ReCAP: Randomized Trial of Suicide Gene Therapy and Prostate Cancer

• Sponsor: Henry Ford Health System (Other)
• Overall Status: Completed
• CT.gov ID: NCT00583492
• Collaborator: (none)
• Enrollment: 44
• Locations: 2
• Arms: 2
• Duration (Months): 69
• Patients Per Site: 22
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a randomized, controlled trial that will test the hypothesis that replication-competent adenovirus-mediated suicide gene therapy in combination with 80 Gy intensity modulated radiotherapy (IRMT)will improve freedom from failure (FFF) relative to 80 Gy IMRT alone in patients with newly-diagnosed prostate cancer with an intermediate-risk profile.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Biological: Ad5-yCD/mutTKSR39rep-ADP; Radiation: IMRT	Phase 2

Detailed Description

OBJECTIVES

This is a randomized, controlled trial that will test the hypothesis that replication-competent adenovirus-mediated suicide gene therapy in combination with 80 Gy intensity modulated radiotherapy (IRMT)will improve freedom from failure (FFF) relative to 80 Gy IMRT alone in patients with newly-diagnosed prostate cancer with an intermediate-risk profile.

The trial contains two treatment arms:

Arm 1- Gene Therapy + IMRT Arm 2- IMRT

The study will be stratified by clinical site and pre-treatment risk factors (e.g., % positive biopsy cores, Gleason score.

• Gleason score 5/6 AND PSA <10 ng/mL; AND >=50% positive biopsy cores

• (Gleason score 5/6 and PSA 10-20 ng/mL) OR (Gleason score 7 and PSA 0 - 20 ng/mL); AND <50% positive biopsy cores

• Gleason score 5/6 and PSA 10-20 ng/mL) OR (Gleason score 7 and PSA 0-20 ng/mL) AND >=50% positive biopsy cores.

An interim safety analysis (Interim Analysis 1) will be conducted after the first 21 patients in the investigational therapy arm, and a total of 42 subjects in both arms, have completed the 90 day toxicity assessment following randomization (phase 2 component). If, at this point, there are no safety concerns as determined by the Data and Safety Monitoring Board (DSMB), the trial will continue as a phase 3 study with two additional interim analyses (Interim Analyses 2 & 3). The primary analysis for treatment efficacy will be based on all randomized subjects.

Primary

To assess the relative efficacy of replication-competent adenovirus-mediated suicide gene therapy in combination with 80 Gy intensity modulated radiotherapy (IMRT) versus 80 Gy IMRT alone in patients with newly-diagnosed prostate cancer with an intermediate-risk profile. The primary endpoint is freedom from failure (FFF) (biochemical or clinical).

Secondary

To assess the difference between the two treatment arms for:

• Acute (<= 90 days) and long-term (> 90 days) toxicity.

• Prostate biopsy status (12 cores) at 2 years.

• Freedom from distant metastases.

• Disease-specific and overall survival.

• Quality of life.

Exploratory

To examine:

• Possible effect of gene therapy on PSA doubling time (PSADT) after PSA failure.

• Possible association between the primary and secondary outcomes and Ad5-yCD/mutTKSR39rep-ADP adenovirus persistence (as measured by adenoviral DNA in blood).

• Possible association between the primary and secondary outcomes and specific immunological endpoints including levels of circulating CD4+ and CD8+ T lymphocytes, T-cell proliferation response, cytotoxic T lymphocyte (CTL) response, and development of antibodies to prostate-specific antigens.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Controlled Trial of Replication-Competent Adenovirus-Mediated Suicide Gene Therapy in Combination With IMRT Versus IMRT Alone for the Treatment of Newly-Diagnosed Prostate Cancer With an Intermediate Risk Profile
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ad5-yCD/mutTKSR39rep-ADP + IMRT Gene Therapy + IMRT	Biological: Ad5-yCD/mutTKSR39rep-ADP; Ad5-yCD/mutTKSR39rep-ADP (1 x 10^12 vp) on day 1 Plus Radiation - 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy Plus 2 week course (weekdays only) of 5-FC and vGCV prodrug therapy
Active Comparator: IMRT Alone IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy	Radiation: IMRT; 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy

Outcome Measures

Primary Outcome Measures

1. Freedom From Biochemical/Clinical Failure (FFF) [5 years]

   Biochemical/Clinical Failure was defined as PSA nadir plus 2 ng/mL

Secondary Outcome Measures

1. Acute >= Grade 3 Treatment-related Toxicity [90 days]

   This metric includes both expected and unexpected events Toxicities were graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 3

2. Positive Prostate Biopsy at 2 Years [2 years]

3. Freedom From Distant Metastases [10 years]

4. Disease-specific Survival [10 years]

5. Decrease in Quality of Life [3 years]

   Quality of Life was measured using the comprehensive Expanded Prostate Cancer Index Composite (EPIC) instrument 19 and 20

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Men with histologically-confirmed adenocarcinoma of the prostate within 180 days prior to registration. To be eligible, the subjects must have one of the following conditions:

• Stage T1 or T2, Gleason Score 7, PSA <= 20 ng/mL, Any number positive biopsy cores

• Stage T1 or T2, Gleason Score 5 or 6, PSA >=10 ng/mL and <20 ng/mL, Any number positive biopsy cores

• Stage T1 or T2, Gleason Score 5 or 6, PSA <10 ng/mL and >=50% positive biopsy cores

• Negative lymph nodes as established by imaging, nodal sampling, or dissection within 90 days prior to registration.

• No evidence of metastatic disease as evaluated by bone scan and CT scan of the abdomen and pelvis within 90 days prior to registration

• Karnofsky performance status >=70

• Subjects must have adequate baseline organ function, as assessed by the following laboratory values, within 30 days before initiating the study

• Adequate renal function with serum creatinine <=1.5 mg/dL or creatinine clearance >=45 mL/min/m2.

• Platelet count > 100,000/μL.

• Absolute neutrophil count > 1,000/μL.

• Hemoglobin > 10.0 g/dL.

• Normal partial thromboplastin time (PTT) and prothrombin (PT).

• Bilirubin < 1.5 mg/dL; SGOT and SGPT < 2.5 times upper limit of normal (ULN).

• Men of child-producing potential must be willing to consent to use effective contraception while on treatment and for at least 3 months afterwards.

• Subjects must possess the ability to give informed consent and express a willingness to meet all of the expected requirements of the protocol for the duration of the study.

Exclusion Criteria:

Subjects with the following conditions will be excluded from the study:

• Stage >= T3.

• Prostate specific antigen (PSA) > 20 ng/mL.

• Gleason score >= 8.

• Prostate volume >120cc.

• Pathologically positive lymph nodes or nodes > 1.5 cm on imaging. Note: nodes > 1.5 cm but biopsy negative are allowed.

• Evidence of M1 metastatic disease.

• Prior invasive malignancy except for non-melanoma skin cancer within 5 years of enrollment.

• Prognosis for survival of < 5 years.

• Prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for any reason.

• Prior radiotherapy, including brachytherapy, to the region of the study cancer that would result in overlap of radiation fields.

• Prior or planned androgen suppression therapy or prior systemic chemotherapy for the study cancer. Note that prior chemotherapy for a different cancer is allowed; however, patients must be >2 years post-completion of chemotherapy at time of registration. Patients on Proscar therapy must stop to be eligible.

• Severe, active co-morbidity defined as:

• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months.

• Transmural myocardial infarction within the last 6 months.

• Acute infection. Acute infection is defined by any viral, bacterial, or fungal infection that requires specific therapy within 72 hours of initiation of the study therapy.

• Positive serological test for HIV at baseline.

• Previous history of liver disease including hepatitis.

• Immunosuppressive therapy including systemic corticosteroids. Use of inhaled and topical corticosteroids is permitted.

• Impaired immunity or susceptibility to serious viral infections.

• Allergy to any product used in the protocol. (If the subject has an allergy to Ciprofloxacin, another antibiotic can be substituted at the discretion of the treating physician.

• Serious medical or psychiatric illness or concomitant medication, which, in the judgment of the principal investigator, might interfere with the subject's ability to respond to or tolerate the treatment or complete the trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21231
2	Henry Ford Health System	Detroit	Michigan	United States	48202

Sponsors and Collaborators

• Henry Ford Health System

Investigators

• Principal Investigator: Benjamin Movsas, M.D., Henry Ford Health System

Study Documents (Full-Text)

None provided.

More Information

Publications

• Freytag SO, Khil M, Stricker H, Peabody J, Menon M, DePeralta-Venturina M, Nafziger D, Pegg J, Paielli D, Brown S, Barton K, Lu M, Aguilar-Cordova E, Kim JH. Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res. 2002 Sep 1;62(17):4968-76.
• Freytag SO, Movsas B, Aref I, Stricker H, Peabody J, Pegg J, Zhang Y, Barton KN, Brown SL, Lu M, Savera A, Kim JH. Phase I trial of replication-competent adenovirus-mediated suicide gene therapy combined with IMRT for prostate cancer. Mol Ther. 2007 May;15(5):1016-23. Epub 2007 Mar 20.
• Freytag SO, Stricker H, Peabody J, Pegg J, Paielli D, Movsas B, Barton KN, Brown SL, Lu M, Kim JH. Five-year follow-up of trial of replication-competent adenovirus-mediated suicide gene therapy for treatment of prostate cancer. Mol Ther. 2007 Mar;15(3):636-42. Epub 2007 Jan 16.
• Freytag SO, Stricker H, Pegg J, Paielli D, Pradhan DG, Peabody J, DePeralta-Venturina M, Xia X, Brown S, Lu M, Kim JH. Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer. Cancer Res. 2003 Nov 1;63(21):7497-506.

• Responsible Party: Benjamin Movsas, M.D., Chairman, Department of Radiation Oncology, Henry Ford Health System
• ClinicalTrials.gov Identifier: NCT00583492
• Other Study ID Numbers: Prostate4809
• First Posted: Dec 31, 2007
• Last Update Posted: Mar 17, 2016
• Last Verified: Feb 1, 2016

• Keywords provided by Benjamin Movsas, M.D., Chairman, Department of Radiation Oncology, Henry Ford Health System: Prostatic Neoplasms; Prostate Cancer; Adenocarinomas; Tumors of the Prostate; Gene Therapy; IMRT
• Additional relevant MeSH terms: Prostatic Neoplasms; Suicide

Study Results

Participant Flow

Arm/Group Title	Gene Therapy + IMRT	IMRT Alone
Arm/Group Description	Gene Therapy + IMRT Ad5-yCD/mutTKSR39rep-ADP: 1 x 10e12 sterile injectable solution, 1 injection on day one Plus Radiation - 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy Plus 2 week course (weekdays only) of 5-FC and vGCV prodrug therapy	IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy
Period Title: Overall Study
STARTED	21	23
COMPLETED	21	23
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Gene Therapy + IMRT	IMRT Alone	Total
Arm/Group Description	Gene Therapy + IMRT Ad5-yCD/mutTKSR39rep-ADP: 1 x 10e12 sterile injectable solution, 1 injection on day one Plus Radiation - 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy Plus 2 week course (weekdays only) of 5-FC and vGCV prodrug therapy	IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy	Total of all reporting groups
Overall Participants	21	23	44
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	8 38.1%	9 39.1%	17 38.6%
>=65 years	13 61.9%	14 60.9%	27 61.4%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	21 100%	23 100%	44 100%
Region of Enrollment (participants) [Number]
United States	21 100%	23 100%	44 100%

Outcome Measures

1. Primary Outcome

Title	Freedom From Biochemical/Clinical Failure (FFF)
Description	Biochemical/Clinical Failure was defined as PSA nadir plus 2 ng/mL
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gene Therapy + IMRT	IMRT Alone
Arm/Group Description	Gene Therapy + IMRT Ad5-yCD/mutTKSR39rep-ADP: 1 x 10e12 sterile injectable solution, 1 injection on day one Plus Radiation - 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy Plus 2 week course (weekdays only) of 5-FC and vGCV prodrug therapy	IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy
Measure Participants	21	23
Number [participants]	20 95.2%	21 91.3%

2. Secondary Outcome

Title	Acute >= Grade 3 Treatment-related Toxicity
Description	This metric includes both expected and unexpected events Toxicities were graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 3
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gene Therapy + IMRT	IMRT Alone
Arm/Group Description	Gene Therapy + IMRT Ad5-yCD/mutTKSR39rep-ADP: 1 x 10e12 sterile injectable solution, 1 injection on day one Plus Radiation - 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy Plus 2 week course (weekdays only) of 5-FC and vGCV prodrug therapy	IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy
Measure Participants	21	23
Number [percentage of adverse events]	4.6	6.0

3. Secondary Outcome

Title	Positive Prostate Biopsy at 2 Years
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gene Therapy + IMRT	IMRT Alone
Arm/Group Description	Gene Therapy + IMRT Ad5-yCD/mutTKSR39rep-ADP: 1 x 10e12 sterile injectable solution, 1 injection on day one Plus Radiation - 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy Plus 2 week course (weekdays only) of 5-FC and vGCV prodrug therapy	IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy
Measure Participants	18	19
Number [participants]	6 28.6%	11 47.8%

4. Secondary Outcome

Title	Freedom From Distant Metastases
Time Frame	10 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gene Therapy + IMRT	IMRT Alone
Arm/Group Description	Gene Therapy + IMRT Ad5-yCD/mutTKSR39rep-ADP: 1 x 10e12 sterile injectable solution, 1 injection on day one Plus Radiation - 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy Plus 2 week course (weekdays only) of 5-FC and vGCV prodrug therapy	IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy
Measure Participants	21	23
Number [participants]	21 100%	23 100%

5. Secondary Outcome

Title	Disease-specific Survival
Time Frame	10 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gene Therapy + IMRT	IMRT Alone
Arm/Group Description	Gene Therapy + IMRT Ad5-yCD/mutTKSR39rep-ADP: 1 x 10e12 sterile injectable solution, 1 injection on day one Plus Radiation - 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy Plus 2 week course (weekdays only) of 5-FC and vGCV prodrug therapy	IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy
Measure Participants	21	23
Number [participants]	21 100%	23 100%

6. Secondary Outcome

Title	Decrease in Quality of Life
Description	Quality of Life was measured using the comprehensive Expanded Prostate Cancer Index Composite (EPIC) instrument 19 and 20
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gene Therapy + IMRT	IMRT Alone
Arm/Group Description	Gene Therapy + IMRT Ad5-yCD/mutTKSR39rep-ADP: 1 x 10e12 sterile injectable solution, 1 injection on day one Plus Radiation - 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy Plus 2 week course (weekdays only) of 5-FC and vGCV prodrug therapy	IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy
Measure Participants	21	23
Number [participants]	0 0%	0 0%

Adverse Events

Arm/Group Title	Gene Therapy + IMRT		IMRT Alone
Arm/Group Description	Gene Therapy + IMRT Ad5-yCD/mutTKSR39rep-ADP: 1 x 10^12 sterile injectable solution, 1 injection on day one Plus Radiation - 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy Plus 2 week course (weekdays only) of 5-FC and vGCV prodrug therapy		IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy IMRT: 40 x 2 Gy for a total dose of 80 Gy or 44 x 1.8 Gy for a total dose of 79.2 Gy
All Cause Mortality
	Gene Therapy + IMRT		IMRT Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Gene Therapy + IMRT		IMRT Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Gene Therapy + IMRT		IMRT Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/21 (100%)		7/23 (30.4%)
Blood and lymphatic system disorders
Neutropenia	7/21 (33.3%)	7	1/23 (4.3%)	1
Thrombocytopenia	10/21 (47.6%)	10	3/23 (13%)	3
Hepatobiliary disorders
Transaminitis	11/21 (52.4%)	11	2/23 (8.7%)	2
Respiratory, thoracic and mediastinal disorders
Flu-like symptoms	16/21 (76.2%)	16	1/23 (4.3%)	1

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.