Intermittent Chemotherapy With or Without Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) for Metastatic Hormone Refractory Prostate Cancer (HRPC)

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT00488982
• Collaborator: Genzyme, a Sanofi Company (Industry)
• Enrollment: 125
• Locations: 4
• Arms: 2
• Duration (Months): 85
• Patients Per Site: 31.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This is a two-arm, randomized Phase II study of intermittent chemotherapy with and without GM-CSF. All patients will receive six 21-day cycles of docetaxel 75 mg/m2 on Day 2 of each cycle and 5 mg prednisone twice a day on Days 1-21. Following six cycles of chemotherapy, eligible subjects will be randomized to no maintenance therapy or to maintenance GM-CSF therapy. The GM-CSF group dose schedule will be 250 mcg/m2 subcutaneous (SQ) daily Days 15-28 every 28 days. Patients in both groups will continue until disease progression at which time GM-CSF will be discontinued and chemotherapy will again be administered.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: Docetaxel; Drug: Docetaxel and GM-CSF	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 125 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study of Intermittent Chemotherapy or Intermittent Chemotherapy With Maintenance GM-CSF in Patients With Previously Untreated Hormone Refractory Prostate Cancer
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Docetaxel + Observation Intermittent docetaxel/prednisone with no maintenance therapy: Patients will discontinue docetaxel/prednisone and undergo observation until disease progression at which time they will re-initiate docetaxel/prednisone. Six cycles of docetaxel/prednisone will again be administered before subsequent discontinuation of chemotherapy	Drug: Docetaxel; Docetaxel 75mg/m2 every 21 days
Experimental: Docetaxel + GM-CSF Intermittent docetaxel/prednisone with maintenance GM-CSF therapy: Patients will discontinue docetaxel/prednisone and will receive maintenance GM-CSF until disease progression at which time, they will discontinue GM-CSF and resume docetaxel/prednisone. Six cycles of docetaxel/prednisone will again be administered before discontinuation of chemotherapy and GM-CSF therapy is re-initiated. GM-CSF dose/schedule will be as previously described (250 mcg/m2 SQ daily, days 15-28 q28 days)	Drug: Docetaxel and GM-CSF; Docetaxel 75mg/m2 every 21 days and GM-CSF 250mcg/m2 SQ days 15-28

Outcome Measures

Primary Outcome Measures

1. Time to Progression [Up to 7 years]

   The Kaplan-Meier product limit method with 95% confidence intervals will be used to estimate the median time to disease progression during initial course of randomized treatment

Secondary Outcome Measures

1. Overall Survival [Up to 7 years]

   The Kaplan-Meier product limit method will be used to estimate the median overall survival

2. Number of Participants With PSA Response to Successive Series of Chemotherapy [Up to 6 years]

   PSA partial response is defined by at least a 50% decline from PSA value from the baseline measurement to 12 weeks of protocol therapy. The decline must be confirmed by a second PSA value obtained 4 or more weeks later For those patients whose PSA have decreased but has not reached response criteria defined above, progressive disease is defined as 25% increase over the nadir PSA value provided that the increase is at least 5ng/mL and is confirmed.

3. Cumulative Duration of Time on and Off Docetaxel-based Therapy [Up to 7 years]

   Median percentage of time will be calculated to summarize the total duration of chemotherapy and amount of docetaxel/prednisone administered while the patient is on study. The same results will be tabulated for each. For the on-chemotherapy period: will be estimated from the date of starting protocol therapy; if a patient received docetaxel on day 2 of a cycle, he will be considered to have received a full 21 days on therapy. For the off-chemotherapy period: will be calculated from the date of starting the observation or GM-CSF period to the date of resuming chemotherapy

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Age over 18 years

2. Histologically documented adenocarcinoma of the prostate

3. Progressive metastatic prostate cancer

4. Castrate levels of testosterone (<50 ng/ml) must be maintained

5. Prior hormonal therapy or medications :

Patients who are receiving an anti-androgen, secondary hormonal therapy (i.e. ketoconazole, aminoglutethimide, megestrol acetate, diethylstilbestrol), 5-alpha reductase inhibitor (i.e. finasteride (Proscar), dutasteride (Avodart)) or herbal prostate medication (i.e. saw palmetto, PC-SPES, PC-PLUS) must discontinue the drug by the date of initiation of chemotherapy on study

1. ≥ 4 weeks since major surgery and fully recovered

2. ≥ 4 weeks since any prior radiation with any toxicity attributable to radiation resolved to ≤grade 1

3. ≥ 8 weeks since the last dose of strontium or samarium

4. Sexually active patients must agree to use adequate contraception

5. Karnofsky Performance Status ≥ 60%

6. Life expectancy >12 weeks

7. Required initial laboratory values Absolute neutrophil count > 1500/ul Platelets > 100,000/ul Hemoglobin > 8.0 g/dl Creatinine ≤ 2.0 X upper limit of normal Bilirubin ≤upper limit of normal (ULN)

aspartate aminotransferase (AST) / alanine aminotransferase (ALT) / alkaline phosphatase: AST AND ALT AND alkaline phosphatase must be within the range allowing for eligibility In determining eligibility, the more abnormal of the 2 values (AST or ALT should be used. An abnormal alkaline phosphatase must be attributed to liver dysfunction and not metastatic bone involvement (i.e elevated gamma-glutamyl transpeptidase (GGTP) or evidence of liver metastases)

Inclusion criteria for late enrolling patients:

1. Age over 18 years

2. Histologically documented adenocarcinoma of the prostate

3. ≤3 cycles of prior docetaxel chemotherapy for metastatic disease permitted prior to enrollment

4. Docetaxel must have been administered on an every 3 week schedule

5. Each docetaxel dose must have been between 60 and 75 mg/m2

6. Castrate levels of testosterone <50 ng/mL

7. Daily use of other steroids (hydrocortisone, dexamethasone) instead of prednisone or no steroids, is permitted up until time of enrollment

8. A Prostate-specific antigen (PSA) level must have been documented within 6 weeks of initiating docetaxel chemotherapy

Exclusion Criteria:

1. Prior systemic chemotherapy for prostate cancer, other than q 3-week docetaxel/prednisone. Prior neoadjuvant or adjuvant chemotherapy is permitted if there was no evidence of disease relapse within 12 months of the last dose of chemotherapy.

2. 3 cycles of q3 week docetaxel/prednisone chemotherapy has already been administered to the patient

3. Peripheral neuropathy >grade 1

4. Prior immunotherapy including systemic GM-CSF or vaccines utilizing GM-CSF; prior G-CSF support of chemotherapy-related neutropenia is permitted

5. Prior biologic agents (i.e.,anti-angiogenic agents, anti-Epithelial Growth Factor Receptor (EGFR) inhibitors)≤ 4 weeks prior to registration

6. More than two prior therapies with an investigational agent, completed ≤ 4 weeks prior to enrollment (no prior immunotherapeutics are allowed)

7. Myocardial infarction or significant change in anginal pattern within the last 6 months, symptomatic congestive heart failure (NYHA Class III or higher) or uncontrolled cardiac arrhythmia

8. Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded

9. Patients with a history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 will be excluded

10. Poorly controlled diabetes (fasting blood glucose >250) despite optimization of medical therapy

Exclusion criteria for late enrolling patients:

1. Prior immunotherapy including systemic GM-CSF or vaccines utilizing GM-CSF; prior G-CSF support for chemotherapy-related neutropenia is permitted

2. Delay of ≥6 weeks between any 2 chemotherapy cycles prior to enrollment on study

3. Cumulative delays ≥8 weeks between chemotherapy cycles prior to enrollment on study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94115
2	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
3	Oregon Health and Science University Cancer Institute	Portland	Oregon	United States	97239
4	University of Washington	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of California, San Francisco
• Genzyme, a Sanofi Company

Investigators

• Principal Investigator: Eric Small, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00488982
• Other Study ID Numbers: 055511; NCI-2011-01269
• First Posted: Jun 20, 2007
• Last Update Posted: Nov 20, 2019
• Last Verified: Oct 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of California, San Francisco: Metastatic Hormone Refractory Prostate Cancer
• Additional relevant MeSH terms: Prostatic Neoplasms; Docetaxel

Study Results

Participant Flow

Pre-assignment Detail	Patients had to complete 6 cycles of induction chemotherapy and have a ≥ 50% decline in prostate-specific antigen to be eligible for randomization.

Arm/Group Title	Pre-Randomization	Docetaxel and Observation	Docetaxel and GM-CSF
Arm/Group Description	Induction chemotherapy for 6 cycles (1 cycle = 21 days) Docetaxel 75mg/m^2 I.V. (intravenous) on day 2 Prednisone 5 mg by mouth (p.o.), twice a day (b.i.d.) from day 1 to 21 (for 21 days)	Docetaxel 75mg/m^2 every 21 days	Docetaxel 75mg/m^2 every 21 days and GM-CSF 250mcg/m^2 subcutaneously days 15-28
Period Title: Induction Chemotherapy
STARTED	125	0	0
6 Cycles Completed	94	0	0
≥ 50% Prostate-specific Antigen Decline	52	0	0
COMPLETED	52	0	0
NOT COMPLETED	73	0	0
Period Title: Induction Chemotherapy
STARTED	0	25	27
COMPLETED	0	13	13
NOT COMPLETED	0	12	14
Period Title: Induction Chemotherapy
STARTED	0	13	13
COMPLETED	0	4	8
NOT COMPLETED	0	9	5
Period Title: Induction Chemotherapy
STARTED	0	4	8
COMPLETED	0	2	3
NOT COMPLETED	0	2	5
Period Title: Induction Chemotherapy
STARTED	0	2	3
COMPLETED	0	1	0
NOT COMPLETED	0	1	3

Baseline Characteristics

Arm/Group Title	All Patients Accrued
Arm/Group Description	There were a total of 125 patients whom were accrued to the study and assigned to at least one course of docetaxel
Overall Participants	125
Age, Customized (years) [Median (Full Range) ]
Median Age Range	70
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	125 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 2.4%
Not Hispanic or Latino	115 92%
Unknown or Not Reported	7 5.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.8%
Asian	2 1.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 3.2%
White	111 88.8%
More than one race	0 0%
Unknown or Not Reported	7 5.6%
Region of Enrollment (participants) [Number]
United States	125 100%
Gleason Score (Count of Participants)
<=6	22 17.6%
7	33 26.4%
8-10	70 56%

Outcome Measures

1. Primary Outcome

Title	Time to Progression
Description	The Kaplan-Meier product limit method with 95% confidence intervals will be used to estimate the median time to disease progression during initial course of randomized treatment
Time Frame	Up to 7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Docetaxel and Observation	Docetaxel and GM-CSF
Arm/Group Description	- Docetaxel 75mg/m^2 every 21 days	Docetaxel 75mg/m^2 every 21 days GM-CSF 250mcg/m2 subcutaneous (SQ) days 15-28
Measure Participants	25	27
Median (95% Confidence Interval) [months]	1.5	3.3

2. Secondary Outcome

Title	Overall Survival
Description	The Kaplan-Meier product limit method will be used to estimate the median overall survival
Time Frame	Up to 7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Docetaxel and Observation	Docetaxel and GM-CSF	Overall Survival
Arm/Group Description	Docetaxel 75mg/m2 every 21 days	Docetaxel 75mg/m2 every 21 days GM-CSF 250mcg/m2 SQ days 15-28	Includes all patients whom received any treatment starting with first course of Docetaxel at Induction
Measure Participants	25	27	125
Median (95% Confidence Interval) [months]	14	28.4	15.6

3. Secondary Outcome

Title	Number of Participants With PSA Response to Successive Series of Chemotherapy
Description	PSA partial response is defined by at least a 50% decline from PSA value from the baseline measurement to 12 weeks of protocol therapy. The decline must be confirmed by a second PSA value obtained 4 or more weeks later For those patients whose PSA have decreased but has not reached response criteria defined above, progressive disease is defined as 25% increase over the nadir PSA value provided that the increase is at least 5ng/mL and is confirmed.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Twenty-six participants total resumed a second course of the Docetaxel, and five participants went on to resume a third course of treatment.

Arm/Group Title	Docetaxel and Observation	Docetaxel and GM-CSF
Arm/Group Description	- Docetaxel 75mg/m2 every 21 days	Docetaxel 75mg/m2 every 21 days GM-CSF 250mcg/m2 SQ days 15-28
Measure Participants	13	13
PSA response to Course 2 chemotherapy	4 3.2%	8 NaN
PSA response to Course 3 chemotherapy	1 0.8%	0 NaN

4. Secondary Outcome

Title	Cumulative Duration of Time on and Off Docetaxel-based Therapy
Description	Median percentage of time will be calculated to summarize the total duration of chemotherapy and amount of docetaxel/prednisone administered while the patient is on study. The same results will be tabulated for each. For the on-chemotherapy period: will be estimated from the date of starting protocol therapy; if a patient received docetaxel on day 2 of a cycle, he will be considered to have received a full 21 days on therapy. For the off-chemotherapy period: will be calculated from the date of starting the observation or GM-CSF period to the date of resuming chemotherapy
Time Frame	Up to 7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Docetaxel and Observation OFF Chemotherapy	Docetaxel and GM-CSF OFF Chemotherapy	Docetaxel + Observation ON Chemotherapy	Docetaxel and GM-CSF ON Chemotherapy
Arm/Group Description	Starting the docetaxel with observation period to date of resuming chemotherapy post initial induction	Starting the docetaxel with GM-CSF period to date of resuming chemotherapy post initial induction	Starting Docetaxel 75mg/m2 and Observation every 21 days for at least 2 days	Starting Docetaxel 75mg/m2 and GM-CSF 250mcg/m2 SQ days 15-28 every 28 days with at least 2 days of Docetaxel
Measure Participants	25	27	25	27
Median (95% Confidence Interval) [months]	24.7	30.9	8.3	7.6

Adverse Events

Time Frame	Any patient receiving at least one dose of the study treatment will be included in the analyses of toxicity during the initial chemotherapy period, but patients who cancel registration before receiving any therapy will not. All grade 3-5, expected and unexpected adverse events (AEs) were collected at all study visits from time of first treatment until at least 28 days following the last dose of study drug.
Adverse Event Reporting Description	Data was not collected per intervention. All patients were assigned to the same treatment of Docetaxel/Prednisone before being assigned to the subsequent therapy arms where they may have received multiple treatment courses with multiple inductions. Abnormal lab values or test results constituted AEs only if they induced clinical signs /symptoms, required therapy, or required dose modification. There were no treatment-associated deaths.
Arm/Group Title	All Accrued Patients
Arm/Group Description	All patients were assigned to received six 21-day cycles of docetaxel 75 mg/m2 on Day 2 of each cycle and 5 mg prednisone twice a day on Days 1-21. Following six cycles of chemotherapy, eligible subjects were randomized to no maintenance therapy or to maintenance GM-CSF therapy. Patients in both groups were followed until disease progression at which time GM-CSF was discontinued and another course of docetaxel and prednisone was administered again.
All Cause Mortality
	All Accrued Patients
	Affected / at Risk (%)	# Events
Total	8/125 (6.4%)
Serious Adverse Events
	All Accrued Patients
	Affected / at Risk (%)	# Events
Total	20/125 (16%)
Infections and infestations
Febrile neutropenia	8/125 (6.4%)	9
Neutropenia	12/125 (9.6%)	14
Other (Not Including Serious) Adverse Events
	All Accrued Patients
	Affected / at Risk (%)	# Events
Total	0/125 (0%)

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.