Akt Inhibitor MK2206 or Everolimus in Treating Patients With Refractory Kidney Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT01239342
• Collaborator: (none)
• Enrollment: 43
• Locations: 8
• Arms: 2
• Actual Duration (Months): 91.7
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized phase II trial studies the side effects and how well Akt inhibitor MK2206 or everolimus works in treating patients with kidney cancer that does not respond to treatment. Akt inhibitor MK2206 and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Everolimus may also stop the growth of kidney cancer by blocking blood flow to the tumor. It is not yet known whether Akt inhibitor MK2206 or everolimus is more effective in treating kidney cancer.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Kidney Carcinoma; Recurrent Renal Cell Carcinoma; Stage III Renal Cell Cancer AJCC v7; Stage IV Renal Cell Cancer AJCC v7	Drug: Akt Inhibitor MK2206; Drug: Everolimus; Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess progression free survival (PFS) of vascular endothelial growth factor (VEGF) therapy refractory renal cell carcinoma (RCC) patients who receive either MK-2206 (Akt inhibitor MK-2206) or everolimus.

2. To assess safety of MK-2206 in patients with VEGF therapy refractory RCC.

SECONDARY OBJECTIVES:

1. To assess overall response rate (ORR) and overall survival (OS). (Clinical) II. To assess time to treatment failure (TTF). (Clinical) III. To determine whether baseline AKT activation is predictive for clinical benefit after treatment with MK-2206 or everolimus. (Pre-clinical/exploratory) IV. To determine whether circulating cytokines and angiogenic factors predict for clinical benefit after treatment with MK-2206 or everolimus. (Pre-clinical/exploratory) V. To assess impact of karyotype on outcome in patients treated with MK-2206 or everolimus. (Pre-clinical/exploratory)

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who are progression free after 1 year may receive a 12 week study drug supply of Akt inhibitor MK2206.

ARM II: Patients receive everolimus PO once daily (QD) on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase 2 Study of MK-2206 in Comparison With Everolimus in Refractory Renal Cell Carcinoma
• Actual Study Start Date: Jan 27, 2011
• Actual Primary Completion Date: Sep 19, 2018
• Actual Study Completion Date: Sep 19, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (Akt inhibitor MK2206) Patients receive Akt inhibitor MK2206 PO on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who are progression free after 1 year may receive a 12 week study drug supply of Akt inhibitor MK2206.	Drug: Akt Inhibitor MK2206; Given PO; Other Names: MK2206 ; Other: Laboratory Biomarker Analysis; Optional correlative studies
Experimental: Arm II (everolimus) Patients receive everolimus PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.	Drug: Everolimus; Given PO; Other Names: 42-O-(2-Hydroxy)ethyl Rapamycin Afinitor Certican RAD 001 RAD001 Votubia Zortress ; Other: Laboratory Biomarker Analysis; Optional correlative studies

Outcome Measures

Primary Outcome Measures

1. Median Progression Free Survival (PFS) in Months [Time interval between date of treatment and date of disease progression, date of death or last follow-up date, whichever occurs first, assessed up to 5 years]

   PFS defined as Time interval between date of treatment and date of disease progression, date of death or last follow-up date, whichever occurs first. Progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a nontarget lesion, or the appearance of new lesions.

Secondary Outcome Measures

1. Clinical Benefit Defined as Number of Participants With Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) [Up to 5 years]

   Clinical benefit defined as participants' with CR+PR+SD assessed using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Repeat radiologic studies to evaluate disease progression or response (in accordance with restaging of disease) every 8 weeks. Complete Response (CR): Disappearance all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): >30% decrease in sum diameters of target lesions, reference baseline sum diameters. Progressive Disease (PD): >20% increase in sum diameters of target lesions, reference smallest sum on study (includes baseline sum if is smallest on study). In addition to relative increase of 20%, sum must demonstrate absolute increase >5 mm. (Note: appearance 1/+ new lesions considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum diameters.

2. Summary of Selected Toxicities Grade 3 or Greater Toxicity Based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [Up to 5 years]

   Adverse Events (AEs) list of reported events with associated intervention agent in a uniform presentation of events. The method of Thall, Simon and Estey (1995, 1996) was used to collect study participants' safety data summarized by treatment arm, category, severity and relevance. Comprehensive listing of AEs collected on study can be found in Adverse Event section separated by severity, Serious and Other AEs and represented by treatment arm, organ system-category within defined severity.

3. Overall Response Rate (ORR) Defined as Complete Response (CR) + Partial Response (PR) [Up to 5 years]

   Response for CR + PR defined by RECIST version 1.1. Repeat radiologic studies to evaluate disease progression or response (in accordance with restaging of disease) every 8 weeks. Complete Response (CR): Disappearance all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): >30% decrease in sum diameters of target lesions, reference baseline sum diameters. Progressive Disease (PD): >20% increase in sum diameters of target lesions, reference smallest sum on study (includes baseline sum if is smallest on study). In addition to relative increase of 20%, sum must demonstrate absolute increase >5 mm. (Note: appearance 1/+ new lesions considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum diameters.

4. Median Overall Survival (OS) in Months [Time interval between the date of treatment and the date of death or last follow-up, assessed up to 5 years]

   Overall survival reported in months as time interval between the date of treatment and the date of death or last follow-up.

5. Time to Failure (TTF) [Time interval between the date of treatment and the date of disease progression, date of death, date of treatment discontinuation due to severe toxicity or last follow-up date, assessed up to 5 years]

   TTF defined as Time interval between the date of treatment and the date of disease progression, date of death, date of treatment discontinuation due to severe toxicity or last follow-up date.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed metastatic or unresectable RCC; all histologies are permitted; patient should have undergone nephrectomy

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan

• Patients must have received, and progressed on an anti-VEGF therapy, including bevacizumab, sorafenib, sunitinib or pazopanib

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin within normal institutional limits

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal

• Serum creatinine =< 1.5 x upper limit of normal (ULN)

• International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x ULN; therapeutic anticoagulation with warfarin is allowed if target INR =< 3 on a stable dose of warfarin or on a stable dose of low molecular weight (LMW) heparin for

2 weeks at time of randomization

• Women of childbearing potential and men must use two forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 8 weeks after the last dose of study drug; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform the treating physician immediately

• Ability to understand and the willingness to sign a written informed consent document

• Serum pregnancy test in female patients of childbearing potential must be negative within 24 hours of enrolling on this study

Exclusion Criteria:

• Patients who received oral tyrosine-kinase inhibitors (TKIs) (sorafenib, sunitinib, or pazopanib) within 2 weeks prior to entering the study, radiotherapy, immunotherapy or chemotherapy within 4 weeks prior to entering the study, bevacizumab within 4 weeks prior to entering the study, or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier (recovered to =< grade 1)

• Patients may not be receiving any other investigational agents; patients may not have received an mammalian target of rapamycin (mTOR) inhibitor

• Patients with known brain metastases should be excluded from this clinical trial

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206 or other agents used in the study

• Patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP4503A4) are ineligible

• Patient should have a hemoglobin A1C value of < 8%; preclinical studies demonstrated the potential of MK-2206 for induction of hyperglycemia in all preclinical species tested; studies also demonstrate a risk of hyperglycemia, hyperlipidemia and hypertriglyceridemia associated with everolimus therapy; patients with diabetes or in risk for hyperglycemia, hyperlipidemia and/or hypertriglyceridemia should not be excluded from trials with MK-2206 or everolimus, but the patient should be well controlled on oral agents (recent [i.e. within 3 months] hemoglobin [Hb]A1C =< 7.0) before the patient enters the trial

• Baseline corrected Fridericia QT interval (QTcF) > 450 msec (male) or QTcF > 470 msec (female) will exclude patients from entry on study

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MK-2206 or everolimus

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

• Individuals who are diagnosed with an intercurrent cancer are excluded, with the exception of non-melanoma skin cancers, and other cancers where curative treatment was completed at least two years ago

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tower Cancer Research Foundation	Beverly Hills	California	United States	90211
2	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
3	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
4	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
5	City of Hope South Pasadena	South Pasadena	California	United States	91030
6	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
7	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania	United States	15232
8	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Eric Jonasch, M.D. Anderson Cancer Center

Study Documents (Full-Text)

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

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01239342
• Other Study ID Numbers: NCI-2010-02270; NCI-2010-02270; NCI 8727; MDA-2010-0247; CDR0000688457; 2010-0247; 8727; 8727; N01CM00038; N01CM00039; N01CM62202; P30CA016672
• First Posted: Nov 11, 2010
• Last Update Posted: Oct 10, 2019
• Last Verified: Sep 1, 2019

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Kidney Neoplasms; Everolimus

Study Results

Participant Flow

Recruitment Details	Recruitment Period: January 27, 2011 to January 9, 2013. All recruitment done in medical clinic settings.

Arm/Group Title	MK2206	Everolimus
Arm/Group Description	Akt inhibitor MK2206 200 mg orally once weekly, courses repeat every 4 weeks.	Everolimus 10 mg orally once daily, courses repeat every 4 weeks.
Period Title: Overall Study
STARTED	29	14
COMPLETED	26	8
NOT COMPLETED	3	6

Baseline Characteristics

Arm/Group Title	MK2206	Everolimus	Total
Arm/Group Description	Akt inhibitor MK2206 200 mg orally once weekly, courses repeat every 4 weeks.	Everolimus 10 mg orally once daily, courses repeat every 4 weeks.	Total of all reporting groups
Overall Participants	29	14	43
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59	63.5	62
Sex: Female, Male (Count of Participants)
Female	8 27.6%	0 0%	8 18.6%
Male	21 72.4%	14 100%	35 81.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3.4%	5 35.7%	6 14%
Not Hispanic or Latino	28 96.6%	9 64.3%	37 86%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 3.4%	0 0%	1 2.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 6.9%	0 0%	2 4.7%
White	26 89.7%	14 100%	40 93%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	29 100%	14 100%	43 100%

Outcome Measures

1. Primary Outcome

Title	Median Progression Free Survival (PFS) in Months
Description	PFS defined as Time interval between date of treatment and date of disease progression, date of death or last follow-up date, whichever occurs first. Progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a nontarget lesion, or the appearance of new lesions.
Time Frame	Time interval between date of treatment and date of disease progression, date of death or last follow-up date, whichever occurs first, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

One participant in each group left study before restaging therefore are excluded from response outcome analysis.

Arm/Group Title	MK2206	Everolimus
Arm/Group Description	Akt inhibitor MK2206 200 mg orally once weekly, courses repeat every 4 weeks.	Everolimus 10 mg orally once daily, courses repeat every 4 weeks.
Measure Participants	28	13
Median (95% Confidence Interval) [Months]	3.68	5.98

2. Secondary Outcome

Title	Clinical Benefit Defined as Number of Participants With Complete Response (CR) + Partial Response (PR) + Stable Disease (SD)
Description	Clinical benefit defined as participants' with CR+PR+SD assessed using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Repeat radiologic studies to evaluate disease progression or response (in accordance with restaging of disease) every 8 weeks. Complete Response (CR): Disappearance all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): >30% decrease in sum diameters of target lesions, reference baseline sum diameters. Progressive Disease (PD): >20% increase in sum diameters of target lesions, reference smallest sum on study (includes baseline sum if is smallest on study). In addition to relative increase of 20%, sum must demonstrate absolute increase >5 mm. (Note: appearance 1/+ new lesions considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum diameters.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

One participant in each group left study before restaging therefore are excluded from outcome analysis.

Arm/Group Title	MK2206	Everolimus
Arm/Group Description	Akt inhibitor MK2206 200 mg orally once weekly, courses repeat every 4 weeks.	Everolimus 10 mg orally once daily, courses repeat every 4 weeks.
Measure Participants	28	13
Complete Response	1 3.4%	0 0%
Partial Response	3 10.3%	0 0%
Stable Disease	11 37.9%	11 78.6%
Progressive Disease	13 44.8%	2 14.3%

3. Secondary Outcome

Title	Summary of Selected Toxicities Grade 3 or Greater Toxicity Based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
Description	Adverse Events (AEs) list of reported events with associated intervention agent in a uniform presentation of events. The method of Thall, Simon and Estey (1995, 1996) was used to collect study participants' safety data summarized by treatment arm, category, severity and relevance. Comprehensive listing of AEs collected on study can be found in Adverse Event section separated by severity, Serious and Other AEs and represented by treatment arm, organ system-category within defined severity.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MK2206	Everolimus
Arm/Group Description	Akt inhibitor MK2206 200 mg orally once weekly, courses repeat every 4 weeks.	Everolimus 10 mg orally once daily, courses repeat every 4 weeks.
Measure Participants	29	14
Hyperglycemia	7	1
Hypertriglyceridemia	1	1
Hyperuricemia	2	0
Lymphocyte count decreased	2	1
Mucositis oral	1	0
Rash maculo-papular	8	0
Pruritus	1	0
Proteinuria	1	0
Pancreatitis	1	0
Lipase increased	1	0
Generalized muscle weakness	1	0
Dyspnea	1	0
Dehydration	2	0

4. Secondary Outcome

Title	Overall Response Rate (ORR) Defined as Complete Response (CR) + Partial Response (PR)
Description	Response for CR + PR defined by RECIST version 1.1. Repeat radiologic studies to evaluate disease progression or response (in accordance with restaging of disease) every 8 weeks. Complete Response (CR): Disappearance all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): >30% decrease in sum diameters of target lesions, reference baseline sum diameters. Progressive Disease (PD): >20% increase in sum diameters of target lesions, reference smallest sum on study (includes baseline sum if is smallest on study). In addition to relative increase of 20%, sum must demonstrate absolute increase >5 mm. (Note: appearance 1/+ new lesions considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum diameters.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

One participant in each group left study before restaging therefore are excluded from response outcome analysis.

Arm/Group Title	MK2206	Everolimus
Arm/Group Description	Akt inhibitor MK2206 200 mg orally once weekly, courses repeat every 4 weeks.	Everolimus 10 mg orally once daily, courses repeat every 4 weeks.
Measure Participants	28	13
Number [percentage of participants]	14.3 49.3%	0 0%

5. Secondary Outcome

Title	Median Overall Survival (OS) in Months
Description	Overall survival reported in months as time interval between the date of treatment and the date of death or last follow-up.
Time Frame	Time interval between the date of treatment and the date of death or last follow-up, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MK2206	Everolimus
Arm/Group Description	Akt inhibitor MK2206 200 mg orally once weekly, courses repeat every 4 weeks.	Everolimus 10 mg orally once daily, courses repeat every 4 weeks.
Measure Participants	29	14
Median (Full Range) [Months]	23.5	15.7

6. Secondary Outcome

Title	Time to Failure (TTF)
Description	TTF defined as Time interval between the date of treatment and the date of disease progression, date of death, date of treatment discontinuation due to severe toxicity or last follow-up date.
Time Frame	Time interval between the date of treatment and the date of disease progression, date of death, date of treatment discontinuation due to severe toxicity or last follow-up date, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

No participants analyzed. Data not collected.

Arm/Group Title	MK2206	Everolimus
Arm/Group Description	Akt inhibitor MK2206 200 mg orally once weekly, courses repeat every 4 weeks.	Everolimus 10 mg orally once daily, courses repeat every 4 weeks.
Measure Participants	0	0

Adverse Events

Time Frame	Adverse events collected through each 28 day course, and reporting for events that occur within 30 Days of the last dose of the investigational agent.
Arm/Group Title	MK2206		Everolimus
Arm/Group Description	Akt inhibitor MK2206 200 mg orally once weekly, courses repeat every 4 weeks.		Everolimus 10 mg orally once daily, courses repeat every 4 weeks.
All Cause Mortality
	MK2206		Everolimus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/14 (0%)
Serious Adverse Events
	MK2206		Everolimus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/29 (24.1%)		2/14 (14.3%)
Gastrointestinal disorders
Abdominal Pain	1/29 (3.4%)		0/14 (0%)
Pancreatitis	1/29 (3.4%)		0/14 (0%)
General disorders
Death NOS	4/29 (13.8%)		1/14 (7.1%)
Infections and infestations
Appendicitis	0/29 (0%)		1/14 (7.1%)
Metabolism and nutrition disorders
Hypercalcemia	2/29 (6.9%)		0/14 (0%)
Dehydration	1/29 (3.4%)		0/14 (0%)
Hyperuricemia	1/29 (3.4%)		0/14 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal bone pain	1/29 (3.4%)		0/14 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/29 (3.4%)		0/14 (0%)
Pleural Effusion	0/29 (0%)		1/14 (7.1%)
Dyspnea	0/29 (0%)		1/14 (7.1%)
Vascular disorders
Thromboembolic event	1/29 (3.4%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	MK2206		Everolimus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/29 (100%)		13/14 (92.9%)
Blood and lymphatic system disorders
Anemia	24/29 (82.8%)		11/14 (78.6%)
Disseminated intravascular coagulation	1/29 (3.4%)		0/14 (0%)
Cardiac disorders
Cardiac disorders - (Other), specify	2/29 (6.9%)		1/14 (7.1%)
Chest pain - cardiac	1/29 (3.4%)		0/14 (0%)
Palpitations	1/29 (3.4%)		0/14 (0%)
Sinus tachycardia	1/29 (3.4%)		0/14 (0%)
Ear and labyrinth disorders
Ear pain	2/29 (6.9%)		0/14 (0%)
Hearing impaired	1/29 (3.4%)		0/14 (0%)
Endocrine disorders
Endocrine disorders - (Other), specify	11/29 (37.9%)		6/14 (42.9%)
Hyperthyroidism	8/29 (27.6%)		2/14 (14.3%)
Hypothyroidism	2/29 (6.9%)		1/14 (7.1%)
Eye disorders
Dry eye	1/29 (3.4%)		0/14 (0%)
Eye disorders - (Other), specify	2/29 (6.9%)		0/14 (0%)
Watering eyes	6/29 (20.7%)		3/14 (21.4%)
Gastrointestinal disorders
Abdominal distension	0/29 (0%)		1/14 (7.1%)
Abdominal pain	8/29 (27.6%)		3/14 (21.4%)
Ascites	1/29 (3.4%)		1/14 (7.1%)
Bloating	0/29 (0%)		1/14 (7.1%)
Constipation	5/29 (17.2%)		4/14 (28.6%)
Diarrhea	11/29 (37.9%)		7/14 (50%)
Dry mouth	1/29 (3.4%)		0/14 (0%)
Dysesthesia	2/29 (6.9%)		1/14 (7.1%)
Dysphagia	1/29 (3.4%)		1/14 (7.1%)
Gastritis	0/29 (0%)		1/14 (7.1%)
Gastroesophageal reflux disease	1/29 (3.4%)		0/14 (0%)
Gastrointestinal disorders - (Other), specify	1/29 (3.4%)		0/14 (0%)
Gastrointestinal pain	0/29 (0%)		2/14 (14.3%)
Mucositis oral	13/29 (44.8%)		7/14 (50%)
Nausea	14/29 (48.3%)		5/14 (35.7%)
Vomiting	9/29 (31%)		2/14 (14.3%)
General disorders
Chills	0/29 (0%)		1/14 (7.1%)
Edema face	1/29 (3.4%)		0/14 (0%)
Edema limbs	10/29 (34.5%)		7/14 (50%)
Fatigue	24/29 (82.8%)		12/14 (85.7%)
Fever	4/29 (13.8%)		2/14 (14.3%)
Flatulence	1/29 (3.4%)		0/14 (0%)
Localized edema	1/29 (3.4%)		0/14 (0%)
Non-cardiac chest pain	2/29 (6.9%)		2/14 (14.3%)
Pain	10/29 (34.5%)		2/14 (14.3%)
Weight loss	4/29 (13.8%)		1/14 (7.1%)
Immune system disorders
Allergic reaction	2/29 (6.9%)		0/14 (0%)
Infections and infestations
Abdominal infection	0/29 (0%)		1/14 (7.1%)
Infections and infestations - (Other), specify	3/29 (10.3%)		5/14 (35.7%)
Lung infection	2/29 (6.9%)		0/14 (0%)
Papulopustular rash	0/29 (0%)		1/14 (7.1%)
Sinusitis	2/29 (6.9%)		1/14 (7.1%)
Upper respiratory infection	3/29 (10.3%)		0/14 (0%)
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications - (Other)	0/29 (0%)		1/14 (7.1%)
Investigations
Activated partial thromboplastin time prolonged	18/29 (62.1%)		3/14 (21.4%)
Alanine aminotransferase increased	4/29 (13.8%)		1/14 (7.1%)
Alkaline phosphatase increased	11/29 (37.9%)		7/14 (50%)
Aspartate aminotransferase increased	5/29 (17.2%)		4/14 (28.6%)
Cholesterol high	17/29 (58.6%)		12/14 (85.7%)
Creatinine increased	25/29 (86.2%)		10/14 (71.4%)
INR increased	1/29 (3.4%)		0/14 (0%)
Investigations - (Other)	0/29 (0%)		1/14 (7.1%)
Lipase increased	1/29 (3.4%)		0/14 (0%)
Lymphocyte count decreased	20/29 (69%)		10/14 (71.4%)
Neutrophil count decreased	1/29 (3.4%)		2/14 (14.3%)
Platelet count decreased	3/29 (10.3%)		5/14 (35.7%)
Serum amylase increased	1/29 (3.4%)		0/14 (0%)
White blood cell decreased	6/29 (20.7%)		4/14 (28.6%)
Metabolism and nutrition disorders
Anorexia	5/29 (17.2%)		3/14 (21.4%)
Dehydration	4/29 (13.8%)		0/14 (0%)
Glucose intolerance	3/29 (10.3%)		1/14 (7.1%)
Hypercalcemia	5/29 (17.2%)		2/14 (14.3%)
Hyperglycemia	28/29 (96.6%)		10/14 (71.4%)
Hyperkalemia	10/29 (34.5%)		4/14 (28.6%)
Hypermagnesemia	1/29 (3.4%)		0/14 (0%)
Hypernatremia	1/29 (3.4%)		0/14 (0%)
Hypertriglyceridemia	20/29 (69%)		12/14 (85.7%)
Hyperuricemia	14/29 (48.3%)		3/14 (21.4%)
Hypoalbuminemia	7/29 (24.1%)		3/14 (21.4%)
Hypocalcemia	4/29 (13.8%)		3/14 (21.4%)
Hypoglycemia	3/29 (10.3%)		0/14 (0%)
Hypokalemia	3/29 (10.3%)		2/14 (14.3%)
Hypomagnesemia	9/29 (31%)		1/14 (7.1%)
Hyponatremia	10/29 (34.5%)		2/14 (14.3%)
Hypophosphatemia	5/29 (17.2%)		1/14 (7.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/29 (6.9%)		2/14 (14.3%)
Back pain	12/29 (41.4%)		5/14 (35.7%)
Bone pain	2/29 (6.9%)		1/14 (7.1%)
Chest wall pain	3/29 (10.3%)		3/14 (21.4%)
Flank pain	1/29 (3.4%)		0/14 (0%)
Gait disturbance	2/29 (6.9%)		0/14 (0%)
Generalized muscle weakness	1/29 (3.4%)		0/14 (0%)
Muscle weakness trunk	1/29 (3.4%)		0/14 (0%)
Muscle weakness upper limb	0/29 (0%)		1/14 (7.1%)
Musculoskeletal and connective tissue disorder - Specify (Other)	2/29 (6.9%)		0/14 (0%)
Neck pain	0/29 (0%)		1/14 (7.1%)
Pain in extremity	3/29 (10.3%)		0/14 (0%)
Nervous system disorders
Ataxia	0/29 (0%)		1/14 (7.1%)
Dizziness	2/29 (6.9%)		0/14 (0%)
Dysgeusia	2/29 (6.9%)		2/14 (14.3%)
Headache	3/29 (10.3%)		3/14 (21.4%)
Nervous system disorders - (Other), specify	0/29 (0%)		1/14 (7.1%)
Neuralgia	1/29 (3.4%)		0/14 (0%)
Paresthesia	1/29 (3.4%)		1/14 (7.1%)
Peripheral sensory neuropathy	1/29 (3.4%)		1/14 (7.1%)
Psychiatric disorders
Anxiety	2/29 (6.9%)		1/14 (7.1%)
Confusion	1/29 (3.4%)		0/14 (0%)
Depression	4/29 (13.8%)		1/14 (7.1%)
Insomnia	2/29 (6.9%)		1/14 (7.1%)
Renal and urinary disorders
Hemoglobinuria	1/29 (3.4%)		0/14 (0%)
Proteinuria	15/29 (51.7%)		12/14 (85.7%)
Urinary frequency	2/29 (6.9%)		0/14 (0%)
Urinary tract infection	1/29 (3.4%)		0/14 (0%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/29 (3.4%)		4/14 (28.6%)
Atelectasis	0/29 (0%)		1/14 (7.1%)
Bronchial infection	1/29 (3.4%)		0/14 (0%)
Cough	3/29 (10.3%)		6/14 (42.9%)
Dyspnea	13/29 (44.8%)		9/14 (64.3%)
Epistaxis	0/29 (0%)		1/14 (7.1%)
Hiccups	1/29 (3.4%)		0/14 (0%)
Hoarseness	1/29 (3.4%)		2/14 (14.3%)
Laryngeal inflammation	1/29 (3.4%)		1/14 (7.1%)
Nasal congestion	1/29 (3.4%)		0/14 (0%)
Pleural effusion	2/29 (6.9%)		3/14 (21.4%)
Pneumonitis	3/29 (10.3%)		4/14 (28.6%)
Productive cough	1/29 (3.4%)		0/14 (0%)
Respiratory, thoracic and mediastinal disorders - (Other), specify	1/29 (3.4%)		1/14 (7.1%)
Sleep apnea	1/29 (3.4%)		0/14 (0%)
Wheezing	1/29 (3.4%)		1/14 (7.1%)
Skin and subcutaneous tissue disorders
Alopecia	3/29 (10.3%)		4/14 (28.6%)
Dry skin	5/29 (17.2%)		1/14 (7.1%)
Nail loss	1/29 (3.4%)		0/14 (0%)
Palmar-plantar erythrodysesthesia syndrome	5/29 (17.2%)		1/14 (7.1%)
Pruritus	9/29 (31%)		2/14 (14.3%)
Rash acneiform	1/29 (3.4%)		6/14 (42.9%)
Rash maculo-papular	24/29 (82.8%)		6/14 (42.9%)
Rash pustular	1/29 (3.4%)		0/14 (0%)
Scalp pain	0/29 (0%)		1/14 (7.1%)
Surgical and medical procedures
Surgical and medical procedures - (Other), specify	2/29 (6.9%)		2/14 (14.3%)
Vascular disorders
Hypertension	3/29 (10.3%)		1/14 (7.1%)
Hypotension	1/29 (3.4%)		0/14 (0%)
Thromboembolic event	1/29 (3.4%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.