Enzalutamide in Combination With Gemcitabine and Cisplatin in Bladder Cancer

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT02300610
• Collaborator: (none)
• Enrollment: 10
• Locations: 2
• Arms: 2
• Actual Duration (Months): 50.2
• Patients Per Site: 5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The main purpose of this study is to find out the dose of enzalutamide that can be safely given with gemcitabine and cisplatin in patients with advanced bladder cancer. Researchers also want to find out the side effects of these drugs when given together. This study will also help in finding out the effect on tumor of the combination of enzalutamide, gemcitabine and cisplatin.

Condition or Disease	Intervention/Treatment	Phase
Bladder Cancer; Carcinoma, Transitional Cell; Renal Pelvis Cancer; Ureter Cancer; Urethra Cancer	Drug: Enzalutamide; Drug: Cisplatin; Drug: Gemcitabine	Phase 1

Detailed Description

For the phase 1 dose escalation phase, the starting dose of enzalutamide will be 80 mg orally once a day (Level 1). The dosing regimen of cisplatin and gemcitabine will be at standard doses of Gemcitabine at 1000 mg/m^2 IV on days 1, 8 and cisplatin at 70 mg/m2 IV on day 1, repeated every 21 days for total of 6 cycles.

Three patients will be treated dose level 1 (enzalutamide 80 mg daily). If 0 patients experience dose limiting toxicity (DLT), dose escalation will be done to level 2 of enzalutamide 160 mg daily. If 1 patient experiences DLT, 3 more patients will be treated at the same dose level; if 1 of 6 experiences DLT, escalate the dose to next level, and if 2 or more of 6 experiences DLT, the dose level 1 (80 mg enzalutamide) will be the recommended dose for dose expansion cohort.

The cohort expansion will then be done by enrolling 12 patients with stage IV bladder cancer, who express androgen receptor (AR) staining of 1+ and above by immunohistochemistry (IHC), to determine the safety and tolerability of cisplatin and gemcitabine with the recommended dose level of enzalutamide (80 mg or 160 mg, depending upon the safety results from dose escalation part) in this expanded cohort of patients with AR + bladder cancer.

Enzalutamide would be continued after completion of 6 cycles of gemcitabine-cisplatin for patients exhibiting a response or stable disease, until they experience disease progression.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/1b Study of Enzalutamide in Combination With Gemcitabine and Cisplatin in Bladder Cancer
• Actual Study Start Date: Feb 11, 2015
• Actual Primary Completion Date: Aug 7, 2017
• Actual Study Completion Date: Apr 19, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Escalation Dose Escalation: Begin with Level 1 dose of enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV).	Drug: Enzalutamide; Enzalutamide orally once a day. Dose Escalation Level 1: 80 mg; Level 2: 160 mg. Dose Expansion at recommended dose level, after dose escalation.; Other Names: MDV3100 XTANDI® ; Drug: Cisplatin; Cisplatin at 70 mg/m^2 IV on day 1, repeated every 21 days for total of 6 cycles.; Other Names: Platinol® Platinol®-AQ ; Drug: Gemcitabine; Gemcitabine at 1000 mg/m^2 IV on days 1, 8, repeated every 21 days for total of 6 cycles.; Other Names: Gemzar ®
Experimental: Dose Expansion Dose Expansion: Enzalutamide at recommended dose level with standard doses of cisplatin and gemcitabine.	Drug: Enzalutamide; Enzalutamide orally once a day. Dose Escalation Level 1: 80 mg; Level 2: 160 mg. Dose Expansion at recommended dose level, after dose escalation.; Other Names: MDV3100 XTANDI® ; Drug: Cisplatin; Cisplatin at 70 mg/m^2 IV on day 1, repeated every 21 days for total of 6 cycles.; Other Names: Platinol® Platinol®-AQ ; Drug: Gemcitabine; Gemcitabine at 1000 mg/m^2 IV on days 1, 8, repeated every 21 days for total of 6 cycles.; Other Names: Gemzar ®

Outcome Measures

Primary Outcome Measures

1. Recommended Dose of Enzalutamide [Up to 6 months]

   Dose Escalation. Maximum Tolerated Dose (MTD) of Enzalutamide when given with Cisplatin and Gemcitabine at standard doses. Dose Level 1: 80 mg Enzalutamide; Dose Level 2: 160 mg Enzalutamide. Dose-Limiting Toxicity (DLT) is defined as any of the following occurring in the first 21 days (cycle 1) of study participation that are considered at least possibly related to enzalutamide administration. Toxicities that are in the opinion of the investigator(s) attributable exclusively to gemcitabine or cisplatin will not be considered DLT. 7 consecutive missed doses (out of 21 doses) of enzalutamide in 21 days due to study drug related toxicity. Missed day 8 dose of gemcitabine in cycle 1 will not be considered DLT. Delay of greater than 3 weeks from scheduled date in initiating cycle 2 due to study drug related toxicity. Discontinuation of a patient due to study drug related toxicity before completing cycle 1.

Secondary Outcome Measures

1. Overall Response Rate (ORR): Complete Response (CR) + Partial Response (PR) [Up to 6 months]

   Dose Expansion. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

2. Progression Free Survival (PFS) [14 months]

   Dose Expansion. PFS is defined as the time from randomization until objective tumor progression or death. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

3. Overall Survival (OS) [Up to 24 Months]

   Dose Expansion. Overall survival is defined as the time from randomization until death from any cause, and is measured in the intent-to-treat population.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Cytologically or histologically confirmed evidence of transitional cell carcinoma of bladder, renal pelvis, ureter or urethra.

• Patients with Stage IV (locally advanced or metastatic) disease. Must have measurable disease, as per Response Evaluation Criteria in Solid Tumors (RECIST).

• Minimum of 4 weeks since any major surgery, completion of radiation.

• Prior treatment with cytotoxic chemotherapy is not a requirement, but allowed only if used in neoadjuvant, adjuvant or for bladder preserving protocols, as long as was administered > 6 months prior to starting study.

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

• Life expectancy 12 weeks or more.

• Must have normal organ and marrow function.

• Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of the administration of the first study treatment. Women must not be lactating.

• Sexually active women of childbearing age and men should be willing to follow birth control guidelines.

• Should be able to swallow enzalutamide and comply with study requirements.

Exclusion Criteria:

• Prior treatment with any cytotoxic chemotherapy in metastatic setting. Prior treatment with cytotoxic chemotherapy is allowed only if used in neoadjuvant, adjuvant or for bladder preserving protocols, as long as was administered > 6 months prior to starting study.

• Have undergone major surgery within 4 weeks prior to study enrollment.

• Chronic treatment with steroids or any other immunosuppressant drugs.

• Should not receive immunization with attenuated live vaccines during study period or within 1 week of study entry.

• History of seizures, predisposing factors for seizures, including underlying brain injury with loss of consciousness within previous 12 months, transient ischemic attack within previous 12 months, cerebral vascular accident or brain arteriovenous malformation.

• Untreated brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases.

• Congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block or a history of acute myocardial infarction within the 6 months preceding enrollment.

• Known history of HIV.

• Have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study.

• Women who are pregnant or breast feeding, or women/men able to conceive and unwilling to practice birth control guidelines.

• Concurrent medications which strongly inhibit or induce CYP enzymes (gemfibrozil, Rifampin, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, bosentan, efavirenz, etravirine, modafinil, nafcillin, St. John's Wort).

• History of stage III or greater cancer, except basal or squamous cell skin cancers adequately treated or any other stage I or II cancer adequately treated and disease-free for ≥ 2 years. Incidental findings of stage I or II prostate cancer that is considered to be cured with radical cystoprostatectomy is allowed.

• Prior use of enzalutamide.

• Radiation therapy via external beam or brachytherapy within 28 days of registration.

• Patients who are ineligible to receive cisplatin: Creatinine clearance of less than 60 mL/minute, hearing loss of 25 decibel (dB) at 2 contiguous frequencies, grade 2 or higher peripheral neuropathy, or New York Heart Association Class III or higher heart failure.

• Allergy/sensitivity to any study drug (gemcitabine, cisplatin, enzalutamide), or drugs chemically related to study drug, or excipients.

• Brain metastases (including treated or stable brain metastases)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
2	University of Minnesota, Masonic Cancer Center	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute

Investigators

• Principal Investigator: Jingsong Zhang, M.D., Ph.D., H. Lee Moffitt Cancer Center and Research Institute
• Study Chair: Shilpa Gupta, M.D., University of Minnesota Masonic Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 13, 2016

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT02300610
• Other Study ID Numbers: MCC-17924
• First Posted: Nov 25, 2014
• Last Update Posted: Aug 1, 2019
• Last Verified: Jun 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: Ureteral Diseases; Urinary Bladder Diseases; Transitional Cell Carcinoma; Bladder; Carcinoma; Renal; Pelvis; Ureter; Urethra
• Additional relevant MeSH terms: Carcinoma; Urinary Bladder Neoplasms; Ureteral Neoplasms; Pelvic Neoplasms; Carcinoma, Transitional Cell; Urethral Neoplasms; Gemcitabine; Cisplatin

Study Results

Participant Flow

Recruitment Details	Participants were recruited at Moffitt Cancer Center and the University of Minnesota Masonic Cancer Center, February 2015 through August 2017.

Arm/Group Title	Dose Escalation: Level 1 Dose	Dose Escalation- Level 2 Dose	Dose Expansion
Arm/Group Description	Dose Escalation: Level 1 dose of 80 mg enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV).	Dose Escalation: Level 2 dose of 160 mg enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV).	Enzalutamide at MTD (160 mg) with standard doses of cisplatin and gemcitabine.
Period Title: Overall Study
STARTED	3	3	4
COMPLETED	2	3	3
NOT COMPLETED	1	0	1

Baseline Characteristics

Arm/Group Title	Dose Escalation: Level 1 Dose	Dose Escalation: Level 2 Dose	Dose Expansion	Total
Arm/Group Description	Dose Escalation: Level 1 dose of 80 mg enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV).	Dose Escalation: Level 2 dose of 160 mg enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV).	Dose Expansion: Enzalutamide at recommended dose level with standard doses of cisplatin and gemcitabine.	Total of all reporting groups
Overall Participants	3	3	4	10
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 66.7%	1 33.3%	2 50%	5 50%
>=65 years	1 33.3%	2 66.7%	2 50%	5 50%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	65	66.6	65	65.5
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	1 25%	1 10%
Male	3 100%	3 100%	3 75%	9 90%
Race/Ethnicity, Customized (Count of Participants)
White Non-Hispanic	3 100%	3 100%	4 100%	10 100%
Black or African American	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Other	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%	3 100%	4 100%	10 100%

Outcome Measures

1. Primary Outcome

Title	Recommended Dose of Enzalutamide
Description	Dose Escalation. Maximum Tolerated Dose (MTD) of Enzalutamide when given with Cisplatin and Gemcitabine at standard doses. Dose Level 1: 80 mg Enzalutamide; Dose Level 2: 160 mg Enzalutamide. Dose-Limiting Toxicity (DLT) is defined as any of the following occurring in the first 21 days (cycle 1) of study participation that are considered at least possibly related to enzalutamide administration. Toxicities that are in the opinion of the investigator(s) attributable exclusively to gemcitabine or cisplatin will not be considered DLT. 7 consecutive missed doses (out of 21 doses) of enzalutamide in 21 days due to study drug related toxicity. Missed day 8 dose of gemcitabine in cycle 1 will not be considered DLT. Delay of greater than 3 weeks from scheduled date in initiating cycle 2 due to study drug related toxicity. Discontinuation of a patient due to study drug related toxicity before completing cycle 1.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

All participants in Dose Escalation arm.

Arm/Group Title	Dose Escalation
Arm/Group Description	Dose Escalation: Begin with Level 1 dose of enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV).
Measure Participants	6
Number [mg]	160

2. Secondary Outcome

Title	Overall Response Rate (ORR): Complete Response (CR) + Partial Response (PR)
Description	Dose Expansion. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

All participants evaluable at time of analysis.

Arm/Group Title	Dose Escalation: Level 1 Dose	Dose Escalation: Level 2 Dose	Dose Expansion
Arm/Group Description	Dose Escalation: Level 1 dose of 80 mg enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV).	Dose Escalation - Level 2 dose of 160 mg enzalutamide (orally) with standard dose of cisplatin and gemcitabine via intravenous (IV).	Dose Expansion: Enzalutamide at MTD (160 mg) with standard doses of cisplatin and gemcitabine.
Measure Participants	3	3	4
Partial Response	0 0%	3 100%	1 25%
Progressive Disease	1 33.3%	0 0%	0 0%
Stable Disease	1 33.3%	0 0%	1 25%
Complete Response	0 0%	0 0%	1 25%
Not Evaluable	1 33.3%	0 0%	1 25%

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Dose Expansion. PFS is defined as the time from randomization until objective tumor progression or death. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
Time Frame	14 months

Outcome Measure Data

Analysis Population Description

All Participants.

Arm/Group Title	Dose Escalation: Level 1 Dose	Dose Escalation: Level 2 Dose	Dose Expansion
Arm/Group Description	Dose Escalation: Level 1 dose of 80 mg enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV).	Dose Escalation - Level 2 dose of 160 mg enzalutamide (orally) with standard dose of cisplatin and gemcitabine via intravenous (IV).	Dose Expansion: Enzalutamide at MTD (160 mg) with standard doses of cisplatin and gemcitabine.
Measure Participants	3	3	4
Median (95% Confidence Interval) [months]	3.81	14.63	7.68

4. Secondary Outcome

Title	Overall Survival (OS)
Description	Dose Expansion. Overall survival is defined as the time from randomization until death from any cause, and is measured in the intent-to-treat population.
Time Frame	Up to 24 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Escalation: Level 1 Dose	Dose Escalation: Level 2 Dose	Dose Expansion
Arm/Group Description	Dose Escalation: Level 1 dose of 80 mg enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV).	Dose Escalation: Level 2 dose of 160 mg enzalutamide (orally) with standard dose of cisplatin and gemcitabine via intravenous (IV).	Dose Expansion: Enzalutamide at MTD (160 mg) with standard doses of cisplatin and gemcitabine.
Measure Participants	3	3	4
Median (95% Confidence Interval) [months]	4.14	14.63	10.03

Adverse Events

Time Frame	2 years, 7 months
Adverse Event Reporting Description	Patient deaths listed in "all cause mortality" occurred after the Adverse Event reporting period, but within the Overall Survival follow-up period.
Arm/Group Title	Dose Escalation: Dose Level 1		Dose Escalation: Level 2 Dose		Dose Expansion
Arm/Group Description	Dose Escalation: Level 1 dose of 80 mg enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV).		Dose Escalation: Level 2 dose of 160 mg enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV).		Dose Expansion: Enzalutamide at MTD (160 mg) with standard doses of cisplatin and gemcitabine.
All Cause Mortality
	Dose Escalation: Dose Level 1		Dose Escalation: Level 2 Dose		Dose Expansion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		2/4 (50%)
Serious Adverse Events
	Dose Escalation: Dose Level 1		Dose Escalation: Level 2 Dose		Dose Expansion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		3/3 (100%)		3/4 (75%)
Gastrointestinal disorders
Nausea	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Oral pain	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Pancreatitis	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	2
Small intestinal obstruction	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Vomiting	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Infections and infestations
Device related infection	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Kidney infection	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Lung infection	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Sepsis	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	1
Urinary tract infection	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Injury, poisoning and procedural complications
Fall	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Investigations
Creatinine increased	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Hypokalemia	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Hyponatremia	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified - Other	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Nervous system disorders
Dysarthria	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Syncope	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Transient ischemic attacks	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Psychiatric disorders
Agitation	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Confusion	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumothorax	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Vascular disorders
Thromboembolic event	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Other (Not Including Serious) Adverse Events
	Dose Escalation: Dose Level 1		Dose Escalation: Level 2 Dose		Dose Expansion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Anemia	2/3 (66.7%)	4	3/3 (100%)	19	4/4 (100%)	9
Leukocytosis	0/3 (0%)	0	1/3 (33.3%)	2	1/4 (25%)	1
Cardiac disorders
Sinus tachycardia	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1
Sinus bradycardia	0/3 (0%)	0	1/3 (33.3%)	2	0/4 (0%)	0
Ear and labyrinth disorders
Tinnitus	0/3 (0%)	0	1/3 (33.3%)	1	2/4 (50%)	2
Hearing impaired	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Eye disorders
Blurred vision	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1
Eye disorders - Other, specify	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	2
Gastrointestinal disorders
Nausea	3/3 (100%)	3	3/3 (100%)	6	3/4 (75%)	4
Vomiting	1/3 (33.3%)	1	3/3 (100%)	3	2/4 (50%)	2
Constipation	1/3 (33.3%)	1	3/3 (100%)	3	1/4 (25%)	1
Diarrhea	1/3 (33.3%)	2	2/3 (66.7%)	3	2/4 (50%)	2
Abdominal pain	1/3 (33.3%)	1	1/3 (33.3%)	1	1/4 (25%)	1
Bloating	0/3 (0%)	0	2/3 (66.7%)	3	0/4 (0%)	0
Dry mouth	0/3 (0%)	0	2/3 (66.7%)	2	0/4 (0%)	0
Gastrointestinal disorders - Other, specify	1/3 (33.3%)	1	1/3 (33.3%)	1	0/4 (0%)	0
Mucositis oral	1/3 (33.3%)	1	1/3 (33.3%)	2	0/4 (0%)	0
Duodenal ulcer	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Flatulence	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Gastrointestinal pain	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Oral pain	0/3 (0%)	0	1/3 (33.3%)	2	0/4 (0%)	0
Pancreatitis	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Rectal pain	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Small intestinal obstruction	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
General disorders
Fatigue	3/3 (100%)	4	3/3 (100%)	5	3/4 (75%)	8
Edema limbs	1/3 (33.3%)	2	0/3 (0%)	0	1/4 (25%)	1
Fever	2/3 (66.7%)	2	0/3 (0%)	0	0/4 (0%)	0
Non-cardiac chest pain	1/3 (33.3%)	1	1/3 (33.3%)	1	0/4 (0%)	0
Chills	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Infusion site extravasation	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Infections and infestations
Urinary tract infection	1/3 (33.3%)	1	1/3 (33.3%)	1	1/4 (25%)	1
Bladder infection	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Catheter related infection	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Rhinitis infective	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Wound infection	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Injury, poisoning and procedural complications
Fall	1/3 (33.3%)	2	2/3 (66.7%)	2	2/4 (50%)	4
Wound complication	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Investigations
Platelet count decreased	3/3 (100%)	3	3/3 (100%)	23	3/4 (75%)	13
Lymphocyte count decreased	0/3 (0%)	0	3/3 (100%)	12	2/4 (50%)	5
Neutrophil count decreased	0/3 (0%)	0	3/3 (100%)	12	2/4 (50%)	5
Alkaline phosphatase increased	0/3 (0%)	0	2/3 (66.7%)	5	2/4 (50%)	4
Creatinine increased	1/3 (33.3%)	3	2/3 (66.7%)	9	1/4 (25%)	2
Weight loss	2/3 (66.7%)	3	1/3 (33.3%)	3	1/4 (25%)	1
White blood cell decreased	0/3 (0%)	0	3/3 (100%)	6	1/4 (25%)	7
Alanine aminotransferase increased	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	2
Aspartate aminotransferase increased	0/3 (0%)	0	1/3 (33.3%)	3	1/4 (25%)	1
Activated partial thromboplastin time prolonged	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Blood bilirubin increased	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Electrocardiogram QT corrected interval prolonged	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Lipase increased	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	2
Metabolism and nutrition disorders
Hypoalbuminemia	2/3 (66.7%)	2	2/3 (66.7%)	7	3/4 (75%)	4
Hyponatremia	3/3 (100%)	7	2/3 (66.7%)	4	2/4 (50%)	2
Anorexia	1/3 (33.3%)	1	2/3 (66.7%)	5	2/4 (50%)	2
Hypomagnesemia	1/3 (33.3%)	1	2/3 (66.7%)	4	2/4 (50%)	3
Hyperkalemia	2/3 (66.7%)	2	1/3 (33.3%)	8	1/4 (25%)	3
Hypokalemia	0/3 (0%)	0	1/3 (33.3%)	1	2/4 (50%)	13
Dehydration	0/3 (0%)	0	1/3 (33.3%)	3	1/4 (25%)	1
Hypercalcemia	0/3 (0%)	0	2/3 (66.7%)	5	0/4 (0%)	0
Hypertriglyceridemia	0/3 (0%)	0	2/3 (66.7%)	3	0/4 (0%)	0
Hyperglycemia	0/3 (0%)	0	1/3 (33.3%)	6	0/4 (0%)	0
Hypermagnesemia	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Hypernatremia	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1
Back pain	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	2
Pain in extremity	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	1
Arthritis	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Bone pain	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Generalized muscle weakness	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Musculoskeletal and connective tissue disorder - Other, specify	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Myalgia	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Nervous system disorders
Dizziness	1/3 (33.3%)	1	1/3 (33.3%)	3	2/4 (50%)	7
Dysgeusia	0/3 (0%)	0	2/3 (66.7%)	2	1/4 (25%)	1
Headache	0/3 (0%)	0	0/3 (0%)	0	3/4 (75%)	4
Syncope	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Presyncope	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Psychiatric disorders
Hallucinations	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1
Anxiety	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Insomnia	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	2
Renal and urinary disorders
Acute kidney injury	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	2
Chronic kidney disease	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	2
Hematuria	1/3 (33.3%)	1	1/3 (33.3%)	1	0/4 (0%)	0
Urinary incontinence	1/3 (33.3%)	1	1/3 (33.3%)	1	0/4 (0%)	0
Renal and urinary disorders - Other, specify	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Urinary frequency	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Urinary retention	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Urinary tract obstruction	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/3 (33.3%)	1	1/3 (33.3%)	1	1/4 (25%)	4
Atelectasis	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Cough	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Epistaxis	0/3 (0%)	0	1/3 (33.3%)	2	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1
Photosensitivity	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Vascular disorders
Hypotension	0/3 (0%)	0	1/3 (33.3%)	1	2/4 (50%)	3
Hypertension	0/3 (0%)	0	2/3 (66.7%)	4	0/4 (0%)	0
Hot flashes	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0
Superficial thrombophlebitis	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	2
Thromboembolic event	1/3 (33.3%)	2	0/3 (0%)	0	0/4 (0%)	0

Limitations/Caveats

This study did not meet the anticipated accrual goal of 24 participants.

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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.