 (8.2%)	5
PARESTHESIA	1/61 (1.6%)	1
PERIPHERAL SENSORY NEUROPATHY	2/61 (3.3%)	2
SEIZURE	2/61 (3.3%)	3
SINUS PAIN	1/61 (1.6%)	1
TREMOR	2/61 (3.3%)	2
Psychiatric disorders
ANXIETY	6/61 (9.8%)	7
DEPRESSION	6/61 (9.8%)	7
INSOMNIA	12/61 (19.7%)	14
PSYCHIATRIC DISORDERS	1/61 (1.6%)	1
Renal and urinary disorders
ACUTE KIDNEY INJURY	3/61 (4.9%)	3
HEMATURIA	9/61 (14.8%)	13
PROTEINURIA	24/61 (39.3%)	62
RENAL AND URINARY DISORDERS	10/61 (16.4%)	15
URINARY FREQUENCY	2/61 (3.3%)	3
URINARY INCONTINENCE	1/61 (1.6%)	2
URINARY RETENTION	3/61 (4.9%)	3
URINARY TRACT PAIN	1/61 (1.6%)	1
URINARY URGENCY	1/61 (1.6%)	1
Reproductive system and breast disorders
BREAST PAIN	1/61 (1.6%)	1
ERECTILE DYSFUNCTION	1/61 (1.6%)	1
GENITAL EDEMA	1/61 (1.6%)	1
REPRODUCTIVE SYSTEM AND BREAST DISORDERS	2/61 (3.3%)	2
TESTICULAR DISORDER	1/61 (1.6%)	1
TESTICULAR PAIN	4/61 (6.6%)	4
Respiratory, thoracic and mediastinal disorders
ADULT RESPIRATORY DISTRESS SYNDROME	1/61 (1.6%)	1
ALLERGIC RHINITIS	3/61 (4.9%)	3
COUGH	25/61 (41%)	34
DYSPNEA	12/61 (19.7%)	17
EPISTAXIS	10/61 (16.4%)	14
HICCUPS	1/61 (1.6%)	1
HOARSENESS	8/61 (13.1%)	8
HYPOXIA	3/61 (4.9%)	3
NASAL CONGESTION	4/61 (6.6%)	4
PNEUMONITIS	4/61 (6.6%)	5
POSTNASAL DRIP	6/61 (9.8%)	8
PRODUCTIVE COUGH	7/61 (11.5%)	8
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS	13/61 (21.3%)	20
SLEEP APNEA	1/61 (1.6%)	1
SNEEZING	2/61 (3.3%)	2
SORE THROAT	2/61 (3.3%)	2
VOICE ALTERATION	4/61 (6.6%)	4
WHEEZING	1/61 (1.6%)	2
Skin and subcutaneous tissue disorders
ALOPECIA	1/61 (1.6%)	1
DRY SKIN	10/61 (16.4%)	12
ERYTHEMA MULTIFORME	1/61 (1.6%)	1
HYPERHIDROSIS	2/61 (3.3%)	2
NAIL RIDGING	1/61 (1.6%)	1
PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME	3/61 (4.9%)	3
PERIORBITAL EDEMA	1/61 (1.6%)	1
PRURITUS	20/61 (32.8%)	24
PURPURA	1/61 (1.6%)	1
RASH ACNEIFORM	1/61 (1.6%)	1
RASH MACULO-PAPULAR	19/61 (31.1%)	27
SKIN AND SUBCUTANEOUS TISSUE DISORDERS	22/61 (36.1%)	32
SKIN HYPERPIGMENTATION	2/61 (3.3%)	2
SKIN ULCERATION	1/61 (1.6%)	1
Social circumstances
MENOPAUSE	1/61 (1.6%)	1
Surgical and medical procedures
SURGICAL AND MEDICAL PROCEDURES	3/61 (4.9%)	4
Vascular disorders
HOT FLASHES	1/61 (1.6%)	1
HYPERTENSION	39/61 (63.9%)	93
HYPOTENSION	5/61 (8.2%)	5
LYMPHEDEMA	1/61 (1.6%)	1
THROMBOEMBOLIC EVENT	2/61 (3.3%)	3
VASCULAR DISORDERS	1/61 (1.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.