Cabozantinib-S-Malate in Treating Patients With Hormone-Resistant Metastatic Prostate Cancer

• Sponsor: Barbara Ann Karmanos Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01812668
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arm: 1
• Duration (Months): 75.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This pilot clinical trial studies cabozantinib-s-malate in treating patients with hormone-resistant metastatic prostate cancer. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Prostate; Hormone-resistant Prostate Cancer; Recurrent Prostate Cancer; Stage IV Prostate Cancer	Drug: cabozantinib-s-malate; Radiation: fluorine F 18 d-FMAU; Procedure: positron emission tomography; Other: pharmacological study; Other: laboratory biomarker analysis	N/A

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the timing, pathophysiology, and magnitude of changes in tumor imaging and pharmacodynamic markers with XL184 (cabozantinib-s-malate) treatment in metastatic castrate resistant prostate cancer.

SECONDARY OBJECTIVES:

1. To estimate the progression-free survival (PFS) achieved with XL184 in metastatic castrate resistant prostate cancer (CRPC) patients.

2. To evaluate the feasibility of the therapy, and the toxicities associated. III. To evaluate overall survival (OS) in metastatic CRPC patients post androgen deprivation therapy (ADT) treated with XL-184.

OUTLINE:

Patients receive cabozantinib-s-malate orally (PO) daily in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks and then periodically thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Trial of Oral Cabozantinib/XL184 in Metastatic Castrate Resistant Prostate Cancer to Explore the Changes in Bone and Tumor Imaging Related Pathways
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Jan 18, 2019
• Actual Study Completion Date: Jun 18, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (cabozantinib-s-malate) Patients receive cabozantinib-s-malate PO daily in the absence of disease progression or unacceptable toxicity.

Drug: cabozantinib-s-malate; Given PO; Other Names: BMS-907351 Cometriq XL184 ; Radiation: fluorine F 18 d-FMAU; Undergo 18F PET/FMAU PET scan; Procedure: positron emission tomography; Undergo 18F PET/FMAU PET scan; Other Names: FDG-PET PET PET scan tomography, emission computed ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Change in PET Standard Uptake Value SUV Levels Pre-treatment to Post-treatment. [Baseline to 4 weeks]

   Change in PET standard uptake value SUV levels (each value measured in g/ml). (post-treatment - pre-treatment)/pre-treatment x 100 , therefore, measured in percentage change from baseline.

Secondary Outcome Measures

1. Time to Progression [From date of registration to date of first documented disease progression, or death from any cause, assessed up to 1 year]

   Summarized via the Kaplan-Meier (K-M) survivorship estimate.

2. Number of Participants With Indicated Toxicities Grade 3 or Higher [Up to 4 weeks post-treatment, about 2 years on average.]

   Type of toxicities graded per National Cancer Institute (NCI) CTCAE version 4.0 Summarized via their frequency distribution and point estimate of the proportion.

3. Number of Participants With Indicated Clinical Response Based on the RECIST Criteria 1.1 [Up to 1 year]

   Number of Participants with Indicated Clinical response based on the RECIST criteria 1.1 summarized via their frequency distribution.

4. PSA Response Based on the RECIST Criteria 1.1 [Up to 1 year]

   Summarized via their frequency distribution, point estimate of the proportion, and the Wilson type 80% CI.

5. PET Response Based on the RECIST Criteria 1.1 [Up to 1 year]

   Summarized via their frequency distribution, point estimate of the proportion, and the Wilson type 80% CI.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• The subject has histologically confirmed prostate adenocarcinoma with radiologic evidence of metastases

• If patient are on anti-androgens, these should be discontinued, at least 4 weeks prior for flutamide and at least 6 weeks for bicalutamide or nilutamide

• At least 14 days should have elapsed from prior radiation therapy to bone metastases from prostate cancer

• The patient has received a maximum of one prior chemotherapy regimen for metastatic prostate cancer

• Patients must demonstrate disease progression on or after most recent systemic therapy, either by prostate-specific antigen (PSA), new bone metastases or by measurable disease criteria per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines

• Patients should have received either luteinizing hormone-releasing hormone (LHRH) analogue, or LHRH analogue and anti- androgen for metastatic prostate cancer

• The patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Bisphosphonate therapy can be continued if started prior to protocol enrollment

• Patients must have blood pressure (BP) readings < 150/90 prior to enrollment

• Absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support

• Platelets >= 100,000/mm^3

• Hemoglobin >= 9 g/dL

• Bilirubin =< 1.5 x the upper limit of normal (ULN); for subjects with known Gilbert's disease, bilirubin =< 3.0 mg/dL

• Serum albumin >= 2.8 g/dl

• Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 50 mL/min; for creatinine clearance estimation, the Cockcroft and Gault equation should be used

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN if no liver involvement, or =< 5 x ULN with liver involvement

• Lipase < 1.5 x the upper limit of normal (except for subjects with adenocarcinoma of the pancreas)

• Urine protein/creatinine ratio (UPCR) =< 1

• Serum phosphorus >= lower limit of normal (LLN)

• The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document

• Patients participating in this trial must also be eligible and willing to sign consent for participation in [2'-18F]-1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)thymine (FMAU) and 18F-flouride positron emission tomography (PET) scans done under separate protocols

• Sexually active subjects (men) must agree to use medically accepted barrier methods of contraception (eg, male condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used by the female partner; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control

• Projected life expectancy of at least 6 months

• No prior history of other malignancies in the last 3 years, except for squamous and basal cell skin cancer

Exclusion Criteria:

• The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment

• Prior treatment with cabozantinib

• The subject has received radiation therapy:

• To the thoracic cavity or gastrointestinal tract within 3 months of the first dose of study treatment

• To bone or brain metastasis within 14 days of the first dose of study treatment

• To any other site(s) within 28 days of the first dose of study treatment

• The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment

• The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment; patients receiving LHRH or gonadotropin-releasing hormone (GnRH) agonists to maintain castrate levels of testosterone or patients on bisphosphonate/denosumab, may be maintained on these agents

• The subject has received any other type of investigational agent within 28 days before the first dose of study treatment

• The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)

• The subject has a primary brain tumor

• The subject has active brain metastases or epidural disease (Note: Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain scans are not required to confirm eligibility)

• The subject has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test results at screening >= 1.3 x the laboratory ULN

• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor xabans (Xa) inhibitors, or antiplatelet agents (eg, clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted

• The subject has experienced any of the following within 3 months before the first dose of study treatment:

• Clinically-significant hematemesis or gastrointestinal bleeding

• Hemoptysis of >= 0.5 teaspoon (2.5 ml) of red blood

• Any other signs indicative of pulmonary hemorrhage

• The subject has radiographic evidence of cavitating pulmonary lesion(s)

• The subject has tumor in contact with, invading or encasing major blood vessels

• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

• Cardiovascular disorders including

• Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening

• Concurrent uncontrolled hypertension defined as sustained BP > 140 mmHg systolic, or > 90 mmHg diastolic despite optimal antihypertensive treatment (BP must be controlled at screening)

• Any of the following within 6 months before the first dose of study treatment:

• Unstable angina pectoris

• Clinically-significant cardiac arrhythmias

• Stroke (including transient ischemic attack [TIA], or other ischemic event)

• Myocardial infarction

• Thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)

• Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

• Any of the following at the time of screening

• Intra-abdominal tumor/metastases invading gastrointestinal (GI) mucosa

• Active peptic ulcer disease

• Inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis

• Any of the following within 6 months before the first dose of study treatment:

• History of abdominal fistula

• Gastrointestinal perforation

• Bowel obstruction or gastric outlet obstruction

• Intra-abdominal abscess. Note: Complete resolution of an intraabdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more that 6 months ago

• GI surgery (particularly when associated with delayed or incomplete healing) within 28 days; Note: Complete healing following abdominal surgery must be confirmed prior to initiating treatment with cabozantinib even if surgery occurred more that 28 days ago

• Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea and esophagus

• Other clinically significant disorders such as:

• Active infection requiring systemic treatment

• Serious non-healing wound/ulcer/bone fracture

• History of organ transplant

• Concurrent uncompensated hypothyroidism or thyroid dysfunction

• History of major surgery within 4 weeks or minor surgical procedures within 1 week before randomization

• The subject is unable to swallow tablets

• The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 470 ms within 28 days before randomization

• The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation

• The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee

• The subject has had evidence within 2 years of the start of study treatment of another malignancy, which required systemic treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201

Sponsors and Collaborators

• Barbara Ann Karmanos Cancer Institute

Investigators

• Principal Investigator: Ulka Vaishampayan, Barbara Ann Karmanos Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 14, 2014

More Information

Publications

None provided.

• Responsible Party: Elisabeth Heath, Principal Investigator, Barbara Ann Karmanos Cancer Institute
• ClinicalTrials.gov Identifier: NCT01812668
• Other Study ID Numbers: 2011-185; NCI-2013-00399
• First Posted: Mar 18, 2013
• Last Update Posted: Aug 5, 2021
• Last Verified: Aug 1, 2021

• Additional relevant MeSH terms: Prostatic Neoplasms; Fluorides

Study Results

Participant Flow

Arm/Group Title	Treatment (Cabozantinib-s-malate)
Arm/Group Description	Patients receive cabozantinib-s-malate PO daily in the absence of disease progression or unacceptable toxicity. cabozantinib-s-malate: Given PO fluorine F 18 d-FMAU: Undergo 18F PET/FMAU PET scan positron emission tomography: Undergo 18F PET/FMAU PET scan pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Cabozantinib-s-malate)
Arm/Group Description	Patients receive cabozantinib-s-malate PO daily in the absence of disease progression or unacceptable toxicity. cabozantinib-s-malate: Given PO fluorine F 18 d-FMAU: Undergo 18F PET/FMAU PET scan positron emission tomography: Undergo 18F PET/FMAU PET scan pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Overall Participants	20
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	6 30%
>=65 years	14 70%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	20 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 25%
White	15 75%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Change in PET Standard Uptake Value SUV Levels Pre-treatment to Post-treatment.
Description	Change in PET standard uptake value SUV levels (each value measured in g/ml). (post-treatment - pre-treatment)/pre-treatment x 100 , therefore, measured in percentage change from baseline.
Time Frame	Baseline to 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cabozantinib-s-malate)
Arm/Group Description	Patients receive cabozantinib-s-malate PO daily in the absence of disease progression or unacceptable toxicity. cabozantinib-s-malate: Given PO fluorine F 18 d-FMAU: Undergo 18F PET/FMAU PET scan positron emission tomography: Undergo 18F PET/FMAU PET scan pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	20
Median (Full Range) [percentage change from baseline]	-56

2. Secondary Outcome

Title	Time to Progression
Description	Summarized via the Kaplan-Meier (K-M) survivorship estimate.
Time Frame	From date of registration to date of first documented disease progression, or death from any cause, assessed up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cabozantinib-s-malate)
Arm/Group Description	Patients receive cabozantinib-s-malate PO daily in the absence of disease progression or unacceptable toxicity. cabozantinib-s-malate: Given PO fluorine F 18 d-FMAU: Undergo 18F PET/FMAU PET scan positron emission tomography: Undergo 18F PET/FMAU PET scan pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	20
Median (90% Confidence Interval) [months]	4.1

3. Secondary Outcome

Title	Number of Participants With Indicated Toxicities Grade 3 or Higher
Description	Type of toxicities graded per National Cancer Institute (NCI) CTCAE version 4.0 Summarized via their frequency distribution and point estimate of the proportion.
Time Frame	Up to 4 weeks post-treatment, about 2 years on average.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cabozantinib-s-malate)
Arm/Group Description	Patients receive cabozantinib-s-malate PO daily in the absence of disease progression or unacceptable toxicity. cabozantinib-s-malate: Given PO fluorine F 18 d-FMAU: Undergo 18F PET/FMAU PET scan positron emission tomography: Undergo 18F PET/FMAU PET scan pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	20
Parkinson like syndrome	1 5%
UTI	1 5%
anemia	2 10%
decreased ALC	2 10%
decreased platelet	1 5%
dehydration	1 5%
diarrhea	1 5%
fatigue	3 15%
foot blisters	1 5%
hyperglycemia	2 10%
hypertension	11 55%
hypophosphatemia	2 10%
increased AST	1 5%
mandibular abscess	1 5%
mucositis	1 5%
pleurisy	1 5%
pneumonia	1 5%
urinary retention	1 5%
weight loss	2 10%

4. Secondary Outcome

Title	Number of Participants With Indicated Clinical Response Based on the RECIST Criteria 1.1
Description	Number of Participants with Indicated Clinical response based on the RECIST criteria 1.1 summarized via their frequency distribution.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

Patients with measurable disease

Arm/Group Title	Treatment (Cabozantinib-s-malate)
Arm/Group Description	Patients receive cabozantinib-s-malate PO daily in the absence of disease progression or unacceptable toxicity. cabozantinib-s-malate: Given PO fluorine F 18 d-FMAU: Undergo 18F PET/FMAU PET scan positron emission tomography: Undergo 18F PET/FMAU PET scan pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	9
Count of Participants [Participants]	6 30%

5. Secondary Outcome

Title	PSA Response Based on the RECIST Criteria 1.1
Description	Summarized via their frequency distribution, point estimate of the proportion, and the Wilson type 80% CI.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cabozantinib-s-malate)
Arm/Group Description	Patients receive cabozantinib-s-malate PO daily in the absence of disease progression or unacceptable toxicity. cabozantinib-s-malate: Given PO fluorine F 18 d-FMAU: Undergo 18F PET/FMAU PET scan positron emission tomography: Undergo 18F PET/FMAU PET scan pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	20
Count of Participants [Participants]	8 40%

6. Secondary Outcome

Title	PET Response Based on the RECIST Criteria 1.1
Description	Summarized via their frequency distribution, point estimate of the proportion, and the Wilson type 80% CI.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cabozantinib-s-malate)
Arm/Group Description	Patients receive cabozantinib-s-malate PO daily in the absence of disease progression or unacceptable toxicity. cabozantinib-s-malate: Given PO fluorine F 18 d-FMAU: Undergo 18F PET/FMAU PET scan positron emission tomography: Undergo 18F PET/FMAU PET scan pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	20
Count of Participants [Participants]	19 95%

Adverse Events

Time Frame	All untoward events that occur after start of therapy through 30 days after the last dose of study treatment are to be recorded, about 12 months on average.
Arm/Group Title	Treatment (Cabozantinib-s-malate)
Arm/Group Description	Patients receive cabozantinib-s-malate PO daily in the absence of disease progression or unacceptable toxicity. cabozantinib-s-malate: Given PO fluorine F 18 d-FMAU: Undergo 18F PET/FMAU PET scan positron emission tomography: Undergo 18F PET/FMAU PET scan pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Treatment (Cabozantinib-s-malate)
	Affected / at Risk (%)	# Events
Total	18/20 (90%)
Serious Adverse Events
	Treatment (Cabozantinib-s-malate)
	Affected / at Risk (%)	# Events
Total	4/20 (20%)
General disorders
fatigue	1/20 (5%)	1
Musculoskeletal and connective tissue disorders
hand foot syndrome	1/20 (5%)	1
Renal and urinary disorders
urinary infection	1/20 (5%)	1
elevated creatinine	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Cabozantinib-s-malate)
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Blood and lymphatic system disorders
anemia	3/20 (15%)	3
decreased ALC	2/20 (10%)	2
edema	5/20 (25%)	5
hypophosphatemia	2/20 (10%)	2
increased ALT	2/20 (10%)	2
increased AST	4/20 (20%)	4
Endocrine disorders
hyperglycemia	2/20 (10%)	2
hypothyroidism	5/20 (25%)	5
Gastrointestinal disorders
GERD	2/20 (10%)	2
constipation	4/20 (20%)	4
diarrhea	9/20 (45%)	9
dysgeusia	6/20 (30%)	6
mucositis	6/20 (30%)	6
nausea	10/20 (50%)	10
vomiting	4/20 (20%)	4
General disorders
dizziness	2/20 (10%)	2
dry mouth	5/20 (25%)	5
fatigue	17/20 (85%)	17
hoarseness	5/20 (25%)	5
weakness	3/20 (15%)	3
weight loss	4/20 (20%)	4
Metabolism and nutrition disorders
chills	3/20 (15%)	3
Musculoskeletal and connective tissue disorders
bone pain	6/20 (30%)	6
hand/foot	3/20 (15%)	3
Nervous system disorders
headache	4/20 (20%)	4
Psychiatric disorders
anorexia	14/20 (70%)	14
Renal and urinary disorders
UTI	2/20 (10%)	2
urinary frequency	3/20 (15%)	3
urinary retention	2/20 (10%)	2
Respiratory, thoracic and mediastinal disorders
dyspnea	4/20 (20%)	4
Skin and subcutaneous tissue disorders
blisters	2/20 (10%)	2
rash	6/20 (30%)	6
Vascular disorders
hypertension	12/20 (60%)	12

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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