Study of TRC105 With Abiraterone and With Enzalutamide in Prostate Cancer Patients Progressing on Therapy

• Sponsor: Cedars-Sinai Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT03418324
• Collaborator: (none)
• Enrollment: 11
• Location: 1
• Arms: 2
• Actual Duration (Months): 20.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This research study is being done to measure the clinical benefit of TRC105 in combination with abiraterone or enzalutamide in metastatic, castration-resistant prostate cancer patients who are taking either abiraterone or enzalutamide and showing signs of biochemical progression without radiographic progression. A patient who is progressing on AR-therapy will continue the same AR-therapy on study with the addition of TRC105. The two arms will accrue in parallel and independently.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: TRC105; Drug: Abiraterone; Drug: Enzalutamide	Phase 2

Detailed Description

This is a Phase II, open-label study of TRC105 (anti-endoglin antibody) in combination with abiraterone or enzalutamide in metastatic, castration-resistant prostate cancer patients who are taking either abiraterone or enzalutamide and showing signs of biochemical progression without radiographic progression. A patient who is progressing on AR-therapy will continue the same AR-therapy on study with the addition of TRC105. The two arms will accrue in parallel and independently.

There will be a 2-week washout of the active AR-targeted therapy prior to initiation of combination therapy. Tumor response should be assessed at a frequency of 8 weeks by CT/MRI chest, abdomen and pelvis as well as bone scan. Patients may continue on therapy until radiographic progression by RECIST 1.1 or PCWG3 criteria.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Bayesian designBayesian design
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of TRC105 (Anti-endoglin Antibody) With Abiraterone and With Enzalutamide in Metastatic, Castration Resistant Prostate Cancer Patients Progressing on Therapy
• Actual Study Start Date: Mar 5, 2018
• Actual Primary Completion Date: Nov 6, 2019
• Actual Study Completion Date: Nov 6, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: TRC105 + Abiraterone Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone	Drug: TRC105; Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks; Other Names: Carotuximab ; Drug: Abiraterone; Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.; Other Names: Zytiga
Experimental: Arm E: TRC105 + Enzalutamide Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide	Drug: TRC105; Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks; Other Names: Carotuximab ; Drug: Enzalutamide; Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.; Other Names: Xtandi

Outcome Measures

Primary Outcome Measures

1. Overall Clinical Benefit [Through study completion, average 24 months]

   Number of participants with stabilization of disease for at least 2 months or disease improvement at any time from start of combination therapy by radiographic and/or biochemical criteria through treatment completion up to an estimated period of 24 months radiographic improvement defined as a PR (At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum. There can be no appearance of new lesions) or CR (Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions) by RECIST 1.1 or improvement by PCWG3 criteria Biochemical response will be defined by PCWG3 criteria Stabilization will be defined as the absence of progression by BOTH radiographic and biochemical criteria

Secondary Outcome Measures

1. Adverse Events From TRC105 and Abiraterone or Enzalutamide [4 months]

   Number of participants with grade 3/4 Adverse Events Related to investigational therapy as assessed Using CTCAE (v.4) up to 4 months from treatment initiation.

2. Progression Free Survival [24 months]

   Time (in Months) from treatment initiation to radiographic and clinical progression over study duration (estimated 24 months) - radiographic criteria measured by RECIST 1.1 [Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions plus an absolute increase of at least 5 mm, taking as reference the smallest sum recorded since the start of study]

3. Clinical Benefit at Two Months [2 months]

   Proportion of participants with stabilization of disease for two months or disease improvement at anytime from start of combination therapy to two months by radiographic and/or biochemical criteria radiographic improvement defined as a PR (At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum. There can be no appearance of new lesions) or CR (Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions) by RECIST 1.1 or improvement by PCWG3 criteria Biochemical response will be defined by PCWG3 criteria Stabilization will be defined as the absence of progression by BOTH radiographic and biochemical criteria

4. Clinical Benefit at Four Months [4 months]

   Proportion of participants with stabilization of disease for at least 4 months or disease improvement at anytime from start of combination therapy to four months by radiographic and/or biochemical criteria radiographic improvement defined as a PR (At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum. There can be no appearance of new lesions) or CR (Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions) by RECIST 1.1 or improvement by PCWG3 criteria Biochemical response will be defined by PCWG3 criteria Stabilization will be defined as the absence of progression by BOTH radiographic and biochemical criteria

5. Clinical Benefit From PSA Serum Concentration (2 Months) [2 months]

   Proportion of participants with stabilization of disease based on PSA serum concentration levels. Stabilization of disease refers to PSA values that do not meet criteria for progression where progression will be defined as a rise in serum PSA that is ≥ 25% and 2 ng/mL above nadir which is confirmed by a second value ≥ 3 weeks later.

6. Clinical Benefit From PSA Serum Concentration (4 Months) [4 months]

   Proportion of participants with stabilization of disease based on PSA serum concentration levels. Stabilization of disease refers to PSA values that do not meet criteria for progression where progression will be defined as a rise in serum PSA that is ≥ 25% and 2 ng/mL above nadir which is confirmed by a second value ≥ 3 weeks later.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. History of metastatic, castration-resistant prostate cancer with rising PSA on either abiraterone or enzalutamide

• PSA rise will be defined as an increase in PSA of 0.2 ng/mL or higher on at least 2 separate occasions greater than 1 week apart while on either abiraterone or enzalutamide

• If there is a drop in serum PSA after the first rise, and the patient has another PSA rise which is greater than the first, the patient will still be considered eligible.

1. ECOG 0-2

2. Resolution of adverse events results as described below.

• Laboratory abnormalities must meet values specified below in criteria #4

• If the patient's most recent line of therapy is treatment with abiraterone or enzalutamide, then all adverse events must be resolved to Grade 2 or better

• If the most recent line of therapy is any other treatment for mCRPC then all Adverse events must be resolved to grade 1 or better, with the exception of fatigue, alopecia and neuropathy (which must resolve to CTCAE grade 2)

1. Adequate organ function defined by:

• AST and ALT < 2.5 x ULN

• Total serum bilirubin < 1.5 x ULN

• Platelets > 60,000

• Hgb > 8.5 g/dL

• Serum Cr <1.5 x ULN or a creatinine clearance > 30.

• INR ≤ 1.2 unless the patient is receiving a direct Factor Xa inhibitor or a direct thrombin inhibitor

1. Patients must be surgically sterile or must agree to use effective contraception during the study and for 3 months following last dose of TRC105. The definition of effective contraception will be based on the judgment of the Principal Investigator or a designated associate. Abstinence from intercourse is an acceptable form of contraception.

Exclusion Criteria:

1. Non-PSA producing prostate cancers- such as small cell prostate cancers or those prostate cancers which exhibit radiographic progression without PSA rise

2. Inability to tolerate standard doses of abiraterone (1000 mg daily) or enzalutamide (160 mg daily).

3. Other prior malignancy requiring active anticancer therapy

4. Prior exposure to TRC105 or any CD105 targeted antibody

5. Any major surgical procedure within 2 weeks of starting therapy

6. Uncontrolled chronic hypertension defined as sustained by systolic pressure (SBP) >150 mmHg or diastolic pressure (DBP) >90 despite optimal therapy.

7. Active bleeding or pathologic conditions that carries a high bleeding risk

8. Use of thrombolytics within 10 days prior to the first day of TRC105

9. Known hypersensitivity to Chinese hamster ovary products or other recombinant human, chimeric, or humanized antibodies

10. A known diagnosis of Osler-Weber-Rendu syndrome

11. Ascites or pericardial or pleural effusion requiring external drainage procedures

12. History of untreated brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Patients with radiated or resected lesions are permitted, provided the lesions are fully treated and inactive, patients are asymptomatic, and no steroids have been administered for at least 28 days. Imaging for CNS disease will not be required for screening unless there is a history of a neurological finding such as new onset weakness or numbness that cannot be explained by other medical history.

13. Acute cardiovascular event within the past 6 months. An acute cardiovascular event will be defined as a myocardial infraction, NYHA Class II or worse congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, percutaneous transluminal coronary angioplasty (PTCA), or CABG. Deep venous thrombosis within 6 months, unless the patient is anti-coagulated without the use of warfarin for at least 2 weeks. In this situation, low molecular weight heparin is preferred.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars Sinai Medical Center	Los Angeles	California	United States	90048

Sponsors and Collaborators

• Cedars-Sinai Medical Center

Investigators

• Principal Investigator: Edwin Posadas, MD FACP, Cedars-Sinai Medical Center Samuel Oschin Comprehensive Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 24, 2017

More Information

Publications

None provided.

• Responsible Party: Edwin Posadas, MD, Medical Director, Urologic Oncology Program, Cedars-Sinai Medical Center
• ClinicalTrials.gov Identifier: NCT03418324
• Other Study ID Numbers: IIT2016-16-POSADAS-TRC105
• First Posted: Feb 1, 2018
• Last Update Posted: Dec 30, 2020
• Last Verified: Dec 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Edwin Posadas, MD, Medical Director, Urologic Oncology Program, Cedars-Sinai Medical Center: Prostate Cancer; Metastatic Prostate Cancer; Castration Resistant Prostate Cancer; Metastatic Castration Resistant
• Additional relevant MeSH terms: Prostatic Neoplasms

Study Results

Participant Flow

Recruitment Details	Study opened to accrual February 5, 2018 and the first patient on study March 5, 2018. As of November 6, 2019, 12 patients have been consented, 11 were enrolled, and 11 were off-treatment and off-study. Study closed to accrual on May 1, 2019, as drug manufacturer has limited drug supply without plans to increase production.
Pre-assignment Detail	Early accrual closure due to manufacturer's limited drug supply.

Arm/Group Title	Arm A: TRC105 + Abiraterone	Arm E: TRC105 + Enzalutamide
Arm/Group Description	Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Abiraterone: Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.	Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Enzalutamide: Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.
Period Title: Overall Study
STARTED	3	8
COMPLETED	2	6
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Arm A: TRC105 + Abiraterone	Arm E: TRC105 + Enzalutamide	Total
Arm/Group Description	Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Abiraterone: Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.	Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Enzalutamide: Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.	Total of all reporting groups
Overall Participants	2	6	8
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	2 33.3%	2 25%
>=65 years	2 100%	4 66.7%	6 75%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	76.5	72	72
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	76.5 (3.53)	67.83 (6.97)	70 (7.25)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	2 100%	6 100%	8 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	2 100%	6 100%	8 100%
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 50%	0 0%	1 12.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	1 50%	6 100%	7 87.5%
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	2 100%	6 100%	8 100%

Outcome Measures

1. Primary Outcome

Title	Overall Clinical Benefit
Description	Number of participants with stabilization of disease for at least 2 months or disease improvement at any time from start of combination therapy by radiographic and/or biochemical criteria through treatment completion up to an estimated period of 24 months radiographic improvement defined as a PR (At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum. There can be no appearance of new lesions) or CR (Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions) by RECIST 1.1 or improvement by PCWG3 criteria Biochemical response will be defined by PCWG3 criteria Stabilization will be defined as the absence of progression by BOTH radiographic and biochemical criteria
Time Frame	Through study completion, average 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: TRC105 + Abiraterone	Arm E: TRC105 + Enzalutamide
Arm/Group Description	Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Abiraterone: Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.	Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Enzalutamide: Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.
Measure Participants	2	6
Overall Clinical Benefit	1 50%	4 66.7%
Radiographic Improvement	1 50%	2 33.3%
Biochemical Response	1 50%	1 16.7%
Stabilization	1 50%	3 50%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: TRC105 + Abiraterone
	Comments	For this study, we are not comparing outcome measures between the two arms
	Type of Statistical Test	Other
	Comments	Binomial proportion (Clopper-Pearson exact confidence interval) for each arm
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Binomial proportion
	Estimated Value	50
	Confidence Interval	(2-Sided) 95%; 1.3 to 98.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated values reflects the percentage of participants with overall clinical benefit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm E: TRC105 + Enzalutamide
	Comments	For this study, we are not comparing outcome measures between the two groups.
	Type of Statistical Test	Other
	Comments	Binomial proportion (Clopper-Pearson exact confidence interval) for each arm
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Binomial proportion
	Estimated Value	66.7
	Confidence Interval	(2-Sided) 95%; 22.3 to 95.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated values reflects the percentage of participants with overall clinical benefit

2. Secondary Outcome

Title	Adverse Events From TRC105 and Abiraterone or Enzalutamide
Description	Number of participants with grade 3/4 Adverse Events Related to investigational therapy as assessed Using CTCAE (v.4) up to 4 months from treatment initiation.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: TRC105 + Abiraterone	Arm E: TRC105 + Enzalutamide
Arm/Group Description	Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Abiraterone: Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.	Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Enzalutamide: Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.
Measure Participants	2	6
Grade 3	1 50%	1 16.7%
Grade 4	0 0%	0 0%

3. Secondary Outcome

Title	Progression Free Survival
Description	Time (in Months) from treatment initiation to radiographic and clinical progression over study duration (estimated 24 months) - radiographic criteria measured by RECIST 1.1 [Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions plus an absolute increase of at least 5 mm, taking as reference the smallest sum recorded since the start of study]
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Median progression free survival (months) (95% confidence interval). Not enough data (insufficient number of participants with events) to establish upper limit.

Arm/Group Title	Arm A: TRC105 + Abiraterone	Arm E: TRC105 + Enzalutamide
Arm/Group Description	Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Abiraterone: Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.	Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Enzalutamide: Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.
Measure Participants	2	6
Median (95% Confidence Interval) [months]	1.64	4.46

4. Secondary Outcome

Title	Clinical Benefit at Two Months
Description	Proportion of participants with stabilization of disease for two months or disease improvement at anytime from start of combination therapy to two months by radiographic and/or biochemical criteria radiographic improvement defined as a PR (At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum. There can be no appearance of new lesions) or CR (Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions) by RECIST 1.1 or improvement by PCWG3 criteria Biochemical response will be defined by PCWG3 criteria Stabilization will be defined as the absence of progression by BOTH radiographic and biochemical criteria
Time Frame	2 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: TRC105 + Abiraterone	Arm E: TRC105 + Enzalutamide
Arm/Group Description	Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Abiraterone: Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.	Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Enzalutamide: Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.
Measure Participants	2	6
Clinical Benefit	1 50%	4 66.7%
Radiographic Improvement	1 50%	1 16.7%
Biochemical Response	1 50%	1 16.7%
Stabilization	1 50%	3 50%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: TRC105 + Abiraterone
	Comments	For this study, we are not comparing outcome measures between the two arms
	Type of Statistical Test	Other
	Comments	Binomial proportion (Clopper-Pearson exact confidence interval) for each arm.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Binomial proportion
	Estimated Value	50
	Confidence Interval	(2-Sided) 95%; 1.3 to 98.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm E: TRC105 + Enzalutamide
	Comments	For this study, we are not comparing outcome measures between the two arms.
	Type of Statistical Test	Other
	Comments	Binomial proportion (Clopper-Pearson exact confidence interval) for each arm.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Binomial proportion
	Estimated Value	66.7
	Confidence Interval	(2-Sided) 95%; 22.3 to 95.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Clinical Benefit at Four Months
Description	Proportion of participants with stabilization of disease for at least 4 months or disease improvement at anytime from start of combination therapy to four months by radiographic and/or biochemical criteria radiographic improvement defined as a PR (At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum. There can be no appearance of new lesions) or CR (Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions) by RECIST 1.1 or improvement by PCWG3 criteria Biochemical response will be defined by PCWG3 criteria Stabilization will be defined as the absence of progression by BOTH radiographic and biochemical criteria
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: TRC105 + Abiraterone	Arm E: TRC105 + Enzalutamide
Arm/Group Description	Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Abiraterone: Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.	Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Enzalutamide: Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.
Measure Participants	2	6
Clinical Benefit	1 50%	3 50%
Radiographic Improvement	1 50%	2 33.3%
Biochemical Response	1 50%	1 16.7%
Stabilization	1 50%	2 33.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: TRC105 + Abiraterone
	Comments	For this study, we are not comparing outcome measures between the two arms.
	Type of Statistical Test	Other
	Comments	Binomial proportion (Clopper-Pearson exact confidence interval) for each arm.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Binomial proportion
	Estimated Value	50
	Confidence Interval	(2-Sided) 95%; 1.3 to 98.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm E: TRC105 + Enzalutamide
	Comments	For this study, we are not comparing outcome measures between the two arms.
	Type of Statistical Test	Other
	Comments	Binomial proportion (Clopper-Pearson exact confidence interval) for each arm.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Binomial proportion
	Estimated Value	50
	Confidence Interval	(2-Sided) 95%; 11.8 to 88.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Clinical Benefit From PSA Serum Concentration (2 Months)
Description	Proportion of participants with stabilization of disease based on PSA serum concentration levels. Stabilization of disease refers to PSA values that do not meet criteria for progression where progression will be defined as a rise in serum PSA that is ≥ 25% and 2 ng/mL above nadir which is confirmed by a second value ≥ 3 weeks later.
Time Frame	2 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: TRC105 + Abiraterone	Arm E: TRC105 + Enzalutamide
Arm/Group Description	Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Abiraterone: Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.	Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Enzalutamide: Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.
Measure Participants	2	6
Count of Participants [Participants]	1 50%	4 66.7%

7. Secondary Outcome

Title	Clinical Benefit From PSA Serum Concentration (4 Months)
Description	Proportion of participants with stabilization of disease based on PSA serum concentration levels. Stabilization of disease refers to PSA values that do not meet criteria for progression where progression will be defined as a rise in serum PSA that is ≥ 25% and 2 ng/mL above nadir which is confirmed by a second value ≥ 3 weeks later.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: TRC105 + Abiraterone	Arm E: TRC105 + Enzalutamide
Arm/Group Description	Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Abiraterone: Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.	Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Enzalutamide: Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.
Measure Participants	2	6
Count of Participants [Participants]	1 50%	3 50%

Adverse Events

Time Frame	2 years
Adverse Event Reporting Description	3 patients consented to Arm A, but only 2 were considered evaluable (1 patient considered unevaluable per physician decision prior to treatment start). 8 patients consented to Arm E, but 6 were considered evaluable. Of the 2 patients not included in Arm E, 1 patient was deemed unevaluable by physician decision prior to starting study treatment, and the other died prior to starting study treatment. Therefore, this number is reflected in All-Cause Mortality, and differs from SAEs and Other.
Arm/Group Title	Arm A: TRC105 + Abiraterone		Arm E: TRC105 + Enzalutamide
Arm/Group Description	Patients progressing on Abiraterone will undergo a washout period and then continue treatment with TRC105 + Abiraterone TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Abiraterone: Patients who are progressing on Abiraterone will undergo a washout period and then continue treatment with standard dosing of Abiraterone plus TRC105.		Patients progressing on Enzalutamide will undergo a washout period and then continue treatment with TRC105 + Enzalutamide TRC105: Patients will receive TRC105 10mg weekly x 4, and then 15 mg/kg every 2 weeks Enzalutamide: Patients who are progressing on Enzalutamide will undergo a washout period and then continue standard treatment with Enzalutamide plus TRC105.
All Cause Mortality
	Arm A: TRC105 + Abiraterone		Arm E: TRC105 + Enzalutamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		1/8 (12.5%)
Serious Adverse Events
	Arm A: TRC105 + Abiraterone		Arm E: TRC105 + Enzalutamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/2 (50%)		0/6 (0%)
Metabolism and nutrition disorders
Hyponatremia	1/2 (50%)	1	0/6 (0%)	0
Renal and urinary disorders
Urinary retention	1/2 (50%)	1	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Cellulitis (peri-mandibular)	1/2 (50%)	1	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A: TRC105 + Abiraterone		Arm E: TRC105 + Enzalutamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Anemia Hemoglobin (Hgb)	2/2 (100%)	7	2/6 (33.3%)	8
Petechiae	1/2 (50%)	1	0/6 (0%)	0
Eye disorders
Cataract	0/2 (0%)	0	1/6 (16.7%)	1
Glaucoma	0/2 (0%)	0	1/6 (16.7%)	3
Redness sclera left eye	0/2 (0%)	0	1/6 (16.7%)	1
Vision decrease (binocular)	0/2 (0%)	0	1/6 (16.7%)	1
Gastrointestinal disorders
Gingival bleeding	2/2 (100%)	3	5/6 (83.3%)	6
Guaiac + Stool	1/2 (50%)	1	0/6 (0%)	0
Nausea	1/2 (50%)	2	3/6 (50%)	4
Geographic Tongue	0/2 (0%)	0	1/6 (16.7%)	1
Lip pain	0/2 (0%)	0	1/6 (16.7%)	1
Oral pain	0/2 (0%)	0	1/6 (16.7%)	1
Vomiting	0/2 (0%)	0	1/6 (16.7%)	1
General disorders
Edema limbs	1/2 (50%)	1	0/6 (0%)	0
Fatigue	2/2 (100%)	2	0/6 (0%)	0
Flu like symptoms	1/2 (50%)	2	2/6 (33.3%)	2
Generalized weakness	1/2 (50%)	2	0/6 (0%)	0
Non-cardiac chest pain	1/2 (50%)	1	0/6 (0%)	0
Infusion related reaction	0/2 (0%)	0	1/6 (16.7%)	1
Localized edema	0/2 (0%)	0	2/6 (33.3%)	2
Pain	0/2 (0%)	0	1/6 (16.7%)	2
Immune system disorders
Allergic reaction	1/2 (50%)	1	0/6 (0%)	0
Infections and infestations
Urinary tract infection	1/2 (50%)	1	0/6 (0%)	0
Laryngitis	0/2 (0%)	0	1/6 (16.7%)	1
MRSA	0/2 (0%)	0	1/6 (16.7%)	1
Rhinitis infective	0/2 (0%)	0	1/6 (16.7%)	1
Tooth infection	0/2 (0%)	0	1/6 (16.7%)	1
Injury, poisoning and procedural complications
Fall	2/2 (100%)	2	1/6 (16.7%)	1
Bruising	0/2 (0%)	0	1/6 (16.7%)	1
Investigations
Weight loss	1/2 (50%)	1	1/6 (16.7%)	3
Platelet count decreased	0/2 (0%)	0	1/6 (16.7%)	1
Metabolism and nutrition disorders
Anorexia	1/2 (50%)	1	0/6 (0%)	0
Hyponatremia	1/2 (50%)	5	1/6 (16.7%)	1
Dehydration	0/2 (0%)	0	2/6 (33.3%)	2
Hypokalemia	0/2 (0%)	0	1/6 (16.7%)	2
Musculoskeletal and connective tissue disorders
Back pain	1/2 (50%)	1	1/6 (16.7%)	3
Myalgia	1/2 (50%)	1	0/6 (0%)	0
Osteonecrosis of jaw	0/2 (0%)	0	1/6 (16.7%)	1
Pain in extremity	0/2 (0%)	0	1/6 (16.7%)	1
Nervous system disorders
Dizziness	1/2 (50%)	2	0/6 (0%)	0
Dysphasia	1/2 (50%)	1	0/6 (0%)	0
Cauda equina	1/2 (50%)	1	0/6 (0%)	0
Right leg sciatica	1/2 (50%)	1	0/6 (0%)	0
Headache	0/2 (0%)	0	3/6 (50%)	3
Memory impairment	0/2 (0%)	0	1/6 (16.7%)	1
Recurrent laryngeal nerve palsy	0/2 (0%)	0	1/6 (16.7%)	1
Psychiatric disorders
Confusion	0/2 (0%)	0	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/2 (50%)	2	0/6 (0%)	0
Cough	1/2 (50%)	1	1/6 (16.7%)	1
Epistaxis	1/2 (50%)	2	6/6 (100%)	10
Pleural effusion	1/2 (50%)	1	0/6 (0%)	0
Hoarseness	0/2 (0%)	0	1/6 (16.7%)	1
Nasal congestion	0/2 (0%)	0	2/6 (33.3%)	2
Skin and subcutaneous tissue disorders
Cellulitis (peri-mandibular)	1/2 (50%)	1	0/6 (0%)	0
Acne	0/2 (0%)	0	1/6 (16.7%)	1

Limitations/Caveats

Early accrual closure due to manufacturer's limited drug supply.

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.